CN-115246867-B - Method for synthesizing 7-ketolithocholic acid by taking BA as raw material

Abstract

The invention discloses a chemical synthesis method of 7-ketolithocholic acid (3 alpha-hydroxy-7-ketone-5 beta-cholestane-24-acid), belonging to the field of organic chemical synthesis. The 7-ketolithocholic acid is synthesized by taking a plant source compound BA as a raw material through the steps of glycol or neopentyl glycol protection, oxidation, wittig reaction, deprotection, reduction, hydrolysis and the like. The raw materials used for synthesizing the 7-ketolithocholic acid are cheap and easy to obtain, the synthetic steps are simple and convenient to operate, the yield is high, the environment is friendly, and the industrial production is convenient.

Inventors

• QIU WENWEI
• LI CHENCHEN
• GU XIANGZHONG
• JIANG CHENGYU
• WU SHULAN
• Ye Rufei

Assignees

• 江苏佳尔科药业集团股份有限公司
• 华东师范大学

Dates

Publication Date

20260512

Application Date

20210427

Claims (16)

1. 1. A method for synthesizing 7-ketolithocholic acid by taking BA as a raw material, which is characterized by comprising the following steps: (a) In a first solvent, protecting BA shown in the formula (1) by ethylene glycol to obtain a compound shown in the formula (2); (b) In a second solvent, carrying out oxidation reaction on the compound of the formula (2) to obtain a compound of the formula (3); (c) In a third solvent, carrying out Wittig reaction on the compound of the formula (3) to obtain a compound of the formula (6); (d) In a fourth solvent, carrying out an oxidation reaction on a compound of the formula (6) to obtain a compound of the formula (7), wherein the oxidation reaction is carried out by dissolving the compound of the formula (6), an oxidant, N-hydroxyphthalimide and acetic acid in the fourth solvent to obtain the compound of the formula (7), the molar ratio of the compound of the formula (6), the oxidant, the N-hydroxyphthalimide and the acetic acid is 1 (1-5): 0-5, wherein the oxidant is one or more selected from Na 2 Cr 2 O 7 、K 2 Cr 2 O 7 , PDC and BPO, the fourth solvent is one or more selected from toluene, acetone, acetonitrile, water, dichloromethane, N-dimethylformamide, ethyl acetate, tertiary butyl alcohol and N-methylpyrrolidone, the temperature of the oxidation reaction is 0-50 ℃, and/or the time of the oxidation reaction is 10-48 h; (e) In a fifth solvent, carrying out glycol removal protection reaction on the compound of the formula (7) under the action of acid to obtain a compound of the formula (8); (f) In a sixth solvent, under the action of a catalyst and hydrogen, carrying out reduction reaction on a compound of a formula (8) under the condition of pressurization to obtain a compound of a formula (9), wherein the catalyst is selected from Raney nickel, the mass ratio of the compound of the formula (8) to the catalyst is 1 (0.1-5), the sixth solvent is selected from one or more of 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol and tert-butanol, the temperature of the reduction reaction is 20-100 ℃, the time of the reduction reaction is 3-24 h, the reaction is carried out under the condition of hydrogen pressurization, and the pressure range of the hydrogen is 0.1-10 MPa; (g) In a seventh solvent, under the action of alkali, carrying out hydrolysis reaction on the compound shown in the formula (9) to obtain 7-ketolithocholic acid shown in the formula (10); Wherein the reaction process of the method is shown in a route (A): Route (A).
