Method for recovering fulvestrant

Abstract

The invention discloses a method for recovering fulvestrant, and aims at recovering fulvestrant with unqualified isomers. According to the method, fulvestrant which is recovered from fulvestrant mother liquor and has an unqualified sulfoxide configuration proportion is adopted as a raw material, a reaction of reducing a sulfoxide group into thioether is carried out, then thioether is oxidized into sulfoxide through an oxidation reaction, and qualified fulvestrant is obtained through treatment. According to the method, the reaction conditions are mild, the purity of the intermediate and the purity of the crude product are high, and qualified fulvestrant can be obtained through simple recrystallization. The method is simple to operate, stable in process and suitable for large-scale production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for recovering fulvestrant. Background Art

[0002] Fulvestrant, with the molecular formula C 32 H 47 F5O3S, chemically named 7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17-β-diol, has the following structural formula:

[0003]

[0004] Fulvestrant is a new 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. Since its launch in the United States in 2002 and approval for marketing in Europe in 2004, its good efficacy and minor side effects have brought new hope to people with postmenopausal breast cancer.

[0005] Fulvestrant has the following two isomers:

[0006]

[0007] Currently, the fulvestrant used clinically is a mixture of the above two isomers. The European Pharmacopoeia clearly stipulates that isomer A:isomer B = 42 - 48:52 - 58. In the existing production process, to prepare a fulvestrant product that meets the quality standards, multiple recrystallization operations are required. The yield of fulvestrant is low, the loss is relatively large, and a large amount of fulvestrant with unqualified isomers exists in the mother liquor. If not recycled, it will cause environmental pollution and great waste of materials, which does not conform to the environmental protection concept of green chemistry and is not conducive to the cost control of production enterprises.

[0008] CN106146599A discloses a preparation method for recovering unqualified isomer ratios, which uses catalytic hydrogenation reduction with flammable and explosive substances such as hydrogen and palladium catalysts, metallic aluminum or zinc, and lithium aluminum hydride. This method has serious safety hazards and three-waste emissions, and is not conducive to industrial production.

[0009] CN107698647A discloses an improved method for recovering fulvestrant with unqualified isomer ratios, which replaces the catalyst with potential safety hazards and environmental pollution in the original process with a halide as a reduction catalyst, reducing three-waste emissions. This process is simple to operate, the materials are safe, and fulvestrant with qualified isomer ratios can be obtained. However, very strong reducing agents or strongly acidic conditions are used, which may lead to the degradation of fulvestrant molecules and thus the formation of many impurities.

[0010] CN115974953A discloses a method for recovering fulvestrant, which aims at recovering fulvestrant with unqualified isomers. This method selects two reduction systems, BH3 / THF solution and zinc powder / acetic acid, to reduce sulfoxide to thioether. Although the recovery rate of fulvestrant reaches about 77.3%, the BH3 / THF solution system is a flammable liquid, sensitive to air and moisture, and requires relatively high reaction conditions; for the zinc powder / acetic acid system, the purity of zinc powder needs to reach 99.999%, and a large amount of zinc salt solids need to be treated after the reaction. It does not reduce the emissions of the three wastes.

[0011] US20220259257A1 discloses a method for preparing thioether by the reduction reaction of waste fulvestrant; the waste fulvestrant is dissolved in an organic solvent such as toluene, tetrahydrofuran, chloroform, acetonitrile, methyltetrahydrofuran, and dioxane. The reaction is carried out at room temperature. A reduction system selected from sodium bisulfite, sodium metabisulfite and iodine and a reducing agent of diiron-nonacarbonylphenylsilane are added to the solution for reaction. After post-treatment, thioether is obtained. Then the thioether is oxidized to sulfoxide, and purified to obtain fulvestrant.

