CZ2014475A3 - Process for preparing abiraterone acetate of high purity applicable in industrial range - Google Patents

Abstract

The present invention relates to a process for the preparation of abiraterone acetate of formula I, which comprises a) preparing abiraterone of formula II, Suzuki by reacting 3-pyridyldiethylborane and a halogenated steroid of formula VI or VII in the presence of a palladium catalyst system, base and solvent, b) acetylating abiraterone to form abiraterone acetate of formula C) isolating abiraterone acetate by crystallization; wherein the palladium catalyst system consists of a palladium acetate catalyst, Pd (OAc), and a triphenylphosphine ligand Ph.sub.3.

Description

Field of technology

The invention relates to an improvement of the process for the preparation of Abiraterone acetate of formula I. The improvement of the process relates to the Suzuki cross-coupling reaction, subsequent acetylation and crystallization (Scheme 1). The process is focused on the use of the most affordable raw materials, reagents, catalyst and ligand while maintaining the yield and quality of the product. Secondly, the improvements focus on the usability of the synthesis process on a larger, industrial scale. The developed process for the preparation of abiraterone of formula II demonstrably leads to the elimination of the formation of impurities and thus to the formation of a suitable active pharmaceutical substance of formula I in high yield, even when prepared on a larger scale.

Scheme 1

vi x = i VII X = Br

3-PyBEt ₂

Prior art

Abiraterone acetate is a medicine used to treat metastatic prostate cancer in men who have not been effective with pharmacological or surgical castration.

v V </

Abiraterone acetate was first described in the patent EF ^ f0jp33 ^ 93 ^ 1. The preparation method of this patent is also described in Potter, G. A .; Barrie, S. E .; Jarman, M .;

Rowlands, MGJ Med. Chem. 1995, 38, 2463-2471. A key step in the three-step synthesis is the Suzuki cross-coupling reaction of the enol triflate of formula III with diethyl 3-pyridylborane (3-PyBEt ₂ ) in the presence of a palladium catalyst (Scheme 2). Enol triflate III is prepared by reacting acetylated dehydroepiandrosterone (Ac-DHEA) with trifluoromethanesulfonic anhydride in a basic medium. The disadvantage of this reaction is both the use of toxic and corrosive trifluoroethanesulfonic anhydride and the need to use an expensive, sterically hindered base (2,6-di-tert-butyl-4-methylpyridine). In addition, in this step, a competitive reaction can take place under the given conditions, the elimination of acetic acid from the compound of formula III, which in the next step leads to the formation of an impurity of formula IV. This ultimately means the need to purify the product by chromatography, which, if prepared on a larger scale, would be a major obstacle to the process.

Patent application WOp7,271 discloses the use of more affordable bases (tertiary or heterocyclic amines such as 2,6-lutidine or triethylamine) in the preparation of the enol triflate of formula III as well as the purification and isolation of the final product I after the Suzuki reaction from the reaction mixture ( also containing the unreacted ketone Ac-DHEA from the previous step in a ratio of 1: 3 in favor of the product I) via the methanesulfonic acid salt, by crystallization from methyl tert-butyl ether. Using these changes, it is possible to obtain the product without chromatography, but in insufficient purity of the salt of product I (96.4%), even after two crystallizations. Another problem is the very low yields resulting from the need for multiple recrystallizations to obtain a satisfactory product I. Another disadvantage is the impending partial hydrolysis of the acetyl group upon release of abiraterone acetate of formula I from the salt, and thus the need for additional acetylation of the resulting by-product II. in the process.

The ΕΡ ^ 21 ^ δφΐ patent and also in the publication (Potter, GA; Hardcastle, IR; Jarman, M. Org. Prep. Proced. Int. 1997, 29, 123-134) describe a four-step synthesis of abiraterone acetate based on a commercially available steroid DHEA (dehydroepiandrosterone, Scheme 3). The first step is to convert the steroid ketone DHEA to the hydrazone of formula V by reaction with hydrazine in ethanol. The second step is the preparation of a halogen derivative and subsequent carrying out a Suzuki reaction of an iodo of formula VI or a bromosteroid of formula VII with diethyl 3-pyridylborane catalyzed by a palladium complex. The final step is the acetylation of the hydroxy group of abiraterone of formula II with acetyl chloride to give abiraterone acetate of formula I.

