Preparation method of fulvestrant

Abstract

The invention provides a preparation method of fulvestrant. According to the technical scheme, (7alpha, 17beta)-7-(9-bromononyl) estra-1, 3, 5 (10)-triene-3, 17-diol-17-acetate (intermediate I) is used as a starting material, fulvestrant is prepared through three-step reaction, the reaction condition is mild, the total molar yield is 52.8%, the HPLC purity of the obtained product fulvestrant can reach 99.8% or above, all the raw materials are domestic, operation is easy and convenient, column chromatography is not needed, and the method is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to a novel method for preparing fulvestrant. Background Art

[0002] Fulvestrant, chemically named (7α, 17β)-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-estra-1,3,5(10)-triene-3,17-diol, has the following structural formula:

[0003] Fulvestrant is an anti-breast cancer drug developed by Astrazeneca. It was first launched in the United States in 2002 and approved by the European Union in 2004. It is a new type of estrogen receptor blocker used to treat postmenopausal patients with advanced breast cancer who are estrogen receptor positive and have failed to respond to anti-estrogen therapy.

[0004] There are many synthetic routes for Fulvestrant, such as WO2006015081. The route is relatively simple, but the difficulty of Michael addition between the parent core and the side chain is relatively large, and at least one column chromatography purification is required later, resulting in an unsatisfactory final product yield. The synthetic route is as follows:

[0005] The synthetic route provided by patent US20060030552 is currently adopted by most domestic manufacturers, especially intermediate I, which has achieved mass production. However, intermediate IV still needs to be purified by column chromatography, otherwise the quality of the final fulvestrant will not meet the requirements. Its synthetic route is as follows:

[0006] The route adopted by US4659516 has to be purified by column chromatography many times because the intermediates are all oily and complex. The synthetic route is as follows:

[0007] In addition, there is patent WO2009039700, which details a method for preparing fulvestrant using estradiol or its analogs as raw materials. However, the conditions of this route are harsh, the final product yield is low, and it is not suitable for large-scale production.

[0008] In general, most of the current synthetic routes for Fulvestrant are too lengthy, and the intermediates are mostly oily, without suitable means of recrystallization purification. Therefore, many steps require column chromatography purification, otherwise the Fulvestrant obtained will not meet the pharmacopoeia quality requirements. This is currently the main obstacle to the industrial production of Fulvestrant. The requirements of the United States Pharmacopoeia USP40-NF35 on the related substances of Fulvestrant are as follows:

[0009] This is the most widely used quality standard for Fulvestrant at home and abroad. There are clear limit requirements for several specific impurities, and the requirements for unknown impurities are more stringent, with all unknown single impurities less than 0.1%. This requires us to carry out necessary purification or control of each intermediate in the production process to ensure that the final product meets the corresponding pharmacopoeia quality standards. In fact, high requirements for product quality standards are a reflection of the core competitiveness of an enterprise. Therefore, it is necessary to develop a method that is simple in route and suitable for industrial production of high-purity Fulvestrant. Summary of the invention

[0010] In order to solve the above problems, the present invention provides a method for preparing fulvestrant.

[0011] We use self-produced intermediates I (purity 98.8%, maximum single impurity 0.3%) and intermediate III (purity 99.7%, maximum single impurity 0.1%) as the main raw materials, and other raw materials are all conventional chemical raw materials. First, intermediate I is hydrolyzed with methanol and hydrobromic acid to obtain intermediate II, and intermediate II is refined once with ethyl acetate. Then the refined intermediate II is dissolved in DMF, condensed with intermediate III under alkaline conditions to obtain intermediate IV, and intermediate IV is oxidized with 15% hydrogen peroxide in ethyl acetate and glacial acetic acid to obtain fulvestrant, and then recrystallized with ethyl acetate three times to obtain high-purity fulvestrant. According to the United States Pharmacopoeia USP40-NF35 method, the relevant substances are detected, and the HPLC purity is greater than 99.8%, and any single impurity is less than 0.06%. Other detection indicators are in full compliance with the United States Pharmacopoeia USP40 standard. The entire process does not require column chromatography, the reaction conditions are mild, and it is suitable for large-scale production.

[0012] The preparation method of the present invention can be represented by the following reaction formula:

[0013] The technical solution of the present invention mainly comprises the following steps: (1) Preparation of Compound II (7α,17β)-7-(9-bromononyl)estra-1,3,5(10)-triene-3,17diol Compound I is hydrolyzed in a hydrohalic acid, and general alcohols or water can be used as solvents. Compound II is generated by reaction at 50-70°C. The use of hydrochloric acid easily leads to bromine-chlorine exchange at the end of the branch chain of compound II, so hydrobromic acid is better. The reaction solvent can be methanol, ethanol, etc., preferably methanol. The reaction temperature should not be too high, otherwise the hydroxy etherification side reaction will be more obvious. If the temperature is too low, the reaction will obviously slow down, affecting the conversion rate of the raw materials. The reaction temperature is preferably 60-65°C, that is, reflux in methanol. (2) Preparation of Compound IV (7α,17β)-7-{9-[(4,4,5,5,5-pentafluoropentyl)thio]nonyl}estra-1,3,5(10)-triene-3,17diol Compound II reacts with compound III in a suitable solvent under alkaline conditions in the temperature range of 0°C to 20°C to obtain compound IV. The solvent used can be DMF, DMAC, etc., and DMAC residue is not easy to remove, preferably DMF. Too high a reaction temperature will make compound III unstable and produce a side reaction of self-condensation into thioether, preferably 5 to 10°C. The base used can be sodium hydroxide, potassium hydroxide or other inorganic strong bases, preferably 30% sodium hydroxide. (3) Preparation of Fulvestrant Compound IV uses a generally mild oxidant at 0-25°C to oxidize the thioether to sulfoxide, wherein the oxidant is sodium periodate, m-chloroperbenzoic acid, and hydrogen peroxide. Hydrogen peroxide is environmentally friendly and easy to remove, and hydrogen peroxide is preferred. Excessive concentration of hydrogen peroxide can easily lead to oxidation of thioether to sulfone, so diluting the concentration of hydrogen peroxide to 15% is beneficial to reduce the generation of peroxide. The obtained crude product of Fulvestrant can be recrystallized using ethyl acetate or toluene. Toluene residues are difficult to remove, so ethyl acetate is preferred. After refining, high-purity Fulvestrant can be obtained. After HPLC detection according to the method for detecting Fulvestrant related substances described in USP40, the product purity is >99.8%, and the maximum single impurity is <0.06%. Specific implementation plan The following embodiments are intended to describe the present invention in more detail so that those skilled in the art can understand it more clearly.

