CN110938106A - Method for preparing obeticholic acid intermediate and obeticholic acid thereof - Google Patents
Method for preparing obeticholic acid intermediate and obeticholic acid thereof Download PDFInfo
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- CN110938106A CN110938106A CN201911181990.2A CN201911181990A CN110938106A CN 110938106 A CN110938106 A CN 110938106A CN 201911181990 A CN201911181990 A CN 201911181990A CN 110938106 A CN110938106 A CN 110938106A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
Abstract
The invention discloses a method for preparing an obeticholic acid intermediate and obeticholic acid thereof, wherein the obeticholic acid intermediate is prepared by taking 3A-hydroxy-6-vinyl-7-oxo-cholanic acid as a raw material through carbonyl reduction and hydroxy protection, the obtained obeticholic acid intermediate contains two benzene ring structures, has strong ultraviolet absorption, and is convenient for using an ultraviolet detector to carry out quality research, so that the quality of the raw material in the last step is ensured to be controllable, and the raw material is in a solid state at room temperature and can be refined by conventional purification means such as recrystallization and the like; and then, the obeticholic acid is obtained by further using palladium-carbon reduction, and the reduction of an olefinic bond is completed firstly in the palladium-carbon reduction process from the reaction process, so that the tracking reaction is convenient, the reaction yield is high, the conversion is complete, and the refining difficulty of the final product is reduced.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for preparing an obeticholic acid intermediate and obeticholic acid thereof.
Background
Obeticholic acid has attracted considerable attention because of its excellent therapeutic effects on a variety of chronic liver diseases, including Primary Biliary Cirrhosis (PBC), nonalcoholic steatohepatitis (NASH), Primary Sclerosing Cholangitis (PSC), and biliary atresia. The structure is as follows:
in 2002, WO2002072598 discloses a synthetic route of obeticholic acid for the first time, and as shown in the following, a compound II reacts with iodoethane under a strong alkaline condition to obtain a compound III, and then the compound III is subjected to reduction hydrolysis to obtain a target compound I. The synthesis line is simple, but the alkylation directly using iodoethane has more side reactions, and the yield is low, so that the method is not suitable for large-scale production.
WO2006122977 improves the synthesis process, and converts a compound V with trimethylsilyl protecting group into a silyl enol ether compound VI under the strong alkali condition, the compound VI reacts with Mukaiyama aldol between acetaldehyde to obtain a compound VII, the compound VII is subjected to hydrogenation reduction by palladium carbon and then epimerization to obtain a compound VIII, and finally, the compound VIII is subjected to reduction carbonyl to obtain obeticholic acid I. The process route has the defects that the compound VII adopts high temperature (90-105 ℃) and strong base (30% of caustic soda) in the hydrogenation process of palladium carbon, and the safety problem is a great challenge besides side reaction elimination easily occurs.
WO2016045480 takes a compound IX as a raw material, and obtains a target compound I through hydroxyl protection, palladium-carbon hydrogenation, carbonyl reduction and deprotection, thereby avoiding hydrogenation conditions of high temperature and strong base. However, the route adopts an ethyl ester compound as a starting material, which is not beneficial to the initial quality control, and adopts-MOM as a hydroxyl protecting group, and related intermediates mostly exist in an oily form, so that the quality control in the process of scale-up production is difficult to realize.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a method for preparing an obeticholic acid intermediate and obeticholic acid thereof, which is used for preparing obeticholic acid by taking a compound XIII (3A-hydroxy-6-vinyl-7-oxo-cholanic acid) as a raw material through reduction, hydroxy protection and reduction synthesis, and solves the problems of more side reactions, low yield and unsuitability for large-scale production in the conventional production method. The raw materials are white solids, are easy to obtain in the market, are convenient for quality control, have mild reaction and few byproducts, and are suitable for large-scale production of obeticholic acid.
The technical scheme is as follows: the invention relates to a method for preparing an obeticholic acid intermediate, which is shown in a formula XV, and the synthetic route is as follows:
in the formula, Bn is benzyl; the specific reaction conditions are as follows:
and (3) carbonyl reduction reaction: dissolving 3A-hydroxy-6-vinyl-7-oxo-cholanic acid and borohydride shown in a general formula XIII in a polar organic solvent 1, mixing and reacting at the temperature of 10-40 ℃ for 8-16 h, quenching after the reaction is finished, extracting and separating, and concentrating to obtain an intermediate XIV;
hydroxyl protection reaction: dissolving the intermediate XIV in a polar organic solvent 2, mixing and reacting with benzyl halide under an alkaline condition, wherein the reaction temperature is 40-60 ℃, the reaction time is 8-16 h, cooling after the reaction is finished, adding toluene and a 5% acetic acid aqueous solution, stirring for layering, and concentrating to obtain an intermediate XV.
