The abiraterone acetate was the ester of formula (Abiraterone acetate) structure.

[0004]

[0005] So far, the search route may abiraterone acetate ester (Abiraterone acetate) are two.

[0006] Patent W09509178, CN 102030798, WO 2006021777, 2006021777, WO2006021776, J.Med.Chem.38,2463-2471,1995, synthetic route reported in the literature like the following formula WO.

[0007]

[0008] The route is DHEA as raw material, with an acetyl group protecting the hydroxyl group, the product obtained is then reacted with trifluoromethanesulfonic anhydride to give triflate product was finally reagent under palladium catalysis, Suzuki coupling reaction with 3-pyridyl diethyl borane, to give an ester of abiraterone acetate.

[0009] Patent GB 2282377,0PPI, 29 (I), 123-134,1997 the reported another method of synthesis.

The synthetic procedure the following formula.

[0010]

[0011] The route is DHEA as raw material, the reaction with hydrazine hydrate, and then reacted with iodine to give the 17-iodo – androsta-5,16-diene–3beta- alcohol, and catalytic agent in the button with Li-yl-pyrazol-diethyl _3_ boron burning Suzuki coupling reaction to give abiraterone, and finally acetylated abiraterone acetate to give abiraterone acetate.

[0012] By comparing the two lines, a synthetic routes can be found with a reagent such as trifluoromethanesulfonic anhydride, 2,6-di-t-butyl-4-methylpyridine and the like are expensive, relatively high chemical costs. In comparison, two synthetic route mild reaction conditions, the reagents are cheap, and therefore have more industrialized prospects. However, according to the synthesis process reported in the literature, the route to industrial production, there are still some technical problems.

[0013] More specifically, to 17- iodo – androsta-5,16-diene–3beta_ when alcohol (2) Synthesis of abiraterone (3) as a raw material for the Suzuki coupling reaction, the solvent is tetrahydrofuran, the solvent high cost; shall reaction refluxed for 4 days, the reaction time is too long. More importantly, when the Suzuki coupling reaction, starting material 17- iodo – male left diene-5,16-ol _3beta_

(2) will react with the impurities abiraterone (3) 4, 4 impurities not removed by recrystallization, can only be purified by column chromatography. If the compound is not 4 Ex, abiraterone prepared by acetylation reaction of abiraterone acetate ester, the impurities will be converted to 4 5 impurities, the impurities by recrystallization 5 likewise not removed, only purified by column chromatography.

[0014]

[0015] The abiraterone acetate ester synthesis, synthesis is reported abiraterone 24h the reaction with acetic anhydride and pyridine at room temperature, the reaction time is too long. The mixture was then evaporated under reduced pressure to be excess acetic anhydride and pyridine, and then crystallized from diethyl ether again, to give the final acetate abiraterone acetate was purified by column chromatography.

[0016] In summary, two synthetic routes reported in the literature of the last two long reaction time and complicated operation, product purification difficult. All this has seriously hampered the industrialization prospects abiraterone acetate esters.It is essential to two synthetic routes to optimize the improvement, in order to achieve the industrial production of abiraterone acetate ester.

] Example 1

Preparation of [0031] 17- (3-pyrazol Li-yl) androsta-5,16-diene-_3beta_ alcohol (abiraterone) of

[0032] A 750ml NMP was added to a 3L three-necked flask, were added with stirring 50gl7_ iodo – androsta-5,16-diene–3beta- alcohol, 88 mg of bis (triphenylphosphine) palladium chloride and diethyl 19.74g yl – (3-pyridyl) borane, and finally adding 345ml 2mol / L Na2CO3 solution. Heating, holding temperature of about 70-80 ° C, TLC monitored the reaction was complete. The reaction was cooled to room temperature, the reaction solution was added 1500ml of water, stirred, filtered and washed with water. Blast drying, 26.3g abiraterone.

[0033] Example 2

[0034] Preparation and purification of abiraterone acetate ester

[0035] The abiraterone 26g 156ml dissolved in pyridine, 52 ml of acetic anhydride was added at room temperature, heating, holding temperature of about 70-80 ° C, the reaction for about 4 h, TLC monitoring of the reaction was complete. The reaction was cooled to room temperature, the ice bath, 560ml of ice water was added to the reaction mixture, the precipitated white solid was stirred 20min, filtered, washed with water. 55 ° C blast drying. The crude product was added to 26ml of ethanol was dissolved by heating to clarify. Water was added 26ml, stirred for lh. Cooled to room temperature and filtered. Blast drying. Abiraterone acetate to give the final acetate 22.lg, HPLC> 99.5%.

