Synthesis method of medroxyprogesterone acetate intermediate impurity
The preparation of medroxyprogesterone acetate intermediate impurities by reacting in organic solvents has solved the problem of insufficient synthesis methods in the prior art, achieved the goal of high yield and high purity, and is suitable for drug research and quality control.
Patent Information
- Application Number
- CN202510337810.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-21
- Publication Date
- 2025-07-25
AI Technical Summary
The prior art lacks efficient and accurate synthetic methods to prepare medroxyprogesterone acetate intermediate impurities, which affects the quality and safety of the drug.
(8R, 9S, 10R, 13S, 14S, 17R)-17-acetyl-10, 13-dimethyl-6-methylene-3-oxo-2,3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradehydro-1H-cyclopentopentane [a]phenylenol-17-acetate was reacted with paraformaldehyde and salt catalyst in an organic solvent, and the medroxyprogesterone acetate intermediate impurities were prepared by controlling the reaction conditions.
It provides a synthesis method with simple operation, high yield and high purity, which reduces the difficulty and cost of synthesis. It is suitable for ordinary laboratories and is suitable for large-scale preparation for research and quality control.
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Figure CN120365341A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of organic chemical synthesis, and particularly to a method for synthesizing impurities of medroxyprogesterone acetate intermediates. Background Art
[0002] Medroxyprogesterone acetate is an artificially synthesized progestin drug, mainly used for treating gynecological diseases such as functional bleeding, amenorrhea, and endometriosis caused by hormonal imbalance. In addition, it is also used in menopausal hormone replacement therapy to counteract the proliferative effect of estrogen on the endometrium, and at high doses, it can be used in the adjuvant therapy of endometrial cancer. In the field of tumor treatment, medroxyprogesterone acetate can be used for palliative treatment or adjuvant treatment of hormone-dependent tumors such as breast cancer, kidney cancer, and prostate cancer.
[0003] As an important steroid hormone drug, medroxyprogesterone acetate has a wide range of clinical applications. However, during its synthesis process, various intermediate impurities are generated. These impurities not only affect the purity and quality of the final product but also have potential impacts on aspects such as the safety and effectiveness of the drug. Accurately synthesizing these intermediate impurities is of great significance for studying their formation mechanisms and establishing effective impurity detection and control methods. However, at present, efficient and precise synthesis methods for certain specific medroxyprogesterone acetate intermediate impurities still need to be further improved and developed.
[0004] As Figure 6 shown, (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-6-methylene-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-acetate (B) is a key intermediate for synthesizing medroxyprogesterone acetate. (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-2,6-dimethylene-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-ethyl formate (C) is an important impurity in the synthesis of this intermediate and is also a key impurity affecting the quality of medroxyprogesterone acetate. Currently, there is no report on the synthesis method of this intermediate impurity (C). Summary of the Invention
[0005] The purpose of the present invention is to provide a synthesis method for impurities of medroxyprogesterone acetate intermediates that is simple to operate, has a considerable yield, and a relatively high purity, so as to meet the related requirements for further analysis, research, and quality control of intermediate impurity (C).
[0006] A method for synthesizing an impurity of medroxyprogesterone acetate intermediate, wherein the impurity of medroxyprogesterone acetate intermediate is prepared by reacting (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-6-methylene-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-acetate (B), paraformaldehyde and a salt catalyst in an organic solvent;
[0007] The chemical structural formula of the impurity of medroxyprogesterone acetate intermediate is shown in Formula (1):
[0008]
[0009] The structure of (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-6-methylene-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-acetate (B) is shown in Formula 2:
[0010]
[0011] Preferably, the synthesis method comprises the following steps:
[0012] S1, adding (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-6-methylene-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-acetate (B), paraformaldehyde and a salt catalyst into organic solvent 1, heating to reflux, and stirring for reaction for 3-6 h;
[0013] S2, after the reaction is completed, distilling off the reaction solvent under reduced pressure; adding water and organic solvent 2 to the dried residue, and stirring for extraction;
[0014] S3, separating layers, evaporating the organic layer to dryness; adding methanol to the dried organic layer and heating to dissolve, adding water, keeping warm for crystal precipitation, filtering, and drying to obtain the medroxyprogesterone acetate intermediate impurity of Formula 1.
