A preparation method of fulvestrant

Abstract

The present invention provides a preparation method of fulvestrant. The preparation method includes the following steps: A sulfonate compound reacts with pentafluoropentanethiol through a substitution reaction to generate 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane, which undergoes an oxidation reaction to obtain 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane. It is converted into a Grignard reagent through a Grignard reaction, and undergoes a Michael addition reaction and an aromatization reaction with dehydroepiandrosterone acetate to obtain fulvestrant. The preparation method of the present invention has mild conditions, easily available raw materials, low cost, and is suitable for industrial production application and promotion.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of fulvestrant. Background Art

[0002] Fulvestrant is a novel anti-breast cancer drug developed by AstraZeneca, mainly used for the treatment of postmenopausal advanced breast cancer with ineffective anti-estrogen therapy and positive estrogen receptor. Fulvestrant was first launched in the United States in 2002 and approved for marketing in Europe in 2004, and its trade name is It has good curative effect and small side effects, and is designated as a single therapy for the treatment of estrogen receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women who have not been previously treated with endocrine therapy or have diseases that recur from anti-estrogen therapy, and in combination with palbociclib for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in women who have previously received endocrine therapy.

[0003] The chemical name of fulvestrant is 7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17-β-diol, and its structural formula is as follows:

[0004]

[0005] The fulvestrant molecule is composed of two parts: a steroid nucleus and a long-chain alkyl group connected to the 7α-position of the steroid. In the prior art, there are two main directions for the synthetic route of fulvestrant. One is to use dehydroepiandrosterone acetate as the nucleus to carry out a series of reactions to obtain fulvestrant, and the other is to use a derivative of estradiol as the starting material as the nucleus to prepare fulvestrant. The 7α-alkyl group is composed of two parts: a nine-carbon fatty chain and a five-carbon fatty chain. The synthetic method is generally either to first connect the nine-carbon chain to the steroid and then connect it with the five-carbon chain, or to connect the nine-carbon chain and the five-carbon chain and then react with the steroid nucleus to obtain the fulvestrant molecule.

[0006] The synthetic route of fulvestrant of the original research pharmaceutical factory AstraZeneca has been disclosed in patents WO2002032922 and WO2003031399. Using dehydroepiandrosterone acetate as the raw material, first at the 7-position, the main side chain is connected through a Grignard reagent Michael addition, and then through LiBr / CuBr2 aromatization reaction, hydrolysis reaction and oxidation reaction, etc., to obtain fulvestrant. The reaction conditions of this route are relatively harsh, and more impurities are generated. The synthetic route is as follows:

[0007]

[0008]

[0009] A synthetic route of fulvestrant disclosed in Patent WO2006015081 also uses dehydroepiandrosterone acetate as the raw material. First, a Grignard reagent Michael addition is carried out to introduce a nine-carbon side chain at the 7-position of dehydroepiandrosterone acetate. Then, it reacts with a pentafluoropentyl mercaptan derivative of a five-carbon chain to synthesize fulvestrant. The reaction conditions of this route are relatively mild. However, the isothiourea hydrobromide produced during the reaction will undergo an oxygen side reaction, generating disulfide impurities and impurities resulting from the nucleophilic substitution of the phenolic hydroxyl group at the 3-position with pentafluoropentyl sulfonate. The synthetic route of this process is as follows:

[0010]

[0011] The synthetic route of fulvestrant disclosed in Patent WO2005077968 uses estradiol as the starting material for the reaction. First, estradiol reacts with 3,4-dihydropyran to protect the hydroxyl group. Then, oxidation with H2O2-pyridinium chlorochromate generates a ketocarbonyl group at the 6-position of the steroid. The ketocarbonyl compound undergoes a nucleophilic substitution reaction with C2F5(CH2)3S(CH2)9Br in the presence of potassium tert-butoxide. Finally, deprotection and oxidation are carried out to prepare fulvestrant. The reaction conditions of this route are complex, the materials and reagents are expensive, which is not conducive to industrial production. The synthetic route is as follows:

[0012]

[0013]

[0014] All the existing disclosed process routes have various defects and deficiencies such as expensive raw materials, harsh reaction conditions, more impurities, high-temperature reactions, unsafe production, and high costs. Therefore, they are not suitable for industrial production applications. Striving to develop a simple, economical, and environmentally friendly preparation technology for fulvestrant, especially seeking a process scheme that can adapt to industrial production, has important practical significance for improving the economic and social benefits of this variety. Summary of the Invention

[0015] The purpose of the present invention is to provide a preparation method of fulvestrant. This method has mild process conditions, helps to control the generation of side reactions and impurities, and improves the yield. The technical solution adopted by the present invention is as follows:

[0016] Synthetic route of fulvestrant:

[0017]

[0018] In the formula, X is p-toluenesulfonyl (Ts), methanesulfonyl (Ms), or trifluoromethanesulfonyl (Tf).

[0019] The specific steps of the preparation method of fulvestrant are as follows:

[0020] (1) The sulfonate compound undergoes a substitution reaction with pentafluoropentanethiol to obtain 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane;

[0021] (2) 1-Bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane undergoes an oxidation reaction in an oxidant and solvent system to obtain 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane;

[0022] (3) 1-Bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane forms a Grignard reagent, and then undergoes an addition reaction and an aromatization reaction with dehydroepiandrosterone acetate to obtain fulvestrant.

[0023] Preferably, the molar ratio of the sulfonate compound to pentafluoropentanethiol in step (1) is 1:1.5 - 2, and the sulfonate compound refers to 9-bromononyl p-toluenesulfonate, 9-bromononyl methanesulfonate, or 9-bromononyl trifluoromethanesulfonate.

[0024] Preferably, the substitution reaction is carried out in a solvent system in the presence of an acid-binding agent base.

[0025] Preferably, the molar ratio of the acid-binding agent base to the sulfonate compound is 2 - 3:1.

[0026] Preferably, the acid-binding agent base is any one or at least two combinations of triethylamine, diethylamine, N,N-diisopropylethylamine, pyridine, piperidine, tri-n-butylamine, trimethylamine, triisopropylamine, aniline, N,N-dimethylaniline, N,N-diethylaniline, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine, N-ethylmorpholine, or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0027] Preferably, it is any one or at least two combinations of toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, methyl tert-butyl ether, or 1,4-dioxane.

[0028] Preferably, the temperature of the substitution reaction is 70 - 100 °C, and the reaction time is 6 - 18 h.

[0029] Preferably, the molar ratio of 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane to the oxidant in step (2) is 1:1 - 1.3.

[0030] Preferably, the oxidant is any one or at least two combinations of m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, or sodium periodate.

[0031] 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.

[0032] Preferably, the temperature of the oxidation reaction is 20 - 30 °C, and the reaction time is 6 - 12 h.

[0033] Preferably, in step (3), the formation of the Grignard reagent is carried out in the temperature range of 35 - 45 °C, and the reaction time is 1 - 3 h.

[0034] Preferably, the temperature of the addition reaction is 0 - 30 °C, and the reaction time is 1 - 3 h.

[0035] Preferably, the aromatization reaction is carried out in the presence of copper bromide and lithium bromide.

[0036] Preferably, the temperature of the aromatization reaction is 20 - 50 °C, and the reaction time is 3 - 6 h.

[0037] Preferably, the molar ratio of 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane to dehydroepiandrosterone acetate is 1 - 1.3:1 - 1.3.