Scheme 3

The key step, the Suzuki reaction, is described for the reaction of an iodosteroid of formula VI with diethyl (3-pyridyl) borane (1 equivalent) in tetrahydrofuran catalyzed by bis (triphenylphosphine) palladium chloride (0.01 equivalent) in a basic medium of 2M aqueous sodium carbonate solution. . The disadvantage of said method is that the conversion of the reaction under these specific conditions is slow and therefore requires stirring at high temperatures (azeotrope reflux ~ 8 ° C) for up to four days. This entails, on the one hand, higher process costs but also one major disadvantage, and that is the amount of bis-steroid of the formula VIII _{A which} increases with reaction time. This impurity is formed by the reaction of an abiraterone product of formula II with 17-iododandrosta 15,16-dien-3β-ol of formula VI catalyzed by palladium (Heck coupling as a competitive reaction). So far, the only effective method for removing impurities of formula VIII is reverse phase chromatography, which is almost unusable as a purification method in the production of product II on a larger scale. Crystallization in this case provides only a very limited space to reduce the amount of impurity of formula VIII.

In the presence of an impurity of formula VIII in product II, in the next step (acetylation) the impurity VIII is also acetylated and leads to the formation of a diacetylated bis-steroid of formula IX, where again there is a problem with very limited purification space due to similarity of bis-steroid physical properties. of formula IX with the product of formula I.

WO 013/030410 discloses a Suzuki coupling of a boronic acid of formula XI derived from the steroid DHEA with 3-pyridyl bromide (Scheme 4). However, the preparation of the intermediate of formula XI requires the use of cryogenic conditions (lithiation and transmetallation of the iodide of formula X).

Scheme 4

IFHCI

Recently, the optimization of Suzuki coupling conditions between 3-pyridyldiethylborane and a bronwsteroid of formula VII has been published in the literature (Org. Process Res. Dev. 2014, 18, 555-558) aimed at shortening the reaction time and streamlining the isolation. However, the use of expensive and only to a limited extent stable tetrakis (triphenylphosphine) palladium as a catalyst complex remains a disadvantage. Another disadvantage of this process for the preparation of abiraterone acetate of formula I could be considered the necessary purification of the product I via acid-base extraction, which serves mainly to remove impurities, especially to reduce the amount of diethyl 3-pyridylborane identified in the final product I.

From the above list of methods and conditions for the preparation of both abiraterone of formula II and the final API of abiraterone acetate of formula I, it is clear that all methods have shortcomings that may pose a problem in product preparation on a larger scale in terms of technology, process cost, or excess impurities in the final API.

The essence of the invention

The invention relates to an efficient, competitive and industrially applicable process for the preparation of abiraterone acetate of formula I, which comprises the following steps:

a) Preparation of abiraterone of formula II in high purity

Suzuki reaction of 3-pyridyldiethylborane (1 to 1.2 equivalents, preferably 1.1 equivalents) and a halogenated steroid of formulas VI and VII

VI x = i

VII X = Br in the presence of palladium acetate (0.1 to 1.5%), preferably as catalyst, and triphenylphosphine (0.2 to 3 mol%, preferably 3%) as ligand in a basic medium of potassium phosphate or carbonate cesium (1 to 3 equivalents, preferably 2 equivalents) at a temperature higher than 50 ° C, preferably at the reflux temperature of an azeotropic solvent mixture (THF / water, MeTHF / water or Toluene / water, preferably THF / water or MeTHF / water in a ratio of 2 : 1.5 or 2: 1), and for a period not exceeding 24 [mu] m, preferably 4 [mu] l.

b) Preparation of abiraterone acetate of formula I in high purity

by crystallization of crude abiraterone acetate I from a suitable solvent. Abiraterone acetate I is prepared by acetylation of abiraterone II under standard conditions (e.g. with acetic anhydride or acetyl chloride in a basic environment of pyridine or triethylamine, in the presence of a catalytic amount of N, N-dimethylaminopyridine).

