Title of Invention	PROCESS FOR THE PREPARING 7alpha- [9-(4,4,5,5,5- PENTAFLUOROPENTYLSULPHINYL) NONYL] OESTRA-1,3,5 –(10)-TRIENE-3,17 beta-DIOL (FULVESTRANT)
Abstract	A novel process for preparing Fulvestrant (XV) comprising following steps; (h) treating the diacetate of formula (VIII) with base in hydroxylated solvent to hydrolyse and obtain 7a-(9-hydroxynonyl)oestra-1,3,5 (10)-triene-3,17-diol(XVI); XVI (i) protecting the phenolic group in the triol (XVI) obtained in step (a) with trityl chloride and base in an organic solvent to get trityl ether (XVII); (j) tosylating trityl ether (XVII) with p-toluene sulphonyl chloride and an amine in a halogenated solvent at temperature between -15°C to 25°C, preferably between -10°C to 5°C, the mixture was concentrated, diluted with hydroxylated solvent and poured in to saturated sodium bicarbonate solution, stirred vigorously for one hour and extracted with halogenated solvent then the organic phase washed with water until neutral and evaporated to obtain the tosylate compound (XVIII); (k) treating the tosylate (XVIII) obtained in step (c) with pentafluoropentane thiol (XII) and sodium hydride in tetrahydrofuran to yield the sulphide compound (XIX); (I) oxidizing the Sulphide (XIX) in hydroxylated solvent with sodium metaperiodate in water, the mixture was concentrated and poured into sodium bicarbonate solution then extracted with halogenated solvent and the organic layer washed with water to neutral and evaporated to yield the sulphoxide compound (XX) in which the trityl group intact at 3-position; (m) hydrolysing the phenolic group in sulphoxide compound (XX) obtained in step (e) with concentrated hydrochloric acid in hydroxylated solvent to get Fulvestrant (XV); (n) Crystallizing the product obtained in step (g) with petroleum ether- ethyl acetate mixture to obtain pure Fulvestrant (XV).

Title of Invention

PROCESS FOR THE PREPARING 7alpha- [9-(4,4,5,5,5- PENTAFLUOROPENTYLSULPHINYL) NONYL] OESTRA-1,3,5 –(10)-TRIENE-3,17 beta-DIOL (FULVESTRANT)

Abstract

A novel process for preparing Fulvestrant (XV) comprising following steps; (h) treating the diacetate of formula (VIII) with base in hydroxylated solvent to hydrolyse and obtain 7a-(9-hydroxynonyl)oestra-1,3,5 (10)-triene-3,17-diol(XVI); XVI (i) protecting the phenolic group in the triol (XVI) obtained in step (a) with trityl chloride and base in an organic solvent to get trityl ether (XVII); (j) tosylating trityl ether (XVII) with p-toluene sulphonyl chloride and an amine in a halogenated solvent at temperature between -15°C to 25°C, preferably between -10°C to 5°C, the mixture was concentrated, diluted with hydroxylated solvent and poured in to saturated sodium bicarbonate solution, stirred vigorously for one hour and extracted with halogenated solvent then the organic phase washed with water until neutral and evaporated to obtain the tosylate compound (XVIII); (k) treating the tosylate (XVIII) obtained in step (c) with pentafluoropentane thiol (XII) and sodium hydride in tetrahydrofuran to yield the sulphide compound (XIX); (I) oxidizing the Sulphide (XIX) in hydroxylated solvent with sodium metaperiodate in water, the mixture was concentrated and poured into sodium bicarbonate solution then extracted with halogenated solvent and the organic layer washed with water to neutral and evaporated to yield the sulphoxide compound (XX) in which the trityl group intact at 3-position; (m) hydrolysing the phenolic group in sulphoxide compound (XX) obtained in step (e) with concentrated hydrochloric acid in hydroxylated solvent to get Fulvestrant (XV); (n) Crystallizing the product obtained in step (g) with petroleum ether- ethyl acetate mixture to obtain pure Fulvestrant (XV).

