CN116284195A - Preparation method of fulvestrant - Google Patents
Preparation method of fulvestrant Download PDFInfo
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- CN116284195A CN116284195A CN202310083448.3A CN202310083448A CN116284195A CN 116284195 A CN116284195 A CN 116284195A CN 202310083448 A CN202310083448 A CN 202310083448A CN 116284195 A CN116284195 A CN 116284195A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention provides a preparation method of fulvestrant, which comprises the following steps: the sulfonate compound and the pentafluoropentylthio undergo substitution reaction to generate 1-bromo-9- (4, 5-pentafluoropentylthio) nonane, which undergoes oxidation reaction to obtain 1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl ] nonane, converting into Grignard reagent by Grignard reaction, and carrying out Michael addition reaction and aromatization reaction with dehydronandrolone acetate to obtain fulvestrant. The preparation method disclosed by the invention is mild in condition, easy in raw material acquisition, low in cost and suitable for industrial production, application and popularization.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of fulvestrant.
Background
Fulvestrant (Fulvestrant) is a novel anti-breast cancer drug developed by the company of aslican and is mainly used for treating postmenopausal advanced breast cancer with ineffective anti-estrogen therapy and positive estrogen receptor. Fulvestrant was first marketed in the united states in 2002 and approved for sale in europe in 2004 under the trade name
Has good efficacy and less side effects, is designated as monotherapy for the treatment of estrogen receptor positive, locally advanced or metastatic breast cancer in postmenopausal women previously untreated with endocrine therapy or suffering from a disease recurring from antiestrogen therapy, and is used in combination with palbociclib for the treatment of Hormone Receptor (HR) positive, human epidermal growth factor receptor 2 (HER 2) negative locally advanced or metastatic breast cancer in women previously receiving endocrine therapy.
Fulvestrant has the chemical name 7 alpha- [9- (4, 5-pentafluoropentylsulfinyl) nonanyl ] estrant-1, 3,5 (10) -triene-3, 17-beta-diol and has the structural formula:
the fulvestrant molecule consists of a steroid mother nucleus and a long side chain alkyl group connected to the 7 alpha-position of the steroid, the synthesis route of fulvestrant in the prior art has two main directions, namely, one is to take dehydronorlong acetate as the mother nucleus to carry out a series of reactions to obtain fulvestrant, the other is to take a derivative of estradiol as a starting material as the mother nucleus to prepare fulvestrant, and the 7 alpha-alkyl group consists of a nine-carbon fatty chain and a five-carbon fatty chain, wherein the synthesis method generally comprises the steps of connecting the steroid with the nine carbon chains firstly, then connecting the nine carbon chains with the five carbon chains, or connecting the nine carbon chains with the five carbon chains and then reacting the nine carbon chains with the steroid mother nucleus to obtain the fulvestrant molecule.
The route for synthesizing fulvestrant from aspartame in pharmaceutical factory is disclosed in patent WO2002032922 and WO2003031399, which takes dehydronorlong acetate as raw material, wherein the main side chain is connected at the 7-position through Michael addition of Grignard reagent, and then LiBr/CuBr 2 Aromatization reaction, hydrolysis reaction, oxidation reaction and the like to obtain fulvestrant, wherein the reaction conditions of the route are more severe, more impurities are generated, and the synthetic route is as follows:
the patent WO2006015081 discloses a synthesis route of fulvestrant, which is also prepared by taking dehydronorlong acetate as a raw material, firstly enabling a nine-carbon branched chain to be connected to the 7-position of dehydronorlong acetate by Michael addition of a Grignard reagent, then reacting with a five-carbon chain pentafluoropentanethiol derivative to obtain fulvestrant, wherein the reaction condition of the route is mild, and the isothiourea hydrobromide generated in the reaction can generate oxygen side reaction to generate disulfide impurities and impurities with nucleophilic substitution of a 3-phenolic hydroxyl group and pentafluoropentanol sulfonate, and the synthesis route of the process is as follows:
the patent WO2005077968 discloses a fulvestrant synthesis route which uses estradiol as a reaction starting material, wherein firstly, the estradiol reacts with 3, 4-dihydropyran to protect hydroxyl, and then H 2 O 2 Oxidation of pyridinium chlorochromate to form a ketocarbonyl group at the 6-position of the steroid, the ketocarbonyl compound being reacted with C in the presence of potassium tert-butoxide 2 F 5 (CH 2 ) 3 S(CH 2 ) 9 Br is subjected to nucleophilic substitution reaction, and finally deprotected and oxidized to prepare fulvestrant, wherein the reaction condition of the route is complex, the material reagent is expensive, the industrial production is not facilitated, and the synthetic route is as follows:
the various technological routes disclosed in the prior art have various defects and deficiencies such as expensive raw materials, harsh reaction conditions, more impurities, high-temperature reaction, unsafe production, higher cost and the like, so the method is not suitable for industrial production and application. Aiming at developing a fulvestrant preparation technology with simple process, economy and environmental protection, particularly a process scheme which can adapt to industrial production, and has important practical significance for improving the economic and social benefits of the variety.
