Synthesis of phosphoramidates

The present invention is directed to a compound of formula (III), its preparation and to its use for the preparation of a compound of formula (IV). The present invention hence is directed to a process for the preparation of compound of formula (III) preferably according to schemes 1, 2, 3, 3-a, 4, 4-a and for the preparation of a compound of formula (IV) from a compound of formula (III) via reduction of the compound of formula (III) . The present invention is further directed to intermediate compounds for preparing the compound of formula (III) and hence compound of formula (IV). Nucleoside phosphoramidates are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of UCV NS5B polymerase, as inhibitors of I ICV replication and for treatment of hepatitis C infection in mammals.

Sofosbuvir ( PS 1-7977 ) is a nucleotide analog inhibitor of HCV NS5B polymerase with IUPAC name (S)-isopropyl 2-(((5)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin- l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)me thoxy)(phenoxy)phosphoryl) amino)propanoate. It has formula

Sofosbuvir and a process for the preparation are disclosed in U.S. Patent No. 7,964,580 B2 and PCT Publication No. WO 2008/121634 A2. The present disclosure provide novel processes for the preparation of sofosbuvir or its pharmaceutically acceptable salts that employ novel intermediates.

I. PROCESS FOR PREPARING A COMPOUND OF FORMULA (IV) FROM A COMPOUND OF

FORMULA (III)

Therefore the present invention is directed to a process for the preparation of a compound of formula (IV)

the process comprising i) providing a compound of formula (III)

(III)

reducing the compound of formula (III) and obtaining the compound of formula (IV).

In the formulae, P, *P and Base are as disclosed hereinbelow.

P is selected from *P or PG, preferably from P*.

With regard to *P, *P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate and phosphoramidate. *P is preferably a pho sphoramidate .

With regard to *P, it is more preferred that *P is a phosphoramidate of structure

wherein

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci-C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N02 and CN; preferably Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl;

P i is Ci-C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl; preferably Ri is Ci-C ₆ alkyl, more preferably isopropyl. Ci-C ₆ alkyl may be optionally substituted with at least one of Ci-C ₆ alkyl and aryl.

R ₂ and R3 are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(C C ₆ alkyl) and CN; preferably R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; more preferably R ₂ and R3 are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

It is hence more preferred that P is a phosphoramidate of structure

wherein

Ar is selected from the group consisting of phenyl and naphtyl, more preferably phenyl

Ri is Ci-C ₆ alkyl, more preferably isopropyl

R ₂ and Pv ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

In the above formulae, the phosphorus atom of the structure

has steric configuration S or R, preferably S.

The preferred *P structure according to the invention is structure:

preferably wherein the phosphorous atom has a steric configuration S.

P can also be PG. PG is a protecting group. PG is preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group. PG is preferably selected from the group consisting of alkyl, benzyl and silyl protecting group. A suitable silyl protecting group according to the invention is for example trimethylsilyl (TMS), triethylsilyl (TES), isopropyldimethylsilyl (PSMS), diethylisopropylsilyl (DEIPS), terbutyldimethylsilyl (TBS), terbutyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS).

Preferably, the present invention relates to said process wherein Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring through a carbon or nitrogen atom. It is preferred that the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine. More preferably Base is uracil.

It is further contemplated that the above formulae include the enantiomers and the diastereomers thereof. Step i)

Any means for providing a compound of formula (III) is suitable according to the present invention. Preferred methods for preparing the compound of formula (III) are disclosed herein below. Step ii)

It is contemplated that reducing of ii) is carried out with a reducing agent. The reducing agent is preferably selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent. Preferably the boron based reducing agent is a borohydride, wherein preferably the borohydrides is selected from the group consisting of NaBH ₄ , LiBH ₄ , Li(Et) ₃ BH. Preferably the aluminium based reducing agent is a lithium- aluminium hydride wherein preferably the lithium- aluminium hydride is selected from the group consisting of LiAlH ₄ and diisobutylaluminium hydride ( DIBAL-H ). More preferably the reducing agent is NaBH . With regard to the temperature, no particular limitation exists with respect to the temperature of the reducing of ii) as far as the reduction occurs. It is preferred that the reducing is carried out at a temperature in the range of from -78 °C to 40 °C, preferably in the range of from -20 °C to 20 °C. With regard to the solvent, no particular limitation exists with respect to the solvent of the reducing of ii) as far as the reduction occurs. It is preferred that the reducing of ii) is carried out in a solvent selected from a protic solvent or a mixture thereof, preferably in a protic solvent selected from the group consisting of methanol, ethanol, isopropanol and water and a mixture thereof. With regard to the molar ratio of the compound of formula (III) relative to the reducing agent the molar ratio is preferably in the range of from 1: 1 to 1: 10, more preferably in the range of from 1:2 to 1:4.

It is further contemplated that in i) the compound of formula (III) is provided wherein P is *P or PG.

Step i')

In case P is PG, it is contemplated that after i) and before ii) the process comprises

i') phosphorylating said compound of formula (III) having P= PG to a compound of formula (Ill)having P= P*.

It is contemplated that the phosphorylating of i') comprises reacting, in the presence of a base or of a Lewis acid, the compound of formula (III) wherein P is PG with a compound of formula *P-X wherein *P is as defined above and X is a leaving group, preferably selected from the group consisting of halogens, mesylate, tosylate, optionally substituted phenol and succinimide. It is preferred that the Lewis acids comprise a twice positively charged ion, preferably a Zn ion, a Mg ion, a Cu ion, or an Fe ion, or a three times positively charged ion, preferably a Mn ion. It is further preferred that the Lewis acids is one or more of ZnBr ₂ , ZnCl ₂ , Znl ₂ , MgBr ₂ , MgBr ₂ · OEt ₂ , CuCl ₂ , Cu(acetylacetonate) ₂ , Fe(II) fumarate, and Mn(acetylacetonate With regard to the temperature, no particular limitation exists with respect to the temperature of the phosphorylating of i') as far as the phosphorylation occurs. It is preferred that the phosphorylating of i') is carried out at a temperature in the range of from -20 °C to 100 °C, more preferably in the range of from 0 °C to 40 °C. With regard to the solvent, no particular limitation exists with respect to the solvent of the phosphorylating of i') as far as the phosphorylating of i') occurs. It is preferred that the phosphorylating of i') or is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl fert-butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

With regard to the molar ratio of the compound of formula (III) wherein P is PG relative to the phosphorylation reagent *P-X, the molar ratio is preferably in the range of from 1: 15 to 1:5. The present invention is preferably directed to a process for the preparation of a compound of formula (IV- a)

the process comprising

i) providing a compound of formula (Ill-a)

ii) reducing the compound of formula (Ill-a) and obtaining the compound of formula (IV- a)

wherein the reducing of ii) is as defined above.

Uses

According to the present invention, it is further provided the use of a reducing agent for stereo selectively reducing the oxo group in position 3' of the furanose ring of the compound of formula (III), wherein the compound of formula (III) is as disclosed above. Preferred compound of formula (III) is a compound of formula (III- a). The reducing agent is preferably selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent. Preferably the boron based reducing agent is a borohydride, wherein preferably the borohydrides is selected from the group consisting of NaBH ₄ , LiBH ₄ , Li(Et) ₃ BH. Preferably the aluminium based reducing agent is a lithium- aluminium hydride wherein preferably the lithium- aluminium hydride is selected from the group consisting of LiAlH ₄ and diisobutyl aluminium hydride ( DIBAL-H ). More preferably the reducing agent is NaBH . II. COMPOUND OF FORMULA (III)

According to the invention it is provided a compound of formula (III)

In formula (III), P is selected from *P or PG.

With regard to *P, it is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate and phosphoramidate. *P is preferably a pho sphoramidate .

With regard to *P, it is more preferred that *P is a phosphoramidate of structure

wherein

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(C _r C ₆ alkyl), C(0)(aryl), COO(C C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N02 and CN; preferably Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl;

P i is Ci-C ₆ alkyl or C3-C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl; preferably Ri is Ci-C ₆ alkyl, more preferably isopropyl. Ci-C ₆ alkyl may be optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C3-C ₆ cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl) and CN; preferably R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; more preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S". It is hence more preferred that P is a phosphoramidate of structure

wherein

Ar is selected from the group consisting of phenyl and naphtyl, more preferably Ar is phenyl

Ri is Ci-C ₆ alkyl, more preferably is isopropyl

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

In the above formulae, the phosphorus atom of the structure

has steric configuration S or R, preferably S.

The preferred *P structure according to the invention is structure:

preferably wherein the phosphorus atom has a steric configuration S.

P can also be PG. PG is a protecting group. PG is preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group. PG is preferably selected from the group consisting of alkyl and benzyl and a silyl protecting group.

With regard to Base, it is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring through a carbon or nitrogen atom. It is preferred that the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine. More preferably the Base is uracil. It is further contemplated that the above formula (III) includes the enantiomers and the diastereomers thereof.

According to the invention, the preferred compound of formula (III) has structure (Ill-a)

wherein preferably the phosphorous atom has a steric configuration S.

According to the present invention, it is further provided a compound of formula (III) obtained or obtainable by a process according to schemes 1, 2, 3-a, 4 and 4-a as disclosed below.

According to the present invention it is further provided the use of the compound of formula (III), preferably of compound of formula (Ill-a) for preparing a compound of formula (IV)

wherein P, *P and Base are as defined above for compound of formula (III). It is preferred that the compound of formula (IV) is of formula (IV-a):

It is preferred that the compound of formula (IV-a) is a compound known as sofosbuvir. III. INTERMEDIATE COMPOUNDS AND PROCESS FOR PREPARING OF A COMPOUND OF FORMULA (III) OR (IV) ACCORDING TO SCHEMES 1 AND 2

According to the present invention processes are provided for preparing compounds of any of formula (III), (Ill-a), (IV) and (IV-a) according to the below schemes 1 and 2. Further according to the invention intermediate processes are provided for preparing the intermediate compounds of formula (I) and (I-a).

SCHEME 1

SCHEME 2 III.l PROCESS FOR PREPARING A COMPOUND OF FORMULA (III)

(a) Process for preparing a compound of formula (III) via (I)

Therefore, the present invention relates to a process for the preparation of a compound of formula (III)

the process comprising

1) providing a compound of formula (I)

fluorinating the compound of formula (I) and obtaining the compound of formula (III), wherein P is *P or PG and Base is as defined below. In formula (I), it is preferred that P is *P.

With regard to *P, *P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate and phosphoramidate. *P is preferably a pho sphoramidate .

With regard to *P it is more preferred that *P is a phosphoramidate of structure

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, C Ce alkoxy, Ci-Ce cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci-C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N02 and CN; preferably Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl; Ri is Ci-C ₆ alkyl or C3-C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl; preferably Ri is Ci-C ₆ alkyl, more preferably isopropyl. Ci-C ₆ alkyl may be optionally substituted with at least one of Ci-C ₆ alkyl and aryl,

R ₂ and R3 are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C3-C6 cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl) and CN; preferably R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; more preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

It is hence more preferred that P is a phosphoramidate of structure

wherein

Ar is selected from the group consisting of phenyl and naphtyl, more preferably phenyl

Ri is Ci-C ₆ alkyl, more preferably isopropyl

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

In the above formulae, the phosphorus atom of the structure

has steric configuration S or R, preferably S.

The preferred *P structure according to the invention is structure:

preferably wherein the phosphorus atom has a steric configuration S.

P can also be PG. PG is a protecting group. PG is preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group. PG is preferably selected from the group consisting of alkyl, benzyl and silyl protecting group. A suitable silyl protecting group according to the invention is for example trimethylsilyl (TMS), triethylsilyl (TES), isopropyldimethylsilyl (PSMS), diethylisopropylsilyl (DEIPS), terbutyldimethylsilyl (TBS), terbutyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS).

Preferably, the present invention relates to said process wherein Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring according to formula (I) or (III) through a carbon or nitrogen atom. It is preferred that the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine. More preferably the Base is uracil.

It is further contemplated that the above formulae include the enantiomers and diastereomers thereof.

Step 1)

Any means for providing a compound of formula (I) is suitable according to the present invention. A preferred method for preparing the compound of formula (I) is disclosed herein below.

Step 2): Fluorination

According to 2), the fluorinating of is carried out with a fluorinating agent selected from the group consisting of an inorganic or an organic fluorinating agent. An organic fluorinating agent is preferred according to the present invention. The inorganic fluorinating agent is preferably selected from the group consisting of metal fluorides such as LiF, KF, CsF, borane complexes of HF. The organic fluorination agent is preferably selected from the group consisting of an amine complex of HF such as triethylamine tris(hydrogen fluoride), pyridinium poly(hydrogen fluoride) and HF-urea, aminosulfur fluoride derivatives such as diethylamino sulfur trifluoride (DAST), (diethylamino)difluorosulfonium tetrafluoroborate (XTal-Fluor E), difluoro(morpholino)sulfonium tetrafluoroborate (XTal- Fluor M), 4-ieri-Butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead), Bis(2- methoxyethyl)aminosulfur trifluoride (Deoxofluor), 2-Pyridinesulfonyl Fluoride (PyFluor), dimethylaminosulfur trifluoride, ammonium fluorides such as tetrabutylammoniumfluorid (TBAF), silicon fluorides such as tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), and combinations thereof. With regard to the temperature, no particular limitation exists with respect to the temperature of the fluorinating of 2) as far as the fluorinating occurs. It is preferred that the fluorinating is carried out at a temperature in the range of from -20 °C to 100 °C, more preferably in the range of from 0 °C to 40 °C. With regard to the solvent, no particular limitation exists with respect to the solvent of the fluorinating of 2) as far as the fluorinating occurs. It is preferred that the fluorinating is carried out in an organic solvent, wherein the organic solvent is preferably selected from the group consisting of dichloromethane, tetrahydrofuran (THF), Methyl fert-butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof. The preferred solvent is dichloromethane, preferably anhydrous dichloromethane.

The term "anhydrous" referred to a solvent means, in the present context, a solvent having a content of less than w/w 1% water, preferably less than 0.5 w/w %, more preferably less than 0.1 w/w %, With regard to the molar ratio of the compound of formula (I) relative to the fluorinating agent, the molar ratio is preferably in the range of from 1 : 15 to 1 :5.

Steps a) and b)

According to the present invention it is further contemplated that the providing of 1) comprises

a) providing a compound of formula (II)

b) oxidizing the compound of formula (II) and obtaining a compound of formula (I),

wherein P and Base are as defined above.

It is contemplated that the oxidizing of b) is carried out with an oxidizing reagent preferably selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane,

- (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant

-Swern type oxidation reagents -such as Dimethyl sulfoxide (DMSO) and suitable activator- -transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO)

More preferably, the oxidizing reagent is selected from the group consisting of hypervalent iodo oxidation reagents and Swern type oxidation reagents. Hypervalent iodine reagents are known in the art: Hypervalent iodine reagents useful in the context of the present invention are for example: Dess-Martin Periodinane, Hydroxy(tosyloxy)iodobenzene, Iodosobenzene diacetate, Iodosobenzene bis(trifluoroacetate), Iodosylbenzene, 2-Iodoxybenzoic Acid, Iodobenzene Dichloride. The reagent Dess-Martin Periodinane is preferred according to the present invention. Swern type oxidation reagents are reagent suitable for carry out the Swern type oxidation. Swern type oxidation reagents are for example dimethyl sulphoxide together with oxalyl chloride.

With regard to the temperature, no particular limitation exists with respect to the temperature of the oxidizing of b) as far as the oxidation occurs. It is preferred that the oxidizing is carried out at a temperature in the range of from -80 °C to 60 °C, more preferably in the range of from -78 °C to 30 °C, more preferably in the range of from -40 °C to 20 °C.

With regard to the solvent, no particular limitation exists with respect to the solvent of the oxidizing of b) as far as the oxidation occurs. It is preferred that the oxidizing is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, more preferably in a solvent selected from the group consisting of dichloromethane, DMSO and a mixture thereof.

With regard to the molar ratio, the molar ratio of the compound of formula (II) relative to the oxidizing agent is preferably in the range of from 1: 1 to 1: 15, preferably in the range of from 1:3 to 1:4. The process is preferably for the preparation of a compound of formula (Ill-a) as defined in paragraph II.

(b) Process for preparing a compound of formula (III) in a process with intermediates of formulae (II) and (I)

According to the present invention it is contemplated a process for the preparation of a compound of formula (III)

using intermediate compounds of formula (II) and (I). The process comprises

a) providing a compound of formula (II)

b) oxidizing the compound of formula (II) and obtaining a compound of formula (I)

c) fluorinating the compound of formula (I) of b) and obtaining the compound of formula (III)

wherein at each occurrence P and Base are as defined above.

The oxidizing of b) is as defined above and the fluorinating of c) is as disclosed above as fluorinating of 2).

The process is preferably for the preparation of a compound of formula (Ill-a) as defined in paragraph II. III.2 PROCESS FOR PREPARING A COMPOUND OF FORMULA (IV) ACCORDING TO SCHEMES 1

AND 2.

(a) Process for preparing a compound of formula (IV) via intermediate compounds (I) and (III) According to the present invention it is further contemplated a process for the preparation of the compound of formula (IV) via intermediate compounds (I) and (III).

The process comprises steps i) and ii) as disclosed above in paragraph "I. PROCESS FOR PREPARING A COMPOUND OF FORMULA (IV) FROM A COMPOUND OF FORMULA (III).)"

The provision of compound of formula (III) of i) comprises

1) providing a compound of formula (I)

2) fluorinating the compound of formula (I) and obtaining the compound of formula (III)

wherein at each occurrence

P and the Base are as defined above.

The fluorinating of 2) is as defined above in paragraph III.1. The compound of formula (III) is reduced according to step ii) as disclosed above in paragraph I. and the compound of formula (IV) is obtained. It is further preferred that step 1) comprises

a) providing a compound of formula (II)

b) oxidizing the compound of formula (II) and obtaining a compound of

(I),

wherein at each occurrence

P and the Base are as defined above.

