The invention relates to a process for preparing β-amino acid derivatives. The process can be used for the preparation of telaprevir or a pharmaceutically acceptable salt or solvate thereof, wherein the process includes an organocatalytic epoxidation reaction which avoids the use of titanium catalysts and thus avoids contamination of the final product with titanium as present in known products. Another embodiment refers to telaprevir a pharmaceutically acceptable salt or solvate thereof as well as to an intermediate product for preparation of the same, wherein the afore-mentioned products are obtained by the process described herein.

Background prior art

Telaprevir is a protease inhibitor that can be used as antiviral drug. By way of example, telaprevir inhibits the hepatitis C virus NS3-4A serine protease. Although some efficient processes for the synthesis of telaprevir or its pharmaceutical acceptable salts are available, it is an object of the present invention to provide an enhanced process that overcomes at least one of the problems of the prior art processes.

The synthesis of telaprevir requires the preparation of an 3-amino-2-hydroxyhexanamide as an intermediate.

EP2039689 A1 refers to the preparation of optically-active 3-amino-2-hydroxypropionic cyclopropylamide derivatives. The process comprises a step of providing an epoxide by HX (X=halogen)-elimination from an optically-active 2-halo-3-hydroxypropionic acid derivative. The document describes the use of Noyori's catalyst (Ru + BINAP) for the generation of this optically-active 2-halo-3-hydroxypropionic acid derivative.

Other epoxidation processes are also known, for example WO2007109023 A1 discloses a process for the preparation of protease inhibitors, the process comprises a step of converting an unsaturated compound into an epoxide by using known methods such as oxidation with peroxides.

WO2008029267 A2 discloses a process for preparing 3-amino-2-hydroxycarboxylic acid amines, which comprises the epoxidation of a trans-α-β unsaturated carboxylic acid or alcohol. Said epoxidation is conducted by using a Sharpless asymmetric epoxidation of an allyl alcohol based on a standard protocol using Ti(OiPr) ₄ , DET (diethyltartrate) and tBuOOH. A further epoxidation process is described by J0rgensen (Journal of the American Chemical Society 2005, 127, 6964) for α,β-unsaturated aldehydes. This epoxidation process uses a sterically-hindered pyrrolidine derivative as catalyst:

The above sterically encumbered chiral pyrrolidine derivative with its "CF ₃ " groups is easily accessible in four steps from L-proline and is used as the catalyst in combination with hydrogen peroxide as the oxidant. According to J0rgensen, the use of L-proline and other chiral pyrrolidine derivatives as the catalyst gave poor or low conversion.

A further epoxidation process is disclosed by Bondzic et al. (Org. Lett., Vol. No. 23, 2010, 5434- 5437). According to this document, a-substituted acroleins can be oxidized by using diphenylprolinol diphenylmethylsilyl ether as catalyst. It is reported that bulky silyl groups on the tertiary alcohol give good results with a-substituted acroleins.

WO2009152474 A2 describes a process for the preparation of 3-amino-N-cyclopropyl-2- hydroxyalkane amide derivatives as key intermediates in the production of HCV inhibitors. The synthesis route comprises a step of reacting an aminoaldehyde with a cyclopropyl isocyanide to obtain an 3-amino-2-hydroxycarboxylic acid amide.

Harbeson et al. (J. Med. Chem. 1994, 37, 2918-2929) also describe the synthesis of 3-amino-2- hydroxycarboxylic acid amides by cyanide addition to an a-amino aldehyde, followed by hydrolysis of the cyanohydrin and amidation.

Summary of the invention

Known processes for the stereoselective preparation of telaprevir intermediates are based on the use of organometallic catalysts for performing epoxidation reactions. The use of such catalysts results in the presence of metal impurities in the final compound. It was surprisingly found within the context of the present invention that (S)-2- (diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine can advantageously be used for the stereoselective epoxidation of α,β-unsaturated aldehydes. The process described herein may improve the synthesis of telaprevir. The process described herein may for example allow avoiding the use of organometallic catalysts. Furthermore, the process described herein can be used instead of a Sharpless epoxidation reaction that is commonly applied. Compared to the Sharpless epoxidation, the process described herein may require a less rigid temperature control, less toxic oxidants and avoids titanium waste. Moreover, the intermediate which is an epoxy acid can be converted into an β-amino acid in a "one pot" reaction, thus reducing process steps.

The present invention thus relates to a process for preparing telaprevir as defined in the claims. It also relates to processes for preparing intermediates of telaprevir and related compounds as defined in the claims. Furthermore, it relates to telaprevir/telaprevir dosage forms and an intermediate of telaprevir as defined in the claims.

List of figures

Figure 1 : Shows an example of a reaction scheme for the synthesis of an intermediate according to Formula 5a for the preparation of telaprevir.

Figure 2: Shows examples of reaction schemes for preparing compounds according to

Formulas 10a and 10'a from 4'a.

Figure 3: Shows examples of reaction schemes for preparing compounds according to

Formula 5a. Detailed description

The invention relates to a process for the preparation of telaprevir of Formula 1

or a pharmaceutically acceptable salt or solvate thereof, wherein the process comprises steps of (i) to (vi). In the process described herein, telaprevir of formula 1 is prepared via the compounds of Formulas 2a, 4a, 4'a, 5a, 6, and 7. Figure 1 shows an example of the process for preparing the intermediate compound according to Formula 5a.

Pharmaceutically acceptable salts may for example be selected from the group consisting of hydrochloride, hydrobromide, acetate, citrate, maleate, succinate, and lactate, benzoate. Pharmaceutically acceptable salts can be obtained by standard methods, for example by addition of the respective acid to telaprevir as free base.