Full Text	Process for preparing 7 α-[9-(4, 4, 5, 5, 5-pentafluoropentylsulphinyl)nonyl] oestra-1,3,5-(10)-triene-3,17P-diol(Fulvestrant) Field of the invention: The present invention relates to a process for the preparation of 7a-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5-(10)-triene-3,17 β -diol (Fulvestrant) and the novel intermediates used there for. Background of the invention: 7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl] estra-1,3,5-(10)-triene-3,17-(3-diol (Fulvestrant) belongs to a class of antiestrogens.lt is completely free of the partial agonist-oestrogen like activity associated with the currently available antiestrogens like tamoxifen. US 4659516 provides a general synthetic route for the preparation of fulvestrant and other similar compounds. The route is clearly described in: Drugs of the future 2001, 26(9): 841 - 850 as Scheme-1. Scheme-l: Synthesis of Fulvestrant (Cont.) Scheme-l: Synthesis of Fulvestrant (Cont.) This route, in practice, has some disadvantages as explained below: US 4659516 describe selective hydrolysis of the Diacetate (VIII) to the Monoacetate (IX). In practice, significant hydrolysis of both the acetyl groups is observed. Hence the Monoacetate (IX) has to be purified to remove the completely hydrolysed product before proceeding to next stage resulting in lower yield of the final product. In addition, in the process, the phenolic group is protected as benzoate(X) which is susceptible to hydrolysis during the preparation of the Sulphide (XIII). As shown In the scheme-l, the Mesylate (XI) Is treated with sodium 4,4,,5,5,5-pentafluorothiopentoxide to yield the Sulphide (XIII).During this reaction pentafluorothiopentoxide can also attack the carbonyl of the benzoate and deprotect phenolic hydroxyl. The mechanism of deprotection is shown below (Scheme II): Thus, is required use of large quantity of pentafuoropentanethiol (XII) as is evident in the experimental procedure given in US 4659516. [Example-32 in which 5 equivalents of the reagent has been used instead of 1 equivalent required for the Mesylate (XI)]. Also we consider it expedient to protect the phenolic group until the oxidation reaction to give the Sulphoxide, as the phenolic group is susceptible to oxidation. WO 02/32922 A1, US 2006/0030552 A1 and WO 2009/039700 describe different synthetic route for the preparation of Fulvestrant. Therefore, it is an object of the present invention to provide a method for preparing Fulvestrant in novel route, which is industrially viable. The present invention adopts the same procedure given in US 4659516 for the preparation of the intermediate Diacetate (VIII) as shown in scheme-l. Synthesis of fulvestrant from the Diacetate (VIII) is carried out by a novel multi-step sequence, which overcomes all the disadvantages of the process of US 4659516. It also affords higher yields of Fulvestrant on commercial scale. Summary of the invention: According to the present invention, a novel process for preparing Fulvestrant (compound XV) comprising; (a) treating the diacetate of formula (VIII) with base in hydroxylated solvent to hydrolyse and obtain 7a-(9-hydroxynonyl)oestra-1,3,5 (10)-triene-3,17-diol(XVI); (b) protecting the phenolic group in the triol (XVI) obtained in step (a) with trityl chloride and base in an organic solvent to get trityl ether (XVII); (c) tosylating trityl ether (XVII) with p-toluene sulphonyl chloride and an amine in a halogenated solvent at temperature between -15°C to 25°C, preferably between -10°C to 5°C, the mixture was concentrated, diluted with hydroxylated solvent and poured in to saturated sodium bicarbonate solution, stirred vigorously for one hour and extracted with halogenated solvent then the organic phase washed with water until neutral and evaporated to obtain the tosylate compound (XVIII); (d) treating the tosylate (XVIII) obtained in step (c) with pentafluoropentane thiol (XII) and sodium hydride in tetrahydrofuran to yield the sulphide compound (XIX); (e) oxidizing the Sulphide (XIX) in hydroxylated solvent with sodium metaperiodate in water, the mixture was concentrated and poured into sodium bicarbonate solution then extracted with halogenated solvent and the organic layer washed with water to neutral and evaporated to yield the sulphoxide compound (XX) in which the trityl group intact at 3-position; (f) hydrolysing the phenolic group in sulphoxide compound (XX) obtained in step (e) with concentrated hydrochloric acid in hydroxylated solvent to get Fulvestrant (XV); (g) Crystallizing the product obtained in step (g) with petroleum ether-ethyl acetate mixture to obtain pure Fulvestrant (XV). The novel process is shown in scheme - III below Scheme-Ill: Synthesis of Fulvestrant (Cont.) Scheme-Ill: Synthesis of Fulvestrant (Cont.) Detailed description of the invention: In accordance with the present invention, Fulvestrant (XV) is manufactured starting from 17p-acetoxy-7a-(9-acetoxynonyl)oestra-1,3,5(10)-triene-3-ol (VIM) a known intermediate already described in US 4659516 (scheme-l). In the present invention, the Diacetate (VIII) is subjected to complete hydrolysis using aqueous 6 N-sodium hydroxide in methanol to yield 7a-(9-hydroxynonyl) oestra-1,3,5 (10)-triene-3,17-diol (Triol XVI in scheme-lll).The latter has been used for the first time for the synthesis of fulvestrant and is the key intermediate in the present invention for the manufacture of fulvestrant. In the present process, the phenolic group in the Triol (XVI) is protected as trityl ether which is not susceptible to base catalyzed hydrolysis. It is also convenient to selectively protect the phenolic group taking the advantage of its acidic nature to create an anion which reacts with trityl chloride avoiding tritylation of hydroxyls at C-17 and nonyl chain under the reaction conditions.Thus ,the Triol-(XVI) is tritylated with trityl chloride to yield trityl ether (XVII). Tosylation of trityl ether (XVII) with p-toluene sulphonyl chloride yields the