[0012] In summary, the prior art has realized the utilization of fulvestrant with unqualified isomer ratio. However, at present, there are problems in the recovery of fulvestrant products with unqualified isomer ratio, such as complex process, high operation difficulty, low recovery rate, and serious increase in the three wastes. Therefore, a new feasible method is needed to treat the fulvestrant mother liquor, obtain fulvestrant products that meet the quality standards, realize the recycling of the fulvestrant mother liquor, and reduce the industrial cost. Summary of the Invention

[0013] Aiming at the problem of unqualified isomer ratio of the crude product recovered from the fulvestrant mother liquor in the prior art, the present invention provides a method for recovering fulvestrant, which overcomes the problems existing in the prior art, such as large potential safety hazards, serious environmental pollution, and non-compliance with quality standards. In this method, the intermediate yield and purity are relatively high, and the qualified fulvestrant product can be obtained by simple recrystallization of the obtained crude product. The treated crude product can be directly reacted after simple concentration treatment of the mother liquor. Other reaction materials are generally easy to obtain, the reaction conditions are mild, the operation is simple and efficient, and it is very suitable for industrial production.

[0014] A method for recovering fulvestrant, the technical solution includes:

[0015] Step 1: Reduction reaction

[0016] In a solvent, the crude product recovered from the fulvestrant mother liquor is subjected to a reduction reaction to generate fulvestrant intermediate I;

[0017]

[0018] Step 2: Oxidation reaction

[0019] In a solvent, the fulvestrant intermediate I undergoes an oxidation reaction to form fulvestrant.

[0020]

[0021] Preferably, a method for recovering fulvestrant, the specific steps include:

[0022] Step 1: Reduction reaction

[0023] Under nitrogen protection, add the crude product recovered from the fulvestrant mother liquor, 3-mercaptopropionic acid and an organic solvent to the reaction flask, start stirring, control the temperature to T1, add a catalyst, and continue the heat preservation reaction; after the reaction is completed, perform post-treatment to obtain the fulvestrant intermediate I.

[0024] Step 2: Oxidation reaction

[0025] Add the fulvestrant intermediate I, a solvent and glacial acetic acid to the reaction flask, stir and cool down, add a hydrogen peroxide solution, control the temperature and stir for the reaction, cool down again after the reaction is completed, and add a sodium sulfite solution to quench the reaction, and perform post-treatment to obtain fulvestrant.

[0026] Preferably, the organic solvent described in Step 1 is selected from one or more of ethyl acetate, acetone, dichloromethane, N,N-dimethylformamide (DMF), dimethylacetamide (DMAC), acetonitrile, tetrahydrofuran, methanol and ethanol, and a more preferred choice is one or two of acetone and dichloromethane.

[0027] Preferably, the mass-volume ratio of the crude product recovered from the fulvestrant mother liquor to the organic solvent in Step 1 is 1:5-20, with the mass in g and the volume in ml; preferably 1:8-10.

[0028] Preferably, the catalyst used in Step 1 is iodine, N-bromosuccinimide (NBS); preferably N-bromosuccinimide (NBS).

[0029] Preferably, the molar ratio of the crude product recovered from the fulvestrant mother liquor to the catalyst in Step 1 is 1:0.05-0.3; preferably 1:0.2.

[0030] Preferably, the mass ratio of the crude product recovered from the fulvestrant mother liquor to 3-mercaptopropionic acid in Step 1 is 1:0.3-0.5; preferably 1:0.4.

[0031] Preferably, the temperature T1 controlled in Step 1 is 0-30°C; preferably 10-20°C.

[0032] Preferably, the reaction time after adding the catalyst in Step 1 is 2-4 hours; preferably 3 hours.

[0033] Further preferably, the post-treatment process in Step 1 is as follows: Add NaOH solution to the reaction flask, add the extraction solvent, stir, let it stand for liquid separation, and discard the aqueous phase; add purified water to the organic phase, stir, let it stand for liquid separation, and discard the aqueous phase; dry the organic phase with anhydrous sodium sulfate, filter off the desiccant, concentrate the organic phase under reduced pressure to dryness, slurry with an ethyl acetate:n-heptane mixed solution, filter by suction, and dry to obtain the fulvestrant intermediate I.

[0034] Preferably, the mass fraction of the NaOH solution is 5-10%.

