A method for preparing dydrogesterone

Abstract

This invention discloses a method for preparing dydrogesterone. Dydrogesterone is prepared by using 3,20-bis(ethylenedioxy)-19-norgestrel-5(10),9(11)diene as the starting material, followed by epoxidation, methylation, hydrogenation, and one-pot hydrolysis to remove hydroxyl groups and dehydrogenate. The preparation method is feasible, low in cost, and produces high-purity products. It has significant economic benefits when applied to industrial production.

Description

Technical Field

[0001] This invention relates to the field of steroidal drug preparation technology, specifically a method for preparing dydrogesterone. Background Technology

[0002] Dydrogesterone's chemical structure is remarkably similar to that of naturally occurring progesterone, except that the methyl group at position 10 is α (naturally it is β) and the hydrogen atom at position 9 is β (naturally it is α). Studies have found that steroid compounds with a 9β,10α structure have significantly different physiological properties compared to those with a 9α,10β structure. Currently, dydrogesterone is widely used for pregnancy maintenance, miscarriage prevention, and treatment of various diseases caused by endogenous progesterone deficiency. Since its global launch in 1961, it has enjoyed a large global market presence. Therefore, the development of its synthetic technology has significant economic and social value. The main reported preparation methods are as follows.

[0003] Westerhof et al. used photosterol as a starting material and obtained the target product dydrogesterone through Oppenauer oxidation, isomerization, catalytic hydrogenation, ozonolysis, addition, sodium dichromate oxidation and dehydrogenation. However, photosterol does not exist in nature and needs to be synthesized artificially through the photoreaction of ergosterol, which is energy-intensive and has a high production safety risk (Recueil, 1960, 79: 771-783.).

[0004] Chinese patent document CN101318982A discloses a photoisomerization reaction using 3-acetoxy-pregn-5,7-diene-20-one as the starting material. However, since there are two carbonyl groups in the 3-acetoxy-pregn-5,7-diene-20-one molecule, these compounds can generate more impurities after photoexcitation, resulting in a significant reduction in actual yield.

[0005] The literature *Recueil des Travaux Chimiques des Pays-Bas* (1971), 90:27-32, reports a method for obtaining dydrogesterone from progesterone via ethylene glycol protection of diketones, bromination, debromination, high-pressure mercury lamp irradiation, and hydrolysis rearrangement. However, this route suffers from low yields in both bromination and debromination steps due to numerous isomers, and the critical irradiation step is energy-intensive and carries significant safety risks. Therefore, the industrialization cost of this preparation method is relatively high.

[0006] All of the above methods for preparing dydrogesterone require photoreaction to achieve chiral transposition at positions 9 and 10, which results in problems such as high energy consumption, significant production safety risks, and high costs. Summary of the Invention

[0007] This invention provides a method for preparing dydrogesterone, which solves the defects of existing dydrogesterone preparation processes, such as long steps, low yield, and the involvement of photoreaction which is not conducive to large-scale industrial production.

[0008] In view of this, the solution of the present invention is as follows:

[0009] A method for preparing dydrogesterone, comprising the following steps:

[0010] S1. Compound 1 was epoxidized with hydrogen peroxide under the action of a base and a first catalyst to obtain compound 2;

[0011] S2. Compound 2 undergoes a Grignard addition reaction in the presence of magnesium methyl bromide to give compound 3;

[0012] S3. Compound 3 undergoes a hydrogenation reaction with hydrogen gas under the action of a second catalyst to obtain compound 4;

[0013] S4. Compound 4 is deprotected from its ketal protection and hydroxyl group under acidic conditions, and then dydrogesterone is obtained by the dehydrogenation reaction of dichlorocyanobenzoquinone.

[0014] The reaction route for the preparation method is as follows:

[0015]

[0016] In a preferred embodiment, in step S1:

[0017] The first catalyst is preferably hexachloroacetone;

[0018] And / or, the base is pyridine, with a volume ratio of (0.05–0.15):1 to compound 1;

[0019] And / or, the hydrogen peroxide content is 50%, and the volume ratio of hydrogen peroxide to compound 1 is (0.2-0.4):1;

[0020] And / or, the temperature of the reaction process is -15 to -20°C;

[0021] And / or, the solvent used in the reaction process is dichloromethane.

[0022] Step S1 also includes a product post-processing step: the reaction product is first allowed to stand and separated into liquids, the organic layer is washed with a saturated salt solution, the solvent is evaporated after absorbing water and drying, crystallization, filtration, and drying are performed to obtain compound 2.