Tosylate (XVIII). It is expedient to selectively tosylate the hydroxyl group of the nonyl chain taking the advantage of the steric hindrance exerted by p-Toluene sulphonyl chloride, a bulky reagent, there by avoiding tosylation at C-17. The Tosylate (XVIII) is treated with pentafluoropentane thiol (XII) in the presence of sodium hydride in THF to yield the Sulphide (XIX). The advantage in our process is the amount of expensive thiol (XII) to be used in the reaction is considerably minimized to about one equivalent compared to 5 equivalents used in process of US 4659516, thus making the process more cost effective. The Sulphide (XIX) is oxidized with sodium metaperiodate to yield the Sulphoxide (XX) with trityl group intact at 3-position. Thus, the phenolic group is protected from any possible oxidation and the trityl group is cleaved finally with methanolic hydrochloric acid to yield fulvestrant (XV). Accordingly, the present invention provides a novel method for preparing fulvestrant A novel process for preparing Fulvestrant (XV) comprising following steps; (i). treating the diacetate of formula (VIII) with base In hydroxylated solvent to hydrolyse and obtain 7a-(9-hydroxynonyl)oestra-1,3,5 (10)-triene-3,17-diol (XVI); 1. XVI (ii). protecting the phenolic group in the triol (XVI) obtained in step (a) with trityl chloride and base in an organic solvent to get trityl ether (XVII); (iii). tosylating trityl ether (XVII) with p-toluene sulphonyl chloride and an amine in a halogenated solvent at temperature between -15°C to 25°C, preferably between -10°C to 5°C, the mixture was concentrated, diluted with hydroxylated solvent and poured in to saturated sodium bicarbonate solution, stirred vigorously for one hour and extracted with halogenated solvent then the organic phase washed with water until neutral and evaporated to obtain the tosylate compound (XVIII); (iv). treating the tosylate (XVIII) obtained in step (c) with pentafluoropentane thiol (XII) and sodium hydride in tetrahydrofuran to yield the sulphide compound (XIX); (v). oxidizing the Sulphide (XIX) in hydroxylated solvent with sodium metaperiodate in water, the mixture was concentrated and poured into sodium bicarbonate solution then extracted with halogenated solvent and the organic layer washed with water to neutral and evaporated to yield the sulphoxide compound (XX) in which the trityl group intact at 3-position; (vi). hydrolysing the phenolic group in sulphoxide compound (XX) obtained in step (e) with concentrated hydrochloric acid in hydroxylated solvent to get Fulvestrant (XV); (vii). Crystallizing the product obtained in step (g) with petroleum ether-ethyl acetate mixture to obtain pure Fulvestrant (XV). The base used in step (i) and (ii) are such as sodium hydroxide, potassium hydroxide, sodium ethoxide, triethyl amine and the like, preferably aqueous solution of sodium hydroxide or potassium hydroxide, more preferably aqueous solution of sodium hydroxide. The hydroxylated solvent used in any of the steps of the process for preparing fulvestrant are such as methanol, ethanol, propanol, 2-propanol, preferably methanol and/or ethanol. The organic solvent used in the process is such as tetrahydrofuran, acetone or acetonitrile. The halogenated solvents are such as dichloromethane, dichloroethane, chloroform and the like, preferably dichloromethane. The amine in step (iii) is a primary amine, secondary amine, tertiary amine and the like, preferably ethylamine, diethylamine, triethylamine, pyridine. Dimethyl amino pyridine. According to the present invention, there are five novel intermediates are involved in the preparation of fulvestrant. Each step involved in this process is involved with new reactants and solvents. The compound of formula (XVI); The compound of formula (XVIII); The compound of formula (XIX) The compound of formula (XX); The compounds of formula (XVI), (XVII), (XVIII), (XIX) and (XX) and process for preparing the compounds such as herein described and exemplified. Example 1 Synthesis of 7a-(9-hydroxynonyl)oestra-1,3,5(10)-triene-3,17p-diol (Triol-XVI): To a stirred solution of 17P-acetoxy-7 α -(9-acetoxynonyl) oestra-1,3,5(10)-triene-3-ol [Diacetate VIII (10 g, 20.08 mmol)] in methanol (100 mL) was added 6N-sodium hydroxide solution (20.1 mL, 120.5 mmol) and the mixture was stirred at room temperature for 120 minutes. After completion of reaction, the reaction mixture was neutralized with aqueous 2N-hydrochloric acid. The product obtained after distilling out methanol was extracted in to dichloromethane, washed with water up to neutral, evaporated and dried to yield Triol XVI (8g, 97%),the structure of which was confirmed by proton magnetic resonance and mass spectroscopy and was used for next reaction without further purification. Example 2 Synthesis of 3-triphenylmethyloxy-7 α -9-(hydroxynonyl)oestra-1,3,5(10)-triene-17\|3-ol(Trity! ether XVII): To a solution of the Triol XVI (10 g, 24.15 mmol) in tetrahydrofuran (200 mL) was added 7.24 mL of 6N-sodium hydroxide solution followed by trityl chloride (12.12 g, 43.47 mmol) and the reaction mixture was stirred for 4 hours at room temperature. After completion of reaction the reaction mixture poured in to saturated sodium bicarbonate solution. The product was extracted with dichloromethane and the organic layer washed to neutral with water, evaporated and dried to yield a crude material which was purified by chromatography to yield a gummy Trityl ether XVII(12.64g,80%), the structure of which was confirmed by proton magnetic resonance and mass spectroscopy and was used for the next stage without further purification. Example 3 Synthesis of 3-triphenylmethyloxy-7a-(9-p-toluenesulphonyloxynonyl)oestra-1,3,5(10)-triene-17\|3-ol (Tosylate-XVIII): To a stirred solution of Trityl ether XVII (10 g, 15.2 mmol) in dichloromethane(100 mL) at -10°C was added triethylamine (4.25 mL, 30.4 mmol) followed by p-toluene sulphonyl chloride (4.36 g, 22.8 mmol). The reaction mixture