Preparation method of cholesterol
By optimizing the cholesterol preparation method and adopting a multi-step reaction optimization, the problems of low cholesterol synthesis yield and high purification difficulty in the existing technology have been solved, realizing the preparation of high-purity and high-yield cholesterol, which is suitable for industrial production.
Patent Information
- Application Number
- CN202511727244.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-24
- Publication Date
- 2026-01-02
AI Technical Summary
Existing cholesterol synthesis processes suffer from low yields, inconvenient operation, high safety risks, and difficult purification, especially animal-derived extraction and plant-derived biosynthesis technologies, which also have low yields, difficult purification, and high safety risks.
A novel method for preparing cholesterol is employed, comprising a 3-position carbonyl ketal protection reaction, a 21-position hydroxyl oxidation to aldehyde reaction, a 21-position aldehyde Grignard reaction, a 21-position hydroxyl oxidation to ketal reaction, a 21-position carbonyl reduction to methylene reaction, a 3-position carbonyl esterification reaction, and a selective reduction reaction of esters and alkenes. By optimizing the reaction conditions and selective reduction steps, the yield and purity are improved.
It achieves a cholesterol yield of over 74.0% and a product purity of over 99%, featuring good selectivity, low cost, and low pollution, making it suitable for industrial production.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the field of pharmaceutical environment chemical technology, in particular to a preparation method of cholesterol. BACKGROUND
[0002] Cholesterol is also called cholestanol, CAS: 57-88-5, English name: Cholesterol, appearance is white or white crystalline powder, melting point: 148~150℃, its structural formula is as follows:
[0003] Cholesterol is an important steroidal compound, which exists widely in animal body. Cholesterol not only participates in the formation of cell membrane, but also is the precursor of bile acid, steroid hormone and vitamin D3. At present, the source of cholesterol mainly includes animal material extraction and plant source biosynthesis. Animal material extraction has low yield, great purification difficulty, great safety risk, limited raw material source, and many regional and national restrictions. In order to solve the disadvantages of animal source cholesterol, plant source biosynthesis technology is developed and popularized.
[0004] The patent CN112608361 discloses a plurality of cholesterol synthesis routes, and the main two routes are as follows: synthesis route one: The synthesis route one takes BA as a starting material, and passes through 21-position hydroxyl sulfonylation reaction, 3-position carbonyl esterification reaction, reduction reaction and Grignard reaction to obtain cholesterol, and the specific route is as follows:
[0005] Synthesis route two: The synthesis route two takes BA as a starting material, and passes through 21-position hydroxyl oxidation reaction, Grignard reaction, 4-position double bond isomerization reaction, 3-position carbonyl reduction reaction and 22-position double bond reduction reaction to obtain cholesterol, and the specific route is as follows:
[0006] The synthesis route one has four reaction steps, the route is short, and the total mass yield can reach 70%~75%, but the disadvantages cannot be ignored. For example, a series of derivatives of p-toluenesulfonyl chloride generated in the esterification reaction of 21-position hydroxyl and p-toluenesulfonyl chloride belong to genetic toxic impurities, which brings challenges to quality control. The synthesis route two has five reaction steps, and the total mass yield reaches more than 52%. The second step of the process route is wittig reaction, which is inconvenient to control and has low yield; the last step is palladium-carbon hydrogenation reduction, which has high safety risk. In order to solve the technical problems in the above two process routes, a new preparation process of cholesterol needs to be developed.
[0007] Therefore, the present application provides a preparation method of cholesterol. SUMMARY
[0008] To solve the above-mentioned at least one technical problem, the present application provides a preparation method of cholesterols.
