2 United States Patent Cristiano et al. US009556219B2 US 9,556,219 B2 Jan. 31, 2017 (a0) Patent No. 4s) Date of Patent: (54) PROCEDURE FOR THE PREPARATION OF ABIRATERONE ACETATE AND INTERMEDIATES THEREOF (71). Applicant; Oton S.P.A., Rodano (Mi) (ET) (72) inventors: Tania Cristiano, Milan (IT); Mareo Alpeglani, Rosavo (IT) (73) Assignee: OLON 81 Rodano (IT) (#) Notice: Subject to any disclaimer, the term ofthis patent is extended or adjusted under 35 USC. 154(b) by 0 days (21) Appl No: 15/114,089 (22) PCT Filed: Jan. 27, 2018 (86) PCT No. §371 OD, (2) Date PCT/AB2015/050613 ul 26, 2016 (87) PCT Pub. No: WO2OIS/HI4518 PCT Pub, Date: Aug. 6 2015 (6) Prior Publication Data US 201610347786.A1 Dee. 1, 2016 G0) Foreign Application Priority Data fan. 28, 2014 (IT) Mi2014A0111 (51) Int. ch C071 43700 coz 3100 (2) US.C cre (2005.01) (200601) (C07 43003 (2013.01), CO7S 31/006 201301) (68) Fleld of Classification Search cc COT] 43/003: COTI 31/006, See application file for complete search history. 66) References Cited FOREIGN PATENT DOCUMENTS wo 9320097 AL 10/1993 wo 2006021777 AL 3/2006 wo 2ors0sseo1 AL 42013, (OTHER PUBLICATIONS. Aadi, ef al: “Palladum-catalysd coupling of aryl and vay Uiftes or halides with 2- diclomethane, 1.2-ticloroethane and ehlorobutane “The reaction i condvted at a temperature ranging betiveen ~70° C, and +30° C, preferably between ~30° C. and 420° C, fora reaction time ranging between I and 20 1, preferably between 3and 10h The conversion is typically greater than 90% and the molar yield is greater than 80% ‘At the end of the reaetion the reaction mixture is quenched, profzably with water of with acidic or base aqueous solutions. The organi phase can be used dire, “as is" or aftr concentation, for the next step, eile (14) canbe isolated by erystallsaton as deserbad below. Pariculrly prefered conditions forthe rilationreetion axe as follows toiling agent triluoromethanesuiphonie anhydride (equivalents: 1.0 0 1.5) base: picoline (equivalents: 0.75 101.5) solvent: methylene chloride “To minimise the formation of impurities, the base is convenivaly added tothe reaction mint, typically ia a time ranging botwoen I and 5 hours, fier the addition of anhydride. When operating under these conditions itis possible to have bth an optimnim conversion of prasterone teiluoroacetate (13) and a tifa intermediate (14) of high purty. Lowering the reaton temperature reduces the for nation of impunis, ) Optional Crystalisation of Trifle (14) ‘The low impurity profile of the organic phase containing teflate (14) enables it to be isolated by'crystllisation, After the concentration of the organic phase, it an be crystallised by adding an organi solvent, preferably an alcohol such as riethanol, of a mixture of solvents. The product thus obiained usually hos a purity exceeding 909%, andthe main impurity is prasterone Wifluoroacetate (13), Optionally, wiflate (14) is recrystallised from alechotie solvents, preferably from methanol. The produet is ot With good yields and very high purty (purity about 99.5%) ‘hillate (14) i a crystalline product characterised by the X-ray powder dillaction (XRPD) profile, IR spectrum and TEANMR, 13C-NMR and 19F-NMR spectra shown in example 9, «Conversion of Teiflate (14) to Abiraterone (2) ‘Tile (14) is preferably converted to abirterone (2) under conditions specified fra Sunuki-Miyaura condenss- tion, also known as the Suzuki rection and well-known to the skilled person, Tifte (18) is condensed. with a S-pyrdylborane or 3-pyridylboronic derivative inthe pes ace of a palladium-based catalyst. “The reaction solvent comprises a mixture consisting of an onganie solvent, preferably tetrahydrofuran, dioxane, meth- yitevakydrofurn, acetonitrile or toluene, and an aqueous Solution containing an alkali bicarbonate, earbonate, hydroxide or carboxylate, such as potasium carbone, sodium carbonate, caesium carbonate or potassium acetate “The 3-pyidyl borane derivative i profebly a daly pyridyl borane “The 3pyridylboronic derivative is preferably 3.pyridyl- boronic acid or an ester thereof. The use of dithyl3- pytiyborane is pariculary prefered The catalyst i preferably’ tetrakis triphenylphosphine palladium, bisteipheny}phosphin)palladium dichloride, or palladium acetate or pallu chloride, in the presence of 5 ligand such a wipieaylphosphineUS 9,556,219 B2 7 ‘The reaction is typically conducted hot, ta temperature ranging between 40° C. andthe retux temperature ofthe mitre Suitable reaction conditions are, for example, those described inthe patentspatent application cited above for s wie (4). A prefred procedure involves reacting tifate (14), isolated or unislated, crude or purified, with diehyi@- pyridyDborane inthe presence of bis(iphenyphosphine) palladium dichloride in a mixture comprising an organic solveat such s tetrabydeofiran, acetone oF methttrax hydra, and an aqueous soltion ofan alkane earbon- Preferably, about 1.0 to 1.