Synthetic method of progesterone impurity G
The intermediate compound 4 is generated by reacting cyclohexanone with lithium diethylamino, and reacting with trifluoromethanesulfonic anhydride and DBU in a specific solvent, which solves the problem of difficulty in obtaining raw materials for research on progesterone impurity G, and realizes the simple and environmentally friendly synthesis of progesterone impurity G, meeting the needs of drug impurity analysis.
Patent Information
- Application Number
- CN202510321269.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-18
- Publication Date
- 2025-07-08
AI Technical Summary
The synthesis method of progesterone impurity G in the prior art has not been disclosed, which makes it difficult to obtain raw materials for research.
The reaction of cyclohexanone with lithium diethylamino was used to produce intermediate compound 4, followed by reaction with trifluoromethanesulfonic anhydride and DBU in a specific solvent, and the progesterone impurity G was obtained by extraction, concentration and column chromatography.
It provides a simple and environmentally friendly synthetic route that can effectively obtain progesterone impurity G for impurity analysis and quality control to ensure drug safety and purity.
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Figure CN120271648A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of compound synthesis, and particularly to a method for synthesizing progesterone impurity G. Background Art
[0002] Progesterone impurity G is an impurity that may appear during the production of progesterone. Progesterone impurity G is mainly used as a reference substance in the research and production of drugs. The presence of this impurity may affect the effectiveness and safety of progesterone raw materials and their preparation products, and is used for analyzing the purity and quality control of progesterone products, which is of great significance in the research of drug impurities.
[0003] Progesterone impurity G, with the chemical name of (8S,9S,10R,13S,14S,17S)-17-(2-cyclohexylideneacetyl)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one, has the chemical formula of C27H38O2 and a molecular weight of 394.29. Its chemical structural formula is shown as follows:
[0004]
[0005] The quality of drugs is an important standard for measuring the quality of drugs. Among them, impurities are the main factors affecting drug purity. If a drug contains impurities exceeding the limit, it may change the physical and chemical constants, cause variations in appearance properties, and affect the stability of the drug. The increase in impurities will also inevitably lead to a decrease in the content or activity of the drug, and a significant increase in toxic and side effects. Therefore, the impurity inspection of drugs is a very important link in controlling drug purity and improving drug quality. However, the synthesis method of progesterone impurity G has not been disclosed in the existing technical documents, making it difficult to obtain research raw materials for progesterone impurity G, and a technology for synthesizing progesterone impurity G is needed. Summary of the Invention
[0006] The main purpose of the present invention is to solve the technical problem that the synthesis method of progesterone impurity G has not been disclosed in the existing technical documents, making it difficult to obtain research raw materials for progesterone impurity G.
[0007] The first aspect of the present invention provides a method for synthesizing progesterone impurity G, which is characterized by including the steps of:
[0008] Step 1: Dissolve cyclohexanone in a first organic solvent, protect it with an inert gas, add lithium diethylamide at a first temperature and stir for a first duration to obtain a first intermediate solution. Dissolve progesterone in a second organic solvent and then add it to the first intermediate solution to obtain a second intermediate solution. Stir the second intermediate solution at a second temperature for a second duration to obtain a third intermediate solution. Extract, concentrate, and perform column chromatography separation on the third intermediate solution to obtain Compound 4. The reaction equation is as follows:
[0009]
[0010] Step 2: Add Compound 4, 4-dimethylaminopyridine, and trifluoromethanesulfonic anhydride to a third organic solvent and react for a third duration to obtain a fourth intermediate solution. Add DBU to the fourth intermediate solution and react at a third temperature for a fourth duration to obtain a fifth intermediate solution. Extract, concentrate, and perform column chromatography separation on the fifth intermediate solution to obtain progesterone impurity G. The reaction equation is as follows:
[0011]
[0012] Optionally, in the first implementation manner of the first aspect of the present invention, the first organic solvent includes any one of hexamethylphosphoramide and toluene.
[0013] Optionally, in the second implementation manner of the first aspect of the present invention, the second organic solvent includes any one of hexamethylphosphoramide and toluene.
[0014] Optionally, in the third implementation manner of the first aspect of the present invention, the third organic solvent includes tetrahydrofuran.
[0015] Optionally, in the fourth implementation manner of the first aspect of the present invention, the extraction, concentration, and column chromatography separation of the third intermediate solution to obtain Compound 4 include:
[0016] Add a sulfuric acid solution to the third intermediate solution, extract and collect the organic phase with ethyl acetate, dry and concentrate with anhydrous sodium sulfate, and perform column chromatography separation with a petroleum ether and ethyl acetate ratio of 1:1 to obtain Compound 4.