[0023] In some embodiments, based on the above steps, the yield of compound 2 obtained in step S1 can reach 70%.

[0024] In a preferred embodiment, in step S2:

[0025] The molar ratio of compound 2 to methyl magnesium bromide is 1:(3-4);

[0026] And / or, the reaction temperature is -5 to 5°C, and the reaction process is carried out under an inert atmosphere;

[0027] And / or, the reaction process uses tetrahydrofuran as a solvent.

[0028] Step S2 also includes a product post-processing step: after the reaction is complete, the reaction is quenched by controlling the temperature below 0°C, the organic layer is washed and dehydrated with saturated brine, the solvent is evaporated, crystals are precipitated, filtered, and dried to obtain compound 3.

[0029] In some embodiments, based on the above steps, the yield of compound 3 obtained in step S2 can reach 70%.

[0030] In a preferred embodiment, in step S3:

[0031] The second catalyst is palladium on carbon;

[0032] And / or, the reaction temperature is 30–40°C, and the reaction pressure is 0.1–0.3 MPa;

[0033] The solvent used in the reaction is tetrahydrofuran.

[0034] Furthermore, step S3 also includes a product post-processing step: after the reaction is complete, the product is filtered, the filtrate is washed with solvent in sequence, then washed with saturated salt solution, then dried by absorbing water, the solvent is evaporated, and the product is dried to obtain compound 4.

[0035] In some embodiments, based on the above steps, the yield of compound 4 obtained in step S3 can reach 90%.

[0036] In a preferred embodiment, during the deketal protection and hydroxyl group removal reaction in step S4:

[0037] The reaction temperature is 80–85℃, and the reaction time is 0.5–2 hours.

[0038] And / or, the solvent used is dioxane.

[0039] In a preferred embodiment, during the dehydrogenation reaction in step S4:

[0040] The reaction temperature is 30-40℃;

[0041] And / or, the mass ratio of compound 4 to dichlorocyanobenzoquinone is 1:(0.55 to 0.58).

[0042] Step S4 also includes a product post-processing step: after the dehydrogenation reaction is completed, the organic layer is allowed to stand and separated. The organic layer is washed sequentially with saturated sodium carbonate and saturated brine, and then the solvent is evaporated, crystallized, filtered, and dried to obtain dydrogesterone.

[0043] In some embodiments, based on the above steps, the yield of dydrogesterone obtained in step S4 can reach 55%.

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] The preparation method of the present invention uses 3,20-bis(ethylenedioxy)-19-norpregn-5(10),9(11)diene as the starting material, and prepares dydrogesterone through epoxidation, methylation, hydrogenation, and one-pot hydrolysis to remove hydroxyl and dehydrogenate. The preparation method is feasible, low in cost, and produces high-purity products. It has significant economic benefits when applied to industrial production. Attached Figure Description

[0046] Figure 1 This is the HPLC chromatogram of dydrogesterone obtained by the preparation method described in this invention.

[0047] Figure 2 This is the mass spectrum of dydrogesterone obtained by the preparation method described in this invention.

[0048] Figure 3 The image shows the 1H NMR spectrum of dydrogesterone obtained by the preparation method described in this invention. Detailed Implementation

[0049] The technical solution of the present invention will now be clearly and completely described in conjunction with preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0050] In the following examples, compound 1, named 3,20-bis(ethylenedioxy)-19-norpregn-5(10),9(11)diene, with CAS number 101387-15-9, can be derived from compound 1. It was prepared using (CAS: 1231-97-6).

[0051] Example 1

[0052] 1) Dissolve 100g of compound 1 (3,20-bis(ethylenedioxy)-19-norpregn-5(10),9(11)diene) in 1L of dichloromethane, pour into a reaction flask, cool to -15℃, add 10mL of pyridine, 30mL of hexachloroacetone, and 30mL of hydrogen peroxide sequentially, and react at -15℃. Monitor the reaction by TLC. After the reaction is complete, perform post-processing. Pour the reaction solution into a separatory funnel and let it stand for ten minutes. Separate the layers. Wash the organic layer once with 500mL of saturated sodium thiosulfate solution, and then once with 500mL of saturated sodium chloride solution. Dry the washed organic layer with 10g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is distilled off, add 200mL of ethyl acetate, stir at 0℃ to crystallize, filter, and dry to obtain 65g of compound 2, yield: 65% by weight.

