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United States Patent (10) Patent No.: US 7,790,910 B2 Macdonald Et Al

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United States Patent (10) Patent No.: US 7,790,910 B2 Macdonald Et Al US007790910B2 (12) United States Patent (10) Patent No.: US 7,790,910 B2 MacDonald et al. (45) Date of Patent: Sep. 7, 2010 (54) PROCESS FOR THE PREPARATION OF 2003/0069434 A1 4/2003 Bohlmann et al. 7OALKYLATED 19-NORSTEROIDS 2005, OO33085 A1 2/2005 Warren et al. (75) Inventors: Peter Lindsay MacDonald, Gentilino FOREIGN PATENT DOCUMENTS (CH); Ettore Bigatti, Balerna (CH): DE 24, 29 O40 1, 1975 Pierluigi Rossetto, Balerna (CH) DE 19622 457 11, 1997 EP O138504 T 1988 (73) Assignee: Sicor Inc., Irvine, CA (US) WO WO93/10741 6, 1993 WO WO99/33855 * 7/1999 (*) Notice: Subject to any disclaimer, the term of this WO WO99,42109 8, 1999 patent is extended or adjusted under 35 WO WOO2,32922 4/2002 U.S.C. 154(b) by 1427 days. WO WOO3,O31399 4/2003 WO WOO3,O45972 6, 2003 (21) Appl. No.: 11/192,071 WO WO98,07740 T 2003 (22) Filed: Jul. 27, 2005 OTHER PUBLICATIONS Bucourt, et al., “New Biospecific Adsorbents For The Purification Of (65) Prior Publication Data Estradiol Receptor'. Journal of Biological Chemistry, 1978, pp. 8221-8228, vol. 253, No. 22. US 2006/OO30552 A1 Feb. 9, 2006 Dasilva, et al., “Synthesis And Structure-Affinity Of A Series of 7alpha-Undecylestradiol Derivatives: A Potential Vector For Related U.S. Application Data Therapy And Imaging Of Estrogen-Receptor-Positive Cancers'. Journal of Medicinal Chemistry, 1990, pp. 430-434, vol. 33, No. 1. (60) sy, priat e.sfas: A.i Skaddan, et al., “Synthesis And Binding Affinities Of Novel Re s proV1S1ona application o, o s , Ille Containing 7.Alpha.-Substituted Estradiol Complexes: Models For on Aug. 9, 2004, provisional application No. 60/591, Breast Cancer Imaging Agents'. Journal of Organic Chemistry, 689, filed on Jul. 27, 2004. 1999, pp. 8108-8121, vol. 64, No. 22. Bowler, et al., Steroids, 1989, vol. 54, 71-99. (51) Int. Cl. Rao, et al., Steroids, 1994, vol. 59, 621-627. CO7I I/00 (2006.01) * cited b (52) U.S. Cl. ...................................................... SS2/628 cited by examiner (58) Field of Classification Search. ... 552A628 Primary Examiner Barbara P Badio See application file for complete search history. (74) Attorney, Agent, or Firm Kenyon & Kenyon LLP (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Processes useful in the preparation of pharmaceutical com 4,659,516 A 4, 1987 Bowler et al. pounds such as fulvestrant and processes for the preparation 5,986,115 A 11/1999 Bohlmann et al. of fulvestrant. 6,288,051 B1 9, 2001 Bittler et al. 6,500,669 B1 12/2002 Essigmann et al. 6,780,855 B2 * 8/2004 Bohlmann et al. .......... 514, 182 5 Claims, 13 Drawing Sheets U.S. Patent Sep. 7, 2010 Sheet 1 of 13 US 7,790,910 B2 ) the S3 CN C ) o7-O O 90 no O On ce his C s O 8 Oo C U.S. Patent Sep. 7, 2010 Sheet 2 of 13 US 7,790,910 B2 olo O nondrolone acetate, 6 dehydro Cp 9294 Cp 9340 FIG.2 U.S. Patent Sep. 7, 2010 Sheet 3 of 13 US 7,790,910 B2 U-- l - 3 CM) s n n o C s h O s U.S. Patent Sep. 7, 2010 Sheet 4 of 13 US 7,790,910 B2 h qs S. no O gld S S. C t 2 st -R CD 2 t C ea C d --- 9 S -)-4- : U.S. Patent Sep. 7, 2010 Sheet 5 of 13 US 7,790,910 B2 olo olo !ghH al-e-r-e- H -SiN O O ". O 929 4 9295 nandrolone acetate, 6 dehydro 9541 FIG.5 U.S. Patent Sep. 7, 2010 Sheet 6 of 13 US 7,790,910 B2 h i s U.S. Patent Sep. 7, 2010 Sheet 7 of 13 US 7,790,910 B2 tri n o k ? N d CD - U.S. Patent Sep. 7, 2010 Sheet 8 of 13 US 7,790,910 B2 93.42 Br |tive 9361 9362 HO “1\1\-1\1\1 SH Cp 9360 (4,4,5,5,5-pentafluoropentane 1-ol-mesylate) O o's F. F 9363 HO 1N1N1N1,N1 F F KOH OH R F 9304 HO A.'1N1N1N1N1 S-X- F V Oxidise F fulvestrant (9305) U.S. Patent Sep. 7, 2010 Sheet 9 of 13 US 7,790,910 B2 OH 9354 HO -n-n-n-n-Br thioured 9388 SN NH2.HBr sodium hydroxide OH 9589 HO '1N1N1N1N1 SH Cp 9360 (4,4,5,5,5-pentofluoropentane 1-ol-mesylate) F F 9304 sodium periodate Or hydrogen peroxide OH F F fulvestront F U.S. Patent Sep. 7, 2010 Sheet 10 of 13 US 7,790,910 B2 93.42 HS ---F F F 9,383 9363 9.504 Sodium periodate Or hydrogen peroxide fulvestront 93.05 U.S. Patent Sep. 7, 2010 Sheet 11 of 13 US 7,790,910 B2 9354 F. F | is-><- F 9.383 F 9304 l sodium periodate O hydrogen peroxide OH fulvestront 93.05 FIG 11 U.S. Patent Sep. 7, 2010 Sheet 12 of 13 US 7,790,910 B2 9363 Oxidotion O o 93.68 hydrolysis 93.05 FIG. 12 U.S. Patent Sep. 7, 2010 Sheet 13 of 13 US 7,790,910 B2 O o 9563 9368 9305 FIG. 13 US 7,790,910 B2 1. 