[0017] Optionally, in the fifth implementation manner of the first aspect of the present invention, the extraction, concentration, and column chromatography separation of the fifth intermediate solution to obtain progesterone impurity G include:
[0018] Add a saturated aqueous solution of citric acid to the fifth intermediate solution, extract and collect the organic phase with ethyl acetate, dry and concentrate with anhydrous sodium sulfate, and perform column chromatography separation with a petroleum ether and ethyl acetate ratio of 2:1 to obtain progesterone impurity G.
[0019] Optionally, in the sixth implementation manner of the first aspect of the present invention, the first temperature includes: -70°C to -50°C, and the first duration includes: 30 min to 60 min.
[0020] Optionally, in the seventh implementation manner of the first aspect of the present invention, the second temperature includes:
[0021] -78°C, and the second duration includes: 1 h to 2 h.
[0022] Optionally, in the eighth implementation manner of the first aspect of the present invention, the third duration includes: 1 h.
[0023] Optionally, in the ninth implementation manner of the first aspect of the present invention, the third temperature includes: 60°C to 75°C, and the fourth duration includes: 1 h to 1.5 h.
[0024] In the embodiments of the present invention, lithium diethylamide and cyclohexanone are added to progesterone as raw materials to synthesize intermediate compound 4. Trifluoromethanesulfonic anhydride, DMAP, and DBU are added to compound 4 in an organic solvent to eliminate the hydroxyl group, and finally progesterone impurity G is obtained. The synthesis route of the present invention is simple to purify and does not use highly toxic and explosive dangerous goods, which conforms to the concept of modern environmental protection and sustainable development. It can facilitate the impurity analysis and research of progesterone API and its preparations, provide a detection method and judgment basis for the production and drug safety of progesterone, and solve the technical problem of difficult acquisition of research raw materials for progesterone impurity G. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 It is a schematic diagram of the synthesis route of the synthesis method of progesterone impurity G in the embodiments of the present invention;
[0026] Figure 2 It is the nuclear magnetic resonance carbon spectrum of the final product of Example 1 of the present invention;
[0027] Figure 3 It is the nuclear magnetic resonance hydrogen spectrum of the final product of Example 1 of the present invention;
[0028] Figure 4 It is the liquid chromatography of the final product of Example 1 of the present invention;
[0029] Figure 5 It is the mass spectrum of the final product of Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS
[0030] The embodiments of the present invention provide a synthesis method of progesterone impurity G.
[0031] Embodiments of the present disclosure will be described in more detail below with reference to the accompanying drawings. Although some embodiments of the present disclosure are shown in the drawings, it should be understood that the present disclosure can be implemented in various forms and should not be construed as limited to the embodiments set forth herein. On the contrary, these embodiments are provided to more thoroughly and completely understand the present disclosure. It should be understood that the drawings and embodiments of the present disclosure are only for exemplary purposes and are not used to limit the protection scope of the present disclosure.
[0032] In the description of the embodiments of the present disclosure, the term "including" and its like should be understood as an open inclusion, that is, "including but not limited to". The term "based on" should be understood as "at least partially based on". The term "one embodiment" or "the embodiment" should be understood as "at least one embodiment". The terms "first", "second", etc. may refer to different or the same objects. There may also be other explicit and implicit definitions hereinafter.
