Process for the synthesis of chenodeoxycholic acid

Abstract

The application relates to a synthesis method of chenodeoxycholic acid, which comprises the following steps: (1) raw material SM and an oxidizing agent are subjected to an oxidation reaction in a solvent to obtain an intermediate IM1; (2) the intermediate IM1 is subjected to a reduction reaction to obtain chenodeoxycholic acid; the oxidizing agent contains dihalogen hydantoin, the dihalogen hydantoin is dichlorohydantoin and / or dibromohydantoin, and a reaction formula is as follows. The synthesis method has the advantages of fast reaction speed, high efficiency, high yield, high purity of the obtained chenodeoxycholic acid product, simple synthesis process and facilitation of batch production, so that the problem of tight supply of chenodeoxycholic acid in the market is effectively solved.

Description

Technical Field

[0001] This invention relates to the fields of organic synthesis and pharmaceutical technology, and in particular to a method for synthesizing chenodeoxycholic acid. Background Technology

[0002] Ursodeoxycholic acid (UDCA) is an active ingredient in bear bile. It is an endogenous bile acid used to treat diseases such as reflux gastritis, cholecystopancreatitis, alcoholic liver disease, primary biliary cirrhosis, and drug-induced hepatitis, and has high medicinal value.

[0003]

[0004] Currently, the key raw material for the chemical synthesis of ursodeoxycholic acid (CDCA) is chenodeoxycholic acid (CDCA). Chenodeoxycholic acid is oxidized to a ketone at the 7-position hydroxyl group, and then the ketone is selectively reduced to β-OH to obtain ursodeoxycholic acid. CDCA is also an important raw material for the artificial preparation of other steroidal drugs, with very high demand. Currently, chenodeoxycholic acid is mainly extracted directly from avian bile, which is insufficient to meet the demand for CDCA. Therefore, providing a simple and efficient chemical method for the synthesis of CDCA is of great significance.

[0005] Summary of the Invention

[0006] Based on this, the purpose of the present invention is to provide a new method for synthesizing chenodeoxycholic acid, including the following technical solutions.

[0007] A method for synthesizing chenodeoxycholic acid includes the following steps:

[0008] (1) The raw material SM and the oxidant undergo an oxidation reaction in a solvent to obtain intermediate IM1;

[0009] (2) Intermediate IM1 is reduced to chenodeoxycholic acid;

[0010] The reaction formula is as follows:

[0011]

[0012] The oxidant contains dihalohydantoin, which is dichlorohydantoin and / or dibromohydantoin.

[0013] In some embodiments, the solvent is water and / or acetonitrile.

[0014] In some embodiments, the solvent is a mixture of water and acetonitrile in a volume ratio of 1-10:1.

[0015] In some embodiments, the solvent is a mixture of water and acetonitrile in a volume ratio of 4-6:1.

[0016] In some embodiments, the molar ratio of the raw material SM to dihalohydantoin is 1:0.3-1.5.

[0017] In some embodiments, the molar ratio of the raw material SM to dihalohydantoin is 1:0.5-0.6.

[0018] In some embodiments, the oxidant also contains hydrogen peroxide.

[0019] In some embodiments, the oxidant consists of dihalohydantoin and hydrogen peroxide.

[0020] In some embodiments, the molar ratio of the raw material SM to hydrogen peroxide is 1:2.5-3.5.

[0021] In some embodiments, the ratio of the raw material SM to the solvent is 1g:5mL-20mL.

[0022] In some embodiments, the ratio of the raw material SM to the solvent is 1g:5mL-15mL.

[0023] In some embodiments, the reaction conditions in step (1) include: pH 7-9, temperature 10°C-70°C, and time 1-8 hours.

[0024] In some embodiments, step (2) includes:

[0025] (a) A mixed solution of intermediate IM1, triethylene glycol, KOH and hydrazine hydrate was reacted at 110℃-140℃ for 1-3 hours;

[0026] (b) Add triethylene glycol to the mixture after the reaction in step (a), and then continue heating the resulting mixture until the internal temperature of the reaction solution is 200°C-220°C, and continue heating until no gas is produced;

[0027] (c) Allow the mixture to cool naturally to room temperature, then pour the reaction solution into water, place it in an ice-water bath, adjust the pH to 1-3, and stir.