2 PROCESS FOR THE PREPARATION OF EP Patent No. 0138504 relates to certain 7.O-substituted 7OALKYLATED 19-NORSTEROIDS derivatives of oestradiol and related steroids which possess antioestrogenic activity. U.S. Pat. No. 4,659,516, EP Patent CROSS REFERENCE TO RELATED No. 0138504 and Bowler, Steroids 1989, 54, 71 describe a APPLICATIONS process for making steroids such as fulvestrant, by which 1.6-conjugate addition of an alkyl group to an estra-4,6-di This application claims the benefit of U.S. provisional ene-3-one gave a ratio of 7C.- to 7 B-epimer of 1.2:1 (isolated). application Ser. Nos. 60/591,689, filed Jul. 27, 2004; 60/600, In WO 02/92322 it is stated that the ratio of epimers obtained 292, filed Aug. 9, 2004; and 60/633,927, filed Dec. 6, 2004, using this process on an industrial scale is 1.9:1. the contents of which are incorporated herein in their entirety 10 U.S. Pat. No. 6,288,051 describes 7O-(5-methylaminopen tyl)-estratrienes. FIELD OF THE INVENTION There remains a need in the art for improved methods of The invention relates to a new processes useful in the preparing fulvestrant and other 7O-alkylated 19-norsteroids. preparation of pharmaceutical compounds such as fulves 15 trant. SUMMARY OF THE INVENTION BACKGROUND The invention relates to A compound of formula (I): There is a growing recognition of the need for effective (I) therapeutic strategies to treat breast cancer patients that are less toxic than chemotherapy. Since the discovery of the hormonal dependency of many breast cancers, endocrine therapy has been extensively investigated. 25 Fulvestrant is a pure antiestrogen that represent a signifi cant breakthrough in the treatment of breast cancer. Despite its pure antagonist activity, studies on ovariectomized rats HO "(CH,n-R have confirmed that fulvestrant, in contrast to Tamoxifen which acts like estrogen to reduce periosteal bone formation, 30 does not alterestrogen-like or antiestrogenic effects. Fulves trant also has some distinct advantages on target organs other wherein than breast tissue. n is an integer ranging from 3 to 14, Fulvestrant is a steroidal pure antiestrogen with a chemical R is selected from the group consisting of Br, Cl, I, free structure similar to estradiol. Studies of estrogen receptor 35 base or a salt form of isothiouronium, or SH: (ER) function have demonstrated that estradiol binding to the R is either hydrogen, Ce alkyl, hydroxyl, protected ER initiate a sequence of events. Fulvestrant antagonizes hydroxy, or halo; estrogen action by occupying the ER and preventing estro R is either hydrogen, Ce alkyl, C- alkenyl, or C. gen-stimulated gene activation, thus interfering with the alkynyl: estrogen related processes essential for cell-cycle comple 40 tion. R is either hydroxy, or a C-acyloxy; Fulvestrant, 7-alpha-9-(4.4.5.5,5pentafluoropentylsul Rs is C alkyl, and phinyl)nonyl-estra-1,3,5(10)-triene-3,17(3-diol, has the fol R is either hydrogen, Ce alkyl, hydroxyl, protected lowing formula: hydroxy, or halo. OH HO fulvestrant WO Patent application No. 02/32922 describes a process 60 In one embodiment, n is 9, R is Br. R. R. and R are for preparing an intermediate compound useful for preparing, hydrogens, R is hydroxy and Rs is methyl. e.g. fulvestrant, which process comprises aromatization of a In one embodiment, n is 9, R is Br. R. R. and R are compound, and thereafter if necessary or desired, carrying hydrogens, R is acetyloxy and Rs is methyl. out one or more of the following steps: (i) removing any 65 In one embodiment, n is 9, R is a hydrobromide salt of hydroxy protecting group; (ii) converting a precursor group to isothiouronium, R. R. and Rare hydrogens, R is acetyloxy a different Such group. and Rs is methyl. US 7,790,910 B2 3 4 In one embodiment, n is 9, R is a hydrobromide salt of wherein isothiouronium, R. R. and R are hydrogens, R is hydroxy n is an integer ranging from 3 to 14, and Rs is methyl. X is either O or S: In one embodiment, n is 9, R is SH, R. R. and R are R is a Co haloalkyl or a hydroxy protecting group: hydrogens, R is acetyloxy and Rs is methyl.
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