[0033] For ease of understanding, the specific process of the embodiments of the present invention will be described below. Please refer to Figure 1 , a schematic diagram of the synthesis route of the synthesis method of progesterone impurity G in the embodiments of the present invention. The synthesis method of progesterone impurity G includes:
[0034] Step 1: Dissolve cyclohexanone in a first organic solvent, protect with an inert gas, add lithium diethylamide at a first temperature and stir for a first period of time to obtain a first intermediate solution. Dissolve progesterone in a second organic solvent and add it to the first intermediate solution to obtain a second intermediate solution. Stir the second intermediate solution at a second temperature for a second period of time to obtain a third intermediate solution. Extract, concentrate, and perform column chromatography separation on the third intermediate solution to obtain compound 4. The reaction equation is as follows:
[0035]
[0036] Step 2: Add compound 4, 4-dimethylaminopyridine, and trifluoromethanesulfonic anhydride to a third organic solvent and react for a third period of time to obtain a fourth intermediate solution. Add DBU to the fourth intermediate solution and react at a third temperature for a fourth period of time to obtain a fifth intermediate solution. Extract, concentrate, and perform column chromatography separation on the fifth intermediate solution to obtain progesterone impurity G. The reaction equation is as follows:
[0037]
[0038] Example 1
[0039] Step 1: Dissolve 2.48 g of cyclohexanone in 50 ml of HMPT (tris(dimethylamino)phosphine, cas: 1608 - 26 - 0). Protect with nitrogen and cool to -70 °C. Then add 25.29 ml of 1 mol / L lithium diethylamide (cas: 816 - 43 - 3) and stir at -70 °C for 30 min. Weigh 7.95 g of progesterone, dissolve it in 50 ml of HMPT, and then add it to the above solution. Stir at -78 °C for 1 hour. After the reaction is completed, add the reaction solution to 100 ml of 1 mol / L H2SO4 aqueous solution, extract with 50 ml of ethyl acetate three times, combine the organic phases, and dry with anhydrous sodium sulfate solid. Finally, concentrate under vacuum, use 200 g of silica gel for column chromatography purification, elute with petroleum ether:ethyl acetate = 1:1, collect the eluate, and concentrate under vacuum to obtain 8.0 g of compound 4 with a yield of 76.26%.
[0040] Step 2: Weigh 5 g of compound 4 and add it to 50 ml of tetrahydrofuran (THF). Then add 1.78 g of 4 - dimethylaminopyridine (DMAP, cas: 1122 - 58 - 3), cool to 0 °C, and slowly add 4.1 g of trifluoromethanesulfonic anhydride (cas: 358 - 23 - 6). After the addition is complete, react at room temperature for 1 hour, then add 1.84 g of DBU (cas: 6674 - 22 - 2), heat to 60 °C, and react for 1 h. Detect the completion of the reaction by TLC. Slowly add the reaction solution to a saturated aqueous solution of citric acid, extract with 50 ml of ethyl acetate three times, combine the organic phases, and dry with anhydrous sodium sulfate solid. Finally, concentrate under vacuum, use 200 g of silica gel for column chromatography purification, elute with petroleum ether:ethyl acetate = 2:1, collect the eluate, and concentrate under vacuum to obtain 3.2 g of progesterone impurity G with a yield of 66.92%.
[0041] Please refer to Figure 2 , Figure 2 the carbon - nuclear magnetic resonance spectrum of the final product of Example 1 of the present invention. Please refer to Figure 3 , Figure 3 the hydrogen - nuclear magnetic resonance spectrum of the final product of Example 1 of the present invention. Please refer to Figure 4 , Figure 4 the liquid - chromatography spectrum of the final product of Example 1 of the present invention. Please refer to Figure 5 , Figure 5 the mass - spectrum of the final product of Example 1 of the present invention. Figures 2 - 5 It shows that the synthesized substance of the present invention is progesterone impurity G.
[0042] Example 2
[0043] Step 1: Dissolve 2.49 g of cyclohexanone in 80 ml of toluene, protect it with nitrogen, cool it down to -70 °C, and then add 25.35 ml of 1 mol / L lithium diethylamide (cas: 816-43-3). Stir and react at -50 °C for 60 min. Weigh 7.97 g of progesterone, dissolve it in 80 ml of toluene, and then add it to the above solution. Stir at -78 °C for 2 hours. After the reaction is completed, add the reaction solution to 100 ml of 1 mol / L H2SO4 aqueous solution, extract it 3 times with 50 ml of ethyl acetate, combine the organic phases, and dry them with anhydrous sodium sulfate solid. Finally, concentrate it under vacuum, use 200 g of silica gel for column chromatography purification, elute with petroleum ether:ethyl acetate = 1:1, collect the eluate, and concentrate it under vacuum to obtain 8.42 g of compound 4 with a yield of 81.67%.
[0044] Step 2: Weigh 5 g of compound 4 and add it to 50 ml of tetrahydrofuran (THF). Then add 1.79 g of 4-dimethylaminopyridine (DMAP) (CAS: 1122-58-3). Cool it down to 0 °C and then dropwise add 3.96 g of trifluoromethanesulfonic anhydride (cas: 358-23-6). After dropping, react at room temperature for 1 hour, then add 1.88 g of DBU (cas: 6674-22-2) and heat it to 75 °C for 1.5 h. Detect the reaction by TLC until it is complete. Slowly add the reaction solution to the saturated aqueous solution of citric acid, extract it 3 times with 50 ml of ethyl acetate, combine the organic phases, and dry them with anhydrous sodium sulfate solid. Finally, concentrate it under vacuum, use 200 g of silica gel for column chromatography purification, elute with petroleum ether:ethyl acetate = 2:1, collect the eluate, and concentrate it under vacuum to obtain 3.62 g of progesterone impurity G with a yield of 75.37%.
