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

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 -

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

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

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

|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

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

fulvestront 93.05

FIG 11 U.S. Patent Sep. 7, 2010 Sheet 12 of 13 US 7,790,910 B2

9363

Oxidotion

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.

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. 5 R is either hydrogen, Ce alkyl, hydroxyl, protected In one embodiment, n is 9, R is SH, R. R. and R are hydroxy, or halo; hydrogens, R is hydroxy and Rs is methyl. R is either hydrogen, Ce alkyl, Calkenyl, or C. The invention also relates to a compound of formula alkynyl: 10 Ra is a C-acyloxy, Rs is C alkyl; and R is either hydrogen, C alkyl, hydroxyl, protected hydroxy, or halo; and Z is a metal halide of the formula R,M, wherein 15 M is a metal atom; and R, is a halogen atom. In one embodiment of the process, n is 9, X is O, R is tertbutyl-dimethylsilyl (TBDMS), R. R. and R are hydro '', Br gens, R is acetyloxy and Rs is methyl. In one embodiment of the process, n is 5. X is O, R is The invention also relates to a process for preparing the TBDMS, R, and R are hydrogens, R is acetyloxy and Rs is compound of formula (II), methyl. In one embodiment of the process, n is 9, X is S, R is 25 —(CH2)CFCF, R. R. and R are hydrogens, R is acety (II) loxy and Rs is methyl. In one embodiment of the process, M is a metal atom selected from the group consisting of magnesium, Zinc, alu minum, copper, copper-lithium and titanium. 30 In one embodiment of the process, M is magnesium. In one embodiment of the process, R, is selected from the group consisting of Cl, Brand I. In one embodiment of the process, R, is Br. 35 In one embodiment of the process, a copper catalyst is a combined in step a) with the 19-nor-androsta-4,6-diene-3- comprising: one of formula (III) and the etheral solvent. a) combining a 19-nor-androsta-4,6-diene-3-one of for In one embodiment of the process, said copper catalystis in mula (III) the form of Cu(DY, wherein Y is Cl, Br or I. 40 In one embodiment of the process, said copper catalyst is Cu(I)Cl. b) (III) In one embodiment of the process, the compound of for mula (II) obtained in step e) has a ratio of 7o- to 7 B-epimer of about 2.5:1 to about 12.1:1. 45 In one embodiment of the process, the compound of for mula (II) obtained in step e) has a ratio of 7o- to 7 B-epimer of about 12.1:1. In one embodiment of the process, the etheral solvent in 50 step a) is selected from the group consisting of diethyl ether, THF and glyme. with an etheral solvent, to obtain a solution; In one embodiment of the process, said etheral solvent is b) cooling the solution to a temperature of about-60° C. to THF. about 30° C.: In one embodiment of the process, the solution of step b) is c) adding to the Solution of step b), in a drop-wise manner, 55 cooled to a temperature of about -20°C. to about -10°C. a solution of the compound of formula (IV) In one embodiment of the process, the reaction mixture in step d) is quenched by one of the reagents selected from the group consisting of NHCl, HCl, water, acetic acid and a (IV) mixture of NHCl with NH-OH. 60 In one embodiment of the process, the reaction mixture is quenched with acetic acid. In one embodiment of the process, the process further comprises converting the compound of formula (II) obtained in an etheral solvent to obtain a reaction mixture; 65 in step e) to fulvestrant. d) quenching the reaction mixture; and The invention further relates to a process for preparing the e) recovering the compound of formula (II); compound of formula (V), US 7,790,910 B2 5 6 wherein R is hydroxy, comprising (V) combining the compound of formula (VI), wherein R is a Rs R4 Coacyloxy, with a Calcohol and mineral acid, at a tem perature of about 50° C. to about 70° C.; wherein R2 n is an integer ranging from 3 to 14, R is either hydrogen, Ce alkyl, hydroxyl, protected hydroxy, or halo; O "CH,n-Br 10 R is either hydrogen, Ce alkyl, C- alkenyl, or C. alkynyl: Rs is C alkyl, and comprising combining a compound of formula (II) R is either hydrogen, Ce alkyl, hydroxyl, protected 15 hydroxy, or halo. In one embodiment of the process, R. R. and Rare hydro (II) gens, and Rs is methyl. Rs R4 In one embodiment of the process, the mineral acid is HBr. In one embodiment of the process, the temperature is about R2 60° C. In one embodiment of the process, the process further comprises converting the obtained product to fulvestrant. The invention further relates to a process for preparing the O "CH-x-R, compound of the formula (I) 25 with acetonitrile and triphenylphosphine dibromide for a suf (I) ficient amount of time for conversion into the compound of formula (V); 30 wherein n is an integer ranging from 3 to 14,

X is O: R is a hydroxy protecting group; R is either hydrogen, Ce alkyl, hydroxyl, protected 35 hydroxy, or halo; Ra is either hydrogen, Co alkyl, C2-alkenyl, or C2 alkynyl: comprising combining the compound of formula (VI)

R is a C-acyloxy, 40 Rs is C alkyl; and (VI) R is either hydrogen, C alkyl, hydroxyl, protected hydroxy, or halo. In one embodiment of the process, n is 9, R is tertbutyl dimethylsilyl (TBDMS), R. R. and R are hydrogens, R is 45 acetyloxy and Rs is methyl. In one embodiment of the process, the compound of for mula (II) is combined with the acetonitrile and triphenylphos phine dibromide at a temperature of about 10°C. to about 12 C. 50 In one embodiment of the process, the process further with a solvent selected from a Caromatic hydrocarbon, a comprises converting the obtained product to fulvestrant. straight or branched C alcohol, a C alkyl amide and The invention further relates to a process for preparing the mixtures thereof and thiourea; and recovering the compound compound of formula (VI) 55 of formula (I) wherein (VI) n is an integer ranging from 3 to 14,

R is a free base or a salt form of isothiouronium; R is either hydrogen, Ce alkyl, hydroxyl, protected 60 hydroxy, or halo; R is either hydrogen, Co alkyl, C2-alkenyl, or C2 alkynyl: R is either hydroxy or Ce acyloxy; 65 Rs is C alkyl; and R is either hydrogen, Ce alkyl, hydroxyl, protected hydroxy, or halo. US 7,790,910 B2 7 8 In one embodiment of the process, n is 9, R is a hydrobro In one embodiment of the process, said aprotic polar mide salt of isothiouronium, R. R. and R are hydrogens, R. organic solvent is dimethylacetamide. is acetyloxy and Rs is methyl. In one embodiment of the process, the process further In one embodiment of the process, n is 9, R is a hydrobro comprises converting the obtained product to fulvestrant. mide Salt of isothiouronium, R. R. and R are hydrogens, R. 5 is hydroxy and Rs is methyl. The invention further relates to a process for preparing the In one embodiment of the process, the solvent is selected compound of the formula (I) from the group consisting of toluene, Xylene, benzene, metha nol, ethanol, propanol, isopropanol, butanol, dimethylaceta (I) mide and mixtures thereof. 10 In one embodiment of the process, the solvent is a mixture of toluene and isopropanol or dimethylacetamide. In one embodiment of the process, the process further comprises converting the obtained product to fulvestrant. The invention further relates to a process for preparing the 15 compound of the formula (VII)

(VII) comprising combining the compound of formula (VII)

(VII)

25 comprising combining compound of the formula (I) 30 HO "(CH,n-SH (I) with 4.4.5.5.5-pentafluoropentane-1-ol mesylate at an ambi 35 ent temperature; combining the obtained reaction mixture with a base in the presence of an organic solvent; and recovering the compound of the formula (I); 40 wherein n is an integer ranging from 3 to 14, with a base in the presence of an apolar protic organic Solvent R is —S (CH) CFCF at ambient temperature; R is either hydrogen, C alkyl, hydroxyl, protected 45 hydroxy, or halo; wherein R is either hydrogen, Co alkyl, C2-alkenyl, or C2 n is an integer ranging from 3 to 14, alkynyl: R is a free base or a salt form of isothiouronium; R is either hydrogen, Ce alkyl, hydroxyl, protected R is either hydroxy or Ce acyloxy; hydroxy, or halo; Rs is C alkyl, and Ra is either hydrogen, Co alkyl, C2-alkenyl, or C2 50 R is either hydrogen, Ce alkyl, hydroxyl, protected alkynyl: hydroxy, or halo. R is either hydroxy or Ce acyloxy; In one embodiment of the process, n is 9, R. R. and Rare Rs is C alkyl; and hydrogens, R is a acetyloxy and Rs is methyl. R is either hydrogen, C alkyl, hydroxyl, protected 55 In one embodiment of the process, n is 9, R. R. and Rare hydroxy, or halo. hydrogens, R is acetyloxy and Rs is methyl. In one embodiment of the process, n is 9, R is a hydrobro mide salt of isothiouronium, R. R. and R are hydrogens, R. In one embodiment of the process, the base is an alkali is acetyloxy and Rs is methyl. metal base. In one embodiment of the process, the base is KOH. In one embodiment of the process, n is 9, R is a hydrobro 60 mide Salt of isothiouronium, R. R. and R are hydrogens, R. In one embodiment of the process, the organic solvent is a is hydroxy and Rs is methyl. Calcohol. In one embodiment of the process, the base is an alkali In one embodiment of the process, the organic solvent is metal base. methanol. In one embodiment of the process, the base is NaOH. 65 In one embodiment of the process, wherein the process In one embodiment of the process, the aprotic polar organic further comprises converting the obtained product to fulves solvent is dimethylacetamide or acetonitrile. trant. US 7,790,910 B2 9 10 The invention further relates to a process for preparing f) aromatizing the A ring of compound 9341 by reacting fulvestrant comprising: compound 9341 with a mixture of lithium bromide and a) combining compound of formula 9294 copper bromide in acetonitrile to obtain a compound of formula 9342 5 9294 9342 - - 10 O