[0036] Example 3

Preparation of [0037] 17- (3-pyridyl) androsta-5,16-diene-_3beta_ alcohol (abiraterone) of

[0038] The IlOL NMP was added to a 3L three-necked flask, were added with stirring 7.5kgl7_ iodo – androsta-5,16-diene–3beta- alcohol, 132 g of bis (triphenylphosphine) palladium chloride and 29.6kg two ethyl – (3-pyridyl) borane and finally 500L2mol / L Na2CO3 solution. To maintain the internal temperature of about 70_80 ° C, TLC monitored the reaction was complete. The reaction was cooled to room temperature, 220L of water was added to the reaction mixture, stirred for 30min, filtered, washed with water. Blast drying, 39.2kg abiraterone.

[0039] Example 4

[0040] Preparation and purification of abiraterone acetate ester

[0041] The abiraterone 39kg dissolved in pyridine 230L, 78L of acetic anhydride was added at room temperature, heating, holding temperature of about 70-80 ° C, the reaction for about 4 h, TLC monitoring of the reaction was complete. The reaction was cooled to room temperature, the ice bath, ice water was added to the 840L reaction solution, stirred 30min, filtered, washed with water, 50_55 ° C blast drying. The crude product was added to 39L of ethanol was dissolved by heating to clarify. Water was added 39L, stirred for lh then cooled to room temperature and filtered. Blast drying. Abiraterone acetate to obtain the final ester 33.2kg, HPLC> 99.5% ο

Abiraterone acetate [17-(3-pyridyl)-5,16-androstadien-33-acetate] is a steroid compound which inhibits selectively and efficiently the enzyme 17-ohydroxylase-C17- 20-lyase, which catalyzes the conversion of dehydroepiandrosterone and androstenedione to testosterone. The inhibition of said enzyme causes a strong decrease of testosterone levels in the patient and therefore this drug is used in the treatment of certain hormone-dependent tumors resistant to chemotherapy such as prostate cancer. This compound has the followin chemical formula:

This product was disclosed for the first time in WO 93/20097, which also provides a synthetic process for its preparation including as last step the reaction of an enol triflate with a pyridine borate by Suzuki coupling (see scheme below). However, this process is not viable in practice, mainly because of the difficulty in preparing the enol trifluorosulfonate at the 17-position 2: this step, apart from proceeding with a poor conversion and low yield, gives place to the impurity tri-unsaturated 3 in a 10% yield, which only may be removed by column chromatography. Further, the product obtained after the subsequent Suzuki coupling must be also purified by column chromatography according to the examples provided therein.

Abiraterone-acetate

The above-mentioned impurity was prevented in later processes (EP 1 781 683 y EP 1 789 432) thanks to the use of alternative bases to that previously employed (i.e. 2,5-ditert-butyl-4-methylpyridine) such as DABCO, DBU or tryethylamine. However, in the sole example described in said documents, whilst the final product is achieved without using any column chromatography, it is obtained in a global yield of scarcely 21 % and shows a purity of only 96.4%.

EP 0 721 461 proposes the use of a vinyl iodide or bromide intermediate instead of the enol triflate, as depicted in the following scheme:

However, the iodo-enol is much less reactive than the triflate in the coupling with the pyridine borane, resulting in long reaction times (48 hours – 4 days) with a part of the starting material unreacted and wherein until a 5% of a dimeric impurity is obtained, which can only be removed by purification by means of reverse phase column chromatograp

Therefore, there is still a need of developing new processes for obtaining 17-(3- pyridyl)-5,16-androstadien-33-ol and related compounds, some of which are of therapeutic interest (e.g. abiraterone acetate) which overcome all or part of the drawbacks associated to the known processes belonging to the state of the art.

The chemical name of abiraterone acetate ⑽) -17- (3- pyridyl) – androsta-5,16-diene-3-acetate, by the oral US Centocor Ortho developed CYP17 inhibitor . As anti-cancer drugs on the market April 28, 2011 by the US Food and Drug Administration (FDA) approval, in combination with prednisone therapy with castration-resistant prostate cancer. Trade name Zyitga. Abiraterone acetate is an oral androgen synthesis inhibitors, capable of inhibiting 17a- hydroxylase / C17,20-lyase (CYP17). Clinical results show that abiraterone acetate can significantly prolong patients with advanced prostate cancer include the use of one or both docetaxel-containing chemotherapy but her condition is still deteriorating lives of patients, the risk of death by 35%, and the side effects of drugs is very small, good safety.