[0015] Preferably, the salt catalyst is one or more of 2-isopropyl-N-methylaniline hydrochloride, 3,5-dimethoxy-N-methylaniline hydrochloride, 2,6-difluoro-N-methylaniline hydrochloride, 4-chloro-N-ethylaniline hydrochloride, 2-(chloromethyl)-N-ethylaniline hydrochloride.
[0016] Preferably, the organic solvent 1 is one or more of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether is preferred.
[0017] Preferably, the organic solvent 2 is methyl tert-butyl ether, ethyl acetate, or n-heptane, and methyl tert-butyl ether is preferred.
[0018] Preferably, the molar ratio of paraformaldehyde to (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-6-methylene-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-acetate (B) is 1.3:1 to 2.0:1, and 1.5:1 is preferred.
[0019] Preferably, the molar ratio of the salt catalyst to (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-6-methylene-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-acetate (B) is 1:1 to 1.5:1, and 1.3:1 is preferred.
[0020] Preferably, the yield of C reaches more than 49%, and the product purity reaches more than 94%; the yield is preferably 49%-67%.
[0021] The present invention has the following technical effects:
[0022] 1. For the synthesis method provided by the present invention, the reaction steps and operating conditions adopted are relatively easy to control, without the need for complex and special instrument equipment, and the entire synthesis process can be completed in an ordinary organic synthesis laboratory, reducing the synthesis difficulty and cost.
[0023] 2. Through exploration of various reaction conditions, the present invention enables the synthesis yield of the target megestrol acetate intermediate impurity to reach a relatively high level, with a yield of up to 67%, providing a guarantee for subsequent large-scale preparation of this impurity for related research.
[0024] 3. The present invention ensures that the final impurity product has a high purity, which is beneficial for accurate property research of this impurity and its use as a reference substance in drug quality control, etc. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 It is a synthetic route diagram of the megestrol acetate intermediate impurity provided by the embodiment of the present invention.
[0026] Figure 2It is the 1H NMR spectrum of Medroxyprogesterone Acetate Intermediate B.
[0027] Figure 3 It is the 1H NMR spectrum of Medroxyprogesterone Acetate Intermediate Impurity C.
[0028] Figure 4 It is the HPLC spectrum of Medroxyprogesterone Acetate Intermediate Impurity C (Example 3).
[0029] Figure 5 It is the synthetic schematic diagram of obtaining Impurity C from Intermediate B.
[0030] Figure 6 It is the synthesis and impurity schematic diagram of Medroxyprogesterone Acetate. Specific Examples
[0031] The following specific examples are used to further illustrate the synthesis method of the present invention, but the present invention is not limited to these examples.
[0032] Compound B is provided by the enterprise in the school-enterprise cooperation project of this item.
[0033] Example 1
[0034] 3.8 g (1 eq) of Compound B, 100 ml of tetrahydrofuran, 390 mg (1.3 eq) of paraformaldehyde and 2.3 g (1.3 eq) of 2,6-difluoro-N-methylaniline hydrochloride were successively added to the reaction flask, heated to reflux, and stirred for 4 h. After the reaction was completed, the reaction solvent was removed by distillation under reduced pressure. 50 ml of water and 50 ml of methyl tert-butyl ether were added to the dried residue, and stirred for extraction for 30 min. After stratification, the organic layer was dried by evaporation. 20 ml of methanol was added and heated to dissolve, 80 ml of water was added, and the mixture was kept at 30 °C for crystallization for 1 h. Then it was cooled to 10 °C again and stirred for 4 h. The mixture was filtered, and the filter cake was washed with a small amount of water and dried to obtain 2.4 g of Compound C, with a yield of 63% and a purity of 96.0%.