In step (i), a compound of Formula 2a is provided:

2a , wherein R-i is a propyl group; and R ₂ is a hydrogen atom.

Preferably, step (i) includes dissolving the compound of Formula 2a in a solvent or mixture of solvents. However, it is also possible to add the compound of Formula 2a neat to the compounds of step (ii). Suitable solvents can be chosen by a person skilled in the art of common practice. Preferably, inert solvents are used. The term "inert solvent" refers to any solvents that do not react with the compounds described herein. Inert solvents suitable in this respect are commonly known. Additionally preferred, the solvent(s) used in step (i)/(ii), (iii) and/or step (iv) is/are selected from the group consisting of ethylacetate, dichloromethane, N,N- dimethylacetamide, dimethyl sulfoxide (DMSO), N-methylpyrrolidone, acetonitrile, methyl tert- butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene and dimethylformamide, hydrocarbon solvents, for example hexane and heptane, alcohols, for example methanol and ethanol, and water; preferably, dichloromethane and water are used in step (i)/(ii), (iii) and/or step (iv). The afore-mentioned solvents or mixtures thereof may also be used in other steps of the process described herein, where applicable. Solvent mixture for the individual steps of (iv): Boc protection reactions are preferably performed with an addition of THF; for the azidation an aqueous Cu-solution can for example be used. Azidation reactions (in step iv) are preferably carried out in water.

In general, if in the processes described herein two or more compounds are brought into contact with each other and are reacted with each other a skilled person can choose a suitable way of bringing the compounds into contact with each other. This can for example be done by dissolving said compounds either separately or as a mixture of compounds or by dissolving one of the compounds and adding to this solution the respective other compound. The order of combining the compounds can be chosen by a person skilled in the art.

The compound of Formula 2a is commercially available and can also be prepared by applying standard synthesis methods. It is preferably used with a purity of at least 97%.

In step (ii), the compound of Formula 2a is brought into contact with a compound of Formula 3

3 wherein R ₅ is methyl or ethyl, preferably methyl (see Example 2).

The compound of Formula 3 is commercially available and can also be prepared by applying standard synthesis methods. It is preferably used with a purity of at least 97%. The compound of Formula 3 is preferably used in stereochemical^ pure form. For example, the enantiomeric purity of the compound of Formula 3 is >99%ee. For the determination of the ee of the catalyst 3 a comparison of the optical rotation is suitable. In general, stereochemical purity/enantiomeric purity can for example be determined by chiral high performance liquid chromatography (HPLC) as known in the art.

Step (ii) is performed in the presence of an oxidant, for example hydrogen peroxide, tBuOOH, cumene hydroperoxide, urea-hydrogen peroxide, preferably hydrogen peroxide, wherein step (ii) yields a compound of Formula 4a, when the compound of Formula 2a is oxidized:

4a _; wherein F^ and R ₂ are as defined above.

The epoxidation process described herein can also be carried out with a compound of Formula 2:

2

In the compounds according to Formulas 2, 4, 4', 5, 9, 10, 10', 1 1 , and 13 as described herein, Ri can be selected from the group consisting of linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof, preferably R-i has 1 -12 carbon atoms, in particular is a linear, branched, or cyclic aliphatic C _r Ci ₂ or C C ₆ group, in addition R-i is preferably a saturated group.

In the compounds according to Formulas 2 and 4 as described herein, R ₂ can be selected from the group consisting of a hydrogen; alkoxy group; linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof; preferably R ₂ is a hydrogen atom or linear, branched, or cyclic aliphatic C Ci ₂ or Ci-C ₆ group, in addition R ₂ is preferably a saturated group; preferably, R ₂ is hydrogen, an Ci- ₆ aliphatic group or an d _-6 alkoxy group; in particular R ₂ is hydrogen. In the compound of Formula 4' R ₂ is a hydroxyl group.

In the compounds according to Formulas 9, 10 and 10' as described herein, R ₂ can be selected from the group consisting of a hydroxyl; alkoxy group; linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof; preferably R ₂ is a linear, branched, or cyclic aliphatic Ci-C ₁₂ or C C ₆ group, in addition R ₂ is preferably a saturated group, in particular, R ₂ is an hydroxyl group in the compounds of Formulas 9a, 10a and 10'a.

In the compounds according to Formulas 5, 5', and 1 1 as described herein, R ₄ can be selected from the group consisting of linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof, preferably R ₄ has 1-12 carbon atoms, in particular R ₄ is a linear, branched, or cyclic aliphatic C-i-C ₁₂ or an C _1-6 group, preferably, R ₄ is saturated; for example R ₄ is cyclopropyl.

Epoxidation of a compound of Formula 2 results in the formation of a compound of Formula 4. This is described in more detail below.

In step (ii) the compound of Formula 3 can for example be used in an amount of 0.01-0.5, in particular 0.02-0.1 , equivalents based on the total amount of the compound of Formula 2/2a. The reaction can be carried out at ambient temperature/room temperature. Step (ii) can for example be carried out for at least 6 hours, preferably for up to 16 hours, at room temperature.

In step (ii) the oxidant, for example hydrogen peroxide, can for example be used in an amount of 1.0-1.5 equivalents based on the total amount of the compound of Formula 2/2a.

