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    PROCESS FOR THE PURIFICATION OF ABIRATERONE ACETATE

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    PROCESS FOR THE PURIFICATION OF ABIRATERONE ACETATE

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    14 views6 pages

    US9340571B2

    Uploaded by

    Enrica Ga
    PROCESS FOR THE PURIFICATION OF ABIRATERONE ACETATE

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
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    of 6
    United States Patent Alpegiani et al, (2) US009340571B2 US 9,340,571 B2 May 17, 2016 (10) Patent No.: 4s) Date of Patent: PROCESS FOR THE PURIFICATION OF ABIRATERONE ACETATE, os) (71) Applicant: OLON S.P.A., Rodano (IT) Inventors: m Marco Alpegianl, Rodano (IT); Tania Cristiano, Milan (TT); Eugenio Cuechett, Rodano IT) OLON Assignee: A., Rodano (MI) (1) Notice: Subject o any disclaimer, the term ofthis patent is extended of adjusted under 35 USC 154(6) by 0 days, Appl.Noz 141436527 PCTFiled: Oct. 21,2013, PCT No. §371 (00). (2) Date: PCTEP2013071930, Apr: 17, 201 7) PCT Pub. Nox WO2014/064032 PCT Pub, Date: May 1, 2014 (6s) Prior Publication Data Us 201610052958 A1 Feb. 25,2016 (60) Foreign Application Priority Data xt. 22,2012 aT) Mi2012001788. (3) Ive cor 4300 BOLD 1532 (2006.01) (200601) 2) C071 43/003 (2013.01); BOLD 15/327 01301) (8) ification Search None See application file for complete search history 656) References Cited FOREIGN PATENT DOCUMENTS, ow 101 768 199 2010 x i2ow 78 42011 wo 99178 4/1098 wo 2o130sseeL 42013, (OTHER PUBLICATIONS Poteet al, "A Convenient, Large-Scale Synthesis of Abiterone ‘Aesate AB Bat Acctoxy-17--Pytidy) Anrost-S16-Diene, Potential New Dru forthe Treatment of Prostate Cancer”, Organic Preparations and Process International, Organic Preparation snd Procedure Co, Newt Highlands, MA, US. vol. 2, No 180 1 1997, pp, 123-128, International Search Report and Writn Opinion of PCT/ED2O13) 171930 of Feb. 4 2014 International Preliminary Report on Patentability of PCTIEP2O13) [71930 of Now. 5, 2014 Primary Examiner (74) Attorney, Agent, or Firm Silvia Salvadori Zina Norhington Davis Silvia Salvadori, PC ABSTRACT Te invention relates toa process forthe purification oferude abiraterone acetate by trectment with polymer resins in aque: ‘us solvent, The purified product is recovered by simple concentration and filtration, on 8 Claims, No Drawings US 9,340,571 B2 1 PROCESS FOR THE PURIFICATION OF ABIRATERONE ACETATE, ‘This application isa U.S. national stae of PCTIED2OL3/ (071930 iledon 21 Oct, 2013, which claims priority trandthe benefit of Italian Application No, MI2012A001788 fled on 22 Oct. 2012, the conten of which are ineoeporated herein by reference in their entireties ‘The invention relates to a process for the purification of ‘nude abiaterone acetate by treatment with polymer resins in ‘aqueous solvent. The purified product is recovered by simple ‘concentration and filtration. BACKGROUND TO THE INVENTION Abiraterone acetate, the chemical name of which is (3B)- 17-G-pyridinyl) androsta-5,16-lien-3-y1 acetate, isthe pro drugoftheactive metabolite abiraterone, selective inhibitor ‘of the enzyme CYPI7, Abiraterone acetate isthe active ingredient ofanovel medi- ‘cameat forthe treatment of prostate carcinoma in adult men, ‘The preparation of abiraterone acetate was orginally dis- closed in EPOG33893, ‘The synthesis scheme involves the conversion of dehy «dneepiandrosterone-3-aeeate (I) to the corresponding enol teiflate (1) by treatment with trlluoromethanesuphonie anhydride and 2,6--ert-butyls-methyipyridine ‘The Suzuki reaction betvcen 3P-acetoxyandrosta-S.16- nic acids such as phosphoric acid, or of carboxylic acids such as formic acid or acetic acid, or other salts such as tris-(2shydroxymethy!