[0035] Example 2
[0036] 3.8 g (1 eq) of Compound B, 100 ml of dioxane, 600 mg (2.0 eq) of paraformaldehyde and 2.3 g (1.3 eq) of 2,6-difluoro-N-methylaniline hydrochloride were successively added to the reaction flask, heated to reflux, and stirred for 4 h. After the reaction was completed, the reaction solvent was removed by distillation under reduced pressure. 50 ml of water and 50 ml of methyl tert-butyl ether were added to the dried residue, and stirred for extraction for 30 min. After stratification, the organic layer was dried by evaporation. 20 ml of methanol was added and heated to dissolve, 80 ml of water was added, and the mixture was kept at 30 °C for crystallization for 1 h. Then it was cooled to 10 °C again and stirred for 4 h. The mixture was filtered, and the filter cake was washed with a small amount of water and dried to obtain 2.3 g of Compound C, with a yield of 60% and a purity of 95.3%.
[0037] Example 3
[0038] 3.8 g (1 eq) of compound B (as shown in the nuclear magnetic resonance hydrogen spectrum of medroxyprogesterone acetate intermediate B, the reactant of the present invention) was successively added to the reaction flask, 100 ml of ethylene glycol dimethyl ether, 450 mg (1.5 eq) of paraformaldehyde, and 2.3 g (1.3 eq) of 2,6-difluoro-N-methylaniline hydrochloride. The temperature was raised to reflux and the reaction was stirred for 4 h. Figure 2 After the reaction was completed, the reaction solvent was removed by distillation under reduced pressure. 50 ml of water and 50 ml of methyl tert-butyl ether were added to the dried residue, and the mixture was stirred and extracted for 30 min. After separation, the organic layer was dried. 20 ml of methanol was added and the temperature was raised to dissolve. 80 ml of water was added, and the mixture was kept at 30 °C for 1 h for crystallization. The temperature was further lowered to 10 °C and stirred for 4 h. The mixture was filtered, the filter cake was washed with a small amount of water, and dried to obtain 2.6 g of compound C, with a yield of 67% and a purity of 97.5%. Its structure was verified to be completely consistent with the expected target impurity structure by nuclear magnetic resonance hydrogen spectrum, carbon spectrum, and mass spectrum.
[0039] This is the nuclear magnetic resonance hydrogen spectrum of impurity C of the product of the present invention. Figure 3 This is the nuclear magnetic resonance hydrogen spectrum of impurity C of medroxyprogesterone acetate intermediate in this example. Figure 4 This is the liquid chromatography spectrum of impurity C of medroxyprogesterone acetate intermediate in this example. Figure 4 The conditions for the corresponding liquid chromatography were as follows: the mobile phase was acetonitrile and 0.2% acetic acid solution, with a volume ratio of 60:40, isocratic elution, a flow rate of 1 ml / min, and a column temperature of 35 °C. Figure 4 The specific content in the lower left table in
[0040]
[0041]
[0042] Example 4
[0043] 3.8 g (1 eq) of compound B was successively added to the reaction flask, 100 ml of diethylene glycol dimethyl ether, 450 mg (1.5 eq) of paraformaldehyde, and 2.4 g (1.3 eq) of 2-isopropyl-N-methylaniline hydrochloride. The temperature was raised to reflux and the reaction was stirred for 4 h. After the reaction was completed, the reaction solvent was removed by distillation under reduced pressure. 50 ml of water and 50 ml of methyl tert-butyl ether were added to the dried residue, and the mixture was stirred and extracted for 30 min. After separation, the organic layer was dried. 20 ml of methanol was added and the temperature was raised to dissolve. 80 ml of water was added, and the mixture was kept at 30 °C for 1 h for crystallization. The temperature was further lowered to 10 °C and stirred for 4 h. The mixture was filtered, the filter cake was washed with a small amount of water, and dried to obtain 2.1 g of compound C, with a yield of 55% and a purity of 94.5%.
