Field of invention:

The present invention relates to a simple and commercially feasible preparation of high purity Fulvestrant. The present invention also provides improved process for the preparation of Fulvestrant intermediates.

Background of the invention:

Fulvestrant is selective estrogen receptor down-regulator and is chemically known as (7a,17p)-7-{^[(^S^^-pentafluoropentyOsulfinylJnonylJestra-l, 3,5(10)-triene-3,17-diol of Formula I and structurally represented as below.

Fulvestrant is disclosed in US4659516 patent and marketed under the brand name of FASLODEX® and it is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

US patent No.4659516 describes a general synthetic process for the preparation of Fulvestrant as shown in scheme I. In this process, the expensive dienone intermediate has been prepared in seven steps involving tedious and complex chemistry, result in low yields, and require time consuming, chromatographic separations. The step of adding the side chain to the 7 position of the dienone steroid is favorable to the preferred a position, however the selectivity is poor, a/ P ratio is 1.9:1. Below is the reported general synthetic scheme-1 for Preparation of Fulvestrant *3

This process is having seven steps from the expensive nandrolone intermediate. And there are no crystalline intermediates between the starting material and the final product. Therefore, isolation and purification between steps is difficult. The yields are low - needing approximately a ratio by weight of 11 of dienone to produce 1 of Fulvestrant. The step of adding the side chain to the 7 position of the dienone steroid is favorable to the preferred a position compared to the unwanted P position at a ratio 1.9:1.

WO 2002032922 application discloses process for the preparation of fulvestrant as shown in below scheme-2.

Scheme-2

In this process for sulfoxidation 2 molar equivalents of 17% w/v hydrogen peroxide solution and acetic acid and ethyl acetate as used in reaction medium. Recrystallization of Fulvestrant is carried out from ethyl acetate. The overall yield of Fulvestrant from dienone is about 30%. The selectivity in the coupling step is still poor. The a/p ratio is only improved to about 2.5:1, the unwanted P -form isomer need to be removed in the final step by special purification procedure.

The inventors of the present of invention have developed an alternate improved process for the preparation of Fulvestrant with high yield and purity. The present process is also commercially viable.

Summary of the Invention:

One aspect of the present invention is to provide a process for the preparation of Fulvestrant comprising the steps of:

a) reacting compound of formula II with 4, 4, 5, 5, 5-pentafluoro-l-pentanethiol (III) in presence of sodium hydroxide solution and acetonitrile solvent to get compound formula-IV,

b) reacting compound of formula-IV with lithium bromide, copper (II) bromide and acetic anhydride mixture solution in presence of acetonitrile solvent to get compound of formula-
V,.

c) treating compound of formula-V with sodium hydroxide in presence of N, N-
dimethylacetamide solvent to get compound of formula-VI,

d) reacting compound of formula-VI with hydrogen peroxide solution in presence of acetic
acid and ethyl acetate as solvent at 20-30°C to get fulvestrant of formula-I.
The present invention is shown in below scheme.

Another aspect of the present invention is to provide a process for the preparation of Fulvestrant comprising the steps of:

a) reacting compound of formula-VII with 4,4, 5, 5, 5-pentafluoro-l-pentanethiol (III) in presence of sodium hydroxide and N,N-dimethyIacetamide solvent get compound formula-VI,

b) reacting compound of formula-VI with hydrogen peroxide solution in presence of acetic acid and ethyl acetate as solvent at 20-30°C to get fulvestrant of fofmula-I.

The above invention is shown in below scheme.

Yet another aspect of the present invention is to provide a process for the preparation of compound of formula-II comprising the steps of:

a) reacting 9-bromo-l-nonanol (formula-VIII) with tert-butyldimethylsilylchloride (formula-IX) in presence of imidazole and methylene chloride solvent to get 9-(dimethyl-t-butylsilyloxy) nonyl bromide (formula-X),

b) reacting 9-(dimethyl-t-butylsilyloxy) nonyl bromide (formula-X)with magnesium in presence of tetrahydrofuran to get 9-(dimethyl-t-butylsilyloxy) nonyl magnesium bromide (formula-XI),

c) reacting insitu 9-(dimethyl-t-butylsiIyloxy) nonyl magnesium bromide (formula-XI) with 17 P -acetyloxy estra-4,6-diene-3-one (fprmula-XII) in presence of copper (I) iodide and tetrahydrofuran at -30°to -40°C to get formula XIII,

d) reacting compound of formula-XIII with triphenylphosphine dibromide in presence of acetonitrile to obtain compound of formula II.