[0003] Currently, the synthesis of abiraterone acetate routes are mainly three: (1) dehydroepiandrosterone acetic acid as a starting material, first-butyl-4-methylpyridine 2,6_ di ( esterified by trifluoromethanesulfonic anhydride, then with diethyl under DTBMP) under catalytic bis-triphenylphosphine palladium chloride – acetate proceeded abiraterone acetate Suzuki coupling (2-pyridyl) borane the total yield of the reaction is 48.7%; short reaction step of the process, but after the first-stage reaction a lot of by-products, to be purified by column chromatography, and the double bonds can not be divided by-products, and therefore remains a need for second-stage reaction column chromatography Analysis and purified by recrystallization complicated operation; (2) DHEA as a starting material, a condensation reaction of a hydrazone with hydrazine hydrate, and the presence (TMG) in 1,1,3,3-tetramethylguanidine ene reaction with iodine to generate iodine compound 17- iodo – male left -5,16_ diene -30- alcohol, then in the catalytic bis-triphenylphosphine palladium dichloride and diethyl – (3-pyridyl ) borane was prepared by Suzuki coupling abiraterone abiraterone acetate to give finally acetylated hydroxyl prepared. The total yield of the reaction is 41.5%. This synthesis step is longer, lower yields, and since the active iodides easy to generate high polymer impurities that can not be removed by recrystallization or column chromatography, can only be purified by preparative chromatography to give A in the Suzuki coupling process Long bit acetate pure, can not meet the requirements of industrial production; (3) in the method (1) was treated with triethylamine instead of DTBMP, reduces the formation of byproducts double bond, then after the reaction the remaining starting material was recrystallized removed. This reaction increases the process steps and the purity of the final product was only 96.4%, the drug does not meet the quality standards.

Example 1

[0021] One method of synthesis of abiraterone acetate, comprising the steps of:

[0022] A, in a 100ml round bottom flask were sequentially added 0 • 95g (5mmol) of p-toluenesulfonyl chloride, 15 mL of toluene, sufficiently stirred to dissolve, to obtain X-solution, (solution cooled to 15 ° C X) at 15 ° C under a slow was added dropwise by molar ratio of 1: 2 was added 1.5mL (lOmmol) 80% hydrazine hydrate to the solution X, dropwise within 5min; 3〇min reaction was continued, white precipitate appears in the flask. TLC analysis of the reaction end point is determined. After completion of the reaction, cold water was added 3〇mllO ° C., Stirred, filtered off with suction, the filter cake was then washed with purified water 3-5 times, and dried to obtain a white crystalline p-toluene sulfonyl hydrazide billion • 82g, 86.3% yield ( literature values: yield 92%).

[0023] B, DHEA -17- Synthesis of p-toluenesulfonyl hydrazone

[0024] In a 100ml round bottom flask were sequentially added in square • 75g CMmo 1) dehydroepiandrosterone (DHEA), 25 mL of methanol, 0.81 g sufficiently stirred to dissolve the p-toluene sulfonyl hydrazide, rt (15_25 ° C), was added O.lmL 0.2 mol .L-1 sulfuric acid, 60 ° C in an oil bath at reflux for 2h, TLC analysis of the reaction end point is determined. After completion of the reaction, the solvent was largely removed by rotary evaporation, a heavy white precipitate appeared in the flask. Was added 30mL of water, filtered off with suction, the filter cake was then washed with purified water 3-5 times to remove water at one thousand bake 50 ° C, to give a white solid 1.27g i.e. -17- Dehydroepiandrosterone p-toluenesulfonyl hydrazone, yield 81.4%.

