CN116143859A - Preparation method of 5α-pregna-3,20-dione - Google Patents

Abstract

The invention discloses a preparation method of 5α-pregna-3,20-dione, which uses gestational enolone as a starting material, and first undergoes a catalytic hydrogenation reaction to obtain 3β-hydroxy-5α-pregna-20-dione ketone, and then obtain 5α-pregna-3,20-diketone through catalytic oxidation reaction; catalytic oxidation is based on 2,2,6,6-tetramethylpiperidine nitrogen oxide as catalyst, N-chlorosuccinyl Amine or N-bromosuccinimide as oxidant, tetrabutylammonium bromide as phase transfer catalyst. The method of the present invention uses gestational enolone as a starting raw material, and obtains 5α-pregna-3,20-dione through two-step reactions, which not only has a short synthetic route, but also has a wide range of raw material sources, and is suitable for large-scale industrial production. The catalytic oxidation system is not only more friendly to the environment, but also has higher reaction yield and product purity.

Description

Preparation method of 5α-pregna-3,20-dione

technical field

The invention belongs to the technical field of preparation of steroid hormone drug intermediates, and in particular relates to a preparation method of 5α-pregna-3,20-dione.

Background technique

5α-pregna-3,20-dione (also known as hydrogenated progesterone), CAS No. 566-65-4, molecular formula C ₂₁ H ₃₂ O ₂ , molecular weight 316.48, melting point 200°C, is used to treat epilepsy The key intermediate of the drug ganaxolone.

Document 1 discloses a synthesis method of ganaxolone, and specifically discloses monoenolone acetate obtained from sisal sapogenin [that is, 3β-hydroxyl-5α-pregn-16-en-20-one Acetate, compound 1] as the starting material, 3β-hydroxy-5α-pregna-20-one acetate [compound 2] was obtained by catalytic hydrogenation, and then 3β-hydroxy-5α-pregna was obtained by alkaline alcoholysis -20-ketone [compound 3], and finally oxidized by Jones to obtain 5α-pregna-3,20-dione [compound 4].

The disadvantages of this method are: (1) The synthetic route is long; (2) The source of monoenolone acetate as a starting material is limited and difficult to obtain; (3) The Jones oxidation reaction will cause a large amount of chromium-containing wastewater, which will cause great environmental pollution. , not suitable for industrialized mass production.

Document 1: He Minghua et al., "Synthesis of Ganaxolone", "Chinese Journal of New Drugs", Vol. 14, No. 8, 2005, pp. 1025-1026.

Contents of the invention

The purpose of the present invention is to solve the above problems and provide a method for preparing 5α-pregna-3,20-dione with short synthetic route, easy to obtain raw materials, less environmental pollution, high reaction yield and product purity .

The technical solution for realizing the purpose of the present invention is: a preparation method of 5α-pregna-3,20-dione, characterized in that: the preparation method of gestational enolone [also known as 3β-hydroxy-pregnant-5-ene-20 -ketone or pregnenolone] as the starting material, first obtain 3β-hydroxyl-5α-pregna-20-one through catalytic hydrogenation reaction, and then obtain 5α-pregna-3,20-dione through catalytic oxidation reaction; The catalytic oxidation uses 2,2,6,6-tetramethylpiperidine nitrogen oxide (TEMPO) as a catalyst, N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS ) as the oxidant and tetrabutylammonium bromide (TBAB) as the phase transfer catalyst.

The synthetic route is as follows:

。

.

The catalytic hydrogenation reaction is carried out in the presence of an organic solvent; the organic solvent is preferably an alcohol solvent; more preferably ethanol; the weight ratio of the pregnant enolone to the organic solvent is 1:40-1 : 60.

The catalytic system used in the catalytic hydrogenation reaction is a palladium/calcium carbonate catalyst; the amount of the palladium/calcium carbonate catalyst is 10% to 50% of the weight of the pregnant enolone.

The temperature of the catalytic hydrogenation reaction is 20-40° C., and the pressure is 0.02-0.06 MPa.

The temperature of the catalytic oxidation reaction is 20-35°C.

The dosage of the 2,2,6,6-tetramethylpiperidine nitrogen oxide is 0.2%-0.6% of the weight of the 3β-hydroxy-5α-pregna-20-one.

The dosage of the tetrabutylammonium bromide is 10%-20% of the weight of the 3β-hydroxy-5α-pregna-20-one.

The weight ratio of the 3β-hydroxy-5α-pregna-20-one to the N-chlorosuccinimide or the N-bromosuccinimide is 1:0.5˜1:1.

