Patent description

Field of the invention

The object of the present invention is a process for the preparation of l-(4-methoxyphi oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridine-3- carboxylic acid amide of formu

as well as the intermediates used in the process. The state of the art

The apixaban of formula 1 is a pharmaceutical active ingredient having an acticoagulant mechanism of action of factor Xa inhibitor, and the product prepared of it is marketed under the tradename of ELIQUIS.

In the international patent application no. WO2003026652 describing the lactam-containing fac- tor Xa inhibitors and their process of preparation the key step of the synthesis leading to l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6 ,7-tetrahydro-lH- pyrazolo[3,4-c]pyridine-3-carboxylic acid ester of formula llai - which can be considered as precursor of apixaban - (the later shown compound 11a, in the case where R represents ethyl)

llai is the cycloaddition reaction of the iodophenyl derivative of formula 2 as shown on Figure 1

with the corresponding ethyl-(2£')-chloro[(4-methoxyphenyl)hydrazono] acetate of formula 3a.

Et0 ₂ C^ ^CI

OMe

3a

The morpholine unit containing intermediate compound obtained from the cycloaddition reaction is to be decomposed in a separate step, requiring the use of another reagent and solvent. The further reaction of the obtained organic ester of formula 4

with the valerolactam of formula 5

5 takes place with difficulty, and requires moreover a highly toxic solvent - dimethyl sulfoxide (DMSO) - and copper(I)iodide catalyst. The yields during the two steps are small (18, respectively 21%). According to the international patent application WO 2003049681 and shown on Figure 2 during the synthesis leading to the ester of formula llai the cycloaddition step with ethyl-(2£)- chloro[(4-methoxyphenyl)hydrazono] acetate of formula 3a is carried out at an earlier stage of the synthesis. The further reaction with the corresponding iodo-derivative of formula 6

6

is cumbersome, high temperature, toxic solvents - dichloromethane (DCM), respectively DMSO - are required which are unfavourable from the technological point of view.

According to the process of the same international patent application WO 2003049681 and shown on Figure 3 the morpholino-dilactam compound of formula 7 to be used for the cycload- dition

7

is produced using a series of inconvenient, cumbersome steps. The morpholine part of the molecule is first to be inserted into the molecule, then, after the cycloaddition, it has to be removed again. The reaction of the iodophenyl derivative of formula 2 with the valerolactam of formula 5 is expensive and requires toxic reagents - copper reagent, respectively caesium carbonate - so it is not advantageous for technological point of view.

According to the process described in the international patent application WO 2007001385 and shown on Figure 4 the key compound of the cycloaddition step is the nitrophenyl lactam of formula 8.

The further reaction steps (reduction, acylation, cyclization) are chemically not advantageous, the chloroacyl-amide cyclization requires drastic conditions, the removal of the so formed contaminants is difficult from the obtained ester of formula 9,

100

respectively from the end product apixaban of formula 1

A different approach is used in the international patent application WO 2012168364. In cycload dition step of the synthesis shown on Figure 5 the unsaturated alcohol derivative of formula 10 wherein Q represents SiMe ₃ or /?-toluenesulfonyl -

10

115

is applied, but the obtained ester of formula 4 - similarly to the methods mentioned above - can be converted with difficulty to the l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl) phe- nyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxy lic acid ester of formula 11a, which can be considered as the precursor of apixaban

120

125 11a

- wherein R represents a linear or branched substituted or unsubstituted Ci-Cs alkyl group, C3-C8 cycloalkyl, or substituted or unsubstituted aralkyl group.

130

The short summary of the invention

At the development of the process of the invention our aim was to elaborate a new process for the synthesis of apixaban of formula 1 which is feasible in a simpler and in a more economical 135 way compared to the earlier methods, gives higher overall yield, realized without toxic reagents and without drastic reaction conditions, passing through crystallized, well purifiable intermediate compounds, resulting in an easily isolable final product and realizable also in an industrial scale.

The object of the invention is a process for the preparation of l-(4-methoxyphenyl)-7-oxo-6-[4- 140 (2-oxopiperidin- l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3 -carboxylic acid amide of formula 1 (apixaban). The process is characterized in that a) the compound 3-chloro-l-[4-(2-oxopiperidin- l-yl) phenyl]-5,6-dihydropyridin-2(lH)-one of formula 12

145

is reacted in a solution or without use of solvent, preferably in basic medium with the methoxy- phenyl-hydrazone derivative of the general formula 3,

3

- wherein R represents a linear or branched chain substituted or unsubstituted Ci-Cs alkyl group, C3-C8 cycloalkyl, respectively substituted or unsubstituted aralkyl group, Z is halogen atom or R'-SC -O-group, preferably chlorine; R' represents a substituted or unsubstituted aryl group, respectively linear or branched chain substituted or unsubstituted Ci-Cs alkyl group, substituted or unsubstituted C3-C8 cycloalkyl group, respectively substituted or unsubstituted aralkyl group; or b) - in a first step, from the compound 3,3-dichloro- l-[4-(2-oxopiperidin-l-yl) phe- nyl]piperidine-2-one of formula 13

in solvent or without it, with the use of a basic reagent or without reagent, only with heating the compound 12 is obtained,

- in a second step, the obtained compound 12, in a solution or without the use of solvent, preferably in basic medium is reacted with the compound of the general formula 3 - wherein R and Z represent as described above - ; or c) - in a first step, from the 5-substituted N-[4-(3,3-dichloro-2-oxopiperidin-l-yl) phe- nyl]valeroyl amide of formula 14 - wherein W represents O-methanesulfonyl (OMs), O-p- toluenesulfonyl (OTs), CI, Br or I -

14 in a solvent with the use of a base the compound 13 is obtained,

- in a second step, from the obtained compound 13, in a solvent or without it, with the use of a basic reagent or without reagent, only with heating the compound 12 is obtained,

- in a third step, the obtained compound of formula 12, in a solution or without the use of sol- vent, preferably in basic medium is reacted with the compound of the general formula 3 - wherein R and Z represent as described above - ; or d) - in a first step, the co-substituted N-[4-(2-oxopiperidin-l-yl)phenyl]-valeroyl amide of formula 15 - wherein W represents as defined above -

15 is reacted in a solvent, with phosphorus pentachloride or with a mixture of phosphoryl chloride and phosphorus pentachloride, and then, if desired, the compound 14 is isolated, optionally purified by suspending in a solvent or by recrystallization.