$ equivalents of dethyl- rysdy) borane and 2 to 10 equivalents of sodium or pots- sium carbonate per mole of tifate (14) are ade to the reaction mixture. More preferably aout 11 to 1.3 equiva lens of dethyl@-pyridy)borane and 31 $5 equivalents of sodium or ptesium carbonate per mole of tifa (14) are ‘added to the rection mixture valuation ofthe stoichiometric rato, whichis dieu v0 conduct when the tiflates are not islatable or not isolated, as in the ease o rift (3) o (6) is paicularly convenient ‘vith wile (14), whichis slstable as a erste solid, the assay value of which can easly be detemined. Its 2s therefore possible to measure the borane derivative acct rately, with benefits in terms of quality and yield of the reaction product ‘The catalyst is preferably added in quantities ranging from 0.001 to 0.020 telat (14) equivalens “The reaction is preferably comictd at refx temper ture, andthe rection and hydrolysis time ranges from 1 0 6 hours, preferably 2 to 4 hours “The prot of the ection is abiraterone (2). The typical conditns ofthe Sonik rection spied foie (14) ‘aise simultaneous hydrolysis of tafluoroacetate atthe 3 position ofthe steroid. Iypicalyabizaterone (2) precipitates from the reaction mixture and can be recovered optionally ‘fer the addition of water tothe reaction mixture andlor Partial concentration of the mixture, hy simple filrtion. ‘The abinterone 2) thus obtained is characterised by a high degree of purity ypically exceeding 98%. Irnecessary it ean be reenysalsed from an panic solvent such as methanol, llamo, isopropanol, actonitile, terahydeo- fan, -metbytetahydrofuran, ethyl acetate, isopropyl scale oF methylene chloride, or @ mixture thereat ‘The product i obtained with good yields and very high purity (995%), Abiraterne (2) can then be converted to abinterone acetate (1) by one ofthe known methods. The acesltion ‘an be conducted, for example, with an aeevlting agent such as acetyl chloride or acetic anhydride ia the presence a ‘an omic ase such as pyridine or wiethylanine. However, ‘we have found that sud conditions are unsatisfactory to obtain biraterone acetate (1) with high yields and purity and above all the operations involving recovery Of the reaction product an elimination ofthe organic has or salts there) Used a aid seeptor in the reaction are laborious This complication will be understood if it is bore in mind that abraterone and the coaesponding acetate ae stuctu ally character by the presence of pyedine azoup. ‘We have unexpectedly found that abirateone (2) can be scsylated oabisterone acetate (1) inte absence of bases ‘or acetylation catalysts, simply by trating abirsterone (2) hot with acetic anhydde. The typical reaction conditions are as fllows: Reagent 1.510 20 aeetic anhydride equivalents per mole «8 ol abiraiewone. More preferably about 10 o 18 aeetie anhydride equivalents » x0 ” 4s so © Solvent without solvent or in aprotic solvent, for example ‘an ester such as ethyl acetate, meth] setae, isopropyl acetate or butyl acetate. ‘Temperature: 20° C. to 85° C., preferably 50°C. 10 75°C. Time: 1 to 20 hours End of reaction: reaction suitably monitored by HPLC; conversion typically 99.5%, ‘Work-up: The amount of acetic anhydride present atthe ‘ed ofthe reaction can be coavenicntly eliminated or drastically reduced by treating the reaction mixture hot with water or an aleobol, preferably a primary aleohol such as methanol. ‘The resting mixture is then treated one or more times \with an aqueous solution of aa alkaline earbonate of bicat- bona to remove the acetic acid formed during the reaction, ‘and any traces of acetic anhydride. The organic phase ean then be treated with decolourising carbon and suitable chelating resins Isolation abiraterone acetate (1) canbe isolated by simple filtration of the concentrated solution, or the residue alter concentration can be crystallised from an orpanic solvent or mixture of solvents, preferably selected from, acetonitrile, methanol, ethanol and isopropyl alcoho, ‘The punity ofthe abiraterone acetate (1) thus obtained is ‘greater than 99.5%, typically 299.8%, Prasterone triluoroacetate (13) isa known product which can be ‘by known