Further, the polar organic solvent 1 is selected from methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or a mixture thereof, and the borohydride salt is selected from potassium borohydride, sodium borohydride or a mixture thereof.
Further, the polar organic solvent 2 is selected from N, N-dimethylformamide, pyridine, methanol, ethanol, tetrahydrofuran or a mixture thereof, and the alkaline substance is selected from one of sodium hydroxide, potassium hydroxide, sodium alkoxide, potassium alkoxide, sodium carbonate, potassium carbonate or ammonium hydroxide.
Further, the amount of the basic substance added under the basic condition is 1 to 3 times of the molar amount of the compound XIV.
The invention also discloses a method for preparing obeticholic acid, which comprises the following synthetic route:
wherein Bn is benzyl, comprising the following steps:
1) reduction reaction of palladium on carbon: dissolving an obeticholic acid intermediate XV in a polar organic solvent 3, reacting at 20-40 ℃ under the relative pressure of 0.5-1.5 MPa by using hydrogen as a hydrogen source and Pd/C as a catalyst under an alkaline condition, and preserving heat for hydrogenation until the hydrogen is not absorbed any more;
2) and (3) collecting obeticholic acid: after the reaction is finished, the obeticholic acid is obtained after separation and purification.
6. The method for preparing obeticholic acid according to claim 5, characterized in that: the obeticholic acid intermediate XV is prepared by the method of any one of claims 1 to 4.
Further, the alkaline substance under alkaline conditions is selected from one of sodium hydroxide, potassium hydroxide, sodium alkoxide, potassium alkoxide, sodium carbonate, potassium carbonate or ammonium hydroxide.
Further, the polar organic solvent 3 is selected from methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or a mixture thereof.
Furthermore, the molar weight of the basic substance compound is 1-3 times of the molar weight of the obeticholic acid intermediate XV.
The invention has the following beneficial effects:
(1) the starting material compound XIII is purchased in the market, and the market can provide a large amount of raw materials with maximum single impurity less than 0.5% and purity more than 98%;
(2) the compound XV contains two benzene ring structures, has strong ultraviolet absorption, is convenient for using an ultraviolet detector to carry out quality research, thereby ensuring that the quality of the raw material in the last step is controllable, is in a solid state at room temperature, and can be refined by conventional purification means such as recrystallization and the like;
(3) and the final step adopts palladium-carbon reduction, the reduction of the olefinic bond is completed firstly in the reaction process, the tracking reaction is convenient, the reaction yield is high, the conversion is complete, and the refining difficulty of the final product is reduced.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further described below with reference to examples:
example 1
Carbonyl reduction reaction
Preparation of Compound XIV
Adding 20ml of ethanol and 4.2g of compound XIII into a 100ml round-bottom flask in sequence, stirring and dissolving the solution, adding 0.95g of sodium borohydride in batches at 10 ℃, reacting for 8 hours fully, adding acetic acid to quench the reaction after the reaction is finished, adding toluene and water, stirring and layering, removing the water phase, washing the organic phase once with 5% acetic acid water solution, drying, and spin-drying to obtain the crude compound XIV which is directly used for the next reaction with the yield of 100%.
Example 2
Hydroxyl radical protection reaction
Preparation of Compound XV
A100 ml round bottom flask was charged with the crude compound XIV prepared in example 1 and completely dissolved in N, N-dimethylformamide, and then 0.46g of potassium carbonate was added, and finally 3.4g of benzyl bromide was added, heated to 40 deg.C, stirred and reacted for 8 hours, cooled after the reaction was completed, and then toluene and a 5% aqueous solution of acetic acid were added, stirred and layered, the aqueous phase was removed, the organic phase was dried and then spun dry, and recrystallized from toluene to obtain 5.5g of intermediate XV refined product, with a yield of 92%.
Example 3
Reduction reaction of palladium on carbon
Preparation of obeticholic acid I
1) Adding 3.0g of compound XV, 50ml of methanol, 0.005g of 10% Pd/C, 0.02g of sodium hydroxide and 100ml of water into a 100ml hydrogenation kettle in sequence, sealing the hydrogenation kettle after the mixture is uniformly stirred, and sequentially using N2And H2Replacing air in the system, controlling the temperature at 20 ℃, controlling the hydrogen pressure at 0.5MPa, and reacting the mixture system for 2 hours under stirring;
2) termination of the reaction, using N in succession2And air displacement system H2；
3) And filtering the mixture to separate Pd/C, removing the solvent by spinning to obtain a crude product of obeticholic acid, and crystallizing and purifying the obeticholic acid by ethyl acetate to obtain a refined product of 1.8g, wherein the yield is 85%.