The above invention is shown in below scheme.

Detailed description of the invention:

One embodiment of the present invention is to provide a process for the preparation of Fulvestrant comprising the steps of:

a) reacting compound of formula II with 4, 4, 5, 5, 5-pentafluoro-l-pentanethiol (III) in presence of sodium hydroxide solution and acetonitrile solvent to get compound formula- IV,

b) reacting compound of formula-IV with lithium bromide, copper (II) bromide and acetic anhydride mixture solution in presence of acetonitrile solvent to get compound of formula-V,

c) treating compound of formula-V with sodium hydroxide in presence of N, N-dimethylacetamide solvent to get compound of formula-VI,

d) reacting compound of formula-VI with hydrogen peroxide solution in presence of acetic acid and ethyl acetate as solvent at 20-30°C to get fulvestrant of formula-I.

The present invention is shown in below scheme.

According to the present invention, compound of formula II is reacted with 4, 4, 5, 5, 5-pentafluoro-1-pentanethiol (III) in presence of sodium hydroxide solution and acetonitrile solvent at 25-30°C to get compound formula-IV and it is reacted with lithium bromide, copper (II) bromide and acetic anhydride mixture solution in presence of acetonitrile solvent to at 15-% 20°C to get compound of formula-V, further it is treated with sodium hydroxide in presence of N, N-dimethylacetamide solvent at 25-30°C to get compound of formula-VI, it is reacted with hydrogen peroxide solution in presence of acetic acid and ethyl acetate as solvent at 20-30°C to get Fulvestrant of formula-I.

Another embodiment of the present invention is to provide a process for the preparation of Fulvestrant comprising the steps of:

a) reacting compound of formula-VII with 4,4, 5, 5, 5-pentafluoro-l-pentanethiol (III) in presence of sodium hydroxide and N,N-dimethylacetamide solvent get compound formula-VI,

b) reacting compound of formula-VI with hydrogen peroxide solution in presence of acetic acid and ethyl acetate as solvent at 20-30°C to get fulvestrant of formula-I.

The above invention is shown in below scheme.

According to the present invention, compound of formula-VII is reacted with 4, 4, 5, 5, 5-pentafluoro-1-pentanethiol (III) in presence of sodium hydroxide and N,N-Dimethylacetamide solvent 25-30°C to get compound formula-VI, further it is reacted with hydrogen peroxide solution in presence of acetic acid and ethyl acetate as solvent at 20-30°C to get Fulvestrant of formula-I.

Yet another aspect of the present invention is to provide a process for the preparation of compound of formula-II comprising the steps of:

a) reacting 9-bromo-l-nonanol (formula-VIII) with tert-butyldimethylsilylchloride (formula-IX) in presence of imidazole and methylene chloride solvent to get 9-(dimethyl-t-butylsilyloxy) nonyl bromide (formula-X),

b) reacting 9-(dimethyl-t-butylsilyloxy) nonyl bromide (formula-X)with magnesium in presence of tetrahydrofuran to get 9-(dimethyI-t-butylsilyloxy) nonyl magnesium bromide (formula-XI)s
c) reacting insitu 9-(dimethyl-t-butylsilyloxy) nonyl magnesium bromide (formula-XI) with 17P -acetyloxy estra-4,6-diene-3-one (formula-XII) in presence of copper (I) iodide and tetrahydrofuran at -30°to -40°C to get formula XIII,

d) reacting compound of formula-XIII with triphenylphosphine dibromide in presence of acetonitrile to obtain compound of formula II.

The above invention is shown in below scheme.

According to the present invention, 9-bromo-l-nonanol (formula-VIII) is reacted with tert-butyldimethylsilylchloride (formuIa-IX) in presence of imidazole and methylene chloride solvent to get 9-(dimethyI-t-butylsilyloxy) nonyl bromide (formula-X), it is reacted with magnesium in presence of tetrahydrofuran to get 9-(dimethyl-t-butylsiIyloxy) nonyl magnesium bromide (formula-XI), further reacting insitu 9-(dimethyl-t-butylsilyloxy) nonyl magnesium bromide (formula-XI) with 17 p -acetyloxy estra~4,6-diene-3-one (formula-XII) in presence of copper (I) iodide and tetrahydrofuran at -30° to -40°C to get formula XIII, it is reacted with triphenylphosphine dibromide in presence of acetonitrile to obtain compound of formula II.

Advantages of the present process:

1. The present process is a simple and feasible for commercially large scale production preparation of high yield and high purity fulvestrant.