techniques fom prasterone (dehydroepiandrosterone) (8), a commercially available Intermediate that is widely used inthe production of steroid erivatives The invention will now be stated bythe flowing examples. Example 1 Synthesis of Prasterone Triluoroacetate Trillate ‘Trifluromethanesulphonic anhydride (47 mL.) and asolu- tion of picline 26 ml) in methylene chloride (200 mL.) are added in sequence oa solution of prasterone triluoroacetate (100 g) in methylene chloride (118 L), aisintaining the temperature a ~25° C. (25° C.), and let under sterng for about 9h. After the alton of water (1.5L), the organic phase is separated and washed with water and aqueous Sodium chloride, concentrated under vacuum and methanol (about 400 ml.) is added, to obtain a precipitate. The solid is filtered, washed with methanol and dried under vacuum, ‘The crde riflat thus obtained (about 130 g; HPLC analysis indicates a content of 118 g of pure teilate and 9.6 g of prasterone tifluoroaeetate) can be used to prepare abirater- ‘ne without furhee purification. Example 2 Synthesis of Abiraterone Inan inert gas environment, diethy1(-pyridylJborane (28 1) bis(eipheaylphosphine)palladium dichloride (1.2) and 2M aqueous solution of sodium carbonate (320 mL.) are added 10 solution of prasterone trifuoroacelate tiflate prepared as described in example 1 (100 g) in tetrahydro~ ran (1.4 L). The resulting mixture is refluxed for about 2 hy its then cooled to room temperature and water (1.0 L) is ‘added, The suspension is cooled 10 0-5°C. and filtered. After ddiying, 42 g of erude abiraterone is obtained (purity about 9886) Example 3 Syuthesis of Abiraterone Acetate Acetic anhydride (438 g) is added 10 a suspension of abiraterone (100 g) in ey! acetate (600 mL.) The solutionUS 9,556,219 B2 7 is refluxed until the eaction is complete (about 10 h); the temperature is then reduced to about 50° C. and methanol (230m) is added. The soltion is maintained under stiing for 2 h, then cooled to ambient temperature, and ethyl acetate (400 mL) and an aqueous solution of sodium car- honate (1.2 L) are added. The phases are separated and the ‘organic phase is treated with decolourising carbon. After ‘concentration under vacuum, the concentrate is taken up ‘with acetonitrile (about 500 mL) to obtain sandy solid, Which is isolated by filtration at 05° C. and dried under ‘vacuum at 40° C. for 16 h (about 80 g; purty: 99.8%), Example 4 Synthesis of Abiraterone Acetate A suspension of abiraterone (50 g) in acetic anhydride (220 g) is heated to 70° C. until the reaction is complete (about 8 h; itis then cooled wo $0° C, (25° C.) and methanol (150 mL) is added. The mixture i maintained under string. 2 at 50° C. for 2 by then cooled to room temperature. Ethyl ‘acetate (350 mi) and an aquedus solution of sodium bicat- tomate (300 ml.) are added, The phases are separated and the ‘onganie phase is treated with docolourising carbon, then ‘concentrated under vacuum and the eonceatrate is taken up 28 ‘with acetonitrile (about 250 mL) to obtain a sandy solid, Which s isolated by filtration and dried under vacuum (about 50 g: purity: 99.8%), Example 5 Synthesis of Abiraterone Inn inen gas environment, dithyl(3-pyridyDhorane (6.9 ‘8, bistipheaylpbosphine) palladium dichloride (03 g) and 8.2M aqueous solution of sodium carbonate (106 ml) are audded to a solution of prasterone tifuoroacetate wiflate prepared as deseribed in example 1 (25) in tetahydrofuran (350 ml). The resulting mixtures refluxed for about 2h it is then cooled to room temperature and water (250 mi.) is aud, The suspension s concentrated under vacuum o hal its volume, and then filtered. 13 g of crude abiraterone is ‘obtained (purity about 90%). Example 6 Synthesis of Abirsterone Acetate Abiraterone obtained 2s describe in example $i aety= lated by the procedure described in example 3. The airater- ‘one aette thus obtained is purited by enstalistion from scooniti (ied 93% ww: purty >89.5%), Example 7 Symthesis of Prasterone TriluoroacetateTritate ‘The preparation described in example 1 is conducted at the temperature of 0 C. (25° C_) for about 6 h. After the ‘adition of water, th organic phase is separated and washed ‘with water and agueous sodium chloride, The solution is ‘concentrated under vacuum and methanol and acetonitile ‘are added 10 obtain a precipitate, which is isolated by filtration and dred under vacuum. The titular produet is ‘obtained with a yield of 115% wiv and 97% purity A product with 99.5% purity is obtained by reeystlisa- tion from methanol 10 Example & Synthesis