Example 4
Carbonyl reduction reaction
Preparation of Compound XIV
Adding 20ml of ethanol and 4.2g of compound XIII into a 100ml round-bottom flask in sequence, stirring and dissolving the solution clearly, adding 0.95g of sodium borohydride in batches at 40 ℃, reacting for 16 hours fully, adding acetic acid to quench the reaction after the reaction is finished, adding toluene and water, stirring and layering, removing the water phase, washing the organic phase once with 5% acetic acid water solution, drying, and spin-drying to obtain the crude product of compound XIV which is directly used for the next reaction with the yield of 100%.
Example 5
Hydroxyl radical protection reaction
Preparation of Compound XV
A100 ml round bottom flask was charged with the crude compound XIV prepared in example 1 and completely dissolved in N, N-dimethylformamide, and then 0.46g of potassium carbonate was added, and finally 3.4g of benzyl bromide was added, heated to 60 deg.C, stirred and reacted for 16 hours, cooled after the reaction was completed, and then toluene and a 5% aqueous solution of acetic acid were added, stirred and layered, the aqueous phase was removed, the organic phase was dried and then spun dry, and recrystallized from toluene to obtain 5.5g of intermediate XV refined product, with a yield of 92%.
Example 6
Reduction reaction of palladium on carbon
Preparation of obeticholic acid I
1) Adding 3.0g of compound XV, 50ml of methanol, 0.05g of 10% Pd/C, 0.01g of sodium hydroxide and 100ml of water into a 100ml hydrogenation kettle in sequence, sealing the hydrogenation kettle after the mixture is uniformly stirred, and sequentially using N2And H2Replacing air in the system, controlling the temperature at 40 ℃, controlling the hydrogen pressure at 1.5MPa, and reacting the mixture system for 3 hours under stirring;
2) termination of the reaction, using N in succession2And air displacement system H2；
3) And filtering the mixture to separate Pd/C, removing the solvent by spinning to obtain a crude product of obeticholic acid, and crystallizing and purifying the obeticholic acid by ethyl acetate to obtain a refined product of 1.8g, wherein the yield is 85%.
Example 7
Preparation of obeticholic acid I
1) And (3) carbonyl reduction reaction: adding 20ml of polar organic solvent ethanol and 4.2g of compound XIII into a 100ml round-bottom flask in sequence, stirring and dissolving the solution clearly, adding 0.95g of sodium borohydride in batches at 30 ℃, fully reacting for 12 hours, adding acetic acid to quench the reaction after the reaction is finished, adding toluene and water, stirring and layering to remove the water phase, washing the organic phase once with 5% acetic acid water solution, drying, and spin-drying to obtain the crude compound XIV which is directly used for the next reaction with the yield of 100%.
Experiments show that the polar organic solvent is methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or a mixture thereof, and has no fundamental influence on the reaction result; the borohydride is potassium borohydride, sodium borohydride or a mixture thereof, and has no fundamental influence on the reaction result;
2) hydroxyl protection reaction: adding the crude compound XIV prepared in the step 1) into a 100ml round-bottom flask, completely dissolving the crude compound XIV into a polar organic solvent N, N-dimethylformamide, adding 0.46g of alkaline substance potassium carbonate, finally adding 3.4g of benzyl bromide, heating to 50 ℃, stirring for reaction for 12 hours, cooling after the reaction is finished, adding toluene and a 5% acetic acid aqueous solution, stirring for layering, removing an aqueous phase, drying an organic phase in a spinning mode after drying, recrystallizing with toluene to obtain 5.5g of an intermediate XV refined product, wherein the yield is 92%;
experiments show that the polar organic solvent is N, N-dimethylformamide, pyridine, methanol, ethanol, tetrahydrofuran or a mixture thereof, and has no obvious influence on experimental results; the alkaline substance is selected from one of sodium hydroxide, potassium hydroxide, sodium alkoxide, potassium alkoxide, sodium carbonate, potassium carbonate or ammonium hydroxide, and has no fundamental influence on the reaction result;
3) reduction reaction of palladium on carbon: adding 3.0g of compound XV, 50ml of polar organic solvent methanol, 0.015g of 10% Pd/C, 0.02g of sodium hydroxide and 50ml of water into a 500ml hydrogenation kettle in sequence, sealing the hydrogenation kettle after the mixture is uniformly stirred, and sequentially using N2And H2Replacing air in the system, controlling the temperature at 30 ℃ and the hydrogen pressure at 1.0MPa, reacting the mixture system for 2 hours under stirring, terminating the reaction, and sequentially using N2And air displacement system H2Filtering the obtained mixture to separate Pd/C, removing the solvent by spinning to obtain a crude product of obeticholic acid, and crystallizing and purifying the obeticholic acid by ethyl acetate to obtain a refined product of 1.8g with the yield of 85%;
experiments show that the polar organic solvent is selected from alcohol, ethanol, n-propanol, isopropanol, tetrahydrofuran or a mixture thereof, and has no obvious influence on experimental results; the alkaline substance is selected from one of sodium hydroxide, potassium hydroxide, sodium alkoxide, potassium alkoxide, sodium carbonate, potassium carbonate or ammonium hydroxide, and has no fundamental influence on the reaction result.