Disclosure of Invention
The invention aims to provide a preparation method of fulvestrant, which has mild process conditions, is beneficial to controlling side reactions and impurity generation and improves yield. The technical scheme adopted by the invention is as follows:
the synthesis route of fulvestrant:
wherein X is p-toluenesulfonyl (Ts), methanesulfonyl (Ms) or trifluoromethanesulfonyl (Tf).
The preparation method of fulvestrant comprises the following specific steps:
(1) Carrying out substitution reaction on the sulfonate compound and pentafluoropentylthio to obtain 1-bromo-9- (4, 5-pentafluoropentylthio) nonane;
(2) 1-bromo-9- (4, 5-pentafluoropentylthio) nonane is subjected to oxidation in an oxidant and solvent system to give 1-bromo-9- [ (4, 5-pentafluoropentylsulfinyl ] nonane;
(3) 1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl ] nonane is subjected to a Grignard reagent, and then is subjected to an addition reaction with dehydronandrolone acetate and an aromatization reaction to obtain fulvestrant.
Preferably, the molar ratio of the sulfonate compound in the step (1) to the pentafluoropentylthiol is 1:1.5-2, and the sulfonate compound is 9-bromononyl tosylate, 9-bromononyl methane sulfonate or 9-bromononyl trifluoro methane sulfonate.
Preferably, the substitution reaction is carried out in a solvent system in the presence of an acid-binding agent base.
Preferably, the molar ratio of the acid-binding agent base to the sulfonate compound is 2-3:1.
Preferably, the acid-binding agent base is any one or a combination of at least two of triethylamine, diethylamine, N-diisopropylethylamine, pyridine, piperidine, tri-N-butylamine, trimethylamine, triisopropylamine, aniline, N-dimethylaniline, N-diethylaniline, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine, N-ethylmorpholine or 1, 8-diazabicyclo [5.4.0] undec-7-ene.
Preferably, the toluene, xylene, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, methyl tert-butyl ether or 1, 4-dioxane, or a combination of at least two thereof.
Preferably, the temperature of the substitution reaction is 70-100 ℃ and the reaction time is 6-18h.
Preferably, the molar ratio of 1-bromo-9- (4, 5-pentafluoropentylthio) nonane to oxidant in step (2) is in the range of 1:1 to 1.3.
Preferably, the oxidant is any one or a combination of at least two of m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid or sodium periodate.
Preferably, the solvent is any one or a combination of at least two of dichloromethane, 1, 2-dichloroethane, chloroform, acetonitrile or methyl tert-butyl ether.
Preferably, the temperature of the oxidation reaction is 20-30 ℃ and the reaction time is 6-12h.
Preferably, the Grignard reagent generated in the step (3) is reacted for 1-3 hours at a temperature ranging from 35-45 ℃.
Preferably, the temperature of the addition reaction is 0-30 ℃ and the reaction time is 1-3h.
Preferably, the aromatization reaction is carried out in the presence of copper bromide and lithium bromide.
Preferably, the temperature of the aromatization reaction is 20-50 ℃ and the reaction time is 3-6h.
Preferably, the molar ratio of 1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl ] nonane to dehydronandrolone acetate is 1-1.3:1-1.3.
As a preferable technical scheme, the preparation method of fulvestrant comprises the following steps of:
(1) In a solvent system in the presence of acid-binding agent alkali, the molar ratio of sulfonate compound to pentafluoropentylthio is 1:1.5-2, and substitution reaction is carried out for 6-18h at 70-100 ℃ to obtain 1-bromo-9- (4, 5-pentafluoropentylthio) nonane, wherein the molar ratio of acid-binding agent alkali to sulfonate compound is 2-3:1;
(2) In the presence of oxidant, 1-bromo-9- (4, 5-pentafluoro amyl thio) nonane is subjected to oxidation reaction at 20-30 ℃ for 6-12h, the molar ratio of the 1-bromo-9- (4, 5-pentafluoropentylthio) nonane to the oxidant is 1:1-1.3, and 1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl ] nonane is obtained;
(3) 1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl ] nonane is reacted for 1-3 hours at a temperature range of 35-45 ℃ to generate a Grignard reagent, then is subjected to addition reaction with dehydronorlong acetate at a temperature of 0-30 ℃ for 1-3 hours, and is subjected to oxidation reaction at a temperature of 20-50 ℃ for 3-6 hours in the presence of copper bromide and lithium bromide to obtain fulvestrant.