The oxidizing of b) is as defined above in paragraph III.1.

It is further preferred that when in the compound of formula (III) of i) P is *P, the process comprises ii) reducing the compound of formula (III) of i) and obtaining the compound of formula (IV) as disclosed above and

when in the compound of formula (III) of i) P is PG the process further comprises i') phosphorylating said compound of formula (III) wherein P is PG to a compound of formula (III) wherein P is P* and

ii) reducing the compound of formula (III) of i') and obtaining the compound of formula (IV).

P, *P, PG and the Base are as defined above. The fluorinating of 2) is as defined above in paragraph III.l. The reducing of ii) and the phosphorylating of i') are as defined above in paragraph I.

(b) Process for preparing a compound of formula (IV) in a process with intermediates of formula (I), (II) and (III)

According to the present invention, it is further provided a process for preparing a compound of formula (IV) in a process with intermediates of formula (I), (II) and (III)

in a process with intermediates of formula (I), (II) and (III). The process comprises

a) providing a compound of formula (II)

b) oxidising the compound of formula (II) and obtaining a compound of formula (I)

c) fluorinating the compound of formula (I) of b) and obtaining the compound of formula (III)

wherein

when in the compound of formula (III) of c) P is *P the process further comprises

ii) reducing the compound of formula (III) of c) and obtaining the compound of formula (IV)

or wherein when in the compound of formula (III) of c) P is PG the process further comprises i') phosphorylating said compound of formula (III) having P=PG to a compound of formula (III) having P=P* and

ii) reducing the compound of formula (III) of i') and obtaining the compound of formula (IV) having P =*P,

P, *P, PG and the Base are as defined above. The oxidising of b) is as defined above in paragraph III.1 The fluorinating of c) is as defined above in paragraph III.1. The phosphorylating of i') is as defined above in paragraph I. The reducing of ii) is as defined above in paragraph I.

According to the present invention, it is further provided a process comprising above step a), wherein the provision of a) of the compound of formula (II) having P=PG comprises

0) protecting a compound of formula (V)

and obtaining a compound of formula (II) having P=PG

According to the invention, the protecting of 0) preferably comprises reacting, in the presence of base, preferable an amine base, the compound of formula (V) with a compound of formula PG-X' wherein PG is as defined above and X' is a leaving group, preferably selected from the group consisting of halogens, mesylate and tosylate.

According to the present invention, it is further provided a process comprising above step a), wherein the provision of a) of the compound of formula (II) having P

0') phosphorylating a compound of formula (V)

and obtaining a compound of formula (II) wherein P is *P

According to the invention, the phosphorylating of 0') comprises reacting, in the presence of a base or of a Lewis acid, the compound of formula (V) with a compound of formula *P-X wherein *P is as defined above and X is a leaving group preferably selected from the group consisting of halogens, mesylate, tosylate, optionally substituted phenol and succinimide.

According to the invention it is preferred that in the processes as disclosed above comprising the use of the compound of formula (I), the compound of formula (I) has structure (I-a)

preferably wherein in the compound of formula (I-a) the phosphorus atom P has a steric configuration S.

According to the invention it is preferred that in the processes as disclosed above comprising the use of the compound of formula (II), the compound of formula (II) has structure (Il-a)

preferably wherein in the compound of formula (Il-a) the phosphorus atom has a steric configuration S. According to the invention it is preferred that in the processes as disclosed above comprising the use of the compound of formula (III), the compound of formula (III) has structure (Ill-a)

preferably in the compound of formula (Ill-a) the phosphorus atom P has a steric configuration S.

According to the invention it is preferred that in the processes as disclosed above, it is provided a compound of formula (IV) of structure (IV-a)

It is further more preferred that in the compound of formula (IV) of structure (IV-a) the phosphorus atom has a steric configuration S.

A preferred reaction scheme according to the present invention is disclosed in scheme 2.

III.3 COMPOUND OF FORMULA (I)

According to the invention it is provided a compound of formula (I).

In formula (I), P is selected from *P or PG.

With regard to *P, it is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate and phosphoramidate. *P is preferably a pho sphoramidate . With regard to *P, it is more preferred that *P is a phosphoramidate of structure

wherein

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(C _r C ₆ alkyl), C(0)(aryl), COO(C C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N02 and CN; preferably Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl;

P i is Ci-C ₆ alkyl or C3-C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl; preferably Ri is Ci-C ₆ alkyl, more preferably isopropyl. Ci-C ₆ alkyl may be optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C3-C ₆ cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl) and CN; preferably R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; more preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

It is hence more preferred that P is a phosphoramidate of structure

wherein

Ar is selected from the group consisting of phenyl and naphtyl, more preferably phenyl

Ri is Ci-C ₆ alkyl, more preferably isopropyl

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

In the above formulae, the phosphorus atom of the structure

has steric configuration S or R, preferably S.

The preferred *P structure according to the invention is structure:

preferably wherein the phosphorus atom has a steric configuration S.

P can also be PG. PG is a protecting group. PG is preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group. PG is preferably selected from the group consisting of alkyl, benzyl and a silyl protecting group.

With regard to Base, it is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring according to formula (I) through a carbon or nitrogen atom. It is preferred that the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine. More preferably the Base is uracil.

It is further contemplated that the above formula (I) includes the enantiomers and the diastereomers thereof.

According to the invention, the preferred compound of formula (I) has structure (I-a)

wherein preferably the phosphorus atom has a steric configuration S.

According to the present invention, it is further provided a compound of formula (I) obtained or obtainable by a process as disclosed below.

According to the present invention, it is further provided a compound of formula (I) or of formula (I-a). III.4 PROCESS FOR PREPARING A COMPOUND OF FORMULA (I)

According to the present invention it is further contemplated a process for preparing a compound of formula (I)

the process comprising

a) providing a compound of formula (II)

(II)

b) oxidizing the compound of formula (II) and obtaining a compound of formula (I),

wherein at each occurrence P, *P, PG and Base are as defined above.

Steps a) and b) are as defined above in paragraph III.1

It is preferred that the compound of formula (I) is of formula (I-a) and the compound of formula (III) is of formula (Ill-a) as defined above. III.5 Uses

According to the present invention, it is further provided the use of a compound of formula (III), obtained or obtainable by a process as disclosed above for preparing a compound of formula (IV) as disclosed above, wherein *P and Base are as defined above. Preferred compound of formula (III) is a compound of formula (III- a). Preferred compound of formula (IV) is a compound of formula (IV-a). According to the present invention, it is further provided the use of a compound of formula (I), as disclosed above for preparing a compound of formula (III) as disclosed above, wherein *P and Base are as defined above. Preferred compound of formula (I) is a compound of formula (I-a). Preferred compound of formula (III) is a compound of formula (Ill-a). According to the present invention, it is further provided the use of a compound of formula (I), as disclosed above for preparing a compound of formula (IV) as disclosed above, wherein *P and Base are as defined above. Preferred compound of formula (I) is a compound of formula (I-a). Preferred compound of formula (IV) is a compound of formula (IV-a). According to the present invention, it is further provided the use of a reducing agent for stereo selectively reducing the oxo group in position 3' of the furanose ring of the compound of formula (III), wherein the compound of formula (III) as disclosed above. Preferred compound of formula (III) is a compound of formula (III- a). The reducing agent is preferably selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent. Preferably the boron based reducing agent is a borohydride, wherein preferably the borohydrides is selected from the group consisting of NaBH ₄ , LiBH ₄ , Li(Et) ₃ BH. Preferably the aluminium based reducing agent is a lithium- aluminium hydride wherein preferably the lithium- aluminium hydride is selected from the group consisting of LiAlH ₄ and diisobutylaluminium hydride ( DIBAL-H ). More preferably the reducing agent is NaBH ₄ .

IV. INTERMEDIATES COMPOUNDSOF FORMULA (VII) AND (VIII) AND PROCESS FOR PREPARING OF A COMPOUND OF FORMULA (III) AND (IV) ACCORDING TO SCHEME 3

According to the present invention processes are provided for preparing a compound of formula (III), (Ill-a), (IV) and (IV-a) according to the below schemes 3 and 3-a. Further according to the invention intermediate processes are provided for preparing the intermediate compounds of formulae (VII), (Vll-a), (VIII), (VHI-a). Intermediate compounds of formulae (VII), (Vll-a), (VIII), (VHI-a) are provided as well.

SCHEME 3 SCHEME 3-A

IV.l PROCESS FOR PREPARING A COMPOUND OF FORMULA (III)

(a) Process for preparing a compound of formula (III) via (VIII)

The present invention relates to a process for the preparation of a compound of formula (III)

the process comprising

1) providing a compound of formula (VIII)

(VIII)

2 ^e ) fluorinating the compound of formula (VIII) and obtaining the compound of formula (III).

Preferably, the present invention relates to said process wherein at each occurrence P is selected from *P or PG.

With regard to *P, *P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate and phosphoramidate. *P is preferably a pho sphoramidate .

With regard to *P, it is more preferred that *P is a phosphoramidate of structure

wherein

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci-C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N02 and CN; preferably Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl;

P i is Ci-C ₆ alkyl or C3-C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl; preferably Ri is Ci-C ₆ alkyl, more preferably isopropyl. Ci-C ₆ alkyl may be optionally substituted with at least one of Ci-C ₆ alkyl and aryl, R ₂ and R ₃ are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C3-C6 cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(C C ₆ alkyl) and CN; preferably R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; more preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

It is hence more preferred that P is a phosphoramidate of structure

wherein

Ar is selected from the group consisting of phenyl and naphtyl, more preferably phenyl

Ri is Ci-C ₆ alkyl, more preferably isopropyl

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

In the above formulae, the phosphorus atom of the structure

has steric configuration S or R, preferably S.

The preferred *P structure according to the invention is structure:

preferably wherein the phosphorus atom P has a steric configuration S. P can also be PG. PG is a protecting group. PG is preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group. PG is preferably selected from the group consisting of alkyl, benzyl and a silyl protecting group.

Preferably, the present invention relates to said process wherein Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring through a carbon or nitrogen atom It is preferred that the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine. More preferably the Base is uracil. It is further contemplated that the above formulae include the enantiomers and diastereomers thereof.

Step 1)

Any means for providing a compound of formula (VIII) is suitable according to the present invention. A preferred method for preparing the compound of formula (VIII) is disclosed herein below.

Step 2 ^e )

According to 2 ^e ) the fluorinating of 2 ^e ) is carried out with an electrophilic fluorinating agent. Preferably the fluorinating of 2 ^e ) is carried out with a electrophilic fluorinating agent which is for example iV-fl.uoro-o-benzenedisulfonimi.de (NFOBS), iV-fluorobenzenesulfonimi.de (NFSI), and l-Chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor).

Steps x) and xx)

According to the present invention it is further contemplated that the providing of 1) comprises

x) providing a compound of formula (VII)

xx) methylating the compound of formula (VII) and obtaining a compound of formula (VIII),

It is contemplated that the methylating of xx) is carried out with a methylating reagent. It is preferred that the methylating reagent is selected from the group consisting of methyl iodide or sulfonic acid methyl ester.

With regard to the temperature, no particular limitation exists with respect to the temperature of the methylation of xx) as far as the methylation occurs. The methylation is carried out at a temperature preferably in the range of from -20 °C to 100 °C, more preferably in the range of from 0 °C to 40 °C.

With regard to the solvent, no particular limitation exists with respect to the solvent of the methylation of xx). The methylation is carried out preferably in a solvent, more preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert-butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof. The preferred solvent is dichloromethane, preferably anhydrous dichlorome thane. The term "anhydrous" referred to a solvent means, in the present context, a solvent having a content of less than w/w 1% water, preferably less than 0.5 w/w % water, more preferably less than 0.1 w/w % water.

With regard to the molar ratio of the compound of formula (VII) relative to the methylating reagent, it is preferably in the range of from 1: 15 to 1:5.

According to the present invention it is further contemplated that the providing of x) preferably comprises

a) providing a compound of formula (VI)

(VI)

b) oxidizing the compound of formula (VI) and obtaining a compound of formula (VII),

P, *P, PG and the Base are as defined above. The oxidizing of b) is carried out with the oxidizing agent and at the conditions as defined above in paragraph III.1 above.

The process is preferably for preparing a compound of formula (Ill-a), wherein the compound of formula (Ill-a) is as disclosed in paragraph II, via intermediates of formula (VHI-a), (VITa) and (Vl-a) wherein the as disclosed herein below.

(b) Process for preparing a compound of formula (III) via intermediates of formulae (VII) and (VIII)

According to the present invention it is further provided a process for preparing a compound of formula (III)

the process comprising

x) providing a compound of formula (VII)

xx) methylating the compound of formula (VII) and obtaining a compound of formula (VIII),

2 ^e ) fluorinating the compound of formula (VIII) of xx) and obtaining compound of formula (III)

wherein P, *P, PG and the Base are as defined above in paragraph IV.1. The methylating of xx) is as defined above in paragraph IV.1 The fluorinating of 2 ^e ) is as defined above in paragraph IV.1.

It is further preferred that step x) comprises

a) providing a compound of formula (VI)

b) oxidising the compound of formula (VI) and obtaining a compound of formula (VII)

P, *P, PG and the Base and the oxidizing of b) is as disclosed above in paragraph III.1. above

The process is preferably for preparing a compound of formula (Ill-a) as disclosed in paragraph II via intermediates of formula (VHI-a), (VITa) wherein the intermediates of formula (VHI-a), (Vll-a) are as disclosed herein below.

(c) Process for preparing a compound of formula (III) via intermediates of formulae (VI), (VII), (VIII)

According to the present invention it is further provided a process for preparing a compound of formula (III)

the process comprising

a) providing a compound of formula (VI)

oxidising the compound of formula (VI) and obtaining a compound of formula (VII)

methylating the compound of formula (VII) and obtaining a compound of formula (VIII)

fluorinating the compound of formula (VIII) of b') and obtaining compound of formula (III)

P, *P, PG and the Base are as defined above. The oxidizing of b) is carried out with the oxidizing agent and at the conditions as defined above in paragraph III.1 The methylating of b') is as defined above in the methylating of xx) of paragraph VI.1. The fluorinating of c ^e ) is as defined above in the fluorinating of 2 ^e ) of paragraph VI.1.

According to the present invention, it is further provided a process, preferably a process as described above comprising steps a), b), b') and c ^e ) wherein the provision of the compound of formula (VI) having P= PG in a) comprises

0*) protecting a compound of formula (V)

and obtaining a compound of formula (VI) having P

P, *P, PG and the Base are as defined above. The protecting of 0') is as defined above in the protecting of 0) of the reactions schemes 1 and 2. According to the present invention, it is further provided a process, preferably a process as described above comprising steps a), b), b') and c) wherein the provision in a) of the compound of formula (VI) having P=*P comprises

0") phosphorylating a compound of formula (V)

(V)

and obtaining a compound of formula (VI) having P

).

Preferably the phosphorylating of 0") comprises reacting, in the presence of a base or of a Lewis acid, the compound of formula (V) with a compound of formula *P-X* wherein *P is as defined above and X* is a leaving group, preferably selected from chloride, substituted phenols, pyrimidines or N-hydroxysuccinimide.

The process is preferably for preparing a compound of formula (Ill-a) wherein the compound of formula (Ill-a) is as disclosed in paragraph II. via intermediates of formula (VHI-a), (VITa) and (Vl-a) wherein the intermediates of formula (VHI-a), (Vll-a) and (Vl-a) are as disclosed herein below.

IV.2 PREPARATION OF A COMPOUND OF FORMULA (IV)

(a) Preparation of a compound of formula (IV) via intermediate (VIII) and (III)

According to the present invention it is further contemplated a process for the preparation of the compound of formula (IV) via intermediate compound of formula (III).

The process comprises steps i) and ii) as disclosed above in paragraph I. It further contemplated that in i) a compound of formula (III) is provided wherein P is *P.

It is further contemplated that step i) comprises

1) providing a compound of formula (VIII)

2 ^e ) fluorinating the compound of formula (VIII) and obtaining the compound of formula (III).

P, *P, PG and the Base are as defined above. The fluorinating of 2 ^e ) is as defined above for fluorinating of 2 ^e ).

According to the present invention it is further preferred that the providing of 1) comprises x) providing a compound of formula (VII)

(VII)

methylating the compound of formula (VII) and obtaining a compound of formula (VIII),

P, *P, PG and the Base are as defined above in paragraph IV.1. The methylating of xx) is as defined above in paragraph IV.1.

According to the present invention it is further preferred that the providing of x) comprises a) providing a compound of formula (VI)

oxidizing the compound of formula (VI) and obtaining a compound of formula (VII)

P, *P, PG and the Base are as defined above in paragraph IV.1. The oxidizing of b) is carried out with the oxidizing agent and at the conditions as defined above in paragraph III. 1 It is further preferably contemplated that

-when in the compound of formula (III) of i) P is PG after i) the process further comprises

i') phosphorylating said compound of formula (III) having P= PG to a compound of formula (III) having P

ii) reducing the compound of formula (III) of i') and obtaining the compound of formula (IV) having P= *P.

P, *P, PG and the Base are as defined above. The reducing of ii) is carried out with the agent and at the conditions as defined above in paragraph I. for the reducing of ii). The phosphorylating of i') is carried out with the agent and at the conditions as defined above in paragraph I. for phosphorylating of i').

The process is preferably for preparing a compound of formula (IV-a) as disclosed in paragraph II via intermediates of formula (VHI-a), (Vll-a) and (Vl-a) as disclosed herein below and via compound of formula (Ill-a) as disclosed above in paragraph II.

(b) Process for preparing a compound of formula (IV) in a process with intermediates of formula (VII), (VIII) and (III)

According to the present invention, it is further provided a process for preparing a compound of formula (IV)

via intermediate compounds of formula (VIII) and (III). The process comprises

x) providing a compound of formula (VII)

methylating the compound of formula (VII) and obtaining a compound of formula (VIII), xxx) fluorinating the compound of formula (VIII) of xx) and obtaining the compound of formula (III)

and wherein

-when in the compound of formula (III) of xxx) P is *P, the process further comprises ii) reducing the compound of formula (III) of xxx) and obtaining the compound of formula (IV)

or

-when in the compound of formula (III) of xxx) P is PG after xxx), the process further comprises

i') phosphorylating said compound of formula (III) having P= PG to a compound of formula (III) having P= P* and

ii) reducing the compound of formula (III) of i') and obtaining the compound of formula (IV) having P= *P.