15 O HO t with an etheral solvent, to obtain a solution; g) combining compound 9342 with C alcohol and a b) adding to the solution of step a), in a drop-wise manner, 20 mineral acid, at a temperature of about 50° C. to about a solution of the compound of formula 93.18 70° C. to obtain a compound of formula 9354

9354 93.18 OH 25

MgBr O

30 HO 1N1 N1 n-1N1 Br; in an etheral solvent to obtain a first reaction mixture com- h) combining compound 9354 with a solvent selected from prising a compound of formula 9295; a Caromatic hydrocarbon, a straight or branched Ca 35 alkylamide and mixtures thereofand thiourea to provide a compound of formula 9388 - 9388 OH -- 40

O '' S NH O '', 45 HO 7 Y NHHBr c) quenching the first reaction mixture; d) recovering compound 9295; and recovering compound 9388; e) combining compound 9295 with acetonitrile and triph- 50 i) combining compound 9388 with a base at ambient tem enylphosphine dibromide for a time sufficient to convert perature to obtain a compound of formula 9389 compound 9295 into a compound of formula 9341 93.89 9341 55 OH

60 HO cu j) combining compound 9389 with 4.4.5.5.5-pentafluoro penatane-1-ol mesylate at an ambient temperature to 65 provide a second reaction mixture and then combining the second reaction mixture with a base to obtain a compound of formula 9304 US 7,790,910 B2 11 12

9304 OH

HO '', y 1Su-1S-1S-1N1 NCH1 CF NCF, and c) quenching the first reaction mixture; k) combining compound 9304 and a mixture of a Ca 15 d) recovering compound 9295; alcohol and an etheral solvent with an aqueous solution e) combining compound 9295 with acetonitrile and triph of an oxidizing agent at a temperature of about 5°C. for enylphosphine dibromide for a time sufficient to convert about 12 hours to provide fulvestrant. compound 9295 into a compound of formula 9341 The invention further relates to a process for preparing fulvestrant comprising: a) combining compound of formula 9294

9341 9294 25

35 with an etheral solvent, to obtain a solution; b) adding to the solution of step a), in a drop-wise manner, 40 f) aromatizing the A ring of compound 9341 by reacting a solution of the compound of formula 93.18 compound 9341 with a mixture of lithium bromide and copper bromide in acetonitrile to obtain a compound of 93.18 formula 9342 -- 45 -Si

MgBr O 9342 50 in an etheral solvent to obtain a first reaction mixture com prising a compound of formula 9295;

HO '', 60

g) combining compound 9342 with a compound of formula 65 93.83 US 7,790,910 B2 13 14 to provide a compound of formula 9363

9363 1sO

CF HO1 ''', NCH1 NCF,a. 15 h) combining at ambient temperature, compound 9363 and a C alcohol with an alkali base to obtain compound 9304

9304 OH

HO cu S NCH1 CF NCF,

30 and i) combining compound 9304 and a mixture of a Ca alcohol and an etheral solvent with an aqueous solution - of an oxidizing agent at a temperature of about 5°C. for O about 12 hours to provide fulvestrant. 35 The invention further relates to a process for preparing fulvestrant comprising a) combining compound of formula 9294 -Si 40 9294 O '',

- c) quenching the first reaction mixture; O 45 d) recovering compound 9295; e) combining compound 9295 with acetonitrile and triph H enylphosphine dibromide for a time sufficient to convert compound 9295 into a compound of formula 9341

50 O 9341 with an etheral solvent, to obtain a solution; - O

b) adding to the solution of step a), in a drop-wise manner, ss a solution of the compound of formula 93.18

93.18

-- 60 '' Br -- O MgBr O f) aromatizing the A ring of compound 9341 by reacting 65 compound 9341 with a mixture of lithium bromide and in an etheral solvent to obtain a first reaction mixture com- copper bromide in acetonitrile to obtain a compound of prising a compound of formula 9295; formula 9342 US 7,790,910 B2 15 16 h) combining compound 9361 with a base at an ambient 93.42 temperature to obtain a compound of formula 9362 - 5

10 9362 HO '',

g) combining compound 9342 with a solvent selected from 15 a Caromatic hydrocarbon, a straight or branched Ca alkylamide and mixtures thereofand thiourea to provide a compound of formula 9361

SH 9361 HO '', --O 25

HO '', S NH 30 i) combining compound 93.62 with 4.4.5.5.5-pentafluoro NHHBr penatane-1-ol mesylate at ambient temperature to pro vide a second reaction mixture followed by combining the second reaction mixture with a base to obtain a and recovering compound 9361. compound of formula 9363

9363

-N

(CH2); a. CF3:

50 j) combining at ambient temperature compound 9363 and a C alcohol with an alkali base to obtain a compound of formula 9304

9304 OH

''', S CF HO 1N1N1 N1\1 N(CH)1 YCF US 7,790,910 B2 17 18 and FIG. 6 is a schematic showing a method for making an k) combining compound 9304 and a mixture of a Ca intermediate, useful in the preparation of fulvestrant, accord alcohol and an etheral solvent with an aqueous solution ing to the method of the invention. of an oxidizing agent at a temperature of about 5°C. for FIG. 7 is a schematic showing a method for making an about 12 hours to provide fulvestrant. intermediate, useful in the preparation of fulvestrant, accord The invention further relates to a process for preparing ing to the method of the invention. fulvestrant comprising FIG. 8 is a schematic showing a method for making full a) reacting a compound of formula 9363 Vestrant according to the method of the invention.

9363

-N

S n (CH2); 1. YCF:

with a mixture of a Calcohol and an etheral solvent with an 25 FIG. 9 is a schematic showing a method for making full aqueous solution of an oxidizing agent at a temperature of Vestrant according to the method of the invention. about 5° C. for about 12 hours to provide a compound of FIG. 10 is a schematic showing a method for making full formula 93.68 Vestrant according to the method of the invention.