[0053] 2) Add 65g of compound 2 to a reaction flask, dissolve it with 650mL of tetrahydrofuran, add 6.5g of lithium chloride, purge with nitrogen three times, lower the temperature to -5℃, add 240mL of tetrahydrofuran solution of methyl magnesium bromide (1mol / L), and maintain the temperature at -5℃. Monitor the reaction by TLC. After the reaction is complete, perform post-processing. Add 650mL of water dropwise to the reaction solution while maintaining the temperature at -5~0℃, allow to stand and separate the layers. Wash the organic layer once with 650mL of saturated sodium chloride solution. Dry the washed organic layer with 6.5g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is distilled off, add 65mL of ethyl acetate, stir at 0℃ to crystallize, filter, and dry to obtain 45g of compound 3, with a yield of 69.2%.

[0054] 3) Add 45g of compound 3 to a hydrogenation reactor, dissolve it with 450mL of tetrahydrofuran, add 1.35g of palladium on carbon, purge with nitrogen three times, heat to 30℃, stir the reaction under hydrogen pressure of 0.2MPa, monitor the reaction by TLC, and perform post-processing after the reaction is complete. Filter, wash the filter cake with 45mL of tetrahydrofuran, and wash the filtrate once with 450mL of saturated sodium chloride solution. Dry the washed organic layer with 4.5g of anhydrous sodium sulfate, distill under reduced pressure until no solvent evaporates, and dry to obtain 39g of compound 4, with a yield of 86.6% by weight.

[0055] 4) Add 39g of compound 4 to a reaction flask, then add 390mL of dioxane and stir. Next, add 45mL of a dioxane solution of hydrogen chloride (4mol / L), heat to 80℃ and react for 1h. Then cool to 30℃, add 22.5g of dichlorocyanobenzoquinone, and maintain the reaction temperature at 30℃. Monitor the reaction by TLC. After the reaction is complete, perform post-processing. Add 390mL of dichloromethane, then add 390mL of water and stir for 1h. Allow to stand for phase separation. Wash the organic layer once with 390mL of saturated sodium carbonate solution, then once with 390mL of saturated sodium chloride solution. Dry the washed organic layer with 3.9g of anhydrous sodium sulfate and distill under reduced pressure until no solvent is distilled off. Crystallize with 39mL of ethyl acetate and 78mL of cyclohexane at 5℃, stir, filter, and dry to obtain 21.5g of dydrogesterone, with a yield of 55.1% by weight. The HPLC chromatogram of the obtained dydrogesterone is shown below. Figure 1 As shown, the purity was 99.97%, and the overall yield based on compound 1 was 26.59%.

[0056] The obtained dydrogesterone mass spectrum and proton NMR spectrum are as follows: Figure 2 , Figure 3 As shown. The proton NMR and mass spectrometry data for dydrogesterone are as follows:

[0057] 1 HNMR (400MHz, CDCl3) δ6.20-6.14(m, 2H, -CH=×2), 5.68(s, 1H, -CH=), 2.61-2.51(m, 2H), 2.47-2.39(m, 2H), 2.30-2.17(m , 2H), 2.14(s, 3H, -CH3), 2.03-1.95(m, 2H), 1.89-1.61(m, 7H), 1.39-1.32(m, 1H), 1.31(s, 3H, -CH3), 0.71(s, 3H, -CH3);

[0058] MS(m / z)calcd for C 21 H 28 O2(M+H) + 313, found 313.

[0059] Example 2

[0060] 1) Dissolve 100g of compound 1 (3,20-bis(ethylenedioxy)-19-norpregn-5(10),9(11)diene) in 1L of dichloromethane, pour into a reaction flask, cool to -20℃, and add 10mL of pyridine, 30mL of hexachloroacetone, and 30mL of hydrogen peroxide sequentially. Maintain the reaction temperature at -20℃ and monitor the reaction by TLC. After the reaction is complete, perform post-processing. Pour the reaction solution into a separatory funnel and let it stand for ten minutes. Separate the layers. Wash the organic layer once with 500mL of saturated sodium thiosulfate solution, and then once with 500mL of saturated sodium chloride solution. Dry the washed organic layer with 10g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is distilled off, add 200mL of ethyl acetate, stir at 5℃ to crystallize, filter, and dry to obtain 66g of compound 2, with a yield of 66%.