2. The present invention also provides a novel preparation method of formula-IV.

The following examples are provided for illustration purpose only and are not intended to limit the scope of invention.

EXPERIMENTAL SECTION:

Example -1: preparation of Estr-4-en-3-one, 17-(acetyIoxy)-7-[9-[(4, 4, 5, 5, 5- pentafluoropentyl) thio] nonyl] - (7a, 17p) To a stirred solution of 25.0 g (0.048 mol) of estr-4-en-3-one, 17-(acetyloxy)-7-[9-bromononyl]-, (7a, 17P) in 187.5 ml of acetonitrile was added of 13.03g (0.067 mol) 4, 4, 5, 5, 5-pentafluoro-l-pentanethiol at 25-30°C. 4.03 g (0.050 mol) of 48% w/w sodium hydroxide solution was added, the solution was further stirred at 25-30°C for 3 hours. Monitored the estr-4-en-3-one, 17-(acetyloxy)-7-[9-bromononyI]-, (7a, 17p) content by HPLC, till below 0.5%. 3.0 g of acetic acid was added. Acetonitrile was removed by distillation under vacuum at a temperature 60°C. The reaction mixture was diluted with 125 ml of water while maintaining at 25-30°C by cooling and extracted with two 125 ml portions of ethyl acetate. Ethyl acetate extracts were combined, washed with 125 ml of water, and dried over anhydrous sodium sulfate. Ethyl acetate was removed by distillation under vacuum at a temperature 60°C to give 29.2 g (96.1%) of estr-4-en-3-one, 17-(acetyloxy)-7-[9-[(4, 4, 5, 5, 5-pentafluoropentyl) thio] nonyl] - (7a, 17P) [formula-IV] of pale brown oily mass with 98.75% purity by HPLC.

ExampIe-2: Preparation of Estra-1, 3, 5(10)-triene-3, 17-diol, 7-[9-[(4, 4, 5, 5, 5-pentafluoropentyl) thio] nonyl] -, 3,17-diacetate, (7a, 17p)- To a stirred solution of 29.0 g (0.045 mol) of estr-4-en-3-one, 17-(acetyloxy)-7-[9-[(4, 4, .5, 5, 5-pentafluoropentyl) thio] nonyl] - (7a, 17p) [formuIa-IV] in 112.5 ml of acetonitrile was added mixed solution of 20.25g (0.090 mol) copper (Il)bromide, 6.25 g (0.072 mol) lithium bromide, 7.40 g (0.072 mol) acetic anhydride in 75 ml of acetonitrile at 15-20°C under nitrogen atmosphere. Further portion of 3.75 g (0.037 mol) of acetic anhydride was added and the solution was further stirred at 15-20°C for 3 hours. Monitored the estr-4-en-3-one, 17-(acetyloxy)-7-[9-[(4, 4, 5, 5, 5-pentafluoropentyl) thio] nonyl] - (7a, 17p) content by HPLC, till below 0.5%. The solution was then added over 1 hour to a stirred mixture of toluene (94 ml) and a solution of thiourea (12.5 g, 0.164 mol) in 94 ml of water cooled to 0-5°C. A solution of 20.63 g (0.1184 mol) dipotassium hydrogen orthophosphate in 62.5 ml of water was added to reaction mass at 0-5°C, precipitated copper/thiourea complex salt was removed by filtration. The organic phase in the filtrate was separated. The solvents were removed by distillation under vacuum at a temperature 60°C. The reaction mixture was diluted with 75 ml of water at 25-30°C by cooling and extracted with two 125 ml portions of toluene. The toluene extracts were combined, washed with two portions of 125 ml of water, and dried over anhydrous sodium sulfate. The toluene was removed by distillation under vacuum at a temperature 60°C to give 30.2 g (97.7 %) of estra-1,3,5(10)-triene-3,17-diol,7-[9-[(4, 4, 5, 5, 5-pentafluoropentyl) thio] nonyl] -, 3,17-diacetate,(7a, 170)- [formula-V] of light yellow oily mass with 98.2% purity by HPLC.