P, *P, PG and the Base are as defined above. The methylating of xx) is as defined above in the methylating of xx) of IV.1. The fluorinating of xxx) is as defined above in the fluorinating of i') of IV.1. The reducing of ii) is carried out with the agent and at the conditions as defined above in paragraph I. in the reducing of ii). The phosphorylating of i') is carried out with the agent and at the conditions as defined above in paragraph I. for the phosphorylating of i').

It is further contemplated that step x) preferably comprises

a) providing a compound of formula (VI)

oxidizing the compound of formula (VI) and obtaining a compound of formula (VII),

P, *P, PG and the Base are as defined above. The oxidizing of b) is carried out with the oxidizing agent and at the conditions as defined above in paragraph III.

The process is preferably for preparing a compound of formula (IV-a) as disclosed in paragraph II via intermediates of formula (VHI-a), (Vll-a) and (Vl-a) as disclosed herein below and via compound of formula (Ill-a) as disclosed above in paragraph II.

(c) Process for preparing a compound of formula (IV) in a process with intermediates of formula (VI), (VII), (VIII) and (III)

According to the present invention it is further provided a process for preparing a compound of formula (IV)

via intermediate compounds of formulas (VI), (VII), (VIII). The process comprises a) providing a compound of formula (VI)

(VI)

b) oxidising the compound of formula (VI) and obtaining a compound of formula (VII)

b') methylating the compound of formula (VII) and obtaining a compound of

formula (VIII)

fluorinating the compound of formula (VIII) of b') and obtaining compound of formula (III)

and

-wherein when in the compound of formula (III) of c ^e ) P is *P

ii) reducing the compound of formula (III) of c ^e ) and obtaining the compound of formula (IV)

or

-wherein when in the compound of formula (III) of c ^e ) P is PG after c ^e ) the process comprises

i') phosphorylating said compound of formula (III) having P=PG to a compound of formula (III) having P= P* and

ii) reducing the compound of formula (III) of i') and obtaining the compound of formula (IV) having P= *P.

P, *P, PG and the Base are as defined above. The oxidizing of b) is carried out with the reagent and at the conditions as defined above in paragraph III. The methylating of b') is as defined above in the methylating of xx) of IV.1. The reducing of ii) is carried out with the reagent and at the conditions as defined above in paragraph I. in the reducing of ii). The phosphorylating of i') is carried out with the reagent and at the conditions as defined above in paragraph I. in the phosphorylating of i'). The fluorinating of c ^e ) is as defined above in the fluorinating of 2 ^e ) in paragraph IV.1.

The process is preferably for preparing a compound of formula (IV-a) as disclosed in paragraph II via intermediates of formula (VHI-a), (Vll-a) and (Vl-a) as disclosed herein below and via compound of formula (Ill-a) as disclosed above in paragraph II.

In the processes for preparing compound of formula (IV) of subparagraphs IV.2 (a), (b) and (c), it is further preferably contemplated that the provision of the compound of formula (VI) having P= PG of a) comprises

0') protecting a compound of formula (V)

(V)

and obtaining a compound of formula (VI) having P

wherein P is PG and

wherein preferably the protecting of 0') comprises reacting, in the presence of base, the compound of formula (V) with a compound of formula PG-X' wherein PG is as defined above and X' is a leaving group, preferably selected from the group consisting of halogens, mesylate and tosylate.

In the processes for preparing compound of formula (IV) of subparagraphs IV.2 (a), (b) and (c), it is further preferably contemplated that the provision of the compound of formula (VI) having P= *P of a) comprises

0) phosphorylating a compound of formula (V)

and obtaining a compound of formula (VI) having P

wherein preferably the phosphorylating of 0) comprises reacting, in the presence of a base or of a Lewis acid, the compound of formula (V) with a compound of formula *P-X* wherein *P is as defined above and X* is a leaving group, preferably selected from chloride, substituted phenols, pyrimidines or N-hydroxysuccinimide.

According to the present invention it is preferred that in the processes of the invention the compound of formula (VIII) has structure (VHI-a)

O (Vlll-a). It is further preferred that the phosphorus atom P of the compound of formula (VIII) and of formula (VIII- a) has a steric configuration S.

As exemplified in Scheme 3-a, according to the present invention it is preferred that in the processes of the invention the compound of formula (VII) has structure (Vll-a)

It is further preferred that the phosphorus atom P of the compound of formula (VII) and of formula (VII- a) has a steric configuration S.

According to the present invention it is preferred that in the processes of the invention the compound of formula (VI) has structure (Vl-a)

It is further preferred that the phosphorus atom P of the compound of formula (VI) and of formula (VI-a) has a steric configuration S.

According to the present invention it is preferred that in the processes of the invention the compound of formula (IV) has structure (IV-a)

It is further preferred that the phosphorus atom P of the compound of formula (IV) and of formula (IV-a) has a steric configuration S. It is hence preferred that the processes disclosed above are for the preparation of a compounds of formulae (III- a) and (IV-a).

IV.3 PROCESS FOR PREPARING COMPOUND OF FORMULA (VIII)

According to the present invention, it is further provided a process for preparing a compound of formula (VIII), the process comprising

x) providing a compound of formula (VII),

(VII)

methylating the compound of formula (VII), and obtaining a compound of formula (VIII),

wherein

P, *P, PG and the Base are as defined above. The methylating of xx) is as defined above in paragraph IV.1. Preferably compound of formula (VII) is of formula (VII- a). Preferably the compound of formula (VIII), is of formula (VHI-a) as defined herein below.

IV. 4 PROCESS FOR PREPARING COMPOUND OF FORMULA (VII)

According to the present invention, it is further provided a process for preparing a compound of formula (VII), the process comprising

a) providing a compound of formula (VI)

oxidizing the compound of formula (VI) and obtaining a compound of formula (VII),

wherein

P, *P, PG and the Base are as defined above. The oxidizing of b) is as defined above in oxidizing of b) in paragraph IV.1. Preferably compound of formula (VI) is of formula (VI- a). Preferably the compound of formula (VII), is of formula (Vll-a) as defined herein below.

It is hence preferred that the processes disclosed above are for the preparation of a compounds of formulae (Vll-a) and (VHI-a).

IV.5 COMPOUND OF FORMULA (VII)

According to the invention, it i a (VII)

wherein P is *P or PG.

With regard to *P, it is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate and phosphoramidate. *P is preferably a phosphoramidate.

With regard to *P, it is more preferred that *P is a phosphoramidate of structure

wherein

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(C _r C ₆ alkyl), C(0)(aryl), COO(C C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N02 and CN; preferably Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl;

P i is Ci-C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl; preferably Ri is Ci-C ₆ alkyl, more preferably isopropyl. Ci-C ₆ alkyl may be optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

P ₂ and P3 are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl) and CN; preferably R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; more preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

It is hence more preferred that P is a phosphoramidate of structure

wherein

Ar is selected from the group consisting of phenyl and naphtyl, more preferably phenyl

Ri is Ci-C ₆ alkyl, more preferably isopropyl

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

In the above formulae, the phosphorus atom P of the structure

has steric configuration S or R, preferably S.

The preferred *P structure according to the invention is structure:

preferably wherein the phosphorus atom P has a steric configuration S.

P can also be PG. PG is a protecting group. PG is preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group. PG is preferably selected from the group consisting of alkyl, benzyl and a silyl protecting group.

With regard to Base, it is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring according to formula (III) through a carbon or nitrogen atom. It is preferred that the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine. More preferably the Base is uracil.

It is further contemplated that the above formula (VII) includes the enantiomers and diastereomers thereof. According to the present invention, it is further provided a compound of formula (VII) obtained or obtainable by a process as disclosed above.

According to the present invention, it is further provided a compound of formula (VII) has structure (VII- a)

wherein preferably the phosphorus atom P has a steric configuration S.

According to the present invention, it is further provided a compound of formula (VII) or (Vll-a) obtained or obtainable by a process as disclosed above.

According to the present invention, it is further provided a mixture comprising a compound of formula (VII) or (Vll-a) as disclosed above.

IV.6 COMPOUND OF FORMULA (VIII)

According to the invention it is further provided a compound useful of formula (VIII)

wherein P is *P or PG.

With regard to *P, it is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate and phosphoramidate. *P is preferably a pho sphoramidate .

With regard to *P, it is more preferred that *P is a phosphoramidate of structure

wherein

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci-C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N02 and CN; preferably Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl;

P i is Ci-C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl; preferably Ri is Ci-C ₆ alkyl, more preferably isopropyl. Ci-C ₆ alkyl may be optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and R3 are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(C C ₆ alkyl) and CN; preferably R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; more preferably R ₂ and R3 are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

It is hence more preferred that P is a phosphoramidate of structure

wherein

Ar is selected from the group consisting of phenyl and naphtyl, more preferably phenyl

Ri is Ci-C ₆ alkyl, more preferably isopropyl

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

In the above formulae, the phosphorus atom P of the structure

has steric configuration S or R, preferably S.

The preferred *P structure according to the invention is structure:

preferably wherein the phosphorus atom P has a steric configuration S.

P can also be PG. PG is a protecting group. PG is preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group. PG is preferably selected from the group consisting of alkyl, benzyl and a silyl protecting group.

With regard to Base, it is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring according to formula (III) through a carbon or nitrogen atom. It is preferred that the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine. More preferably the Base is uracil.

It is further contemplated that the above formula (VIII) includes the enantiomers and diastereomers thereof.

The preferred configuration of the methyl on the furanose ring is such that after the fluorination reaction the methyl is projecting toward the viewer and the F is projecting away from the viewer as depicted in formula (III) and (Ill-a).

According to the present invention, it is further provided a compound of formula (VIII) obtained or obtainable by a process as disclosed above.

According to the present invention, it is further provided a compound of formula (VIII) having structure (VIITa)

wherein preferably the phosphorus atom P has a steric configuration S. The methyl on the furanose ring has configuration S and/or R. Compound of formula (VHI-a) with respect to the configuration of carbon atom of the furanose ring bearing the methyl can comprise diastereoisomers having the S and the R configuration at this carbon atom or diastereoisomers having only configuration R at this carbon atom or only configuration S at this carbon atom. The configuration is preferably such that after the fluorination reaction the methyl is projecting toward the viewer and the F is projecting away from the viewer as depicted in formula (III) and (Ill-a).

According to the present invention, it is further provided a compound of formula (VIII) or (VIITa) obtained or obtainable by a process as disclosed above. According to the present invention, it is further provided a mixture comprising a compound of formula (VIII) or (VIITa) as disclosed above.

IV.7 Uses According to the present invention, it is further provided the use of a compound of formula (III) as disclosed, preferably prepared according to a process as disclosed above, for preparing a compound of formula (IV) as disclosed above, wherein *P and Base are as defined above. Preferred compound of formula (III) is a compound of formula (III- a). Preferred compound of formula (IV) is a compound of formula (IV-a).

According to the present invention, it is further provided the use of a compound of formula (VIII), as disclosed above for preparing a compound of formula (IV) as disclosed above, wherein *P and Base are as defined above. Preferred compound of formula (VIII) is a compound of formula (VHI-a). Preferred compound of formula (IV) is a compound of formula (IV-a).

According to the present invention, it is further provided the use of a compound of formula

(VII) , as disclosed above for preparing a compound of formula (IV) as disclosed above, wherein *P and Base are as defined above. Preferred compound of formula (VII) is a compound of formula (Vll-a). Preferred compound of formula (IV) is a compound of formula (IV-a).

According to the present invention, it is further provided the use of a compound of formula (VI), as disclosed above for preparing a compound of formula (IV) as disclosed above, wherein *P and Base are as defined above. Preferred compound of formula (VI) is a compound of formula (Vl-a). Preferred compound of formula (IV) is a compound of formula (IV-a). According to the present invention, it is further provided the use of a compound of formula

(VIII) , as disclosed above for preparing a compound of formula (III) as disclosed above, wherein *P and Base are as defined above. Preferred compound of formula (VIII) is a compound of formula (VIII- a). Preferred compound of formula (III) is a compound of formula (III- a).

According to the present invention, it is further provided the use of a compound of formula (VII), as disclosed above for preparing a compound of formula (III) as disclosed above, wherein *P and Base are as defined above. Preferred compound of formula (VII) is a compound of formula (Vll-a). Preferred compound of formula (III) is a compound of formula (Ill-a).

According to the present invention, it is further provided the use of a compound of formula (VI), as disclosed above for preparing a compound of formula (III) as disclosed above, wherein *P and Base are as defined above. Preferred compound of formula (VI) is a compound of formula (Vl-a). Preferred compound of formula (III) is a compound of formula (Ill-a).

According to the present invention, it is further provided the use of a reducing agent for stereo selectively reducing the oxo group in position 3' of the furanose ring of the compound of formula (III), wherein the compound of formula (III) as disclosed above. Preferred compound of formula (III) is a compound of formula (III- a). The reducing agent is preferably selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent. Preferably the boron based reducing agent is a borohydride, wherein preferably the borohydrides is selected from the group consisting of NaBH ₄ , LiBH ₄ , Li(Et) ₃ BH. Preferably the aluminium based reducing agent is a lithium- aluminium hydride wherein preferably the lithium- aluminium hydride is selected from the group consisting of LiAlH ₄ and diisobutylaluminium hydride ( DIBAL-H ). More preferably the reducing agent is NaBH .

V. INTERMEDIATES OF FORMULA (X) AND (XI) AND PROCESS FOR

PREPARING A COMPOUND OF FORMULA (III) AND (IV) ACCORDING TO SCHEME 4 AND 4-A According to the present invention processes are provided for preparing a compound of formula (III), (Ill-a), (IV) and (IV-a) according to the below schemes 4 and 4-a. Further according to the invention intermediate compound and processes are provided for preparing the intermediate compounds of formulae (XI) and (Xl-a).

SCHEME 4

V.l PROCESS FOR PREPARING A COMPOUND OF FORMULA (III)

(a) Process for preparing a compound of formula (III) via a compound of formula (IX)

The present invention hence further relates to a process for the preparation of a compound of formula (III)

the process comprising

1) providing a compound of formula (XI)

2) fluorinating the compound of formula (XI) and obtaining the compound of formula (III).

Preferably, the present invention relates to said process wherein at each occurrence P is selected from *P or PG.

With regard to *P, it is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate and phosphoramidate. *P is preferably a pho sphoramidate .

With regard to *P it is more preferred that *P is a phosphoramidate of structure

wherein

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci-C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N02 and CN; preferably Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl;

Ri is Ci-C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl; preferably Ri is Ci-C ₆ alkyl, more preferably isopropyl. Ci-C ₆ alkyl may be optionally substituted with at least one of Ci-C ₆ alkyl and aryl,

R ₂ and R3 are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci-

C ₆ alkyl), COONH ₂ , COONH(C C ₆ alkyl) and CN; preferably R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; more preferably R ₂ and R3 are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

It is hence more preferred that P is a phosphoramidate of structure

wherein

Ar is selected from the group consisting of phenyl and naphtyl, more preferably phenyl

Ri is Ci-C ₆ alkyl, more preferably isopropyl

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

In the above formulae, the phosphorus atom of the structure

has steric configuration S or R, preferably S.

The preferred *P structure according to the invention is structure:

preferably wherein the phosphorus atom P has a steric configuration S.

P can also be PG. PG is a protecting group. PG is preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group. PG is preferably selected from the group consisting of alkyl, benzyl and a silyl protecting group.

Preferably, the present invention relates to said process wherein Base in formula (III) is uracil.

It is further contemplated that the above formulae include the enantiomers and diastereomers thereof. Step 1)

There is no limitation in the provision of compound of formula (IX) of 1).

According to the present invention it is preferred that the providing of 1) comprises

a) providing a compound of formula (X)

oxidizing the compound of formula (X) and obtaining a compound of formula

P is as defined above.

Compound of formula (X) is a known compound. It is disclosed in patent application US20140271547.

Step b)

It is contemplated that the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane,

- (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant -Swern type oxidation reagents -such as Dimethyl sulfoxide (DMSO) and suitable activator-

-transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO) wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents.

More preferably, the oxidizing reagent is selected from the group consisting of hypervalent iodo oxidation reagents and Swern type oxidation reagents.

With regard to the temperature, no particular limitation exists with respect to the temperature of the oxidizing of b) as far as the oxidation occurs. It is preferred that the oxidizing is carried out at a temperature in the range of from -80 °C to 60 °C, more preferably in the range of from -78 °C to 30 °C, more preferably in the range of from -40 °C to 20 °C.

With regard to the solvent, no particular limitation exists with respect to the solvent of the oxidizing of b) as far as the oxidation occurs. It is preferred that the oxidizing is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, more preferably in a solvent selected from the group consisting of dichloromethane, DMSO and a mixture thereof. With regard to the molar ratio, the molar ratio of the compound of formula (X) relative to the oxidizing agent is preferably in the range of from 1 : 1 to 1 : 15, preferably in the range of from 1 :3 to 1 :4.

Step 2)

According to 2) the fluorinating is carried out with a fluorinating agent selected from the group consisting of an inorganic or an organic fluorinating agent. An organic fluorinating agent is preferred according to the present invention. The inorganic fluorinating agent is preferably selected from the group consisting of metal fluorides such as LiF, KF, CsF, borane complexes of HF. The organic fluorination agent is preferably selected from the group consisting of an amine complex of HF such as triethylamine tris(hydrogen fluoride), pyridinium poly(hydrogen fluoride) and HF-urea, aminosulfur fluoride derivatives such as die thylamino sulfur trifluoride (DAST), (diethylamino)difluorosulfonium tetrafluoroborate (XTal-Fluor E), difluoro(morpholino)sulfonium tetrafluoroborate (XTal-Fluor M), 4-tert- Butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead), Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor), 2-Pyridinesulfonyl Fluoride (PyFluor), dime thylamino sulfur trifluoride, ammonium fluorides such as tetrabutylammoniumfluorid (TBAF), silicon fluorides such as tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), and combinations thereof. The fluorinating agent is more preferably (diethylamino)difluorosulfonium tetrafluoroborate (XTal-Fluor E).