2. 2. A method for synthesizing 7-ketolithocholic acid by taking BA as a raw material, which is characterized by comprising the following steps: (h) In an eighth solvent, performing oxidation reaction on BA shown in the formula (1) to obtain a compound shown in the formula (4); (i) In a ninth solvent, carrying out Wittig reaction on the compound of the formula (4) to obtain a compound of the formula (5); (j) In a tenth solvent, protecting the compound of the formula (5) by ethylene glycol or neopentyl glycol to obtain a compound of the formula (6); (d) In a fourth solvent, carrying out an oxidation reaction on a compound of the formula (6) to obtain a compound of the formula (7), wherein the oxidation reaction is carried out by dissolving the compound of the formula (6), an oxidant, N-hydroxyphthalimide and acetic acid in the fourth solvent to obtain the compound of the formula (7), the molar ratio of the compound of the formula (6), the oxidant, the N-hydroxyphthalimide and the acetic acid is 1 (1-5): 0-5, wherein the oxidant is one or more selected from Na 2 Cr 2 O 7 、K 2 Cr 2 O 7 , PDC and BPO, the fourth solvent is one or more selected from toluene, acetone, acetonitrile, water, dichloromethane, N-dimethylformamide, ethyl acetate, tertiary butyl alcohol and N-methylpyrrolidone, and/or the temperature of the oxidation reaction is 0-50 ℃, and the time of the oxidation reaction is 10-48 h; (e) In a fifth solvent, carrying out glycol or neopentyl glycol protection reaction on the compound of the formula (7) under the action of acid to obtain a compound of the formula (8); (f) In a sixth solvent, under the action of a catalyst and hydrogen, carrying out a reduction reaction on a compound of a formula (8) under the condition of pressurization to obtain a compound of a formula (9), wherein the catalyst is selected from Raney nickel, the mass ratio of the compound of the formula (8) to the catalyst is 1 (0.1-5), the sixth solvent is selected from one or more of 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol and tert-butanol, the temperature of the reduction reaction is 20-100 ℃, the time of the reduction reaction is 3-24 h, the reaction is carried out under the condition of hydrogen pressurization, and the pressure range of the hydrogen is 0.1-10 MPa; (g) In a seventh solvent, under the action of alkali, carrying out hydrolysis reaction on the compound shown in the formula (9) to obtain 7-ketolithocholic acid shown in the formula (10); wherein the reaction process of the method is shown in a route (B): ; Route (B).
3. 3. The method of claim 1, wherein R is a C1 to C20 alkyl group.
4. 4. The method of claim 1, wherein in the step (a), the ethylene glycol protection reaction is that BA, ethylene glycol and p-toluenesulfonic acid shown in the formula (1) are dissolved in a first solvent to generate an ethylene glycol protection reaction to obtain a compound shown in the formula (2), wherein the molar ratio of BA, ethylene glycol and p-toluenesulfonic acid shown in the formula (1) is 1 to 50 (0.01 to 1), and/or the first solvent is one or more selected from benzene, toluene, ethyl acetate, tetrahydrofuran and hexane, and/or the temperature of the ethylene glycol protection reaction is 50 to 130 ℃, and/or the time of the ethylene glycol protection reaction is 2 to 36 h.
5. 5. The method of claim 1, wherein in the step (a), the ethylene glycol protection reaction is that BA, ethylene glycol, paratoluenesulfonic acid and triethyl orthoformate shown in the formula (1) are dissolved in a first solvent to generate an ethylene glycol protection reaction to obtain a compound shown in the formula (2), wherein the molar ratio of BA, ethylene glycol, paratoluenesulfonic acid and triethyl orthoformate shown in the formula (1) is 1 (1-50) and 0.01-1 and 1-20, and/or the first solvent is one or more selected from benzene, toluene, ethyl acetate, tetrahydrofuran and hexane, and/or the temperature of the ethylene glycol protection reaction is 0-50 ℃, and/or the time of the ethylene glycol protection reaction is 2-36 h.