[0038] As a preferred technical solution, a method for preparing fulvestrant according to the present invention includes the following steps:

[0039] (1) In a solvent system in the presence of an acid-binding agent base, a sulfonate compound and pentafluoropentanethiol are in a molar ratio of 1:1.5 - 2, and at 70 - 100 °C, a substitution reaction is carried out for 6 - 18 h to obtain 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane, and the molar ratio of the acid-binding agent base to the sulfonate compound is 2 - 3:1;

[0040] (2) In the presence of an oxidizing agent, 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane is oxidized at 20 - 30 °C for 6 - 12 h, and the molar ratio of 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane to the oxidizing agent is 1:1 - 1.3 to obtain 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane;

[0041] (3) 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane forms a Grignard reagent in the temperature range of 35 - 45 °C for a reaction time of 1 - 3 h, and then reacts with dehydroepiandrosterone acetate at 0 - 30 °C for an addition reaction of 1 - 3 h, and in the presence of copper bromide and lithium bromide, an oxidation reaction is carried out at 20 - 50 °C for 3 - 6 h to obtain fulvestrant.

[0042] The technical solution of the present invention first docks a cheap and easily available sulfonate compound with pentafluoropentanethiol and oxidizes it to obtain a side chain containing a sulfinyl group. The interaction between the Mg metal center of the Grignard reagent and the O atom of the sulfinyl group tends to form a cyclic transition state, which is beneficial for the Grignard reagent to participate in the reaction. At the same time, it is not necessary to carry out an oxidation reaction after connecting the side chain to the steroid nucleus, thereby reducing the generation of side reactions, being more beneficial for controlling impurities in the entire synthesis route, making the entire synthesis process relatively simple, and the reaction conditions being relatively mild.

[0043] Compared with the prior art, the present invention has the following beneficial effects: the process conditions are mild, reducing the generation of impurities, which is beneficial for the quality control of the fulvestrant API; secondly, the reagent raw materials used in the process route of the present invention are easily available, and the yield is relatively high. The technical solution is reasonable and environmentally friendly, which is beneficial for industrial promotion and can be mass-produced to meet the usage requirements. Specific embodiments

[0044] The technical solution of the present invention will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments are only for helping to understand the present invention and should not be regarded as specific limitations on the present invention.

[0045] Example 1:

[0046] (1) Preparation of 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane:

[0047] 9-bromononyl p-toluenesulfonate (50 g, 0.13 mol), triethylamine (27 g, 0.27 mol) were dissolved in toluene (800 mL), cooled in an ice bath, and pentafluoropentanethiol (39 g, 0.2 mol) was slowly added dropwise. The temperature was raised to 100 °C and reacted for 6 h. The organic solvent was removed by reduced pressure concentration, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and rotary evaporated to dryness under reduced pressure to obtain 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane (47 g), with a yield of 89% and an HPLC purity of 95.5%.

[0048] (2) Preparation of 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane:

[0049] 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane (45 g, 0.11 mol) was dissolved in dichloromethane (400 mL), cooled in an ice bath, and m-chloroperbenzoic acid (19.5 g, 0.11 mol) was slowly added. The temperature was kept at 20 °C and reacted for 12 h. The organic solvent was removed by reduced pressure concentration, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and rotary evaporated to dryness under reduced pressure to obtain 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane (42 g), with a yield of 90%.

[0050] (3) Preparation of fulvestrant:

[0051] 1-Bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane (40 g, 96 mmol) was added to a reaction flask, together with magnesium turnings (5 g), THF (300 mL) and 1 iodine granule. The temperature was slowly raised to 45 °C and the reaction was completed (1 h). After cooling to room temperature, the unreacted magnesium turnings settled, and the supernatant Grignard reagent was taken for use. Dehydronandrolone acetate (39 g, 0.12 mol) was added to the reaction flask, dissolved in THF (350 mL), cooled in an ice bath, and the above Grignard reagent solution was slowly added dropwise. The reaction was carried out at 0 °C for 3 h. LiBr (9 g), CuBr2 (25 g) and acetonitrile (500 mL) were added, and the reaction was carried out at 50 °C for 3 h. The organic solvent was removed by concentration under reduced pressure. Dichloromethane was added for extraction, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure by rotary evaporation. The crude product was recrystallized from a mixed solvent of ethyl acetate - n-heptane and dried in vacuo to obtain fulvestrant (50 g), with a yield of 86% and an HPLC purity of 99.2%.