[0025] C, 17- (3- pyridyl) androsta-5,16-diene–30- _ Synthesis of alcohol

[0026] In a 100ml round bottom flask was added 0.91g (2mmol) -17- Dehydroepiandrosterone p-toluenesulfonyl hydrazone, 25mLl, 4- dioxane, 〇.27g (3 mmol of) lithium tert-butoxide, 0_012g (0.013mmol) Pd2 (dba) 3,0.023g stirred for five minutes to fully dissolve the (0_005mmol) Xphos, at room temperature, wherein Pd2 (dba) 3 were added under nitrogen, and then quickly added 0.39g (2.5mmol) 3- bromo pyridine, 95 ° C oil bath reactor 12h, TLC analysis of the reaction end point is determined. After the reaction, ice water was added 30mL0 ° C, thoroughly shaken, ethyl acetate was added 20mL of acetic acid, liquid separation, was extracted with ethyl acetate (1 〇ml each, extracted three times) and the combined organic phase was dried over anhydrous sodium sulfate (by lg / ml was added over anhydrous sodium ratio) sulfate, filtered, and the filtrate rotary evaporated to give a pale yellow solid which was recrystallized from n-hexane (20ml) to give a white solid that is 17- (3-pyridyl) – male stay -5, 16- -3P- diene alcohols, a yield of 42.6%.

[0027] D, Synthesis of abiraterone acetate

[0028] In 0.39gl7- successively added 100mL round bottom flask (3-pyridyl) – androsta-5,16-diene-fir -3 – ol, 3〇111 dagger diethyl ether, 0.15mL (0.25mmol) triethylamine amine, are hook stirring, was slowly added dropwise 0.3 mL (2mm〇l) of acetyl chloride, the reaction stirred at room temperature Jiao 3h, TLC analysis of the reaction end point is determined. The mixture was then suction filtered, the filtrate was decolorized with charcoal, rotary evaporation, to give a white solid, i.e. abiraterone acetate product yield of 80.6%.

[0029] Example 2

[0030] A, in a 100ml round bottom flask were added 1. (^ (5.311111101) p-toluenesulfonyl chloride, 15 mL of toluene, sufficiently stirred to dissolve to give the solution X, at 15 ° C was slowly added dropwise 1 • 7mL (12mmol) X 80% hydrazine hydrate to the solution in dropwise within 5min; reaction was continued for 30min, a white precipitate appeared .TLC analysis to determine the end of the reaction after the completion of the reaction flask was added 30ml 10 ° C water with stirring, suction filtered, then the filter cake. washed 3-5 times purified water, was dry, i.e., p-toluenesulfonyl hydrazide to give white crystals 0.93 g, 86.7% yield (literature: yield 92%).

[0031] B, DHEA -17- Synthesis of p-toluenesulfonyl hydrazone

[0032] successively added 0 • 97g (3mmo 1) dehydroepiandrosterone (DHEA) in a 100ml round bottom flask, 25 mL of methanol, 1 • 08g p-toluene sulfonyl hydrazide, fully dissolved with stirring at room temperature, was added O.lmL 0.2mol • L_1 sulfuric acid, 60 ° C in an oil bath at reflux for 2h, TLC analysis of the reaction end point is determined. After completion of the reaction, the solvent was largely removed by rotary evaporation, a heavy white precipitate appeared in the flask. Was added 30mL of water, filtered off with suction, the filter cake was then washed with purified water 3-5 times, 5 (TC drying under removal of water, to give a white solid 1.43g i.e. Dehydroepiandrosterone p-toluenesulfonyl hydrazone -17- yield 80.9%.

[0033] C, 17- (3- pyridyl) -30- _ male left diene -5,16-ol Synthesis

[0034] In a 100ml round bottom flask was added in 1.32g (3 mmol of) -17- Dehydroepiandrosterone p-toluenesulfonyl hydrazone, 25mLl, 4- dioxane, 0.35g (4mmol) of lithium t-butoxide, 0.012g (0.013_ol) Pd2 (dba) 3,0.023g stirring for five minutes under fully dissolved (0.005mmol) Xphos, at room temperature, wherein Pd2 (dba) 3 were added under nitrogen, and then quickly added 0.48g (3mmol) 3- bromo pyridine, 80 ° C oil bath and the reaction 19h, TLC analysis of the reaction end point is determined. After the reaction, 30mL of ice water was added, shaken well, 2〇mL ethyl acetate was added, liquid separation, was extracted with 30ml ethyl acetate (10ml each, extracted three times) and the combined organic phases were scaled lg / ml was added anhydrous dried over sodium sulfate, filtered, and the filtrate was rotary evaporated to give a pale yellow solid which was recrystallized from 20ml of n-hexane to give a white solid that is 17- (3-pyridyl) – androsta-5,16-diene–3P- alcohol, 42 • 6% yield.