In step (ii) the compound of Formula 4/4a can be isolated and purified, for example it can be purified by filtration over a silicagel plug, for example by using a pentane/diethyl ether mixture. In general, the reaction products described herein can be isolated after each reaction step. Suitable methods for isolating compounds are known in the art and comprise for example the washing of the organic layer with an aqueous salt solution (e.g. brine), separation of the organic layer, drying of said organic layer and removal of the organic solvent in vacuo. Dependent on the specific conditions used, the work-up may further include acid and/or base washes. Furthermore, the compounds may be purified by using chromatography techniques.

In step (iii), R ₂ in the compound of Formula 4a of step (ii) is oxidized, thereby obtaining a compound of Formula 4'a

4'a wherein Ri is a propyl group; and R ₂ is a hydroxyl group. Step (iii) can also be carried out with a compound of Formula 4 as described below.

The oxidizing agent in step (iii) can for example be selected from the group consisting of pyridinium chlorochromate (PCC), CrCVI-kSCVacetone (Jones reagent), RuCI ₃ .2H ₂ 0/Nal0 ₄ , sodium hypochlorite in the presence of 2,2,6,6- tetramethylpiperidinyloxy free radical (TEMPO); preferably, the oxidizing agent is sodium hypochlorite in the presence of 2,2,6,6- tetramethylpiperidinyloxy free radical (TEMPO).

Step (iii) can for example be carried out for a time period of 10 minutes to 10 hours at a temperature of 15°C or below, preferably between 0° and 15°C.

The oxidizing agent can for example be used in catalytic amounts in the presence of stoichiometric co-oxidants.

In step (iii), a phase transfer catalyst, preferably a quaternary ammonium salt, especially preferred is aliquate 336 (mixture of C8 (octyl) and C10 (decyl) chains (tricaprylylmethylammonium chloride trioctylmethylammonium chloride) with C8 predominating) can additionally be used.

In step (iii) the compound of Formula 4'a/4' can be isolated, for example by extraction from the reaction mixture with an organic solvent.

In step (iv), the compound of Formula 4'a/4' of step (iii) is subjected to reaction steps comprising (1 ) an azidation of the epoxide group;

(2) reducing the formed azide group thereby providing an amine (see Figure 2);

(3) performing an amide coupling reaction with cyclopropylamine in the presence of one or more coupling agents, either before or after said azidation/reduction step, wherein if the amine of step (2) is used for coupling with cyclopropylamine, said amine is protected with a protective group before the coupling reaction; and

(4) obtaining a compound of Formula 5a/5 wherein is a propyl group; R ₃ is hydrogen after deprotection; and R ₄ is cyclopropyl.

The above reaction step (3) can be carried out either before or after the azidation step and either before or after the reduction of the azide group (see Figure 3). Azidation of the above ester and amide is described in WO2008029267 A2 and WO2007109023 A1.

In step (iv), the compound of Formula 5a can be isolated, for example by extraction from the reaction mixture with an organic solvent. The compound of Formula 5a can be purified by methods known in the art.

The azidation can for example be conducted by using NaN ₃ in an amount of 1 to 2 equivalents based on the amount of the compound of Formula 4'a/4'. The azidation can for example be conducted in the presence of 0.02 to 0.2 equivalents, preferably 0.1 equivalents Cu(N0 ₃ ) ₂ . Water can for example be used as solvent for the azidation. Suitable conditions for carrying out azidation reactions are known in the art. For example, the azidation can be carried out at temperature of about 50°C-80°C for a period of 0.5 to 3 hours.

The azide group can be reduced in order to obtain an amine. This reduction can for example be carried out by using hydrogen in the presence of palladium on charcoal and water or by using NaBH ₄ in the presence of water. Suitable conditions for reducing azide groups are known in the art. For example, the reduction can be carried out by using hydrogen and Pd/C at room temperature for a period of 0.5 to 3 hours.

The amine coupling reaction in step (iv) and/or step (v) can for example be carried in the presence of a base and one or more coupling agents selected from the group consisting of dicyclohexylcarbodiimide (DCC), diispropylcarbodiimide (DIC), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC), 1-hydroxy-benzotriazole (HOBt) or 1- hydroxy-7-aza-benzotriazole (HOAt), 0-Benzotriazole-N,N,N',N'-tetramethyl-uronium- hexafluoro-phosphate (HBTU), 0-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 0-(6-Chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HCTU), O-(Benzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (TBTU), (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) (PyBOP), preferably TBTU is used in step (iv).

A preferred coupling agent used in step (v) is a substituted 1 ,3,5,2,4,6-trioxatriphosphorinane- 2,4,6-trioxide, preferably a compound of Formula 8 ^R 3. O °

0= P - -R ₃ wherein R ₃ is a saturated or unsaturated, branched, cyclic or linear, substituted or unsubstituted C- o hydrocarbon compound, preferably, R ₃ is n-propyl or phenyl. Thus, preferred coupling agents are 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P) and 2,4,6- triphenyl-1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide. If a compound of Formula 8 is used as coupling agent, it is preferred to use it as the only coupling agent. Also preferred coupling agents are carbodiimides such as diispropylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride and N,N'-dicyclohexylcarbodiimide. Carbodiimides are known in the art. However, it is also possible to use other coupling agents known in the art such as uranium coupling agents. For an overview of possible coupling reagents, reference is made to Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447-2467.

The amine coupling in step (iv) and/or step (v) can for example be carried by using an amount of 1 to 2 equivalents of cyclopropylamine based on the amount of the compound of Formula 5a and wherein the solvent is dichloromethane or dimethylformamide. Suitable conditions for coupling reactions are known in the art. Reference is also made to the patent application EP12159923.7. For example, the reaction can be started at a temperature of about 0°C by adding all components and reaction is then completed at room temperature for a period of several hours such as 10-24 hours.