A suitable solvent for crystallization from the viewpoint of reducing the content of bissteroid impurity of formula IX is acetonitrile, C1-C4 alcohol, or a mixture of C1-C4 alcohol and water, preferably a mixture of eranol with water, a mixture of 2-propanol and water is used from alcohols and mixtures thereof with water. water or pure 2-propanol.

An improved process for the preparation of abiraterone acetate of formula I is shown in the following scheme

Scheme 5

vi x = i

VII X = Br

Table 1 lists a selection of the most important experiments that led to the invention.

Table 1

Try* Base Proportion of individual components in the reaction mixture (%); determined by UPLC II (Abirateron) VI (ship derivative) Vlil (Bis-steroid) Bipyridine 12h 48h 120h 12h 48h 120h 12h 48h 120h 12h 48h 120h 1 3eq. Na ₂ CO 3 42.1 51.4 92.0 40.1 28.3 0.7 0.6 1.1 1.5 1.6 2.3 - 2 2Á ^ω O < 90.6 82.3 85.7 1.7 1.7 1.4 0.2 1.1 1.9 0.5 0.9 0.8 3 3eq. CS2CO3 67.5 75.5 78.2 10.3 1.6 1.3 1.2 1.4 2 1.9 3.9 4.1 * 1.1 eq. 3-PyBEt _2.1 mol% Pd (PP h ₃ ) ₂ Cl ₂ , THF / H ₂ O, ref ux; note: eq = eq ent

Surprisingly, extensive experiments have shown that the use of potassium phosphate as a base in the Suzuki cross-coupling reaction of a halogen steroid of formulas VI or VII with diethyl 3-pyridylborane significantly increased the conversion over time, allowing the reaction time to be shortened from days (Experiment 1, Table 1). - comparative experiment using the conditions of the patent EFjpjf2lJl6ipi - almost complete conversion was achieved only after five days (after 12 hours the conversion was only 60%) for several hours (experiment 2-object of the invention - already after 12 hours 98% conversion was achieved). Also by using cesium carbonate (experiment 3 - subject of the invention) it is possible to reduce the reaction time to less than 48 hours (1.6% of the starting iododerivative of formula VI after 48 hours).

This aspect is also very important from the point of view of the formation of impurities, especially in the formation of the impurity of the formula VIII.

This is because a reduction in the reaction time demonstrably leads to a reduction in the impurity content of the formula VIII in the abiraterone product of the formula II. This is evident from monitoring the amount of impurity of formula VIII at the time when the same trend was observed in all experiments (Table 1), i.e. the amount of impurity of formula VIII increases with increasing reaction time.

Furthermore, it has surprisingly been found that this effect is maintained using the affordable Pd (OAc) 2 / PPh ₃ catalyst system and thus increases the competitiveness of this method compared to methods using catalysts such as tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride. or [1,1-Bis (diphenylphosphino) ferrocene] palladium dichloride (complex with dichloromethane) used in the prior art for the Suzuki cross-coupling reaction of a halogen steroid of formulas VI or VII with diethyl 3-pyridylborane.

Table 2 compares the experiments that led to this finding.

Table 2.