was stirred at -10°C for 24 hours.After completion of reaction, the mixture was concentrated, diluted with methanol and poured in to saturated sodium bicarbonate solution, stirred vigorously for one hour and the product was extracted with dichloromethane, the organic phase washed with water until neutral and evaporated to yield the Tosylate XVIII(12g,97%) ,the structure of which was confirmed by proton magnetic resonance and mass spectroscopy and was used for the next reaction without further purification. Example 4 Synthesis of 3-triphenylmethyloxy-7a-[9-n-(4,4,5,5,5-pentafIuoropentylthio)nonyl] oestra-1,3,5(10)-triene-17 β -ol (Sulphide-XIX): A solution of sodium 4,4,5,5,5-pentafluorothiopentoxide [generated from 4,4,5,5,5-pentafluoropentane thiol (2.8 g 14.4 mmol) and a 60 % dispersion of sodium hydride in mineral oil (0.74 g , 18 mmol)] in tetrahydrofuran (60 mL) was added to a solution of the Tosylate XVIII (10 g, 0.012 mol) in tetrahydrofuran (60 mL) and the reaction mixture was stirred at laboratory temperature for 2 hours. After completion of reaction, the reaction mixture was concentrated under reduced pressure and poured into water.The oil separated was extracted into dichloromethane, washed until neutral with water and organic layer was concentrated to yield the Sulphide XIX (7g, 68%), the structure of which was confirmed by proton magnetic resonance and mass spectroscopy and was used in the next stage without further purification. Example 5 Synthesis of 3-triphenylmethyloxy-7a-[9-n-(4,4,5,5,5-pentafluoropentylsulphinyl) nonyl] oestra-1,3,5(10)-triene-17p-ol (Sulphoxide-XX): A solution of sodium metaperiodate (3.085 g, 14.4 mmol) in water (10 mL) was added to a solution of the Sulphide XIX (10 g, 12 mmol) in methanol(200 mL) and the mixture was stirred at laboratory temperature for 24 hours and completion of reaction was checked by TLC. The reaction mixture was concentrated and poured in to sodium bicarbonate solution. The product was extracted with dichloromethane and the organic layer washed with water to neutral and evaporated to yield the Sulphoxide XX (9.8g, 96%),the structure of which was confirmed by proton magnetic resonance and mass spectroscopy and was used in the next stage without further purification. Example 6 Synthesis of 7a-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5-(10)-triene-3,17 β -diol (Fulvestrant-XV): To a stirred solution of the Sulphoxide XX (10 g, 11.79 mmol) in 100 mL methanol was added concentrated hydrochloric add (2.08 mL, 23.58 mmol) and the solution was stirred at laboratory temperature for 2 hours and reaction completion checked by TLC. Reaction solution concentrated completely and a residue dissolved in dichloromethane, washed with water to neutral, dichloromethane solution concentrated completely and dried to yield a pale yellow gummy solid, which on crystallization from petroleum ether-ethyl acetate mixture yields pure Fulvestrant XV(5.36g,75%),the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. We claim: 1. A novel process for preparing Fulvestrant (XV) comprising following steps; (h) treating the diacetate of formula (VIII) with base in hydroxylated solvent to hydrolyse and obtain 7a-(9-hydroxynonyl)oestra-1,3,5 (10)-triene-3,17-diol(XVI); XVI (i) protecting the phenolic group in the triol (XVI) obtained in step (a) with trityl chloride and base in an organic solvent to get trityl ether (XVII); (j) tosylating trityl ether (XVII) with p-toluene sulphonyl chloride and an amine in a halogenated solvent at temperature between -15°C to 25°C, preferably between -10°C to 5°C, the mixture was concentrated, diluted with hydroxylated solvent and poured in to saturated sodium bicarbonate solution, stirred vigorously for one hour and extracted with halogenated solvent then the organic phase washed with water until neutral and evaporated to obtain the tosylate compound (XVIII); (k) treating the tosylate (XVIII) obtained in step (c) with pentafluoropentane thiol (XII) and sodium hydride in tetrahydrofuran to yield the sulphide compound (XIX); (I) oxidizing the Sulphide (XIX) in hydroxylated solvent with sodium metaperiodate in water, the mixture was concentrated and poured into sodium bicarbonate solution then extracted with halogenated solvent and the organic layer washed with water to neutral and evaporated to yield the sulphoxide compound (XX) in which the trityl group intact at 3-position; (m) hydrolysing the phenolic group in sulphoxide compound (XX) obtained in step (e) with concentrated hydrochloric acid in hydroxylated solvent to get Fulvestrant (XV); (n) Crystallizing the product obtained in step (g) with petroleum ether- ethyl acetate mixture to obtain pure Fulvestrant (XV). 2. The process as claimed in claim 1, wherein the base used in step (a) and (b) are such as sodium hydroxide, potassium hydroxide, sodium ethoxide, triethyl amine and the like, preferably aqueous solution of sodium hydroxide, potassium hydroxide, sodium ethoxide, more preferably aqueous solution of sodium hydroxide. 3. The process as claimed in claim 1, wherein hydroxylated solvent used in any of the steps are such as methanol, ethanol, propanol, 2-propanol, preferably methanol and/or ethanol; organic solvent are such as tetrahydrofuran.acetone or acetonitrile; halogenated solvents are such as dichloromethane, dichloroethane, chloroform and the like, preferably dichloromethane; the amine in step (c) is a primary amine, secondary amine, tertiary amine and the like, preferably ethylamine, diethylamine, triethylamine, pyridine, Dimethyl amino pyridine. 4. The compound of formula (XVI); 5. The compound of formula (XVII); 6. The compound of formula (XVIII); 7. The compound of formula (XIX) 8. The compound of formula (XX); 9. The compounds of formula (XVI), (XVII), (XVIII), (XIX) and (XX) and process for preparing the compounds such as herein described and exemplified. 10. A novel process for preparing Fulvestrant is such as herein described and exemplified.