[0028] In some embodiments, step (2) includes:

[0029] (a) A mixed solution of intermediate IM1, triethylene glycol, KOH and hydrazine hydrate was reacted for 2 hours at a temperature of 125℃-127℃;

[0030] (b) Triethylene glycol is added to the mixture after the reaction in step (a), and the resulting mixture is then heated until the internal temperature of the reaction solution is 208°C-212°C and no gas is produced.

[0031] (c) Allow the reaction solution to cool naturally to room temperature, then pour it into water, place it in an ice-water bath, adjust the pH to 2, and stir.

[0032] In some embodiments, the molar ratio of intermediate IM1, triethylene glycol, KOH and hydrazine hydrate in step (a) is 1:6-8:4-6:1.5-3.

[0033] In some embodiments, the molar ratio of the triethylene glycol added in step (b) to the intermediate IM1 is 7-17:1.

[0034] This invention uses chenodeoxycholic acid as a raw material. Under the oxidation of a specific oxidant (containing dichlorohydantoin and / or dibromohydantoin), the ortho-hydroxyl group of the carboxyl group can be selectively oxidized to obtain the ketone compound of intermediate IM1. The intermediate ketone is then reduced to obtain chenodeoxycholic acid, thus obtaining a new method for synthesizing chenodeoxycholic acid that is very simple and convenient.

[0035] Furthermore, by combining dihalohydantoin and hydrogen peroxide and reacting in a specific solvent (a mixture of water and acetonitrile), the efficiency and selectivity of the oxidation reaction can be further improved, thereby further increasing the yield and purity of the obtained intermediate IM1 ketone compound.

[0036] The synthesis method of the present invention has a fast reaction rate, high efficiency, high yield, and high purity of the obtained chenodeoxycholic acid product. Furthermore, the synthesis process is simple and conducive to mass production, thereby effectively solving the problem of the shortage of chenodeoxycholic acid in the market. Detailed Implementation

[0037] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments are merely illustrative of the present invention and should not be construed as limiting the invention.

[0038] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention.

[0039] The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product, or device that includes a series of steps is not limited to the steps or modules listed, but may optionally include steps not listed, or may optionally include other steps inherent to such process, method, product, or device.

[0040] In this invention, "multiple" refers to two or more. "And / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A alone, A and B simultaneously, or B alone. The character " / " generally indicates that the preceding and following related objects have an "or" relationship.

[0041] The following are specific examples.

[0042] The synthetic route of chenodeoxycholic acid in the following examples is as follows:

[0043]

[0044] Example 1

[0045] The method for synthesizing chenodeoxycholic acid provided in this embodiment includes the following experimental steps:

[0046] (1) In a 100 mL single-necked flask, add 10 mL of water, 2 mL of acetonitrile, and 1 g (2.45 mmol) of SM sequentially. Stir until homogeneous, adjust the pH to 7-8 with sodium hydroxide, and ensure the SM is completely dissolved. Then, add 0.24 g (1.23 mmol, 0.5 eq) of dichlorohydantoin and 0.71 mL (7.3 mmol, 3 eq) of 35% hydrogen peroxide sequentially. After the addition is complete, heat to 50 °C and stir for 2 hours. TLC detection shows the starting material has disappeared. Cool to room temperature, adjust the pH to 1-2, extract with ethyl acetate, wash with saturated brine, dry, and evaporate to dryness before proceeding to the next step. 0.75 g of intermediate IM is obtained, with a yield of 74.6%. HPLC (normalization method) purity: 90%.

[0047] 1 HNMR (400MHz, DMSO-d6): δ (ppm) 12.28 (s, 1H), 4.39 (s, 1H), 4.15 (s, 1H), 3.56- 3.61(m,2H),3.31(m,1H),3.14-3.20(m,1H),2.40-2.45(m,1H),2.13-2.20(m,1 H),1.88-1.98(m,2H),1.62-1.82(m,4H),1.31-1.48(m,6H),1.09-1.26(m,7H) ,0.92-0.93(d,J=6.5,3H),0.86-0.89(m,1H),0.83(s,3H),0.64(s,3H).ESI-MS m / z: 407.28.