With regard to the temperature, no particular limitation exists with respect to the temperature of the fluorinating of 2) as far as the fluorinating occurs. It is preferred that the fluorinating is carried out at a temperature in the range of from -20 °C to 100 °C, more preferably in the range of from 0 °C to 40 °C.

With regard to the solvent, no particular limitation exists with respect to the solvent of the fluorinating of 2) as far as the fluorinating occurs. It is preferred that the fluorinating is carried out in an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert-butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

With regard to the molar ratio of the compound of formula (XI) relative to the fluorinating agent it is preferably in the range of from 1: 15 to 1:5.

The process as disclosed above is preferably for the preparation of the compound of formula (Ill-a) as disclosed above.

(b) Process for the preparation of compound of formula (III) with intermediate of formula (X) and of formula (XI)

According to the present invention it is further contemplated a process for the preparation of a compound of formula (III)

g intermediate compounds of formula (X) and (XI). The process comprises

a) providing a compound of formula (X)

b) oxidizing the compound of formula (X) and obtaining a compound of formula (XI)

c) fluorinating the compound of formula (XI) of b) and obtaining the compound of formula (III)

wherein at each occurrence P and Base are as defined above.

The oxidizing of b) is carried out with the reagent and at the conditions as defined above in paragraph III. The fluorinating of c) is carried out with the agent and at the conditions as defined above in paragraph III.

The process as disclosed above is preferably for the preparation of the compound of formula (Ill-a) as disclosed above. V.2 PROCESS FOR PREPARING A COMPOUND OF FORMULA (IV)

(a) Process for preparing compound of formula (IV) via compound of formula (III) and of formula (XI)

According to the present invention it is further contemplated a process for the preparation of the compound of formula (IV) via intermediate compound of formula (III). The process comprises steps i) and ii) as disclosed above in paragraph I. It is further contemplated that step i) providing the compound of formula (III) comprises

1) providing a compound of formula (XI)

2) fluorinating the compound of formula (XI) and obtaining the compound of formula (III) as disclosed above.

P, P* and PG are as defined above.

The fluorinating of 2) is carried out with the reagent and at the conditions as defined above in paragraph III. in the fluorinating of 2).

It is preferred that step 1) comprises

a) providing a compound of formula (X)

oxidizing the compound of formula (X) and obtaining a compound of formula

(xi).

P, P* and PG are as defined above.

The oxidizing of b) is carried out with the agent and at the conditions as defined above in paragraph III.

In the above process is further preferably contemplated that

when in i) the compound of formula (III) P is *P, the above process comprises ii) reducing the compound of formula (III) of i) and obtaining the compound of formula (IV).

In the above processes is further preferably contemplated that

when in the compound of formula (III) of i) P is PG before ii) the process comprises i') phosphorylating said compound of formula (III) having P= PG to a compound of formula (III) having P= P* and

ii) reducing the compound of formula (III) of i') and obtaining the compound of formula (IV) having P= *P. The reducing of (ii) is carried out with the reagent and at the conditions as defined above in paragraph I. and the phosphorylating of i') is carried out with the reagent and at the conditions as defined above in paragraph I.

The process as disclosed above is preferably for the preparation of the compound of formula (IV-a) as disclosed above.

(b) Process for preparing compound of formula (IV) via compound of formulae (X), (XI) and (III)

According to the present invention it is further contemplated a process for the preparation of the compound of formula (IV) via intermediate compounds of formula (X), (XI) and (III). The process comprises steps i) and ii) as disclosed above. It is further contemplated that step i) providing the compound of formula (III) comprises a) providing a compound of formula (X)

oxidizing the compound of formula (X) and obtaining a compound of formula

(xi).

c) fluorinating the compound of formula (XI) and obtaining the compound of formula (III), wherein P, P* and PG are as defined above. The reducing of step (ii) is carried out with the reagent and at the conditions as defined above in paragraph I. The fluorinating of 2) is carried out with the reagent and at the conditions as defined above in paragraph III. The oxidizing of b) is carried out with the agent and at the conditions as defined above in paragraph III.

In the above process, it is contemplated that

when in i) the compound of formula (III) P is *P, the above process comprises ii) reducing the compound of formula (III) of i) and obtaining the compound of formula (IV). the above process it is contemplated that

when in the compound of formula (III) of i) P is PG the process comprises

i') phosphorylating sad compound of formula (III) having P= PG to a compound of formula (III) having P= P* and

ii) reducing the compound of formula (III) of i') and obtaining the compound of formula (IV) having P= *P.

P, *P, PG and the Base are as defined above. The oxidizing of b) is carried out with the agent and at the conditions as defined above in paragraph III. The reducing of ii) is carried out with the reagent and at the conditions as defined above in paragraph I. in the reducing of ii). The phosphorylating of i') is carried out with the reagent and at the conditions as defined above in paragraph I. in the phosphorylating of i'). The fluorinating of 2) is carried out with the agent and at the conditions as defined above in paragraph III.

The process as disclosed above is preferably for the preparation of the compound of formula (IV-a) as disclosed above.

V.3 PROCESS FOR PREPARING THE COMPOUND OF FORMULA (XI)

According to the present invention it is further preferred a process for preparing a compound of formula (XI), the process comprising

a) providing a compound of formula (X)

b) oxidizing the compound of formula (X) and obtaining a compound of formula (XI) wherein

P, *P and PG are as disclosed above. The oxidizing of b) is as defined above in the oxidizing of b) according to scheme 4.

According to the invention it is preferred that in the processes of the invention the compound of formula (X) has structure (X-a)

It is further preferred that the phosphorous atom P has a steric configuration S.

According to the invention it is further preferred that in the processes of the invention the compound of formula (XI) has structure (Xl-a)

It is further preferred that the phosphorous atom P has a steric configuration S.

COMPOUND OF FORMULA (X)

According to the invention, it is provided a compound of formula (X)

wherein P is *P or PG.

With regard to *P, it is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate and phosphoramidate. *P is preferably a pho sphoramidate .

With regard to *P, it is more preferred that *P is a phosphoramidate of structure

wherein

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(O)(Ci-C ₆ alkyl), C(O)(aryl), COO(Ci-C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), NO2 and CN; preferably Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl;

Ri is Ci-C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl; preferably Ri is Ci-C ₆ alkyl, more preferably isopropyl. Ci-C ₆ alkyl may be optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and R3 are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, F, CI, Br, I, NO ₂ , COOH, CHO, C(O)(Ci-C ₆ alkyl), C(O)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl) and CN; preferably R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; more preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

It is hence more preferred that P is a phosphoramidate of structure

wherein

Ar is selected from the group consisting of phenyl and naphtyl, more preferably phenyl

Ri is Ci-C ₆ alkyl, more preferably isopropyl

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

In the above formulae, the phosphorus atom P of the structure

has steric configuration S or R, preferably S.

The preferred *P structure according to the invention is structure:

preferably wherein the phosphorus atom P has a steric configuration S.

P can also be PG. PG is a protecting group. PG is preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group. PG is preferably selected from the group consisting of alkyl, benzyl and a silyl protecting group.

It is further contemplated that the above formula (X) includes the enantiomers and the diastereomers thereof.

The preferred configuration of the methyl on the furanose ring is such that after the fluorination reaction the methyl is projecting toward the viewer and the F is projecting away from the viewer as depicted in formula (III) and (Ill-a).

According to the present invention, it is further provided a compound of formula (X) having structure (X-a)

wherein preferably the phosphorus atom P has a steric configuration S. The methyl on the furanose ring has configuration S and/or R. The preferred configuration of the methyl on the furanose ring is such that after the fluorination reaction the methyl is projecting toward the viewer and the F is projecting away from the viewer as depicted in formula (III) and (Ill-a)

According to the present invention, it is further provided a compound of formula (X), preferably of formula (X-a) obtained or obtainable by a process as disclosed below.

According to the present invention, it is further provided a mixture comprising a compound of formula (X) or (X-a) as disclosed above. V.5 COMPOUND OF FORMULA (XI)

According to the present i of formula (XI)

wherein P is *P or PG.

With regard to *P, it is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate and phosphoramidate. *P is preferably a pho sphoramidate . With regard to *P, it is more preferred that *P is a phosphoramidate of structure

wherein

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(C _r C ₆ alkyl), C(0)(aryl), COO(C C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N02 and CN; preferably Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl; Ri is Ci-C ₆ alkyl or C3-C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl; preferably Ri is Ci-C ₆ alkyl, more preferably isopropyl. Ci-C ₆ alkyl may be optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C3-C6 cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl) and CN; preferably R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; more preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

It is hence more preferred that P is a phosphoramidate of structure

wherein

Ar is selected from the group consisting of phenyl and naphtyl, more preferably phenyl

P i is Ci-C ₆ alkyl, more preferably isopropyl

P2 and P3 are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl; preferably R ₂ and R ₃ are one H and the other methyl so as that the methyl group in the above formula projects away from the viewer. The resulting configuration according to the CIP description is "S".

In the above formulae, the phosphorus atom of the structure

has steric configuration S or R, preferably S.

The preferred *P structure according to the invention is structure:

preferably wherein the phosphorus atom P has a steric configuration S.

P can also be PG. PG is a protecting group. PG is preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group. PG is preferably selected from the group consisting of alkyl and benzyl and a silyl protecting group.

It is further contemplated that the above formula (XI) includes the enantiomers and diastereomers thereof. According to the present invention, it is further provided a compound of formula (XI) obtained or obtainable by a process as disclosed above. According to the present invention, it is further provided a compound of formula (XI) having structure (XI- a)

wherein preferably the phosphorus atom P has a steric configuration S. According to the present invention, it is further provided a compound of formula (XI) or (XI- a) obtained or obtainable by a process as disclosed below.

According to the present invention, it is further provided a mixture comprising a compound of formula (XI) or (X-a) as disclosed above.

V.6 Uses

According to the present invention, it is further provided the use of a compound of formula (III) as disclosed, preferably prepared according to a process as disclosed above using intermediate (XI), for preparing a compound of formula (IV) as disclosed above, wherein *P and Base is uracil. Preferred compound of formula (III) is a compound of formula (Ill-a). Preferred compound of formula (XI) is a compound of formula (ΧΙ-a). Preferred compound of formula (IV) is a compound of formula (IV-a).

According to the present invention, it is further provided the use of a compound of formula (XI), as disclosed above for preparing a compound of formula (III), wherein *P is as defined above and Base is uracil. Preferred compound of formula (XI) is a compound of formula (XI- a). Preferred compound of formula (III) is a compound of formula (Ill-a).

According to the present invention, it is further provided the use of a compound of formula (XI), as disclosed above for preparing a compound of formula (IV), wherein *P is as defined above and Base is uracil. Preferred compound of formula (XI) is a compound of formula (XI- a). Preferred compound of formula (IV) is a compound of formula (IV-a).

According to the present invention, it is further provided the use of a compound of formula (X), as disclosed above for preparing a compound of formula (III), wherein *P is as defined above and Base is uracil. Preferred compound of formula (X) is a compound of formula (X- a). Preferred compound of formula (III) is a compound of formula (Ill-a).

According to the present invention, it is further provided the use of a compound of formula (X), as disclosed above for preparing a compound of formula (IV), wherein *P is as defined above and Base is uracil. Preferred compound of formula (X) is a compound of formula (XI- a). Preferred compound of formula (IV) is a compound of formula (IV-a).

According to the present invention, it is further provided the use of a reducing agent for stereo selectively reducing the oxo group in position 3' of the furanose ring of the compound of formula (III), wherein the compound of formula (III) as disclosed above. Preferred compound of formula (III) is a compound of formula (III- a). The reducing agent is preferably selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent. Preferably the boron based reducing agent is a borohydride, wherein preferably the borohydrides is selected from the group consisting of NaBH ₄ , LiBH ₄ , Li(Et) ₃ BH. Preferably the aluminium based reducing agent is a lithium- aluminium hydride wherein preferably the lithium- aluminium hydride is selected from the group consisting of LiAlH ₄ and diisobutylaluminium hydride ( DIBAL-H ). More preferably the reducing agent is NaBH ₄ . The compound of formula (III) is preferably obtained according to scheme 4 using the compound of formula (IX) as intermediate compound or as starting material.

Process for preparing a compound of formula (IV) from a compound of formula (III)

A process for the preparation of a compound of formula (IV)

process comprising

providing a compound of formula (III)

(III)

ii) reducing the compound of formula (III) wherein P is *P and obtaining the compound of formula (IV)

wherein at each occurrence

P is *P or PG a wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting alkyl, benzyl and a silyl protecting group, and

Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring according through a carbon or nitrogen atom wherein the formulae include the enantiomers and diastereomers thereof.

The process of embodiment 1, wherein P is *P.

The process of embodimen a phosphoramidate of structure

wherein

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci-C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N02 and CN;

Ri is Ci-C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

P ₂ and R ₃ are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C ₃ -C6 cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl) and CN.

The process of embodiment 3, wherein the phosphorus atom of the structure

has steric configuration S or R, preferably S.

The process of embodiment 3 or 4, wherein

Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl,

Ri is Ci-C ₆ alkyl, preferably isopropyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and R3 are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl.

The process of any of e P has structure

preferably wherein the phosphorus atom P has a steric configuration S.

The process of embodiment 1, wherein P is PG.

The process of embodiment 7, wherein the PG is selected from the group consisting of alkyl, benzyl and a silyl protecting group.

The process of any of embodiments 1 to 8, wherein the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine.

The process of any of embodiments 1 to 9, wherein the Base is uracil. The process of any of embodiments 1 to 10, wherein the reducing of ii) is carried out with a reducing agent selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent, wherein preferably the boron based reducing agent is a borohydride and the aluminium based reducing agent is a lithium- aluminium hydride and

wherein preferably the borohydrides is selected from the group consisting of NaBH ₄ , LiBH ₄ , Li(Et) ₃ BH, and

wherein preferably the lithium- aluminium hydride is selected from the group consisting of LiAlH ₄ and diisobutyl aluminium hydride (DIBAL-H ).

The process of any of embodiments 1 to 11, wherein the reducing of ii) is carried out at a temperature in the range of from -78 °C to 40 °C, preferably in the range of from - 20 °C to 20 °C

The process of any of embodiments 1 to 12, wherein the reducing of ii) is carried out in a solvent selected from a protic solvent or a mixture thereof, preferably in a protic solvent selected from the group consisting of methanol, ethanol, isopropanol and water and a mixture thereof.

The process of any of embodiments 1 to 13, wherein the molar ratio of the compound of formula (III) relative to the reducing agent is in the range of from 1:1 to 1: 10, preferably in the range of from 1:2 to 1:4.

The process of any of embodiments 1 to 14, wherein in i) in the compound of formula (III) P is PG and wherein before ii) the process comprises

i') phosphorylating said compound of formula (III) having P= PG to a compound of formula (III) having P= P*.

The process of embodiment 15, wherein the phosphorylating of i') comprises reacting, preferably in the presence of a base or of a Lewis acid, the compound of formula (III) wherein P is PG with a compound of formula *P-X wherein *P is as defined above and X is a leaving group, preferably selected from the group consisting of halogens, mesylate, tosylate, optionally substituted phenol and succinimide.

The process of embodiment 15 or 16, wherein the phosphorylating of i') is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

The process of any of embodiments 15 to 17, wherein the phosphorylating of i') is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- biityl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

The process of any of embodiments 15 to 18, wherein in i') to the molar ratio of the compound of formula (III) wherein P is PG relative to the phosphorylation reagent *P- X, the molar ratio is preferably in the range of from 1: 15 to 1:5. The process of any of embodiments 15 to 19, for preparing a compound of formula (IV-a)

the process comprising

i) providing a compound of formula (Ill-a)

ii) reducing the compound of formula (Ill-a) and obtaining the compound of formula (IV-a), wherein the reducing is according to any of embodiments 11 to 14.

COMPOUND OF FORMULA (III)

A compound of formula

wherein P and Base are as defined according to any of embodiments 1 to 10, preferably P is defined according to embodiment 6.

22. The compound of embodiment 21 of formula (Ill-a)

23. Use of the compound of formula (III) or (III-a) according to embodiment 21 or 22 for preparing a compound of formula (IV) or (IV-a) according to any of embodiments 1 to 10 and 20. Use of a reducing agent, preferably a reducing agent according to embodiment 11 for reducing the oxo group on the furanose ring of the compound of formula (III) for preparing a compound of formula (IV) wherein the compound of formula (III) is according to embodiments 21 to 22 and the compound of formula (IV) is according to any of embodiments 1 to 10 and 20.

III. INTERMEDIATE COMPOUNDS AND PROCESS FOR PREPARING OF A COMPOUND OF FORMULA (III) OR (IV) ACCORDING TO SCHEMES 1 AND 2

III.l PROCESS FOR PREPARING A COMPOUND OF FORMULA (III)

(a) Process for preparing a compound of formula (III) via (I)

1. A process for the preparation of a compound of formula (III)

the process comprising

1) providing a compound of formula (I)

2) fluorinating the compound of formula (I) and obtaining the compound of formula (III)

wherein at each occurrence

P is P or PG a wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting alkyl, benzyl and a silyl protecting group, and

Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring according through a carbon or nitrogen atom and wherein the formulae include the enantiomers and diastereomers thereof.

2. The process of embodiment 1, wherein P is *P.

3. The process of embodiment 1 or 2, wherein *P is a phosphoramidate of structure

wherein

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci-C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N02 and CN;

Ri is Ci-C ₆ alkyl or C ₃ -C10 cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and R3 are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl) and CN.

The process of embodiment 3, wherein the phosphorus atom of the structure

has steric configuration S or R, preferably S.