[0035] Preferably, the extraction solvent is dichloromethane or ethyl acetate.

[0036] Preferably, the volume ratio of the ethyl acetate:n-heptane mixed solution is 1:20-25.

[0037] Preferably, the solvent in Step 2 is anhydrous methanol, anhydrous ethanol, acetonitrile, or ethyl acetate; the mass-to-volume ratio of the fulvestrant intermediate I to the organic solvent is 1:3-10, with the mass in g and the volume in ml; preferably 1:4-6.

[0038] Preferably, the mass ratio of the fulvestrant intermediate I to glacial acetic acid in Step 2 is 1:0.6-1.0; preferably 1:0.9.

[0039] Preferably, the molar ratio of the fulvestrant intermediate to hydrogen peroxide in Step 2 is 1:2-3; preferably 1:2.5.

[0040] Preferably, the hydrogen peroxide in Step 2 is 30% hydrogen peroxide solution.

[0041] Preferably, the temperature for cooling with stirring in Step 2 is 0-25°C; preferably 0-5°C.

[0042] Preferably, the temperature for temperature-controlled stirring in Step 2 is 10-25°C; preferably 20-25°C; the stirring time is 8-10 hours.

[0043] Preferably, the temperature for re-cooling in Step 2 is 0-5°C.

[0044] Further preferably, the post-treatment process in Step 2 is as follows:

[0045] Add ethyl acetate and purified water to the reaction flask, stir, let it stand for liquid separation, wash the organic layer with saturated brine, dry the organic phase with anhydrous sodium sulfate; filter by suction, concentrate the filtrate under reduced pressure at 55-60°C until no liquid flows out, and recrystallize with ethyl acetate to obtain white fulvestrant.

[0046] Further preferably, the volume ratio of the ethyl acetate to the purified water is 1:1.5-3.5; preferably 1:2.

[0047] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0048] 1. The present invention provides a method for recovering fulvestrant, which not only solves the problem of isomer ratio, but also solves other quality problems of fulvestrant.

[0049] 2. The reaction conditions of this method are mild, the purity of intermediates and crude products is relatively high, and qualified fulvestrant can be obtained through simple recrystallization. The operation is simple, the process is stable, and it is suitable for scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 It is the HPLC chromatogram of fulvestrant intermediate I in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0051] The present invention will be further described below through examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention fall within the scope of protection of the present invention.

[0052] Reduction reaction

[0053] Example 1

[0054] Under nitrogen protection, 20 g (0.0330 mol) of the recovered crude product of the fulvestrant mother liquor (after concentration), 160 ml of dichloromethane dried with molecular sieve, and 8.0 g (0.0754 mol) of 3-mercaptopropionic acid were added to the reaction flask. The mixture was stirred and cooled to 10 - 20 °C, and 1.17 g (0.0066 mol) of N-bromosuccinimide (NBS) was slowly added; the reaction continued for 3 hours; after the reaction was completed, 100 ml of 5% NaOH solution was added to the reaction flask, 100 ml of dichloromethane was added, and the mixture was stirred for 10 minutes, then left to stand for liquid separation. The organic phase was added with 100 ml of purified water, stirred for 10 minutes, and left to stand for liquid separation; the organic phase was dried with anhydrous sodium sulfate, the desiccant was filtered off, and the organic phase was concentrated under reduced pressure to dryness to obtain a pale yellow oily substance. 200 g of ethyl acetate:n-heptane (volume ratio 1:20) was added for pulping and stirring, then filtered by suction and dried to obtain white fulvestrant intermediate I with a molar yield of 96.3% and an HPLC purity of 99.019%.