Claims (9)
1. A method of preparing an obeticholic acid intermediate, characterized by: the structural general formula of the intermediate is shown as formula XV, and the synthetic route is as follows:
in the formula, Bn is benzyl; the specific reaction conditions are as follows:
and (3) carbonyl reduction reaction: dissolving 3A-hydroxy-6-vinyl-7-oxo-cholanic acid and borohydride shown in a general formula XIII in a polar organic solvent 1, mixing and reacting at the temperature of 10-40 ℃ for 8-16 h, quenching after the reaction is finished, extracting and separating, and concentrating to obtain an intermediate XIV;
hydroxyl protection reaction: dissolving the intermediate XIV in a polar organic solvent 2, mixing and reacting with benzyl halide under an alkaline condition, wherein the reaction temperature is 40-60 ℃, the reaction time is 8-16 h, cooling after the reaction is finished, adding toluene and a 5% acetic acid aqueous solution, stirring for layering, and concentrating to obtain an intermediate XV.
2. The method for preparing obeticholic acid intermediate according to claim 1, characterized in that: the polar organic solvent 1 is selected from methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or a mixture thereof, and the borohydride salt is selected from potassium borohydride, sodium borohydride or a mixture thereof.
3. The method for preparing obeticholic acid intermediate according to claim 1, characterized in that: the polar organic solvent 2 is selected from N, N-dimethylformamide, pyridine, methanol, ethanol, tetrahydrofuran or a mixture thereof, and the alkaline substance is selected from one of sodium hydroxide, potassium hydroxide, sodium alkoxide, potassium alkoxide, sodium carbonate, potassium carbonate or ammonium hydroxide.
4. The method for preparing obeticholic acid intermediate according to claim 1, characterized in that: the addition amount of the alkaline substance under the alkaline condition is 1-3 times of the molar weight of the compound XIV.
5. The method for preparing obeticholic acid is characterized in that the synthetic route is as follows:
wherein Bn is benzyl, comprising the following steps:
1) reduction reaction of palladium on carbon: dissolving an obeticholic acid intermediate XV in a polar organic solvent 3, reacting at 20-40 ℃ under the relative pressure of 0.5-1.5 MPa by using hydrogen as a hydrogen source and Pd/C as a catalyst under an alkaline condition, and preserving heat for hydrogenation until the hydrogen is not absorbed any more;
2) and (3) collecting obeticholic acid: after the reaction is finished, the obeticholic acid is obtained after separation and purification.
6. The method for preparing obeticholic acid according to claim 5, characterized in that: the obeticholic acid intermediate XV is prepared by the method of any one of claims 1 to 4.
7. The method for preparing obeticholic acid according to claim 5, characterized in that: the alkaline substance under the alkaline condition is selected from one of sodium hydroxide, potassium hydroxide, sodium alkoxide, potassium alkoxide, sodium carbonate, potassium carbonate or ammonium hydroxide.
8. The method for preparing obeticholic acid according to claim 5, characterized in that: the polar organic solvent 3 is selected from methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or a mixture thereof.
9. The method for preparing obeticholic acid according to claim 7, characterized in that: the molar weight of the basic substance compound is 1-3 times of the molar weight of the intermediate XV of the obeticholic acid.
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| WO2021109883A1 (en) * | 2019-12-04 | 2021-06-10 | 博瑞生物医药（苏州）股份有限公司 | Method for use in preparing obeticholic acid |
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