Try* Catalytic System Base Proportion of individual components in the reaction mixture (%); determined by UPLC II VI Vlil Bipyridine 1 1mol% PdCl ₂ (PPh ₃ ) ₂ 3eq. K ₃ PO ₄ 90.6 1.70 0.20 0.50 2 1mol% Pd (OAc) ₂ / 2mol% PPh ₃ ^ω τ / O < 80.1 1.00 0.80 0.90 3 1 mol% PdCl ₂ (PPh ₃ ) ₂ 3eq. CS2CO3 67.5 10.3 1.20 1.90 4 1mol% Pd (OAc) ₂ / 2mol% PPh ₃ 3eq. Cs ₂ CO ₃ 82.3 1.20 1.20 1.10 * 1.1 eq. 3 -PyBEt ₂ , THF / H ₂ O, 12h, reflux

The reaction reported in the fourth experiment (Experiment 4, Table 2) shows an even better conversion using the catalyst system Pd (OAc) 2 / PPh3 = 1/2 in combination with cesium carbonate, where already after 12 hours an excellent conversion of over 98% was achieved.

To better understand the limits of use of these conditions, several experiments were performed focusing mainly on the amount of catalyst and ligands used {Pd (OAc) ₂ / PPh ₃ }, excess K ₃ PO ₄ and diethyl (3-pyridyl) borane, but also the possibility of using other halogen derivative than iodide VI. The results are summarized in Table 3.

Table 3

Try Change from the original method Time (h) Isolated yield (%) Purity of crystalline product II (%) Impurity content in the product (%) VI (VII) Vlil Γ - 21 88 97.3 0.47 0.10 2 1 eq. K PC) 3 4 20 81 73.4 17.4 0.32 3 2 eq. K PC) 3 4 22 84 97.9 0.55 - 4 0.5mol% Pd (OAc) _{2, PPh3} 1mol%, 2 eq. K3PO4 20 80 97.4 0.98 0.12 5 1 eq. 3-PyBEt ₂ 45 89 88.9 2.25 0.62 6 VII instead of VI; 2 eq. K.PO ₄ 21 73 95.6 1.11 - * 1.1 eq. 3-PyBEt _2.1 mol% Pd (OAc) _{21 2} mol% ^D h ₃ P, 3eq. K ₃ PO ₄ , THF / water, reflux.

The results show that it is possible to reduce the amount of base, potassium phosphate, from an initial excess of three equivalents to an excess of 2 equivalents, without significantly limiting the yield or purity (comparison of Experiments 1 and 3, Table 3).

In case the amount of catalyst can be observed nearly identical result (comparison experiments 1 and 4, Table 3), even using half the amount of catalyst {0, ^ 1¾ Pd (OAc) _2, 1-Nol ^ Ph ₃ P}.

It is also possible to use a bromoderivative of steroid VII in the reaction under these conditions (Experiment 6, Table 3), then under the reaction conditions which form part of the invention, a yield of 73% of Abiraterone II with a purity of 95.6% was obtained. an improved process for the preparation of abiraterone acetate I in high purity and high yield.

The process comprises the reaction of an iodide VI or bromide VII steroid in the presence of a Pd (OAc) ₂ / Ph ₃ P catalyst system.

The ratio of Pd (OAc) ₂ catalyst to Ph ₃ P ligand is 1: 2.

The amount of catalyst is 0.1 to 1.5%, preferably 1 ^{of the} catalyst is used.

Potassium phosphate or cesium carbonate is used as the base in the reaction in an excess of 1 to 3 equivalents, preferably 2 equivalents of potassium phosphate are used.

The reaction is carried out in a solvent mixture of THF / water, MeTHF / water, toluene / water. Preferably a mixture of THF / water or MeTHF / water in a ratio of 2: 1.5 or 2.1 is used. The reaction is carried out at a temperature higher than 50 ° C, preferably at the reflux temperature of the azeotropic solvent mixture.

The reaction time is at most 24 μl, preferably the reaction is carried out for 4 hours.

The invention is further elucidated in the following examples. These are purely illustrative and do not limit the scope of the invention in any way.