[0045] Example 3
[0046] Step 1: Dissolve 7.39 g of cyclohexanone in 150 ml of HMPT (tris(dimethylamino)phosphine, cas: 1608-26-0), protect it with nitrogen, cool it down to -70 °C, and then add 75 ml of 1 mol / L lithium diethylamide (cas: 816-43-3). Stir and react at -70 °C for 30 min. Weigh 23.67 g of progesterone, dissolve it in 150 ml of HMPT (tris(dimethylamino)phosphine, cas: 1608-26-0), and then add it to the above solution. Stir at -78 °C for 1 hour. After the reaction is completed, add the reaction solution to 200 ml of 1 mol / L H2SO4 aqueous solution, extract it 3 times with 150 ml of ethyl acetate, combine the organic phases, and dry them with anhydrous sodium sulfate solid. Finally, concentrate it under vacuum, use 200 g of silica gel for column chromatography purification, elute with petroleum ether:ethyl acetate = 1:1, collect the eluate, and concentrate it under vacuum to obtain 20.48 g of compound 4 with a yield of 68.94%.
[0047] Step 2: Weigh 10 g of Compound 4 and add it to 100 ml of tetrahydrofuran (THF). Then add 3.55 g of 4-dimethylaminopyridine (DMAP) (CAS: 1122-58-3). Cool the mixture to 0 °C and then slowly add 8.31 g of trifluoromethanesulfonic anhydride (CAS: 358-23-6). After the addition is complete, stir the reaction mixture at room temperature for 1 hour. Then add 3.83 g of DBU (CAS: 6674-22-2) and heat the reaction mixture to 60 °C for 1 h. Monitor the reaction progress by TLC until the reaction is complete. Slowly add the reaction mixture dropwise to a saturated aqueous solution of citric acid. Extract the mixture three times with 150 ml of ethyl acetate and combine the organic phases. Dry the combined organic phases over anhydrous sodium sulfate. Finally, concentrate the solution under vacuum and purify it by column chromatography using 200 g of silica gel. Elute the column with a mixture of petroleum ether:ethyl acetate = 2:1 and collect the eluate. Concentrate the eluate under vacuum to obtain 5.08 g of progesterone impurity G with a yield of 63.65%.
[0048] Example 4
[0049] Step 1: Dissolve 3.43 g of cyclohexanone in 100 ml of HMPT (tris(dimethylamino)phosphine, CAS: 1608-26-0). Protect the reaction system with nitrogen and cool the solution to -70 °C. Then add 35.21 ml of 1 mol / L lithium diethylamide (CAS: 816-43-3) and stir the reaction mixture at -70 °C for 60 min. Weigh 11.01 g of progesterone and dissolve it in 100 ml of HMPT. Then add the progesterone solution to the above reaction mixture. Stir the reaction mixture at -78 °C for 2 hours. After the reaction is complete, add the reaction mixture to 100 ml of 1 mol / L aqueous H2SO4 solution. Extract the mixture three times with 100 ml of ethyl acetate and combine the organic phases. Dry the combined organic phases over anhydrous sodium sulfate. Finally, concentrate the solution under vacuum and purify it by column chromatography using 200 g of silica gel. Elute the column with a mixture of petroleum ether:ethyl acetate = 1:1 and collect the eluate. Concentrate the eluate under vacuum to obtain 11.2 g of Compound 4 with a yield of 78.16%.
[0050] Step 2: Weigh 8.2 g of Compound 4 and add it to 50 ml of tetrahydrofuran (THF). Then add 2.42 g of 4-dimethylaminopyridine (DMAP) (CAS: 1122-58-3). Cool the mixture to 0 °C and then slowly add 5.65 g of trifluoromethanesulfonic anhydride (CAS: 358-23-6). After the addition is complete, stir the reaction mixture at room temperature for 1 hour. Then add 3.05 g of DBU (CAS: 6674-22-2) and heat the reaction mixture to 60 °C for 1 h. Monitor the reaction progress by TLC until the reaction is complete. Slowly add the reaction mixture dropwise to a saturated aqueous solution of citric acid. Extract the mixture three times with 100 ml of ethyl acetate and combine the organic phases. Dry the combined organic phases over anhydrous sodium sulfate. Finally, concentrate the solution under vacuum and purify it by column chromatography using 200 g of silica gel. Elute the column with a mixture of petroleum ether:ethyl acetate = 2:1 and collect the eluate. Concentrate the eluate under vacuum to obtain 5.07 g of progesterone impurity G with a yield of 64.36%.