[0009] The present application is realized by the following technical scheme: a preparation method of cholesterols, the method comprising the following steps: S1: 3-position carbonyl ketal protection reaction: uniformly mix BA, ethylene glycol, p-toluene phosphoric acid and triethyl orthoformate, control the temperature at 40-60 DEG C, react for 2-8 h, cool to-10-10 DEG C, control the temperature for 1-5 h, filter, dry at 40-70 DEG C, and obtain compound IM1; S2: 21-position hydroxyl oxidized to aldehyde reaction: uniformly mix compound IM1, dichloromethane and 4-hydroxy-TEMPO, add 2% by mass sodium bicarbonate and 2% by mass sodium bromide aqueous solution, control the temperature at-10-10 DEG C, add 8%-13% by mass sodium hypochlorite aqueous solution, control the temperature and react for 1-3 h, add 10% by mass sodium thiosulfate aqueous solution, stand for 20 min, separate the layers, concentrate the organic phase under normal pressure to 40 DEG C, stir at 10-30 DEG C for 1 h, filter, and dry at 40-70 DEG C to obtain compound IM2; S3: 21-position aldehyde group Grignard reaction: uniformly mix compound IM2 and tetrahydrofuran, control the temperature at 20-45 DEG C, add 0.5-1.5 mol / L isopentyl magnesium chloride tetrahydrofuran solution, control the temperature at 50-65 DEG C, react for 2-8 h, control the temperature below 30 DEG C, add 30% by mass glacial acetic acid aqueous solution, stand for 20 min, separate the layers, discard the water phase, concentrate the organic phase under normal pressure to 68 DEG C, stir at-10-10 DEG C for 1-3 h, filter, and dry at 40-70 DEG C to obtain compound IM3; S4: 21-position hydroxyl oxidized to ketone reaction: uniformly mix compound IM3 and acetone, control the temperature at-10-10 DEG C, add Jones reagent, react for 1-3 h, add isopropyl alcohol to make the reaction system non-oxidizing, add water to the reaction system, concentrate out acetone, control the temperature at 10-30 DEG C, stir for 1 h, filter, and dry at 40-70 DEG C to obtain compound IM4; S5: 21-position carbonyl reduced to methylene reaction: uniformly mix compound IM4 and dimeric ethylene glycol, add potassium hydroxide and 85% by mass hydrazine hydrate, distill and heat to 180-200 DEG C, control the temperature and react for 2-4 h, cool to 70-80 DEG C, add 5% by mass hydrochloric acid aqueous solution to adjust the pH value to 1-2, control the temperature and react for 1-6 h at 60-80 DEG C, add 30% by mass liquid alkali to adjust the pH value to 5-7, cool to 10-30 DEG C, add water, stir for 1 h, filter, and dry at 70-100 DEG C to obtain compound IM5; S6: 3-position carbonyl ester reaction: compound IM5, dichloromethane, acetic anhydride are mixed uniformly, p-toluene phosphoric acid is added, temperature is controlled at 30-50°C, reaction is carried out for 3-8h, water is added, and the mixture is left to stand for 20min, and then the mixture is separated into two layers, the organic phase is concentrated under normal pressure to 40°C, stirring is carried out at -10-10°C for 1-3h, filtration is carried out, and drying is carried out at 40-70°C to obtain compound IM6; S7: selective reduction reaction of ester and olefin: compound IM6, methanol, tetrahydrofuran, and water are mixed uniformly, a 30% sodium hydroxide aqueous solution is added to adjust the pH value to 8-10, sodium borohydride and cerium chloride heptahydrate are added, temperature is controlled at 25-45°C, reaction is carried out for 4-8h, acetone is added to make the system non-reducing, and the mixture is concentrated under normal pressure to 70°C, and then the temperature is lowered to 10-30°C, dichloromethane is added, and the mixture is separated into two layers, the mixture is stirred until the solution is clear, the mixture is left to stand for 20min, the mixture is separated into two layers, the water phase is discarded, the organic phase is concentrated under normal pressure to 40°C, stirring is carried out at -10-10°C for 1-3h, filtration is carried out, and drying is carried out at 40-70°C to obtain the finished product of cholesterols.
[0010] Preferably, in the S1: the mass ratio of the BA to ethylene glycol is 1:1-3; the mass ratio of the BA to p-toluene sulfonic acid is 1:0.01-0.1; the mass ratio of the BA to triethyl orthoformate is 1:0.5-1.5.
[0011] Preferably, in the S2: the mass ratio of the compound IM1 to dichloromethane is 1:2-6; the mass ratio of the compound IM1 to 4-hydroxy-TEMPO is 1:0.002-0.01; the mass ratio of the compound IM1 to a 2% sodium bicarbonate and 2% sodium bromide aqueous solution is 1:0.5-1.5; the mass ratio of the compound IM1 to sodium hypochlorite aqueous solution is 1:2-5; the mass ratio of the compound IM1 to sodium thiosulfate aqueous solution is 1:0.5-1.5.
[0012] Preferably, in the S3: the mass ratio of the compound IM2 to tetrahydrofuran is 1:2-6; the mass ratio of the compound IM2 to isopentyl magnesium chloride tetrahydrofuran solution is 1:2-8; the mass ratio of the compound IM2 to glacial acetic acid aqueous solution is 1:1-3.