[0048] (2) In a 10 mL single-necked flask, add 0.75 g of IM1 (90% purity, 1.66 mmol), 1.76 g of triethylene glycol (11.63 mmol, 7 eq), 0.49 g of KOH (8.66 mmol, 5.2 eq), and 0.23 g of hydrazine hydrate (3.66 mmol, 2.2 eq) sequentially. Heat the mixture to 126 °C and maintain the temperature for 2 hours. TLC detection showed that the starting material had disappeared. Add 2 g of triethylene glycol (14.54 mmol) and continue heating the mixture until the temperature in the reaction solution reaches 210 °C. React for 3 hours until no gas is produced. After the reaction is complete, turn off the heating and allow it to cool naturally to room temperature. Then pour the reaction solution into 40 mL of water and place it in an ice-water bath using 12 M... The pH was adjusted to 2 with HCl and stirred for 30 min. A white flocculent substance was produced. The substance was passed through cotton wool, and the solid was dissolved in 20 mL of ethyl acetate. Column chromatography yielded 362 mg (0.923 mmol) of CDCA, with a yield of 55.6% (based on the actual HPLC content of IM1).

[0049] 1 HNMR: (400MHz, CDCl-d) δ (ppm) 3.85 (s, 1H), 3.46 (m, 1H), 2.22-2.37 (m, 2H), 1 .66-1.93(m,8H),1.14-1.46(m,16H),0.86-0.95(m,6H),0.66(s,3H).ESI-MS m / z: 415.28(M+23) + .

[0050] Example 2

[0051] The method for synthesizing chenodeoxycholic acid provided in this embodiment includes the following experimental steps:

[0052] (1) In a 100 mL single-necked flask, add 10 mL of water, 2 mL of acetonitrile, and 1 g (2.45 mmol) of SM sequentially. Stir until homogeneous, adjust the pH to 7-8 with sodium hydroxide, and ensure the SM is completely dissolved. Then, add 0.15 g (0.74 mmol, 0.3 eq) of dichlorohydantoin and 0.71 mL (7.3 mmol, 3 eq) of 35% hydrogen peroxide sequentially. After the addition is complete, heat to 50 °C and stir for 2 hours. TLC detection shows the starting material has disappeared. Cool to room temperature, adjust the pH to 1-2, extract with ethyl acetate, wash with saturated brine, dry, and evaporate to dryness before proceeding to the next step. 0.60 g of intermediate IM is obtained, with a yield of 60.3%. HPLC (normalization method) purity: 88%.

[0053] (2) In a 10 mL single-necked flask, add 0.60 g of IM1 (88% purity, 1.30 mmol), 1.36 g of triethylene glycol (9.08 mmol, 7 eq), 0.38 g of KOH (6.78 mmol, 5.2 eq), and 0.18 g of hydrazine hydrate (2.9 mmol, 2.2 eq) in sequence. Heat the mixture to 126 °C and keep it at that temperature for 2 hours. TLC detection showed that the starting material had disappeared. Add 2 g of triethylene glycol (14.54 mmol) and continue heating the mixture until the temperature in the reaction solution rises to 210 °C. React for 3 hours until no gas is produced. After the reaction is complete, turn off the heating and let it cool naturally to room temperature. Then pour the reaction solution into 40 mL of water, place it in an ice-water bath, adjust the pH to 2 with 12 M HCl, and stir for 30 min. White flocculent matter is produced. Pass the solid through cotton wool, dissolve it in 20 mL of ethyl acetate, and column chromatography to obtain 283 mg of CDCA.

[0054] Example 3

[0055] The method for synthesizing chenodeoxycholic acid provided in this embodiment includes the following experimental steps:

[0056] (1) In a 100 mL single-necked flask, add 10 mL of water, 2 mL of acetonitrile, and 1 g (2.45 mmol) of SM sequentially. Stir until homogeneous, adjust the pH to 7-8 with sodium hydroxide, and ensure the SM is completely dissolved. Then, add 0.72 g (3.68 mmol, 1.5 eq) of dichlorohydantoin and 0.71 mL (7.3 mmol, 3 eq) of 35% hydrogen peroxide sequentially. After the addition is complete, heat to 50 °C and stir for 2 hours. TLC detection shows the starting material has disappeared. Cool to room temperature, adjust the pH to 1-2, extract with ethyl acetate, wash with saturated brine, dry, and evaporate to dryness before proceeding to the next step. 0.80 g of intermediate IM is obtained, with a yield of 80.2%. HPLC (normalization method) purity: 85%.