[0044] Example 5
[0045] Add 3.8 g (1 eq) of compound B, 100 ml of tetrahydrofuran, 450 mg (1.5 eq) of paraformaldehyde, and 2.6 g (1.3 eq) of 3,5-dimethoxy-N-methylaniline hydrochloride into the reaction flask in sequence. Heat up to reflux and stir the reaction for 4 h. After the reaction is completed, remove the reaction solvent by distillation under reduced pressure. Add 50 ml of water and 50 ml of methyl tert-butyl ether to the dried residue, stir and extract for 30 min. Separate the layers and evaporate the organic layer to dryness. Add 20 ml of methanol, heat up to dissolve, add 80 ml of water, keep the temperature at 30 °C for crystallization for 1 h, then cool down to 10 °C again, keep the temperature and stir for 4 h, filter, wash the filter cake with a small amount of water, and dry it to obtain 2.0 g of compound C, with a yield of 53% and a purity of 94.3%.
[0046] Example 6
[0047] Add 3.8 g (1 eq) of compound B, 100 ml of ethylene glycol dimethyl ether, 450 mg (1.5 eq) of paraformaldehyde, and 2.5 g (1.3 eq) of 4-chloro-N-ethylaniline hydrochloride into the reaction flask in sequence. Heat up to reflux and stir the reaction for 4 h. After the reaction is completed, remove the reaction solvent by distillation under reduced pressure. Add 50 ml of water and 50 ml of methyl tert-butyl ether to the dried residue, stir and extract for 30 min. Separate the layers and evaporate the organic layer to dryness. Add 20 ml of methanol, heat up to dissolve, add 80 ml of water, keep the temperature at 30 °C for crystallization for 1 h, then cool down to 10 °C again, keep the temperature and stir for 4 h, filter, wash the filter cake with a small amount of water, and dry it to obtain 1.9 g of compound C, with a yield of 49% and a purity of 95.7%.
[0048] Example 7
[0049] Add 3.8 g (1 eq) of compound B, 100 ml of ethylene glycol diethyl ether, 450 mg (1.5 eq) of paraformaldehyde, and 3.0 g (1.3 eq) of 2-(chloromethyl)-N-ethylaniline hydrochloride into the reaction flask in sequence. Heat up to reflux and stir the reaction for 4 h. After the reaction is completed, remove the reaction solvent by distillation under reduced pressure. Add 50 ml of water and 50 ml of methyl tert-butyl ether to the dried residue, stir and extract for 30 min. Separate the layers and evaporate the organic layer to dryness. Add 20 ml of methanol, heat up to dissolve, add 80 ml of water, keep the temperature at 30 °C for crystallization for 1 h, then cool down to 10 °C again, keep the temperature and stir for 4 h, filter, wash the filter cake with a small amount of water, and dry it to obtain 2.3 g of compound C, with a yield of 58% and a purity of 96.2%.
[0050] Comparative Example 1
[0051] 3.8 g (1 eq) of compound B, 100 ml of ethylene glycol dimethyl ether, 450 mg (1.5 eq) of paraformaldehyde, and 2.0 g (1.3 eq) of triethylamine hydrochloride were successively added to a reaction flask. The temperature was raised to reflux and the mixture was stirred for reaction for 6 h. After the reaction was completed, the reaction solvent was removed by distillation under reduced pressure. 50 ml of water and 50 ml of methyl tert-butyl ether were added to the dried residue, and the mixture was stirred and extracted for 30 min. After liquid separation, the organic layer was dried by evaporation. 20 ml of methanol was added and the temperature was raised to dissolve. 80 ml of water was added, and the mixture was kept at 30 °C for crystallization for 1 h. Then the temperature was lowered to 10 °C again, and the mixture was kept stirring for 4 h. The mixture was filtered, the filter cake was washed with a small amount of water, and then dried to obtain 1.0 g of compound C, with a yield of 26% and a purity of 92.2%.