[0013] Preferably, in the S4, the mass ratio of the compound IM3 to the acetone is 1:2-6; The preparation method of the Jones reagent is as follows: 0.4 W of chromium trioxide is dissolved in 2 W of water, temperature is controlled at 20-30 DEG C, 0.8 W of concentrated sulfuric acid is added, and mixing is uniform; the mass ratio of the compound IM3 to the Jones reagent is 1:1.0-3.0; the mass ratio of the compound IM3 to the isopropyl alcohol is 1:0.3-1.0; and the mass ratio of the compound IM3 to the water is 1:2-6.
[0014] Preferably, in the S5, the mass ratio of the compound IM4 to the acetone is 1:2-6; The mass ratio of the compound IM4 to the acetone is 1:2-6; The mass ratio of the compound IM4 to the potassium hydroxide is 1:0.5-1.5; The mass ratio of the compound IM4 to the hydrazine hydrate is 1:0.5-1.5; The mass ratio of the compound IM4 to the water is 1:2.0-5.0.
[0015] Preferably, in the S6, the mass ratio of the compound IM5 to the dichloromethane is 1:2-6; The mass ratio of the compound IM5 to the dichloromethane is 1:2-6; The mass ratio of the compound IM5 to the acetic anhydride is 1:0.5-1.0; The mass ratio of the compound IM5 to the p-toluenesulfonic acid is 1:0.01-0.1; The mass ratio of the compound IM5 to the water is 1:0.5-1.5.
[0016] Preferably, in the S7, the mass ratio of the compound IM6 to the methanol is 1:0.5-1.5; The mass ratio of the compound IM6 to the methanol is 1:0.5-1.5; The mass ratio of the compound IM6 to the tetrahydrofuran is 1:2-4; The mass ratio of the compound IM6 to the reaction water is 1:0.5-1.0; The mass ratio of the compound IM6 to the sodium borohydride is 1:0.3-1.0; The mass ratio of the compound IM6 to the cerium chloride heptahydrate is 1:0.02-0.1; The mass ratio of the compound IM6 to the dichloromethane is 1:5-10; The mass ratio of the compound IM6 to the water for layer separation is 1:2.0-4.0.
[0017] The reaction route of the application is as follows:
[0018] Compared with the prior art, the present application has the following beneficial effects: 1. In the step of synthesizing IM3 from IM2, the present application uses Grignard reaction of the aldehyde group at position 21 with isopentyl magnesium chloride to construct the side chain of cholesterol, which is safer, easier to control and has higher yield compared with Wittig reaction; 2. In the step of synthesizing IM5 from IM4, the present application uses Wolff-Kishner-Huang Minglong reaction to convert carbonyl into methylene, which can avoid the destruction of the steroid structure and ensure the yield and quality of the reaction; 3. In the step of synthesizing cholesterol from IM5, the present application adds a catalytic amount of cerium chloride and sodium borohydride reduction system to improve the reduction efficiency of ester groups, improve the selectivity of double bond reduction, and reduce the generation of by-products; 4. The quality yield of cholesterol prepared by the present application is above 74.0%, the product purity is above 99%, and the content is above 98%.
[0019] 5. The present application also has the characteristics of good selectivity, low cost and small pollution, and the method is stable and easy to realize industrial production. DETAILED DESCRIPTION
[0020] The technical solutions of the present application will be further described below in combination with examples. The test materials used in the examples can be purchased through conventional channels.