According to the technical scheme, firstly, the cheap and easily available sulfonate compound is used for butt joint with the pentafluoropentanethiol and is oxidized to obtain the side chain containing the sulfinyl, the interaction between the Mg metal center of the format reagent and the O atom of the sulfinyl tends to form a cyclic transition state, the format reagent is facilitated to participate in the reaction, meanwhile, the oxidation reaction is not required to be carried out after the side chain is connected with the downward steroid parent nucleus, so that the generation of side reaction is reduced, the impurity control of the whole synthesis route is more facilitated, the whole synthesis procedure is simpler, and the reaction condition is milder.
Compared with the prior art, the invention has the following beneficial effects: the process condition is mild, the generation of impurities is reduced, and the quality control of fulvestrant bulk drug is facilitated; the method has the advantages of easy obtainment of the raw materials of the reagents used in the process route, higher yield, reasonable technical scheme, environmental friendliness, contribution to industrialized popularization and capability of mass production to meet the use requirements.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1:
(1) Preparation of 1-bromo-9- (4, 5-pentafluoropentylthio) nonane:
9-bromononyl tosylate (50 g,0.13 mol), triethylamine (27 g,0.27 mol) are dissolved in toluene (800 mL), cooled in an ice bath, and Pentafluoropentylthiol (39 g,0.2 mol) is slowly added dropwise, the temperature is raised to 100 ℃ for reaction for 6h, the organic solvent is removed by decompression concentration, dichloromethane extraction, saline washing, anhydrous sodium sulfate drying and decompression rotary evaporation to dryness are carried out, and 1-bromo-9- (4, 5-pentafluoroethylthio) nonane (47 g) is obtained, the yield is 89%, the HPLC purity is 95.5%.
(2) Preparation of 1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl ] nonane:
1-bromo-9- (4, 5-pentafluoropentylthio) nonane (45 g,0.11 mol) was dissolved in methylene chloride (400 mL), cooled in an ice bath, and m-chloroperoxybenzoic acid (19.5 g,0.11 mol) was slowly added thereto, followed by reaction at 20℃for 12 hours, concentration under reduced pressure to remove the organic solvent, extraction with methylene chloride, aqueous saline solution, drying over anhydrous sodium sulfate, and spin-evaporation under reduced pressure to dryness to give 1-bromo-9- [ (4, 5-pentafluoropentylsulfinyl ] nonane (42 g) in a yield of 90%.
(3) Preparation of fulvestrant:
1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl]Nonane (40 g,96 mmol) is added into a reaction bottle, magnesium chips (5 g), THF (300 mL) and 1 particle of iodine are added, the temperature is slowly raised to 45 ℃ to react completely (1 h), the mixture is cooled to room temperature, unreacted magnesium chips settle, and a supernatant Grignard reagent is taken for standby; adding dehydronorbornyl acetate (39 g,0.12 mol) into a reaction bottle, adding THF (350 mL) for dissolving, cooling in ice bath, slowly dripping the Grignard reagent solution, reacting at 0deg.C for 3h, adding LiBr (9 g) and CuBr 2 (25g) Acetonitrile (500 mL), keeping the temperature at 50 ℃ for 3h, concentrating under reduced pressure to remove the organic solvent, adding dichloromethane for extraction, washing with common salt, drying with anhydrous sodium sulfate, evaporating under reduced pressure to dryness, and mixing the crude product with ethyl acetate-n-heptaneRecrystallization and vacuum drying gave fulvestrant (50 g) in 86% yield with 99.2% HPLC purity.
Example 2
(1) Preparation of 1-bromo-9- (4, 5-pentafluoropentylthio) nonane:
9-bromononylmethane sulfonate (60 g,0.2 mol), N-diisopropylethylamine (65 g,0.5 mol) were dissolved in tetrahydrofuran (1100 mL), cooled in an ice bath, and pentafiuoropentylthiol (66 g,0.34 mol) was slowly added dropwise thereto, reacted at 70℃for 18 hours, concentrated under reduced pressure to remove the organic solvent, extracted with methylene chloride, washed with common salt, dried over anhydrous sodium sulfate, and distilled under reduced pressure to dryness to give 1-bromo-9- (4, 5-pentafiuoropentylthio) nonane (73 g) in 92% yield and 95.5% HPLC purity.