Image overview:

Giant. 1 - Evaluation: internal peak normalization method

Giant. 2 - Evaluation: by the method of internal normalization of peaks

Exemplary embodiments

Method of analysis of the intermediate of formula II

Examine by liquid chromatography (Ph.Eur. 2.2.29):

Chromatographic conditions:

Instrument: Chemicals: UPLC system with UV / VIS or PDA acetonitrile R1 detector water for chromatography R ammonium dihydrogen phosphate R tetrahydrofuran for chromatography R Column: - dimensions: - stationary phase: length = 100 mm, inner diameter = 4.6 mm Ascentis Express Phenyl-Hexyl 2.7 μm

- temperature: Mobile phase: 30 ° C A: Dissolve 0.58 g of ammonium dihydrogen phosphate R in 1000 ml of water for chromatography R. B: acetonitrile R1

- elution:

gradient

Time [min] Mobile phase [% v / v] Mobile phase B [% v / v] 0 75 25 1 75 25 10 10 90 16 0 100 17.5 75 25 19 75 25

flow rate:

spray:

Sample temperature:

Detection:

0.8 ml / min

2.0 μΙ ° C

UV 215 nm time: 19.0 min

Sample solvent: tetrahydrofuran for chromatography R: acetonitrile = 10:30 (v / v)

Sample concentration: 2 mg / ml

Typical retention and relative retention times (reference peak RRT1 is II).

II: approx. 8.1 min

Vlil RRT 0.82 VI RRT 1.23 IV RRT 1.41 3-PyBEt ₂ RRT 1.90

Correction factor: VI1.6

IV0.42

3-PyBEt ₂ 0.25 other impurities 0.8 -1.2 (without correction)

Evaluation: by the method of internal normalization of peaks - Fig. ^

Method of analysis of Abiraterone acetate I

Examine by liquid chromatography (Ph.Eur. 2.2.29):

Chromatographic conditions:

Instrument: UPLC system with UV / VIS or PDA detector Chemicals: acetonitrile R1 water for chromatography R ammonium dihydrogen phosphate R

Column:

- dimensions: - stationary phase: length = 100 mm, inner diameter = 4.6 mm Ascentis Express Phenyl-Hexyl 2.7 pm - temperature: Mobile phase: 30 ° C A: Dissolve 0.58 g of ammonium dihydrogen phosphate R in 1000 ml of water for chromatography R. B: acetonitrile R1 - elution: gradient

Time [min] Mobile phase [% v / v] Mobile phase B [% v / v] 0 75 25 1 75 25 10 10 90 16 0 100 17.5 75 25 19 75 25

flow rate: 0.8 ml / min injection: 2.0 μΙ

Sample temperature: 15 ° C

Detection: UV 255 nm time: 19 _f 0min

Sample solvent: acetonitrile R1

Sample concentration: 2 mg / ml

Typical retention and relative retention times (RRT 1 reference peak is Abiraterone acetate

.Λ

Abiraterone acetate I: approx. 10.3 min

II RRT 0.78 IX RRT 1.42

Evaluation: by the method of internal normalization of peaks - Fig. 2

Preparation of abiraterone intermediate of formula II

Example 1 (General method of performing experiments 1 to 3 from Table 1)

Weigh 600 mg (1.51 mmol) of the iodo derivative of formula VI, 244 mg (1.1 eq., 1.66 mmol) of diethyl (3-pyridyl) borane, 3 equivalents (4.52 mmol) of base (according to Table 1) into a flask. ) and 10.6 mg of bis (triphenylphosphine) palladium chloride (1%). The flask was whispered and then evacuated and inertized 3 times (Argon). To this mixture, 6 ml of tetrahydrofuran and 4.5 ml of distilled water were added under an inert atmosphere of argon. The reaction mixture is heated in an 80 ° C bath. samples are taken continuously from the reaction mixture, the results of purity analyzes for individual experiments and samples are summarized in Table 1.