The total amount of coupling agent(s) that can be used in the processes described herein can for example be from 0.8 to 6 equivalents, preferably from 0.9 to 4 equivalents, further preferred from 1 to 2 equivalents, based on the total amount of the compound that is to be reacted with the amine compound (e.g. compound according to Formula 4'a, 9a, 10'). If more than one coupling agent is used, the different types of coupling agents can be used in the same or different amounts. For example, they can be used in an amount of more than 1 equivalent based on the amount of the compound that is to be reacted with the amine compound. Further preferred, each coupling agent is used in an amount of 1 to 2 equivalents.

In the process described herein, the sequence of reaction steps in step (iv) can for example be conducted in the following order (option a): (1 ) firstly conducting the azidation of the epoxide group of the compound of Formula 4'a step (iii), for example by conducting the azidation as described herein, thereby obtaining compound of Formula 9a

, wherein R-i is a propyl group; and R ₂ is a hydroxyl group;

(2) reducing the resulting azide group to obtain an amine of Formula 10a

, wherein Ri is a propyl group; R ₂ is a hydroxyl group; and R ₃ is a hydrogen atom

(see Figure 2);

(3) protecting the resulting amine with a protective group, thereby obtaining a compound of Formula 10'a (see Figure 2)

wherein Ri and R ₂ are as defined above; and R ₃ is a protective group, preferably a carbamate group, preferably a Boc group; and

(4) subjecting the compound of Formula 10'a to said amine coupling reaction with cyclopropylamine in the presence of one or more coupling agents, thereby obtaining a compound of Formula 5'a

wherein Ri is a propyl group; R ₃ is a protective group, preferably a carbamate group, preferably a Boc group; and R ₄ is cyclopropyl;

(5) deprotecting the amine group, thereby obtaining a compound of Formula 5a, wherein R ₃ is hydrogen.

Examples of protecting groups for the purpose of the invention are for example described in T. W. Greene & P.G.M Wuts, "Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons, Inc. (2006). The deprotecting agent and conditions for carrying out the deprotection reaction can be chosen of common knowledge depending on the protective group that is used (see e.g. the afore-mentioned reference: T. W. Greene & P.G.M Wuts, "Protective Groups in Organic Synthesis").

The process steps of Boc-protection of amino acid derivatives and coupling thereof with amines can be carried out as described by Harbeson et al. (J. Med. Chem. 1994, 37, 2918-2929) and Avolio et al. (Bioorg. Med. Chem. Lett 19, (2009) 2295-2298) as described above.

In a further embodiment, in option (a) as described above, the reaction sequence is carried out without isolating the compound of Formula 9a, which is directly reduced with hydrogen in the presence of palladium on charcoal and the resulting compound of Formula 10a, wherein R ₃ is hydrogen, is then brought into contact with Boc ₂ 0 either with diisopropylethylamine (DIPEAytetrahydrofurane (THF)/H ₂ 0 or NaOH/H ₂ 0/dioxane to provide the compound of Formula 10'a, wherein R ₃ is Boc.

As an alternative, the sequence of reaction steps in step (iv) can for example be conducted in the following order (option b):

(1 ) conducting the azidation of the epoxide of the compound of Formula 4'a of step (iii), thereby obtaining a compound of Formula 9a,

is a propyl group; and R ₂ is a hydroxyl group;

(2) subjecting the compound of Formula 9a to said amine coupling reaction with cyclopropylamine in the presence of one or more coupling agents, thereby obtaining a compound of Formula 1 1 a

wherein R-i is as defined above; and R ₄ is cyclopropyl;

(3) reducing the azide group to thereby obtain a compound of Formula 5a,

wherein and R ₄ are defined above; and R ₃ is hydrogen.

As a further option, the sequence of reaction steps in step (iv) can for example be conducted in the following order (option c): (1 ) subjecting the compound of Formula 4'a of step (iii) to said amine coupling reaction with cyclopropylamine in the presence of one or more coupling agents, thereby obtaining a compound of Formula 12a

12a

wherein Ft] is as defined above; and R ₄ is cyclopropyl;

(2) conducting said azidation of the epoxide, thereby obtaining a compound of Formula 1 1 a

wherein Ri is as defined above; and R ₄ is cyclopropyl; and

(3) reducing the resulting azide group to thereby obtain a compound of Formula 5a,

wherein and R ₄ are as defined above; and R ₃ is hydrogen.

The solvent(s) used in steps (i)/(ii), (iii) and/or (iv) can for example be selected from the group consisting of ethylacetate, dichloromethane, Ν,Ν-dimethylacetamide, dimethyl sulfoxide, N- methylpyrrolidone, acetonitrile, methyl tert-butyl ether, methyltetrahydrofuran, tetrahydrofuran, toluene, dimethylformamide, hydrocarbon solvents, for example hexane and heptane, alcohols, for example methanol and ethanol, and water. Preferably, dichloromethane and water are used in step (ii) and (iii). Preferably, water is used in the azidation and reduction in step (iv) and DCM or DMF for the amidation of the free acid. Suitable amount(s) of solvent(s) can be chosen by a person skilled in the art. The use of lower amounts of solvents leading to higher concentrations may provide for a faster reaction rate.