[0021] Example 1 Step (1), 3-carbonyl ketal protection reaction: 100g of BA, 100g of ethylene glycol, 10g of p-toluenesulfonic acid, and 150g of orthoformic acid triethyl ester are uniformly mixed, the temperature is controlled at 40℃, and the reaction is carried out for 8h, then the temperature is lowered to 10℃, the temperature is controlled for 1h, filtration is carried out, and drying is carried out at 40℃ to obtain 109.2g of compound IM1, with a mass yield of 109.2%; Step (2), oxidation of 21-hydroxyl to aldehyde: 1000g of compound IM1, 2000g of dichloromethane, and 0.204g of TEMPO are uniformly mixed, 1500g of a 2% sodium bicarbonate aqueous solution and 2% sodium bromide aqueous solution are added, the temperature is controlled at 10℃, 500g of an 8% sodium hypochlorite aqueous solution is added, the temperature is controlled for 2h, 150g of a 10% sodium thiosulfate aqueous solution is added, and the mixture is left to stand for 20min, then the layers are separated, the organic phase is concentrated at normal pressure to 40℃, the temperature is controlled at 10℃ for 1h, filtration is carried out, and drying is carried out at 40℃ to obtain 95.3g of compound IM2, with a mass yield of 95.3%; Step (3), Grignard reaction of aldehyde group at position 21: 90 g of compound IM2, 180 g of tetrahydrofurfurane were uniformly mixed, the temperature was controlled at 20 °C, 720 g of isopentyl magnesium chloride tetrahydrofurfurane solution with a molar concentration of 0.5 mol / L was added, the temperature was controlled at 50 °C, and the reaction was carried out for 2 h, the temperature was controlled below 30 °C, 90 g of 30% acetic acid aqueous solution was added, and the mixture was statically placed for 20 min, then the mixture was separated into two layers, the water phase was discarded, the organic phase was concentrated at normal pressure to 68 °C, the mixture was stirred at -10 °C for 1 h, then the mixture was filtered, and the filter cake was dried at 40 °C to obtain 97.2 g of compound IM3, with a mass yield of 108%; Step (4), oxidation of hydroxyl group at position 21 into ketone: 100 g of compound IM3, 200 g of acetone were uniformly mixed, the temperature was controlled at 10 °C, 100 g of Jones reagent (preparation method: 40 g of chromium trioxide was dissolved in 200 g of water, the temperature was controlled at 20-30 °C, and 80 g of concentrated sulfuric acid was added dropwise) was added, the reaction was carried out for 3 h, 30 g of isopropyl alcohol was added to make the reaction system non-oxidizing, 200 g of water was added to the reaction system, the acetone was concentrated, the temperature was controlled at 10 °C, and the mixture was stirred for 1 h, then the mixture was filtered, and the filter cake was dried at 40 °C to obtain 95.8 g of compound IM4, with a mass yield of 95.8%; Step (5), reduction of carbonyl group at position 21 into methylene: 90 g of compound IM4, 180 g of dimeric ethylene glycol were uniformly mixed, 45 g of potassium hydroxide and 45 g of 85% hydrazine hydrate were added, the mixture was stirred and distilled to heat to 180 °C, the temperature was controlled for reaction for 4 h, the temperature was lowered to 70 °C, 5% hydrochloric acid aqueous solution was added to adjust the pH value to 1, the temperature was controlled at 60 °C for reaction for 6 h, 30% liquid alkali was added to adjust the pH value to 5, the temperature was lowered to 10 °C, 180 g of water was added, the mixture was stirred for 1 h, then the mixture was filtered, and the filter cake was dried at 70 °C to obtain 73.9 g of compound IM5, with a mass yield of 82.1%; Step (6), esterification of carbonyl group at position 3: 70 g of compound IM5, 140 g of dichloromethane, 70 g of acetic anhydride were uniformly mixed, 0.7 g of p-toluene phosphoric acid was added, the temperature was controlled at 50 °C, and the reaction was carried out for 8 h, 105 g of water was added, the mixture was statically placed for 20 min, then the mixture was separated into two layers, the water phase was discarded, the organic phase was concentrated at normal pressure to 40 °C, the mixture was stirred at 10 °C for 1 h, then the mixture was filtered, and the filter cake was dried at 40 °C to obtain 74.2 g of compound IM6, with a mass yield of 106%; Step (7), selective reduction of ester and olefin: 70 g of compound IM6, 35 g of methanol, 280 g of tetrahydrofuran, 35 g of water were mixed uniformly, a 30% sodium hydroxide aqueous solution was added to adjust the pH value to 8, 21 g of sodium borohydride and 1.4 g of cerium chloride heptahydrate were added, the temperature was controlled at 25°C, and the reaction was carried out for 8 h. Acetone was added to make the system non-reducing, and the system was concentrated at normal pressure to 70°C. The temperature was lowered to 10°C, 350 g of dichloromethane and 140 g of water were added, the system was stirred until it was clear, and then it was left to stand for 20 min. The layers were separated, the organic phase was concentrated at normal pressure to 40°C, and the system was stirred at -10°C for 1 h. Filtration was carried out, and the system was dried at 40°C to obtain 55.6 g of cholesterols, with a mass yield of 79.4%. The overall yield of cholesterols prepared from BA was 74.4%. The purity of cholesterols was 99.2%, and the content was 98.7%.