Full Text

Process for preparing 7 α-[9-(4, 4, 5, 5, 5-pentafluoropentylsulphinyl)nonyl] oestra-1,3,5-(10)-triene-3,17P-diol(Fulvestrant)

Field of the invention:
The present invention relates to a process for the preparation of 7a-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5-(10)-triene-3,17 β -diol (Fulvestrant) and the novel intermediates used there for.

Background of the invention:
7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl] estra-1,3,5-(10)-triene-3,17-(3-diol (Fulvestrant) belongs to a class of antiestrogens.lt is completely free of the partial agonist-oestrogen like activity associated with the currently available antiestrogens like tamoxifen.

US 4659516 provides a general synthetic route for the preparation of fulvestrant and other similar compounds. The route is clearly described in: Drugs of the future 2001, 26(9): 841 - 850 as Scheme-1.

Scheme-l: Synthesis of Fulvestrant (Cont.)

Scheme-l: Synthesis of Fulvestrant (Cont.)

This route, in practice, has some disadvantages as explained below:

US 4659516 describe selective hydrolysis of the Diacetate (VIII) to the Monoacetate (IX). In practice, significant hydrolysis of both the acetyl groups is observed. Hence the Monoacetate (IX) has to be purified to remove the completely hydrolysed product before proceeding to next stage resulting in lower yield of the final product. In addition, in the process, the phenolic group is protected as benzoate(X) which is susceptible to hydrolysis during the preparation of the Sulphide (XIII). As shown In the scheme-l, the Mesylate (XI) Is treated with sodium 4,4,,5,5,5-pentafluorothiopentoxide to yield the Sulphide (XIII).During this reaction pentafluorothiopentoxide can also attack the carbonyl of the benzoate and deprotect phenolic hydroxyl. The mechanism of deprotection is shown below (Scheme II):

Thus, is required use of large quantity of pentafuoropentanethiol (XII) as is evident in the experimental procedure given in US 4659516. [Example-32 in which 5 equivalents of the reagent has been used instead of 1 equivalent required for the Mesylate (XI)]. Also we consider it expedient to protect the phenolic group until the oxidation reaction to give the Sulphoxide, as the phenolic group is susceptible to oxidation.
WO 02/32922 A1, US 2006/0030552 A1 and WO 2009/039700 describe different synthetic route for the preparation of Fulvestrant.
Therefore, it is an object of the present invention to provide a method for preparing Fulvestrant in novel route, which is industrially viable.
The present invention adopts the same procedure given in US 4659516 for the preparation of the intermediate Diacetate (VIII) as shown in scheme-l. Synthesis of fulvestrant from the Diacetate (VIII) is carried out by a novel multi-step sequence, which overcomes all the disadvantages of the process of US 4659516. It also affords higher yields of Fulvestrant on commercial scale.
Summary of the invention:
According to the present invention, a novel process for preparing Fulvestrant (compound XV) comprising;
(a) treating the diacetate of formula (VIII) with base in hydroxylated solvent to hydrolyse and obtain 7a-(9-hydroxynonyl)oestra-1,3,5 (10)-triene-3,17-diol(XVI);
(b) protecting the phenolic group in the triol (XVI) obtained in step (a) with trityl chloride and base in an organic solvent to get trityl ether (XVII);

(c) tosylating trityl ether (XVII) with p-toluene sulphonyl chloride and an amine in a halogenated solvent at temperature between -15°C to 25°C, preferably between -10°C to 5°C, the mixture was concentrated, diluted with hydroxylated solvent and poured in to saturated sodium bicarbonate solution, stirred vigorously for one hour and extracted with halogenated solvent then the organic phase washed with water until neutral and evaporated to obtain the tosylate compound (XVIII);
(d) treating the tosylate (XVIII) obtained in step (c) with pentafluoropentane thiol (XII) and sodium hydride in tetrahydrofuran to yield the sulphide compound (XIX);
(e) oxidizing the Sulphide (XIX) in hydroxylated solvent with sodium metaperiodate in water, the mixture was concentrated and poured into sodium bicarbonate solution then extracted with halogenated solvent and the organic layer washed with water to neutral and evaporated to yield the sulphoxide compound (XX) in which the trityl group intact at 3-position;
(f) hydrolysing the phenolic group in sulphoxide compound (XX) obtained in step (e) with concentrated hydrochloric acid in hydroxylated solvent to get Fulvestrant (XV);
(g) Crystallizing the product obtained in step (g) with petroleum ether-ethyl acetate mixture to obtain pure Fulvestrant (XV).
The novel process is shown in scheme - III below

Scheme-Ill: Synthesis of Fulvestrant (Cont.)

