CN110305178B

CN110305178B - Synthetic method of ursodeoxycholic acid

Info

Publication number: CN110305178B
Application number: CN201910657023.2A
Authority: CN
Inventors: 欧松; 张和平; 楼秋霞; 梁待亮; 杨琳; 娄良; 沈惠宾; 阮宇峰; 曾湘华
Original assignee: Zhongshan Belling Biotechnology Co ltd
Current assignee: Zhongshan bailing Biotechnology Co.,Ltd.
Priority date: 2019-07-19
Filing date: 2019-07-19
Publication date: 2020-07-03
Anticipated expiration: 2039-07-19
Also published as: CN110305178A

Abstract

The invention belongs to the technical field of synthetic chemistry application and biological medicine, and particularly relates to a novel method for synthesizing ursodeoxycholic acid from cholic acid, which comprises the steps of modifying 12-position hydroxyl of cholic acid into an easily-leaving group after 3, 7-position hydroxyl of the cholic acid is properly protected, using a sulfur nucleophile to attack and replace 12-position hydroxyl into a thioether group, using Raney Ni to reduce and remove the 12-position thioether group to obtain protected 3-hydroxyl-7-ketocholic acid, and carrying out asymmetric reduction or enzyme catalytic reduction on the compound to obtain the ursodeoxycholic acid. The method avoids the oxidation state raising process of the 12 th site, has simple and convenient operation, mild reaction conditions and excellent yield of each step, and has obvious advantages compared with the prior hydrazine hydrate reduction through 12 carbonyl.

Description

Synthetic method of ursodeoxycholic acid

Technical Field

The invention belongs to the technical field of synthetic chemistry application and biological medicine, and particularly relates to a novel method for synthesizing ursodeoxycholic acid from cholic acid.

Background

Bile is a product continuously secreted by human or vertebrate liver cells, is a viscous colored alkaline liquid with bitter taste, and comprises, in addition to water, mainly bile acids, bile salts and cholesterol pigments, and in addition, small amounts of cholesterol, fatty acids, lecithin, electrolytes, proteins, etc. The bile of animal which is common nowadays is generally bird bile, pig bile, ox bile, bear bile and snake bile, etc. The bile acid is the main component of the bile, accounts for about 50-70% of the total amount of the bile, the physiological action of the bile is mainly exerted by the bile acid, and when the bile acid is used as a medicament, the bile acid can be used for clearing heat, relieving spasm and cough, regulating blood pressure, strengthening heart and benefiting gallbladder, inhibiting bacteria and resisting inflammation, regulating immunity and the like, has strong activity, small side effect and low price, and is popular with wide medicament users.

Ursodeoxycholic acid (UDCA) is the main component of bear bile, has the chemical name of 3a,7 β -dihydroxy-5 β -cholestane-24-acid, has the same molecular formula and different stereo structure with chenodeoxycholic acid and taurocholic acid, and is chemically called isomer according to the structural relationship of the two compounds.

Ursodeoxycholic acid is a non-toxic hydrophilic cholic acid, can competitively inhibit the absorption of toxic endogenous cholic acid in ileum, and can reduce the concentration of endogenous vegetable cholic acid in blood and liver cells to achieve the effect of resisting cholestasis by activating a signal network consisting of calcium ions and protein kinase C and activating division active protein kinase to enhance the secretory capacity of cholestasis liver cells. Ursodeoxycholic acid also competitively displaces toxic bile acid molecules on cell membranes and organelles, preventing liver cells and bile duct cells from being damaged by more toxic bile acids. Clinically, ursodeoxycholic acid is mainly used for dissolving cholesterol type hepatobiliary calculus, Primary Biliary Cirrhosis (PBC) and chronic hepatitis C, is also used for alcoholic liver diseases, non-alcoholic fatty liver, benign recurrent intrahepatic cholestasis and congenital cholecystic dilatation, and is an important medicine for treating hepatobiliary diseases. The medicine is mainly prepared from chenodeoxycholic acid extracted and purified from chicken and duck bile in China, and a target product ursodeoxycholic acid is obtained through 7-position oxidation and high stereoselectivity reduction. With the increasing demand of domestic and foreign markets for ursodeoxycholic acid, the sources of chickens and ducks are increasingly tense, and cholic acid from big livestock such as flocks and herds becomes an important raw material of the ursodeoxycholic acid.

The core chemical step of synthesizing ursodeoxycholic acid from cholic acid is the elimination of 12-hydroxyl group of cholic acid. The elimination process of the prior art is to oxidize the 12-hydroxyl to carbonyl and then reduce the carbonyl to methylene by using a Huang Minlon modified hydrazine hydrate reduction method or reduce the carbonyl by using zinc powder under acidic conditions. Huang Minlon reduction and zinc powder reduction under acidic conditions have unstable yield and more side reactions, and the oxidation state of hydroxyl is firstly increased and then reduced in the process, so that the method is not an atom economic reaction.

Chinese patent application CN102453071A reports a preparation method for directly extracting and synthesizing chenodeoxycholic acid and ursodeoxycholic acid from pig bile paste or leftovers, which has the following problems: hyodeoxycholic acid is not extracted, but the property of hyodeoxycholic acid is similar to that of chenodeoxycholic acid, so that the additional value is reduced, and the steric effect of the subsequent reaction is increased; the oxidation reaction of bromine water is strong and difficult to control, and side reactions are more, such as peroxide 3, 7-diketolithocholic acid, thus the conversion rate is reduced and impurities are increased; as the metal sodium and the metal potassium belong to active metals, the hydrogenation reaction is strong, not only is difficult to control, but also has potential safety hazard and must be stored in paraffin or kerosene; the purification process is insufficient, and impurities such as hyodeoxycholic acid, incompletely reacted chenodeoxycholic acid, over-reacted 3, 7-diketolithocholic acid derivatives and the like cannot be removed only by one-step acidification and precipitation.

Chinese patent application CN102477059A reports a high purity tauroursodeoxycholic acid and its preparation method, which has the following problems: the synthesized mixed anhydride is unstable, is easy to decompose when meeting water and racemize when meeting heat, so that the conversion rate is low, and the low-temperature reaction condition is difficult to control; and triethylamine and ethyl chloroformate in the used raw materials have certain toxicity, residues of the triethylamine and the ethyl chloroformate are easy to adsorb and embed in coarse crystals, and the residues are difficult to remove by water washing because the residues are insoluble in water.

Disclosure of Invention

In order to solve the technical problems, the invention provides the synthesis method of ursodeoxycholic acid, which has the advantages of mild reaction conditions, simple operation, less prepared byproducts, high yield and high purity.

In order to achieve the above purpose, the invention provides the following technical scheme:

a synthetic method of ursodeoxycholic acid comprises the following preparation methods:

(1) dissolving cholic acid in a solvent, adding an oxidant, and stirring for reaction to obtain an intermediate 1 (7-keto-3, 12-dihydroxycholanic acid);

(2) adding the intermediate 1 into an alcohol solvent for esterification reaction, evaporating the solvent after the reaction is finished, adding an acylation reagent for reaction, and processing to obtain an intermediate 2;

(3) dissolving the dried intermediate 2 in an organic solvent, cooling, adding a sulfonylation reagent for reaction, and processing to obtain an intermediate 3;

(4) dissolving the intermediate 3 in a solvent, adding a sulfhydryl nucleophilic reagent, reacting, and treating to obtain an intermediate 4 (the 12-carbon has a thioether group);

(5) dissolving the intermediate 4 in a solvent, adding a reducing agent, heating, carrying out reduction desulfurization reaction, filtering after the reaction is finished to obtain a filtrate, adding alcohol and alkali into the filtrate, carrying out hydrolysis reaction, and then carrying out acidification treatment to obtain an important intermediate 5 (7-ketocholic acid) in ursodeoxycholic acid synthesis;

(6) adding the intermediate 5 into an alcohol solvent, and carrying out reduction reaction to obtain a final product ursodeoxycholic acid;

preferably, in the step (1), the oxidant is at least one of bromine, bleaching water, PCC (pyridinium chlorochromate), PDC (pyridinium dichromate);

preferably, in step (1), the oxidizing agent is a 7- β dehydrogenase;

preferably, in step (1), the reaction is effected in an electrolytic cell by a bromide-mediated indirect electro-oxidation process;

preferably, in the step (1), the molar ratio of the oxidant to the cholic acid is 1-3: 1;

preferably, in step (2), the esterification reaction is carried out under acid-catalyzed or base-catalyzed conditions;

preferably, in step (2), the acylating agent is an acid anhydride or an acid chloride;

preferably, in the step (2), the mole ratio of the acylating agent to cholic acid is 10-30: 1;

preferably, in the step (2), the reaction temperature after adding the acylating agent is 90-100 ℃;

preferably, in the step (3), the sulfonylation reagent is at least one of tosylate, benzene sulfonyl chloride, methane sulfonyl chloride and trifluoromethanesulfonic anhydride; preferably trifluoromethanesulfonic anhydride;

preferably, in the step (3), the amount of the sulfonylation reagent is 1-2: 1;

preferably, in the step (3), the temperature of the reaction is 0-40 ℃;

preferably, in step (4), the thiol nucleophile is at least one of methyl mercaptan, ethyl mercaptan, propyl mercaptan, benzyl mercaptan, thiophenol, 2-mercaptobenzothiazole, 5-phenyl-mercaptotetrazole, 5-methylmercaptotetrazole, 2-mercaptopyridine, thioglycolic acid and thioglycolate salt, mercaptopropanol, dimercaptopropanol, ethanedithiol, and propanedithiol; preferably: at least one of 2-mercaptobenzothiazole, 5-phenyl-mercaptotetrazole, 5-methylmercaptotetrazole, and 2-mercaptopyridine;

preferably, in step (4), the molar ratio of the sulfhydryl nucleophile to cholic acid is 1-3: 1;

preferably, in the step (4), the solvent is at least one of dimethylformamide, dimethyl sulfoxide, methyl pyrrolidone and hexamethylphosphoric triamide;

preferably, in the step (4), the reaction is carried out in the presence of an organic base or an inorganic base, wherein the amount of the organic base or the inorganic base is not less than that of the intermediate 3;

preferably, in step (4), the reaction is carried out at 0-100 ℃; preferably 20 to 80 ℃;

preferably, in the step (4), the reaction is carried out under the protection of nitrogen or argon; coupling and oxidation of sulfydryl are reduced, and generation of impurities is further reduced;

preferably, in the step (5), the reducing agent is Raney Ni. The dosage of Raney Ni is more than one time of that of cholic acid, the actual utilization rate of Ranry Ni is low in the reaction, the dosage of Raney is greatly more than the theoretical consumption, and the yield and the speed of the reaction can be accepted only by adding more than 5mol of Raney Ni into each mol of substrate.

Preferably, Raney is used in an amount of: the Raney Ni is added in an amount of 5-20mol per mol of cholic acid substrate.

Preferably, in the step (5), the solvent is at least one of an alcohol solvent, a ketone solvent, a halogenated alkane solvent, an ether solvent or an amine solvent;

preferably, the alcoholic solvent is selected from methanol or ethanol; the ketone reagent is selected from acetone or butanone; the halogenated alkane solvent is dichloromethane or chloroform; the ether solvent is at least one of tetrahydrofuran, n-butyl ether, methyl tert-butyl ether and dioxane; the amine solvent is dimethylformamide or hexamethylphosphoric triamide;

preferably, in the step (5), the reduction desulfurization reaction is carried out at a temperature of 0-100 ℃;

preferably, in step (6), the reagent used for the reduction is 7- α -dehydrogenase;

preferably, in step (6), the reduction is carried out under catalytic hydrogenation conditions using a chiral ruthenium catalyst;

preferably, in step (6), the reagent used for the reduction is metallic sodium or metallic potassium.

Compared with the prior art, the invention has the following technical effects:

(1) the invention has mild reaction conditions, simple operation, good specificity and less byproducts, and the ursodeoxycholic acid prepared by the method has higher yield and purity;

(2) the use of the sulfhydryl nucleophilic reagent transforms the 12-carbon into a structure containing thioether groups, does not need oxidation, and has milder reaction conditions and lower cost;

(3) raney Ni is reduced and desulfurized in a solvent to realize direct reduction of hydroxyl to methylene, and further, protecting groups on 3-hydroxyl and ester protection of carboxyl are conveniently removed, so that next synthesis of ursodeoxycholic acid is carried out, the whole process flow is easy to realize, and industrial production is easy to realize.

Detailed Description

Example 1

(1) cholic acid 4.08g (10mmol) was suspended in dichloromethane 100ml, after dissolution with stirring, PCC 2.8g (13mmol) was added, stirring at room temperature, the reaction was followed by TLC until consumption of cholic acid was complete, the reaction was stopped, rapid filtration was carried out using a silica gel plug to remove the black chromium salt and the silica gel layer was washed with dichloromethane 100 ml. Merging the filtrates; evaporation to dryness to give a brown cream solid as intermediate 1;

(2) dissolving the intermediate 1 in 100ml of methanol, adding 5 mu l of sulfuric acid, heating and refluxing, tracking by TLC after two hours until the esterification reaction is finished, evaporating the mixture of the esterification reaction to dryness, directly adding 20ml of acetic anhydride into viscous residue, slowly heating to 90 ℃, keeping the temperature at 90 ℃ for 2 hours, and tracking by TLC until the reaction is finished. The reaction mixture was cooled to room temperature, poured into 200ml of water, and the precipitated white solid was filtered off and then recrystallized using methanol, or silica gel column chromatography, with dichloromethane: 50 parts of methanol: 1, passing through a column to obtain a relatively pure intermediate 2;

(3) the intermediate 2 is fully dried in a vacuum drying oven until the water content is lower than 0.1 percent, and then the next reaction can be carried out; dissolving dried intermediate 2 in dichloromethane 50ml, cooling to below 5 deg.C, adding methanesulfonyl chloride 2.2g

(11mmol), dropwise adding 2.2g (22mmol) of triethylamine, reacting at 2 ℃ after dropwise adding, tracking by TLC (thin layer chromatography) until the reaction is complete, adding 20ml of 5% sodium bicarbonate aqueous solution into the reaction system after the reaction is complete, stirring for layering, separating a dichloromethane layer, washing with water, and evaporating to dryness to obtain an intermediate 3;

(4) dissolving the intermediate 3 in 50ml of dimethylformamide, adding 1.9g (15mmol) of benzylmercaptan and 1.5g (15mmol) of triethylamine, stirring at 25 ℃, reacting under the protection of nitrogen, tracking by TLC until the reaction is complete, after the reaction is complete, pouring the dimethylformamide solution into 200ml of water, stirring, filtering out a precipitated white solid, and fully washing with water to obtain an intermediate 4.

(5) The intermediate 4 is dissolved in 20ml of ethylene glycol dimethyl ether, 5.0g of Raney Ni is added, the reaction is carried out at 25 ℃, the TLC tracking is carried out, and the reaction is stopped when the raw material point disappears. Filtering the reaction mixture to remove black nickel slag, adding 50ml of methanol and 20ml of 40% sodium hydroxide aqueous solution into the filtrate, reacting for 2 hours at 25 ℃, tracking by TLC, adjusting the pH value of the solution to be acidic by adding hydrochloric acid after the hydrolysis reaction is completed, and separating out white solid to be filtered to obtain an intermediate 5 (7-ketocholic acid);

(6) the intermediate 5 is reduced in an alcohol solvent by using metal potassium, and then is acidified and purified to obtain ursodeoxycholic acid, wherein the yield is 91.6%, and the purity is 99.7%.

Example 2

(1) suspending cholic acid 4.08g (10mmol) in n-pentanol 100ml water 10ml solvent, stirring for dissolving, adding 7- β dehydrogenase 0.5g (10mmol), stirring at room temperature, tracking reaction by TLC, stopping reaction until cholic acid is completely consumed, filtering with diatomite and microporous filter membrane to remove enzyme, washing silica gel layer with n-pentanol 50ml, combining filtrates, evaporating to dryness to obtain white pasty solid as intermediate 1;

(2) intermediate 1 was dissolved in 100ml of methanol, 5 μ l of sulfuric acid was added, followed by heating and refluxing, TLC tracking after two hours, the esterification reaction was completed, the mixture of this esterification reaction was evaporated to dryness, the viscous residue was added 100ml of dichloromethane, stirred to dissolve and cooled to below 0 ℃, 1.44g (12mmol) of pivaloyl chloride and 1.31g (13mmol) of triethylamine were added, followed by slow heating to room temperature and reaction at room temperature for 2 hours, TLC tracking reaction was completed. The reaction mixture was poured into 200ml of water, and the precipitated white solid was filtered off and then recrystallized using methanol, or silica gel column chromatography, with dichloromethane: 50 parts of methanol: 1, passing through a column to obtain a relatively pure intermediate 2;

(3) fully drying the intermediate 2 in a vacuum drying oven until the water content is lower than 0.1%; dissolving the dried intermediate 2 in 50ml of trichloromethane, cooling to below 5 ℃, adding 5.64g (20mmol) of trifluoromethanesulfonic anhydride, dropwise adding 2.2g (22mmol) of triethylamine, reacting at 40 ℃ after the dropwise addition is finished, tracking by TLC (thin layer chromatography) until the reaction is complete, then adding 20ml of 5% sodium bicarbonate aqueous solution into the reaction system, stirring for layering, separating the trichloromethane layer, washing with water, and then evaporating to dryness to obtain an intermediate 3;

(4) dissolving the intermediate 3 in 50ml of methyl pyrrolidone, adding 2.83g (30mmol) of ethylene glycol dithiol and 1.58g (11mmol) of tripropylamine, stirring at 100 ℃, carrying out reaction under the protection of argon, tracking by TLC until the reaction is complete, then pouring the methyl pyrrolidone solution into 200ml of water, stirring, filtering out precipitated white solid, and fully washing with water to obtain an intermediate 4.

(5) Dissolving the intermediate 4 in 20ml of butanone, adding Raney Ni4.3g, reacting at 2 ℃, tracking by TLC, stopping the reaction when the raw material point disappears, filtering the reaction mixture to remove black nickel slag, adding 50ml of methanol and 20ml of 40% sodium hydroxide aqueous solution into the filtrate, reacting for 2 hours at 25 ℃, tracking by TLC, completing the hydrolysis reaction, pouring the reaction mixture into 50ml of water, adding hydrochloric acid to adjust the pH value of the solution to be acidic, separating out white solid, and filtering to obtain an intermediate 5 (7-ketocholic acid);

(6) the intermediate 5 is reduced in an alcohol solvent by using 7- α -dehydrogenase, and then is acidified and purified to obtain ursodeoxycholic acid with the yield of 93.2% and the purity of 99.6%.

Example 3

(1) suspending cholic acid 4.08g (10mmol) in dichloromethane 100ml, stirring to dissolve, adding PDC11.3g (30mmol), stirring at room temperature, tracking the reaction by TLC until the consumption of cholic acid is complete, stopping the reaction, rapidly filtering by using a silica gel plunger, removing black chromium salt, and washing the silica gel layer by using dichloromethane 100 ml. Merging the filtrates; evaporation to dryness to give a brown cream solid as intermediate 1;

(3) the intermediate 2 is fully dried in a vacuum drying oven until the water content is lower than 0.1 percent, and then the next reaction can be carried out; dissolving the dried intermediate 2 in 50ml of dichloromethane, cooling to below 5 ℃, adding 2.2g (11mmol) of methane sulfonyl chloride, dropwise adding 2.2g (22mmol) of triethylamine, reacting at 2 ℃ after dropwise adding, tracking by TLC (thin layer chromatography) until the reaction is complete, adding 20ml of 5% sodium bicarbonate aqueous solution into a reaction system after the reaction is complete, stirring for layering, separating a dichloromethane layer, washing with water, and evaporating to dryness to obtain an intermediate 3;

(4) dissolving the intermediate 3 in 50ml of dimethylformamide, adding 1.1g (10mmol) of thiophenol and 1.5g (15mmol) of triethylamine, stirring at 1 ℃, reacting under the protection of nitrogen, tracking by TLC (thin layer chromatography) until the reaction is complete, then pouring the dimethylformamide solution into 200ml of water, stirring, filtering out a precipitated white solid, and fully washing with water to obtain an intermediate 4;

(5) the intermediate 4 was dissolved in 20ml of hexamethylphosphoric triamide, 17.0g of Raney Ni was added, the reaction was carried out at 100 ℃ and the reaction was stopped when the starting material point disappeared by TLC tracing. Filtering the reaction mixture to remove black nickel slag, adding 50ml of methanol and 20ml of 40% sodium hydroxide aqueous solution into the filtrate, reacting for 2 hours at 25 ℃, tracking by TLC, adjusting the pH value of the solution to be acidic by adding hydrochloric acid after the hydrolysis reaction is completed, and separating out white solid to be filtered to obtain an intermediate 5 (7-ketocholic acid);

(6) the intermediate 5 is reduced by using a chiral ruthenium catalyst under the condition of catalytic hydrogenation, and then is acidified and purified to obtain ursodeoxycholic acid, wherein the yield is 92.8% and the purity is 99.8%.

Comparative example 1 (different amount of thiol nucleophile compared to example 1)

(4) dissolving the intermediate 3 in 50ml of dimethylformamide, adding 1.18g (9.5mmol) of benzylmercaptan and 1.5g (15mmol) of triethylamine, stirring at 25 ℃, reacting under the protection of nitrogen, tracking by TLC until the reaction is complete, after the reaction is complete, pouring the dimethylformamide solution into 200ml of water, stirring, filtering out a precipitated white solid, and fully washing with water to obtain an intermediate 4.

(6) the intermediate 5 is reduced in an alcohol solvent by using metal potassium, and then is acidified and purified to obtain ursodeoxycholic acid, wherein the yield is 77% and the purity is 91.1%.

Comparative example 2 (different Raney Ni reducing agent than in example 1)

(5) The intermediate 4 is dissolved in 20ml of ethylene glycol dimethyl ether, 2.0g of Raney Ni is added, the reaction is carried out at 25 ℃, the TLC tracking is carried out, and the reaction is stopped when the raw material point disappears. Filtering the reaction mixture to remove black nickel slag, adding 50ml of methanol and 20ml of 40% sodium hydroxide aqueous solution into the filtrate, reacting for 2 hours at 25 ℃, tracking by TLC, adjusting the pH value of the solution to be acidic by adding hydrochloric acid after the hydrolysis reaction is completed, and separating out white solid to be filtered to obtain an intermediate 5 (7-ketocholic acid);

(6) the intermediate 5 is reduced in an alcohol solvent by using metal potassium, and then is acidified and purified to obtain ursodeoxycholic acid, wherein the yield is 75% and the purity is 92.9%.

Comparative example 3 (different reaction conditions compared to example 1)

(2) dissolving the intermediate 1 in 100ml of methanol, adding 5 mu l of sulfuric acid, heating and refluxing, tracking by TLC after two hours until the esterification reaction is finished, evaporating the mixture of the esterification reaction to dryness, directly adding 20ml of acetic anhydride into viscous residue, slowly heating to 60 ℃, keeping the temperature at 60 ℃ for 2 hours, and tracking by TLC until the reaction is finished. The reaction mixture was cooled to room temperature, poured into 200ml of water, and the precipitated white solid was filtered off and then recrystallized using methanol, or silica gel column chromatography, with dichloromethane: 50 parts of methanol: 1, passing through a column to obtain a relatively pure intermediate 2;

(6) the intermediate 5 is reduced by using metal potassium in an alcohol solvent, and then is acidified and purified to obtain ursodeoxycholic acid, wherein the yield is 83.2 percent, and the purity is 94.3 percent.

The embodiment shows that the synthetic method of ursodeoxycholic acid provided by the invention has high yield and purity, and is a simple and efficient synthetic process.

The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.

Claims

1. A synthetic method of ursodeoxycholic acid comprises the following preparation methods:

(1) dissolving cholic acid in solvent, adding oxidant, reacting to obtain intermediate 1

；

(2) Adding the intermediate 1 into an alcohol solvent for esterification reaction, evaporating the solvent after the reaction, and adding an acylation reagent for reaction to obtain an intermediate 2;

(3) dissolving the dried intermediate 2 in an organic solvent, adding a sulfonylation reagent for reaction to obtain an intermediate 3;

(4) dissolving the intermediate 3 in a solvent, adding a sulfhydryl nucleophilic reagent, and reacting to obtain an intermediate 4;

(5) dissolving the intermediate 4 in a solvent, adding a reducing agent, carrying out reduction desulfurization reaction, filtering to obtain a filtrate, adding alcohol and alkali into the filtrate, carrying out hydrolysis reaction, and then carrying out acidification treatment to obtain an intermediate 5;

wherein, in the step (1), the oxidant is PCC, PDC or 7- β dehydrogenase.

2. The method for synthesizing ursodeoxycholic acid according to claim 1, wherein in the step (1), the molar ratio of the oxidant to cholic acid is 1-3: 1.

3. the method for synthesizing ursodeoxycholic acid according to claim 2, wherein in the step (2), the mole ratio of the acylating agent to cholic acid is 10-30: 1; the reaction temperature after the addition of the acylating agent is 90-100 ℃.

4. The method for synthesizing ursodeoxycholic acid according to claim 3, wherein in the step (3), the sulfonylation reagent is at least one of tosyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, and trifluoromethanesulfonic anhydride; in the step (3), the dosage of the sulfonylation reagent is 1-2: 1; in the step (3), the reaction temperature is 0-40 ℃.

5. The method of claim 4, wherein the sulfonylating agent is trifluoromethanesulfonic anhydride.

6. The method according to any one of claims 1 to 5, wherein in step (4), the thiol nucleophile is at least one of methyl mercaptan, ethyl mercaptan, propyl mercaptan, benzyl mercaptan, thiophenol, 2-mercaptobenzothiazole, 5-phenyl-mercaptotetrazole, 5-methylmercaptotetrazole, 2-mercaptopyridine, thioglycolic acid and thioglycolate, mercaptopropanol, dimercaptopropanol, ethanedithiol, and propanedithiol.

7. The method according to claim 6, wherein in the step (4), the thiol nucleophile is at least one of 2-mercaptobenzothiazole, 5-phenyl-mercaptotetrazole, 5-methylmercaptotetrazole, and 2-mercaptopyridine; the molar ratio of the sulfhydryl nucleophilic reagent to the cholic acid is 1-3: 1; the solvent is at least one of dimethylformamide, dimethyl sulfoxide, methyl pyrrolidone and hexamethylphosphoric triamide.

8. The method for synthesizing ursodeoxycholic acid according to claim 6, wherein in the step (4), the reaction is carried out in the presence of an organic base or an inorganic base, wherein the amount of the organic base or the inorganic base is not less than that of the intermediate 3; the reaction is carried out at 0-100 ℃; the reaction is carried out under the protection of nitrogen or argon.

9. The method for synthesizing ursodeoxycholic acid according to claim 8, wherein, in the step (4), the reaction is performed at 20-80 ℃.

10. The method for synthesizing ursodeoxycholic acid according to claim 8, wherein, in the step (5), said reducing agent is Raney Ni; the dosage of the reducing agent is not less than that of the intermediate 4;

the solvent is at least one of an alcohol solvent, a ketone solvent, a halogenated alkane solvent, an ether solvent or an amine solvent;

the alcohol solvent is selected from methanol or ethanol; the ketone reagent is selected from acetone or butanone; the halogenated alkane solvent is dichloromethane or chloroform;

the ether solvent is at least one of tetrahydrofuran, n-butyl ether, methyl tert-butyl ether and dioxane; the amine solvent is dimethylformamide or hexamethylphosphoric triamide;

the reduction desulfurization reaction is carried out at the temperature of 0-100 ℃.

11. The method for synthesizing ursodeoxycholic acid according to claim 10, wherein in the step (6), the reagent used for the reduction is at least one of 7- α -dehydrogenase, metallic sodium, and metallic potassium.

12. The method for synthesizing ursodeoxycholic acid according to claim 10, wherein in the step (6), said reduction is performed under catalytic hydrogenation conditions using a chiral ruthenium catalyst.