6. 6. The method of claim 1, wherein in the step (b), the oxidation reaction is carried out by dissolving the compound of formula (2), TEMPO, sodium bicarbonate, tetrabutylammonium bromide and an oxidant in a second solvent to obtain the compound of formula (3), wherein the molar ratio of the compound of formula (2), TEMPO, sodium bicarbonate, tetrabutylammonium bromide and the oxidant is 1 (0-1) to (0-20) to (0-1) to (1-5), and/or the oxidation reaction is carried out under the action of the oxidant, wherein the oxidant is one or more selected from N-chlorosuccinimide, N-bromosuccinimide and 2-iodoxybenzoic acid, and/or the second solvent is one or more selected from dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide and water, and/or the oxidation reaction is carried out at a temperature of 0-30 ℃ for 2-8 h.
7. 7. The method of claim 1, wherein in the step (C), the Wittig reaction is that the compound of formula (3) and the ethoxyformylmethylene triphenylphosphine are dissolved in a third solvent to generate Wittig reaction to obtain the compound of formula (6), wherein the molar ratio of the compound of formula (3) to the ethoxyformylmethylene triphenylphosphine is 1 (1-5), and/or the third solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran and hexane, and/or the temperature of the Wittig reaction is 50-130 ℃, and/or the time of the Wittig reaction is 2-8 h.
8. 8. The method of claim 1, wherein in the step (C), the Wittig reaction is that the compound of formula (3), sodium hydride and triethyl phosphonoacetate are dissolved in a third solvent to generate Wittig reaction, so as to obtain the compound of formula (6), wherein the molar ratio of the compound of formula (3), sodium hydride and triethyl phosphonoacetate is 1 to 5 (1 to 5), and/or the third solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran and hexane, and/or the temperature of the Wittig reaction is 0 to 30 ℃, and/or the time of the Wittig reaction is 2 to 8 h.
9. 9. A process according to claim 2, wherein in step (h), the oxidation reaction is carried out by dissolving BA, TEMPO, sodium bicarbonate, tetrabutylammonium bromide and an oxidant shown in formula (1) in an eighth solvent to obtain a compound shown in formula (4), wherein the molar ratio of BA, TEMPO, sodium bicarbonate, tetrabutylammonium bromide and the oxidant shown in formula (1) is 1 (0-1) to (0-20) to (0-1) to (1-5), and/or the oxidation reaction is carried out under the action of the oxidant, wherein the oxidant is one or more selected from N-chlorosuccinimide, N-bromosuccinimide and 2-iodoxybenzoic acid, and/or the eighth solvent is one or more selected from dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide and water, and/or the oxidation reaction is carried out at a temperature of 0-30 ℃ for 2-8 h.
10. 10. The method according to claim 2, wherein in the step (i), the Wittig reaction is that the compound of formula (4), the methoxyformylmethylene triphenylphosphine or the ethoxyformylmethylene triphenylphosphine or the propoxyformylmethylene triphenylphosphine is dissolved in a ninth solvent to generate a Wittig reaction to obtain the compound of formula (5), wherein the molar ratio of the compound of formula (4), the methoxyformylmethylene triphenylphosphine or the ethoxyformylmethylene triphenylphosphine or the propoxyformylmethylene triphenylphosphine is 1 (1-5), and/or the ninth solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran and hexane, and/or the temperature of the Wittig reaction is 50-130 ℃, and/or the time of the Wittig reaction is 2-8 h.
11. 11. The method of claim 2, wherein in the step (i), the Wittig reaction is that the compound of formula (4), sodium hydride, methyl phosphonoacetate diethyl ester or triethyl phosphonoacetate or propyl phosphonoacetate diethyl ester is dissolved in a ninth solvent to generate the Wittig reaction to obtain the compound of formula (5), wherein the ninth solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran and hexane, and/or the molar ratio of the compound of formula (4), sodium hydride, methyl phosphonoacetate diethyl ester or triethyl phosphonoacetate or propyl phosphonoacetate diethyl ester is 1 (1-5), and/or the temperature of the Wittig reaction is 0-30 ℃ and/or the time of the Wittig reaction is 2-8 h.