[0022] Example 2 Step (1), 3-ketone protection reaction: 100 g of BA, 300 g of ethylene glycol, 1 g of p-toluenesulfonic acid, and 100 g of triethyl orthoformate were mixed uniformly, the temperature was controlled at 60°C, and the reaction was carried out for 2 h. The temperature was lowered to -10°C, and the temperature was controlled for 5 h. Filtration was carried out, and the system was dried at 70°C to obtain 110 g of compound IM1, with a mass yield of 109%. Step (2), oxidation of the 21-hydroxyl group to an aldehyde: 100 g of compound IM1, 600 g of dichloromethane, and 1 g of 4-hydroxy-TEMPO were mixed uniformly. 50 g of a 2% sodium bicarbonate aqueous solution and 50 g of a 2% sodium bromide aqueous solution were added, the temperature was controlled at -10°C, 200 g of a 13% sodium hypochlorite aqueous solution was added, the temperature was controlled, and the reaction was carried out for 3 h. 50 g of a 10% sodium thiosulfate aqueous solution was added, the system was left to stand for 20 min, the layers were separated, the aqueous phase was discarded, and the organic phase was concentrated at normal pressure to 40°C. The system was stirred at 30°C for 1 h, filtration was carried out, and the system was dried at 70°C to obtain 95.2 g of compound IM2, with a mass yield of 95.2%. Step (3), Grignard reaction of the 21-aldehyde group: 90 g of compound IM2 and 540 g of tetrahydrofuran were mixed uniformly. The temperature was controlled at 45°C, 180 g of a 1.5 mol / L isopentyl magnesium chloride tetrahydrofuran solution was added, the temperature was controlled at 65°C, and the reaction was carried out for 6 h. The temperature was controlled below 30°C, 270 g of a 30% glacial acetic acid aqueous solution was added, the system was left to stand for 20 min, the layers were separated, the aqueous phase was discarded, and the organic phase was concentrated at normal pressure to 68°C. The system was stirred at 10°C for 3 h, filtration was carried out, and the system was dried at 70°C to obtain 97.8 g of compound IM3, with a mass yield of 108.7%. Step (4), oxidation of the hydroxyl group at position 21 to a ketone: 100 g of compound IM3, 600 g of acetone were mixed uniformly, the temperature was controlled at -10°C, 300 g of Jones reagent (preparation method: 40 g of chromium trioxide was dissolved in 200 g of water, the temperature was controlled at 20-30°C, and 80 g of concentrated sulfuric acid was added dropwise) was added, the reaction was carried out for 1 h, 100 g of isopropyl alcohol was added to make the reaction system non-oxidizing, 600 g of water was added to the reaction system, the acetone was concentrated out, the temperature was controlled at -10°C, and stirring was carried out for 1 h, filtration was performed, and drying was carried out at 70°C to obtain 96.0 g of compound IM4, with a mass yield of 96.0%. Step (5), reduction of the carbonyl group at position 21 to a methylene group: 90 g of compound IM4, 540 g of dimeric ethylene glycol were mixed uniformly, 135 g of potassium hydroxide and 135 g of 85% hydrazine hydrate were added, the temperature was increased to 200°C by distillation and stirring, the temperature was controlled for 2 h, the temperature was decreased to 80°C, 5% hydrochloric acid aqueous solution was added to adjust the pH value to 2, the temperature was controlled for 1 h, 30% liquid alkali was added to adjust the pH value to 7, the temperature was decreased to 30°C, 450 g of water was added, stirring was carried out for 1 h, filtration was performed, and drying was carried out at 100°C to obtain 73.2 g of compound IM5, with a mass yield of 81.3%. Step (6), esterification of the carbonyl group at position 3: 70 g of compound IM5, 420 g of dichloromethane and 35 g of acetic anhydride were mixed uniformly, 7 g of p-toluenesulfonic acid was added, the temperature was controlled at 30°C, the reaction was carried out for 3 h, 70 g of water was added, standing was carried out for 20 min, the layers were separated, the organic phase was concentrated at normal pressure to 40°C, stirring was carried out at 10°C for 3 h, filtration was performed, and drying was carried out at 70°C to obtain 73.8 g of compound IM6, with a mass yield of 105.4%. Step (7), selective reduction of the ester and olefin: 70 g of compound M6, 135 g of methanol, 140 g of tetrahydrofuran, 70 g of water were mixed uniformly, 30% sodium hydroxide aqueous solution was added to adjust the pH value to 10, 70 g of sodium borohydride and 7 g of cerium chloride heptahydrate were added, the temperature was controlled at 45°C, the reaction was carried out for 4 h, acetone was added to make the system non-reducing, the system was concentrated at normal pressure to 70°C, the temperature was decreased to 30°C, 700 g of dichloromethane and 280 g of water for layer separation were added, the system was stirred until it was clear, standing was carried out for 20 min, the layers were separated, the water phase was discarded, the organic phase was concentrated at normal pressure to 40°C, stirring was carried out at 10°C for 3 h, filtration was performed, and drying was carried out at 70°C to obtain 56.8 g of cholesterols, with a mass yield of 81.1%. The total mass yield of cholesterols prepared from BA was 75.3%. The purity of cholesterols was 99.1%, and the content was 98.6%.