[0055] Example 2

[0056] Under nitrogen protection, 20 g (0.0330 mol) of the crude product recovered from the fulvestrant mother liquor (after concentration), 160 ml of dichloromethane dried over molecular sieve, and 6.0 g (0.0565 mol) of 3-mercaptopropionic acid were added to the reaction flask. The mixture was stirred and cooled to 10 - 20 °C, and 0.30 g (0.0017 mol) of N-bromosuccinimide (NBS) was slowly added. The reaction was continued for 3 hours. After the reaction was completed, 100 ml of 5% NaOH solution was added to the reaction flask, followed by 100 ml of dichloromethane. The mixture was stirred for 10 minutes, allowed to stand for liquid separation. The organic phase was added with 100 ml of purified water, stirred for 10 minutes, and allowed to stand for liquid separation again. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the organic phase was concentrated under reduced pressure to dryness to obtain a pale yellow oil. 200 g of ethyl acetate:n-heptane (1:20) was added for pulping and stirring, followed by suction filtration and drying to obtain white fulvestrant intermediate I with a molar yield of 92.2% and an HPLC purity of 99.007%.

[0057] Example 3

[0058] Under nitrogen protection, 20 g (0.0330 mol) of the crude product recovered from the fulvestrant mother liquor (after concentration), 160 ml of dichloromethane dried over molecular sieve, and 10.0 g (0.0942 mol) of 3-mercaptopropionic acid were added to the reaction flask. The mixture was stirred and cooled to 10 - 20 °C, and 1.76 g (0.0099 mol) of N-bromosuccinimide (NBS) was slowly added. The reaction was continued for 3 hours. After the reaction was completed, 100 ml of 5% NaOH solution was added to the reaction flask, followed by 100 ml of dichloromethane. The mixture was stirred for 10 minutes, allowed to stand for liquid separation. The organic phase was added with 100 ml of purified water, stirred for 10 minutes, and allowed to stand for liquid separation again. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the organic phase was concentrated under reduced pressure to dryness to obtain a pale yellow oil. 200 g of ethyl acetate:n-heptane (1:20) was added for pulping and stirring, followed by suction filtration and drying to obtain white fulvestrant intermediate I with a molar yield of 93.8% and an HPLC purity of 99.011%.

[0059] Example 4

[0060] Under nitrogen protection, 20 g (0.0330 mol) of the crude product recovered from the fulvestrant mother liquor (after concentration), 160 ml of dichloromethane dried with molecular sieve, and 8.0 g (0.0754 mol) of 3-mercaptopropionic acid were added to the reaction flask. The mixture was stirred and cooled to 10 - 20 °C, and 1.68 g (0.0066 mol) of iodine was slowly added. The reaction was continued for 3 hours. After the reaction was completed, 100 ml of 5% NaOH solution was added to the reaction flask, followed by 100 ml of dichloromethane. The mixture was stirred for 10 minutes, allowed to stand for liquid separation. The organic phase was added with 100 ml of purified water, stirred for 10 minutes, and allowed to stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the organic phase was concentrated under reduced pressure to dryness to obtain a pale yellow oil. 200 g of ethyl acetate:n-heptane (1:20) was added for pulping and stirring, followed by suction filtration and drying to obtain white fulvestrant intermediate I with a molar yield of 94.9% and an HPLC purity of 99.009%.

[0061] Example 5

[0062] Under nitrogen protection, 20 g (0.0330 mol) of the crude product recovered from the fulvestrant mother liquor (after concentration), 160 ml of acetonitrile dried with molecular sieve, and 8.0 g (0.0754 mol) of 3-mercaptopropionic acid were added to the reaction flask. The mixture was stirred and cooled to 25 - 30 °C, and 1.17 g (0.0066 mol) of N-bromosuccinimide (NBS) was slowly added. The reaction was continued for 3 hours. After the reaction was completed, 100 ml of 5% NaOH solution was added to the reaction flask, followed by 100 ml of dichloromethane. The mixture was stirred for 10 minutes, allowed to stand for liquid separation. The organic phase was added with 100 ml of purified water, stirred for 10 minutes, and allowed to stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the organic phase was concentrated under reduced pressure to dryness to obtain a pale yellow oil. 200 g of ethyl acetate:n-heptane (volume ratio 1:20) was added for pulping and stirring, followed by suction filtration and drying to obtain white fulvestrant intermediate I with a molar yield of 93.5% and an HPLC purity of 99.011%.