12. 12. The method of claim 2, wherein in the step (j), the ethylene glycol or neopentyl glycol protection reaction refers to the dissolution of the compound of formula (5), ethylene glycol or neopentyl glycol and paratoluenesulfonic acid in a tenth solvent, and the ethylene glycol or neopentyl glycol protection reaction is carried out to obtain the compound of formula (6), wherein the molar ratio of the compound of formula (5), ethylene glycol or neopentyl glycol and paratoluenesulfonic acid is 1 (1-50): 0.01-1, and/or the tenth solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran and hexane, and/or the temperature of the ethylene glycol or neopentyl glycol protection reaction is 50-130 ℃, and/or the time of the ethylene glycol or neopentyl glycol protection reaction is 2-36 h.
13. 13. The method of claim 2, wherein in the step (j), the ethylene glycol or neopentyl glycol protection reaction refers to the dissolution of the compound of formula (5), ethylene glycol or neopentyl glycol, paratoluenesulfonic acid and triethyl orthoformate in a tenth solvent to generate an ethylene glycol protection reaction to obtain the compound of formula (6), wherein the molar ratio of the compound of formula (5), ethylene glycol or neopentyl glycol, paratoluenesulfonic acid and triethyl orthoformate is 1 (1-50): 0.01-1): 1-20, and/or the tenth solvent is one or more selected from benzene, toluene, ethyl acetate, tetrahydrofuran and hexane, and/or the temperature of the ethylene glycol or neopentyl glycol protection reaction is 0-50 ℃, and/or the time of the ethylene glycol or neopentyl glycol protection reaction is 2-36 h.
14. 14. The method of claim 1, wherein in the step (e), the de-glycol protection reaction is that the compound of formula (7) and acid are dissolved in a fifth solvent to generate the de-glycol protection reaction to obtain the compound of formula (8), wherein the molar ratio of the compound of formula (7) and the acid is 1 (1-50), and/or the fifth solvent is one or more selected from tetrahydrofuran, ethyl acetate, methanol, dichloromethane, diethyl ether, water, toluene and acetone, and/or the acid is one or more selected from concentrated sulfuric acid, concentrated hydrochloric acid and p-toluenesulfonic acid, and/or the temperature of the de-glycol protection reaction is 0-50 ℃, and/or the time of the de-glycol protection reaction is 1-10 h.
15. 15. The method of claim 2, wherein in the step (e), the de-ethylene glycol or neopentyl glycol protection reaction refers to that the compound of formula (7) and acid are dissolved in a fifth solvent, the de-ethylene glycol or neopentyl glycol protection reaction is carried out, the compound of formula (8) is obtained, the molar ratio of the compound of formula (7) and the acid is 1 (1-50), and/or the fifth solvent is one or more selected from tetrahydrofuran, ethyl acetate, methanol, methylene dichloride, diethyl ether, water, toluene and acetone, and/or the acid is one or more selected from concentrated sulfuric acid, concentrated hydrochloric acid and p-toluenesulfonic acid, and/or the temperature of the de-ethylene glycol or neopentyl glycol protection reaction is 0-50 ℃, and/or the time of the de-ethylene glycol or neopentyl glycol protection reaction is 1-10 h.
16. 16. The method according to claim 1 or 2, wherein in the step (g), the molar ratio of the compound of formula (9) to the base is 1 (1-5), and/or the seventh solvent is selected from one or more of 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, tert-butanol, methanol and ethanol, and/or the base is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide and lithium hydroxide, and/or the temperature of the hydrolysis reaction is 20-80 ℃, and/or the time of the hydrolysis reaction is 3-24 h.