[0061] 2) Add 66g of compound 2 to a reaction flask, dissolve it with 660mL of tetrahydrofuran, add 6.6g of lithium chloride, purge with nitrogen three times, lower the temperature to 5℃, add 244mL of tetrahydrofuran solution of methyl magnesium bromide (1mol / L), and maintain the reaction temperature at 5℃. Monitor the reaction by TLC. After the reaction is complete, perform post-processing. Add 660mL of water dropwise to the reaction solution at -5~0℃, allow to stand and separate the layers. Wash the organic layer once with 660mL of saturated sodium chloride solution. Dry the washed organic layer with 6.6g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is distilled off, add 66mL of ethyl acetate, stir at 5℃ to crystallize, filter, and dry to obtain 44g of compound 3, with a yield of 66.6%.

[0062] 3) Add 44g of compound 3 to a hydrogenation reactor and dissolve it with 440mL of tetrahydrofuran. Add 1.32g of palladium on carbon, purge with nitrogen three times, heat to 40℃, and stir the reaction under hydrogen pressure of 0.2MPa. Monitor the reaction by TLC. After the reaction is complete, perform post-processing. Filter the mixture, wash the filter cake with 44mL of tetrahydrofuran, and wash the filtrate once with 440mL of saturated sodium chloride solution. Dry the washed organic layer with 4.4g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is distilled off, and dry to obtain 38g of compound 4, with a yield of 86.3% by weight.

[0063] 4) Add 38g of compound 4 to a reaction flask, then add 380mL of dioxane and stir. Next, add 43mL of a dioxane solution of hydrogen chloride (4mol / L), heat to 85℃ and react for 1h, then cool to 40℃. Add 21.3g of dichlorocyanobenzoquinone, and maintain the reaction temperature at 40℃. Monitor the reaction by TLC. After the reaction is complete, perform post-processing. Add 380mL of dichloromethane, then add 380mL of water and stir for 1h. Allow to stand for phase separation. Wash the organic layer once with 380mL of saturated sodium carbonate solution, then once with 380mL of saturated sodium chloride solution. Dry the washed organic layer with 3.8g of anhydrous sodium sulfate and distill under reduced pressure until no solvent is distilled off. Crystallize with 38mL of ethyl acetate and 76mL of cyclohexane at 10℃, filter, and dry to obtain 20.2g of dydrogesterone, with a yield of 53.1% by weight. The HPLC purity was 99.95%, and the overall yield based on compound 1 was 24.99%.

[0064] Example 3

[0065] 1) Dissolve 100g of compound 1 (3,20-bis(ethylenedioxy)-19-norpregn-5(10),9(11)diene) in 1L of dichloromethane, pour into a reaction flask, cool to -18℃, add 10mL of pyridine, 30mL of hexachloroacetone, and 30mL of hydrogen peroxide sequentially, and react at -18℃. Monitor the reaction by TLC. After the reaction is complete, perform post-processing. Pour the reaction solution into a separatory funnel and let it stand for ten minutes. Separate the layers. Wash the organic layer once with 500mL of saturated sodium thiosulfate solution, and then once with 500mL of saturated sodium chloride solution. Dry the washed organic layer with 10g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is distilled off, add 200mL of ethyl acetate, stir at 0℃ to crystallize, filter, and dry to obtain 64g of compound 2, yield: 64% by weight.

[0066] 2) Add 64g of compound 2 to a reaction flask, dissolve it with 640mL of tetrahydrofuran, add 6.4g of lithium chloride, purge with nitrogen three times, lower the temperature to 0℃, add 236mL of tetrahydrofuran solution of methyl magnesium bromide (1mol / L), and maintain the reaction temperature at 0℃. Monitor the reaction by TLC. After the reaction is complete, perform post-processing. Add 640mL of water dropwise to the reaction solution at -5~0℃, allow to stand and separate the layers. Wash the organic layer once with 640mL of saturated sodium chloride solution. Dry the washed organic layer with 6.4g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is distilled off, add 64mL of ethyl acetate, stir at 3℃ to crystallize, filter, and dry to obtain 43.5g of compound 3, with a yield of 68%.

[0067] 3) Add 43.5 g of compound 3 to a hydrogenation reactor, dissolve it with 435 mL of tetrahydrofuran, add 1.29 g of palladium on carbon, purge with nitrogen three times, heat to 35 °C, and stir the reaction under hydrogen pressure of 0.2 MPa. Monitor the reaction by TLC. After the reaction is complete, perform post-processing. Filter, wash the filter cake with 43 mL of tetrahydrofuran, and wash the filtrate once with 435 mL of saturated sodium chloride solution. Dry the washed organic layer with 4.3 g of anhydrous sodium sulfate, distill under reduced pressure until no solvent is distilled off, and air dry to obtain 37.8 g of compound 4, with a yield of 86.9% by weight.