}-aminomethane hydrochloride (TRIS-HC). The molarity ofthe buifer solutions can range between 10and300mM, preferably between 1Oand 100mM. > ‘The solvent concentration in the starting mixture must be suchas to allow the formation of hydrophobic bonds between the product and the resin, and generally ranges between 30 and 80%, ‘The elution (in isocratic or gradient mode) is preferably performed with mixtures at increasing solvent concentra- tions. ‘The elution rte can range between 0.5 and 2.0 volumes of solvent to volume of resin per hou. ‘The eluate is typically collected in fractions and analysed byastitableanalysistechnique suchas TLC, GC ot HPLC, to ‘establish the procedure for collection of the factions contain ing abiraterone witha high degroe of purity, and optionally the fractions containing significant impurities, Under the optimum operating conditions, the factions of abiraterone acetate with high purity areusually colleted after 4-8 bed volumes ofelueat mixture, “The entire chromatography process, including regenera- lion ofthe resin, typically requires 6 to 12 bed volumes of stuent ‘The fractions containing abiraterone acetate with a purity above 99.5% are concentrated under vacuum to a residual volume amounting to $402 of the ntial volume. In this way the solvent is partly or totally removed and the abiraterone acetate is insolbilised in the remaining aqueous phase, ‘The product is then recovered by filtration or centrifuga tion, and the crystals are washed with 2 minimal amount of water. ‘The product loss inthe mother liquors usually below 19%. ‘The product can be dred under vacuum ata temperature generally ranging between 30 and 60° C. ‘Typically, a white erysalfne product is obtained, with an HPLC purity ranging between 99.5 and 99.8% and an assay above 9%, The resins used forthe purification to which the preseat patent application relates canbe reused numerous ties. tis not necessary o regenerate the resin after each chromatogra- phy rua. The resin ean easily be regenerated in accordance ‘withthe manufacturer's insrections afte a given number of cycles. » ” 6 “The process will now be further illustrated the following, examples. Example 1 ‘Synthesis of Crude Abiraterone Acetate Via Vinyl Trilate I Trifworomethanesulphonic anhydride (137 mL) and picoline (75 ml. in methylene ehiovide (2.5 1) are aed in Sequence fo a solution of prasterone acetate (250g in meth ylene chloride (25 1), maintaining the temperature at between ~5°C. and 0°C, and ff under tiring. for about 2 bh After adding eold water (3.71; 02°C) without exceeding the temperature of 10" C., the organic phase i separated and ‘washed witha cold aqueous solution of 2N HCtand then with ‘aqueous sodium chloride. The mixture is then concentrated ‘under wactum, to obtain an oiy esd (about 340). ‘The cde vinyl trifle thus obtained (about a 41 mixture of vinyl trilate and prasterone acetate) i taken up with tt- ‘ahydrofiran (3.7 [). Diethyl@-pyridy))borane (00 g), bis (tiphenylphosphine)palladium Il chloride (3.8 g) and a 2M sodium carbonate aqueous solution (1 L) are Joa under inet gas environment. The resulting mixture is reluxed for about 1h, then cooled to room temperature and ethyl acetate QS L) and water (25 L) are added. The agueous phase is backentracted with ethyl acetate (14 L), the combined ‘onzanie phases are treated with decoloarising carbon (about 100 ), and then concentrated under vacuum to obtain crude abiraterone acetate a an cl (320 g purity about 879%: assay 51%) Example 2 Synthesis of Crude Abiraterone Acetate Via Vinyl Todide VII 17-lodoandrosta-5,16-dien-3f-ol [Organic Preparations ‘and Procedures Int, 29, 123-134 (1997)} (00 g) in tetra

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