[0063] Example 6

[0064] Under nitrogen protection, 20 g (0.0330 mol) of the crude product recovered from the mother liquor of fulvestrant (after concentration), 160 ml of acetone dried with molecular sieve, and 8.0 g (0.0754 mol) of 3-mercaptopropionic acid were added to the reaction flask. The mixture was stirred and cooled to 0 - 5 °C, and 1.17 g (0.0066 mol) of N-bromosuccinimide (NBS) was slowly added. The reaction was continued for 3 hours. After the reaction was completed, 100 ml of 5% NaOH solution was added to the reaction flask, followed by 150 ml of ethyl acetate. The mixture was stirred for 10 minutes, allowed to stand for liquid separation. The organic phase was added with 100 ml of purified water, stirred for 10 minutes, and allowed to stand for liquid separation again. The organic phase was dried with anhydrous sodium sulfate, the desiccant was filtered off, and the organic phase was concentrated under reduced pressure to dryness to obtain a pale yellow oil. 200 g of ethyl acetate:n-heptane (volume ratio 1:20) was added for pulping and stirring, followed by suction filtration and drying to obtain white fulvestrant intermediate I with a molar yield of 91.5% and an HPLC purity of 99.011%.

[0065] Example 7

[0066] Under nitrogen protection, 20 g (0.0330 mol) of the crude product recovered from the mother liquor of fulvestrant (after concentration), 160 ml of dichloromethane dried with molecular sieve, and 5.0 g (0.0471 mol) of 3-mercaptopropionic acid were added to the reaction flask. The mixture was stirred and cooled to 10 - 20 °C, and 1.17 g (0.0066 mol) of N-bromosuccinimide (NBS) was slowly added. The reaction was continued for 3 hours. After the reaction was completed, 100 ml of 5% NaOH solution was added to the reaction flask, followed by 100 ml of dichloromethane. The mixture was stirred for 10 minutes, allowed to stand for liquid separation. The organic phase was added with 100 ml of purified water, stirred for 10 minutes, and allowed to stand for liquid separation again. The organic phase was dried with anhydrous sodium sulfate, the desiccant was filtered off, and the organic phase was concentrated under reduced pressure to dryness to obtain a pale yellow oil. 200 g of ethyl acetate:n-heptane (volume ratio 1:20) was added for pulping and stirring, followed by suction filtration and drying to obtain white fulvestrant intermediate I with a molar yield of 91.9% and an HPLC purity of 99.019%.

[0067] Example 8

[0068] Under nitrogen protection, 20 g (0.0330 mol) of the crude product recovered from the mother liquor of fulvestrant (after concentration), 160 ml of dichloromethane dried with molecular sieve, and 8.0 g (0.0754 mol) of 3-mercaptopropionic acid were added to the reaction flask. The mixture was stirred and cooled to 10 - 20 °C, and 2.05 g (0.0115 mol) of N-bromosuccinimide (NBS) was slowly added. The reaction continued for 3 hours. After the reaction was completed, 100 ml of 5% NaOH solution was added to the reaction flask, followed by 100 ml of dichloromethane. The mixture was stirred for 10 minutes, allowed to stand for liquid separation. The organic phase was added with 100 ml of purified water, stirred for 10 minutes, and allowed to stand for liquid separation again. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the organic phase was concentrated under reduced pressure to dryness to obtain a pale yellow oily substance. 200 g of ethyl acetate:n-heptane (volume ratio 1:20) was added for pulping and stirring, followed by suction filtration and drying to obtain white fulvestrant intermediate I with a molar yield of 94.7% and an HPLC purity of 98.986%.