[0052] Example 2

[0053] (1) Preparation of 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane:

[0054] 9-Bromononyl methanesulfonate (60 g, 0.2 mol) and N,N-diisopropylethylamine (65 g, 0.5 mol) were dissolved in tetrahydrofuran (1100 mL), cooled in an ice bath, and pentafluoropentanethiol (66 g, 0.34 mol) was slowly added dropwise. The temperature was raised to 70 °C and the reaction was carried out for 18 h. The organic solvent was removed by concentration under reduced pressure. Dichloromethane was added for extraction, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure by rotary evaporation to obtain 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane (73 g), with a yield of 92% and an HPLC purity of 95.5%.

[0055] (2) Preparation of 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane:

[0056] 1-Bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane (73 g, 0.18 mol) was dissolved in 1,2-dichloroethane (600 mL), cooled in an ice bath, and 27.5% hydrogen peroxide (26 g, 0.21 mol) was slowly added dropwise. The reaction was carried out at 30 °C for 9 h. The organic solvent was removed by concentration under reduced pressure. Dichloromethane was added for extraction, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure by rotary evaporation to obtain 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane (70 g), with a yield of 92%.

[0057] (3) Preparation of fulvestrant:

[0058] 1-Bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane (70 g, 0.17 mol) was added to a reaction flask, followed by magnesium turnings (6 g), THF (800 mL), and 1 iodine granule. The temperature was slowly raised to 35 °C and the reaction was completed (3 h). After cooling to room temperature, the unreacted magnesium turnings settled, and the supernatant Grignard reagent was taken for use. Dehydroepiandrosterone acetate (41 g, 0.13 mol) was added to the reaction flask, dissolved in THF (500 mL), cooled in an ice bath, and the above Grignard reagent solution was slowly added dropwise. The reaction was carried out at 20 °C for 2 h. LiBr (12 g), CuBr2 (30 g), and acetonitrile (400 mL) were added, and the reaction was carried out at 30 °C for 4 h. The organic solvents were removed by concentration under reduced pressure, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was recrystallized from a mixed solvent of ethyl acetate - n-heptane and dried in vacuo to obtain fulvestrant (69 g), with a yield of 87% and an HPLC purity of 99.2%.

[0059] Example 3

[0060] (1) Preparation of 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane:

[0061] 9-Bromononyl trifluoromethanesulfonate (95 g, 0.27 mol) and pyridine (63 g, 0.8 mol) were dissolved in methyl tert-butyl ether (2000 mL), cooled in an ice bath, and pentafluoropentanethiol (103 g, 0.53 mol) was slowly added dropwise. The temperature was raised to 90 °C and the reaction was carried out for 12 h. The organic solvents were removed by concentration under reduced pressure, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane (97 g), with a yield of 91% and an HPLC purity of 95.5%.

[0062] (2) Preparation of 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane:

[0063] 1-Bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane (96 g, 0.24 mol) was dissolved in methyl tert-butyl ether (800 mL), cooled in an ice bath, and sodium periodate (67 g, 0.31 mol) was slowly added. The reaction was carried out at 30 °C for 6 h. The organic solvents were removed by concentration under reduced pressure, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane (92 g), with a yield of 92%.

[0064] (3) Preparation of fulvestrant:

[0065] 1-Bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane (90 g, 0.22 mol) was added to a reaction flask, followed by magnesium turnings (10 g), THF (1500 mL), and 1 iodine crystal. The temperature was slowly raised to 40 °C and the reaction was allowed to proceed to completion (2 h). After cooling to room temperature, the unreacted magnesium turnings settled, and the supernatant Grignard reagent was taken for use. Dehydronandrolone acetate (68 g, 0.22 mol) was added to the reaction flask and dissolved in THF (800 mL). The solution was cooled in an ice bath, and the above Grignard reagent solution was slowly added dropwise. The reaction was carried out at 30 °C for 1 h. LiBr (20 g), CuBr2 (50 g), and acetonitrile (400 mL) were added, and the reaction was carried out at 20 °C for 6 h. The organic solvent was removed by concentration under reduced pressure. The residue was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was recrystallized from a mixed solvent of ethyl acetate and n-heptane and dried in vacuo to obtain fulvestrant (110 g), with a yield of 84% and an HPLC purity of 99.2%.