Scheme-Ill: Synthesis of Fulvestrant (Cont.)

Detailed description of the invention:
In accordance with the present invention, Fulvestrant (XV) is manufactured starting from 17p-acetoxy-7a-(9-acetoxynonyl)oestra-1,3,5(10)-triene-3-ol (VIM) a known intermediate already described in US 4659516 (scheme-l). In the present invention, the Diacetate (VIII) is subjected to complete hydrolysis using aqueous 6 N-sodium hydroxide in methanol to yield 7a-(9-hydroxynonyl) oestra-1,3,5 (10)-triene-3,17-diol (Triol XVI in scheme-lll).The latter has been used for the first time for the synthesis of fulvestrant and is the key intermediate in the present invention for the manufacture of fulvestrant.

In the present process, the phenolic group in the Triol (XVI) is protected as trityl ether which is not susceptible to base catalyzed hydrolysis. It is also convenient to selectively protect the phenolic group taking the advantage of its acidic nature to create an anion which reacts with trityl chloride avoiding tritylation of hydroxyls at C-17 and nonyl chain under the reaction conditions.Thus ,the Triol-(XVI) is tritylated with trityl chloride to yield trityl ether (XVII). Tosylation of trityl ether (XVII) with p-toluene sulphonyl chloride yields the Tosylate (XVIII). It is expedient to selectively tosylate the hydroxyl group of the nonyl chain taking the advantage of the steric hindrance exerted by p-Toluene sulphonyl chloride, a bulky reagent, there by avoiding tosylation at C-17. The Tosylate (XVIII) is treated with pentafluoropentane thiol (XII) in the presence of sodium hydride in THF to yield the Sulphide (XIX). The advantage in our process is the amount of expensive thiol (XII) to be used in the reaction is considerably minimized to about one equivalent compared to 5 equivalents used in process of US 4659516, thus making the process more cost effective. The Sulphide (XIX) is oxidized with sodium metaperiodate to yield the Sulphoxide (XX) with trityl group intact at 3-position. Thus, the phenolic group is protected from any possible oxidation and the trityl group is cleaved finally with methanolic hydrochloric acid to yield fulvestrant (XV).

Accordingly, the present invention provides a novel method for preparing fulvestrant
A novel process for preparing Fulvestrant (XV) comprising following steps;

(i). treating the diacetate of formula (VIII) with base In hydroxylated solvent to hydrolyse and obtain 7a-(9-hydroxynonyl)oestra-1,3,5 (10)-triene-3,17-diol (XVI);

1. XVI
(ii). protecting the phenolic group in the triol (XVI) obtained in step (a) with trityl chloride and base in an organic solvent to get trityl ether (XVII);

(iii). tosylating trityl ether (XVII) with p-toluene sulphonyl chloride and an amine in a halogenated solvent at temperature between -15°C to 25°C, preferably between -10°C to 5°C, the mixture was concentrated, diluted with hydroxylated solvent and poured in to saturated sodium bicarbonate solution, stirred vigorously for one hour and extracted with halogenated solvent then the organic phase washed with water until neutral and evaporated to obtain the tosylate compound (XVIII);

(iv). treating the tosylate (XVIII) obtained in step (c) with pentafluoropentane thiol (XII) and sodium hydride in tetrahydrofuran to yield the sulphide compound (XIX);

(v). oxidizing the Sulphide (XIX) in hydroxylated solvent with sodium metaperiodate in water, the mixture was concentrated and poured into sodium bicarbonate solution then extracted with halogenated solvent and the organic layer washed with water to neutral and evaporated to yield the sulphoxide compound (XX) in which the trityl group intact at 3-position;

(vi). hydrolysing the phenolic group in sulphoxide compound (XX) obtained in step (e) with concentrated hydrochloric acid in hydroxylated solvent to get Fulvestrant (XV);
(vii). Crystallizing the product obtained in step (g) with petroleum ether-ethyl acetate mixture to obtain pure Fulvestrant (XV).

The base used in step (i) and (ii) are such as sodium hydroxide, potassium hydroxide, sodium ethoxide, triethyl amine and the like, preferably aqueous solution of sodium hydroxide or potassium hydroxide, more preferably aqueous solution of sodium hydroxide.
The hydroxylated solvent used in any of the steps of the process for preparing fulvestrant are such as methanol, ethanol, propanol, 2-propanol, preferably methanol and/or ethanol.
The organic solvent used in the process is such as tetrahydrofuran, acetone or acetonitrile.