[0057] (2) In a 10 mL single-necked flask, add 0.80 g of IM1 (85% purity, 1.67 mmol), 1.76 g of triethylene glycol (11.7 mmol, 7 eq), 0.49 g of KOH (8.69 mmol, 5.2 eq), and 0.22 g of hydrazine hydrate (3.7 mmol, 2.2 eq) in sequence. Heat the mixture to 126 °C and keep it at that temperature for 2 hours. TLC detection showed that the starting material had disappeared. Add 2 g of triethylene glycol (14.54 mmol) and continue heating the mixture until the temperature in the reaction solution rises to 210 °C. React for 3 hours until no gas is produced. After the reaction is complete, turn off the heating and let it cool naturally to room temperature. Then pour the reaction solution into 40 mL of water, place it in an ice-water bath, adjust the pH to 2 with 12 M HCl, and stir for 30 min. White flocculent matter is produced. Pass the solid through cotton wool, dissolve it in 20 mL of ethyl acetate, and column chromatography to obtain 357 mg of CDCA.

[0058] Example 4

[0059] (1) In a 100 mL single-necked flask, add 10 mL of water, 2 mL of acetonitrile, and 1 g (2.45 mmol) of SM sequentially. Stir until homogeneous, adjust the pH to 7-8 with sodium hydroxide, and ensure complete dissolution of SM. At 10-20 °C, add 0.24 g (1.23 mmol, 0.5 eq) of dichlorohydantoin and 0.71 mL (7.3 mmol, 3 eq) of 35% hydrogen peroxide sequentially. After addition, maintain the temperature at 10-20 °C and stir for 5 hours. TLC detection shows the starting material has disappeared. Cool to room temperature, adjust the pH to 1-2, extract with ethyl acetate, wash with saturated brine, dry, and evaporate to dryness before proceeding to the next step. 0.77 g of intermediate IM is obtained, with a yield of 73.4%. HPLC (normalization method) purity: 91%.

[0060] (2) In a 10 mL single-necked flask, 0.77 g of IM1 (91% purity, 1.72 mmol), 1.81 g of triethylene glycol (12.00 mmol, 7 eq), 0.50 g of KOH (8.95 mmol, 5.2 eq), and 0.236 g of hydrazine hydrate (3.79 mmol, 2.2 eq) were added sequentially. The mixture was heated to 126 °C and kept at that temperature for 2 hours. TLC detection showed that the starting material had disappeared. 2 g of triethylene glycol (14.54 mmol) was added, and the mixture was heated until the temperature in the reaction solution reached 210 °C. The reaction was continued for 3 hours until no gas was produced. After the reaction was complete, the heating was turned off, and the mixture was allowed to cool naturally to room temperature. The reaction solution was then poured into 40 mL of water and placed in an ice-water bath. The pH was adjusted to 2 with 12 M HCl and stirred for 30 min. White flocculent matter was produced. The solid was passed through cotton wool and dissolved in 20 mL of ethyl acetate. Column chromatography yielded 376 mg of CDCA.

[0061] Example 5

[0062] The method for synthesizing chenodeoxycholic acid provided in this embodiment includes the following experimental steps:

[0063] (1) In a 100 mL single-necked flask, add 10 mL of water, 2 mL of acetonitrile, and 1 g (2.45 mmol) of SM sequentially. Stir until homogeneous, adjust the pH to 7-8 with sodium hydroxide, and ensure the SM is completely dissolved. Then, add 0.35 g (1.23 mmol, 0.5 eq) of dibromohydantoin and 0.71 mL (7.3 mmol, 3 eq) of 35% hydrogen peroxide sequentially. After the addition is complete, heat to 60 °C and stir for 2 hours. TLC detection shows the starting material has disappeared. Cool to room temperature, adjust the pH to 1-2, extract with ethyl acetate, wash with saturated brine, dry, and evaporate to dryness before proceeding to the next step. 0.84 g of intermediate IM is obtained, with a yield of 84.5%. HPLC (normalization method) purity: 89%.

[0064] (2) In a 10 mL single-necked flask, add 0.84 g of IM1 (89% purity, 1.85 mmol), 1.95 g of triethylene glycol (12.9 mmol, 7 eq), 0.54 g of KOH (9.62 mmol, 5.2 eq), and 0.254 g of hydrazine hydrate (4.07 mmol, 2.2 eq) in sequence. Heat the mixture to 126 °C and keep it at that temperature for 2 hours. TLC detection showed that the starting material had disappeared. Add 2 g of triethylene glycol (14.54 mmol) and continue heating the mixture until the temperature in the reaction solution rises to 210 °C. React for 3 hours until no gas is produced. After the reaction is complete, turn off the heating and let it cool naturally to room temperature. Then pour the reaction solution into 40 mL of water, place it in an ice-water bath, adjust the pH to 2 with 12 M HCl, and stir for 30 min. White flocculent matter is produced. Pass the solid through cotton wool, dissolve it in 20 mL of ethyl acetate, and column chromatography to obtain 404 mg of CDCA.