¹ H NMR (500.13 MHz, CDCl ₃ ) δ 8.62 (d, J = 1.6 Hz, 1H), 8.46 (dd, J = 4.7, 1.1 Hz, 1H), δ .65 (dt, J = 7.9, 1.8 Hz, 1H), 7.22 (dd, J = 7.8, 4.8 Hz, 1H), 6.00 - 5.99 (m, 1H ), 5.40 - 5.38 (m, 1H), 3.56 - 3.51 (m, 1H), 2.39 - 2.21 (m, 3H), 2.13 - 2.00 (m , 3H), 1.91 - 1.84 (m, 2H), 1.76 (dt, J = 10.8, 4.9 Hz, 1H), 1.71 - 1.42 (m, 7 H), 1 , 14-1.04 (m, 2H), 1.p7 (s, 3H), 1.04 (s, 3H);

¹³ C NMR (125.76 MHz, CDCl 3) δ 151.6, 147.9, 147.8, 141.1, 133.7, 132.9, 129.2, 123.0, 121.3, 71.6, 57, 5, 50.3, 47.3, 42.3, 37.1, 36.7, 35.2, 31.8, 31.6, 31.5, 30.4, 20.8, 19.3, 16.6.

Example 2 (Experiment No. 4, Table 2)

600 mg (1.51 mmol) of the iodo derivative of formula VI), 244 mg (1.66 mmol) of diethyl (3-pyridyl) borane, 3.5 mg of palladium acetate are weighed into a flask. (1%) and 10 mg (2%) of triphenylphosphine. The mixture was diluted with 6 mL of tetrahydrofuran and a solution of cesium carbonate [1.47 g CS 2 CO 3 (4.5 mmol) in 4.5 mL water] was added. The reaction mixture is heated under reflux for 12 hours under a nitrogen atmosphere in a bath of t = 80 ° C. After cooling, the mixture is diluted with 2 ml of water. The resulting suspension was stirred in an ice bath for 1 hour. After suction filtration, washing with water and drying (16 h in a vacuum oven at 45 [deg.] C.), 0.45 g (85%) of Abiraterone of the formula II are obtained with a purity of 88.21% (determined by UPLC). The NMR spectrum corresponds to the NMR record of Abiraterone of formula II.

Example 3 (Experiment No. 1, Table 3)

Weigh 6 g (15 mmol) of iodide derivative VI, 2.44 g (16.6 mmol) of diethyl (3-pyridyl) borane, 34 mg of palladium acetate into a flask. (1 mmol) and 79 mg (2.7%) of triphenylphosphine. The mixture is diluted with 60 ml of tetrahydrofuran and a solution of potassium phosphate [5.55 g of K ₃ PO ₄ (45 mmol) in 45 ml of distilled water] is added. The reaction mixture is heated under reflux for 21 hours under an inert atmosphere of nitrogen in a bath at 80 ° C. After cooling, the mixture is diluted with 20 ml of distilled water. The resulting suspension was stirred in an ice bath for 1 hour. After suction filtration, washing with water and drying (16 h in a vacuum oven at 45 [deg.] C.), 4.65 g (88%) of Abiraterone are obtained with a purity of 97.25% (determined by UPLC; content of formula VI 0.47%, content of formula VIII) is 0 ₍ 10%) The NMR spectrum corresponds to the NMR record of Abiraterone of formula II.

Example 4 (Experiment No. 6, Table 3)

1.5 g (4.3 mmol) of the bromo derivative of formula VII, 0.69 g (4.7 mmol) of diethyl (3-pyridyl) borane and 10 mg of palladium acetate are weighed into a flask. (1 πτοϊ &) and 25 mg (2 πτοο ^ ώ) of triphenylphosphine. The mixture was diluted with 17 mL of tetrahydrofuran and a solution of potassium phosphate [1.83 g of K 3 PO 4 (8.6 mmol) in 13 mL of water] was added. The reaction mixture is heated under reflux for 21 hours under a nitrogen atmosphere in a bath rt = 80 ° C. After cooling, the mixture is diluted with 6 ml of water. The resulting suspension was stirred in an ice bath for 1 hour. After suction filtration, washing with water and drying (16 h in a vacuum oven at 45 [deg.] C.), 1.10 g (73%) of Abiraterone are obtained with a purity of 95.59% (UPLC determined; 3-PyBEt ₂ content 1.14%, VII is 1.11%). The NMR spectrum corresponds to the NMR record of Abirateron II.