The oxidizing agent is preferably N-chlorosuccinimide.

The catalytic oxidation reaction is carried out in the presence of potassium carbonate; the weight ratio of the 3β-hydroxyl-5α-pregna-20-one to the potassium carbonate is 1:0.3˜1:0.6.

The catalytic oxidation reaction is carried out in the presence of an organic solvent; the organic solvent is one of dichloromethane, dichloroethane, and chloroform; the 3β-hydroxyl-5α-pregna-20- The weight ratio of the ketone to the organic solvent is 1:13˜1:20.

The positive effect that the present invention has:

(1) The method of the present invention uses pregnant enolone as a starting material to obtain 5α-pregna-3,20-dione through two-step reactions, which not only has a short synthesis route, but also has a wide range of raw material sources, and is suitable for large-scale industrial production.

(2) The method of the present invention uses 2,2,6,6-tetramethylpiperidine nitrogen oxide as a catalyst, N-chlorosuccinimide or N-chlorosuccinimide as an oxidant, tetra-n-butyl Ammonium bromide is used as a phase transfer catalyst to catalyze the oxidation of 3β-hydroxy-5α-pregna-20-one to prepare 5α-pregna-3,20-dione under alkaline conditions. The catalytic oxidation reaction is not only more environmentally friendly , and the reaction yield and product purity are high.

(3) The method of the present invention adopts a palladium/calcium carbonate catalytic system, so as to ensure that 3β-hydroxy-5α-pregna-20-one is obtained.

Detailed ways

(Example 1)

This example prepares 3β-hydroxy-5α-pregna-20-one by catalytic hydrogenation of pregnant enolone, the specific method is as follows:

Add 24.00kg of pregnant enolone to 1200kg of ethanol, then add 3.60kg of palladium/calcium carbonate catalyst, vacuumize, replace with hydrogen for 3 times, then pass in hydrogen, keep the temperature and pressure at 30°C and 0.04MPa React to complete.

After the reaction, replace with nitrogen, filter, wash, combine, concentrate the filtrate to remove ethanol, cool down to 10°C for crystallization, centrifuge, and dry at 70-80°C to obtain 23.52kg of 3β-hydroxy-5α-pregna-20-one , The weight yield is 98.0%.

(Example 2)

This example prepares 5α-pregna-3,20-dione by catalytic oxidation of 3β-hydroxy-5α-pregna-20-one. The specific method is as follows:

20.00kg of 3β-hydroxy-5α-pregna-20-one obtained in Example 1 was added to 260kg of dichloromethane, and after stirring and dissolving, 0.04kg of 2,2,6,6-tetramethylpiperene was first added Pyridine nitrogen oxide, then add the solution that is prepared by 8.00kg of potassium carbonate, 2.20kg of tetrabutylammonium bromide and 120kg of water, and finally add 10.00kg of N-chlorosuccinimide. Insulate the reaction at 22°C until complete.

After the reaction, add a solution prepared by 5.00kg of sodium sulfite and 25.00kg of water, stir evenly, concentrate at 50°C until there is no dichloromethane, cool down to 5°C for crystallization, centrifuge, wash with water, and dry at 80-90°C to obtain The crude product of 5α-pregna-3,20-dione was 19.80kg.

Add 19.80 kg of the above crude product to 150 kg of dichloromethane, then add 2.00 kg of activated carbon, stir and decolorize for 50 minutes, filter, wash, combine, concentrate the filtrate until crystals are precipitated, add ethyl acetate, concentrate to no dichloromethane, and cool down Crystallize at 5°C, centrifuge filter, wash, and dry at 70-80°C to obtain 18.80 kg of finished product 5α-pregna-3,20-dione with a purity of 99.3% and a weight yield of 94.0%.

(comparative example 1)

The difference between this comparative example and Example 2 is that no phase transfer catalyst tetrabutylammonium bromide is added, and no target product is generated as a result.

(Comparative example 2 to comparative example 3)

The preparation method of each comparative example is basically the same as that of Example 2, and the differences are shown in Table 1.

Table 1

Example 2 Comparative example 2 Comparative example 3 oxidizing agent 10.00kg of NCS (75mol) 5.58kg of NaClO (75mol) 5.58kg of NaClO (75mol) Tetrabutylammonium bromide 2.20kg 2.20kg / product weight 18.8kg 17.0kg 14.0kg Product purity 99.3% 99.0% 98.8% weight yield 94.0% 85.0% 70.0%

(Example 3)

This example still prepares 3β-hydroxy-5α-pregna-20-one by catalytic hydrogenation of pregnant enolone, the specific method is as follows:

Add 10.00g of pregnant enolone to 600g of ethanol, then add 3.00g of palladium/calcium carbonate catalyst, vacuumize, replace with hydrogen for 3 times, then pass in hydrogen, keep the temperature and pressure at 25°C and 0.05MPa React to complete.