Example-3: Preparation of 7 a-[9-(4,4,5,5,5-pentafluoropentylsulfanyl)nonyl]estra-l,3,5,(10)-triene-3,17p-diol
To a stirred solution of 30.0 g (0.044 mol) of estra-l,3,5(10)-triene-3,17-diol,7-[9-[(4, 4, 5, 5, 5-pentafluoropentyl) thio] nonyl] -, 3,17-diacetate,(7a, 170)- [formula-V] in 75 ml of N,N-dimethylacetamide was added dropwise of 42.5 g (0.531 mol) of 48% w/w sodium hydroxide solution at 25-30°C ,the solution was further stirred at 25-30°C for 3 hours. Monitored the estra-1, 3, 5(10)-triene-3,17-diol, 7-[9-[(4,4,5, 5, 5-pentafluoropentyl) thio] nonyl] -, 3,17-diacetate, (7a, 170) - content by HPLC, till hydrolysis was complete. The reaction mixture was then added to 225 ml of water at 25-30°C. 13.75 g (0.229 mol) of acetic acid was added and extracted with two 150 ml portions of toluene. The toluene extracts were combined, washed with two portions of 100 ml of water, and dried over anhydrous sodium sulfate. The toluene was removed by distillation under vacuum at a temperature 60°C to give 25.3 g (96.5%) of 7 a-[9-(4,4,5,5,5-pentafluoropentylsulfanyl)nonyl]estra-l,3,5,(10)-triene-3,17p-diol [formula-VI] of brown oily mass with 95.5% purity by HPLC.

Example- 4: Preparation of Fulvestrant

To a stirred solution of 25.0 g (0.042 mol) of 7a-[9-(4,4,5,5,5-pentafluoropentylsulfanyl) nonyl]estra-l,3,5,(10)-triene-3,17p-diol [formula-V] in 144 ml of ethyl acetate was added 14.25g (0.237 mol) acetic acid at25-30°C under nitrogen atmosphere. 15.75 g (0.086 mol) of 18.5% w/w aqueous hydrogen peroxide was added at 20-25°C for 1 hour and the solution was further stirred at 20-25°C for 21 hours. Monitored the 7a-[9-(4s4,5,5,5-pentafluoropentylsulfanyl)nonyl]estra-l,3,5,(10)-triene-3,17p-diol content by HPLC, till below 0.5%. A further portion of 75 ml of ethyl acetate was added, and excess hydrogen peroxide was destroyed a solution of sodium sulfite (5.75 g) in 60 ml water. The mixture was further diluted with 75 ml of water. The mixture was neutralized with a diluted solution of sodium hydroxide solution (16.25 g of 48% w/w sodium hydroxide was diluted with 50 ml of water) at 20-25°C. The organic phase was separated. The aqueous phase was extracted with two potions of 50 ml of ethyl acetate. The ethyl acetate extracts were combined, washed with 125 ml of water, and dried over anhydrous sodium sulfate. The ethyl acetate was removed by distillation under vacuum at a temperature 60°C to give a 26.2 g of Fulvestrant crude solid mass, then crude solid mass was recrystallized from 80 ml of ethyl acetate to give 19.5 g Fulvestrant with off white solid. 19.5 g Fulvestrant was leached with 187.5 ml of n-heptane at 50-55°C. Then n-heptane leached Fulvestrant was twice recrystallized from 62.5 ml of ethyl acetate .After the final crystallization the product was dried under vacuum at 55-60°C to give 15.50 g of Fulvestrant USP grade quality material with HPLC purity is 99.8%.

Example-5: Preparation of 7 a-[9-(4,4,5,5,5-pentafluoropentylsulfanyI)nonyl]estra-l,3,5,(10)-triene-3,17p-diol To a stirred solution of 40.0 g (0.078 mol) of estra-ls3,5(10)-trine-3)17-dioIJ7-(9-bromononyl)-17-acetate, (7a, 17(3) [formula-VII] in 160 ml of N,N-dimethyl acetamide was added of 21 g (0.108 mol) 4, 4, 5, 5, 5-pentafluoro-l-pentanethiol in 40 ml of N,N-dimethyl acetamide at 25-30°C. 80 g (1.00 mol) of 48% w/w sodium hydroxide solution was added, the solution was further stirred at 25-30°C for 3 hours. Monitored the estra-1, 3, 5(10)-trine-3, 17-dioI, 7-(9-bromononyl)-, 17-acetate, (7a, 17P) content by HPLC, till below 0.5%. The reaction mixture was then added to 600 ml of water at 25-30°C. 56.0 g (0.933 mol) of acetic acid was added to reaction mass at 25-30°C. Reaction mixture was extracted with two 400 ml portions of toluene. The toluene extracts were combined, washed with two portions of 200 ml of water, and dried over anhydrous sodium sulfate. The toluene was removed by distillation under vacuum at a temperature 60°C to give 44.6 g (98%) of 7 a-[9-(4,4,5,5,5-pentafluoropentylsulfanyl)nonyl]estra-l,3,5,(10)-triene-3,17p-diol [formula-VI] of brown oily mass with 96.5% purity by HPLC.