In step (v), the compound of Formula 5a is brought into contact with a compound of Formula 6

, in the presence of one or more coupling agents, thereby obtaining a compound of Formula 7,

The compound of Formula 6 can for example be prepared as described in the patent application EP12159923.7. It is also possible to prepare the compound of Formula 6 by applying the methods described in WO2010/126881. Regarding the methods and conditions for coupling the compounds of Formula 5a and 6 in order to obtain a compound of Formula 7, reference is also made to EP12159923.7 and WO2010/126881. For example, the compound of Formula 5a can be added in the form of a suspension (for example in dichloromethane) to a reaction mixture comprising the compound of Formula 6 and optionally the coupling agent(s). Optionally, said suspension can comprise an organic base, such as tertiary amine bases like diisopropylethylamine, N-methylmorpholine, and triethylamine, or an inorganic base such as potassium carbonate, sodium carbonate or sodium bicarbonate.

A suitable reaction temperature for step (v) can be chosen by a person skilled in the art. For example, the step of combining the compound of Formula 5a with the other compounds can be carried out at 0°C to room temperature (for example for a time of 1 minute to 1 hour) and the reaction can then be completed at 0°C to 50°C (for example for a time of 1 hour to 12 hours). Additionally preferred, after completion of the reaction, the reaction mixture is quenched by addition of water followed by acidification. Additionally preferred, the compound of Formula 7 is then isolated by using the same or a similar method as described above. Preferred coupling agents and amounts of coupling agents are described above.

The solvent(s) used in step (v)/(vi) is/are selected from the group consisting of ethylacetate, dichloromethane, Ν,Ν-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methylpyrrolidone, acetonitrile, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene and N,N- dimethylformamide, preferably toluene, N-methylpyrrolidone, Ν,Ν-dimethylacetamide, N,N- dimethylformamide, methyl tert-butyl ether, 2-methyltetrahydrofuran or dichloromethane, and most preferably N,N-dimethylacetamide, Ν,Ν-dimethylformamide, and dichloromethane, and most preferably N,N-dimethylformamide.

In step (vi), the compound of Formula 7 is oxidized, thereby obtaining telaprevir of Formula 1 , or a pharmaceutically acceptable salt or solvate thereof. Regarding the methods and conditions for oxidizing the compound of Formula 7 in order to obtain telaprevir, reference is also made to EP12159923.7 and WO2010/126881.

The oxidizing agent in step (vi) is known to someone skilled in the art, preferably it is selected from the group of hypervalent iodine oxidants, comprising the Dess-Martin periodinane (1 ,1 ,1- Tris(acetyloxy)-1 ,1-dihydro-1 ,2-benziodoxol-3-(1 H)-one) or IBX (2-iodoxybenzoic acid), or sodium hypochlorite in the presence of 2,2,6,6- tetramethylpiperidinyloxy free radical (TEMPO), preferably, the oxidizing agent sodium hypochlorite in the presence of 2,2,6,6- tetramethylpiperidinyloxy free radical (TEMPO). Suitable amounts of oxidizing agent(s) can be chosen by a person skilled in the art of common practice. For example, the oxidizing agent can be used in an amount of 0.9-2 equivalents, preferably, from 0.9 to 1.2 equivalents, based on the total amount of the compound of Formula 7. TEMPO can be used in catalytic amounts. Particular suitable is a combination of a catalytic amount of TEMPO with KBr, NaHC0 ₃ , and NaOCI in dichloromethane. Process steps (v) and (vi) can be carried out as described in EP12159923.7 and WO2010/126881.

Step (vi) can additionally comprise adding compounds such as acids to the reaction mixture to provide pharmaceutically acceptable salts of telaprevir.

Additionally preferred, step (vi) comprises a further step of isolating telaprevir or a pharmaceutically acceptable salt or solvate thereof. Optionally, the obtained telaprevir or its pharmaceutically acceptable salt or solvate is precipitated and for example filtered off, washed with solvent and dried. Prior to isolating the product, a flash chromatography may be applied for purification. It is also preferred to isolate telaprevir, or a pharmaceutically acceptable salt or solvate thereof by crystallization.

In step (vi), telaprevir of Formula 1 , a pharmaceutically acceptable salt or solvate thereof is obtained in amorphous form, crystalline form or as cocrystals.

The present invention also refers to a process for the preparation of a compound of Formula 4

⁴ , wherein F^ is as defined above, for example Ri is a propyl group; and R ₂ is as defined above, for example R ₂ is a hydrogen atom;

comprising the steps of:

i) providing a compound of Formula 2

2 , wherein and R ₂ are as defined above; ii) bringing the compound of Formula 2, into contact with a compound of Formula 3

3 , wherein R ₅ is methyl or ethyl; in the presence of an oxidant, for example hydrogen peroxide, tBuOOH, cumene hydroperoxide, urea-hydrogen peroxide, preferably hydrogen peroxide, thereby obtaining a compound of Formula 4, wherein and R ₂ are as defined above. Step (ii) can be carried out as described in relation to the compound of Formula 2a herein.

The invention also related to a process for the preparation of a compound of Formula 9 or 10

wherein ^ is as defined above, for example R _! is a propyl group; R ₂ is as defined above; for example R ₂ is a hydroxyl group; and R ₃ is hydrogen. The process comprises the steps (a) and

(b):

Step (a) includes providing a compound of Formula 4

4 , wherein Ri and R ₂ are as defined above, by applying any methods for preparing a compound of Formula 4 as described herein. If R ₂ is hydrogen in the compound of Formula 4, the compound of Formula 4 is oxidized to provide Formula 4' wherein R ₂ is hydroxyl.

Step (b) includes subjecting the compound of Formula 4/4' to reaction steps of:

firstly conducting an azidation of the epoxide group of the compound of Formula 4/4' of step (a) thereby obtaining a compound of Formula 9 as defined above; and optionally reducing the resulting azide group to obtain an amine of Formula 10. The azidation and reduction steps can be carried out by using any method as described herein. Compounds of Formula 9 and 10 can be prepared in analogy to the process as described in relation to the compounds of Formula 9a and 10a herein.