[0014] Preparation of Compound II Add 6KG (11.56mol) of compound I (HPLC: 98.8%) and 60L of methanol to a 100L reactor, add 12KG of 45% hydrobromic acid (66.7mol), heat to 60-65°C, the solid gradually dissolves, reflux for 1.5 hours, cool to 5-10°C, a large amount of white solid precipitates, filter, wash the filter cake with an appropriate amount of methanol and drain to obtain 5.7KG of white solid. Use ethyl acetate for recrystallization, vacuum dry the obtained wet product at 50-55°C for 8 hours, and obtain 4.47KG of white solid, with a molar yield of 81.2%. HPLC: 99.2%.

[0015] Preparation of Compound IV Add 4.47KG of compound II (9.35mol) and 25L of DMF to a 100L reactor, dissolve and cool to 0℃, add 4,4,5,5,5-pentafluoropentanethiol 1.82KG (9.38mol). Add 1.7KG of 30% liquid caustic soda, control the internal temperature at 5-10℃, and keep 5-10℃ for 30 minutes. Follow with TLC (ethyl acetate: petroleum ether = 1:4), the spot of compound II disappears, and the reaction is over. Add 30L of water and 30L of ethyl acetate for extraction. After the extraction is complete, wash the upper oil layer twice with saturated brine. Dry with anhydrous sodium sulfate for 2 hours, and concentrate to dryness under reduced pressure at 55-60℃ to obtain 5.4KG of oil, HPLC: 98.5%, molar yield: 97.6%.

[0016] Preparation of Fulvestrant Add 15KG of ethyl acetate to a 100-liter reactor, add 5.4KG (9.15mol) of compound IV and 3.1KG of glacial acetic acid, cool to 10°C, add 4.1KG (18.09mol) of 15% hydrogen peroxide, control the internal temperature at 15-20°C, and keep the temperature at 15-20°C for 6-8 hours. TLC (ethyl acetate: petroleum ether = 1:3) tracking, compound IV spots disappear, add 20L of 5% sodium sulfite aqueous solution, extract with 20L of saturated brine, and stand for stratification. The upper ethyl acetate layer is washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, added 10KG of ethyl acetate to dissolve, stirred at 8-10°C for crystallization for 30 minutes, and filtered to obtain about 4.9KG of crude fulvestrant product. The crude product was refined three times with ethyl acetate 2.5 times the weight of the wet product each time, and after obtaining the refined product, it was vacuum dried at 60-65°C for 50-60 hours to obtain 3.7KG of the finished product. HPLC: 99.84%, molar yield: 66.6%, isomer B:isomer A=54.1:45.9. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 Structural formula of Compound I. Figure 2 Structural formula of compound II. Figure 3 Structural formula of compound III. Figure 4 Structural formula of compound IV. Figure 5 It is a product obtained in the preparation of fulvestrant in a specific implementation scheme, and its liquid phase spectrum of related substances is detected according to the United States Pharmacopoeia USP40-NF35 method.

Claims

1. A method for preparing fulvestrant, characterized in that: The following steps are involved: Compound I is mixed with a hydrohalic acid in a reaction solvent and reacted within a specific temperature range to generate compound II.

2. Compound II is mixed with compound III in a reaction solvent, and reacts with a base within a specific temperature range to form compound IV.

3. Compound IV is oxidized in a reaction solvent using an oxidant within a specific temperature range and for a certain period of time to generate Fulvestrant.

4. The preparation method according to claim 1, wherein the reaction solvent is one or two of methanol, ethanol, isopropanol or water. The preparation method according to claim 1 , wherein the specific temperature range is 50 to 70° C.

6. The preparation method according to claim 1, wherein the hydrohalic acid is hydrochloric acid or hydrobromic acid, and the molar ratio of the hydrohalic acid to the compound I is 5 to 10:

1.

7. The preparation method according to claim 2, wherein the reaction solvent is DMF or DMAC.

8. The preparation method according to claim 2, wherein the alkali is sodium hydroxide or potassium hydroxide.

9. The preparation method according to claim 2, wherein the specific temperature range is 0 to 20°C.

10. The preparation method according to claim 2, wherein the molar ratio of compound III to compound II is 1 to 1.5:

1.

11. The preparation method according to claim 3, wherein the reaction solvent is one or two of ethyl acetate and glacial acetic acid.

12. The preparation method according to claim 3, wherein the oxidant is sodium periodate, m-chloroperbenzoic acid or hydrogen peroxide, etc. The molar ratio of the oxidant to compound IV is 1 to 3:

1.

13. The preparation method according to claim 3, wherein the specific temperature range is 10 to 25°C.

14. The preparation method according to claim 3, wherein the certain period of time is 6 to 8 hours.

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