The halogenated solvents are such as dichloromethane, dichloroethane, chloroform and the like, preferably dichloromethane.
The amine in step (iii) is a primary amine, secondary amine, tertiary amine and the like, preferably ethylamine, diethylamine, triethylamine, pyridine. Dimethyl amino pyridine.
According to the present invention, there are five novel intermediates are involved in the preparation of fulvestrant. Each step involved in this process is involved with new reactants and solvents.
The compound of formula (XVI);

The compound of formula (XVIII);

The compound of formula (XIX)

The compound of formula (XX);

The compounds of formula (XVI), (XVII), (XVIII), (XIX) and (XX) and process for preparing the compounds such as herein described and exemplified.
Example 1
Synthesis of 7a-(9-hydroxynonyl)oestra-1,3,5(10)-triene-3,17p-diol (Triol-XVI):
To a stirred solution of 17P-acetoxy-7 α -(9-acetoxynonyl) oestra-1,3,5(10)-triene-3-ol [Diacetate VIII (10 g, 20.08 mmol)] in methanol (100 mL) was added 6N-sodium hydroxide solution (20.1 mL, 120.5 mmol) and the mixture was stirred at room temperature for 120 minutes. After completion of reaction, the reaction mixture was neutralized with aqueous 2N-hydrochloric acid. The product obtained after distilling out methanol was extracted in to dichloromethane, washed with water up to neutral, evaporated and dried to yield Triol XVI (8g, 97%),the structure of which was confirmed by proton magnetic resonance and mass spectroscopy and was used for next reaction without further purification.
Example 2
Synthesis of 3-triphenylmethyloxy-7 α -9-(hydroxynonyl)oestra-1,3,5(10)-triene-17|3-ol(Trity! ether XVII):
To a solution of the Triol XVI (10 g, 24.15 mmol) in tetrahydrofuran (200 mL) was added 7.24 mL of 6N-sodium hydroxide solution followed by trityl chloride (12.12 g, 43.47 mmol) and the reaction mixture was stirred for 4 hours at room temperature. After completion of reaction the reaction mixture poured in to saturated sodium bicarbonate solution. The product was extracted with dichloromethane and the organic layer washed to neutral with water, evaporated and dried to yield a crude material which was purified by chromatography to yield a gummy Trityl ether XVII(12.64g,80%), the structure of which was confirmed by

proton magnetic resonance and mass spectroscopy and was used for the next stage without further purification.
Example 3
Synthesis of 3-triphenylmethyloxy-7a-(9-p-toluenesulphonyloxynonyl)oestra-1,3,5(10)-triene-17|3-ol (Tosylate-XVIII):
To a stirred solution of Trityl ether XVII (10 g, 15.2 mmol) in dichloromethane(100 mL) at -10°C was added triethylamine (4.25 mL, 30.4 mmol) followed by p-toluene sulphonyl chloride (4.36 g, 22.8 mmol). The reaction mixture was stirred at -10°C for 24 hours.After completion of reaction, the mixture was concentrated, diluted with methanol and poured in to saturated sodium bicarbonate solution, stirred vigorously for one hour and the product was extracted with dichloromethane, the organic phase washed with water until neutral and evaporated to yield the Tosylate XVIII(12g,97%) ,the structure of which was confirmed by proton magnetic resonance and mass spectroscopy and was used for the next reaction without further purification.
Example 4
Synthesis of 3-triphenylmethyloxy-7a-[9-n-(4,4,5,5,5-pentafIuoropentylthio)nonyl] oestra-1,3,5(10)-triene-17 β -ol (Sulphide-XIX):
A solution of sodium 4,4,5,5,5-pentafluorothiopentoxide [generated from 4,4,5,5,5-pentafluoropentane thiol (2.8 g 14.4 mmol) and a 60 % dispersion of sodium hydride in mineral oil (0.74 g , 18 mmol)] in tetrahydrofuran (60 mL) was added to a solution of the Tosylate XVIII (10 g, 0.012 mol) in tetrahydrofuran (60

mL) and the reaction mixture was stirred at laboratory temperature for 2 hours. After completion of reaction, the reaction mixture was concentrated under reduced pressure and poured into water.The oil separated was extracted into dichloromethane, washed until neutral with water and organic layer was concentrated to yield the Sulphide XIX (7g, 68%), the structure of which was confirmed by proton magnetic resonance and mass spectroscopy and was used in the next stage without further purification.
Example 5
Synthesis of 3-triphenylmethyloxy-7a-[9-n-(4,4,5,5,5-pentafluoropentylsulphinyl) nonyl] oestra-1,3,5(10)-triene-17p-ol (Sulphoxide-XX):
A solution of sodium metaperiodate (3.085 g, 14.4 mmol) in water (10 mL) was added to a solution of the Sulphide XIX (10 g, 12 mmol) in methanol(200 mL) and the mixture was stirred at laboratory temperature for 24 hours and completion of reaction was checked by TLC. The reaction mixture was concentrated and poured in to sodium bicarbonate solution. The product was extracted with dichloromethane and the organic layer washed with water to neutral and evaporated to yield the Sulphoxide XX (9.8g, 96%),the structure of which was confirmed by proton magnetic resonance and mass spectroscopy and was used in the next stage without further purification.