[0052] Comparative Example 2
[0053] 3.8 g (1 eq) of compound B, 100 ml of dioxane, 1.2 g (1.5 eq) of aqueous formaldehyde solution, and 1.9 g (1.3 eq) of aniline hydrochloride were successively added to a reaction flask. The temperature was raised to reflux and the mixture was stirred for reaction for 8 h. After the reaction was completed, the reaction solvent was removed by distillation under reduced pressure. 50 ml of water and 50 ml of methyl tert-butyl ether were added to the dried residue, and the mixture was stirred and extracted for 30 min. After liquid separation, the organic layer was dried by evaporation. 20 ml of methanol was added and the temperature was raised to dissolve. 80 ml of water was added, and the mixture was kept at 30 °C for crystallization for 1 h. Then the temperature was lowered to 10 °C again, and the mixture was kept stirring for 4 h. The mixture was filtered, the filter cake was washed with a small amount of water, and then dried to obtain 0.7 g of compound C, with a yield of 18% and a purity of 90.4%.
[0054] Comparative Example 3
[0055] 3.8 g (1 eq) of compound B, 100 ml of tetrahydrofuran, 450 mg (1.5 eq) of paraformaldehyde, and 1.2 g (1.3 eq) of dimethylamine hydrochloride were successively added to a reaction flask. The temperature was raised to reflux and the mixture was stirred for reaction for 4 h. After the reaction was completed, the reaction solvent was removed by distillation under reduced pressure. 50 ml of water and 50 ml of methyl tert-butyl ether were added to the dried residue, and the mixture was stirred and extracted for 30 min. After liquid separation, the organic layer was dried by evaporation. 20 ml of methanol was added and the temperature was raised to dissolve. 80 ml of water was added, and the mixture was kept at 30 °C for crystallization for 1 h. Then the temperature was lowered to 10 °C again, and the mixture was kept stirring for 4 h. The mixture was filtered, the filter cake was washed with a small amount of water, and then dried to obtain 1.3 g of compound C, with a yield of 33% and a purity of 94.6%.
Claims
1. A method for synthesizing an impurity of medroxyprogesterone acetate intermediate, wherein the impurity of medroxyprogesterone acetate intermediate is prepared by reacting (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-6-methylene-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-acetate (B), paraformaldehyde and a salt catalyst in an organic solvent; The chemical structural formula of the impurity of medroxyprogesterone acetate intermediate is shown in Formula (1): The structure of (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-6-methylene-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-acetate (B) is shown in Formula 2:
2. The synthesis method according to claim 1, wherein Comprising the following steps: S1, adding (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-6-methylene-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-acetate (B), paraformaldehyde and a salt catalyst into organic solvent 1, heating to reflux, and stirring for reaction for 3 - 6 h; S2, after the reaction is completed, distilling off the reaction solvent under reduced pressure; adding water and organic solvent 2 to the dried residue, and stirring for extraction; S3, separating layers, evaporating the organic layer to dryness; adding methanol to the dried organic layer, heating to dissolve, adding water, keeping warm for crystallization, filtering, and drying to obtain the medroxyprogesterone acetate intermediate impurity of Formula 1.
3. The synthesis method according to claim 1 or 2, characterized in that, The salt catalyst is one or more of 2-isopropyl-N-methylaniline hydrochloride, 3,5-dimethoxy-N-methylaniline hydrochloride, 2,6-difluoro-N-methylaniline hydrochloride, 4-chloro-N-ethylaniline hydrochloride, 2-(chloromethyl)-N-ethylaniline hydrochloride.
4. The synthesis method according to claim 1 or 2, characterized in that The organic solvent 1 is one or more of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, preferably ethylene glycol dimethyl ether.
5. The synthesis method according to claim 1 or 2, characterized in that, The organic solvent 2 is methyl tert-butyl ether, ethyl acetate, n-heptane, preferably methyl tert-butyl ether.
6. The synthesis method according to claim 1 or 2, characterized in that The molar ratio of paraformaldehyde to (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-6-methylene-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-acetate (B) is 1.3:1 to 2.0:1, preferably 1.5:
1.
7. The synthesis method according to claim 3, characterized in that, The molar ratio of the salt catalyst to (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-6-methylene-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-acetate (B) is from 1:1 to 1.5:1, preferably 1.3:
1.
8. The synthesis method according to claim 7, wherein The yield is over 49%, and the product purity reaches over 94%; the yield is preferably 49%-67%.