9368

S HO N (CH2)3 1 YCF: and 45 FIG. 11 is a schematic showing a method for making full b) combining at ambient temperature compound 93.68 and Vestrant according to the method of the invention. a C alcohol with an alkali base to obtain fulvestrant. FIG. 12 is a schematic showing a method for making full Vestrant according to the method of the invention. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 13 is a schematic showing a method for making full 50 Vestrant according to the method of the invention. FIG. 1 is a schematic showing a method for making an DETAILED DESCRIPTION OF THE INVENTION intermediate, useful in the preparation of fulvestrant, accord ing to the method of the invention. The phrase “precursor group, as used herein, means a FIG. 2 is a schematic showing a method for making an 55 functional group that can be readily converted to another intermediate, useful in the preparation of fulvestrant, accord functional group. Accordingly, the phrase “a group R or a ing to the method of the invention. precursor group thereof means a group R or a group that can FIG. 3 is a schematic showing a method for making an be readily converted to R. As a representative example, intermediate, useful in the preparation of fulvestrant, accord esters are a precursor group for an alcohol because the ester 60 can be readily hydrolyzed to provide the alcohol. ing to the method of the invention. The phrase “hydroxy protecting group' or “protected FIG. 4 is a schematic showing a method for making an hydroxy, as used herein means a group that can replace the intermediate, useful in the preparation of fulvestrant, accord hydrogen of a hydroxyl, i.e., the hydrogen of an —OH group, ing to the method of the invention. and then be subsequently be removed and replaced by a FIG. 5 is a schematic showing a method for making an 65 hydrogen to reform the hydroxyl group. The hydroxyl pro intermediate, useful in the preparation of fulvestrant, accord tecting group prevents the hydroxyl from reacting under a ing to the method of the invention. given set of conditions, which typically are necessary to per US 7,790,910 B2 19 20 form a reaction at another part of a molecule. After reaction at trobenzyl carbonate; p-nitrobenzyl carbonate; S-benzyl the other part of the molecule, the hydroxyl protecting group thiocarbonate: 4-ethoxy-1-naphthyl carbonate; and methyl can be removed to provide the hydroxyl group. A list of dithiocarbonate; Suitable hydroxyprotecting groups can be found in Protective protecting groups with assisted cleavage including, but not Groups in Organic Synthesis. Third Edition, John Wiley, New limited to, 2-iodobenzoate: 4-azidobutyrate: 4-nitro-4-meth York 1999. Representative hydroxyl protecting groups ylpentanoate; o-(dibromomethyl)benzoate: 2-formylbenze include, but are not limited to: alkyl oraryl ethers, silyl ethers and esters. nesulfonate, 2-(methylthiomethoxy)ethyl carbonate: 4-(me Representative hydroxyl protecting groups include, but are thylthiomethoxy)-butyrate; and not limited to: 10 2-(methylthiomethoxymethyl)benzoate: methyl ethers including, but not limited to, methoxym miscellaneous esters including, but not limited to, 2.6- ethyl: methylthiomethyl; t-butylthiomethyl: (phenyldimeth dichloro-4-methylphenoxyacetate; 2,6-dichloro-4-(1,1,3,3- yldiyl)methoxy-methyl; benzyloxymethyl; p-methoxyben tetramethyl-butyl)phenoxyacetate; 2,4-bis(1,1-dimethylpro Zyl-oxymethyl; (4-methoxyphenoxy)methyl; pyl)-phenoxy-acetate; chlorodiphenylacetate; isobutyrate; guaiacolmethyl; t-butoxymethyl, 4-pentenyloxymethyl; 15 monosuccinoate; (E)-2-methyl-2-butenoate (tigloate); siloxymethyl: 2-methoxyethoxymethyl; 2.2.2-trichloroet o-(methoxycarbonyl)benzoate; p-benzoate; a-naphthoate; hoxymethyl; bis(2-chloroethoxy)methyl: 2-(trimethylsilyl) nitrate; alkyl N,N,N',N'-tetramethylphosphorodiamidate: ethoxymethyl; tetrahydropyran-2-yl: 3-bromotetrahydropy N-phenylcarbamate; borate; dimethylphosphinothioyl; and ran-2-yl: 1-methoxycyclohexyl, 4-methoxytetrahydropyran 2,4-dinitrophenyl-Sulfenate; 2-yl: 4-methoxytetrahydrothiopyran-2-yl; 4-methoxytetrahydrothiopyran-2-yl-S.S.-dioxido: 1-(2- Sulfonates including, but not limited to, methanesulfonate chloro-4-methyl)phenyl-4-methoxypiperidin-4-yl: 1,4-di (mesylate); benzylsulfonate; and tosylate; and oxan-2-yl; tetrahydrofuranyl; tetrahydrothiofuranyl; and 2.3, silyl derivatives including, but not limited to, di-t-butylsi 3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7- lylene group: 1.3-(1,1,3,3-tetraisopropyldisiloxanylidene) methanobenzofuran-2-yl; 25 derivative; tetra-t-butoxydisiloxane-1,3-diylidene derivative: ethyl ethers including, but not limited to, 1-ethoxyethyl: cyclic carbonates; cyclic boronates; ethylboronate; and phe 1-(2-chloroethoxy)ethyl: 1-methyl-1-methoxyethyl: 1-me nylboronate. thyl-i-benzyloxy-2-fluoroethyl; 2.2.2-trichloroethyl: 2-trim A preferred hydroxy protecting groups is SiRRoRo ethylsilylethyl: 2-(phenylselenyl)ethyl; t-butyl; allyl; p-chlo wherein R. R. and Ro are alkyl or branched alkyl contain rophenyl; p-methoxyphenyl; and 2,4-dinitrophenyl, 30 benzyl ethers including, but not limited to, benzyl; p-meth ing 1 to 6 carbon atoms. Most preferably, Rs and R are oxybenzyl: 3,4-dimethoxybenzyl: o-nitrobenzyl; p-nitroben methyl and Rio is t-butyl. Zyl; p-halobenzyl; 2,6-dichlorobenzyl; p-cyanobenzyl; Throughout this specification the rings of the compounds p-phenylbenzyl: 2- and 4-picolyl: 3-methyl-2-picolyl-N-ox of the invention are designated using the lettering convention ide; diphenylmethyl; pp'-dinitrobenzhydryl; 5-dibenzosub 35 ally used for designating the rings of a steroid as depicted eryl; triphenylmethyl; a-naphthyldiphenylmethyl; p-methox below: yphenyldiphenylmethyl; di(p-methoxyphenyl) phenylmethyl; tri(p-methoxyphenyl)methyl: 4-(4-bromo phenacyloxy)phenyldiphenylmethyl; 4.4"14"-tris(4,5- dichlorophthalimidophenyl)methyl: 4,4',4'-tris 40 (levulinoyloxyphenyl)methyl: 4,4',4'-tris (benzoyloxyphenyl)methyl: 3-(imidazol-1-ylmethyl)bis(4, 4"-dimethoxyphenyl)-methyl: 1,1-bis(4-methoxyphenyl)-1- pyrenylmethyl; 9-anthryl; 9-(9-phenyl)xanthenyl; 9-(9- phenyl-10-oxo)anthryl; 1,3-benzodithiolan-2-yl: and 45 benzisothiazolyl S.S.-dioxido: silyl ethers including, but not limited to, trimethylsilyl: Accordingly, the A ring of a steroid is the most left ring of the triethylsilyl; triisopropylsilyl dimethylisopropylsilyl; dieth compound of formula as drawn above. ylisopropylsilyl dimethylthexylsilyl; t-butyldimethylsilyl: The term 'aromatizing, as used herein, means changing a t-butyl-diphenylsilyl; tribenzylsilyl; tri-p-xylylsilyl; triph 50 ring structure that is not aromatic, i.e., either unsaturated or enylsilyl; diphenylmethylsilyl; and t-butylmethoxyphenylsi partially Saturated, to a ring systems that is aromatic, i.e., a lyl; ring system that has a cyclic cloud of 4n+2 delocalized II esters including, but not limited to, formate; benzoylfor electrons. mate; acetate; chloroacetate; trichloroacetate; methoxyac One aspect of the present invention is a compound of etate; triphenylmethoxyacetate; phenoxyacetate; p-chlo 55 rophenoxyacetate; p-(phosphate)phenylacetate; formula (I): 3-phenylproprionate: 4-oxopentanoate (levulinate); 4.4-(eth ylenedithio)pentanoate; pivaloate; adamantoate; crotonate; 4-methoxycrotonate; benzoate; p-phenylbenzoate; and 2.4.6- (I) trimethylbenzoate: 60 carbonates including, but not limited to, methyl carbonate; 9-fluorenyl-methylcarbonate; ethyl carbonate; 2.2.2-trichlo roethyl carbonate: 2-(trimethylsilyl)ethyl carbonate: 2-(phe nylsulfonyl)ethyl carbonate: 2-(triphenylphosphono)ethyl carbonate; isobutyl carbonate; vinyl carbonate; allyl carbon 65 ate; p-nitrophenyl carbonate; benzyl carbonate; p-methoxy benzyl carbonate; 3,4-dimethoxybenzyl carbonate; o-ni US 7,790,910 B2 21 22 wherein comprising: n is an integer ranging from 3 to 14, a) combining a 19-nor-androsta-4,6-diene-3-one of for R is selected from the group consisting of Br, Cl, I, free mula (III) base or a salt form of isothiouronium, or SH: 5 R is either hydrogen, Ce alkyl, hydroxyl, protected (III) hydroxy, or halo; R is either hydrogen, Ce alkyl, C- alkenyl, or C alkynyl: 10 R is either hydroxy, or a C-acyloxy; Rs is C alkyl; and R is either hydrogen, C alkyl, hydroxyl, protected hydroxy, or halo. Preferably, n is 9, R is Br, R. R. and Rare hydrogens, R. 15 with an etheral Solvent, to obtain a solution; and is hydroxy and Rs is methyl. Said compound of formula (I) b) adding to the Solution of step a), in a drop-wise manner, correspond to compound 9354 in FIG. 7. a solution of the compound of formula (IV) Preferably, n is 9, R is Br, R. R. and Rare hydrogens, R. is acetyloxy and Rs is methyl. Said compound of formula (I) correspond to compound 9342 in FIG. 6. (IV) (CH2)n Preferably, n is 9, R is a hydrobromide salt of isothiouro 1 Yx n nium, R. R. and R are hydrogens, R is acetyloxy and Rs is R methyl. Said compound of formula (I) correspond to com pound 9361 in FIG.8. 25 Preferably, n is 9, R is a hydrobromide salt of isothiouro in an etheral solvent to obtain a reaction mixture. nium, R. R. and R are hydrogens, R is hydroxy and Rs is wherein methyl. Said compound of formula (I) correspond to com n is an integer ranging from 3 to 14, pound 9388 in FIG.9. 30 X is either O or S: Preferably, n is 9, R is SH, R. R. and R are hydrogens, R is a Co haloalkyl or a hydroxy protecting group; Ra is acetyloxy and Rs is methyl. Said compound of formula R. R. Rs and R are as defined above: (I) correspond to compound 93.62 in FIG. 8. Ra is a C-acyloxy; and Preferably, n is 9, R is SH, R. R. and R are hydrogens, Z is a metal halide of the formula R,M, wherein 35 M is a metal atom; and R is hydroxy and Rs is methyl. Said compound of formula (I) R, is a halogen atom; correspond to compound 93.89 in FIG. 9. In one embodiment, the solution is cooled to a temperature Another aspect of the present invention is a compound of of about -60° C. to about 30° C. formula In one embodiment, the method further comprises quench 40 ing the reaction mixture. In one embodiment, the invention further comprises recov Compound 9341 (in Figure 5) ering the compound of formula (II). After combining the compound of formula (IV) and the compound of formula (III), the resulting reaction mixture can 45 be analyzed using conventional methods, known to those skilled in the art, to determine completion of the reaction. For example, the reaction mixture may be analyzed by thin layer chromatography (TLC), high pressure liquid chromatogra phy (HPLC), gas chromatography (GC), mass spectrometry 50 (MS), or nuclear magnetic resonance (NMR). Br In one embodiment, the addition of the compound of for ''', mula (IV) to the solution of the compound of formula (III) is done over a time period of at least about 1 minute. Typically, Another aspect of the present invention is a process for the addition of the compound of formula (IV) to the solution 55 of the compound of formula (III) is done over a time period of preparing the compound of formula (II), at least about 30 minutes, preferably at least about 60 minutes, more preferably at least about 90 minutes, and most prefer (II) ably at least about 120 minutes. Preferably, the addition is