[0023] Example 3 Step (1), 3-position carbonyl ketal protection reaction: 100 g of BA, 200 g of ethylene glycol, 5 g of p-toluenesulfonic acid, 50 g of triethyl orthoformate were mixed uniformly, controlled at 50°C, reacted for 5 h, cooled to 0°C, controlled at 3 h, filtered, dried at 50°C, to obtain 109.1 g of compound 109.1 g of IM1, mass yield 109.1%; Step (2), oxidation of 21-position hydroxyl to aldehyde: 100 g of compound IM1, 400 g of dichloromethane, 0.6 g of 4-hydroxy-TEMPO were mixed uniformly, 100 g of a 2% mass fraction sodium bicarbonate and 2% mass fraction sodium bromide aqueous solution was added, controlled at 0°C, 350 g of 10% mass fraction sodium hypochlorite aqueous solution was added, controlled at 0°C, reacted for 1 h, 350 g of 10% mass fraction sodium thiosulfate aqueous solution was added, stood for 20 min, separated into layers, the aqueous phase was discarded, the organic phase was concentrated at normal pressure to 40°C, stirred at 20°C for 1 h, filtered, dried at 55°C, to obtain 95.8 g of compound IM2, mass fraction 95.8%; Step (3), Grignard reaction of 21-position aldehyde group: 90 g of compound IM2, 360 g of tetrahydrofuran were mixed uniformly, controlled at 30°C, 450 g of 1.0 mol / L isopentyl magnesium chloride tetrahydrofuran solution was added, controlled at 60°C, reacted for 5 h, controlled at 30°C or below, 180 g of 30% mass fraction glacial acetic acid aqueous solution was added, stood for 20 min, separated into layers, the aqueous phase was discarded, the organic phase was concentrated at normal pressure to 68°C, stirred at 0°C for 2 h, filtered, dried at 50°C, to obtain 96.8 g of compound IM3, mass yield 107.6%; Step (4), oxidation of 21-position hydroxyl to ketone: 100 g of compound IM3, 400 g of acetone were mixed uniformly, controlled at 0°C, Jones reagent (preparation method: 40 g of chromium trioxide was dissolved in 200 g of water, controlled at 20~30°C, 80 g of concentrated sulfuric acid was added dropwise), reacted for 2 h, 60 g of isopropyl alcohol was added to make the reaction system non-oxidizing, 400 g of water was added to the reaction system, the acetone was concentrated, controlled at 20°C, stirred for 1 h, filtered, dried at 50°C, to obtain 96.3 g of compound IM4, mass yield 96.3%; Step (5), reduction of 21-position carbonyl to methylene: 90 g of compound IM4, 360 g of dimeric ethylene glycol were mixed uniformly, 90 g of potassium oxide, 90 g of 85% mass fraction hydrazine hydrate were added, the distillation was stirred and heated to 190°C, controlled at 3 h, cooled to 75°C, 5% mass fraction hydrochloric acid aqueous solution was added to adjust the pH value to 1.5, controlled at 70°C for 4 h, 30% mass fraction liquid alkali was added to adjust the pH value to 6, cooled to 20°C, 270 g of water was added, stirred for 1 h, filtered, dried at 80°C, to obtain 73.6 g of compound IM5, mass yield 81.8%; Step (6), carbonyl group at 3-position esterification: 70 g of compound IM5, 280 g of dichloromethane, 569 g of acetic anhydride were mixed uniformly, 4.20 g of p-toluene phosphoric acid was added, temperature was controlled at 40 °C, reaction was carried out for 5 h, 35 g of water was added, and the mixture was stood for 20 min, then the mixture was separated into two layers, the organic phase was concentrated under normal pressure to 40 °C, the mixture was stirred at 0 °C for 2 h, then the mixture was filtered and dried at 55 °C to obtain 73.8 g of compound IM6, mass yield 105.4%. Step (7), selective reduction of ester and olefin: 70 g of compound IM6, 70 g of methanol, 210 g of tetrahydrofuran, 56 g of water were mixed uniformly, 30% sodium hydroxide aqueous solution was added to adjust pH value to 9, 42 g of sodium borohydride and 4.2 g of cerium chloride heptahydrate were added, temperature was controlled at 30 °C, reaction was carried out for 6 h, acetone was added to make the system non-reducing, the mixture was concentrated under normal pressure to 70 °C, the temperature was lowered to 20 °C, 560 g of dichloromethane and 210 g of water were added, the mixture was stirred until the solution was clear, the mixture was stood for 20 min, then the mixture was separated into two layers, the water phase was discarded, the organic phase was concentrated under normal pressure to 40 °C, the mixture was stirred at 0 °C for 2 h, then the mixture was filtered and dried at 55 °C to obtain 55.5 g of cholesterols, mass yield 79.3%, total yield of cholesterols prepared from BA 74.0%. The purity of cholesterols was 99.4%, and the content was 98.8%.