Example 6
Synthesis of 7a-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5-(10)-triene-3,17 β -diol (Fulvestrant-XV):
To a stirred solution of the Sulphoxide XX (10 g, 11.79 mmol) in 100 mL methanol was added concentrated hydrochloric add (2.08 mL, 23.58 mmol) and the solution was stirred at laboratory temperature for 2 hours and reaction completion checked by TLC. Reaction solution concentrated completely and a residue dissolved in dichloromethane, washed with water to neutral, dichloromethane solution concentrated completely and dried to yield a pale yellow gummy solid, which on crystallization from petroleum ether-ethyl acetate mixture yields pure Fulvestrant XV(5.36g,75%),the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.

We claim:
1. A novel process for preparing Fulvestrant (XV) comprising following steps;

(h) treating the diacetate of formula (VIII) with base in hydroxylated solvent to hydrolyse and obtain 7a-(9-hydroxynonyl)oestra-1,3,5 (10)-triene-3,17-diol(XVI); XVI

(i) protecting the phenolic group in the triol (XVI) obtained in step (a) with trityl chloride and base in an organic solvent to get trityl ether (XVII);

(j) tosylating trityl ether (XVII) with p-toluene sulphonyl chloride and an amine in a halogenated solvent at temperature between -15°C to 25°C, preferably between -10°C to 5°C, the mixture was concentrated, diluted with hydroxylated solvent and poured in to saturated sodium bicarbonate solution, stirred vigorously for one hour and extracted with halogenated solvent then the organic phase washed with water until neutral and evaporated to obtain the tosylate compound (XVIII);

(k) treating the tosylate (XVIII) obtained in step (c) with pentafluoropentane thiol (XII) and sodium hydride in tetrahydrofuran to yield the sulphide compound (XIX);

(I) oxidizing the Sulphide (XIX) in hydroxylated solvent with sodium metaperiodate in water, the mixture was concentrated and poured into sodium bicarbonate solution then extracted with halogenated solvent and the organic layer washed with water to neutral and evaporated to yield the sulphoxide compound (XX) in which the trityl group intact at 3-position;

(m) hydrolysing the phenolic group in sulphoxide compound (XX) obtained in step (e) with concentrated hydrochloric acid in hydroxylated solvent to get Fulvestrant (XV);

(n) Crystallizing the product obtained in step (g) with petroleum ether- ethyl acetate mixture to obtain pure Fulvestrant (XV).

2. The process as claimed in claim 1, wherein the base used in step (a) and (b) are such as sodium hydroxide, potassium hydroxide, sodium ethoxide, triethyl amine and the like, preferably aqueous solution of sodium hydroxide, potassium hydroxide, sodium ethoxide, more preferably aqueous solution of sodium hydroxide.

3. The process as claimed in claim 1, wherein hydroxylated solvent used in any of the steps are such as methanol, ethanol, propanol, 2-propanol, preferably methanol and/or ethanol; organic solvent are such as tetrahydrofuran.acetone or acetonitrile; halogenated solvents are such as dichloromethane, dichloroethane, chloroform and the like, preferably dichloromethane; the amine in step (c) is a primary amine, secondary amine, tertiary amine and the like, preferably ethylamine, diethylamine, triethylamine, pyridine, Dimethyl amino pyridine.

4. The compound of formula (XVI);

5. The compound of formula (XVII);

6. The compound of formula (XVIII);

7. The compound of formula (XIX)

8. The compound of formula (XX);

9. The compounds of formula (XVI), (XVII), (XVIII), (XIX) and (XX) and process for preparing the compounds such as herein described and exemplified.

10. A novel process for preparing Fulvestrant is such as herein described and exemplified.

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Patent Number

279317

Indian Patent Application Number

1643/CHE/2010

PG Journal Number

03/2017

Publication Date

20-Jan-2017

Grant Date

18-Jan-2017

Date of Filing

14-Jun-2010

Name of Patentee

GLAND PHARMA LTD

Applicant Address

6-3-865/1/2, FLAT NO: 201, GREENLAND APARTMENTS, AMEERPET, HYDERABAD - 500 016

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. GOLLAGUNTA NADAMUNI	GLAND PHARMA LTD, 6-3-865/1/2, FLAT NO: 201, GREENLAND APARTMENTS, AMEERPET, HYDERABAD - 500 016
2	DR. CHIDAMBARAM .SUBRAMANIAN VENKATESAN.	GLAND PHARMA LTD, 6-3-865/1/2, FLAT NO: 201, GREENLAND APARTMENTS, AMEERPET, HYDERABAD - 500 016
3	PICHANDI MOHANRAJ SENTHILKUMAR	GLAND PHARMA LTD, 6-3-865/1/2, FLAT NO: 201, GREENLAND APARTMENTS, AMEERPET, HYDERABAD - 500 016
4	PAIDALA RAGHAVENDAR REDDY	GLAND PHARMA LTD, 6-3-865/1/2, FLAT NO: 201, GREENLAND APARTMENTS, AMEERPET, HYDERABAD - 500 016

PCT International Classification Number

C07J

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA