CN115385976A - Method for synthesizing obeticholic acid - Google Patents
Method for synthesizing obeticholic acid Download PDFInfo
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- CN115385976A CN115385976A CN202210992203.8A CN202210992203A CN115385976A CN 115385976 A CN115385976 A CN 115385976A CN 202210992203 A CN202210992203 A CN 202210992203A CN 115385976 A CN115385976 A CN 115385976A
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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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a method for synthesizing obeticholic acid, which specifically comprises the following steps: the method is characterized in that 3 alpha-hydroxy-7-oxo-5 beta-cholanic acid (II) is used as an initial raw material, a formula (III) is obtained through a ring closing reaction and hydroxy protection, the formula (III) reacts with ethyl acetate under an alkaline condition to obtain a formula (IV), the formula (IV) is acetylated to obtain a formula (V), and the formula (V) is reduced and deprotected to obtain the obenzoic acid (I).
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals and medicines, in particular to a method for synthesizing obeticholic acid.
Background
Obeticholic Acid (product name Ocaliva) is a new generation of Primary Biliary Cirrhosis (PBC) treatment drug developed by Intercept pharmaceutical, inc., which was approved by FDA in the United states and marketed earlier than 27.5.2016 and approved by the European Union at 12.12.2016, and is a globalized drug for treating Primary Biliary Cirrhosis (PBC), which was the first drug approved for PBC treatment in the last 20 years.
Obeticholic acid is an orally bioavailable semi-synthetic bile acid derivative and an agonist of the nuclear bile acid receptor Farnesoid X Receptor (FXR), and can be used to reduce liver exposure to bile acids. After oral administration, obeticholic acid targets and binds to FXR expressed in the liver and intestinal tract, activating FXR-mediated bile acids, inflammation, fibrosis, and metabolic pathways. This inhibits the production of bile acids in the hepatocytes, increases the transport of bile acids from the hepatocytes, and thereby reduces exposure of the liver to bile acids. FXR plays an important role in bile acid balance and is involved in liver and intestinal inflammation and liver fibrosis. Obeticholic acid has the following structural formula:
the currently predominant synthetic route for obeticholic acid is based on the following route:
the method uses trimethylsilyl protective group hydroxyl, converts ketone into enol silyl ether under the strong alkali condition, reacts with acetaldehyde under the action of boron trifluoride diethyl etherate, reduces olefinic bond through palladium-carbon hydrogenation, and finally reduces carbonyl through sodium borohydride and simultaneously carries out epimerization to obtain obeticholic acid I. The process route has the defects that the stability of the trimethylsilyl protecting group is poor, the trimethylsilyl protecting group is easy to remove in the reaction process, and meanwhile, anhydrous acetaldehyde is required for the reaction with acetaldehyde, is volatile and has strong irritation, and is inconvenient to use.
Disclosure of Invention
The invention provides a method for synthesizing obeticholic acid, which takes 3 alpha-hydroxy-7-oxo-5 beta-cholanic acid (II) as an initial raw material, and obtains a formula (III) through ring closing reaction and hydroxy protection, the formula (III) reacts with ethyl acetate under an alkaline condition to obtain a formula (IV), the formula (IV) is acetylated to obtain a formula (V), and the formula (V) is reduced and deprotected to obtain the obeticholic acid (I).
The specific synthetic route of the invention is summarized as follows:
in order to achieve the purpose, the invention provides the following technical scheme, and the method for synthesizing obeticholic acid specifically comprises the following steps:
1) Preparation of formula (III)
Wherein:
r is hydrogen, methyl, ethyl, propyl, isopropyl or tert-butyl;
g is benzyl, p-methoxybenzyl
Adding 3 alpha-hydroxy-7-oxo-5 beta-cholanic acid (II) into a proper solvent, adding amino alcohol with proper equivalent, reacting completely at a proper temperature, performing proper post-treatment, adding sodium hydrogen and benzyl halide or substituted benzyl halide with proper equivalent, reacting completely, and performing proper post-treatment to obtain a compound shown in a formula (III); wherein:
the initial raw material is 3 alpha-hydroxy-7-oxo-5 beta-cholanic acid (II); suitable solvents are toluene, xylene, preferably toluene, xylene; the amino alcohol is ethanolamine, 2-aminopropanol, 2-aminobutanol, 2-aminopentanol, 2-amino-3-methylbutanol, 2-amino-3,3-dimethylbutanol, preferably ethanolamine, 2-aminopropanol, 2-aminobutanol, 2-amino-3-methylbutanol, 2-amino-3,3-dimethylbutanol; the molar ratio of formula (II) to aminoalcohol is 1:1 to 1:1.2, preferably 1:1. 05 to 1:1.1; the molar ratio of formula (II) to sodium hydrogen is 1:1 to 1:1.2, preferably 1:1.1 to 1:1.2; the molar ratio of formula (ii) to benzyl halide or substituted benzyl halide is 1:1 to 1:1.2, preferably 1: 1.1-1: 1.2;
2) Preparation of formula (IV)
Dispersing the formula (III) and ethyl acetate into a proper solvent, adding a proper equivalent of sodium alkoxide, stirring at a proper temperature to react completely, and performing proper post-treatment to obtain a formula (IV); wherein:
suitable solvents are toluene, DMSO, DMF or mixtures thereof, preferably toluene, DMSO, DMF or mixtures thereof; the base is sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, preferably sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the molar ratio of formula (iii) to base is 1:1 to 1:6, preferably 1: 1.5-1: 4
3) Preparation of formulae (V) and (VI)
Adding the formula (IV) into a proper solvent, adding equivalent alkali and an acetylation reagent, stirring to react completely, and carrying out proper post-treatment to obtain a formula (V) and a formula (VI); wherein:
suitable solvents are tetrahydrofuran, 2-methyltetrahydrofuran, preferably tetrahydrofuran, 2-methyltetrahydrofuran; the base is pyridine, 2-methylpyridine, 2,6-dimethylpyridine, triethylamine, diisopropylethylamine and DBU, and is preferably pyridine, 2-methylpyridine, 2,6-dimethylpyridine, diisopropylethylamine and DBU; the acetylating agent is acetic anhydride or acetyl chloride, preferably acetic anhydride or acetyl chloride.
4) Synthesis of obeticholic acid form (I)
Adding a formula (V) and a formula (VI) into a proper solvent, adding alkali after hydrogen is reduced for a period of time under the action of a metal catalyst, continuously stirring for completely reacting, and carrying out proper post-treatment to obtain the obenzoic acid (I), wherein:
suitable solvents are methanol, ethanol, preferably methanol, ethanol; the metal catalyst is Pd/C or RanneyNi, preferably RanneyNi; the alkali is sodium hydroxide or potassium hydroxide, preferably sodium hydroxide or potassium hydroxide.
Detailed description of the preferred embodiments
The present invention will be further described by the following examples, however, the present invention is not limited to the following examples, which do not limit the scope of the present invention in any way. Certain changes and modifications within the scope of the claims, which may be made by one skilled in the art, are also considered to be within the scope of the invention.
The present invention will be described in more detail below by way of examples.
EXAMPLE 1 preparation of Obeticholic acid from 3 alpha-hydroxy-7-oxo-5 beta-cholanic acid
The method comprises the following steps: preparation of the formula III-a
10kg of 3 alpha-hydroxy-7-oxo-5 beta-cholanic acid 2.12kg of 2-aminopropanol catalytic amount of boric acid and phenylboronic acid are added into 80L of toluene, water is separated by heating until the reaction is completed, the mixture is washed to be neutral, water is continuously separated from an organic layer, the water content is controlled to be less than 0.5 percent, the temperature is reduced to 0-10 ℃, 1.7kg of 40 percent sodium hydrogen is added in batches, after the uniform stirring, 3.6kg of benzyl chloride is added, after the completion of the reaction, the temperature is raised to room temperature, the mixture is stirred until the reaction is completed, and after extraction and concentration, 12.07kg of formula III-a is obtained, the yield is 90.7 percent, and the purity is 98.5 percent.
2) Preparation of formula IV-a
3.6kg of sodium methoxide is added into the mixed solution of 10kg of the compound III-a, 80L of toluene, 20L of ethyl acetate and 10L of MSO in batches, then the reaction solution is heated to 45-55 ℃, stirred and reacted completely, and after acid-base washing, the organic layer is concentrated to obtain 9.53kg of IV-a with the yield of 88.2 percent.
3) Preparation of formula V-a and formula VI-a
Adding 5kg of IV-a into 4L of mixed solution of acetic anhydride, 2L of pyridine and 4L of 2-methyltetrahydrofuran, heating to 50-60 ℃, stirring to react completely, adding water for layering, and concentrating an organic layer to obtain 5.24kg of a mixture of V-a and a formula VI-a (5:1), wherein the yield is 97.5%.
4) Synthesis of obeticholic acid
Adding 5kg of a mixture of V-a and a formula VI-a (5:1) into 20L of methanol, adding 6kg of RanneyNi, replacing with argon for three times, replacing with hydrogen for three times, then increasing the pressure, stirring, reacting for 2-4 hours, then pressing 10L of 10% potassium hydroxide methanol solution, continuing to hydrogenate until the reaction is finished, filtering, concentrating, recrystallizing the crude product to obtain 3.07kg of obeticholic acid, wherein the yield is 82.1%, the chemical purity is 99.4%, and the optical purity is 99.1%. 1 HNMR(600MHz,DMSO)δ(ppm)11.9(s,1H),4.29(d,1H),4.03(d,1H),3.49(s,1H),3.13(d,1H),2.01-2.31(m,2H),0.80-2.3(m,34H),0.67(s,3H)。
EXAMPLE 2 preparation of Obeticholic acid from 3 alpha-hydroxy-7-oxo-5 beta-cholanic acid
The method comprises the following steps: preparation of the formula III-b
10kg of 3 alpha-hydroxy-7-oxo-5 beta-cholanic acid 2.93kg of 2-amino 3-methylbutanol catalytic amount of boric acid and phenylboronic acid are added into 80L of toluene, the mixture is heated to be dehydrated to be completely reacted, the reaction mixture is washed to be neutral, the organic layer is continuously dehydrated, the water content is controlled to be less than 0.3 percent, the temperature is reduced to 0 to 10 ℃, 1.86kg of 40 percent sodium hydrogen is added in batches, after the uniform stirring, 4.5kg of p-methoxybenzyl chloride is added, after the reaction is completed, the temperature is raised to room temperature, the reaction is completely stirred, and after extraction and concentration, 13.52kg of formula III-a is obtained, the yield is 91.4 percent, and the purity is 98.5 percent.
2) Preparation of formula IV-b
3.6kg of sodium ethoxide is added into the mixed solution of 10kg of the formula III-b, 80L of toluene, 20L of ethyl acetate and 10L of LDMF in batches, then the reaction solution is heated to 50-55 ℃, stirred and reacted completely, and after acid-base washing, the organic layer is concentrated to obtain 9.39kg of IV-b, and the yield is 87.5%.
3) Preparation of formula V-b and formula VI-b
Adding 5kg of IV-b into a mixed solution of 2L of 2-methylpyridine and 4L of 2-methyltetrahydrofuran, controlling the temperature to be 0-10 ℃, dropwise adding 1.5kg of acetyl chloride, heating to room temperature after dropwise adding, stirring to react completely, adding water for layering, and concentrating an organic layer to obtain 5.09kg of a mixture (3:2) of V-b and a formula VI-b, wherein the yield is 95.4%.
4) Synthesis of obeticholic acid
Adding 5kg of a mixture (3:2) of V-b and a formula VI-b into 25L of ethanol, adding 6.5kg of gRanneyNi, replacing with argon for three times, replacing with hydrogen for three times, then increasing the pressure, stirring, reacting for 2-4 hours, then pressing into 10L of 10% sodium hydroxide methanol solution, continuing to hydrogenate until the reaction is finished, filtering, concentrating, recrystallizing the crude product to obtain 2.48kg of obeticholic acid, wherein the yield is 78.3%, the chemical purity is 99.3%, and the optical purity is 99.1%. 1 HNMR(600MHz,DMSO)δ(ppm)11.9(s,1H),4.29(d,1H),4.03(d,1H),3.49(s,1H),3.13(d,1H),2.01-2.31(m,2H),0.80-2.3(m,34H),0.67(s,3H)。
Claims (7)
1. A method for synthesizing obeticholic acid is characterized in that 3 alpha-hydroxy-7-oxo-5 beta-cholanic acid (II) is used as an initial raw material, a formula (III) is obtained through ring closing reaction and hydroxy protection, the formula (III) reacts with ethyl acetate under the alkaline condition to obtain a formula (IV), the formula (IV) is acetylated to obtain a formula (V), and the formula (V) is reduced and deprotected to obtain obeticholic acid (I);
the specific synthetic route is as follows:
wherein:
r is hydrogen, methyl, ethyl, propyl and ethyl. And (3) an isopropyl group. A tertiary butyl group;
g is benzyl or p-methoxybenzyl.
2. The method for synthesizing obeticholic acid according to claim 1, characterized by comprising the following steps:
1) Preparation of formula (III)
Wherein:
r is hydrogen, methyl, ethyl, propyl, isopropyl or tert-butyl;
g is benzyl, p-methoxybenzyl
Adding 3 alpha-hydroxy-7-oxo-5 beta-cholanic acid type (II) into a proper solvent, adding amino alcohol with proper equivalent weight, after complete reaction at a proper temperature, performing proper post-treatment, adding sodium hydrogen and benzyl halide or substituted benzyl halide with proper equivalent weight, after complete reaction, performing proper post-treatment to obtain a formula (III);
2) Preparation of formula (IV)
Dispersing the formula (III) and ethyl acetate into a proper solvent, adding a proper equivalent of alkali, stirring at a proper temperature to react completely, and performing proper post-treatment to obtain a formula (IV);
3) Preparation of the formulae (V) and (VI)
Adding the formula (IV) into a proper solvent, adding equivalent alkali and an acetylation reagent, stirring to react completely, and carrying out proper post-treatment to obtain a formula (V) and a formula (VI);
4) Synthesis of obeticholic acid form (I)
Adding the formula (V) and the formula (VI) into a proper solvent, reducing the mixture by hydrogen for a period of time under the action of a metal catalyst, adding alkali, continuously stirring the mixture to react completely, and carrying out proper post-treatment to obtain the obeticholic acid type (I).
3. The method for synthesizing obeticholic acid according to claim 2, characterized in that the starting material in step (1) is 3 α -hydroxy-7-oxo-5 β -cholanic acid (ii); suitable solvents are toluene, xylene; the amino alcohol is ethanolamine, 2-aminopropanol, 2-aminobutanol, 2-aminopentanol, 2-amino-3-methylbutanol, 2-amino-3,3-dimethylbutanol; the molar ratio of formula (II) to aminoalcohol is 1:1 to 1:1.2; the molar ratio of formula (II) to sodium hydrogen is 1:1 to 1:1.2; the molar ratio of the formula (II) to the benzyl halide or the substituted benzyl halide is 1:1 to 1:1.2.
4. the method for synthesizing obeticholic acid according to claim 2, characterized in that in step (2); suitable solvents are toluene, DMSO, DMF or mixtures thereof; the base is sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the molar ratio of formula (iii) to base is 1:1 to 1:6.
5. the method for synthesizing obeticholic acid according to claim 2, wherein in step (3), the suitable solvent is tetrahydrofuran, 2-methyltetrahydrofuran; the base is pyridine, 2-methylpyridine, 2,6-dimethylpyridine, triethylamine, diisopropylethylamine or DBU; the acetylating agent is acetic anhydride or acetyl chloride.
6. A process for the synthesis of obeticholic acid according to claim 2, characterized in that the suitable solvents in step (4) are methanol, ethanol; the metal catalyst is Pd/C or RanneyNi; the alkali is sodium hydroxide or potassium hydroxide.
7. The method for synthesizing obeticholic acid according to claim 2, characterized in that raw materials are readily available, operation is simple, yield is high, purity is high, and the method is suitable for industrial production.
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| CN202210992203.8A CN115385976A (en) | 2022-08-17 | 2022-08-17 | Method for synthesizing obeticholic acid |
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Application publication date: 20221125 |