Preparation of the final product Abiraterone acetate I

Example 5

To a suspension of 4.35 g (12.5 mmol) of Abiraterone vorce II and 18 mg (1%) of dimethylaminopyridine in 18 mL of pyridine was added dropwise 2.35 mL (25 mmol) of acetic anhydride at room temperature over 15 minutes. The mixture was stirred at room temperature. Activated carbon was added to the resulting solution and stirred for an additional 30 minutes. After suction filtration through celite and washing with 5 ml of pyridine, 35 ml of water are added dropwise to the filtrate cooled in an ice bath. The resulting suspension was stirred for 1 h in an ice bath. After suction filtration, washing with water and drying (16 h in a vacuum oven at 45 [deg.] C.), 3.73 g (77%) of Abiraterone acetate of the formula I are obtained with a purity of 99.17%; melting point = 141.3-142.8 ° C.

If necessary, the product is purified by crystallization from acetonitrile or from an ethanol / water mixture.

1 H NMR (500.13 MHz, CDCl 3) δ 8.62 (d, J = 1.6 Hz, 1H), 8.47 (dd, J = 4.7, 1.2 Hz, 1H), 7.65 (dt, J = 7.9, 1.8 Hz, 1H), 7.22 (dd, J = 7.8, 4.8 Hz, 1H), 6.00 - 5.98 (m, 1H) , 5.43 - 5.41 (m, 1H), 4.64 - 4.58 (m, 1H), 2 _f 40 - 2.30 (m, 2H), 2.27 (ddd, J = 15.8,

6.5, 3.3 Hz, 1H), 2.10 - 2.01 (m, 3H), 2.04 (s, 3H), 1.92 - 1.84 (m, 2 H), 1.85 - 1.55 (m, 6H), 1.49 (td, J = 12.3, 4.9, 1H), 1.20-1.12 (m, 1H) 1.11-1.05 (m, 1H) 1.09 (s, 3 H), 1.05 (s, 3 H);

13 C NMR (125.76 MHz, CDCl 3) δ 170.5, 151.6, 147 * 9, 147.8, 140.0, 133.6, 132 * 9,

129.2, 123.0, 122.3, 73.8, 57.4, 50.2, 47.3, 38.1, 36.9, 36.7, 35.2, 31.8, 31.5, 30.4, 27.7, 21.4, 20.8, 19.2, 16.5.

Example 6

To a suspension of 300 mg (0.86 mmol) of Abiraterone II and 4 mg (4'-nonol) of dimethylaminopyridine in 3 mL of methyl ethyl ketone was added 0.12 mL (0.86 mmol) of triethylamine and dropwise was added dropwise over 10 minutes at room temperature. , 12 mL (1.29 mmol) of acetic anhydride. The mixture was heated in an 80 ° C bath for 2 h. After cooling, the solution is filtered through a pad of activated carbon. 6 ml of water are added dropwise to the filtrate cooled in an ice bath. After stirring for 1 hour in an ice bath, the resulting suspension is filtered off with suction to give 243 mg of abiraterone acetate with a purity of 99.41%; melting point = 144.0-145.2 ° C. The NMR spectrum corresponds to the NMR record of Abiraterone acetate of formula I. If necessary, the product is purified by crystallization from acetonitrile or from an ethanol / water mixture.

Example 7

To a suspension of 300 mg (0.86 mmol) of Abiraterone of formula II and 6 mg (6 mol%) of dimethylaminopyridine in 3 ml of 2-methyltetrahydrofuran was added 0.12 ml (0.86 mmol) of triethylamine and stirred at room temperature for 10 minutes at room temperature. 0.12 ml (1.29 mmol) of acetic anhydride are added dropwise. The mixture was heated in an 80 ° C bath for 2 h. After cooling, the solution is filtered through a pad of activated carbon. The solvent was distilled off from the filtrate under reduced pressure, and the crude product was stirred in 2 ml of acetonitrile. Aspiration gave 194 mg of abiraterone acetate with a purity of 99.26%; melting point - 145.8-146.6 ° C. The NMR spectrum corresponds to the NMR record of Abiraterone acetate of formula I. If necessary, the product is purified by crystallization from acetonitrile or from an ethanol / water mixture.