Description

Method for synthesizing 7-ketolithocholic acid by taking BA as raw material Technical Field The invention belongs to the technical field of organic chemical synthesis/drug synthesis, relates to a method for synthesizing 7-ketolithocholic acid, and in particular relates to a method for synthesizing 7-ketolithocholic acid by taking 21-hydroxy-20-methyl pregna-4-ene-3-one (BA) as a raw material. Background Obeticholic acid (trade name Ocaliva) is a potent agonist of farnesol receptor X (FarnesoidX receptor, FXR) developed by intelcet pharmaceutical company in the united states, and is used to treat primary biliary cirrhosis. In addition, obeticholic acid is also a candidate for the treatment of non-alcoholic steatohepatitis (NASH), currently in phase III clinical trials. Ursodeoxycholic acid (Ursodeoxycholic acid, UDCA) is a first-line therapeutic drug of Primary Biliary Cirrhosis (PBC) approved by the FDA in the United states, can also effectively treat gall-stone diseases and chronic liver diseases clinically, and has wide market prospect. 7-Ketolithocholic acid is an important intermediate for chemical synthesis of obeticholic acid and ursodeoxycholic acid. Therefore, it is important to develop a synthetic route of 7-ketolithocholic acid which is environment-friendly, high in yield, low in cost and suitable for industrialization. The synthesis of 7-ketolithocholic acid has two main methods: One is to prepare 7-ketolithocholic acid (CN 1912192A, J.Chinese medicine industry, 2015,46 (10): 1058-1059, etc.) by electrolysis or oxidation using chenodeoxycholic acid as raw material. However, the product needs column chromatography purification, which is not suitable for industrial production; The chemical synthesis method using cholic acid as raw material mainly includes the following synthetic routes. The first route is to selectively protect 3 alpha-hydroxyl by reaction of cholic acid with chloroformylethyl ester, NBS selectively oxidizes 7 alpha-hydroxyl, then dehydrates 12 alpha-hydroxyl with phosphorus oxychloride, hydrolyzes sodium hydroxide, and hydrogenates and reduces unsaturated double bonds with platinum dioxide to obtain 7-ketolithocholic acid (Journal of Labelled Compounds and Radiopharmaceuticals,1979,16 (3): 421-434.). The method needs dangerous and expensive reagent (such as POCl 3、PtO2) in the process of preparing the 7-ketolithocholic acid, has long reaction time and low yield (26 percent), is not suitable for mass production, and has the following reaction formula: In the second route, after the cholic acid is subjected to methyl esterification, 3 alpha-hydroxyl and 7 alpha-hydroxyl are subjected to acetylation protection, sodium hypochlorite oxidizes 12 alpha-hydroxyl, yellow crotyl reduces C-12 carbonyl, the ester group of C-24 is hydrolyzed, and sodium hypobromite oxidizes C-7 hydroxyl into ketone to obtain 7-ketolithocholic acid (WO 2014020024A 1). The method needs a high-temperature yellow cron reaction in the process of preparing the 7-ketolithocholic acid, has higher requirements on equipment and low yield (58.94 percent), is not suitable for mass production, and has the following reaction formula: The currently reported 7-ketolithocholic acid synthesis routes have the problems of excessively complicated steps, low yield, large pollution, expensive raw materials and the like, and the existing 7-ketolithocholic acid synthesis routes reported above all use animal cholic acid substances (chenodeoxycholic acid, cholic acid) as starting raw materials, but because diseases such as avian influenza, mad cow disease, swine streptococcosis, african swine fever and the like occur, people doubt the safety of animal-derived raw materials, so that the development of a plant-derived raw material-based efficient 7-ketolithocholic acid synthesis method has important significance and industrial value. Disclosure of Invention The invention overcomes the defects of the prior art, and takes 21-hydroxy-20-methyl pregna-4-en-3-one ((20S) -21-hydroxy-20-methylpregn-4-en-3-one) which is also called BA (bisnoralcohol) as a raw material and is obtained by biological fermentation of plant sterol, and the 7-ketolithocholic acid is synthesized through the steps of glycol or neopentyl glycol protection, oxidation, wittig reaction, deprotection, reduction and the like. The method for efficiently and simply chemically synthesizing the 7-ketolithocholic acid provided by the invention has the advantages of low price and easiness in obtaining the plant source raw material BA, high safety, mild reaction conditions, simple and convenient post-treatment, low production cost and convenience in industrial production. The raw material 21-hydroxy-20-methyl pregna-4-en-3-one ((20S) -21-hydroxy-20-methylpregn-4-en-3-one) is also called BA (bisnoralcohol) from fermentation of grease process offcut phytosterol, is a green raw material of plant source, has the annual output of kiloton, has low price, well avoids the infection problem o