Claims

1. A preparation method of fulvestrant, characterized in that, It includes the following steps: (1) The sulfonate compound undergoes a substitution reaction with pentafluoropentanethiol. The substitution reaction is carried out in a solvent system in the presence of an acid-binding agent base. The sulfonate compound and pentafluoropentanethiol are in a molar ratio of 1:1.5 - 2, at 70 - 100 °C, and the substitution reaction is carried out for 6 - 18 h to obtain 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane. The molar ratio of the acid-binding agent base to the sulfonate compound is 2 - 3:1, to obtain 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane: In the formula, X is p-toluenesulfonyl (Ts), methanesulfonyl (Ms), or trifluoromethanesulfonyl (Tf); (2) 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane undergoes an oxidation reaction in an oxidizing agent and a solvent system. 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane undergoes an oxidation reaction at 20 - 30 °C for 6 - 12 h. The molar ratio of 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane to the oxidizing agent is 1:1 - 1.3, to obtain 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane, to obtain 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane: (3) 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane generates a Grignard reagent, and then undergoes an addition reaction and an aromatization reaction with dehydroepiandrosterone acetate. The aromatization reaction is carried out in the presence of copper bromide and lithium bromide. 1-bromo-9-[(4,4,5,5-pentafluoropentyl)sulfinyl]nonane generates a Grignard reagent in the temperature range of 35 - 45 °C for a reaction time of 1 - 3 h, and then reacts with dehydroepiandrosterone acetate at 0 - 30 °C for an addition reaction of 1 - 3 h. In the presence of copper bromide and lithium bromide, an oxidation reaction is carried out at 20 - 50 °C for 3 - 6 h to obtain fulvestrant:

2. The preparation method of fulvestrant according to claim 1, characterized in that, In step (1), the molar ratio of the sulfonate compound to pentafluoropentanethiol is 1:1.5 - 2; the sulfonate compound refers to 9-bromononyl p-toluenesulfonate, 9-bromononyl methanesulfonate, or 9-bromononyl trifluoromethanesulfonate; 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,N-diisopropylethylamine, pyridine, piperidine, tri-n-butylamine, trimethylamine, triisopropylamine, aniline, N,N-dimethylaniline, N,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,N-dimethylformamide, N,N-dimethylacetamide, methyl tert-butyl ether, or 1,4-dioxane; The temperature of the substitution reaction is 70 - 100 °C, and the reaction time is 6 - 18 h.

3. The preparation method of fulvestrant according to claim 1, characterized in that, The molar ratio of 1-bromo-9-(4,4,5,5,5-pentafluoropentylthio)nonane to the oxidizing agent described in step (2) is 1:1 - 1.3; The oxidizing agent is any one or a combination of at least two of m-chloroperbenzoic acid, hydrogen peroxide, peracetic 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 tert-butyl ether; The temperature of the oxidation reaction is 20 - 30 °C, and the reaction time is 6 - 12 h.

4. A preparation method of fulvestrant according to claim 1, characterized in that, The formation of the Grignard reagent described in step (3) is carried out in the temperature range of 35 - 45 °C, and the reaction time is 1 - 3 h; The temperature of the addition reaction is 0 - 30 °C, and the reaction time is 1 - 3 h; The temperature of the aromatization reaction is 20 - 50 °C, and the reaction time is 3 - 6 h; The molar ratio of 1-bromo-9-[(4,4,5,5-tetrafluoropentyl)sulfinyl]nonane to dehydroepiandrosterone acetate is 1 - 1.3:1 - 1.3.

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