The process of embodiment 3 or 4, wherein

Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl,

Ri is Ci-C ₆ alkyl, preferably isopropyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and R3 are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl.

The process of any of embodiments 1 to 5, wherein *P has structure

preferably wherein the phosphorus atom P has a steric configuration S.

The process of embodiment 1, wherein P is PG. The process of embodiment 7, wherein the PG is selected from the group consisting of alkyl, benzyl and a silyl protecting group.

The process of any of embodiments 1 to 8, wherein the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine, wherein preferably the Base is uracil.

The process of any of embodiments 1 to 9, wherein the Base is uracil.

The process of any of embodiments 1 to 10, wherein the fluorinating of 2) is carried out with a fluorinating agent selected from the group consisting of an inorganic or an organic fluorinating agent, preferably an organic fluorinating agent, wherein the inorganic fluorinating agent is preferably selected from the group consisting of metal fluorides such as LiF, KF, CsF, borane complexes of HF and wherein the organic fluorination agent is preferably selected from the group consisting of an amine complex of HF such as triethylamine tris(hydrogen fluoride), pyridinium poly(hydrogen fluoride) and HF-urea, aminosulfur fluoride derivatives such as diethylamino sulfur trifluoride (DAST), (diethylamino)difluorosulfonium tetrafluoroborate (XTal-Fluor E), difluoro(morpholino)sulfonium tetrafluoroborate (XTal-Fluor M), 4-ie/t-Butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead), Bis(2- methoxyethyl) amino sulfur trifluoride (Deoxofluor), 2-Pyridinesulfonyl Fluoride (PyFluor), dimethylamino sulfur trifluoride, ammonium fluorides such as tetrabuty 1 am mon i umf 1 uorid (TBAF), silicon fluorides such as tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), and combinations thereof.

The process of any of embodiments 1 to 11, wherein the fluorinating of 2) is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

The process of any of embodiments 1 to 12, wherein the fluorinating of 2) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- biityl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

The process of any of embodiments 11 to 13, wherein the molar ratio of the compound of formula (I) relative to the fluorinating agent is in the range of from 1 : 15 to 1 :5. The process of any of embodiments 1 to 14, wherein 1) comprises

a) providing a compound of formula (II)

oxidizing the compound of formula (II) and obtaining a compound of formula

(I),

16. The process of embodiment 15, wherein the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane,

- (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant

-Swern type oxidation reagents -such as Dimethyl sulfoxide (DMSO) and suitable activator-

-transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO) wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents.

17. The process of embodiment 15 or 16, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from -78

°C to 30 °C, more preferably in the range of from -40 °C to 20 °C.

18. The process of any of embodiments 15 to 17, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane, DMSO and a mixture thereof.

19. The process of any of embodiments 16 to 18, wherein the molar ratio of the compound of formula (II) relative to the oxidizing agent is in the range of from 1: 1 to 1:15, preferably in the range of from 1:3 to 1:4.

(b) Process for preparing a compound of formula (III) in a process with intermediates of formula (II) and (I)

A process for the preparation of a compound of formula (III)

the process comprising

a) providing a compound of formula (II)

b) oxidizing the compound of formula (II) and obtaining a compound of formula (I)

c) fluorinating the compound of formula (I) of b) and obtaining the compound of formula (III)

wherein at each occurrence

P is *P or PG a wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting alkyl, benzyl and a silyl protecting group, and

Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring according through a carbon or nitrogen atom and wherein the formulae include the enantiomers and diastereomers thereof.

The process of embodiment 20, wherein P is *P.

The process of embodiment 20 or 21, wherein *P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably *P is a phosphoramidate.

The process of embodiment 21 or 22, wherein *P is a phosphoramidate as defined according to any of embodiments 3 to 6.

The process of embodiment 20, wherein P is PG.

The process of embodiment 20 or 24, wherein PG is selected from the group consisting of alkyl, benzyl and a silyl protecting group. The process of any of embodiments 20 to 25, wherein the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane,

- (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant -Swern type oxidation reagents -such as DMSO and suitable activator- -transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO) wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents.

The process of any of embodiments 20 to 26, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from - 78 °C to 30 °C, more preferably in the range of from -40 °C to 20 °C.

The process of any of embodiments 20 to 27, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane and DMSO and a mixture thereof.

The process of any of embodiments 26 to 28, wherein the molar ratio of the compound of formula (II) relative to the oxidizing agent is in the range of from 1 : 1 to 1 : 15, preferably in the range of from 1 :3 to 1 :4.

The process of any of embodiments 20 to 29 wherein the fluorinating of c) is carried out with fluorinating agent selected from the group consisting of an inorganic or an organic fluorinating agent, preferably an organic fluorinating agent, wherein the inorganic fluorinating agent is preferably selected from the group consisting of metal fluorides such as LiF, KF, CsF, borane complexes of HF and wherein the organic fluorination agent is preferably selected from the group consisting of an amine complex of HF such as triethylamine tris(hydrogen fluoride), pyridinium poly(hydrogen fluoride) and HF-urea, aminosulfur fluoride derivatives such as diethylamino sulfur trifluoride (DAST), (diethylamino)difluorosulfonium tetrafluoroborate (XTal-Fluor E), difluoro(morpholino)sulfonium tetrafluoroborate (XTal-Fluor M), 4-ieri-Butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead), Bis(2- methoxyethyl) amino sulfur trifluoride (Deoxofluor), 2-Pyridinesulfonyl Fluoride (PyFluor), dimethylamino sulfur trifluoride, ammonium fluorides such as tetrabuty 1 am mon i iimfl uorid (TBAF), silicon fluorides such as tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), and combinations thereof.

The process of any of embodiments 20 to 30, wherein the fluorinating of c) is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C. 32. The process of any of embodiments 20 to 31, wherein the fluorinating of c) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

33. The process of any of embodiments 30 to 32, wherein in c) the molar ratio of the compound of formula (I) relative to the fluorinating agent is in the range of from 1: 15 to 1:5.

34. The process of any of embodiments 1 to 33, for preparing a compound of formula (III- a)

preferably wherein the phosphorus atom P has a steric configuration S.

III.2 PROCESS FOR PREPARING A COMPOUND OF FORMULA (IV) ACCORDING TO SCHEMES 1 AND 2.

(a) Process for preparing a compound of formula (IV) with intermediate compounds (I) and (III)

35. A process for the preparation of a compound of formula (IV)

the process comprising

i) providing a compound of formula (III)

ii) reducing the compound of formula (III) wherein P is *P and obtaining the compound of formula (IV)

wherein at each occurrence

P is *P or PG a wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably *P is a phosphoramidate, wherein the phosphoramidate is preferably as defined according to any of embodiments 3 to 6 and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting alkyl, benzyl and a silyl protecting group and Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring through a carbon or nitrogen atom, wherein preferably the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine, wherein preferably the Base is uracil and wherein the formulae include the enantiomers and the diastereomers thereof.

The process of embodiment 35, wherein the reducing of ii) is carried out with a reducing agent selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent, wherein preferably the boron based reducing agent is a borohydride and the aluminium based reducing agent is a lithium- aluminium hydride and

wherein preferably the borohydrides is selected from the group consisting of NaBH ₄ , LiBH ₄ , Li(Et) ₃ BH, and

wherein preferably the lithium- aluminium hydride is selected from the group consisting of LiAlH ₄ and diisobutyl aluminium hydride (DIBAL-H ).

The process of embodiment 35 or 36, wherein the reducing of ii) is carried out at a temperature in the range of from -78 °C to 40 °C, preferably in the range of from -20

The process of any of embodiments 35 to 37, wherein the reducing of ii) is carried out in a solvent selected from a protic solvent or a mixture thereof, preferably in a protic solvent selected from the group consisting of methanol, ethanol, isopropanol and water and a mixture thereof.

The process of any of embodiments 36 to 38, wherein the molar ratio of the compound of formula (III) relative to the reducing agent is in the range of from 1:1 to 1: 10, preferably in the range of from 1:2 to 1:4.

The process of any of embodiments 35 to 39, wherein i) comprises

1) providing a compound of formula (I)

2) fluorinating the compound of formula (I) and obtaining the compound of formula

(III)

wherein at each occurrence

P is P or PG wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably *P is a phosphoramidate, and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group.

Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring according to formula (I) or (III) through a carbon or nitrogen atom, wherein preferably the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine, wherein preferably the Base is uracil.

41. The process of embodiment 40, wherein P is *P.

42. The process of embodiment 40 or 41, wherein *P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably *P is a phosphoramidate, wherein the phosphoramidate is preferably as defined in any of embodiments 3 to 6.

43. The process of embodiment 40, wherein P is PG.

44. The process of embodiment 40 or 43, wherein PG is selected from the group consisting alkyl, benzyl and a silyl protecting group.

45. The process of any of embodiments 40 to 44, wherein the fluorinating of 2) is carried out with a fluorinating agent selected from the group consisting of an inorganic or an organic fluorinating agent, preferably an organic fluorinating agent, wherein the inorganic fluorinating agent is preferably selected from the group consisting of metal fluorides such as LiF, KF, CsF, borane complexes of HF and wherein the organic fluorination agent is preferably selected from the group consisting of an amine complex of HF such as triethylamine tris(hydrogen fluoride), pyridinium poly(hydrogen fluoride) and HF-urea, aminosulfur fluoride derivatives such as diethylamino sulfur trifluoride (DAST), (diethylamino)difluorosulfonium tetrafluoroborate (XTal-Fluor E), difluoro(morpholino)sulfonium tetrafluoroborate (XTal-Fluor M), 4-ieri-Butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead), Bis(2- methoxyethyl) amino sulfur trifluoride (Deoxofluor), 2-Pyridinesulfonyl Fluoride (PyFluor), dimethylamino sulfur trifluoride, ammonium fluorides such as tetrabutylammoniumfluorid (TBAF), silicon fluorides such as tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), and combinations thereof.

The process of any of embodiments 40 to 45, wherein the fluorinating of 2) is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

The process of any of embodiments 40 to 46, wherein the fluorinating of 2) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of THF, MTBE, Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

The process of any of embodiments 45 to 47, wherein the molar ratio of the compound of formula (I) relative to the fluorinating agent is in the range of from 1: 15 to 1:5. The process of any of embodiments 40 to 48, wherein 1) comprises

a) providing a compound of formula (II)

b) oxidizing the compound of formula (II) and obtaining a compound of formula (I).

The process of embodiment 49, wherein the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane, - (2,2,6, 6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant -Swern type oxidation reagents -such as DMSO and suitable activator- -transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO)

wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents.

The process of embodiment 49 or 50, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from -78 °C to 30 °C, more preferably in the range of from -40 °C to 20 °C. The process of any of embodiments 49 to 51, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane, DMSO and a mixture thereof.

The process of any of embodiments 50 to 52, wherein in a) the molar ratio of the compound of formula (II) relative to the oxidizing agent is in the range of from 1 : 1 to 1:15, preferably in the range of from 1:3 to 1:4.

The process of any of embodiments 35 to 53, wherein

-when in the compound of formula (III) of i) P is *P, the process comprises ii) reducing the compound of formula (III) of i) and obtaining the compound of formula (IV) as disclosed above and

- when in the compound of formula (III) of i) P is PG the process further comprises i') phosphorylating said compound of formula (III) wherein P is PG to a compound of formula (III) wherein P is P* and

ii) reducing the compound of formula (III) of i') and obtaining the compound of formula (IV)

wherein P, *P, PG and the Base are according to any of embodiments 1 to 10 the fluorinating of 2) is according to any of embodiments 11 to 14, the reducing of ii) is according to any of embodiments 35 to 39.

The process of embodiment 54, wherein phosphorylating of i') comprises reacting, preferably in the presence of a base or of a Lewis acid, the compound of formula (III) having P= PG with a compound of formula *P-X wherein *P is as defined in any of embodiments 1 to 6 and X is a leaving group, preferably selected from the group consisting of halogens, mesylate, tosylate, optionally substituted phenol and succinimide.

The process of embodiment 54 or 55, wherein the phosphorylating of i') is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C

The process of any of embodiments 54 to 56, wherein the phosphorylating of i') is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

The process of any of embodiments 54 to 57, wherein in i') the molar ratio of the compound of formula (III) wherein P is PG relative to the phosphorylation reagent *P- X is in the range of from 1: 15 to 1:5. The process of any of embodiments 35 to 58 for preparing a compound of formula

(IV), preferably for preparing a compound of formula (IV-a)

preferably wherein the phosphorus atom P has a steric configuration S..

(b) Process for preparing a compound of formula (IV) in a process with intermediates of formula (I), (II) and (III)

A process for the preparation of a compound of formula (IV)

the process comprising

a) providing a compound of formula (II)

b) oxidising the compound of formula (II) and obtaining a compound of formula (I)

c) fluorinating the compound of formula (I) of b) and obtaining the compound of formula (III)

and wherein when in the compound of formula (III) of c) P is *P, the process further comprises ii) reducing the compound of formula (III) of c) and obtaining the compound of formula (IV)

or when in the compound of formula (III) of c) P is PG the process further comprises i') phosphorylating said compound of formula (III) having P= PG to a compound of formula (III) having P= P* and

ii) reducing the compound of formula (III) of i') and obtaining the compound of formula (IV) having P= *P,

wherein at each occurrence

P is *P or PG and wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably

*P is a phosphoramidate and,

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group and

Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring through a carbon or nitrogen atom, wherein preferably the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine, wherein preferably the Base is uracil and wherein the formulae include the enantiomers and diastereomers thereof.

The process of embodiment 60, wherein P is *P.

The process of embodiment 60 or 61, wherein *P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably *P is a phosphoramidate, wherein the phosphoramidate is preferably as defined in any of embodiments 3 to 6.

The process of embodiment 60, wherein P is PG.

The process of embodiment 60 or 63, wherein PG is as defined in embodiment 7 or 8.

The process of any of embodiments 60 to 64, wherein the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane,

- (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant -Swern type oxidation reagents -such as DMSO and suitable activator- -transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO) wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents.

66. The process of any of embodiments 60 to 65, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from - 78 °C to 30 °C, more preferably in the range of from -40 °C to 20 °C.

67. The process of any of embodiments 60 to 66, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane and DMSO and a mixture thereof.

68. The process of any of embodiments 65 to 67, wherein the molar ratio of the compound of formula (II) relative to the oxidizing agent is in the range of from 1 : 1 to 1 : 15, preferably in the range of from 1 :3 to 1 :4.

69. The process of any of embodiments 60 to 68 wherein the fluorinating of c) is carried out with fluorinating agent selected from the group consisting of an inorganic or an organic fluorinating agent, preferably an organic fluorinating agent, wherein the inorganic fluorinating agent is preferably selected from the group consisting of metal fluorides such as LiF, KF, CsF, ammonium fluorides such as tetrabutylammoniumfluorid (TBAF), silicon fluorides such as tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), borane complexes of HF and wherein the organic fluorination agent is preferably selected from the group consisting of an amine complex of HF such as triethylamine tris(hydrogen fluoride), pyridinium poly(hydrogen fluoride) and HF-urea, aminosulfur fluoride derivatives such as diethylamino sulfur trifluoride (DAST), (diethylamino)difluorosulfonium tetrafluoroborate (XTal-Fluor E), difluoro(morpholino)sulfonium tetrafluoroborate (XTal-Fluor M), 4-ieri-Butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead), Bis(2- methoxyethyl) amino sulfur trifluoride (Deoxofluor), 2-Pyridinesulfonyl Fluoride (PyFluor), dimethylamino sulfur trifluoride, and combinations thereof.

70. The process of embodiments 60 to 69, wherein the fluorinating of c) carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

71. The process of any of embodiments 60 to 70 wherein the fluorinating of c) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl ether ( MTBE ), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

72. The process of any of embodiments 69 to 71, wherein in c) the molar ratio of the compound of formula (I) relative to the fluorinating agent is in the range of from 1 : 15 to 1 :5. The process of any of embodiments 60 to 72, wherein the reducing of ii) is carried out with a reducing agent selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent, wherein preferably the boron based reducing agent is a borohydride and the aluminium based reducing agent is a lithium- aluminium hydride and

wherein preferably the borohydrides is selected from the group consisting of

NaBH ₄ , LiBH , Li(Et) ₃ BH, and

wherein preferably the lithium- aluminium hydride is selected from the group consisting of LiAlH ₄ and diisobutylaluminium ydride ( DIBAL-H ).

The process of any of embodiments 60 to 73, wherein the reducing of ii) is carried out at a temperature in the range of from -78 °C to 40 °C, preferably in the range of from - 20 °C to 20 °C.

The process of any of embodiments 60 to 74, wherein the reducing of ii) is carried out in a solvent selected from a protic solvent and a mixture thereof, preferably in a protic solvent selected from the group consisting of methanol, ethanol, isopropanol and water and a mixture thereof.

The process of any of embodiments 73 to 75, wherein in ii) the molar ratio of the compound of formula (III) relative to the reducing agent is in the range of from 1 : 1 to 1:10, preferably in the range of from 1:2 to 1:4.

The process of any of embodiments 60 to 76, wherein phosphorylating of i') comprises reacting, in the presence of a base or of a Lewis acid, the compound of formula (III) having P=PG with a compound of formula *P-X wherein *P is as defined in any of embodiments 1 to 6 and X is a leaving group, preferably selected from the group consisting of halogens, mesylate, tosylate optionally substituted phenol and succinimide.

The process of any of embodiments 60 to 77 wherein the phosphorylating of i') is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

The process of any of embodiments 60 to 78, wherein the provision of a) of the compound of formula (II) having P= PG comprises

0) protecting a compound of formula (V)

and obtaining a compound of formula (II) having P= PG

80. The process of embodiment 79, wherein the protecting of 0) comprises reacting, in the presence of base, preferable an amine base, the compound of formula (V) with a compound of formula PG-X' wherein PG is as defined in embodiment 7 or 8 and X' is a leaving group, preferably selected from the group consisting of halogens, mesylate and tosylate.