slow enough to prevent any substantiative color changes in 60 the mixture. It was found that the slower the addition, the better the isomer ratio obtained (other factors being unchanged). The addition time, however, may be governed by practical concerns (such as efficient use of available reactors) and it is not usually worthwhile to extend the addition period 65 beyond 5 hours. In another embodiment, addition of the compound of for mula (IV) to the solution of the compound of formula (III) is US 7,790,910 B2 23 24 done at a specified rate, i.e., mol equivalents of compound of The compound of formula (II) may be recovered by any formula (IVi) per equivalent of compound of formula (III) per method known in the art. Preferably, traces of the used cata time unit. For example, the average rate of adding the com lyst are removed, for example, by reaction with ammonium, pound of formula (IV) to the solution of the compound of followed by separation of the compound of formula (II) from formula (III) can range from about 0.001 mol equivalents to 5 about 1 mol equivalents of compound of formula (IV) per the reaction mixture, for example, by evaporation of the Sol equivalent of compound of formula (III) per minute. Prefer vents. The compound of formula (II) may be purified by any ably, the average rate of addition ranges from about 0.002 to methods known in the art, such as chromatography. about 0.100 molequivalents of compound of formula (IV) per Compounds 92.95 and 9331, obtained as described above, equivalent of compound of formula (III) per minute. More 10 may be further converted to fulvestrant. preferably, the average rate of addition ranges from about Another aspect of the present invention is a process for 0.005 to about 0.020 molequivalents of compound of formula preparing the compound of formula (V), (IV) per equivalent of compound of formula (III) per minute. Preferably, n is 9, X is O, R is tertbutyl-dimethylsilyl (TBDMS), R. R. and R are hydrogens, R is acetyloxy and 15 (V) Rs is methyl. Said compound of formula (III) corresponds to Compound 9294 in FIG. 1, said compound of formula (IV) corresponds to Compound 9318 in FIG. 1, and the obtained compound of formula (II) corresponds to Compound 9295 in FIG 1. Alternatively, n is 5, X is O, R is TBDMS, R, and R are hydrogens, R is acetyloxy and Rs is methyl. Said compound of formula (III) corresponds to Compound 9294 in FIG. 2, said compound of formula (IV) corresponds to Compound 25 9339 in FIG. 2, and the obtained compound of formula (II) comprising combining a compound of formula (II) corresponds to Compound 9340 in FIG. 2. Alternatively, n is 9, X is S, R is —(CH2)CFCF, R. R. and R are hydrogens, R is acetyloxy and Rs is methyl. Said (II) compound of formula (III) corresponds to Compound 9294 in 30 FIG. 3, said compound of formula (IV) corresponds to Com pound 9330 in FIG.3, and the obtained compound of formula (II) corresponds to Compound 9331 in FIG. 3. M in the compound of formula (IV) is a metal atom 35 selected from the group consisting of magnesium, Zinc, alu minum, copper, copper-lithium (i.e., a lithium dialkylcopper reagent), and titanium. The preferred metal atom is Mg. R, is a halogen atom selected from the group consisting of Cl, Br and I. Preferably, R is Br. 40 with acetonitrile and triphenylphosphine dibromide for a suf When the metal is Mg, a copper catalyst should be used, ficient amount of time for conversion into the compound of preferably of the form Cu(I)Y, wherein Y is Cl, Br or I, and formula (V) most preferably Cu(I)Cl. wherein The compound of formula (II) obtained by this method has n is an integer ranging from 3 to 14, a ratio of 7o- to 7f8-epimer of about 2.5:1 to about 12.1:1. 45 In one embodiment, the compound of formula (II), has a X is O: ratio of 7C. to 73 epimer (isomer ratio) of at least about 3:1. R is a hydroxy protecting group; Preferably, the compound of formula (II) has a 7C. to 7 Bratio R. R. Rs and R are as defined above; and of at least about 7:1. More preferably, the compound of for Ra is a C-acyloxy, mula (II) has a 7C. to 7B ratio of at least about 10:1. Most 50 Preferably, n is 9, X is O, R is tertbutyl-dimethylsilyl preferably, the compound of formula (II) has a 7C. to 7 Bratio (TBDMS), R. R. and R are hydrogens, R is acetyloxy and of at least about 12:1. Rs is methyl. Said compound of formula (II) corresponds to The etheral solvent may be selected from the group con sisting of diethyl ether, THF and glyme. The preferred Compound 9295 in FIG.4, and said compound of formula (V) etheral solvent is THF. 55 corresponds to Compound 9341 in FIG. 4. Preferably, the solution of stepb) is cooled to a temperature Preferably, the compound of formula (II) is combined with of about -20° C. to about -10° C. the acetonitrile and triphenylphosphine dibromide at a tem perature of about 10° C. to about 12°C. The compound of The etheral solution of the compound of the formula (IV) is formula (V) may be obtained by any methods known in the added in a dropwise manner, in order to avoid a local accu 60 mulation of it. The reaction mixture is stirred constantly, for art, and then it may be further purified by dissolution in the same reason. The dropwise addition of the compound of toluene and removal of the by-products formed during the formula (IV) is what renders the high 7O/7f8-epimer ratio. reaction. The reaction mixture in step d) may be quenched by one of The compound of formula (V) may be also prepared via the the reagents selected from the group consisting of NHCl, 65 formation of intermediates, as depicted in FIG. 5. HCl, water, acetic acid and a mixture of NHCl with NH-OH. Compound 9341, obtained as described above, may be The preferred reagent is acetic acid. further converted to fulvestrant. US 7,790,910 B2 25 26 Another aspect of the present invention is a process for Preferably, n is 9, R is a hydrobromide salt of isothiouro preparing the compound of formula (VI) nium, R. R. and R are hydrogens, R is acetyloxy and Rs is methyl. Said compound of formula (VI) corresponds to Com pound 9342 in FIG. 8, and said compound of formula (I) (VI) 5 corresponds to Compound 9361 in FIG. 8. Preferably, n is 9, R is a hydrobromide salt of isothiouro nium, R. R. and R are hydrogens, R is hydroxy and Rs is methyl. Said compound of formula (VI) corresponds to Com pound 9354 in FIG. 9, and said compound of formula (I) 10 corresponds to Compound 9388 in FIG. 9. A C aromatic hydrocarbon may be toluene, Xylene or benzene. A straight or branched Calcohol may be metha nol, ethanol, propanol, isopropanol or butanol. A C alkyl amide may be dimethylacetamide. Most preferably the sol wherein R is hydroxy, comprising 15 vent a mixture of toluene and isopropanol or dimethylaceta mide. combining the compound of formula (VI), wherein R is a Compounds 93.61 and 9388, obtained as described above, Coacyloxy, with a Calcohol and mineral acid, at a tem may be further converted to fulvestrant. perature of about 50° C. to about 70° C. One aspect of the present invention is a process for prepar Preferably, R. R. and R are hydrogens, and Rs is methyl. ing the compound of the formula (VII) Said compound of formula (VI), wherein R is a acetyloxy corresponds to Compound 9342 in FIG. 7, and said com pound of formula (VI) wherein R is hydroxy corresponds to (VII) Compound 9354 in FIG. 7. Preferably, the mineral acid is HBr. Preferably, the tem 25 perature of the reaction is about 60° C. Compound 9354, obtained as described above, may be further converted to fulvestrant.

