Method for synthesizing hydrogenated progesterone

Abstract

The invention relates to a method for synthesizing hydrogenated progesterone, which is characterized in that pregnenolone is taken as a substrate, in the presence of a transition metal catalyst, dehydrogenation oxidation of 3-hydroxyl and hydrogenation reduction of 5-alkene are simultaneously realized through a hydrogen automatic transfer reaction'one-pot method ', and the hydrogenated progesterone is directly obtained.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing steroid compounds, and specifically to a method for synthesizing pregnane compounds. Background Art

[0002] Hydroxyprogesterone, also known as dihydroxyprogesterone, CAS: 566-65-4, is a key intermediate of ganaxolone. The original research drug of ganaxolone, a treatment for rare genetic epilepsy launched by Marinus Pharmaceuticals Inc, has been listed overseas.

[0003] Patent documents CN116143859, WO2019209850, and WO2016061527 disclose that pregnenolone is used as a raw material, which is catalytically hydrogenated to obtain allopregnenolone, and then oxidized to obtain hydroxyprogesterone. The route is as follows:

[0004]

[0005] "Chinese Journal of New Drugs", Vol. 14, No. 8, 1025-1026 (2005) reported that pregnenolone acetate is used as a raw material, which is catalytically hydrogenated to obtain allopregnenolone acetate, then hydrolyzed to obtain allopregnenolone, and finally oxidized to obtain hydroxyprogesterone. The route is as follows:

[0006]

[0007] Chinese patent CN116715715 discloses that androsterone is used as a raw material, and hydroxyprogesterone is obtained through Wittig reaction, hydroboration-oxidation reaction, and Corey oxidation reaction. The route is as follows:

[0008]

[0009] The above two routes have problems such as long reaction routes, low yields, and high consumption of raw materials and solvents.

[0010] Tetrahedron Letters, 26(7).831-832(1985) and Synthetic Communications, 22(12), 1655-1660(1992) reported that progesterone is used as a raw material, and sodium dithionite is used as a reducing agent to selectively reduce and directly obtain hydroxyprogesterone. The route is as follows:

[0011]

[0012] Although the route only requires a one-step reaction, it uses progesterone as the raw material for hydrocortisone. Since progesterone is actually a widely used bulk drug, the process using progesterone as the bulk drug has a relatively high raw material cost. In summary, the technical solutions in the prior art all have problems such as long reaction routes, low yields, and relatively high raw material prices. Therefore, providing a method for synthesizing hydrocortisone with low raw material prices, high reaction yields, and less material consumption has become an urgent problem to be solved in the prior art. Summary of the Invention

[0013] To solve the aforementioned technical problems, we unexpectedly found in the research that by optimizing the process conditions, a cascade reaction of the "one-pot method" can be used to achieve automatic hydrogen transfer with a transition metal catalyst as the carrier, and pregnenolone can be directly converted into hydrocortisone.

[0014] The technical solution provided by the present invention is as follows

[0015] A method for synthesizing hydrocortisone, using pregnenolone (CAS: 145-13-1) as a substrate, in the presence of a transition metal catalyst, simultaneously achieving dehydrogenation of 3-hydroxy and hydrogenation reduction of 5-ene through an automatic hydrogen transfer reaction of the "one-pot method" to directly obtain hydrocortisone. The reaction formula is

[0016]

[0017] The reaction solvent is methanol, ethanol, isopropanol, toluene, 1,2-dichloroethane, and tetrahydrofuran. The volume-weight ratio of the solvent to the substrate is 5-10, and the reaction temperature is 25°C - 80°C; the transition metal catalyst is selected from palladium on carbon, [RhCl(-)-DIOP], (PNHPPh)CoCl 2 、[RuCl 2 (PPh 3 ) 3 、[(dippp) 3 (Pd-H) 2 )](OTf) 2， The weight percentage ratio of the transition catalyst to the substrate dosage is 5% - 20%.

[0018] For the method for synthesizing hydrocortisone described above, further, the reaction solvent is preferably tetrahydrofuran, the volume-weight ratio of the solvent to the substrate is 10, the reaction temperature is 55°C - 60°C, and the transition metal catalyst is palladium on carbon; the weight percentage ratio of the transition catalyst to the substrate dosage is 10%.

[0019] For the method for synthesizing hydrocortisone described above, further, after the reaction is completed, the crude product is obtained by filtration, tetrahydrofuran with a volume-weight ratio of 2 to the substrate is added, and it is slurried for 2 hours, and then filtered and dried to obtain the refined hydrocortisone product.

[0020] A method for synthesizing hydrocortisone provided by the present invention utilizes a hydrogen autotransfer "one-pot method" to simultaneously achieve dehydrogenation oxidation and hydrogenation reduction, directly obtaining hydrocortisone from pregnenolone. The reaction is more concise, has high atom economy, simple post-treatment, is environmentally friendly, and achieves the purpose of reducing costs, energy consumption, and three wastes. Specific Embodiments

[0021] The following combines examples to further describe in detail the specific embodiments of the present invention. The following examples are used to illustrate the present invention but are not used to limit the scope of the present invention.

[0022] Example 1

[0023] Pregnenolone (10 g), palladium on carbon (1 g), and tetrahydrofuran (100 mL) were added to a reaction flask, heated to 55 - 60 °C and reacted for 24 hours. TLC detected that the raw materials had completely reacted. Filtered and washed with tetrahydrofuran (20 mL). The filtrate was concentrated to obtain a crude product (5.5 g). The crude product was slurried with tetrahydrofuran (50 mL) for 2 hours, filtered, and dried to obtain white solid hydrocortisone (8.4 g). Weight yield: 84%, HPLC purity: 97.5%.

[0024] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for synthesizing hydrogenated progesterone, characterized in that: Using pregnenolone as a substrate, in the presence of a transition metal catalyst, the 3-hydroxyl dehydrogenation and 5-ene hydrogenation reduction are simultaneously achieved in one pot through a hydrogen autotransfer reaction to directly obtain hydrogenated progesterone. The reaction formula is: The reaction solvent is methanol, ethanol, isopropanol, toluene, 1,2-dichloroethane or tetrahydrofuran, the volume weight ratio of the solvent to the substrate is 5 to 10, and the reaction temperature is 25°C to 80°C; the transition metal catalyst is selected from palladium carbon, [RhCl(-)-DIOP], (PNHPPh)CoCl2, [RuCl2(PPh3)3], [(dippp)3(Pd-H)2)](OTf) 2， The weight percentage ratio of the transition catalyst to the substrate is 5% to 20%.

2. A method for synthesizing hydrogenated progesterone according to claim 1, characterized in that: The reaction solvent is tetrahydrofuran, the volume weight ratio of the solvent to the substrate is 10, the reaction temperature is 55° C. to 60° C., the transition metal catalyst is palladium carbon, and the weight percentage ratio of the transition catalyst to the substrate is 10%.

3. A method for synthesizing hydrogenated progesterone according to claim 2, characterized in that: After the reaction is completed, the crude product is filtered to obtain a crude product, tetrahydrofuran is added at a volume weight ratio of 2 to the substrate, the mixture is slurried for 2 hours, filtered and dried to obtain a refined hydrogenated progesterone product.

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