ExampIe-6: Recrystallization process of fulvestrant

15 g of Fulvestrant was dissolved in 180 ml of ethyl acetate at 50-55°C under nitrogen atmosphere. Clear solution was filtered on micro filter paper and filtrate was cooled to 25-30°C under nitrogen atmosphere and further stirred the mass for 1 hour. Mass was further cooled to 0-5°C and further stirred the mass for 1 hour. Solid was filtered and was dried under vacuum at 55-60°C to give 13.2 g (88% w/w) of Fulvestrant USP grade quality material with HPLC purity is 99.9 % purity by HPLC.

ExampIe-7: Preparation of 9-(dimethyI-t-butylsilyIoxy) nonyl bromide To a stirred solution of 100 g (0.448 mol) of 9-bromo-l-nonanol (formula-VIII) in 400 ml of methylene chloride was added 64 g (0.941 mol) imidazole at 25-30°C. 84.32 g (0.562 mol) tert-butyldimethylsilylchloride in 200 ml methylene chloride solution was added and the solution was further stirred at 25-30°C for 3 hours. Imidazole hydrochloride salt was filtered .Methylene chloride was removed by distillation under vacuum at a temperature 50°C to give 141.2 g (93.3%) of 9-(dimethyl-t-butylsiIyloxy) nonyl bromide [formula-X] of pale brown oily mass with 95.1 % purity by GC.

Example-8: Preparation of 9-(dimethyl-t-butyIsilyloxy) nonyl magnesium bromide To a stirred mass of 9.96 g (0.415 mol) of magnesium in 100 ml of tetrahydrofuran and raised the mass temperature to 40-45°C and was added catalytically quantity of iodine. 5% of 9-(dimethyl-t-butylsilyloxy) nonyl bromide (formula-X) in tetrahydrofuran solution was added. Reaction mixture was heated to reflux, and (140 g, and 0.415 mol) of 9-(dimethyl-t-butylsilyloxy) nonyl bromide in 350 ml of tetrahydrofuran solution was added. The solution was further stirred at reflux for 2 hours. Reaction mass was cooled to 25-30°C and reaction mass was used for next stage as in-situ.

Example-9: Preparation of 17P-acetyIoxy -7a-[9-(dimethyl-t-butyl-silyloxy) nonyl] oestra-4-ene-3-one To a stirred solution of 60.0 g (0.1910 mol) of 17 p -acetyloxy estra-4,6-diene-3-one (formula-XII) in 600 ml of tetrahydrofuran was added 9.08 g of copper (I) iodide, reaction mixture was cooled to -30°C to -40°C. 9-(dimethyl-t-butylsilyloxy) nonyl magnesium bromide (formuIa-XI) in-situ mass was added, at -30 to - 40°C and further stirred at -30°C to -40°C for 1 hour, was added 50 g of acetic acid below -5°C. 400 ml of 12% ammonium chloride solution was added below 10°C. Reaction mixture temperature was raised to 25-30°C. Organic layer was separated and organic layer was further washed with 400 ml of 12% ammonium chloride solution. Tetrahydrofuran was removed by distillation under vacuum, mass was diluted with 400 ml of methylene chloride at 25-30°C by cooling. The methylene chloride mass was washed with two portions of 200 ml of water, and dried over anhydrous sodium sulfate. The methylene chloride was removed by distillation under vacuum to give crude mass and crude mass was purified by column chromatography using hexane and ethyl acetate to give 65.0 g of yellow oily mass 170-acetyIoxy -7a-[9-(dimethyl-t-butyI-silyloxy) nonyl] oestra-4-ene-3-one of with 90 % purity by HPLC.

Example-10: Preparation of estr-4-en-3-one, 17-(acetyloxy)-7-[9-bromononyl]-, (7a, 17p) To a stirred solution of 174.4 g (0.666 mol) of triphenylphosphine in 1800 ml of acetonitrile was cooled to 15°C to 20°C. 106.6 g bromine (0.666 mol) was added and the reaction mixture was further stirred at 15°C to 20°C for 1 hour. 103 g (0.18 mol) of 170-acetoxy -7ct-[9-(dimethyI-t-butyl-silyloxy) nonyl] oestra-4-ene-3-one was added, at 15°C to 20°C. Stirred the mass for at 15°C to 20°C for 1 hour. Monitored the 17p-acetoxy -7