[0069] Example 9 Oxidation reaction, i.e., the preparation of fulvestrant:

[0070] 18.0 g (0.0305 mol) of fulvestrant intermediate, 100 ml of ethyl acetate and 16.2 g of glacial acetic acid were added to the reaction flask. The mixture was stirred and cooled to 0 - 5 °C, and 8.60 g of 30% hydrogen peroxide solution was added. The temperature was controlled at 25 °C and the reaction was stirred for 10 hours. After the reaction was completed, the temperature was cooled to 0 - 5 °C and 10% sodium sulfite solution was added dropwise to quench the reaction. 160 ml of ethyl acetate and 320 ml of purified water were added to the reaction flask, stirred for 10 minutes, and allowed to stand for liquid separation. The organic layer was washed with 50 ml of saturated brine, and the organic phase was dried over anhydrous sodium sulfate; suction filtration was carried out, and the filtrate was concentrated under reduced pressure until no liquid flowed out at 60 °C to obtain 18.3 g of a pale yellow oily substance. The crude product was recrystallized from ethyl acetate to obtain 16.2 g of white fulvestrant with a molar yield of 87.5%, an HPLC purity of 99.802%, and isomer A:isomer B = 46.643:53.357 (isomer A:isomer B = 42 - 48:52 - 58).

Claims

1. A method for recovering fulvestrant, characterized in that: Step 1: Reduction reaction In a solvent, the crude product recovered from the fulvestrant mother liquor undergoes a reduction reaction to generate fulvestrant intermediate I; Step 2: Oxidation reaction In a solvent, fulvestrant intermediate I undergoes an oxidation reaction to generate fulvestrant; 2. The method according to claim 1, wherein The specific steps include: Step 1: Reduction reaction Under nitrogen protection, add the crude product recovered from the fulvestrant mother liquor, 3-mercaptopropionic acid and an organic solvent into the reaction flask, start stirring, control the temperature to T1, add a catalyst, and continue the heat preservation reaction; after the reaction is completed, perform post-treatment to obtain fulvestrant intermediate I; Step 2: Oxidation reaction Add fulvestrant intermediate I, a solvent and glacial acetic acid into the reaction flask, stir and cool down, add hydrogen peroxide solution, control the temperature and stir for the reaction, cool down again after the reaction is completed, dropwise add sodium sulfite solution to quench the reaction, and perform post-treatment to obtain fulvestrant.

3. The method according to claim 2, wherein The organic solvent described in Step 1 is selected from one or more of ethyl acetate, acetone, dichloromethane, N,N-dimethylformamide (DMF), dimethylacetamide (DMAC), acetonitrile, tetrahydrofuran, methanol and ethanol, preferably one or two of acetone and dichloromethane.

4. The method according to claim 2, wherein The catalyst used in Step 1 is iodine, N-bromosuccinimide (NBS); preferably N-bromosuccinimide (NBS).

5. The method according to claim 2, wherein The molar ratio of the crude product recovered from the fulvestrant mother liquor to the catalyst in Step 1 is 1:0.05 - 0.3; preferably 1:0.

2.

6. The method according to claim 2, wherein The mass ratio of the crude product recovered from the fulvestrant mother liquor to 3-mercaptopropionic acid in Step 1 is 1:0.3 - 0.5; preferably 1:0.

4.

7. The method according to claim 2, wherein The temperature T1 controlled in Step 1 is 0 - 30°C; preferably 10 - 20°C.

8. The method according to claim 2, wherein The post-treatment process in Step 1 is: add NaOH solution to the reaction flask, add an extraction solvent, stir, let it stand and separate the layers, discard the aqueous phase; add purified water to the organic phase, stir, let it stand and separate the layers, discard the aqueous phase; dry the organic phase with anhydrous sodium sulfate, filter off the desiccant, concentrate the organic phase under reduced pressure to dryness, slurry with an ethyl acetate:n-heptane mixed solution, filter by suction, and dry to obtain fulvestrant intermediate I.

9. The method according to claim 8, wherein The extraction solvent is dichloromethane or ethyl acetate.

10. The method according to claim 2, wherein The solvent described in Step 2 is anhydrous methanol, anhydrous ethanol, acetonitrile, ethyl acetate; the temperature for stirring and cooling in Step 2 is 0 - 25°C; the temperature for controlling the temperature and stirring in Step 2 is 10 - 25°C; the stirring time is 8 - 10 hours; the temperature for cooling down again in Step 2 is 0 - 5°C.

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