For example, step (b) in the afore-mentioned process can be carried out by

ba) bringing the compound of Formula 4/4' into contact with NaN ₃ , Cu(N0 ₃ ) ₂ , H ₂ 0 in order to obtain a compound of Formula 9;

bb) bringing the compound of Formula 4/4' into contact with

(1 ) NaN ₃ , Cu(N0 ₃ ) ₂ , H ₂ 0; and NaBH ₄ , or

(2) NaN ₃ , Cu(N0 ₃ ) ₂ , H ₂ 0; and Pd/C, H ₂ ;

in order to obtain a compound of Formula 10

wherein R ₃ is hydrogen.

The invention also relates to a process for the preparation of a compound of Formula 5

is a propyl group; R ₃ is hydrogen; and R ₄ is as defined above, for example R ₄ is cyclopropyl;

comprising the steps of:

A) (1 ) providing a compound of Formula 9

is a propyl group; and

R ₂ is as defined above, for example R ₂ is a hydroxyl group; wherein the compound of Formula 9 can be prepared by using the methods described herein;

(2) bringing the compound of Formula 9 into contact with cyclopropylamine in the presence of one or more coupling agent with, thereby obtaining a compound of Formula 1 1 wherein is as defined above and R ₄ is as defined above, for example is cyclopropyl,

(3) reducing the azide group, thereby providing a compound of Formula 5 as defined above; or

B) (1 ) providing a compound of Formula 10

is as defined above; for example is a propyl group; R ₂ is as defined above, for example R ₂ is a hydroxyl group; and R ₃ is hydrogen, by applying the process as described herein;

(2) providing a protecting group to the amine of Formula 10, thereby providing a compound of Formula 10', wherein R ₃ is a protective group, preferably a carbamate group, preferably a Boc group;

(3) bringing the compound of Formula 10' into contact with H ₂ NR ₄ , wherein R is as defined above, preferably cyclopropylamine, in the presence of one or more coupling agent with, thereby obtaining a compound of Formula 5'

is as defined above, R ₄ is as defined above, for example cyclopropyl and R ₃ is a protective group;

(4) deprotecting the compound of Formula 5' in order to obtain a compound of Formula 5 wherein R ₃ is hydrogen.

The invention also refers to a process for the preparation of a pharmaceutical composition or pharmaceutical dosage form comprising telaprevir of Formula 1 , or a pharmaceutically acceptable salt or solvate thereof, comprising the process steps as described herein, and further comprising formulating the obtained telaprevir of Formula 1 , or a pharmaceutically acceptable salt or solvate thereof into a pharmaceutical composition or pharmaceutical dosage form.

The preparation comprises the process steps as described above and further comprises formulating the obtained telaprevir of Formula 1 or a pharmaceutically acceptable salt or solvate thereof (the aforementioned compounds may also be referred to as active pharmaceutically compounds, API) into a pharmaceutical composition or pharmaceutical dosage form. The step of formulating the API into a dosage form may be carried out by applying techniques known in the art. For example, the API can be formulated into tablets by using direct compression, dry or wet granulation processes, spray-coating processes or the like. The API may be formulated as an acid solution or as a solid.

The invention also refers to a compound of Formula 5a or a composition comprising a compound of Formula 5a

, wherein a propyl group;

R ₃ is hydrogen; and R ₄ is cyclopropyl; obtainable or obtained by the process described herein, wherein the compound of Formula 5 or the composition comprising a compound of Formula 5a has a metal content such as titanium or ruthenium content of less than 20 ppm.

The invention also refers to telaprevir of Formula 1 or a composition comprising telaprevir of Formula 1

, or a pharmaceutically acceptable salt or solvate thereof, obtainable or obtained by the process as described herein, and having a metal content such as titanium or ruthenium content of less than 20 ppm. Telaprevir of Formula 1 or a pharmaceutically acceptable salt or solvate thereof, which is prepared by using the process described herein has an epimeric impurity which is the same as 6/depends on the purity of 6.

A further aspect relates to telaprevir of Formula 1 , a pharmaceutically acceptable salt or solvate thereof, obtainable or obtained by the process described herein.

Examples

The following examples describe the present invention in detail, but are not to be construed to be in any way limiting for the present invention. In the examples below, the following abbreviations have the following meanings. Any abbreviations not defined have their generally accepted meaning. Unless otherwise stated, all temperatures are in degrees Celsius (°C).

DMF: dimethylformamide; EtOAc: ethyl acetate; DCM/CH ₂ CI ₂ : dichloromethane; TEMPO: (2,2,6,6-Tetramethylpiperidin-1-yl)-oxyl; Eq.: equivalents; TMSOTf: Trimethylsilyl trifluoromethanesulfonate; aliquate 336™: mixture of C8 (octyl) and C10 (decyl) chains (Tricaprylylmethylammonium chloride or Trioctylmethylammonium chloride) with C8 predominating; rt: room temperature; Room temperature is defined herein as a temperature range of 20-25°C; DiPEA: diisopropylethyiamine; TBTU: O-(Benzotriazoi-l-yl)- Ν,Ν,Ν',Ν'- tetramethyluronium tetrafluoroborate; Boc ₂ 0: Di-tert-butyl dicarbonate; CDI: carbonyldiimidazole.