After the reaction, replace with nitrogen, filter, wash, combine, concentrate the filtrate to remove ethanol, cool down to 10°C to crystallize, filter, and dry at 70-80°C to obtain 9.80 g of 3β-hydroxy-5α-pregna-20-one , The weight yield is 98.0%.

(Example 4)

This example still prepares 3β-hydroxy-5α-pregna-20-one by catalytic hydrogenation of pregnant enolone, the specific method is as follows:

Add 10.00g of pregnant enolone to 500g of ethanol, then add 2.00g of palladium/calcium carbonate catalyst, vacuumize, replace with hydrogen for 3 times, then pass in hydrogen, keep the temperature and pressure at 30°C and 0.04MPa React to complete.

After the reaction, replace with nitrogen, filter, wash, combine, concentrate the filtrate to remove ethanol, cool down to 5°C to crystallize, filter, and dry at 70-80°C to obtain 9.76g of 3β-hydroxy-5α-pregna-20-one , The weight yield is 97.6%.

(Example 5)

This example still prepares 3β-hydroxy-5α-pregna-20-one by catalytic hydrogenation of pregnant enolone, the specific method is as follows:

Add 10.00g of pregnant enolone to 400g of ethanol, then add 1.00g of palladium/calcium carbonate catalyst, vacuumize, replace with hydrogen for 3 times, then pass in hydrogen, keep the temperature and pressure at 35°C and 0.03MPa React to complete.

After the reaction, replace with nitrogen, filter, wash, combine, concentrate the filtrate to remove ethanol, cool down to 10°C for crystallization, filter, and dry at 70-80°C to obtain 9.70 g of 3β-hydroxy-5α-pregna-20-one , The weight yield is 97.0%.

(Example 6)

This example still prepares 5α-pregna-3,20-dione by catalytic oxidation of 3β-hydroxy-5α-pregna-20-one, the specific method is as follows:

Add 10.00g of 3β-hydroxy-5α-pregna-20-one into 150g of dichloromethane, stir and dissolve, then add 0.03g of 2,2,6,6-tetramethylpiperidine nitrogen oxide , then add a solution prepared by 5.00g of potassium carbonate, 1.50g of tetrabutylammonium bromide and 60g of water, and finally add 10.00g of N-chlorosuccinimide, after the addition is complete, keep the temperature at 30°C for reaction to complete.

After the reaction, add a solution prepared by 2.50g of sodium sulfite and 12.50g of water, stir evenly, concentrate at 50°C until there is no dichloromethane, cool down to 15°C to crystallize, filter, wash with water, and dry at 80-90°C to obtain 9.80 g of the crude product of 5α-pregna-3,20-dione.

Add 9.80 g of the above crude product to 100 g of dichloromethane, then add 1.00 g of activated carbon, stir for decolorization for 50 minutes, filter, wash, combine, concentrate the filtrate until crystals are precipitated, add ethyl acetate, concentrate to no dichloromethane, and cool down Crystallize at 10°C, filter, wash, and dry at 70-80°C to obtain 9.22 g of finished product 5α-pregna-3,20-dione with a purity of 99.2% and a refined yield of 92.2%.

(Example 7)

This example still prepares 5α-pregna-3,20-dione by catalytic oxidation of 3β-hydroxy-5α-pregna-20-one, the specific method is as follows:

Add 10.00g of 3β-hydroxy-5α-pregna-20-one into 200g of dichloroethane, stir and dissolve, then add 0.06g of 2,2,6,6-tetramethylpiperidine for nitrogen oxidation Then add a solution prepared by 3.00g of potassium carbonate, 1.00g of tetrabutylammonium bromide and 60g of water, and finally add 6.00g of N-bromosuccinimide, after adding, keep warm at 32°C React to complete.

After the reaction, add a solution prepared by 2.50g of sodium sulfite and 12.50g of water, stir evenly, concentrate at 50°C until there is no dichloroethane, cool down to 10°C to crystallize, filter, wash with water, and dry at 80-90°C. 9.70 g of crude 5α-pregna-3,20-dione was obtained.

Add 9.70 g of the above crude product to 50 g of dichloromethane, then add 0.50 g of activated carbon, stir for decolorization for 45 minutes, filter, wash, combine, concentrate the filtrate until crystals are precipitated, add ethyl acetate, concentrate to no dichloromethane, and cool down Crystallize at 5°C, filter, wash, and dry at 70-80°C to obtain 8.94g of 5α-pregna-3,20-dione finished product with a purity of 99.1% and a refined yield of 89.4%.