[0035] D, Synthesis of abiraterone acetate

[0036] In 0.41gl7- successively added 100mL round bottom flask (3-pyridyl) -! -33- androst-5,16-diene-ol, ^ 3〇 diethyl ether, 0.2mL (0 • 3 round 〇1 ) of triethylamine, stir, slowly added dropwise 0.3mL (2mmol) of acetyl chloride, the reaction was stirred at room temperature for 3h, TLC analysis of the reaction end point is determined. The mixture was then suction filtered, the filtrate was decolorized with charcoal, rotary evaporation, to give a white solid, i.e. abiraterone acetate product yield of 81 • 2%.

[0037] Example 3

[0038] A, were added in a 100ml round-bottomed flask 1.08g (5.7mmo 1) p-toluenesulfonyl chloride, 15 mL of toluene, sufficiently stirred to dissolve to give the solution X, at 15 ° C was slowly added dropwise 1 • 8mL (13mmo 1 ) of 80% hydrazine hydrate to the solution X, dropwise within 5min; reaction was continued for 30min, a white precipitate appeared in the flask. TLC analysis of the reaction end point is determined. After completion of the reaction, water 30ml 10 ° C with stirring, filtered off with suction, the filter cake was then washed with purified water 3-5 times, and dried to obtain a white crystalline p-toluene sulfonyl hydrazide 0.94g, 85.6% (Yield literature values: yield 92%).

[0039] B, DHEA -17- Synthesis of p-toluenesulfonyl hydrazone

[0040] 1 • 18g were added in a 100ml round bottom flask (3.3 mmol) Dehydroepiandrosterone, 25 mL of methanol, 1.28 g of p-toluene sulfonyl hydrazide, fully dissolved with stirring at room temperature, was added O.lmL 0.2mol • I / a sulfate, an oil bath at reflux for 2h, TLC analysis of the reaction end point is determined. After completion of the reaction, the solvent was largely removed by rotary evaporation, a heavy white precipitate appeared in the flask. Was added 30mL of water, filtered off with suction, the filter cake was then washed with purified water 3-5 times, 5 (TC drying under removal of water, to give a white solid 1.51g i.e. Dehydroepiandrosterone p-toluenesulfonyl hydrazone -17- yield 80.9%.

[0041] C, 17- (3- pyridyl) – androst _5,16- diene synthetic alcohols -3P-

[0042] Add l_45g (3.2mmol) -17- Dehydroepiandrosterone p-toluenesulfonyl hydrazone, 25mLl, 4- dioxane, 0 • 35g in 100ml round bottom flask (4mmol) of lithium tert-butoxide, 0.012 g (0.013mmol) Pd2 (dba) 3,0.023g (0.005ramol) Xphos, fully dissolved after stirred at room temperature for five minutes, wherein Pd2 (dba) 3 were added under nitrogen, then added rapidly 0 • 60g (4mmol) 3 – bromopyridine, 120 ° C oil bath and the reaction 9h, TLC analysis of the reaction end point is determined. After the reaction, 30mL of ice water was added, shaken well, was added 20mL of ethyl acetate, separated, extracted with 30ml ethyl acetate (10ml each, extracted three times) and the combined organic phases were scaled lg / ml was added over anhydrous sodium to intervene sulfate, filtered, and the filtrate rotary evaporated to give a pale yellow solid which was recrystallized from burning 2〇ml n-hexyl, i.e. 17_ to give a white solid (3-Jie ratio piperidyl) – androst -5,16_ diene -30- alcohols, a yield of 43.1%.

[0043] D, Synthesis of abiraterone acetate

[0044] successively added in a round bottom flask i〇〇mL 0.52gl7- (3- pyridyl) -! -30- androst-5,16-diene-ol, ^ 3〇 diethyl ether, 0.25mL (0.36mmol) triethylamine, stir, slowly added dropwise 0.35 mL (2.2 mmol) of acetyl chloride, the reaction was stirred at room temperature for 3h, TLC analysis of the reaction end point is determined. The mixture was then suction filtered, the filtrate was decolorized with charcoal, rotary evaporation, to give a white solid, i.e. abiraterone acetate product yield of 81.8%.

[0045] In each of the above embodiments, the improved synthetic route abiraterone acetate to DHEA as raw materials by the condensation of p-toluenesulfonyl hydrazide, and then reacted with 3-bromopyridine coupling occurs, acetylation, etc. 3 target product was synthesized from abiraterone acetate, 43.4% overall yield.Route and the mild reaction conditions, readily available and inexpensive raw materials, low production cost.