(2) Preparation of 1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl ] nonane:
1-bromo-9- (4, 5-pentafluoroetentylthio) nonane (73 g,0.18 mol) was dissolved in 1, 2-dichloroethane (600 mL), cooled in an ice bath, 27.5% hydrogen peroxide (26 g,0.21 mol) was slowly added dropwise thereto, the reaction was carried out at 30℃for 9 hours, the organic solvent was removed by concentrating under reduced pressure, extraction was carried out by adding methylene chloride, washing with brine, drying over anhydrous sodium sulfate, and spin-evaporating under reduced pressure to dryness to give 1-bromo-9- [ (4, 5-pentafluoroethyl) sulfinyl ] nonane (70 g) in 92% yield.
(3) Preparation of fulvestrant:
1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl]Nonane (70 g,0.17 mol) is added into a reaction bottle, magnesium chips (6 g), THF (800 mL) and 1 particle of iodine are added, the temperature is slowly raised to 35 ℃ to react completely (3 h), the mixture is cooled to room temperature, unreacted magnesium chips settle, and a supernatant Grignard reagent is taken for standby; adding dehydronorbornyl acetate (41 g,0.13 mol) into a reaction bottle, adding THF (500 mL) for dissolving, cooling in ice bath, slowly dripping the Grignard reagent solution, reacting at 20deg.C for 2h, adding LiBr (12 g) and CuBr 2 (30g) Acetonitrile (400 mL), heat preservation at 30 ℃ for 4h, reduced pressure concentration to remove organic solvent, adding dichloromethane for extraction, brine, anhydrous sodium sulfate for drying, reduced pressure rotary evaporation to dryness, recrystallizing the crude product by ethyl acetate-n-heptane mixed solvent, and vacuum drying to obtain fulvestrant (69 g), wherein the yield is 87%, and the HPLC purity is 99.2%.
Example 3
(1) Preparation of 1-bromo-9- (4, 5-pentafluoropentylthio) nonane:
9-bromononyltrifluoromethane sulfonate (95 g,0.27 mol), pyridine (63 g,0.8 mol) were dissolved in methyl tertiary butyl ether (2000 mL), cooled in an ice bath, and pentafiuoropentylthiol (103 g,0.53 mol) was slowly added dropwise thereto, reacted at 90℃for 12 hours, concentrated under reduced pressure to remove the organic solvent, extracted with methylene chloride, washed with common salt, dried over anhydrous sodium sulfate, and distilled under reduced pressure to dryness to give 1-bromo-9- (4, 5-pentafiuoropentylthio) nonane (97 g) in a yield of 91% and an HPLC purity of 95.5%.
(2) Preparation of 1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl ] nonane:
1-bromo-9- (4, 5-pentafluoroetentylthio) nonane (96 g,0.24 mol) was dissolved in methyl tert-butyl ether (800 mL), cooled in an ice bath, sodium periodate (67 g,0.31 mol) was slowly added, the reaction was carried out at 30℃for 6 hours, the organic solvent was removed by concentration under reduced pressure, extraction was carried out by adding methylene chloride, washing with common salt, drying over anhydrous sodium sulfate, and spin-evaporating under reduced pressure to dryness to give 1-bromo-9- [ (4, 5-pentafluoroetentylsulfinyl ] nonane (92 g) in 92% yield.
(3) Preparation of fulvestrant:
1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl]Nonane (90 g,0.22 mol) is added into a reaction bottle, magnesium chips (10 g), THF (1500 mL) and 1 particle of iodine are added, the temperature is slowly raised to 40 ℃ to react completely (2 h), the mixture is cooled to room temperature, unreacted magnesium chips settle, and a supernatant Grignard reagent is taken for standby; adding dehydronorbornyl acetate (68 g,0.22 mol) into a reaction bottle, adding THF (800 mL) for dissolving, cooling in ice bath, slowly dripping the Grignard reagent solution, reacting at 30deg.C for 1h, adding LiBr (20 g) and CuBr 2 (50g) Acetonitrile (400 mL), heat preservation at 20 ℃ for 6h, reduced pressure concentration to remove organic solvent, adding dichloromethane for extraction, brine, anhydrous sodium sulfate for drying, reduced pressure rotary evaporation to dryness, recrystallizing the crude product by ethyl acetate-n-heptane mixed solvent, and vacuum drying to obtain fulvestrant (110 g), wherein the yield is 84%, and the HPLC purity is 99.2%.