- in a second step, from the resulted compound 14, in solvent, by applying a base the compound 13 is obtained,

- in a third step, from the obtained compound 13, in a solvent or without it, with the use of a basic reagent or without reagent, only with heating the compound 12 is obtained, - in a fourth step, the obtained compound of formula 12, in a solution or without use of solvent, preferably in basic medium is reacted with the compound of the general formula 3 - wherein R and Z represent as above - ; or e) - in a first step, by acylation of the solution or suspension of the l-(4-aminophenyl)-2- piperidinone of formula 16

16

with a 5-substituted valeric acid derivative of formula 18 - wherein W represents as above; L represents CI, Br or I -

18

in the presence of a base the compound of formula 15 is prepared,

- in a second step, the obtained compound 15 is reacted in a solvent, with phosphorus pentachlo- ride or with a mixture of phosphoryl chloride and phosphorus pentachloride, and then, if desired, the compound 14 is isolated, optionally purified by suspending in a solvent or by recrystalliza- tion,

- in a third step, from the resulting compound 14 in solvent, by applying a base the compound 13 is obtained,

- in a fourth step, from the obtained compound 13, in a solvent or without it, with the use of a basic reagent or without reagent, only with heating the compound 12 is obtained,

- in a fifth step, the obtained compound of formula 12, in a solution or without using solvent, preferably in basic medium is reacted with the compound of the general formula 3 - wherein R and Z represent as above -, then the ester 11a obtained as a result from the above process variants a), b), c), d) or e) is purified, if desired, by known process, or the ester 11a is converted into a salt of formula lib lib

- wherein M represents any metal ion, ammonium ion, or mono-, di-, or tri-Ci-Cs alkyl substituted ammonium ion - or into a carboxylic acid of formula 11c

11c

and followed by this conversion, if desired, the so obtained compound lib or 11c is purified and the purified compound 11a, lib, or 11c is converted to apixaban 1.

In a preferred embodiment of the process according to the invention, the reaction of compounds of formula 12 and 3 is carried out

- in basic medium, where the base applied is advantageously triethylamine,

- without use of solvent, or

- in solvent, where the solvent used is preferably 1 -butanol, ethyl acetate, dichloromethane, water or the mixture of at least two or more of these.

In another preferred embodiment of the process according to the invention the preparation of the compound of formula 12 from the compound 3,3-dichloro-l-[4-(2-oxopiperidin-l-yl) phe- nyl]piperidin-2-one of formula 13 is carried out

- using a basic reagent, which basic reagent is preferably lithium carbonate, in a solvent, wherein the solvent used is preferably N,N-dimethylacetamide; or

- without the use of reagents, only by heating, in a so-called thermic reaction. In a further preferred embodiment of the process according to the invention the preparation of the compound of formula 13 from the 5-substituted compound N-[4-(3,3-dichloro-2- oxopiperidin- l-yl)phenyl]valeroyl amide of formula 14 is carried out

- in a solvent, which solvent is preferably ethanol,

- by applying a base, which base is preferably potassium carbonate.

In a further preferred embodiment of the process according to the invention the preparation of the compound of formula 14 is carried out with the chlorination of the co-substituted N-[4-(2- oxopiperidin- l-yl)phenyl]-valeroyl amide compound of formula 15 with phosphorus pentachlo- ride or with a mixture of phosphoryl chloride and phosphorus pentachloride, in a solvent - which solvent is preferably dichloromethane.

In a further preferred embodiment of the process according to the invention the compound of formula 15 is prepared by acylation of l-(4-aminophenyl)-2-piperidinone of formula 16 with a 5- substituted valeric acid derivative of formula 18 in such a way that the solution or suspension of the compound 16 is reacted in the presence of a base with the 5-substituted valeric acid derivative 18 - wherein W represents O-methanesulfonyl (OMs), O-^-toulenesulfonyl (OTs), CI, Br or I; L represents CI, Br or I -, the solvent used in the acylation reaction is preferably dichloromethane or ethyl acetate, the base is preferably triethylamine. Further the object of the invention is the l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-c arboxylic acid sodium salt of formula lib - wherein M represents sodium - and its solvates.

Further the object of the invention is the hydrate of the sodium salt of formula lib formed with 0-5 moles of water.

Further the object of the invention is the sodium salt tetrahydrate of the l-(4-methoxyphenyl)-7- oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridine-3- carboxylic acid of formula lib.

Further the object of the invention is the sodium salt tetrahydrate of the l-(4-methoxyphenyl)-7- oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridine-3- carboxylic acid of formula lib which shows an X-ray powder diffraction pattern having the following characteristic peaks - measured with CuKai beams - at reflection angle °2Θ (±0,2 °2Θ): 14.95; 17.43; 21.59; 22,02.

Further the object of the invention is the sodium salt tetrahydrate of the l-(4-methoxyphenyl)-7- oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridine-3- carboxylic acid of formula lib which shows an X-ray powder diffraction pattern having the following characteristic peaks - measured with CuKai beams - at reflection angle 2Θ (±0,2 °2Θ) of 10.99; 12.68; 14.62; 14.95; 17.43; 19.61; 20.97; 21.59; 22.02; 23;51 ; 25.11 ; 25,66.

Further the object of the invention is the compound 3-chloro-l-[4-(2-oxopiperidin-l-yl)phenyl]- 5,6-dihydropyridin-2(lH)-one of formula 12.

Further the object of the invention is the 3,3-dichloro- l-[4-(2-oxopiperidin-l- yl)phenyl]piperidine-2-one compound of formula 13. Further the object of the invention is the 5-substituted N-[4-(3,3-dichloro-2-oxopiperidin- l- yl)phenyl]valeroyl amide of formula 14 - wherein W represents O-methanesulfonyl (OMs), O-p- toluenesulfonyl (OTs), CI, Br or I.

Further the object of the invention is the co-substituted N-[4-(2-oxopiperidin- l-yl)phenyl]valeroyl amide of formula 15 - wherein W represents O-methanesulfonyl (OMs), 0-/?-toluenesulfonyl (OTs), CI, Br or I.

Surprisingly, during the development of the process according to the invention we found that, if within the above described reaction conditions, with the use of the above mentioned reagents the following synthesis sequence - its process shown on Figure 6. - is realized then the objective set can be achieved:

In the first step of the process, by the acylation of the l -(4-aminophenyl)-2-piperidinone of formula 16 with the 5-substituted valeric acid derivative of formula 18 - wherein W represents O- methanesulfonyl (OMs), O-jo-toluenesulfonyl (OTs), CI, Br or I; L is CI, Br or I - the co- of formula 15 - wherein W repreinone of formula 16 is for example

17

In the second step of the process the compound of formula 15 is reacted in a solvent of a temperature ranged between 0° C and the boiling point of the particular solvent, preferably between 20- 40° C with phosphorus pentachloride or with a mixture of phosphoryl chloride and phosphorus pentachloride to obtain the 5-substituted N-[4-(3,3-dichloro-2-oxopiperidin- l-yl)phenyl]valeroyl amide of formula 14 - wherein W represents as above.

In the third step of the process, from the compound of formula 14 in solvent, at a temperature between 30-70° C, preferably 40-60° C, most preferably between 50-55° C, using a base the compound 3,3-dichloro- l-[4-(2-oxopiperidin-l-yl)phenyl]piperidin-2-one of formula 13 is obtained.

In the fourth step of the process from the compound of formula 13 in solvent or without it, at a temperature between 20-150° C, using a basic reagent the compound 3-chloro- l-[4-(2- oxopiperidin- l-yl)phenyl]-5,6-dihydropyridin-2(lH)-one of formula 12 is obtained.

In the fifth step of the process the cycloaddition reaction of the compound of formula 12 and of the methoxyphenyl-hydrazone derivative of general formula 3 - wherein R represents a linear or branched substituted or unsubstituted Ci-Cs alkyl group, C ₃ -Cs cycloalkyl, or substituted or un- substituted aralkyl group; Z represents halogen atom or R'-S02-0- group, preferably chlorine; R' represents a substituted or unsubstituted aryl group, respectively linear or branched chain substituted or unsubstituted Ci-Cg alkyl group, substituted or unsubstituted C ₃ -Cs cycloalkyl group, respectively substituted or unsubstituted aralkyl group, and as the result of this reaction the product of formula 11a considered as the precursor of apixaban is obtained, from which the com- pound apixaban of formula 1 is produced in one or more steps.

For example, the apixaban of formula 1 is prepared from the ester of formula 11a in one step by converting the ester of formula 11a with formamide in a known manner to an amide, i.e. apixaban of formula 1.

In case of a multi-step method, for example, the ester of formula 11a is hydrolysed to give the salt of formula lib - wherein M represents any metal ion, ammonium ion, or group mono-, di- or tri-Ci-Cs-alkyl-substituted ammonium ion, - and then, if desired, from the salt of formula lib the acid of formula 11c is liberated and this latter is converted to an amide, i.e. apixaban of formula 1.

Before further processing the compounds 11a, lib, 11c are purified, if desired.

Detailed description of the invention

The compounds 12, 13, 14 and 15 are not known in the literature.

In our work we found that the ester of formula 11a may easily be prepared with the cycloaddi- tion reaction of compounds 12 and 3 as shown in Figure 6, and the cycloaddition step takes place surprisingly with full regioselectivity. The obtained 11a hydrolysable ester can in situ be hydrolysed to give the salt of formula lib - wherein M represents any metal ion, ammonium ion, or mono-, di- or tri-Ci-Cg alkyl substituted ammonium group -, respectively to give the acid of formula 11c which largely facilitates the easy isolation of the substance. The compounds lib and 11c are in fact crystalline compounds, so they can be separated from the side products of the cycloaddition reaction, i.e. the contaminants of the product by a simple filtration. The compounds of the general formula 11 - wherein Y is COOR or COOM, COOH (where R and M represent as above) -

11

can in turn be converted using known methods to the desired apixaban compound of formula 1. An object of our invention is the preparation of the ester of formula 11a. In our process the compound of formula 12 is reacted in solution or without use of a solvent, preferably in basic medium, at a temperature between 0 and 120° C, preferably between 40 and 85° C with the compound of formula 3, where in the formula 3 the meaning of R represents as above and Z is halogen atom or R'-SC -O- group, preferably chlorine; R' represents a substituted or unsubstituted aryl group, respectively linear or branched chain substituted or unsubstituted Ci- Cs alkyl group, substituted or unsubstituted C3-C8 cycloalkyl group, respectively substituted or unsubstituted aralkyl group.

The solvent used may be an alcohol containing a Ci-Cs linear or branched chain alkyl, cycloalkyl, aralkyl group, preferably a C1-C6 aliphatic alcohol, more preferably a C2-C4 alcohol, most preferably 1-butanol. Suitable solvents in the cycloaddition reaction are further the esters of Ci- C ₄ carboxylic acids formed with C1-C4 alcohols, preferably ethyl, propyl or butyl acetate, most preferably ethyl acetate. Suitable solvents are further the NN-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dioxane, dichloromethane, chloroform and water, or a mixture of two or more of the above solvents.