[0068] 4) Add 37.8 g of compound 4 to a reaction flask, then add 378 mL of dioxane and stir. Next, add 43 mL of a dioxane solution of hydrogen chloride (4 mol / L), heat to 83 °C and react for 1 h. Then cool to 35 °C, add 21.3 g of dichlorocyanobenzoquinone, and maintain the reaction temperature at 35 °C. Monitor the reaction by TLC. After the reaction is complete, perform post-processing. Add 378 mL of dichloromethane, then add 378 mL of water and stir for 1 h. Allow to stand and separate the layers. Wash the organic layer once with 378 mL of saturated sodium carbonate solution, then once with 378 mL of saturated sodium chloride solution. Dry the washed organic layer with 3.7 g of anhydrous sodium sulfate and distill under reduced pressure until no solvent is distilled off. Crystallize with 38 mL of ethyl acetate and 76 mL of cyclohexane at 8 °C, stir, filter, and dry to obtain 20.8 g of dydrogesterone, with a yield of 55% by weight. The HPLC purity was 99.96%, and the overall yield based on compound 1 was 25.73%.

[0069] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing dydrogesterone, characterized in that the steps include... include: S1. Compound 1 was epoxidized with hydrogen peroxide under the action of a base and a first catalyst to obtain compound 2; The first catalyst is hexachloroacetone; S2. Compound 2 undergoes a Grignard addition reaction in the presence of magnesium methyl bromide to give compound 3; S3. Compound 3 undergoes a hydrogenation reaction with hydrogen gas under the action of a second catalyst to obtain compound 4; S4. Compound 4 is deprotected from its ketal protection and hydroxyl group under acidic conditions, and then dydrogesterone is obtained by the dehydrogenation reaction of dichlorocyanobenzoquinone. The reaction route for the preparation method is as follows: 。 2. The preparation method according to claim 1, characterized in that, In step S1, the base is pyridine, and the volume ratio of pyridine to compound 1 is (0.05-0.15):1; And / or, the hydrogen peroxide content is 50%, and the volume ratio of hydrogen peroxide to compound 1 is (0.2-0.4):1; And / or, the temperature of the reaction process is -15 to -20°C; And / or, the solvent used in the reaction process is dichloromethane.

3. The preparation method according to claim 1, characterized in that, In step S1, the reaction product is first allowed to stand and separated. The organic layer is washed with a saturated salt solution, dried after absorbing water, and the solvent is evaporated. After crystallization, filtration, and drying, compound 2 is obtained.

4. The preparation method according to claim 1, characterized in that, In step S2, the molar ratio of compound 2 to magnesium methyl bromide is 1:(3-4). And / or, the reaction temperature is -5 to 5°C, and the reaction process is carried out under an inert atmosphere; And / or, the reaction process uses tetrahydrofuran as a solvent.

5. The preparation method according to claim 1, characterized in that, In step S2, after the reaction is complete, the reaction is quenched by controlling the temperature below 0°C, the organic layer is washed and dehydrated with saturated brine, the solvent is evaporated, crystals are precipitated, filtered, and dried to obtain compound 3.

6. The preparation method according to claim 1, characterized in that, In step S3, the second catalyst is palladium on carbon; And / or, the reaction temperature is 30–40°C, and the reaction pressure is 0.1–0.3 MPa; And / or, the solvent used in the reaction is tetrahydrofuran.

7. The preparation method according to claim 1, characterized in that, In step S3, after the reaction is complete, the mixture is filtered, and the filtrate is washed with solvent in sequence, then washed with saturated salt solution, then dried by absorbing water, and the solvent is evaporated. After drying, compound 4 is obtained.

8. The preparation method according to claim 1, characterized in that, In step S4, during the deketalization and hydroxyl removal reaction: the reaction temperature is 80–85°C, the reaction time is 0.5–2 h, and / or the solvent used is dioxane.

9. The preparation method according to claim 1, characterized in that, During the dehydrogenation reaction in step S4: the reaction temperature is 30-40℃, and / or the mass ratio of compound 4 to dichlorocyanobenzoquinone is 1:(0.55~0.58).

10. The preparation method according to claim 1, characterized in that, In step S4, after the dehydrogenation reaction is completed, the organic layer is allowed to stand and separated. The organic layer is washed sequentially with saturated sodium carbonate and saturated brine, and then the solvent is evaporated, crystals are precipitated, filtered, and dried to obtain dydrogesterone.

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