A further aspect of the present invention is a process for 30 preparing the compound of the formula (I) HO "(CH,n-SH

(I) comprising combining a compound of the formula (I)

35 (I)

40 comprising combining the compound of formula (VI) 45

(VI) with a base in the presence of an apolar protic organic Solvent at ambient temperature; 50 wherein n is an integer ranging from 3 to 14, R is a free base or a salt form of isothiouronium; R. R. Rs and R are as defined above; and R is either hydroxy or Ce acyloxy. 55 Preferably, n is 9, R is a hydrobromide salt of isothiouro nium, R. R. and R are hydrogens, R is acetyloxy and Rs is with a solvent selected from a Caromatic hydrocarbon, a methyl. Said compound of formula (VII) corresponds to straight or branched C alcohol, a C alkyl amide and Compound 93.62 in FIG. 8, and said compound of formula (I) mixtures thereof and thiourea; and recovering the compound 60 corresponds to Compound 9361 in FIG. 8. of formula (I) Preferably, n is 9, R is a hydrobromide salt of isothiouro nium, R. R. and R are hydrogens, R is hydroxy and Rs is wherein methyl. Said compound of formula (VII) corresponds to n is an integer ranging from 3 to 14, Compound 93.89 in FIG.9, and said compound of formula (I) R is a free base or a salt form of isothiouronium; 65 corresponds to Compound 9388 in FIG. 9. R. R. Rs and R are as defined above; and Preferably, the base is an alkali metal base such as NaOH R is either hydroxy or Ce acyloxy. and KOH. Most preferably, the base is NaOH. The aprotic US 7,790,910 B2 27 28 polar organic solvent may be dimethylacetamide or acetoni Another aspect of the invention is a process for preparing trile. Preferably, the aprotic polar organic solvent is dimethy fulvestrant comprising lacetamide. a) combining compound of formula 9294 Compounds 93.62 and 9389, obtained as described above, may be further converted to fulvestrant. 9294 Another aspect of the present invention is a process for - preparing the compound of the formula (I) O

10 (I)

15 O with an etheral solvent, to obtain a solution; b) adding to the Solution of step a), in a drop-wise manner, a solution of the compound of formula 93.18

93.18 comprising combining the compound of formula (VII) -- HS (VII) 25 MgBr O

in an etheral solvent to obtain a first reaction mixture com 30 prising a compound of formula 9295;

HO '(CH)n-SH

35 with 4.4.5.5.5-pentafluoropentane-1-ol mesylate, followed by combining the obtained reaction mixture with a base in the presence of an organic solvent; -Si wherein 40 n is an integer ranging from 3 to 14, '', R is —S (CH2)CFCF R. R. Rs and R are as defined above; and c) quenching the first reaction mixture; R is either hydroxy or C-acyloxy. 45 d) recovering compound 9295; In one embodiment, the compound of formula (VII) and e) combining compound 9295 with acetonitrile and triph 4.4.5.5.5-pentafluoropentane-1-ol mesylate are contacted at enylphosphine dibromide for a time sufficient to convert com ambient temperature. pound 9295 into a compound of formula 9341 Preferably, n is 9, R. R. and R are hydrogens, R is a 50 acetyloxy and Rs is methyl. Said compound of formula (I) 9341 corresponds to Compound 9363 in FIG. 8, and said com pound of formula (VII) corresponds to Compound 93.62 in FIG 8. Preferably, n is 9. R. R. and R are hydrogens, R is 55 acetyloxy and Rs is methyl. Said compound of formula (I) corresponds to Compound 9304 in FIG. 9, and said com pound of formula (VII) corresponds to Compound 93.89 in FIG. 9. 60 Preferably, the base is an alkali metal base such as NaOH ''', and KOH. Most preferably, the base is KOH. Preferably, the organic solvent is a Calcohol. Most preferably, the organic f) aromatizing the A ring of compound 9341 by reacting Solvent is methanol. 65 compound 9341 with a mixture of lithium bromide and cop Compounds 9363 and 9304, obtained as described above, per bromide in acetonitrile to obtain a compound of formula may be further converted to fulvestrant. 9342 US 7,790,910 B2 29 30 Another aspect of the invention is a process for preparing fulvestrant comprising: 93.42 a) combining compound of formula 9294

5 O O 9294

10 - O

'' Br; HO H

15 g) combining compound 9342 with C alcohol and a mineral acid, at a temperature of about 50° C. to about 70° C. O to obtain a compound of formula 9354 2O with an etheral solvent, to obtain a solution; 9354 b) adding to the Solution of step a), in a drop-wise manner, OH a solution of the compound of formula 93.18 25

93.18

HO 1N1N1,N1N1

MgBr O h) combining compound 9354 with a compound of formula is 9383 HS(CH2)CFCF 93.83; in the presence of an amide and an alkali base to obtain in an etheral solvent to obtain a first reaction mixture com compound 9304 prising a compound of formula 9295;

9304 OH

HO ''', 1N1N1N1N1 S N(CH)1 CF YCF: and i) combining compound 9304 and a mixture of a Ca 55 alcohol and an etheral Solvent with an aqueous solution of an

oxidizing agent at a temperature of about 5° C. for about 12 O hours to provide fulvestrant. Fulvestrant can be recovered by any methods known in the 60 art, such as evaporating the solvents, and can be further puri fied by crystallization from a Caromatic hydrocarbon. In one embodiment, the solution of the compound of for- 65 mula 93.18 is added to the solution of the compound of for mula 9294 at a temperature of about -60° C. to about 30° C. US 7,790,910 B2 31 32 c) quenching the first reaction mixture; h) combining compound 9354 with a solvent selected from d) recovering compound 9295; a Caromatic hydrocarbon, a straight or branched Calkyl e) combining compound 9295 with acetonitrile and triph- amide and mixtures thereof and thiourea to provide a com enylpho sphine dibromidefora time sufficient to convertcom- pound of formula 9388 pound 9295 into a compound of formula 9341 5

9341 - 10 9388

O OH

S NH O ''', Br; HO Y f) aromatizing the A ring of compound 9341 by reacting NHHBr compound 9341 with a mixture of lithium bromide and cop- 20 per bromide in acetonitrile to obtain a compound of formula 93.42 93.42 and recovering compound 9388; 25 - i) combining compound 9388 with a base at ambient tem O O perature to obtain a compound of formula 9389

93.89 w Br; HO '', OH 35 g) combining compound 9342 with C alcohol and a mineral acid, at a temperature of about 50° C. to about 70° C. to obtain a compound of formula 9354

9354 40 HO '1N1N1N1\-1SAw

45 j) combining compound 9389 with 4.4.5.5.5-pentafluoro penatane-1-olmesylate at an ambient temperature to provide HO "1S-1N1-1a-1: a second reaction mixture and then combining the second reaction mixture with a base to obtain a compound of formula 9304

9304 OH

HO ''', 1N1N1 N1-1 S N(CH)1 CF YCF US 7,790,910 B2 33 34 and c) quenching the first reaction mixture; k) combining compound 9304 and a mixture of a Ca d) recovering compound 9295; alcohol and an etheral Solvent with an aqueous solution of an oxidizing agent at a temperature of about 5° C. for about 12 e) combining compound 9295 with acetonitrile and triph hours to provide fulvestrant. 5 enylphosphine dibromide for a time sufficient to convert com Fulvestrant can be recovered by any methods known in the pound 9295 into a compound of formula 9341 art, such as evaporating the solvents, and can be further puri fied by crystallization from a Caromatic hydrocarbon. In one embodiment, the solution of the compound of for mula 93.18 is added to the solution of the compound of for 10 mula 9294 at a temperature of about -60° C. to about 30° C. 9341 Another aspect of the invention is a process for preparing fulvestrant comprising: a) combining compound of formula 9294 15 9294

25 O f) aromatizing the A ring of compound 9341 by reacting compound 9341 with a mixture of lithium bromide and cop with an etheral solvent, to obtain a solution; per bromide in acetonitrile to obtain a compound of formula b) adding to the solution of step a), in a drop-wise manner, 9342 a solution of the compound of formula 93.18 30

93.18 9342 -- 35 HS - MgBr O in an etheral solvent to obtain a first reaction mixture com 40 prising a compound of formula 9295;

HO '', 45

g) combining compound 9342 with a compound of formula 9383 50

to provide a compound of formula 9363

9363

HO N(CH1(CH2)3 NCF US 7,790,910 B2 35 36 h) combining at ambient temperature, compound 9363 and a C alcohol with an alkali base to obtain compound 9304