[0065] Example 6

[0066] The method for synthesizing chenodeoxycholic acid provided in this embodiment includes the following experimental steps:

[0067] (1) In a 100 mL single-necked flask, add 10 mL of water, 2 mL of acetonitrile, and 1 g (2.45 mmol) of SM sequentially. Stir until homogeneous, adjust the pH to 7-8 with sodium hydroxide, and ensure the SM is completely dissolved. Then, add 0.35 g (1.23 mmol, 0.5 eq) of dibromohydantoin sequentially. After the addition is complete, raise the temperature to 60 °C and stir for 3 hours. TLC analysis shows that the starting material has not disappeared (the reaction time was further extended to 8 hours, but the starting material still did not disappear). Cool to room temperature, adjust the pH to 1-2, extract with ethyl acetate, wash with saturated brine, dry, and evaporate to dryness before proceeding to the next step. 0.80 g of intermediate IM was obtained, with a yield of 80.3%. HPLC (normalization method) purity: 45%.

[0068] (2) In a 10 mL single-necked flask, add 0.80 g of IM1 (content: 45%, 0.88 mmol), 0.93 g of triethylene glycol (6.19 mmol, 7 eq), 0.26 g of KOH (4.58 mmol, 5.2 eq), and 0.12 g of hydrazine hydrate (1.94 mmol, 2.2 eq) in sequence. Heat the mixture to 126 °C and keep it at that temperature for 2 hours. TLC detection showed that the starting material had disappeared. Add 2 g of triethylene glycol (14.54 mmol) and continue heating the mixture until the temperature in the reaction solution rises to 210 °C. React for 3 hours until no gas is produced. After the reaction is complete, turn off the heating and let it cool naturally to room temperature. Then pour the reaction solution into 40 mL of water, place it in an ice-water bath, adjust the pH to 2 with 12 M HCl, and stir for 30 min. White flocculent matter is produced. Pass the solid through cotton wool, dissolve it in 20 mL of ethyl acetate, and column chromatography to obtain 192 mg of CDCA.

[0069] Example 7

[0070] The method for synthesizing chenodeoxycholic acid provided in this embodiment includes the following experimental steps:

[0071] (1) In a 100 mL single-necked flask, add 12 mL of acetonitrile and 1 g (2.45 mmol) of SM sequentially, stir well, adjust the pH to 7-8 with sodium hydroxide, and after the SM is completely dissolved, add 0.24 g (1.23 mmol, 0.5 eq) of dichlorohydantoin and 0.71 mL (7.3 mmol, 3 eq) of 35% hydrogen peroxide sequentially. After the addition is complete, heat to 50 °C and stir for 2 hours. TLC detection shows that the starting material has not disappeared (the reaction time is further extended to 8 hours, and the starting material still has not disappeared). Cool to room temperature, adjust the pH to 1-2, extract with ethyl acetate, wash with saturated brine, dry, and evaporate to dryness to proceed directly to the next step. 0.95 g of intermediate IM is obtained, with a yield of 95.4%. HPLC (normalization method) purity: 42%.

[0072] (2) In a 10 mL single-necked flask, add 0.95 g of IM1 (42% purity, 0.98 mmol), 1.03 g of triethylene glycol (6.83 mmol, 7 eq), 0.29 g of KOH (5.10 mmol, 5.2 eq), and 0.134 g of hydrazine hydrate (2.16 mmol, 2.2 eq) in sequence. Heat the mixture to 126 °C and keep it at that temperature for 2 hours. TLC detection showed that the starting material had disappeared. Add 2 g of triethylene glycol (14.54 mmol) and continue heating the mixture until the temperature in the reaction solution rises to 210 °C. React for 3 hours until no gas is produced. After the reaction is complete, turn off the heating and let it cool naturally to room temperature. Then pour the reaction solution into 40 mL of water, place it in an ice-water bath, adjust the pH to 2 with 12 M HCl, and stir for 30 min. White flocculent matter is produced. Pass the solid through cotton wool, dissolve it in 20 mL of ethyl acetate, and column chromatography to obtain 214 mg of CDCA.