[0024] For the method embodiments, in order to simply describe, they are all expressed as a series of action combinations, but those skilled in the art should know that the present application is not limited by the action sequence described, because according to the present application, certain steps can be performed in other sequences or simultaneously. Secondly, those skilled in the art should know that the embodiments described in the specification are all preferred embodiments, and the actions and components involved are not necessarily necessary for the present application.
[0025] The above describes in detail the method for preparing cholesterols from bisnor alcohol provided by the present application, the principles and implementation manners of the present application are described by using specific examples, and the above embodiment description is only used to help understand the method of the present application and its core idea; at the same time, for those skilled in the art, according to the idea of the present application, the specific implementation manner and application range will be changed, and according to the above, the content of the specification should not be understood as a limitation of the present application.
Claims
1. A method for preparing cholesterol, characterized in that, The method includes the following steps: S1: 3-position carbonyl ketal protection reaction: BA, ethylene glycol, p-toluenephosphite and triethyl orthoformate were mixed evenly, and the temperature was controlled at 40-60℃ for 2-8 h. The mixture was then cooled to -10-10℃ and the temperature was controlled at 1-5 h. The mixture was filtered and dried at 40-70℃ to obtain compound IM1. S2: Oxidation of 21-hydroxyl group to aldehyde: Compound IM1, dichloromethane, and 4-hydroxy-TEMPO were mixed evenly, and an aqueous solution of sodium bicarbonate (2% by mass) and sodium bromide (2% by mass) was added. The temperature was controlled at -10 to 10℃. An aqueous solution of sodium hypochlorite (8% to 13% by mass) was added, and the reaction was carried out for 1 to 3 hours. An aqueous solution of sodium thiosulfate (10% by mass) was added, and the mixture was allowed to stand for 20 minutes. The layers were separated, the aqueous phase was discarded, and the organic phase was concentrated at atmospheric pressure to 40℃. The mixture was stirred at 10 to 30℃ for 1 hour, filtered, and dried at 40 to 70℃ to obtain compound IM2. S3: Grignard reaction of aldehyde group at position 21: Mix compound IM2 and tetrahydrofuran evenly, control the temperature at 20~45℃, add isopentyl magnesium chloride tetrahydrofuran solution with a molar concentration of 0.5~1.5mol / L, control the temperature at 50~65℃, react for 2~8h, control the temperature below 30℃, add 30% glacial acetic acid aqueous solution, let stand for 20min, separate the layers, discard the aqueous phase, concentrate the organic phase at normal pressure to 68℃, stir at -10~10℃ for 1~3h, filter, dry at 40~70℃ to obtain compound IM3; S4: Oxidation of the 21-hydroxyl group to ketone: Mix compound IM3 and acetone evenly, control the temperature at -10~10℃, add Jones reagent, react for 1~3h, add isopropanol to make the reaction system non-oxidizing, add water to the reaction system, concentrate acetone, control the temperature at 10~30℃, stir for 1h, filter, dry at 40~70℃ to obtain compound IM4. S5: Reduction of the carbonyl group at position 21 to methylene: Compound IM4 and polyethylene glycol are mixed evenly, potassium hydroxide and hydrazine hydrate (85% by mass) are added, the mixture is stirred and distilled, and the temperature is raised to 180-200℃. The reaction is carried out for 2-4 hours under controlled temperature. The temperature is then lowered to 70-80℃, and 5% hydrochloric acid aqueous solution is added to adjust the pH to 1-2. The reaction is carried out for 1-6 hours under controlled temperature of 60-80℃, and 30% liquid alkali is added to adjust the pH to 5-7. The temperature is then lowered to 10-30℃, water is added, the mixture is stirred for 1 hour, filtered, and dried at 70-100℃ to obtain compound IM5. S6: Esterification reaction of carbonyl group at 3-position: Mix compound IM5, dichloromethane and acetic anhydride evenly, add p-toluenephosphoric acid, control the temperature at 30~50℃, react for 3~8h, add water, let stand for 20min, separate into layers, discard the aqueous phase, concentrate the organic phase to 40℃ at normal pressure, stir at -10~10℃ for 1~3h, filter, dry at 40~70℃ to obtain compound IM6; S7: Selective reduction reaction of esters and alkenes: Mix compound IM6, methanol, tetrahydrofuran, and reaction water evenly, add 30% sodium hydroxide aqueous solution to adjust the pH to 8-10, add sodium borohydride and cerium chloride heptahydrate, and react at 25-45℃ for 4-8 hours. Add acetone to make the system non-reducible, concentrate at atmospheric pressure to 70℃, cool to 10-30℃, add dichloromethane and water for layering, stir to dissolve, let stand for 20 minutes, separate into layers, discard the aqueous phase, concentrate the organic phase at atmospheric pressure to 40℃, stir at -10 to 10℃ for 1-3 hours, filter, and dry at 40-70℃ to obtain cholesterol product.