Example 1 - Preparation of the catalyst (S)-2-(diphenyl ((trimethylsilyl)oxy)methyl)pyrrolidine (Compound of Formula 3)

OSi(R ₅ ) ₃

3 R ₅ = e Triethylamine (715 μΙ_, 5.13 mmol) was added to a solution of (S)-(-)-a,a-Diphenyl-2- pyrrolidinemethanol (1 g, 3.95 mmol) in CH ₂ CI ₂ (20 mL) at 0°C under N ₂ , followed by TMSOTf (928 μΐ_, 5.13 mmol). After 1 h, water was added, the layers were separated and the aqueous layer was extracted with CH ₂ CI ₂ (3x 20mL). The combined organic layers were dried over MgS0 ₄ , filtered and the solvent was removed under reduced pressure. Purification by column chromatography (silicagel, cyclohexan: EtOAc 3:1→1 :1 ) gave 1.22g (93%yield).

1H NMR (500MHz, CDCI ₃ ): δ = 7.45 (m, 2H), 7.35 (m, 2H), 7.29-7.23 (m, H), 7.21 (m, 2H), 4.03 (t, J = 7.40Hz, 1 H), 2.85 (m, 1 H), 2.80 (m, 1 H), 1.64 (bs, 1 H), 1.61-1.52 (m, 3H), 1.37 (m, 1 H), 0.09 (s, 9H). ,3R)-3-propyloxirane-2-carbaldehyde (Compound of Formula 4a) To a solution of (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (700 mg, 2.15 mmol) in CH ₂ CI ₂ (44 mL) was added trans-hexenal (compound of Formula 2a, 2.49 mL, 21.5 mmol), followed by the slow addition of hydrogenperoxide (1.75 mL, 50% aq., 25.8 mmol). The reaction mixture was stirred over night at ambient temperature, then filtered over a silicagel plug with the help of pentane:diethyl ether (3:1 ) and the solvent was removed under reduced pressure.

1H NMR (500MHz, CDCI ₃ ): δ =9.01 (d, J = 6.30Hz, 1 H), 3.23 (ddd, J = 6.11 , 4.94, 1.81 Hz, 1 H), 3.16 (dd, J = 6.30, 1.90Hz, 1 H), 1.65 (m, 2H), 1.52 (m, 2H), 0.98 (t, J = 7.43Hz, 3H). ,3R)-3-propyloxirane-2-carboxylic acid (Compound of Formula 4'a)

4'a

To a solution of (2S,3R)-3-propyloxirane-2-carbaldehyde (3.5g, 30.66 mmol) in CH ₂ CI ₂ (56 mL) at 0°C was added TEMPO (48 mg, 0.31 mmol), KBr (4.3 mL, 0.75M in water, 0.31 mmol) and aliquate 336 (700 pL, 1.55 mmol). Aqueous sodium hypochlorite (26 mL, 0.80M, 20.8 mmol) was brought to pH 9 with sodium bicarbonate and added dropwise by addition funnel without exceeding an internal temperature of 10 °C. After addition was completed, the reaction mixture brought to rt and stirred for additional 2h. pH was adjusted to 12 with 1 M NaOH and the layers were separated. The organic layer was washed with 1 M NaOH (20 mL). The aqueous layers were combined, pH adjusted to pH <2 with 6M HCI, and extracted with CH ₂ CI ₂ . The combined extracts were dried over Na ₂ S0 ₄ and the solvent was removed under reduced pressure to give 1.8 g of the epoxyacid. ¹ H NMR (500MHz, CDCI ₃ ): δ = 10.17 (bs, 1 H), 3.25 (d, J = 1.9Hz, 1 H), 3.20 (ddd, J = 6.23, 4.65, 1.65Hz, 1 H), 1.68-1.58 (m, 2H), 1.54-1.46 (m, 2H), 0.97 (t, J = 7.25Hz, 3H)

¹³ C N R (125MHz, CDCI ₃ ): δ = 174.94, 58.89, 52.46, 33.35, 18.99, 13.68. Example 4 - (2S,3S)-3-azido-2-hydroxyhexanoic acid (Compound of Formula 9a)

To (2S,3R)-3-propyloxirane-2-carboxylic acid (compound of Formula 4'a, 1.31g, 10.1 mmol) in water (10 mL) was added NaN3 (982 mg, 15.1 mmol) and a 0.1 M Cu(N0 ₃ ) ₂ solution (9.9 ml_, 1 mmol). The reaction mixture was heated at 65 °C for 1.5h. After cooling to rt the pH was adjusted to pH 2 with HCI. Purification by RP column chromatography (RP 18, H ₂ 0 with 1 %MeOH to 100% MeOH) was followed by column chromatography (silicagel, heptane: EtOAc 2:1 with 0.5%AcOH) gave 533 mg (31 % yield).

¹ H NMR (500MHz, CDCI ₃ ): δ = 4.43 (d, J = 3.15Hz, 1 H), 3.65 (dt, J = 10.08, 3.47Hz, 1 H), 1.75 (m, 1 H), 1.60-1.48 (m, 2H), 1.43 (m, 1 H), 0.97 (t, J = 7.10Hz, 3H)

1 ³ C NMR (125MHz, CDCI ₃ ): δ = 176.37, 73.32, 64.34, 31.14, 19.60, 13.65.

Example 5 - (2S,3S)-3-azido-N-cyclopropyl-2-hydroxyhexanamide (Compound of Formula

To (2S,3S)-3-azido-2-hydroxyhexanoic acid (compound of Formula 9a, 954 mg, 5.51 mmol) in CH ₂ CI ₂ (30 mL) at 0°C was added DIPEA (2.83 mL, 13.9 mmol), cyclopropylamine (420 μΐ_, 6.06 mmol) and TBTU (1.85 g, 5.78 mmol). After addition the reaction mixture was stirred for 18 h at rt. Water was added and the aqueous layer was extracted with CH ₂ CI ₂ the combined organic layers were dried with MgS0 ₄ and the solvent removed under reduced pressure. Purification by column chromatography (silicagel, heptane: EtOAc 2:1 ) gave 80 mg of crystalline amide.