9304 OH

HO ''', y 1N1-1-1S-1 NCH1 CF NCF,

15 and i) combining compound 9304 and a mixture of a Ca alcohol and an etheral Solvent with an aqueous solution of an oxidizing agent at a temperature of about 5° C. for about 12 hours to provide fulvestrant. Fulvestrant can be recovered by any methods known in the art, such as evaporating the solvents, and can be further puri fied by crystallization from a Caromatic hydrocarbon. 25 -Si In one embodiment, the solution of the compound of for mula 93.18 is added to the solution of the compound of for '', mula 9294 at a temperature of about -60° C. to about 30° C. Another aspect of the invention is a process for preparing c) quenching the first reaction mixture; fulvestrant comprising 30 d) recovering compound 9295; a) combining compound of formula 9294 e) combining compound 9295 with acetonitrile and triph enylphosphine dibromide for a time sufficient to convert com pound 9295 into a compound of formula 9341

35 9341 9294

45 '',

f) aromatizing the A ring of compound 9341 by reacting 50 compound 9341 with a mixture of lithium bromide and cop per bromide in acetonitrile to obtain a compound of formula with an etheral solvent, to obtain a solution; 9342 b) adding to the solution of step a), in a drop-wise manner, a solution of the compound of formula 93.18 55 9342 93.18 - -- 60 -Si

MgBr O

65 HO 'e, in an etheral solvent to obtain a first reaction mixture com prising a compound of formula 9295; US 7,790,910 B2 37 38 g) combining compound 9342 with a solvent selected from h) combining compound 9361 with a base at an ambient a Caromatic hydrocarbon, a straight or branched Calkyl temperature to obtain a compound of formula 9362 amide and mixtures thereof and thiourea to provide a com pound of formula 9361 9362 O

9361 10

SH 15 HO '',

S NH HO '', Y NHHBr i) combining compound 93.62 with 4.4.5.5.5-pentafluoro penatane-1-ol mesylate (compound 9360) at ambient tem perature to provide a second reaction mixture followed by combining the second reaction mixture with a base to obtain and recovering compound 9361. a compound of formula 9363

9363

HO N(CH1(CH2)3 NCF

45 j) combining at ambient temperature compound 9363 and a C alcohol with an alkali base to obtain a compound of formula 9304

9304 OH

''', S CF HO 1N1,N1 N1-1 N(CH)1 YCF US 7,790,910 B2 39 40 and copper(I) iodide. After stirring for 10 minutes a solution of 10 k) combining compound 9304 and a mixture of a Ca grams of 173 hydroxy estra 4.6 diene 3 one acetate, Cp 9294 alcohol and an etheral Solvent with an aqueous solution of an (i.e., 6-dehydro-19-nortestosterone acetate), in tetrahydrofu oxidizing agent at a temperature of about 5° C. for about 12 ran was added, and stirring continued for 90 minutes. After hours to provide fulvestrant. 5 quenching with acetic acid, the product 17 B-hydroxy-7C-9- Fulvestrant can be recovered by any methods known in the 1,1-dimethylethyl)dimethylsilyloxynonyl-estr-4-en-3- art, such as evaporating the solvents, and can be further puri fied by crystallization from a Caromatic hydrocarbon. oneacetate, Cp 9295, was examined by HPLC analysis and In one embodiment, the solution of the compound of for found to have a 7C/7 Bratio of 2.3:1. mula 93.18 is added to the solution of the compound of for 10 mula 9294 at a temperature of about -60° C. to about 30° C. Comparative Example Repeating WO 02/32922 Another aspect of the invention is a process for preparing fulvestrant comprising Following the method of Example 2 of WO 02/32922, the a) reacting a compound of formula 9363 7C/7 B ratio obtained was 2.5:1.

9363

HO N(CH1(CH2) NCF,

30 with a mixture of a Calcohol and an etheral solvent with an aqueous solution of an oxidizing agent at a temperature of about 5° C. for about 12 hours to provide a compound of formula 93.68