81. The process of any of embodiments 60 to 80, wherein in a) the provision of the compound of formula (II) having P= *P comprises

0') phosphorylating a compound of formula (V)

(V)

and obtaining a compound of formula (II) having P= *P

82. The process of embodiment 81, wherein the phosphorylating of 0') comprises reacting, in the presence of a base or of a Lewis acid, the compound of formula (V) with a compound of formula *P-X wherein *P is as defined in any of embodiments 1 to 6 and X is a leaving group preferably selected from the group consisting of halogens, mesylate, tosylate optionally substituted phenol and succinimide.

83. The process of any of embodiments 1 to 82, wherein the compound of formula (I) has structure (I- a)

preferably wherein the phosphorus atom P has a steric configuration S.

The process of any of embodiments 15 to 34 and 49 to 83, wherein the compound of formula (II) has structure (Il-a)

preferably wherein the phosphorus atom P has a steric configuration S.

85. The process of any of embodiments 1 to 84, wherein the compound of formula (III) has structure (

preferably wherein the phosphorus atom P has a steric configuration S.

86. The process of any of embodiments 35 to 85, wherein the compound of formula (IV) has structure (IV- a)

preferably wherein the phosphorus atom P has a steric configuration S.

Compound of formula (I)

A compound of formula (I)

wherein

P is *P or PG, wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate and PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and silyl protecting group Base is selected from the group consisting of a purinyl residue or a pyrimidinyl residue linked to the furanose ring according to formula (I) through a carbon or nitrogen atom and wherein the formula include the enantiomers and diastereomers thereof.

88. The compound of embodiment 87, wherein *P is selected from the group consisting of pho sphoramidate .

89. The compound of embo is a pho sphoramidate of structure

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(C _r C ₆ alkyl), C(0)(aryl), COO(C C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N0 ₂ and CN;

Ri is Ci-C ₆ alkyl or C3-C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and Pv ₃ are independently H or Ci-C ₆ alkyl optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci-C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl) and CN.

90. The compound of embodiment 89, wherein the phosphorus atom of the structure

has steric configuration S or R, preferably S.

91. The compound of embodiment 98 or 90, wherein

Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl,

Ri is Ci-C ₆ alkyl, preferably isopropyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl. 92. The compound of any of embodiments 89 to 91, wherein *P has structure

93. The compound of any of embodiments 87 to 92, wherein Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring according to formula (III) through a carbon or nitrogen atom, wherein preferably the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine, wherein preferably the Base is uracil.

94. The compound of any of embodiments 87 to 93, wherein the Base is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, guanine, protected guanine, adenine, protected adenine, thymine and protected thymine.

95. The compound of any of embodiments 87 to 94, wherein the compound of formula (I) has structure (I- a)

preferably wherein the phosphorus atom P has a steric configuration S.

96. A mixture comprising a compound of formula (I) or (I-a) according to any of embodiments 87 to 95.

III.4 PROCESS FOR PREPARING A COMPOUND OF FORMULA (I)

97. A process for preparing a compound of formula (I)

the process comprising

a) providing a compound of formula (II)

b) oxidizing the compound of formula (II) and obtaining a compound of formula

(I),

wherein P and Base are defined according to any of embodiments 1 to 10 and wherein preferably P is *P and *P is as defined according to according to any of embodiments 3 to 6.

98. The process of embodiment 97, wherein the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane, - (2,2,6, 6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant -Swern type oxidation reagents -such as DMSO and suitable activator- -transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N- Oxide

(TPAP/NMO)

wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents.

99. The process of embodiment 97 or 98, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from -78

°C to 30 °C, more preferably in the range of from -40 °C to 20 °C.

100. The process of any of embodiments 97 to 99, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane, DMSO and a mixture thereof.

101. The process of any of embodiments 97 to 100, wherein the molar ratio of the compound of formula (II) relative to the oxidizing agent is in the range of from 1 : 1 to 1: 15, preferably in the range of from 1:3 to 1:4.

III.5

102. Use of a compound of formula (III), preferably of formula (Ill-a) as defined according to any of embodiments 1 to 10 for preparing a compound of formula (IV), preferably of formula (IV-a), wherein the compound of formula (IV) and of formula (IV-a) is defined according to any of embodiments 1 to 10.

103. Use of a compound of formula (I), preferably of formula (I-a) as defined according to any of embodiments 87 to 95 for preparing a compound of formula (IV), preferably of formula (IV-a), wherein the compound of formula (IV) and of formula (IV-a) is defined according to any of embodiments 1 to 10.

104. Use of a reducing agent for stereoselectively reducing the oxo group in position 3' of the furanose ring of the compound of formula (III), wherein the compound of formula (III) is according to any of embodiments 1 to 10 and the reducing agent is as defined according to embodiment 36.

IV. INTERMEDIATES COMPOUNDS (VII) AND (VIII) AND PROCESS FOR PREPARING OF A COMPOUND OF FORMULA (III) AND (IV) ACCORDING TO SCHEME 3

IV.l PROCESS FOR PREPARING A COMPOUND OF FORMULA (III)

(a) Process for preparing a compound of formula (III) via (VIII)

1. A process for the preparation of a compound of formula (III)

the process comprising

1) providing a compound of formula (VIII)

2 ^e ) fluorinating the compound of formula (VIII) and obtaining the compound of formula (III)

wherein at each occurrence

P is selected from *P or PG, wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably *P is a phosphoramidate, and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group.

Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring through a carbon or nitrogen atom, wherein preferably the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine, wherein preferably the Base is uracil and wherein the formulae include the enantiomers and the diastereomers thereof.

The process of embodiment 1, wherein P is *P.

The process of embodiment l or 2, wherein *P is a phosphoramidate of structure

wherein

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(C _r C ₆ alkyl), C(0)(aryl), COO(C C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N02 and CN;

Ri is Ci-C ₆ alkyl or C3-C ₁ 0 cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and Pv ₃ are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C3-C ₆ cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl) and CN.

The process of embodiment 3, wherein the phosphorus atom of the structure

has steric configuration S or R, preferably S.

The process of embodiment 3 or 4, wherein

Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl,

Ri is Ci-C ₆ alkyl, preferably isopropyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and R ₃ are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl.

The process of any of embodiments 1 to 5, wherein *P has structure

preferably wherein the phosphorus atom P has a steric configuration S.

The process of embodiment 1, wherein P is PG.

The process of embodiment 1 or 7, wherein the PG is selected from the group consisting of alkyl, benzyl and a silyl protecting group.

The process of any of embodiments 1 to 8, wherein Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring through a carbon or nitrogen atom, wherein preferably the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine.

The process of any of embodiments 1 to 9, wherein the Base is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, guanine, protected guanine, adenine, protected adenine, thymine and protected thymine, wherein preferably the Base is uracil.

The process of any of embodiments 1 to 10, wherein the fluorinating of 2 ^e ) is carried out with a electrophilic fluorinating agent for example N-fluoro-o- benzenedisulfonimide (NFOBS), N-fluorobenzenesulfonimide (NFSI), and 1 - Chloromethy!-4-fluoro- 1 ,4-diazoniabicyclo[2.2.2 joctane bis(tetrafluoroborate) (Selectfluor).

The process of any of embodiments 1 to 11, wherein 1) comprises

x) providing a compound of formula (VII)

methylating the compound of formula (VII) and obtaining a compound of formula (VIII),

The process of embodiment 12, wherein the methylating of xx) is carried out with a methylating reagent selected from the group consisting of methyl iodide or sulfonic acid methyl ester.

The process of embodiment 12 or 13, wherein the methylation of xx) is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

The process of any of embodiments 12 to 14, wherein the methylation of xx) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

The process of any of embodiments 13 to 15, wherein in xx) the molar ratio of the compound of formula (VII) relative to the methylating reagent is in the range of from 1: 15 to 1:5.

The process of any of embodiments 12 to 16, wherein x) comprises

a) providing a compound of formula (VI)

b) oxidizing the compound of formula (VI) and obtaining a compound of formula

(VII),

The process of embodiment 17, wherein the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane,

- (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant

-Swern type oxidation reagents -such as Dimethyl sulfoxide (DMSO) and suitable activator-

-transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO) wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents.

The process of embodiment 17 or 18, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from -78 °C to 30 °C, more preferably in the range of from -40 °C to 20 °C. 20. The process of any of embodiments 17 to 19, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane, DMSO and a mixture thereof.

21. The process of any of embodiments 18 to 20, wherein the molar ratio of the compound of formula (VI) relative to the oxidizing agent is in the range of from 1: 1 to 1: 15, preferably in the range of from 1:3 to 1:4.

22. The process of any of embodiments 1 to 21, for preparing a compound of formula (III- a)

preferably wherein the phosphorus atom P has a steric configuration S.

(b) Process for preparing a compound of formula (III) via intermediates of formulae (VII), (VIII)

23. A process for the preparation of a compound of formula (III)

the process comprising

x) providing a compound of formula (VII)

(VII)

methylating the compound of formula (VII) and obtaining a compound of formula (VIII),

fluorinating the compound of formula (VIII) of xx) and obtaining compound of formula (III)

wherein P, *P, PG and the Base are defined according to any of embodiments 1 to 10, wherein *P is preferably according to any of embodiments 3 to 6 and Base is preferably according to embodiment 9 to 10 and wherein the formulae include the enantiomers and diastereomers thereof.

The process of embodiment 23, wherein the methylating of xx) is as according to any of embodiments 12 to 16.

The process of embodiment 23 or 24, wherein the fluorinating of 2 ^e ) is carried out with an electrophilic fluorinating agent as defined according to embodiment 11.

The process according to any of embodiments 23 to 25, wherein step x) comprises a) providing a compound of formula (VI)

oxidising the compound of formula (VI) and obtaining a compound of formula wherein P, *P, PG and the Base are defined according to any of embodiments 1 to 10, wherein *P is preferably according to any of embodiments 3 to 6 and Base is preferably according to embodiment 9 to 10 and wherein the formulae include the enantiomers and diastereomers thereof.

The process of embodiment 26, wherein the oxidizing of b) is carried out according to any of embodiments 17 to 21.

The process of any of embodiments 23 to 27, for preparing a compound of formula

preferably wherein the phosphorus atom P has a steric configuration S. (c) Process for preparing a compound of formula (III) via intermediates of formulae (VI), (VII), (VIII)

A process for the preparation of a compound of formula (III)

the process comprising

a) providing a compound of formula (VI)

oxidising the compound of formula (VI) and obtaining a compound of formula (VII)

b') methylating the compound of formula (VII) and obtaining a compound of

formula (VIII)

fluorinating the compound of formula (VIII) of b') and obtaining compound of formula (III)

wherein P, *P, PG and the Base are defined according to any of embodiments 1 to 10, wherein *P is preferably according to any of embodiments 3 to 6 and Base is preferably according to embodiment 9 to 10 and wherein the formulae include the enantiomers and diastereomers thereof.

The process of embodiment 29, wherein the oxidizing of b) is carried out according to any of embodiments 17 to 21. The process of embodiment 29 or 30, wherein the methylating of b') is as defined according to the methylating of xx) according to any of embodiments 12 to 16.

The process of any of embodiments 29 to 31, wherein the fluorinating of c ^e ) is as defined according to the fluorinating of 2 ^e ) according to embodiment 11.

The process of any of embodiments 17 to 22 and 26 to 32, wherein in a) the provision of the compound of formula (VI) having P= PG comprises

0*) protecting a compound of formula (V)

and obtaining a compound of formula (VI) having P

The process of embodiment 33, wherein the protecting of 0*) comprises reacting, in the presence of base, preferable an amine base, the compound of formula (V) with a compound of formula PG-X' wherein PG is as defined according to embodiment 7 or 8 and X' is a leaving group, preferably selected from the group consisting of halogens, mesylate and tosylate.

The process of any of embodiments 17 to 22 and 26 to 32,, wherein in a) the provision of the compound of formula (VI) having P=*P comprises

0") phosphorylating a compound of formula (V)

and obtaining a compound of formula (VI) having P=*P

The process of embodiment 35, wherein the phosphorylating of 0") comprises reacting, in the presence of a base or of a Lewis acid, the compound of formula (V) with a compound of formula *P-X* wherein *P is as defined in any of embodiments 1 to 6 and X* is a leaving group preferably selected from the group consisting of X* is a leaving group, preferably selected from chloride, substituted phenols, pyrimidines or N-hydroxysuccinimide. The process of any of embodiments 1 to 36, for preparing a compound of formula (III a)

preferably wherein the phosphorus atom P has a steric configuration S.

IV.2 PREPARATION OF A COMPOUND OF FORMULA (IV)

(a) Preparation of a compound of formula (IV) via intermediate (VIII) and (III)

38. A process for the preparation of a compound of formula (IV)

the process comprising

i) providing a compound of formula (III)

ii) reducing the compound of formula (III) and obtaining the compound of formula (IV)

and wherein when in the compound of formula (III) P is PG, the process, before (ii) further comprises

i') phosphorylating said compound of formula (III) having P= PG to a compound of formula (III) having P= P*

wherein

P is *P or PG wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably *P is a phosphoramidate, and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring through a carbon or nitrogen atom, wherein preferably the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine, wherein preferably the Base is uracil and wherein the formulae include the enantiomers and diastereomers thereof.

The process of embodiment 38, wherein P is *P.

The process of embodiment 38 or 39, wherein *P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably *P is a phosphoramidate, wherein the phosphoramidate is preferably as defined in any of embodiments 3 to 6.

The process of embodiment 38, wherein P is PG.

The process of embodiment 38 or 41, wherein PG is selected from the group consisting of alkyl, benzyl and a silyl protecting group.

The process of any of embodiments 38 to 42, wherein Base is selected from the group consisting of an optionally protected pyrimidinyl residue and an optionally protected purinyl residue wherein the residue is linked to the furanose ring through a carbon or nitrogen atom, wherein preferably the pyrimidinyl residue is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, and the purinyl residue is selected from the group consisting of guanine, protected guanine, adenine, protected adenine, thymine and protected thymine.

The process of any of embodiments 38 to 43, wherein the Base is selected from the group consisting of uracil, protected uracil, cytosine, protected cytosine, guanine, protected guanine, adenine, protected adenine, thymine and protected thymine, wherein preferably the Base is uracil.

The process of any of embodiments 38 to 44, wherein the reducing of ii) is carried out with a reducing agent selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent, wherein preferably the boron based reducing agent is a borohydride and the aluminium based reducing agent is a lithium- aluminium hydride and

wherein preferably the borohydrides is selected from the group consisting of

NaBH ₄ , LiBH , Li(Et) ₃ BH, and

wherein preferably the lithium- aluminium hydride is selected from the group consisting of LiAlH ₄ and diisobutylaluminium ydride ( DIBAL-H ).

The process of any of embodiments 38 to 45 wherein the reducing of ii) is carried out at a temperature in the range of from -78 °C to 40 °C, preferably in the range of from - 20 °C to 20 °C The process of any of embodiments 38 to 46, wherein the reducing of ii) is carried out in a solvent selected from a protic solvent or a mixture thereof, preferably in a protic solvent selected from the group consisting of methanol, ethanol, isopropanol and water and a mixture thereof.

The process of any of embodiments 45 to 47, wherein the molar ratio of the compound of formula (III) relative to the reducing agent is in the range of from 1:1 to 1: 10, preferably in the range of from 1:2 to 1:4.

The process of any of embodiments 38 to 48, wherein i) comprises

1) providing a compound of formula (VIII)

2 ^e ) fluorinating the compound of formula (VIII) and obtaining the compound of formula (III)

wherein at each occurrence

P, *P or PG and base are as defined in any of embodiments 1 to 10, preferably P is *P wherein *P is as defined according to any of embodiments 3 to 6.

The process of embodiment 49, wherein the fluorinating of 2 ^e ) is carried out with a fluorinating agent as defined according to embodiment 11.

The process of embodiment 49 or 50, wherein 1) comprises

x) providing a compound of formula (VII))

methylating the compound of formula (VII) and obtaining a compound of formula (VIII),

wherein at each occurrence

P and Base are as defined in any of embodiments 1 to 10, preferably P is *P wherein *P is as defined according to any of embodiments 3 to 6.

The process of embodiment 51, wherein the methylating of xx) is carried out according to any of embodiments 12 to 16.

The process of embodiment 51 or 52, wherein x) comprises

a) providing a compound of formula (VI)

oxidizing the compound of formula (VI) and obtaining a compound of formula

(VII)

The process of embodiment 53, wherein the oxidizing of b) is carried out as defined according to any of embodiments 17 to 21.

The process of any of embodiments 38 to 54, wherein the phosphorylating of i') comprises reacting, preferably in the presence of a base or of a Lewis acid, the compound of formula (III) having P=PG with a compound of formula *P-X wherein *P is as defined in any of embodiments 1 to 6 and X is a leaving group, preferably selected from the group consisting of halogens, mesylate, tosylate optionally substituted phenol and succinimide.

The process of any of embodiments 38 to 55, wherein the phosphorylating of i') is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C

The process of any of embodiments 38 to 56, wherein the phosphorylating of i') is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- biityl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

The process of any of embodiments 55 to 57, wherein in i') the molar ratio of the compound of formula (III) wherein P is PG relative to the phosphorylation reagent *P- X is in the range of from 1: 15 to 1:5.

The process of any of embodiments 38 to 58, for preparing a compound of formula (IV), preferably a compound of formula (IV-a)

preferably wherein the phosphorus atom P has a steric configuration S.

(b) Process for preparing a compound of formula (IV) in a process with intermediates of formula (VII), (VIII) and (III)

A process for the preparation of a compound of formula (IV)

the process comprising

x) providing a compound of formula (VII)

(VII)

methylating the compound of formula (VII) and obtaining a compound of formula (VIII),

xxx) fluorinating the compound of formula (VIII) of xx) and obtaining the compound of formula (III)

and wherein

-when in the compound of formula (III) of xxx) P is *P, the process further comprises ii) reducing the compound of formula (III) of xxx) and obtaining the compound of formula (IV)

or

-when in the compound of formula (III) of xxx) P is PG after xxx) the process further comprises

i') phosphorylating said compound of formula (III) having P= PG to a compound of formula (III) having P= P* and ii) reducing the compound of formula (III) of i') and obtaining the compound of formula (IV) having P= *P

wherein P, *P, PG and the Base are defined according to any of embodiments 1 to 10, preferably *P is defined according to any of embodiments 3 to 6 and Base is defined according to embodiment 9 or 10 and wherein the formulae include the enantiomers and the diastereomers thereof.