2. The method for preparing cholesterol according to claim 1, characterized in that, In S1: The mass ratio of BA to ethylene glycol is 1:1~3; The mass ratio of BA to p-toluenesulfonic acid is 1:0.01~0.1; The mass ratio of BA to triethyl orthoformate is 1:0.5~1.
5.
3. The method for preparing cholesterol according to claim 1, characterized in that, In S2: The mass ratio of compound IM1 to dichloromethane is 1:2~6; The mass ratio of compound IM1 to 4-hydroxy-TEMPO is 1:0.002~0.01; The mass ratio of the compound IM1 to the aqueous solution containing 2% sodium bicarbonate and 2% sodium bromide is 1:0.5~1.
5. The mass ratio of compound IM1 to the sodium hypochlorite aqueous solution is 1:2~5; The mass ratio of compound IM1 to the mass ratio of the sodium thiosulfate aqueous solution is 1:0.5~1.
5.
4. The method for preparing cholesterol according to claim 1, characterized in that, In S3: The mass ratio of compound IM2 to tetrahydrofuran is 1:2~6; The mass ratio of the compound IM2 to the isopentyl magnesium chloride tetrahydrofuran solution is 1:2~8; The mass ratio of the compound IM2 to the aqueous glacial acetic acid solution is 1:1~3.
5. The method for preparing cholesterol according to claim 1, characterized in that, In step S4, the mass ratio of compound IM3 to acetone is 1:2~6; The preparation method of the Jones reagent is as follows: Dissolve 0.4W chromium trioxide in 2W water, control the temperature at 20~30℃, add 0.8W concentrated sulfuric acid, and mix well; the mass ratio of the compound IM3 to the Jones reagent is 1:1.0~3.0; the mass ratio of the compound IM3 to the isopropanol is 1:0.3~1.0; the mass ratio of the compound IM3 to the water is 1:2~6.
6. The method for preparing cholesterol according to claim 1, characterized in that, In S5: The mass ratio of compound IM4 to polyethylene glycol is 1.2 to 6; The mass ratio of compound IM4 to potassium hydroxide is 1:0.5~1.5; The mass ratio of the compound IM4 to the hydrazine hydrate is 1:0.5~1.5; The mass ratio of the compound IM4 to the water is 1:2.0~5.
0.
7. The method for preparing cholesterol according to claim 1, characterized in that, In S6: The mass ratio of compound IM5 to dichloromethane is 1:2~6; The mass ratio of compound IM5 to acetic anhydride is 1:0.5~1.0; The mass ratio of compound IM5 to p-toluenesulfonic acid is 1:0.01~0.1; The mass ratio of the compound IM5 to the water is 1:0.5~1.
5.
8. The method for preparing cholesterol according to claim 1, characterized in that, In S7: The mass ratio of compound IM6 to methanol is 1:0.5~1.5; The mass ratio of compound IM6 to tetrahydrofuran is 1:2~4; The mass ratio of compound IM6 to the mass of water used in the reaction is 1:0.5~1.0; The mass ratio of compound IM6 to sodium borohydride is 1:0.3~1.0; The mass ratio of compound IM6 to cerium chloride heptahydrate is 1:0.02~0.1; The mass ratio of compound IM6 to dichloromethane is 1:5~10; The mass ratio of the compound IM6 to the mass of the stratified water is 1:2.0~4.0.