(Example 8)

This example still prepares 5α-pregna-3,20-dione by catalytic oxidation of 3β-hydroxy-5α-pregna-20-one, the specific method is as follows:

Add 10.00g of 3β-hydroxy-5α-pregna-20-one into 130g of dichloromethane, stir and dissolve, then add 0.03g of 2,2,6,6-tetramethylpiperidine nitrogen oxide , then add a solution prepared by 3.00g of potassium carbonate, 1.50g of tetrabutylammonium bromide and 60g of water, and finally add 5.00g of N-chlorosuccinimide, after the addition is complete, keep the temperature at 20°C for reaction to complete.

After the reaction, add a solution prepared by 2.50g of sodium sulfite and 12.50g of water, stir evenly, concentrate at 50°C until there is no dichloromethane, cool down to 5°C for crystallization, filter, wash with water, and dry at 80-90°C to obtain 9.85 g of the crude product of 5α-pregna-3,20-dione.

Add 9.85 g of the above crude product to 80 g of dichloromethane, then add 1.00 g of activated carbon, stir for 50 minutes to decolorize, filter, wash, combine, concentrate the filtrate until crystals are precipitated, add ethyl acetate, concentrate to no dichloromethane, and cool down Crystallize at 5°C, filter, wash, and dry at 70-80°C to obtain 9.32 g of finished product 5α-pregna-3,20-dione with a purity of 99.4% and a weight yield of 93.2%.

Claims (10)

1. A preparation method for 5α-pregna-3,20-dione, characterized in that: it is a starting material with gestational enolone, and first obtains 3β-hydroxyl-5α-pregna-dione through catalytic hydrogenation reaction 20-ketone, and then obtain 5α-pregna-3,20-dione through catalytic oxidation reaction; the catalytic oxidation uses 2,2,6,6-tetramethylpiperidine nitrogen oxide as catalyst, N-chloro Subsuccinimide or N-bromosuccinimide is the oxidizing agent, and tetrabutylammonium bromide is the phase transfer catalyst. 2. The preparation method of 5α-pregna-3,20-dione according to claim 1, characterized in that: the catalytic hydrogenation reaction is carried out in the presence of an organic solvent; the organic solvent is ethanol; The weight ratio of the pregnant enolone to the organic solvent is 1:40˜1:60. 3. The preparation method of 5α-pregna-3,20-dione according to claim 1 is characterized in that: the catalytic system adopted in the catalytic hydrogenation reaction is a palladium/calcium carbonate catalyst; the palladium/calcium carbonate The dosage of the catalyst is 10%-50% of the weight of the pregnant enolone. 4. The preparation method of 5α-pregna-3,20-dione according to claim 1, characterized in that: the temperature of the catalytic hydrogenation reaction is 20-40° C., and the pressure is 0.02-0.06 MPa. 5. The preparation method of 5α-pregna-3,20-dione according to claim 1, characterized in that: the temperature of the catalytic oxidation reaction is 20-35°C. 6. the preparation method of 5α-pregna-3,20-dione according to claim 1 is characterized in that: the consumption of described 2,2,6,6-tetramethylpiperidine nitrogen oxide is the 0.2% to 0.6% of the weight of 3β-hydroxy-5α-pregna-20-one. 7. The preparation method of 5α-pregna-3,20-dione according to claim 1, characterized in that: the amount of tetrabutylammonium bromide is 3β-hydroxy-5α-pregna- 10% to 20% of the weight of 20-ketone. 8. The preparation method of 5α-pregna-3,20-dione according to claim 1, characterized in that: the 3β-hydroxy-5α-pregna-20-one and the N-chlorosuccinate The weight ratio of the imide or the N-bromosuccinimide is 1:0.5˜1:1. 9. The preparation method of 5α-pregna-3,20-dione according to claim 1, characterized in that: the catalytic oxidation reaction is carried out in the presence of potassium carbonate; the 3β-hydroxyl-5α - The weight ratio of pregna-20-one to the potassium carbonate is 1:0.3-1:0.6. 10. The preparation method of 5α-pregna-3,20-dione according to claim 1, characterized in that: the catalytic oxidation reaction is carried out in the presence of an organic solvent; the organic solvent is dichloro One of methane, dichloroethane, and chloroform; the weight ratio of the 3β-hydroxy-5α-pregna-20-one to the organic solvent is 1:13˜1:20.