The process of embodiment 60, wherein the methylating of xx) is carried out with a methylating reagent selected from the group consisting of methyl iodide or sulfonic acid methyl ester.

The process of embodiment 60 or 61, wherein the methylation of xx) is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

The process of any of embodiments 60 to 62, wherein the methylation of xx) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

The process of any of embodiments 60 to 63, wherein the molar ratio of the compound of formula (VII) relative to the methylating reagent is in the range of from 1: 15 to 1:5 The process of any of embodiments 60 to 64, wherein the fluorinating of xxx) is carried out with a fluorinating agent as defined according to embodiment 11.

The process of any of embodiments 60 to 65, wherein the reducing of ii) is carried out with a reducing agent selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent, wherein preferably the boron based reducing agent is a borohydride and the aluminium based reducing agent is a lithium- aluminium hydride and

wherein preferably the borohydrides is selected from the group consisting of

NaBH ₄ , LiBH , Li(Et) ₃ BH, and

wherein preferably the lithium- aluminium hydride is selected from the group consisting of LiAlH ₄ and diisobutylaluminium hydride ( DIBAL-H ).

The process of any of embodiments 60 to 66, wherein the reducing of ii) is carried out temperature in the range of from -78 °C to 40 °C, preferably in the range of from -20 °C to 20 °C.

The process of any of embodiments 60 to 67, wherein the reducing of ii) is carried out in a solvent selected from a protic solvent and a mixture thereof, preferably in a protic solvent selected from the group consisting of methanol, ethanol, isopropanol and water and a mixture thereof. 69. The process of any of embodiments 66 to 68, wherein the molar ratio of the compound of formula (III) relative to the reducing agent is in the range of from 1:1 to 1: 10, preferably in the range of from 1:2 to 1:4.

70. The process of any of embodiments 60 to 69, wherein x) comprises

a) providing a compound of formula (VI)

b) oxidizing the compound of formula (VI) and obtaining a compound of formula

(VII),

71. The process of embodiment 70, wherein the oxidizing of b) is carried out with an oxidizing reagent as defined according to embodiment 18.

72. The process of embodiment 70 or 71, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from -78 °C to 30 °C, more preferably in the range of from -40 °C to 20 °C.

73. The process of any of embodiments 70 to 72, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane and DMSO and a mixture thereof.

74. The process of any of embodiment 71 to 73, wherein the molar ratio of the compound of formula (II) relative to the oxidizing agent is in the range of from 1: 1 to 1:15, preferably in the range of from 1:3 to 1:4.

75. The process of any of embodiments 60 to 74 for preparing a compound of formula (IV), preferably a compound of formula (IV-a)

preferably wherein the phosphorus atom P has a steric configuration S. (c) Process for preparing a compound of formula (IV) in a process with intermediates of formula (VI), (VII), (VIII) and (HI)

A process for the preparation of a compound of formula (IV)

the process comprising

a) providing a compound of formula (VI)

oxidising the compound of formula (VI) and obtaining a compound of formula (VII)

b') methylating the compound of formula (VII) and obtaining a compound of

formula (VIII)

c ^e ) fluorinating the compound of formula (VIII) of b') and obtaining the compound of formula (III)

(III)

and

-when in the compound of formula (III) of c ^e ) P is *P

ii) reducing the compound of formula (III) of c ^e ) and obtaining the compound of formula (IV)

or

-when in the compound of formula (III) of c ^e ) P is PG after c ^e ) the process further comprises i') phosphorylating said compound of formula (III) having P= PG to a compound of formula (III) having P= P* and

ii) reducing the compound of formula (III) of i') and obtaining the compound of formula (IV)

wherein P, *P, PG and the Base are defined according to any of embodiments 1 to 10, preferably *P is defined according to any of embodiments 3 to 6 and Base is defined according to embodiment 9 or 10 and wherein the formulae include the enantiomers and diastereomers thereof.

77. The process of embodiment 76 wherein the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane,

- (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant

-Swern type oxidation reagents -such as Dimethyl sulfoxide (DMSO) and suitable activator-

-transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO) wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents.

78. The process of embodiment 76 or 77, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from -78 °C to 30 °C, more preferably in the range of from -40 °C to 20 °C.

79. The process of any of embodiments 76 to 78, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane and DMSO and a mixture thereof.

80. The process of any of embodiments 77 to 79, wherein in b) the molar ratio of the compound of formula (II) relative to the oxidizing agent is in the range of from 1 : 1 to 1: 15, preferably in the range of from 1:3 to 1:4.

81. The process of any of embodiments 76 to 80, wherein the methylating of b') is carried out with a methylating reagent selected from the group consisting of methyliodide or sulfonic acid methyl ester.

82. The process of any of embodiments 76 to 81, wherein the methylation of b') is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

83. The process of any of embodiments 76 to 82, wherein the methylation of b') is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

84. The process of any of embodiments 81 to 83, wherein in b') the molar ratio of the compound of formula (VII) relative to the methylating reagent is in the range of from 1: 15 to 1:5

85. The process of any of embodiments 76 to 84, wherein the fluorinating of c ^e ) is carried out with fluorinating agent as defined according to embodiment 11.

86. The process of embodiments 76 to 85, wherein the fluorinating of c ^e ) carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

87. The process of any of embodiments 76 to 86, wherein the fluorinating of c ^e ) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

88. The process of any of embodiments 85 to 87, wherein in c ^e ) the molar ratio of the compound of formula (VIII) relative to the fluorinating agent is in the range of from 1: 15 to 1:5.

89. The process of any of embodiments 76 to 88, wherein phosphorylating of i') comprises reacting, in the presence of a base or of a Lewis acid, the compound of formula (III) having P=PG with a compound of formula *P-X wherein *P is as defined in any of embodiments 1 to 6 and X is a leaving group, preferably selected from the group consisting of halogens, mesylate, tosylate optionally substituted phenol and succinimide.

90. The process of any of embodiments 76 to 89, wherein the phosphorylating of i') is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

91. The process of any of embodiments 76 to 90, wherein the phosphorylating of i') is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl ether ( MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

92 The process of any of embodiments 76 to 91, wherein the molar ratio of the compound of formula (III) having P= PG relative to the phosphorylation reagent *P-X is in the range of from 1: 15 to 1:5

93. The process of any of embodiments 76 to 92, wherein the reducing of ii) is carried out with a reducing agent selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent, wherein preferably the boron based reducing agent is a borohydride and the aluminium based reducing agent is a lithium- aluminium hydride and

wherein preferably the borohydrides is selected from the group consisting of

NaBH ₄ , LiBH ₄ , Li(Et) ₃ BH, and

wherein preferably the lithium- aluminium hydride is selected from the group consisting of LiAlH ₄ and diisobutylaluminium ydride ( DIBAL-H ).

94. The process of any of embodiments 84 to 105, wherein the reducing of ii) is carried out at a temperature in the range of from -78 °C to 40 °C, preferably in the range of from -20 °C to 20 °C.

95. The process of any of embodiments 84 to 106, wherein the reducing of ii) is carried out in a solvent selected from a protic solvent and a mixture thereof, preferably in a protic solvent selected from the group consisting of methanol, ethanol, isopropanol and water and a mixture thereof.

96. The process of any of embodiments 93 to 96, wherein the molar ratio of the compound of formula (III) relative to the reducing agent is in the range of from 1:1 to 1: 10, preferably in the range of from 1:2 to 1:4.

97. The process of any of embodiments 76 to 96, for preparing a compound of formula (IV), preferably a compound of formula (IV-a)

preferably wherein the phosphorus atom P has a steric configuration S.

98. The process of any of embodiments 17 to 22, 26 to 37, 53 to 59, 70 to 97, wherein in a) the provision of the compound of formula (VI) having P= PG of a) comprises 0') protecting a compound of formula (V)

(V)

and obtaining a compound of formula (VI) having P

(VI)

wherein P is PG. 99. The process of embodiment 98, wherein the protecting of 0') comprises reacting, in the presence of base, the compound of formula (V) with a compound of formula PG- X' wherein PG is as defined embodiments 7 or 8 and X' is a leaving group, preferably selected from the group consisting of halogens, mesylate and tosylate.

100. The process of any of embodiments 17 to 22, 26 to 37, 53 to 59, 70 to 97, wherein in a) the provision of the compound of formula (VI) having P= *P comprises

0) phosphorylating a compound of formula (V)

and obtaining a compound of formula (VI) having P

The process of embodiment 100, wherein the phosphorylating of 0) comprises reacting, in the presence of a base or of a Lewis acid, the compound of formula (V) with a compound of formula *P-X* wherein *P is as defined in any of embodiments 2 to 6 and X* is a leaving group, preferably selected from chloride, substituted phenols, pyrimidines or N-hydroxysuccinimide.

The process of any of embodiments 1, 12, 23, 29, 49, 51, 60, 76, 88 wherein the compound of formula (VIII) has structure (VIITa)

preferably wherein the phosphorus atom P has a steric configuration S.

103. The process of any of embodiments 12, 16, 17, 23, 26, 29, 51, 53, 60, 64, 70, 76, 84, wherein the compound of formula (VII) has structure (Vll-a)

preferably wherein the phosphorus atom P has a steric configuration S.

The process of any of embodiments 17, 21, 26, 29, 35, 53, 70, 76, 100, 101, wherein the compound of formula (VI) has structure (Vl-a)

preferably wherein the phosphorus atom P has a steric configuration S.

The process of any of embodiments 38 to 104, wherein the compound of formula (IV) has structure (IV- a)

preferably wherein the phosphorus atom P has a steric configuration S.

IV.3 PROCESS FOR PREPARING COMPOUND OF FORMULA (VIII)

106. A process for preparing a compound of formula (VIII), the process comprising

x) providing a compound of formula (VII)

methylating the compound of formula (VII) and obtaining a compound of formula (VIII),

wherein P, *P, PG and the Base are defined according to any of embodiments 1 to 10, preferably *P is defined according to any of embodiments 3 to 6 and Base is defined according to embodiment 9 or 10 and wherein the formulae include the enantiomers and diastereomers thereof. 107. The process of embodiment 106, wherein the methylating of xx) is carried out with a methylating reagent selected from the group consisting of methyl iodide or sulfonic acid methyl ester.

108. The process of embodiment 106 or 107, wherein the methylation of xx) is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

109. The process of any of embodiments 106 to 108, wherein the methylation of xx) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

110. The process of any of embodiments 107 to 109, wherein in xx) the molar ratio of the compound of formula (VII) relative to the methylating reagent is in the range of from 1: 15 to 1:5

111. The process of any of embodiments 106 to 110, for preparing a compound of formula (Vlll-a)

IV. 4 PROCESS FOR PREPARING COMPOUND OF FORMULA (VII)

112. A process for preparing a compound of formula (VII), the process comprising

a) providing a compound of formula (VI)

oxidizing the compound of formula (VI) and obtaining a compound of formula (VII),

wherein P, *P, PG and the Base are defined according to any of embodiments 1 to 10, preferably *P is defined according to any of embodiments 3 to 6 and Base is defined according to embodiment 9 or 10 and wherein the formulae include the enantiomers and diastereomers thereof.

113. The process of embodiment 112, wherein the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane,

- (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant -Swern type oxidation reagents -such as Dimethyl sulfoxide (DMSO) and suitable activator-

-transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO) wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents.

114. The process of embodiment 112 or 113, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from -78

°C to 30 °C, more preferably in the range of from -40 °C to 20 °C.

115. The process of any of embodiments 112 to 114, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane, DMSO and a mixture thereof.

116. The process of any of embodiments 113 to 115, wherein the molar ratio of the compound of formula (VI) relative to the oxidizing agent is in the range of from 1 : 1 to 1: 15, preferably in the range of from 1:3 to 1:4.

117. The process of any of embodiments 112 to 116, for preparing a compound of formula (Vll-a).

IV.5 COMPOUND OF FORMULA (VII)

118. A compound of formul

P is *P or PG, wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate preferably a benzyl protected phosphate, phosphoramidate and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of halogens, mesylate and tosylate.

Base is selected from the group consisting of a purinyl residue or a pyrimidinyl residue linked to the furanose ring according to formula (III) through a carbon or nitrogen atom and wherein the formula includes the enantiomers and diastereomers thereof.

119. The compound of embodiment 118, wherein *P is selected from the group consisting of phosphoramidate. 120. The compound of embodiment 118 or 119, wherein *P is selected from the group consisting of phosphoramidate, preferably wherein *P is defined according to embodiments 3 to 6.

121. The compound of any of embodiments 118 to 120, wherein Base is defined according to embodiment 9 or 10.

122. The compound of any of embodiments 118 to 121, wherein the compound of formula (VII) has structure (Vll-a)

preferably wherein the phosphorus atom P has a steric configuration S.

123. A compound of formula (VII) of any of embodiments 118 to 122, obtainable or obtained by a process according to any of embodiments 112 to 117.

124. A mixture comprising a compound of formula (VII) as defined according to any of embodiments 118 to 123.

COMPOUND OF FORMULA (VIII)

A compound of formul

wherein

P is *P or PG, wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl and a silyl protecting group

Base is selected from the group consisting of a purinyl residue or a pyrimidinyl residue linked to the furanose ring according to formula (I) through a carbon or nitrogen atom and wherein the formula includes the enantiomers and diastereomers thereof.

126. The compound of embodiment 125, wherein *P is selected from the group consisting of phosphoramidate.

127. The compound of embodiment 125 or 126, wherein *P is defined according to embodiments 3 to 6.

128. The compound of any of embodiments 125 to 127, wherein Base is defined according to embodiment 9 or 10.

129. The compound of any of embodiments 125 to 128, wherein the compound of formula (VIII) has structure (VHI-a)

preferably wherein the phosphorus atom P has a steric configuration S.

130. A compound of formula (VIII) as defined according to any of embodiments 125 to 129 obtainable or obtained by a process according to any of embodiments 106 to 111.

131. A mixture comprising a compound of formula (VIII) or (VHI-a) according to any of embodiments 125 to 130. IV.7 Uses

132. Use of a compound of formula (III) as defined according to any of embodiments 1 to 10, for preparing a compound of formula (IV), wherein P and Base of the compound of formula (IV) are defined as in the compound of formula (III).

133. Use of a compound of formula (VIII) according to any of embodiments 125 to 129 for preparing a compound of formula (IV), wherein compound of formula (IV) is as defined in embodiments 1 to 10.

134. Use of a reducing agent for stereo selectively reducing the oxo group in position 3' of the furanose ring of the compound of formula (III), wherein the compound of formula (III) is according to any of embodiments 1 to 10 and the reducing agent is as defined according to embodiment 45.

V. INTERMEDIATES (X) AND (XI) AND PROCESS FOR PREPARING OF A COMPOUND OF

FORMULA (III) AND (IV) ACCORDING TO SCHEME 4 AND 4-A

V.l PROCESS FOR PREPARING A COMPOUND OF FORMULA (III)

(a) Process for preparing a compound of formula (III) via a compound of formula (IX)

1. A process for the preparation of a compound of formula (III)

the process comprising

1) providing a compound of formula (XI)

2) fluorinating the compound of formula (XI) and obtaining the compound of formula (III)

wherein at each occurrence

P is selected from *P or PG, wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, preferably benzyl protected phosphoramidate, preferably *P is a phosphoramidate, and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl or silyl protecting groups Base is uracil and wherein the formulae above include the enantiomers and diastereomers thereof.

The process of embodiment 1, wherein P is *P.

The process of embodiment 1 or 2, wherein *P is a hosphoramidate of structure

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, each optionally substituted with at least one of Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ cycloalkyl, aryl, F, CI, Br, I, COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci-C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl), N0 ₂ and CN;

Ri is Ci-C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and P3 are independently H or Ci-C ₆ alkyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of OH, Ci-C ₆ alkoxy, aryl, heteroaryl, Ci-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, F, CI, Br, I, N0 ₂ , COOH, CHO, C(0)(Ci-C ₆ alkyl), C(0)(aryl), COO(Ci- C ₆ alkyl), COONH ₂ , COONH(Ci-C ₆ alkyl) and CN.

The process of embodiment 3, wherein the phosphorus atom of the structure

has steric configuration S or R, preferably S.

The process of embodiment 3 or 4, wherein

Ar is selected from the group consisting of phenyl and naphtyl optionally substituted with Ci-C ₆ alkyl,

Ri is Ci-C ₆ alkyl, preferably isopropyl wherein Ci-C ₆ alkyl is optionally substituted with at least one of Ci-C ₆ alkyl and aryl;

R ₂ and R3 are independently H or Ci-C ₆ alkyl, wherein preferably Ci-C ₆ alkyl is methyl.

The process of any of embodiments 1 to 5, wherein *P has structure

preferably wherein the phosphorus atom P has a steric configuration S.

The process of embodiment 1, wherein P is PG.

The process of embodiment 1 or 7, wherein the PG is selected from the group consisting of alkyl, benzyl or silyl protecting groups.