[0051] In the embodiment of the present invention, lithium diethylamide and cyclohexanone are added to progesterone as raw materials to synthesize intermediate compound 4. Trifluoromethanesulfonic anhydride, DMAP, and DBU are added to compound 4 in an organic solvent to eliminate the hydroxyl group, and finally progesterone impurity G is obtained. The synthesis route of the present invention is simple to purify and does not use highly toxic, explosive and other dangerous substances, which conforms to the modern environmental protection and sustainable development concepts. It can facilitate the impurity analysis and research of progesterone raw materials and their preparations, provide a detection method and judgment basis for the production and drug safety of progesterone, and solve the technical problem that it is relatively difficult to obtain research raw materials for progesterone impurity G.
[0052] Although the subject matter has been described in language specific to structural features and / or methodological acts, it is to be understood that the subject matter defined in the appended claims is not necessarily limited to the specific features or acts described above. On the contrary, the specific features and acts described above are merely example forms of implementing the claims.
Claims
1. A method for synthesizing progesterone impurity G, characterized in that, Including the steps: Step 1: Dissolve cyclohexanone in a first organic solvent, under the protection of an inert gas, add lithium diethylamide at a first temperature and stir for a first duration to obtain a first intermediate solution. Dissolve progesterone in a second organic solvent and then add it to the first intermediate solution to obtain a second intermediate solution. Stir the second intermediate solution at a second temperature for a second duration to obtain a third intermediate solution. Extract, concentrate, and perform column chromatography separation on the third intermediate solution to obtain Compound 4. The reaction equation is as follows: Step 2: Add Compound 4, 4-dimethylaminopyridine, and trifluoromethanesulfonic anhydride to a third organic solvent and react for a third duration to obtain a fourth intermediate solution. Add DBU to the fourth intermediate solution and react at a third temperature for a fourth duration to obtain a fifth intermediate solution. Extract, concentrate, and perform column chromatography separation on the fifth intermediate solution to obtain progesterone impurity G. The reaction equation is as follows:
2. The synthesis method of progesterone impurity G according to claim 1, wherein The first organic solvent includes any one of hexamethylphosphoramide and toluene.
3. The synthesis method of progesterone impurity G according to claim 1, characterized in that, The second organic solvent includes any one of hexamethylphosphoramide and toluene.
4. The synthesis method of progesterone impurity G according to claim 1, wherein The third organic solvent includes tetrahydrofuran.
5. The synthesis method of progesterone impurity G according to claim 1, wherein The extracting, concentrating, and performing column chromatography separation on the third intermediate solution to obtain Compound 4 includes: Adding a sulfuric acid solution to the third intermediate solution, extracting and collecting the organic phase with ethyl acetate, drying and concentrating with anhydrous sodium sulfate, and performing column chromatography separation with a ratio of petroleum ether to ethyl acetate of 1:1 to obtain Compound 4.
6. The synthesis method of progesterone impurity G according to claim 1, characterized in that, The extracting, concentrating, and performing column chromatography separation on the fifth intermediate solution to obtain progesterone impurity G includes: Adding a saturated aqueous solution of citric acid to the fifth intermediate solution, extracting and collecting the organic phase with ethyl acetate, drying and concentrating with anhydrous sodium sulfate, and performing column chromatography separation with a ratio of petroleum ether to ethyl acetate of 2:1 to obtain progesterone impurity G.
7. The synthesis method of progesterone impurity G according to claim 1, characterized in that, The first temperature includes: -70°C to -50°C, and the first duration includes: 30 min to 60 min.
8. The synthesis method of progesterone impurity G according to claim 1, characterized in that, The second temperature includes: -78°C, and the second duration includes: 1 h to 2 h.
9. The synthesis method of progesterone impurity G according to claim 1, characterized in that The third duration includes: 1 h.
10. The synthesis method of progesterone impurity G according to claim 1, characterized in that, The third temperature includes: 60°C to 75°C, and the fourth duration includes: 1 h to 1.5 h.