Base applied in the cycloaddition reaction may be an inorganic or organic base. The inorganic base may be an alkali metal carbonate, hydroxide, alkoxide, or hydride, preferably sodium or potassium carbonate, hydroxide or hydride, and alkaline earth metal carbonate, hydroxide or hydride, preferably calcium hydroxide or calcium hydride. Organic bases may be aliphatic or cyclic tertiary amines, preferably triethylamine. A further object of our invention is the preparation of the salt of formula lib.

In the cycloaddition reaction first the directly obtained product 11a was isolated from the reaction mixture. The primary product 11a was preferably in situ further reacted and the secondary product, the lib salt obtained from the reaction was isolated. The lib salt may be for example lithium, sodium, potassium or caesium salt, ammonium salt or alkaline earth metal salt, preferably sodium salt - in this case, M represents sodium. During our work we found that the sodium salt is a well-crystallizing substance, which allows the recovery of the product by simple filtration. As a result, the isolation of the compound of general formula 11 can be efficiently solved with less solvent used. During our work we found that the above lib salts are new. The second- ary product may also be an 11c carboxylic acid, having similarly advantageous properties.

A further object of our invention are the unsolvated respectively solvated forms of the salts of formula lib. Further the invention relates to the lib sodium salt - in this case, M represents sodium - and more particularly the hydrate of the lib sodium salt formed with 0-5 moles of water.

Further the invention relates to the lib sodium salt tetrahydrate. Further the invention relates to the sodium salt tetrahydrate of the l-(4-methoxyphenyl)-7-oxo-6- [4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazo lo[3,4-c]pyridine-3-carboxylic acid of formula lib characterizable with the powder diffractogram according to Figure 7 and detailed in table 1, which shows an X-ray powder diffraction pattern having the following characteristic peaks - measured with CuKai beams - at reflection angle °2Θ (±0,2 °2Θ): 10.99; 12.68; 14.62; 14.95; 17.43; 19.61 ; 20.97; 21.59; 22.02; 23;51; 25.11; 25.66; and its most characteristic X-ray powder diffraction peaks are the followings: °2Θ (±0,2 °2Θ): 14,95; 17.43; 21.59; 22,02. Table 1

The position of the X-ray powder diffraction peaks characteristic for the sodium salt tet- rahydrate compound lib and the relative intensities (relative intensity >2%)

Relative inten¬

Peak 2Θ (°) d (A)

sity (%)

1 10.99 8.05 25

2 12.68 6.98 29

3 14.62 6.05 19

4 14.95 5.92 100

5 17.43 5.08 37

6 17.91 4.95 9

7 18.22 4.87 2

8 18.90 4.69 3

9 19.61 4.52 25

10 20.97 4.23 24

11 21.59 4.11 88

12 22.02 4.03 53

13 22.82 3.89 8

14 23.51 3.78 23

15 24.55 3.62 9

16 25.11 3.54 20

17 25.66 3.47 17

18 26.68 3.34 11

19 27.72 3.22 7

20 28.19 3.16 7

21 29.14 3.06 9

22 30.11 2.97 13

23 30.78 2.90 6

24 31.02 2.88 6

25 31.63 2.83 3

26 31.86 2.81 4

27 32.13 2.78 9

28 32.32 2.77 13 29 33.23 2.69 5

30 34.02 2.63 3

The X-ray diffraction data were obtained with the following measurement conditions:

Equipment: Bruker D8 Advance X-ray diffractometer

Radiation: CuKai ( λ=1.54060 A), CuK ₂ (λ^ 1.54439 A)

Accelerating voltage: 40 kV

Anode heating current: 40 mA

Equipment: Gobel-mirror (the optical structure generating the parallel beams), 9-position sample changer, transmission measurement arrangement

Detector: Bruker LynxEye line detector

Soller: 2.5°

Slits: Source side: 0.6 mm divergence slit

Diffracted side: 8 mm inlet slit

Measuring range: continuous Θ/Θ scan, 4-35°2θ

Time of a single step: 1.2 s

Step interval: 0.02°2Θ

Sample Preparation: unpowdered sample placed between Mylar foils, measured at room temperature

Sample rotation speed: 0.5 round/second

Number of measuring cycles: 1

Measurement time: 35 minutes

Figure 8 shows the thermogravimetric curve of the sodium salt tetrahydrate of the l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6 ,7-tetrahydro-lH-pyrazolo[3,4- c] pyridine- 3 -carboxylic acid of formula lib. The thermogravimetric figure clearly shows that the sample's mass is loss 12.9% when heated up to 200° C, which corresponds to the theoretical water content (12.99%) of tetrahydrate compound of formula lib. No other thermic process can be perceived on the curve.

The thermogravimetric measurement conditions were as follows:

Equipment: Perkin Elmer Pyris 1 TGA thermogravimetric analyzer Atmosphere: N ₂ stream (20 ml/min)

Temperature 25° C - 350° C 10° C/min heating rate

Sample pan: platinum

A further object of our invention is the preparation of the acid of formula 11c.

In the course of our work preferably the secondary product lib was isolated, then in the next step the preparation of the acid 11c took place, thereby the purity of our product was further increased. In the course of the preparation of the 11c acid the lib salt was reacted in solvent with the corresponding acid and the so obtained acid was isolated by filtration. The solvent used was water or a mixture of water and one additional solvent. Further applicable solvents are Ci-C ₆ alcohols such as ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol or pentanol, pref- erably 1-butanol; esters of these alcohols formed with Ci-C ₆ acids such as ethyl acetate, propyl acetate, butyl acetate, preferably butyl acetate; as well as tetrahydrofuran, dioxane, acetone, acetonitrile, formamide, NN-dimethylformamide and N,N-dimethylacetamide. The used acid is inorganic or organic acid. Among inorganic acids, for example aqueous hydrochloric acid, sulfuric or phosphoric acid, preferably aqueous hydrochloric acid was used. The organic acid used was for example formic acid, acetic acid, chloroacetic acid, propionic acid, preferably acetic acid.

The obtained acid 11c, when needed, can be purified by recrystallization or by suspending it in a solvent. Suitable solvents include for example dimethylformamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, Ci-Cs alcohols, water, acetonitrile, acetone, or any mixtures of these, more preferably alkoxy-alcohols, NN-dimethylacetamide and water, and mixtures thereof in any composition.

Further objects of our invention are the compound 3-chloro-l-[4-(2-oxopiperidin-l-yl)phenyl]- 5,6-dihydropyridin-2 (lH)-one of formula 12 - which is the key compound of the preparation of the compounds of general formula 11 -, and the preparation of the compound 12 from the compound 3,3-dichloro-l-[4-(2-oxopiperidin-l-yl)phenyl]piperidin-2-on e of formula 13. According to our process the compound of formula 12 is obtained from the compound of formula 13 in solvent or without it, with the use of a basic reagent at a temperature between 20-150° C, preferably 80-130° C, most preferably between 115-125° C. The reaction can also be induced without reagent in a so called thermic reaction, only by heating.

The solvent used is a polar aprotic solvent such as NN-dimethylacetamide, NN- dimethylformamide, acetonitrile and polar protic solvents such as Ci-Cs alcohols, water or a mixture thereof in any ratio, preferably NN-dimethylacetamide.

The basic reagent is an alkali metal carbonate, bicarbonate, hydroxide or hydride, wherein the alkali metal is lithium, sodium, potassium or caesium, preferably lithium. Moreover, suitable reagents are alkaline earth metal hydroxide, carbonate or hydride, too. The most preferred base used in our process is lithium carbonate.

The compound 12 can easily be prepared from the compound 13 also in industrial setting.

Further our invention relates to the compound 3,3-dichloro-l-[4-(2-oxopiperidin-l- yl)phenyl]piperidine-2-one of formula 13 as well as its preparation from the 5-substituted N-[4- (3,3-dichloro-2-oxopiperidin-l-yl)phenyl]valeroyl amide of formula 14.

Based on a further essential element of our invention the simple access to the compound 13 was allowed by our surprising observation, that during the chlorination of the compound 15 the alicy- clic moiety of the molecule reacts selectively, to yield the pure compound 14 which, in solvent, at a temperature between 30-70° C, preferably 40-60° C, most preferably between 50-55° C provides the compound 13.

The compound 13 can easily be obtained clean also in plant scale from the compound 14. The solvents preferably used during our process were Ci-Cs-alcohols, acetonitrile, tetrahydrofuran, dioxane, acetone, NN-dimethylformamide, NN-dimethylacetamide, water, or any mixture thereof, more preferably methanol, ethanol, isopropyl alcohol, 1-butanol, or any mixture thereof, most preferably ethanol. The base used in our process is preferably an alkali metal carbonate, bicarbonate, hydroxide, hydride, respectively alkaline earth metal hydroxide or hydride, most prefera- bly potassium carbonate.

Further objects of our invention are the compound 14 and its preparation from the compound 15. In our work we have surprisingly found that in the course of the chlorination the compound 15 with phosphorus pentachloride the cyclic moiety reacts selectively, thus allowing the preparation of the compound 13. It has been further observed that in addition to simultaneous use with phos- phoryl chloride and phosphorus pentachloride a particularly good selectivity can be achieved. In our procedure the compound 15 is reacted with phosphorus pentachloride or phosphoryl chloride, then with phosphorus pentachloride in solvent, at a temperature range between 0° C and the boiling point of the given solvent, preferably between 20-40° C, then the compound 14 is isolat- ed, and, if necessary, purified by suspending it in a solvent or by recrystallization.

The solvent used in our process is for example carbon tetrachloride, chloroform, dichloro- methane, 1 ,2-dichloroethane, 1 ,2,2-trichloroethane, preferably chloroform, dichloromethane, 1 ,2- dichloroethane, most preferably dichloromethane. The solvent used to clean the product may be acetone, ethyl methyl ketone, 2-pentanone, 3-pentanone, Ci-C6-alcohols, the esters of these formed with Ci-C ₆ organic acid, the solvent used in the purification may be acetonitrile, tetrahy- drofuran, dioxane, or a mixture thereof in any ratio, more preferably ethyl methyl ketone, butyl acetate, or mixture thereof. Further our invention relates to the compound 15 and its preparation from the compound 16.

The compound 15 is prepared from the compound 16 obtained by reduction using known method from the commercially available compound 17, and in a manner that the compound 16 is acylat- ed with the compound 18. In the course of our acylation process the solution or suspension of the compound 16 is reacted in the presence of a base with the 5-substituted valeric acid derivative 18.

The solvents suitable for the acylation reaction are preferably dichloromethane, chloroform, tet- rahydrofuran, dioxane, esters of Ci-C6-alcohols formed with Ci-C ₆ acids, more preferably di- chloromethane, tetrahydrofuran or ethyl acetate, most preferably ethyl acetate.

Suitable bases are preferably tertiary amines, alkali metal carbonates, hydrogen carbonates, alkaline earth metal hydroxides and carbonates, preferably an organic base, most preferably triethyl- amine.

The solution according to the invention has the advantage that the sodium salt of formula lib and the compounds 12, 13, 14 and 15 are substances of high melting point, and well crystallizing per se, easily purifiable, easily isolable by filtration which are outstandingly suitable as interme- diates for a pharmaceutical manufacturing process.

Another advantage of the invention according to the invention is that there is no need to apply drastic conditions - high temperature, toxic reagents - at any of the steps of the synthetic pathway shown on Figure 6, thanks to which the pathway, compared to the known processes, is real- izable in a more simple and more economical way also in an industrial scale. The invention has the further advantage that in the course of the chlonnation of the compound 15 with the application of phosphorus pentachloride or a simultaneous use of phosphoryl chloride and phosphorus pentachloride the cyclic moiety of the molecule reacts selectively, allowing the preparation of the compound 14 and through it the compound 13.

The invention has the additional advantage that the synthetic pathway shown in Figure 6 is a process for the preparation of apixaban of formula 1 which process has a better overall yield than the earlier processes, is passing through crystalline and easily purifiable intermediates and pro- vides an easily isolable final product.

Our process is illustrated in the following examples, without limiting the scope of the protection to the specific examples.

The abbreviations, respectively symbols used in the examples have the following meaning:

aqueous 1-butanol: a mixture of 6 ml water and 100 ml 1-butanol

MEK: ethyl methyl ketone

DCM: dichloromethane

DMA:N,N-dimethylacetamide

Example 1

The preparation of l-(4-aminophenyl)-2-piperidinone of formula 16

40.0 g (0.182 mole) nitrophenyl lactam of formula 17 is suspended in 400 ml of methanol, 4.0 g of 10% palladium on bone char catalyst (containing approx. 50% water) is added, then hydro- genation is performed for 4 hours under 5 bar pressure. After filtering the catalyst off the obtained solution is evaporated. After drying 33.9 g (0.178 mole, 98%) of beige substance is obtained. Mp.: 183-186° C.

IR ( Br, cm ^"1 ): 3440, 3325, 3216, 2951, 1643, 1617, 1518, 1433, 1327, 1292, 1162.

HNMR (DMSO-d ₆ , 400 MHz): 6.84 (d, 2H, J = 8.6 Hz), 6.52 (d, 2H, J = 8.6 Hz), 5.03 (s, 2H), 3.46 (t, 2H, J = 5.9 Hz), 2.31 (t, 2H, J = 6.0 Hz), 1.80 (m, 2H), 1.78 (m, 2H).

CNMR (DMSO-de, 100 MHz): 168.71, 147.13, 132.57, 127.08, 113.88, 51.64, 32.74, 23.32, 21.23. Example 2

Preparation of 5-bromo-N-[4-(2-oxopiperidin-l-yl)phenyl]-valeroyl amide of formula 15a

15a 20.0 g (0.105 mole) l-(4-aminophenyl)-2-piperidinone of formula 16 is suspended in ethyl acetate, then 22.2 mL (16.2 g, 0.16 mole) of triethylamine is added, then under argon atmosphere - with continuous stirring and external cooling - 16.4 mL solution of (24.4 g, 0.122 mole) 5- bromo-valeroyl chloride of formula 18a

18a

with ethyl acetate is added dropwise. The obtained suspension is further stirred at room temperature. The main volume of the solvent is evaporated under reduced pressure, then after water added the remaining ethyl acetate is also distilled off. The suspension is cooled to room temperature and stirred with diluted aqueous hydrochloric acid. The solid substance is filtered and washed on the filter with water and /-butyl methyl ether. After drying 35.0 g (0.099 mole, 94%) of off-white substance is obtained. Mp.: 186-190° C.

IR (KBr, cm ^"1 ): 3268, 3126, 2942, 1681, 1628, 1542, 1517, 1410, 1332, 1255.

HNMR (DMSO-d ₆ , 400 MHz): 9.93 (s, 1H), 7.55 (d, 2H, J = 8.8 Hz), 7.17 (d„ 2H, J = 8.7 Hz), 3.56 (t, 2H, J = 6.6 Hz), 3.55 (t, 2H, J = 5.1 Hz), 2.36 (t, 2H, J = 6.7 Hz), 2.34 (t, 2H, J = 7.3 Hz), 1.84 (m, 2H), 1.83 (m, 2H), 1.82 (m, 2H), 1.71 (m, 2H).

CNMR (DMSO-de, 100 MHz): 170.94, 168.89, 138.78, 137.28, 126.65, 119.43, 51.12, 35.44, 34.93, 32.74, 31.91, 23.91, 23.20, 21.11. Example 3

Preparation of 5-bromo-A^-[4-(3,3-dichloro-2-oxopiperidin-l-yl)phenyl]valer oyl amide of formula 14a

40.0 g (0,113 mole) of compound of formula 15a obtained in example 2 is dissolved in DCM, then under argon atmosphere, with continuous stirring 22.1 mL (36.5 g, 0.24 mole) of phospho- rus oxychloride is added dropwise. Under mild heating and stirring a warm solution of 97.2 g (0.467 mole) of phosphorus pentachloride prepared with DCM is added dropwise. Stirring is continued for 1 additional hour. The solution is cooled down and added to a mixture of crushed ice and water. To the obtained two phase mixture DCM is added and then separated. Water and solid sodium bicarbonate are added to the organic phase. The solid substance is filtered, the phases are separated. The organic layer is dried over sodium sulfate. After filtering off the drying agent, a significant part of the DCM is distilled off. The suspension is heated and under vigorous stirring butyl acetate is added dropwise. The crystalline substance is filtered off, washed and dried. 31.9 g (0.076 mole, 67%) of beige substance is obtained. Mp.: 179-181° C. Example 4

Purification of 5-bromo-A ^r -[4-(3,3-dichloro-2-oxopiperidin-l-yl)phenyl]valeroyl amide of formula 14a

31.9 g of the substance of formula 14a obtained in example 3 is suspended in MEK, a little DCM is added and under stirring heated up to a temperature of 75° C. After brief stirring butyl acetate is added dropwise to the mixture, then it is cooled to room temperature and stirred further on. The solid substance is filtered off, washed on the filter twice with a mixture of MEK and butyl acetate and dried. 28.5 g (89%) of beige substance is obtained. Mp.: 181-184° C.

Example 5

Purification of 5-bromo-A ^r -[4-(3,3-dichloro-2-oxopiperidin-l-yl)phenyl]valeroyl amide of formula 14a

1.0 g of the substance of formula 14a obtained in example 3 is dissolved in hot MEK, then it is slowly cooled to room temperature. The crystalline substance is filtered off, washed on the filter with MEK and isopropyl alcohol. After drying 0.68 g substance is obtained. Mp.: 182-186° C.

For the analytical characterization the substance is recrystallized from ethanol. Mp.: 182-186° C. IR (KBr, cm ^"1 ): 3320, 2961, 1689, 1652, 1601, 1530, 1409, 1323, 1196.

HNMR (DMSO-de, 400 MHz): 10.01 (s, 1H), 7.62 (d, 2H, J = 8.6 Hz), 7.28 (d, 2H, J = 8.6 Hz), 3.70 (t, 2H, J = 6.0 Hz), 3.57 (t, 2H, J = 6.6 Hz), 2.92 (t, 2H, J = 5.8 Hz), 2.35 (t, 2H, J = 7.3 Hz), 2.10 (m, 2H), 1.85 (qn, 2H, J = 7.3 Hz), 1.71 (qn, 2H, J = 7.3 Hz).

CNMR (DMSO-de, 100 MHz): 171.10, 162.70, 138.22, 137.48, 126.51, 119.64, 85.12, 51.59, 43.31, 35.46, 34.94, 31.90, 23.88, 20.53. Example 6

Preparation of 3,3-dichloro-l-[4-(2-oxopiperidin-l-yl)phenyl]piperidin-2-on e compound of formula 13.

25.0 g (59.2 mmol) of substance of formula 14a obtained in example 4 is suspended in ethanol, 26.2 g of potassium carbonate is added, then heated up to an internal temperature of 52-54° C, and is stirred for a further 4 hours at this temperature. The suspension is cooled down and the solid substance is filtered off, and washed with ethanol on the filter. After drying 50.7 g of substance is obtained. The product is stirred with water, the remaining solid is filtered off, and it is washed on the filter with 10% acetic acid, then with water. After drying 17.7 g (51.9 mmol, 88%) of the title compound is obtained. Mp.: 211-214° C

IR (KBr, cm ⁴ ): 2951, 1665, 1644, 1506, 1454, 1410, 1346, 1303, 1230, 1202.

HNMR (DMSO-de, 400 MHz): 7.33 (d, 2H, J = 8.8 Hz), 7.30 (d, 2H, J = 8.8 Hz), 3.74 (t, 2H, J = 6.0 Hz), 3.61 (t, 2H, J = 5.5 Hz), 2.93 (t, 2H, J = 6.0 Hz), 2.39 (t, 2H, J = 6.2 Hz), 2.12 (qn, 2H, J = 6.0 Hz), 1.85 (m, 4H).

CNMR (DMSO-de, 100 MHz): 169.05, 162.72, 142.46, 140.20, 126.91, 126.45, 85.03, 51.47, 50.87, 43.21, 32.71, 23.11, 20.99, 20.50.

Example 7

The preparation of 3-chloro-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6-dihydropyridi n-2(lH)- one of formula 12 20.0 g (58.6 mmol) of substance of formula 13 obtained from example 6 is suspended in DMA, then with stirring 2.48 g (33.6 mmol) of lithium carbonate is added and the mixture is stirred at 120° C. At the end of reaction the solution is cooled to room temperature and acidified with hydrochloric acid. The precipitated substance is filtered off and washed. After drying 15.7 g (51.5 mmol, 88%) of the title substance is obtained. Mp.: 208-210° C.

IR ( Br, cm ^"1 ): 2959, 1663, 1642, 1514, 1468, 1403, 1339, 1306, 1211.

HNMR (DMSO-de, 400 MHz): 7.33 (d, 2H, J = 8.8 Hz), 7.28 (d, 2H, J = 8.9 Hz), 7.06 (t, 1H, J = 4.6 Hz), 3.85 (t, 2H, J = 6.9 Hz), 3.60 (t, 2H, J = 5.8 Hz), 2.61 (dd, 2H, J = 6.9, 4.8 Hz), 2.39 (t, 2H, J = 6.2 Hz), 1.85 (m, 2H), 1.83 (m, 2H).

CNMR (DMSO-d ₆ , 100 MHz): 169.06, 159.29, 141.56, 140.41, 138.87, 126.61, 126.42, 125.73, 50.98, 48.54, 32.76, 24.99, 23.17, 21.07.

Example 8

The preparation of sodium salt tetrahydrate (wherein M represents Na) of {l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6 ,7-tetrahydro-lH- pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula lib

14.56 g (47.8 mmol) of the substance of formula 12 obtained in the example 7 is suspended in 1- butanol under argon atmosphere, then 17.10 g (66.6 mmol) of ethyl-(2£ ^' )-chloro[(4- methoxyphenyl)hydrazono] acetate of formula obtained of formula 3a is added. The mixture is heated above 70° C internal temperature with continuous stirring, then 37.0 mL (27.0 g, 267 mmol) triethylamine mixed in with 1-butanol is added. To the obtained solution 8.3 g (208 mmol) of sodium hydroxide in aqueous solution is added dropwise. The solution is filtered and then stirred at a temperature above 50° C for two hours. The suspension is cooled, filtered, washed on the filter and dried. 22.6 g of material containing a small amount of sodium chloride is obtained.

Example 9

The preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 11c

0,73 g (2.4 mmol) of the substance of formula 12 obtained in the example 7 is suspended in 1- butanol under argon atmosphere, then 0.83 (3.2 mmol) of ethyl-(2£)-chloro[(4- methoxyphenyl)hydrazono] acetate of formula 3a is added. The mixture is heated above 70° C internal temperature, then 1.8 mL (1.31 g, 13.0 mmol) triethylamine mixed with 1-butanol is added. To the obtained solution is slightly cooled back and 0.40 g (10.0 mmol) of sodium hydroxide in aqueous solution is added dropwise. The solution is stirred at a temperature between 50-60° C for two hours. An aqueous solution of 1.4 g concentrated acetic acid is added and then it is acidified with 1 : 1 hydrochloric acid. The solid substance is filtered and washed. After drying 0.68 g (1.5 mmol, 62%) of the title substance is obtained. Mp.: 274-276° C.

Example 10

The preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 11c

21.8 g substance of formula lib obtained in Example 8 is suspended in water, 55 mL of 1 - butanol is added and the mixture is heated. Activated carbon is added to the solution, stirred while hot, then the carbon is filtered off and washed. 2.7 g (45 mmol) of concentrated acetic acid in a solution prepared with 10 mL water is added dropwise to the hot solution under vigorous stirring. The mixture is cooled to room temperature, the precipitated substance is filtered off and washed. After drying 13.6 g (29.5 mmol) of the title substance is obtained. Mp.: 276-278° C. IR (KBr, cm ^"1 ): 3407, 2904, 2534, 1710, 1667, 1613, 1516, 1255, 1151.

HNMR (DMSO-d ₆ , 400 MHz): 13.19 (bs, 1H), 7.44 (d, 2H, J = 8.9 Hz), 7.35 (d, 2H, J = 8.7 Hz), 7.28 (d, 2H, J = 8.7 Hz), 7.00 (d, 2H, J = 9.0 Hz), 4.06 (t, 2H, J = 6.5 Hz), 3.80 (s, 3H), 3.59 (t, 2H, J = 5.9 Hz), 3.19 (t, 2H, J = 6.5 Hz), 2.38 (t, 2H, J = 6.2 Hz), 1.85 (m, 2H), 1.84 (m, 2H). CNMR (DMSO-de, 100 MHz): 169.02, 163.06, 159.39, 156.66, 141.58, 139.91, 139.48, 133.06, 132.71, 126.98, 126.86, 126.50, 126.17, 113.61, 55.64, 50.99, 50.93, 32.77, 23.17, 21.39, 21.07.

Example 11

The preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide (apixaban) of formula 1

12.5 g (27.1 mmol) of substance of formula 11c obtained in example 10 is suspended in DMA, then under argon atmosphere 8.0 g (49.3 mmol) of carbonyldiimidazole (CDI) is added, and the mixture is heated to 60° C, and it is maintained at this temperature for 1 hour. Then 18.8 mL (13.7 g, 136 mmol) of triethylamine and 6.25 g (81 mmol) of ammonium acetate are added to the mixture. The stirring is continued for 1 hour. Water is added to the mixture and the suspension is slowly cooled to 20° C. The precipitated substance is filtered off and washed. After drying 11.36 g (24.7 mmol, 91%) of off-white substance is obtained. Mp.: 236-238° C.

Example 12

The purification of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide (apixaban) of formula 1

3.0 g substance of formula 1 obtained in Example 11 is suspended in the mixture of 15 mL 1- butanol and 6 mL water, then 0.05 g sodium bicarbonate is added. The solution is stirred at 60° C temperature for 4 hours. Cooled to room temperature, the solid substance is filtered and washed. After drying 2.8 g substance is obtained. Mp.: 237-239° C.

Example 13

The purification of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide (apixaban) of formula 1 3.0 g substance of formula 1 obtained in Example 11 is suspended in hot aqueous 1-butanol, the solution is filtered while hot and then cooled to room temperature. The precipitated substance is filtered off and washed. After drying 2.6 g of white crystalline substance is obtained. Mp.: 237- 239° C. IR (KBr, cm ^"1 ): 3484, 3312, 1682, 1630, 1595, 1519, 1295, 1256.

HNMR (DMSO-d ₆ , 400 MHz): 7.74 (s, 1H), 7.50 (d, 2H, J = 9.0 Hz), 7.46 (s, 1H), 7.35 (d, 2H, J = 8.9 Hz), 7.27 (d, 2H, J = 8.9 Hz), 7.00 (d, 2H, J = 9.0 Hz), 4.04 (t, 2H, J = 6.6 Hz), 3.80 (s, 3H), 3.58 (t, 2H, J = 6.0 Hz), 3.20 (t, 2H, J = 6.6 Hz), 2.38 (t, 2H, J = 6.3 Hz), 1.84 (m, 2H), 1.83 (m, 2H).

CNMR (DMSO-de, 100 MHz): 169.03, 163.37, 159.30, 156.81, 141.66, 141.54, 139.98, 133.15, 132.74, 127.01, 126.50, 126.18, 125.41, 113.57, 55.66, 51.11, 51.01, 32.78, 23.19, 21.23, 21.09.

Example 14

The preparation of sodium salt tetrahydrate of l-(4-methoxyphenyl)-7-oxo-6-[4-(2- oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4 -c]pyridine-3-carboxylic acid of formula lib (wherein M represents Na)

0.46 g (1 mmol) l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin- l-yl)phenyl]-4, 5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 11c is suspended in aqueous 1-butanol, then 92 mg (1.1 mmol) of sodium bicarbonate is added. The suspension is heated with stirring until dissolution, and then slowly cooled to room temperature. The precipitated substance is filtered, washed and air dried. After drying 0.42 g (0.76 mmol, 76%) of white crystalline substance is obtained. Mp.: 360-364° C

IR (KBr, cm ^"1 ): 3454, 3260, 2954, 1666, 1646, 1576, 1537, 1512, 1464, 1435, 1383, 1335, 1305, 1285, 1251, 1166, 1145, 1022, 834.

HNMR (DMSO-de, 400 MHz): 7.45 (d, J=9.0 Hz, 2H); 7.34 (d, J=8.7 Hz, 2H); 7.26 (d, J=8.7 Hz, 2H); 6.94 (d, J=9.0 Hz, 2H); 4.00 (t, J=6.6Hz, 2H); 3.79 (s, 3H); 3.59 (t, J=5.5 Hz, 2H); 3.18 (t, J=6.6 Hz, 2H); 2.38 (t, J=6.4 Hz, 2H); 1.85 (m, 4H). Elemental analysis: C H N

Calculated (%) 54.15 5.63 10.10

Measured (%): 53.93 5.47 10.05