Example 8

Abiraterone acetate (1 g) with a purity of 99.17% (0.22% IX) was dissolved in 5 ml of acetonitrile at reflux. Crystallization occurs during spontaneous cooling. The resulting suspension was stirred in an ice bath for 1 h. After suction filtration and washing with 1 ml of acetonitrile, 0.87 g of abiraterone acetate with a purity of 99.83% (0.09% IX) is obtained; melting point = 146.2-147.3 C.

Example 9

Abiraterone acetate (120 mg) with a purity of 84.63% (0.17% IX) was dissolved in 5 mL of EtOH / water (1: 1) at reflux. The hot solution is filtered through a pad of activated carbon and crystallizes upon cooling. The resulting suspension was stirred in an ice bath for 1 h. After suction filtration and washing with 1 ml of EtOH / water (1: 1), 40 mg of abiraterone acetate are obtained with a purity of 84.03% (0.02% IX).

Example 10

Abiraterone acetate (1 g) with a purity of 99.17% (0.22% IX) was dissolved in 60 ml of EtOH / water (1: 1) at reflux. Crystallization occurs during spontaneous cooling. The resulting suspension was stirred in an ice bath for 1 h. After suction filtration and washing with 5 ml of EtOH / water (1: 1), 0.95 g of abiraterone acetate with a purity of 99.70% (0.16% IX) are obtained; melting point = 145.5-146.6 ° C.

Claims (9)

Patent claims PF A process for the preparation of abiraterone acetate of formula I which includes a) preparation of abiraterone of formula II Suzuki reaction of 3-pyridyldiethylborane and a halogenated steroid of formula VI or VII iyil) X = Br in the presence of a palladium catalyst system, a base and a solvent b) acetylation of abiraterone to give abiraterone acetate of formula I c) isolation of abiraterone acetate by crystallization, characterized in that the palladium catalyst system consists of a palladium acetate catalyst - Pd (OAc) ₂ and a triphenylphosphine ligand - Ph ₃ P. Preparation process according to Claim 1, characterized in that the catalyst ratio Pd (OAc) ₂ and the ligand Ph ₃ P is 1: 2. Preparation process according to Claims 1 to 2, characterized in that the catalyst is used in an amount of 0.1 to 1.5% by weight, preferably 1% by weight of catalyst. Preparation process according to Claim 1, characterized in that the base is potassium phosphate or cesium carbonate in an amount of 1 to 3 equivalents. Preparation process according to Claim 4, characterized in that the potassium phosphate base is used in an amount of 2 equivalents. Preparation process according to Claims 1 to 5, characterized in that the solvent is chosen from the group of mixed solvents tetrahydrofuran-THF / water, methyltetrahydrofuran-MeTHF / water, toluene / water, preferably a THF / water or MeTHF / water mixture is used. in a ratio of 2: 1.5 or 2: 1. Process according to Claims 1 to 6, characterized in that the reaction of 3-pyridyldiethylborane and the halogenated steroid of the formula VI or VII is carried out at a temperature higher than 50 ° C, preferably at the reflux temperature of the azeotropic solvent mixture, and for a maximum of 24 | ί, preferably 4 [mu] l. Process according to Claim 1, characterized in that the abiraterone acetate is crystallized from acetonitrile or a C 1 -C 4 alcohol, optionally a mixture of a C 1 -C 4 alcohol and water. Process according to Claim 8, characterized in that the abiraterone acetate is crystallized from a mixture of ethanol and water, or a mixture of 2-propanol and water, or pure 2-propanol.