9368

HO N(CH1(CH2); NCF,

50 and Example 1 b) combining at ambient temperature compound 93.68 and Preparation of the Grignard Reagent Cp 93.18 a C alcohol with an alkali base to obtain fulvestrant. (9-(dimethyl-tert-butylsilyloxy)nonyl Magnesium This method is depicted schematically in FIG. 13. 55 Bromide) The compound of formula 9363 can be made by any method of the invention. To a mixture of 100 g of 1-bromononanol, 33 g of imida Zole and 250 g of dimethylformamide was added 70.2 g of EXAMPLES tert-butyl-chlorodimethylsilane and the reaction mixture was stirred for 2 hours. 60 The mixture was diluted with 750 g of water and 220g of Comparative Example Repeating EP 138504 toluene, and the phases separated. The aqueous phase was re-extracted with 90 g of toluene. Following the method of Example 1 of EP 138504, to the The combined organic phases were washed with 100 g of Grignard reagent, Cp 93 18, formed from 24.2 grams of 65 water, and evaporated under vacuum at 80°. The residue of 9-bromo-1-nonanol TBDMS (i.e., 9-(dimethyl-t-butylsiloxy) 9-bromo-1-nonanol TBDMS was dissolved in 500 g of anhy nonyl bromide), cooled to -30°C., were added 6.6 grams of drous tetrahydrofuran. US 7,790,910 B2 41 42 In a 2 L flask fitted with stirrer, heating bath, condenser, 9-(dimethyl-tert-butylsilyloxy)nonyl magnesium bromide, nitrogen atmosphere, and thermometer 10.88g of magnesium Cp 93.18. (i.e., the Grignard reagent from 9-bromo-1-nonanol turnings and 100 g of tetrahydrofuran were charged and TBDMS) was added dropwise over 75 minutes. 10 grams of heated up to 45°. acetic acid was added and stirring was continued for 30 min A small amount of 9-bromo-1-nonanol TBDMS was added utes at room temperature. The flask was then opened to the to initiate the reaction, and then the remaining solution was atmosphere and a solution of 10 grams of ammonium chlo added dropwise at Such a rate as to maintain the reaction ride plus 15 grams of a 25% ammonium hydroxide solution in mixture at reflux. 73 grams of water was added and stirring was continued for 2 When addition was finished the reaction mixture was hours. The phases were separated and the upper phase was refluxed for another hour, then cooled to about 40° C. and re-extracted with a solution of 5 grams ammonium chloride filtered under nitrogen through a sintered glass in-line filter 10 plus 0.5 grams of a 25% ammonium hydroxide solution in 37 (to remove some residual magnesium) and diluted to about grams of water. The upper phase was separated and the Sol 1.15 L. The Solution of reagent was kept at room temperature vent was evaporated under reduced pressure to provide an under nitrogen. oily residue that contained 16.2 grams of 173-hydroxy-7C.- 9-1,1-dimethylethyl)dimethylsilyloxynonyl-estr-4-en Example 2 15 3-one acetate, Cp 9295, by HPLC assay (89% of theoretical) having a 7C/7f8 ratio of 9.2:1 Preparation of Cp 92.95 from Cp 9294 (Depicted in FIG. 1) Example 4 10 grams of nandrolone acetate, Cp 9294 (6 dehydro 17? Preparation of Cp 9295 from Cp 9294 (Depicted in hydroxy estra 4.6 diene 3 one acetate), was dissolved in 60 FIG. 1) grams of tetrahydrofuran and 1.5 grams of copper(I) chloride added. The Suspension was cooled under a nitrogen atmo 5 grams of nandrolone acetate (6 dehydro 17B hydroxy sphere to -20°C. and 117 grams of a ca. 0.39M solution of the estra 4.6 diene 3 one acetate), Cp 9294, was dissolved in 60 Grignard reagent, Cp 93 18, formed from 9-bromo-1-nonanol 25 grams of tetrahydrofuran and 0.5 grams of copper(I) bromide TBDMS (9-(dimethyl-tert-butylsilyloxy)nonyl magnesium added. The Suspension was cooled under nitrogen atmo bromide) was added dropwise over 120 minutes. 10 grams of sphere to -15° C. and 90 grams of a ca. 0.39M solution of acetic acid was then added, and stirring continued for 30 9-(dimethyl-tert-butylsilyloxy)nonyl magnesium bromide, minutes at room temperature. The flask was then opened to Cp 93.18. (i.e., the Grignard reagent from 9-bromo-1-nonanol the atmosphere and a solution of 10 grams of ammonium 30 TBDMS) was added dropwise over 120 minutes. After chloride plus 15 grams of a 25% ammonium hydroxide solu another hour, 5.4 grams of acetic acid was added and stirring tion in 73 grams of water was added and stirring was contin continued for 60 minutes at room temperature. The flask was ued for 2 hours. The phases were separated and the upper then opened to the atmosphere and a solution of 7 grams of phase washed with a solution of 5 grams ammonium chloride ammonium chloride plus 10 grams of a 25% ammonium in 37 grams of water. The upper phase was separated and the hydroxide solution in 50 grams of water was added and stir Solvent was evaporated under reduced pressure to provide an 35 ring was continued for 12 hours. The phases were separated oily residue which was dissolved in dichloromethane (100 and the upper phase washed with a solution of 2 grams ammo grams) and further washed with 50 grams of water. The lower nium chloride in 10 grams of water. The upper phase was then phase was separated and the solvent was evaporated under separated and the solvent evaporated under reduced pressure reduced pressure to provide an oil (26.0 grams) containing to provide an oily residue that was dissolved in dichlo 16.9 grams of 17 B-hydroxy-7C-9-1,1-dimethylethyl)dim 40 romethane (100 grams) and further washed with 50 grams of ethylsilyloxynonyl-estr-4-en-3-one acetate, Cp 9295, by water. The lower phase was separated and the solvent evapo HPLC assay (93% of theoretical) having a 7C/7B ratio of rated under reduced pressure to provide oil, Cp 9295, (18.0 12.1:1. grams) with a 7o/7B ratio of 7.1:1 by HPLC. The oil was further purified by chromatography using 200 grams of silica gel, eluting with 5% ethyl acetate in toluene. 45 Example 5 The main fraction, after evaporation of the solvent, yielded Cp 9295 as an oil (16.8 grams) containing 15.9 grams of Preparation of Cp 9295 from Cp 9294 (Depicted in 17 B-hydroxy-7C-9-1,1-dimethylethyl)dimethylsilyloxy FIG. 1) nonyl-estr-4-en-3-one acetate by HPLC assay (87.5%) hav ing an 7-alpha/7-beta ratio of 96.4:3.6. A later fraction (0.5 50 5 grams of nandrolone acetate (6 dehydro 17B hydroxy grams) contained mainly the 7-3 isomer (7C/7 Bratio ca 1:3). estra 4.6 diene 3 one acetate, Cp 9294) was dissolved in 50 The rate of adding 9-(dimethyl-tert-butylsilyloxy)nonyl grams of tetrahydrofuran and 2.5 grams of copper (I) iodide magnesium bromide, Cp 9318 was: 0.04.1 moles of 9-(dim added. The Suspension was cooled under nitrogen atmo ethyl-tert-butylsilyloxy)nonyl magnesium bromide were sphere to -20° C. and 85 grams of a ca. 0.30M solution of added to 0.032 moles of nandrolone acetate in 120 minutes. 9-(dimethyl-tert-butylsilyloxy)nonyl magnesium bromide, This translates into 1.28 molequivalents in 120 minutes, oran 55 Cp 93.18. (i.e., the Grignard reagent from 9-bromo-1-nonanol average of ca. 0.011 mol equivalents per minute. TBDMS) was added dropwise over 120 minutes while main taining the temperature of the reaction mixture between -10° Example 3 C. and -20°C. After the addition of 60 grams of the Grignard reagent the reaction was shown by HPLC analysis to be Preparation of Cp 92.95 from Cp 9294 (Depicted in 60 incomplete, but to contain the product 17 B-hydroxy-7C-9- FIG. 1) 1,1-dimethylethyl)dimethylsilyloxynonyl-estr-4-en-3- one acetate, Cp 9295, with a 7C/7B ratio of 8.0:1. After 10 grams of nandrolone acetate (6 dehydro 17B hydroxy complete addition and another hour of stirring, 4.5 grams of estra 4.6 diene 3 one acetate), Cp 9294, was dissolved in 54 acetic acid was added, and stirring continued for 30 minutes grams of tetrahydrofuran and 1 gram of copper (I) chloride 65 at room temperature. The flask was then opened to the atmo added. The Suspension was cooled under nitrogen atmo sphere and a solution of 7.5 grams of ammonium chloride in sphere to -20° C. and 146 grams of a 0.346M solution of 80 grams of water was added and stirring was continued for US 7,790,910 B2 43 44 12 hours. The phases were separated and the upper phase was solution of hydrochloric acid 32% (15g) in water (45g) and washed with a solution of 2 grams ammonium chloride in 10 kept at 5° C. to 10° C. for 30-60 minutes. The reaction mixture grams of water. The upper phase was separated and the Sol is neutralised by charging a solution of ammonium hydroxide vent evaporated under reduced pressure to provide oil (13.9 solution 25% (15g) in distilled apyrogenic water (45 g) and grams) with a 7of7B ratio of 7.7:1 by HPLC. evaporated under vacuum to an oily residue. The residue was dissolved in dichloromethane, extracted with water, and Example 6 evaporated to an oily residue. Weight of crude Cp 9297 obtained: ca. 150 g. Preparation of Cp 9331 from Cp 9294 (Depicted in The oily residue is dissolved in dichloromethane (975 g) FIG. 3) 10 and triethylamine (60g), cooled to between 0°C. and 5°C., and treated at this temperature with methanesulfonyl chloride 10 grams of nandrolone acetate (6 dehydro 17B hydroxy (48 g). The temperature of the reaction mixture is brought to estra 4.6 diene 3 one acetate), Cp 9294, are dissolved in 60 between 20°C.-25° C. and the mixture is stirred at this tem grams of tetrahydrofuran and 1.5 grams of copper(I) chloride perature for 30 to 60 minutes. are added. The Suspension is cooled under nitrogen atmo 15 sphere to -20°C., and 117 grams of a ca. 0.39M solution of With starting material absent, a solution of sodium chloride 9-(4.4.5.5.5-pentafluoropentyl)thiononyl magnesium bro (75 g) in water (1125 g) is added and the mixture stirred for mide, Cp 9330, are added dropwise over 120 minutes. 