[0073] Comparative Example 1

[0074] The method for synthesizing chenodeoxycholic acid provided in this comparative example includes the following experimental steps:

[0075] In a 100 mL single-necked flask, 10 mL of water, 2 mL of acetonitrile, and 1 g (2.45 mmol) of SM were added sequentially. The mixture was stirred until homogeneous. The pH was adjusted to 7-8 with sodium hydroxide until the SM was completely dissolved. Then, 1.68 g of sodium hypochlorite aqueous solution (5% NaClO, 1.23 mmol) and 0.71 mL (7.3 mmol, 3 eq) of 35% hydrogen peroxide were added sequentially. After the addition was complete, the temperature was raised to 50 °C, and the reaction was stirred for 2 hours. TLC analysis showed that the starting material had disappeared. The mixture was cooled to room temperature, the pH was adjusted to 1-2, and the product was extracted with ethyl acetate, washed with saturated brine, dried, and evaporated to dryness to obtain 0.92 g of the product. HPLC (normalization method) purity: 4%. No further steps were performed.

[0076] Comparative Example 2

[0077] The method for synthesizing chenodeoxycholic acid provided in this comparative example includes the following experimental steps:

[0078] In a 100 mL single-necked flask, 10 mL of water, 2 mL of acetonitrile, and 1 g (2.45 mmol) of SM were added sequentially. The mixture was stirred until homogeneous. The pH was adjusted to 7-8 with sodium hydroxide until the SM was completely dissolved. 0.71 mL (7.3 mmol, 3 eq) of 35% hydrogen peroxide was added. After the addition was complete, the temperature was raised to 50 °C, and the reaction was stirred for 2 hours. TLC analysis showed that the starting material had disappeared. The mixture was cooled to room temperature, the pH was adjusted to 1-2, and the sample was extracted with ethyl acetate. The extract was then washed with saturated brine, dried, and evaporated to dryness to obtain 0.86 g of the product. HPLC (normalization method) purity: 10%. No further steps were performed.

[0079] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0080] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for synthesizing chenodeoxycholic acid, characterized in that, Includes the following steps: (1) The raw material SM and the oxidant undergo an oxidation reaction in a solvent to obtain intermediate IM1; (2) Intermediate IM1 is reduced to chenodeoxycholic acid; The reaction formula is as follows: The oxidant is composed of dihalohydantoin and hydrogen peroxide, wherein the dihalohydantoin is dichlorohydantoin and / or dibromohydantoin. The solvent is a mixture of water and acetonitrile with a volume ratio of 1-10:

1.

2. The method for synthesizing chenodeoxycholic acid according to claim 1, characterized in that, The solvent is a mixture of water and acetonitrile with a volume ratio of 4-6:

1.

3. The method for synthesizing chenodeoxycholic acid according to claim 1, characterized in that, The molar ratio of the raw material SM and dihalohydantoin is 1:0.3-1.

5.

4. The method for synthesizing chenodeoxycholic acid according to claim 3, characterized in that, The molar ratio of the raw material SM and dihalohydantoin is 1:0.5-0.

6.

5. The method for synthesizing chenodeoxycholic acid according to claim 1, characterized in that, The molar ratio of the raw material SM to hydrogen peroxide is 1:2.5-3.

5.

6. The method for synthesizing chenodeoxycholic acid according to any one of claims 1-5, characterized in that, The ratio of the raw material SM to the solvent is 1g: 5mL-20mL.

7. The method for synthesizing chenodeoxycholic acid according to claim 6, characterized in that, The ratio of the raw material SM to the solvent is 1g: 5mL-15mL.

8. The method for synthesizing chenodeoxycholic acid according to any one of claims 1-5, characterized in that, The reaction conditions in step (1) include: pH 7-9, temperature 10℃-70℃, and time 1 hour-8 hours.

9. The method for synthesizing chenodeoxycholic acid according to any one of claims 1-5, characterized in that, Step (2) includes: (a) A mixed solution of intermediate IM1, triethylene glycol, KOH and hydrazine hydrate was reacted at 110℃-140℃ for 1-3 hours; (b) Add triethylene glycol to the mixture after the reaction in step (a), and then continue heating the resulting mixture until the internal temperature of the reaction solution is 200°C-220°C, and continue heating until no gas is produced; (c) Cool naturally to room temperature, then pour the reaction solution into water, place in an ice-water bath, adjust the pH to 1-3, and stir to obtain the final product.

10. The method for synthesizing chenodeoxycholic acid according to claim 9, characterized in that, The molar ratio of intermediate IM1, triethylene glycol, KOH and hydrazine hydrate in step (a) is 1:6-8:4-6:1.5-3; and / or the molar ratio of the triethylene glycol added in step (b) to intermediate IM1 is 7-17:1.

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