¹ H NMR (500MHz, CDCI ₃ ): δ = 6.71 (bs, 1 H), 4.21 (t, J = 4.42Hz, 1 H), 3.69 (dt, J = 9.75, 3.62Hz, 1 H), 3.28 (d, J = 4.73Hz, 1 H), 2.74 (m, 1 H), 1.61 (m, 1 H), 1.53 (m, 1 H), 1.48-1.36 (m, 2H), 0.94 (t, J = 7.25Hz, 3H), 0.81 (m, 2H), 0.53 (m, 2H)

1 ³ C NMR (125MHz, CDCI ₃ ): δ = 171.81 , 73.82, 64.50, 30.44, 22.26, 19.40, 13.76, 6.49, 6.43 Example 6 - (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (compound of Formula

To (2S,3S)-3-azido-N-cyclopropyl-2-hydroxyhexanamide (compound of Formula 1 1a, 78 mg, 0.370 mmol) in water (10 mL) was added Pd/C (40 mg, 10%Pd on C, 0.037 mmol) and the mixture was stirred under H ₂ atmosphere for 2 h. The catalyst was filtered off over celite and lyophilisation gave 5a.

¹ H NMR (500MHz, CDCI ₃ ): δ = 7.50 (bs, 1 H), 3.89 (d, J = 5.05Hz, 1 H), 3.09 (bs, 1 H), 2.73 (m, 1 H), 1.53-1.41 (m, 2H), 1.33-1.24 (m, 2H), 0.92 (t, J = 7.08Hz, 3H), 0.77 (m, 2H), 0.51 (m, 2H) ¹³ C NMR (125MHz, CDCI ₃ ): δ = 173.87, 73.65, 53.49, 33.91 , 22.05, 19.07, 13.94, 6.37, 6.25.

Example 7 - (2S,3S)-3-amino-2-hydroxyhexanoic acid (compound of Formula 10a)

To (2S,3R)-3-propyloxirane-2-carboxylic acid (compound of Formula 4'a, 1.8g, 13.8 mmol) in water (13 mL) was added NaN ₃ (1.33g, 20.5 mmol) and a 0.1 M Cu(N0 ₃ ) ₂ solution (13 mL, 1.3 mmol). The reaction mixture was heated at 65°C for 1 h. After cooling to 0°C NaBH ₄ (1g, 26.4 mmol) was added in small portions and stirred for 1 h. The reaction was brought to rt and the pH was adjusted to pH 2 with HCI. Purification with ion-exchange resin DOWEX 50W8-400 prepacked with 0.1 M HCI, gave after eluting with 0.1 M NH ₄ OH and lyophilisation 100mg of the amino acid.

¹ H NMR (500MHz, D ₂ 0): δ = 3.96 (d, J = 3.45Hz, 1 H), 2.97 (m, 1 H), 1.43 (m, 1 H), 1.29 (m, 3H), 0.86 (t, J = 7.10Hz, 3H)

¹³ C NMR (125MHz, D ₂ 0): δ = 179.37, 76.65, 52.91 , 32.99, 32.99, 18.94, 13.32. Example 8 - tert-butyl ((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)carbama te

3-amino-2-hydroxyhexanoic acid (compound of Formula 10a) was dissolved in 1 M NaOH (10mL) and a solution of Boc ₂ 0 (1.7g, 8mmol) in dioxane (10mL) was added. After 3.5h at rt, water was added and the aqueous layer extracted with Et ₂ 0. The pH of the aqueous layer was adjusted to pH 2 with 2M HCI and extracted with Et ₂ 0. The combined ethereal layers were dried over Na ₂ S0 ₄ and the solvent was removed under reduced pressure.

The crude Boc protected acid was dissolved in DMF (10ml_) and a solution of CDI (1.2g, 7.4 mmol) in DMF (10mL) was added at rt. The mixture was stirred for 1.5h then cyclopropylamine (0.5 mL, 7 mmol) was added. As conversion was not completed after 6h an additional amount of CDI (0.5g, 3mmol) and cyclopropylamine (0.3 mL, 4.2mmol) and stirring was continued for 72h. The reaction was quenched by the addition of an aqueous K ₂ C0 ₃ solution (6g/100mL) and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na ₂ S0 ₄ . The solvent removed under reduced pressure. Purification by column chromatography (silicagel, heptane: EtOAc 3:2) gave 280 mg of amide.

Cited literature

EP 2039689 A1 ;

WO 2007/022459 A2;

WO 2007/109023 A1 ;

WO 2008/029267 A2;

WO 2009/152474 A2;

WO 2010/126881 A2;

Bondzic et al. "Asymmetric epoxidation of a-substituted acroleins catalyzed by diphenylprolinol silyl ether" (Org. Lett., Vol. No. 23, 2010, 5434-5437);

T. W. Greene & P.G.M Wuts, "Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons, Inc. (2006); 701-802;

Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447-2467;

Harbeson et al. "Stereospecific synthesis of peptidyl a-keto amides as inhibitors of calpain" (J. Med. Chem. 1994, 37, 2918-2929);

Jorgensen "Asymmetric organocatalytic epoxidation of α,β-unsaturated aldehydes with hydrogen peroxide" (Journal of the American Chemical Society 2005, 27, 6964).