The process of any of embodiments 1 to 8, wherein the fluorinating of 2) is carried out with a fluorinating agent selected from the group consisting of an inorganic or an organic fluorinating agent, preferably an organic fluorinating agent, wherein the inorganic fluorinating agent is preferably selected from the group consisting of metal fluorides such as LiF, KF, CsF, borane complexes of HF and wherein the organic fluorination agent is preferably selected form the group consisting of an amine complex of HF such as triethylamine tris(hydrogen fluoride), pyridinium poly(hydrogen fluoride) and HF-urea, aminosulfur fluoride derivatives such as diethylamino sulfur trifluoride (DAST), (diethylamino)difluorosulfonium tetrafluoroborate (XTal-Fluor E), difluoro(morpholino)sulfonium tetrafluoroborate

(XTal-Fluor M), 4-ie/t-Butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead), Bis(2- methoxyethyl) amino sulfur trifluoride (Deoxofluor), 2-Pyridinesulfonyl Fluoride (PyFluor), dimethylamino sulfur trifluoride, ammonium fluorides such as tetrabuty 1 am mon i umfl uorid (TBAF), silicon fluorides such as tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), and combinations thereof, more preferably the fluorinating agent is (diethylamino)difluorosulfonium tetrafluoroborate (XTal-Fluor E).

The process of any of embodiments 1 to 9, wherein the fluorinating of 2) is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

The process of any of embodiments 1 to 10, wherein the fluorinating of 2) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

The process of any of embodiments 9 to 11, wherein in 2) the molar ratio of the compound of formula (I) relative to the fluorinating agent is in the range of from 1: 15 to 1:5.

The process of any of embodiments 1 to 12, wherein 1) comprises a) providing a compound of formula (X) (X)

b) oxidizing the compound of formula (X) and obtaining a compound of formula

(XI) wherein P is as defined according to any of embodiments 1 to 8, preferably P is

*P wherein *P is preferably according to any of embodiments 1 to 6.

The process of embodiment 13, wherein the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane,

- (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant

-Swern type oxidation reagents -such as Dimethyl sulfoxide (DMSO) and suitable activator-

-transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO) wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents.

The process of embodiment 13 or 14, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from -78

°C to 30 °C, more preferably in the range of from -40 °C to 20 °C.

The process of any of embodiments 13 to 15, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane, DMSO and a mixture thereof.

The process of any of embodiments 14 to 16, wherein in b) the molar ratio of the compound of formula (X) relative to the oxidizing agent is in the range of from 1 : 1 to 1: 15, preferably in the range of from 1:3 to 1:4.

The process of any of embodiments 1 to 17, for preparing a compound of formula (III- a)

preferably wherein the phosphorus atom P has a steric configuration S. (b) Process for the preparation of compound of formula (III) with intermediate of formula (X) and (XI)

19. A process for the preparation of a compound of formula (III)

the process comprising

a) providing a compound of formula (X)

b) oxidizing the compound of formula (X) and obtaining a compound of formula (XI)

c) fluorinating the compound of formula (XI) of b) and obtaining the compound of formula (III)

wherein at each occurrence P and Base are as defined according to any of embodiments 1 to 8, preferably P is *P wherein *P is preferably defined according to any of embodiments 3 to 6 and wherein the formulae include the enantiomers and diastereomers thereof.

20. The process of embodiment 19, wherein the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane, - (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant -Swern type oxidation reagents -such as DMSO and suitable activator- -transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO) wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents.

21. The process of embodiment 19 or 20, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from -78 °C to 30 °C, more preferably in the range of from -40 °C to 20 °C. 22. The process of any of embodiments 19 to 21, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane and DMSO and a mixture thereof.

23. The process of any of embodiments 20 to 22, wherein the molar ratio of the compound of formula (II) relative to the oxidizing agent is in the range of from 1: 1 to 1: 15, preferably in the range of from 1:3 to 1:4.

24. The process of any of embodiments 19 to 23, wherein the fluorinating of c) is carried out with fluorinating agent as defined according to embodiment 9.

25. The process of any of embodiments 19 to 24, wherein the fluorinating of c) is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

26. The process of any of embodiments 19 to 25, wherein the fluorinating of c) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl. ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

27. The process of any of embodiments 24 to 26, wherein the molar ratio of the compound of formula (XI) relative to the fluorinating agent is in the range of from 1: 15 to 1:5.

28. The process of any of embodiments 19 to 27, for preparing a compound of formula (Ill-a)

preferably wherein the phosphorus atom P has a steric configuration S.

V.2 PROCESS FOR PREPARING COMPOUND OF FORMULA (IV)

(a) Process for preparing compound of formula (IV) via compound of formula (III) and (XI)

29. A process for the preparation of a compound of formula (IV)

the process comprising

i) providing a compound of formula (III)

and

ii) reducing the compound of formula (III) and obtaining the compound of formula (IV) and

wherein when in i) in the compound of formula (III) P is PG, the process comprises, after i) and before ii),

i') phosphorylating said compound of formula (III) wherein P is PG to a compound of formula (III) wherein P is P* and

P is selected from *P or PG, wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably

*P is a phosphoramidate, and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl or silyl protecting groups and wherein the formulae include the enantiomers and diastereomers thereof.

The process of embodiment 29, wherein *P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably *P is a phosphoramidate, wherein the phosphoramidate is preferably as defined according to any of embodiments 3 to 6.

The process of embodiment 29, wherein P is PG.

The process of embodiment 29 or 31, wherein the PG is selected from the group consisting of alkyl, benzyl or silyl protecting groups.

The process of any of embodiments 29 to 32, wherein the reducing of ii) is carried out with a reducing agent selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent, wherein preferably the boron based reducing agent is a borohydride and the aluminium based reducing agent is a lithium- aluminium hydride and

wherein preferably the borohydrides is selected from the group consisting of

NaBH ₄ , LiBH ₄ , Li(Et) ₃ BH, and

wherein preferably the lithium- aluminium hydride is selected form the group consisting of LiAlH ₄ and diisobutylaluminium hydride ( DIBAL-H ).

The process of any of embodiments 29 to 33, wherein the reducing of ii) is carried out at a temperature in the range of from -78 °C to 40 °C, preferably in the range of from - 20 °C to 20 °C.

The process of any of embodiments 29 to 34, wherein the reducing of ii) is carried out in a solvent selected from a protic solvent or a mixture thereof, preferably in a protic solvent selected from the group consisting of methanol, ethanol, isopropanol and water and a mixture thereof.

The process of any of embodiments 33 to 35, wherein the molar ratio of the compound of formula (III) relative to the reducing agent is in the range of from 1:1 to 1: 10, preferably in the range of from 1:2 to 1:4.

The process of any of embodiments 29 to 36, wherein phosphorylating of i') comprises reacting, in the presence of a base or of a Lewis acid, the compound of formula (III) wherein P is PG with a compound of formula *P-X wherein *P is as defined in any of embodiments 1, 3 to 6 and X is a leaving group, preferably selected from the group consisting of halogens, mesylate, tosylate optionally substituted phenol and succinimide.

The process of any of embodiments 29 to 37, wherein the phosphorylating of i') is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

The process of any of embodiments 29 to 38, wherein the phosphorylating of Γ) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- biityl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

The process of any of embodiments 37 to 40, wherein in i') the molar ratio of the compound of formula (III) wherein P is PG relative to the phosphorylation reagent *P- X is in the range of from 1: 15 to 1:5

The process of any of embodiments 29 to 40, wherein i) comprises

1) providing a compound of formula (XI)

2) fluorinating the compound of formula (XI) and obtaining the compound of formula (III)

wherein at each occurrence

P is as defined according to any of embodiments 1 to 8, preferably P is *P and wherein *P is preferably defined according to any of embodiments 3 to 6.

The process of embodiment 41, wherein the fluorinating of 2) is carried out with a fluorinating agent as defined according to embodiment 9.

The process of embodiment 41 or 42, wherein the fluorinating of 2) is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

The process of any of embodiments 41 to 43, wherein the fluorinating of 2) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl. ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

The process of any of embodiments 42 to 44, wherein the molar ratio of the compound of formula (I) relative to the fluorinating agent is in the range of from 1: 15 to 1:5.

The process of any of embodiments 41 to 45, wherein 1) comprises

a) providing a compound of formula (X)

b) oxidizing the compound of formula (X) and obtaining a compound of formula

(XI) wherein P is as defined according to any of embodiments 1 to 8, preferably P is

*P and wherein *P is preferably defined according to any of embodiments 3 to 6.

The process of embodiment 46, wherein the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane,

- (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant

-Swern type oxidation reagents -such as Dimethyl sulfoxide (DMSO) and suitable activator-

-transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO) wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents. 48. The process of embodiment 46 or 47, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from -78 °C to 30 °C, more preferably in the range of from -40 °C to 20 °C.

49. The process of any of embodiments 46 to 48, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane, DMSO and a mixture thereof.

50. The process of any of embodiments 46 to 49, wherein in b) the molar ratio of the compound of formula (VI) relative to the oxidizing agent is in the range of from 1 : 1 to 1: 15, preferably in the range of from 1:3 to 1:4.

51. The process of any of embodiments 29 to 50, for preparing a compound of formula (IV-a)

preferably wherein the phosphorus atom P has a steric configuration S.

(b) Process for preparing compound of formula (IV) via compound of formula (X), (XI) and (III)

52. A process for the preparation of a compound of formula (IV)

the process comprising

a) providing a compound of formula (X)

b) oxidizing the compound of formula (X) and obtaining a compound of formula (XI)

c) fluorinating the compound of formula (XI) of b) and obtaining the compound of formula (III)

and when in the compound of formula (III) of c) P is *P the process further comprises ii) reducing the compound of formula (III) of c) and obtaining the compound of formula (IV)

or when in the compound of formula (III) of c) P is PG the process further comprises i') phosphorylating said compound of formula (III) having P= PG to a compound of formula (III) having P is P* and

ii) reducing the compound of formula (III) of i') and obtaining the compound of formula (IV) having P is *P,

wherein at each occurrence

P is *P or PG and wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably

*P is a phosphoramidate and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl or silyl protecting groups and wherein the formulae include the enantiomers and diastereomers thereof.

The process of embodiment 52, wherein P is *P.

The process of embodiment 52 or 53, wherein *P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, phosphoramidate, preferably *P is a phosphoramidate, wherein the phosphoramidate is preferably as defined in any of embodiments 3 to 6.

The process of embodiment 52, wherein P is PG.

The process of embodiment 52 or 55, wherein PG is as defined in embodiment 7 or 8.

The process of any of embodiments 52 to 56, wherein the oxidizing of b) is carried out with an oxidizing reagent selected from the group consisting of

-hypervalent iodo oxidation reagents such as Dess-Martin periodinane,

- (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) and optionally an oxidant -Swern type oxidation reagents -such as DMSO and suitable activator- -transition metal based oxidizing reagent,

-tetrapropylammonium perruthenate/N-Methylmorpholine-N-Oxide (TPAP/NMO) wherein preferably the oxidizing reagent is selected from the group consisting of- hypervalent iodo oxidation reagents and Swern type oxidation reagents. The process of any of embodiments 52 to 57, wherein the oxidizing of b) is carried out at a temperature in the range of from -80 °C to 60 °C, preferably in the range of from - 78 °C to 30 °C, more preferably in the range of from -40 °C to 20 °C.

The process of any of embodiments 52 to 58, wherein the oxidizing of b) is carried out in a solvent selected from the group consisting of dichloromethane, THF, ethyl acetate, DMSO, benzene, toluene, MTBE and a mixture thereof, preferably in a solvent selected from the group consisting of dichloromethane and DMSO and a mixture thereof.

The process of any of embodiments 57 to 59, wherein the molar ratio of the compound of formula (II) relative to the oxidizing agent is in the range of from 1: 1 to 1: 15, preferably in the range of from 1:3 to 1:4.

The process of any of embodiments 52 to 60, wherein the fluorinating of c) is carried out with fluorinating agent as defined according to embodiment 9.

The process of any of embodiments 52 to 61, wherein the fluorinating of c) is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

The process of any of embodiments 52 to 62, wherein the fluorinating of c) is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

The process of any of embodiments 61 to 63, wherein the molar ratio of the compound of formula (XI) relative to the fluorinating agent is in the range of from 1: 15 to 1:5. The process of any of embodiments 52 to 64, wherein in c) in the compound of formula (III) P is PG and wherein after c) the process comprises

i') phosphorylating said compound of formula (III) wherein P is PG to a compound of formula (III) wherein P is P*.

The process of embodiment 65, wherein phosphorylating of i') comprises reacting, in the presence of a base or of a Lewis acid, the compound of formula (III) wherein P is PG with a compound of formula *P-X wherein *P is as defined in any of embodiments 1, 3 to 6 and X is a leaving group, preferably selected from the group consisting of halogens, mesylate, tosylate optionally substituted phenol and succinimide.

The process of any of embodiments 52 to 66, wherein the phosphorylating of Γ) is carried out at a temperature in the range of from -20 °C to 100 °C, preferably in the range of from 0 °C to 40 °C.

The process of any of embodiments 52 to 67, wherein the phosphorylating of i') is carried out in a solvent, preferably an organic solvent, wherein the organic solvent is preferably selected from the group consisting of tetrahydrofuran (THF), Methyl tert- butyl ether (MTBE), Dioxan, methylene chloride, toluene, acetonitrile and acetone and a mixture thereof.

69. The process of any of embodiments 66 to 68, wherein the molar ratio of the compound of formula (III) wherein P is PG relative to the phosphorylation reagent *P-X is in the range of from 1: 15 to 1:5

70. The process of any of embodiments 52 to 69, wherein step ii) is carried out after i').

71. The process of any of embodiments 52 to 70, wherein the reducing of ii) is carried out with a reducing agent selected from the group consisting of a boron based reducing agent and an aluminium based reducing agent, wherein preferably the boron based reducing agent is a borohydride and the aluminium based reducing agent is a lithium- aluminium hydride and

wherein preferably the borohydrides is selected from the group consisting of NaBH ₄ , LiBH , Li(Et) ₃ BH, and

wherein preferably the lithium- aluminium hydride is selected form the group consisting of LiAlH ₄ and diisobutylaluminium hydride ( DIBAL-H ).

72. The process of any of embodiments 52 to 71, wherein the reducing of ii) is carried out at a temperature in the range of from -78 °C to 40 °C, preferably in the range of from - 20 °C to 20 °C.

73. The process of any of embodiments 52 to 72, wherein the reducing of ii) is carried out in a solvent selected from a protic solvent and a mixture thereof, preferably in a protic solvent selected from the group consisting of methanol, ethanol, isopropanol and water and a mixture thereof.

74. The process of any of embodiments 71 to 73 wherein in ii) the molar ratio of the compound of formula (III) wherein P is *P relative to the reducing agent is in the range of from 1: 1 to 1: 10, preferably in the range of from 1:2 to 1:4.

75. The process of any of embodiments 52 to 74, for preparing a compound of formula (IV-a)

preferably wherein the phosphorus atom P has a steric configuration S.

The process of any of embodiments 13 to 28 and 46 to 75, wherein the compound of formula (X) has structure (I-a)

preferably wherein the phosphorus atom P has a steric configuration S.

The process of any of embodiments 1 to 28 and 41 to 76, wherein the compound of formula (XI) has structure (XI- a)

preferably wherein the phosphorus atom P has a steric configuration S.

V.3 PROCESS FOR PREPARING THE COMPOUND OF FORMULA (XI)

78. A process for preparing a compound of formula (XI), the process comprising a) providing a compound of formula (X)

b) oxidizing the compound of formula (X) and obtaining a compound of formula (XI) wherein

P is according to any of embodiments 1 to 8, preferably P is *P wherein *P is preferably defined according to any of embodiments 3 to 6 and wherein the oxidizing of b) is preferably according to any of embodiments 13 to 17 and wherein the formulae include the enantiomers and diastereomers thereof.

79. The process of embodiment 78, wherein the compound of formula (X) has structure

wherein preferably the phosphorous atom P has a steric configuration S.

80. The process according to embodiments 78 or 79, wherein the compound of formula

(XI) has structure (Xl-a)

wherein preferably the phosphorous atom P has a steric configuration S.

COMPOUND OF FORMULA (X)

A compound of formula (X)

P is *P or PG, wherein

*P is selected from the group consisting of phosphate, monophosphate, diphosphate, triphosphate, protected phosphate, preferably benzyl protected phosphate, phosphoramidate and

PG is a protecting group, preferably a protecting group of a primary OH group, wherein preferably the protecting group of a primary OH group is selected from the group consisting of alkyl, benzyl or silyl protecting group and wherein the formula includes the enantiomers and diastereomers thereof.

The compound of embodiment 81, wherein *P is selected from the group consisting of pho sphoramidate .

The compound of embodiment 81 or 82, wherein *P is a phosphoramidate as defined according to embodiments 3 to 6.

COMPOUND OF FORMULA (XI)

A compound of formula (XI)

(IX)

wherein P is defined according to any of embodiments 1 to 8, preferably P is *P wherein *P is preferably defined according to any of embodiments 3 to 6 and wherein the formula includes the enantiomers and diastereomers thereof.

85. The compound of embodiment 84, obtained or obtainable according to the process of any of embodiments 78 to 80.

V.6 Uses

86. Use of a compound of formula (X) according to any of embodiments 81 to 83 for preparing a compound of formula (IV) wherein *P is as defined according to embodiments 1, 3 to 6. 87. Use of a compound of formula (X) according to any of embodiments 81 to 83 for preparing a compound of formula (III) wherein *P is as defined according to embodiments 1, 3 to 6.

88. Use of a compound of formula (XI) according to embodiments 84 or 85, for preparing a compound of formula (IV), wherein *P is as defined according to embodiments 1, 3 to 6.

89. Use of a compound of formula (XI) according to embodiments 84 or 85, for preparing a compound of formula (III), wherein *P is as defined according to embodiments 1, 3 to 6.

Examples

Example 1: Preparation of the compound of formula (IlV-a) from the compound of formula (Ill-a)

55 mg of the compound of formula (Ill-a) having S configuration at the phosphorus atom was diluted in 5 ml ethanol and 3 ml water. To the slightly turbic solution 12 mg sodium borohydride was added. The mixture was stirred for 75 min until complete conversion was observed. To the mixture 10ml methylene chloride was added and water was added. The organic phase was separated and washed with brine. After removal of the organic solvent via distillation 31 mg of the compound of formula (IV-a) (sofosbuvir) was isolated (identified via HPLC and 1H-NMR)

Cited prior art

- WO 2008/ 12 1634

- US20140271547