10 2-3 hours at room temperature. The phases are separated and grams of acetic acid are then added, and stirring continued for the lower (organic) phase again extracted with a solution of 30 minutes at room temperature. The flask is then opened to sodium chloride (75 g) in water (1125 g). The lower (organic) the atmosphere and a solution of 10 grams of ammonium phase is evaporated at atmospheric pressure to an oily residue. chloride plus 15 grams of a 25% ammonium hydroxide solu Weight of crude Cp 9326 obtained: ca. 175 g. tion in 73 grams of water are added and stirring is continued for 2 hours. The phases are separated and the upper phase is The oily residue is dissolved in acetonitrile (375 g) and washed with a solution of 5 grams ammonium chloride in 37 lithium bromide (41.2 g) added. The mixture is heated at grams of water. The upper phase is then separated and the 25 55-60° C. for 1.5-2 hours, and then evaporated under vacuum solvent evaporated to provide an oily residue which is dis to an oily residue. The residue is dissolved in toluene (650 g) solved in dichloromethane (100 grams) and is further washed and the solution stirred at 35 to 40° C. with a solution of with 50 grams of water. Evaporation of the lower phase gives sodium chloride (75 g) in water (1125 g) for 0.5 hours. The an oil containing 17 B-hydroxy-7C-9-(4.4.5.5.5-pentafluo phases are separated and the upper (organic) phase is washed ropentyl)thiononyl-estr-4-en-3-one acetate, Cp 9331, with 30 with water (375 g) and then evaporated to an oily residue. a 7C/7B ratio of 9.1:1 by HPLC assay. Weight of crude Cp 9341 obtained: ca. 165 g. Ifrequired, the product may be further purified by chroma Example 7 tography on silica gel (1120 grams) eluting with toluene. Weight of pure Cp 9341 obtained: 95g. Preparation of Cp 9341 from Cp 92.95 Direct 35 Synthesis (Depicted in FIG. 4) Example 9 190 grams of crude Cp 9295 (17 B-hydroxy-7C-9-11 Preparation of Cp 9342 by Aromatization of Cp 9341 dimethylethyl)dimethylsilyloxynonyl-estr-4-en-3-one (Depicted in FIG. 6) acetate), prepared from 75 grams of 6-dehydronandrolone 40 acetate using conditions of Example 4, are dissolved in 100 grams of acetonitrile and added to a suspension at 10-12°C. 37 grams of Cp 9341 and 6.15 grams of lithium bromide of triphenylphosphine dibromide (prepared by addition of are dissolved in 629 grams of acetonitrile and 18.5 grams of 140 grams of bromine to 240 grams of triphenylphosphine in copper (II) bromide added. The mixture was stirred at ambi 1200 grams of acetonitrile). The temperature is allowed to ent temperature for 7 hours, and then diluted with a solution rise to ambient temperature and after 0.5 hours conversion 45 of 74 grams of ammonium chloride in 942 grams of water. into Cp 9341 is complete by HPLC. The suspension is diluted The mixture is further diluted with 37 grams of ammonium with 1000 grams oftoluene, neutralised with ca. 112 grams of hydroxide solution 25% and 185 grams of ethyl acetate and ammonium hydroxide solution 25%, and the phases are sepa left overnight under agitation in an open flask. The phases are rated. The upper (organic) phase is washed with water (100g) separated and the upper (organic) phase is evaporated to an and then evaporated to an oily residue. The residue is taken up 50 oily residue, which is dissolved in 500 grams of dichlo in toluene and stirred at 5-10°C. in order to precipitate most romethane and washed with 370 grams of water. The phases of the triphenylphosphine oxide by-product. The by-product are separated and the lower (organic) phase is evaporated to is filtered off and rinsed with toluene and the filtrate purified an oily residue. Weight of Cp 9342 obtained: 36.5g by chromatography on silica gel (1250 grams) eluting with toluene. Weight of pure Cp 9341 obtained: 87 g. 55 Example 10 Example 7 Preparation of Cp 93.54 from Cp 9342 (Depicted in FIG. 7) Preparation of Cp 9341 from Cp 9295 Indirect Synthesis (Depicted in FIG. 8) 60 To 61.7 grams of Cp 93.42 in 494 grams of methanol was added 123.4 grams of hydrobromic acid 48% and the mixture 190 grams of crude Cp 9295 (17 B-hydroxy-7C-9-11 was heated at 60° C. for 0.8 hours. The mixture was slowly dimethylethyl)dimethylsilyloxynonyl-estr-4-en-3-one cooled to 5°C. and seeded with a crystal of Cp 93.54. After 1 acetate), prepared from 75 grams of 6-dehydronandrolone hour the suspension was filtered and the crystals rinsed with acetate (Cp 9294) using conditions of Example 4, are dis 65 a cold mixture of 100 grams methanol and 30 grams of water. solved in 750 grams of methanol and cooled to between 5°C. After drying under vacuum at 60° C. to constant weight, 46 and 10° C. under nitrogen. The solution is treated with a grams of Cp 93.54 were obtained. US 7,790,910 B2 45 46 Example 11 9388) was heated at 80° C. for 16 hours, cooled to 20/25° C. and treated with 5.3 grams of Cp 9360 (prepared as in Preparation of Cp 9360 example 10) followed by 5.05 grams of sodium hydroxide solution 50%. After 1 hour the reaction mixture was neutra A solution of 70.5 grams of 4.4.5.5.5-pentafluoropentane 5 lised with 7.5 grams of acetic acid, diluted with water, and 1-ol in 1330 grams of dichloromethane was cooled under extracted with toluene/ethyl acetate (1:1). Evaporation of the nitrogen and diluted with 59 grams of triethylamine followed organic phase under vacuum gave an oily residue of Cp 9304. by 54.5 grams of methanesulfonyl chloride. The solution was The crude product is purified by chromatography on silica kept at 20°C. for 2 hours and then diluted with 1000 grams of gel eluting with toluene/ethyl acetate (95:5) to provide puri water and agitated overnight. Evaporation of the organic 10 fied Cp 9304. phase afforded 109 grams of Cp 9360. Example 15 Example 12 Preparation of Cp 9304 from Cp 93.54 Direct Preparation of Cp 9304 from Cp 9342 via Cp 9361, Process (Depicted in FIG. 11) Cp 93.62 and Cp 9363 (Depicted in FIG. 8 and Part 15 of FIG. 10) To a solution of 20.5 grams of Cp 93.54 in 100 grams of dimethylacetamide was added 109 grams of a 10% solution of 29 grams of Cp 93.42 are heated at 80° C. for 16 hours in Cp 93.83 (prepared from Cp 93.82 from example 10), followed 198 grams of toluene and 99 grams of isopropanol with 5.3 by 10.3 grams of sodium hydroxide solution 50%. After 1 grams (1.25 equivalents) of thiourea. The reaction mixture is hour the reaction mixture was neutralised with 15 grams of evaporated under vacuum to an oily residue which is Cp 93.61 acetic acid, diluted with water, and extracted with toluene? that is diluted with 250 grams of dimethylacetamide, fol ethyl acetate (1:1). Evaporation of the organic phase under lowed by combining with 13.7 g of Cp 9360 (prepared in vacuum gave 30 grams of Cp 9304. The crude product was example 11) and treating at room temperature for 1 hour with purified by chromatography on silica gel (250 grams) eluting 22.3 grams of sodium hydroxide solution 50% to give Cp 25 with toluene/ethyl acetate (95:5) to give 25.3 grams of pure 9363. Hydrolysis of the 17-acetate group is this carried out by Cp 9304. treatment at room temperature for 1 hour with a solution of 5 grams of potassium hydroxide in 45 grams of methanol. The Example 16 reaction mixture is diluted with water and extracted with a mixture of toluene and ethyl acetate (1:1). Evaporation of the Preparation of Fulvestrant (Cp 9305) from Cp extracts afforded 36 grams of crude Cp 9304. 30 The crude product was purified by chromatography on 9363 Indirect Process (Depicted in FIG. 12) silica gel (290 grams) eluting with toluene? ethyl acetate (95: A solution of 40.5 grams of Cp 9363 in 320 grams tetrahy 5) to give 21 grams of pure Cp 9304. drofuran and 81 grams methanol was cooled to 5° C. and Example 13 treated with a warm solution of 27 grams Sodium (meta) 35 periodate in 183 grams water. The mixture was allowed to Preparation of Cp 9304 from Cp 9342 (Depicted in stand at room temperature overnight, concentrated under FIG. 10) vacuum and then dissolved in dichloromethane, extracted with water and evaporated to give 40 grams of Cp 93.68 40 grams of Cp 9360 (prepared according to Example 11) 40 (fulvestrant 17-acetate). were heated at 80°C. for 16 hours with 14.8 grams of thiourea The oily residue of Cp 93.68 (40 grams) was dissolved in and 345 grams of dimethylacetamide to give 400 grams of a 320 grams of methanol under nitrogen and treated for 3 hours 10% solution of Cp 93.83. at room temperature with a solution of 20 grams of potassium To 90.7 grams of the 10% solution of Cp 93.83 was added hydroxide in 128 grams methanol. After neutralisation with a solution of 18.5 grams of Cp 9342 in 76 grams of dimethy 30 grams of acetic acid, the reaction mixture was concen lacetamide and the mixture was cooled to room temperature 45 trated under vacuum and then dissolved in dichloromethane, and treated with 9 grams of sodium hydroxide solution 50% extracted with water and evaporated. The oily residue was for 0.6 hours. After neutralisation with 15 grams of acetic crystallised from 400 grams of toluene, then dried under acid, the reaction mixture was then poured into water and vacuum to constant weight. 26.6 grams of fulvestrant were extracted with toluene. Evaporation of the organic phase obtained. afforded 30 grams of Cp 9363. 50 30 grams of Cp 9363 were dissolved in 185 grams of Example 17 methanol under nitrogen and the solution treated for 4 hours at room temperature with a solution of 9.25 grams of potas Preparation of Fulvestrant (CP9305) from Cp sium hydroxide in methanol. After neutralization with 13.9 9304 Direct Process (Depicted in FIG.9) grams of acetic acid the mixture was evaporated under 55 vacuum, then dissolved in dichloromethane, extracted with A solution of 41 grams of Cp 9304 in 328 grams tetrahy water and evaporated to provide crude Cp 9304. drofuran and 82 grams methanol was cooled to 5° C. and The crude product is purified by chromatography on silica treated with a warm solution of 27 grams Sodium (meta) gel eluting with toluene/ethyl acetate (95:5) to provide puri periodate in 185 grams water. The mixture was allowed to fied Cp 9304. 60 stand at room temperature overnight, concentrated under Example 14 vacuum and then dissolved in dichloromethane, extracted with water, evaporated, and crystallised from toluene to give Preparation of Cp 9304 from Cp 93.54 Indirect 28 grams of Cp 9305 (fulvestrant). Further purification can be Process (Depicted in FIG.9) effected by recrystallisation from ethyl acetate. 65 The present invention is not to be limited in scope by the A mixture of 10 grams of Cp 93.54 and 1.91 grams of specific embodiments disclosed in the examples which are thiourea in 100 grams of dimethylacetamide (to give Cp intended as illustrations of a few aspects of the invention and US 7,790,910 B2 47 48 any embodiments that are functionally equivalent are within 2. A process for preparing the compound of formula (I) as the scope of this invention. Indeed, various modifications of claimed in claim 1, comprising combining the compound of the invention in addition to those shown and described herein formula (VI) will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims. 5 A number of references have been cited, the entire disclo- (VI) sure of which are incorporated herein by reference. Rs

We claim: R 1. A compound of formula (I): 10

R. G. (I) HO "CH-Br

5 15 wherein in and R. R. Rs and R are as defined in claim 1 R2 and R is a C-acyloxy, with a Calcohol and mineral acid, at a temperature of about 50° C. to about 70° C. 3. The process of claim 2, wherein the mineral acid is HBr. 2O 4. The process of claim 2 or claim3, wherein the tempera ture is about 60° C. 5. The process of claim 2, further comprising converting wherein n is 9; R is Br; R. R. and R are hydrogens; R is the obtained product to fulvestrant. hydroxy and Rs is methyl. k . . . .