of Prasterone TriluoroacetateTrillate 5 Triflyoromethanesulpbonic anhydride (25 mi.) at=10° C. (45°C), and sodium carbonate (35g) in potions, are added in sequence toa solution of prasterone tifluoroaceate (50 2) in methylene chloride (0.8 L1) The solution is maint under string for about 12 b, and water is then added, The 1 onganie phase is separated and washed with water and agneous sodium chloride, The solution is concentrated under vacuum and methanol is added, followed by acetonitle (methanot/acetonitrile ratio 2:1; about 300 mL.) to obtain a precipitate. The solid is filtered, washed with methanol and vied under vacuum (about 60 g, purty >98%), Example 9 (Characterisation of Prasterone Triluorcacetate “Trillate Prasteonetrifloroacetae trifle isa crystalline product characterised by the X-ray powder diffraction (XRPD) pro- file, IR spectrum and ‘H-NMR, "C-NMR and "°F-NMR 2 spectra reported below: XRPD ‘The XRPD diftectogram was obtained with the inst rmentation and under the conitions described below: Ditfactometer: Broker D2 Goniometer:thetatheta Radiation: CuKar @=1.S419 A) Detector: |-timensional LYNXEYE Scanning: continoous Voltage: KV 30, mA 10 Seanning interval 2.6-40° 20 Increment: 002° 20 Time per inerement: 53 see The XRPD spectrum is substantially as shown in FIG. 1, ao and comprises the peaks, at 2theta (20) angle values, reported in Table 1 x0 TABLE 1 Teniy Relive 4s eat) as Tins Bs 5 nm re) ne 16s ons 151 PH ory 42 59 os so © R ‘The IR spectrum (1% KBr pellet) was acquired in trans- mitiance mode using a Perkin Flmer Specinim 1000 spee- twophotomete, and is reported in FIG. 2. 1 comprises characteristic absorption bands at 2962, 1778, 1741, 1633, 1229 and 1155 cay inter alia,US 9,556,219 B2 uw NMR ‘The NMR spectra were acquired with a Varian Mercury 300 spectrometer using deuterated chloroform as solvent ‘The "H-NMR spectrum is reported in FIG. 3, and shows (inter ala) the following chemical shits & (ppm): 5.59, m, 1H; 5.4, d, 1-5 He, 1H; 481, m, 1H; 10-25, m, steroid 1.08, 5 2CH. spectrum (Attached Proton “Test) is reported in FIG. 4, and shows (inter ala) the following chemical shits 8 (ppm): 159, 139, 2-C; 128.1, 1146, 2-CH— 157, 118, 2 CFs; 78.7, O-CH, ‘The °F-NMR spectaum is reported in FIG. 8, and shows the following chemical shifts ® (ppm): 109, 111, 2 CF. ‘The invention claimed is: 1, Process forthe preparation of abiaterone (2) or abi- raterone acetate (1) \which comprises the following steps 8) converting prasterone teiluoroacetate (13) » x0 ” 4s so 12 to the trifate (14) +) optional crystallizing (14) ©) converting (14) to abiraterone (2) 4) optional converting abirsterone (2) to abiraterone acetate (1, 2. Process forthe preparation of abiraterone (2) according to claim 1 3. Process according to claim 2 wherein step a is eatid ‘out in the presence of tflating agent anhydride, and of a base selected from the group consisting of aromatic oF aliphatic tertiay amines oF inorganic bases in an organic solvent 4, Process according to claim 2 wherein the optional cenystallizing of (14) takes place in an alcoholic solvent 5, Process according to claim 2 wherein (14) is condensed instep ¢) witha 3-pyridylborane or +pyridylboronie deriva- tive in the presence of a palladium-based catalyst in a reaction solvent comprising a mixture consisting of an organic solvent and an aqueous solution containing an alkali bicarbonate, carbonate, hydroxide or carboxylate 6. Process according to claim 4 for the preparation of abiraterone acetate (1). 7. Process according to claim 6 wherein step d) comprises the reaction of abiraterone (2) with acetic anhydride in the absence of bases or acetylation catalyst. 8, Process according o claim 7 wherein step d) is carted ‘out without solvent. 9, Process according to claim 7 wherein step d) is cartied ‘out in an aproti solvent. 10, Process according to claim 9 wherein the aprotic solvent is an ester selected ftom ethyl acetate, methyl ‘acetate, isopropyl acetate and butyl acetate, 1, Process for the preparation of abiraterone acetate (1) comprising the acetylation of abiraterone (2) with acetic ‘anhydride in the absence of bases or acetylation catalysts. 12. Process according to claim 11 wherein the acetylation of abiraterone (2) is carried out inthe absence of solvent 13. Process according to claim 12 wherein the acetylation of abiraterone (2) is carried out in an aprotic solvent. 14, Process according to claim 13 wherein the aprotic solvent is an ester selected from ethyl acetate, mie vette, isopropyl acetate and butyl acetate