Claims (5)
1. The preparation method of fulvestrant is characterized by comprising the following steps of:
(1) The sulfonate compound and the pentafluoropentylthio undergo substitution reaction to obtain 1-bromo-9- (4, 5-pentafluoropentylthio) nonane:
wherein X is p-toluenesulfonyl (Ts), methanesulfonyl (Ms) or trifluoromethanesulfonyl (Tf);
(2) 1-bromo-9- (4, 5-pentafluoropentylthio) nonane is oxidized in an oxidant and solvent system to give 1-bromo-9- [ (4, 5-pentafluoropentylsulfinyl ] nonane:
(3) 1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl ] nonane to form a grignard reagent, and then carrying out addition reaction and aromatization reaction with dehydronandrolone acetate to obtain fulvestrant:
2. the process for the preparation of fulvestrant according to claim 1, wherein the molar ratio of sulfonate compound to pentafluoropentylthiol in step (1) is 1:1.5-2; the sulfonate compound refers to 9-bromononyl p-toluenesulfonate, 9-bromononyl methane sulfonate or 9-bromononyl trifluoro methane sulfonate;
the substitution reaction is carried out in a solvent system in the presence of an acid-binding agent base;
the molar ratio of the acid binding agent base to the sulfonate compound is 2-3:1;
the acid-binding agent base is any one or a combination of at least two of triethylamine, diethylamine, N-diisopropylethylamine, pyridine, piperidine, tri-N-butylamine, trimethylamine, triisopropylamine, aniline, N-dimethylaniline, N-diethylaniline, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine, N-ethylmorpholine or 1, 8-diazabicyclo [5.4.0] undec-7-ene;
any one or a combination of at least two of toluene, xylene, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, methyl tertiary butyl ether or 1, 4-dioxane;
the temperature of the substitution reaction is 70-100 ℃ and the reaction time is 6-18h.
3. A process for the preparation of fulvestrant according to claim 1 and/or claim 2, wherein the molar ratio of 1-bromo-9- (4, 5-pentafluoropentylthio) nonane to oxidant in step (2) is 1:1-1.3;
the oxidant is any one or the combination of at least two of m-chloroperoxybenzoic acid, hydrogen peroxide, peroxyacetic acid or sodium periodate;
the solvent is any one or a combination of at least two of dichloromethane, 1, 2-dichloroethane, chloroform, acetonitrile or methyl tertiary butyl ether;
the temperature of the oxidation reaction is 20-30 ℃ and the reaction time is 6-12h.
4. A process for the preparation of fulvestrant according to claims 1-3 wherein the grignard generating reagent of step (3) is reacted for 1-3 hours at a temperature in the range of 35-45 ℃;
the temperature of the addition reaction is 0-30 ℃ and the reaction time is 1-3h;
the aromatization reaction is carried out in the presence of copper bromide and lithium bromide;
the temperature of the aromatization reaction is 20-50 ℃ and the reaction time is 3-6h;
the molar ratio of the 1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl ] nonane to the dehydronandrolone acetate is 1-1.3:1-1.3.
5. A process for the preparation of fulvestrant according to any of claims 1-4 comprising the steps of:
(1) In a solvent system in the presence of acid-binding agent alkali, the molar ratio of sulfonate compound to pentafluoropentylthio is 1:1.5-2, and substitution reaction is carried out for 6-18h at 70-100 ℃ to obtain 1-bromo-9- (4, 5-pentafluoropentylthio) nonane, wherein the molar ratio of acid-binding agent alkali to sulfonate compound is 2-3:1;
(2) In the presence of oxidant, 1-bromo-9- (4, 5-pentafluoro amyl thio) nonane is subjected to oxidation reaction at 20-30 ℃ for 6-12h, the molar ratio of the 1-bromo-9- (4, 5-pentafluoropentylthio) nonane to the oxidant is 1:1-1.3, and 1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl ] nonane is obtained;
(3) 1-bromo-9- [ (4, 5-pentafluoropentyl) sulfinyl ] nonane is reacted for 1-3 hours at a temperature range of 35-45 ℃ to generate a Grignard reagent, then is subjected to addition reaction with dehydronorlong acetate at a temperature of 0-30 ℃ for 1-3 hours, and is subjected to oxidation reaction at a temperature of 20-50 ℃ for 3-6 hours in the presence of copper bromide and lithium bromide to obtain fulvestrant.
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