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CN-116836213-B - 7-Ketolithocholic acid intermediate and synthesis method and application thereof

CN116836213BCN 116836213 BCN116836213 BCN 116836213BCN-116836213-B

Abstract

The invention provides a synthetic method of 7-ketolithocholic acid or an intermediate thereof, which is prepared by a novel intermediate I-1. The method can take plant sterol degradation product bispinol as a starting material, and obtain 7-ketolithocholic acid or an intermediate thereof through oxidation reaction, knoevenagel reaction (or wittig reaction), hydrogenation reaction, esterification reaction, ketal protection reaction, allylic oxidation reaction, ketal removal protection reaction and hydrogenation reaction. The method has the advantages of easily obtained raw materials, high yield, simple and mild reaction conditions and suitability for industrial production.

Inventors

  • YANG YINGQUAN
  • YUAN HAITAO
  • Zhou Fanlong
  • WANG FEI
  • WU HUCHENG

Assignees

  • 苏州恩泰新材料科技有限公司

Dates

Publication Date
20260505
Application Date
20220607
Priority Date
20220325

Claims (20)

  1. 1. A method for preparing a compound of formula I is characterized by comprising the steps of carrying out hydrogenation reaction on a compound I-1 under the action of a catalyst to obtain the compound of formula I, Wherein, R 1 is H, C 1-6 alkyl; the reaction is carried out in the presence of a solvent selected from the group consisting of amide solvents.
  2. 2. The method of claim 1, wherein R 1 is methyl, ethyl, propyl, or t-butyl.
  3. 3. The method of claim 1, wherein the catalyst is selected from a Raney Ni catalyst, a Pd/C catalyst, a Pt/C catalyst, or a Ru/C catalyst.
  4. 4. The method according to claim 1, wherein the amide-based solvent is selected from at least one of N, N-dimethylformamide, N-dimethylacetamide, formamide, N-methylpyrrolidone, N-methylformamide, N-methylacetamide, and N, N-dimethylpropylurea.
  5. 5. The method of claim 1, wherein when R 1 is C 1-6 alkyl in the compound of formula I, further comprising hydrolyzing the compound of formula I wherein R 1 is C 1-6 alkyl to provide a compound of formula I wherein R 1 is H;
  6. 6. An intermediate compound I-1 as shown below: Wherein R 1 has the definition as defined in claim 1.
  7. 7. A process for preparing the compound I-1 as claimed in claim 6, comprising, Wherein R 1 has the definition in claim 1, R 2 is C 1-6 alkyl; h) Carrying out allylic oxidation reaction on the compound I-3 to obtain a compound I-2; i) The compound I-2 is subjected to glycol removal protection to obtain a compound I-1 with R 1 being C 1-6 alkyl, or the compound I-2 is subjected to glycol removal protection and hydrolysis reaction to obtain a compound I-1 with R 1 being H.
  8. 8. The process according to claim 7, wherein in step h) the reaction is carried out in the presence of an oxidizing agent and a catalyst.
  9. 9. The process according to claim 8, wherein step h) is carried out under the following reaction system h1 or h 2: The method comprises the steps of h1, oxidizing agent is oxygen or air, and catalyst is a reaction system of N-hydroxyphthalimide and cobalt acetate; And h2, oxidizing agent is tert-butyl peroxide, and catalyst is a reaction system of manganese (III) acetate, manganese (III) acetate dihydrate or cuprous iodide.
  10. 10. The method of claim 9 wherein a free radical initiator is also added to h 1.
  11. 11. The method of claim 10, wherein the free radical initiator is benzoyl peroxide.
  12. 12. The process according to claim 7, wherein in step i) the desethylene glycol protection reaction is carried out under the action of an acid selected from at least one of concentrated sulfuric acid, concentrated hydrochloric acid and p-toluenesulfonic acid, and the hydrolysis reaction is carried out under alkaline conditions.
  13. 13. The method according to claim 12, wherein the hydrolysis reaction is performed in the presence of sodium hydroxide, potassium hydroxide.
  14. 14. The method according to claim 7, wherein the preparation method of the compound I-3 comprises the following method one or the following method two: The method comprises the following steps: Wherein R 2 has the definition of claim 7; b) Combining Compound I-8 with Carrying out Knoevenagel condensation reaction to obtain a compound I-7, or carrying out a condensation reaction on the compound I-8 and the compound I-7 Carrying out wittig reaction to obtain a compound I-7, wherein R 3 、R 4 is C 1-6 alkyl; d) Performing glycol protection on the compound I-7 to obtain a compound I-5; f) Carrying out reduction reaction on the compound I-5 to obtain a compound I-3; The second method is as follows: Wherein R 2 has the definition of claim 7; c) Combining Compound I-8 with Carrying out Knoevenagel condensation reaction to obtain a compound I-6, wherein R 5 、R 6 is C 1-6 alkyl or R 5 、R 6 and the connected carbon atom form C 3-8 cycloalkyl; e) Reacting the compound I-6 with R 2 OH to obtain a compound I-4; g) And (3) protecting the compound I-4 by glycol to obtain a compound I-3.
  15. 15. The method of claim 14 wherein R 3 、R 4 is ethyl and R 5 、R 6 is methyl.
  16. 16. The process according to claim 14, wherein the Knoevenagel condensation reaction of step b) is carried out in the presence of a catalyst, which is DMAP.
  17. 17. The process according to claim 14, characterized in that step d) is carried out under the action of a catalyst selected from catalyst a selected from p-toluene sulphonic acid or concentrated sulphuric acid and/or catalyst B selected from trimethyl orthoformate, triethyl orthoformate or trimethyl orthoacetate.
  18. 18. The process according to claim 14, wherein step f) is carried out under the action of a catalyst, said catalyst being Pd/C.
  19. 19. The method according to claim 14, wherein step e) is performed under the action of a catalyst selected from at least one of concentrated sulfuric acid, p-toluene sulfonic acid and hydrochloric acid.
  20. 20. The process according to claim 14, characterized in that step g) is carried out under the action of a catalyst selected from catalyst a selected from p-toluene sulphonic acid or concentrated sulphuric acid and/or catalyst B selected from trimethyl orthoformate, triethyl orthoformate or trimethyl orthoacetate.

Description

7-Ketolithocholic acid intermediate and synthesis method and application thereof The invention claims priority from a prior application entitled "7-ketolithocholic acid intermediate and its synthesis method and application", filed by the national intellectual property agency of China at 3 and 25 of 2022, with patent application number 2022103218915. The entirety of this prior application is incorporated by reference into the present invention. Technical Field The invention belongs to the field of medicine synthesis, and particularly relates to a 7-ketolithocholic acid intermediate, and a synthesis method and application thereof. Background 7-Ketolithocholic acid (7-Ketolithocholic acid), CAS number 4651-67-6, molecular formula C 24H38O4, molecular weight 390.56, structural formula shown below: 7-ketolithocholic acid is an important pharmaceutical intermediate. Chenodeoxycholic acid (Tetrahedron Letters Volume 24,Issue 24,1983,Pages 2487-2490), ursodeoxycholic acid (J.org.chem.1993, 58, 499-501), obeticholic acid (J.Med.chem.2002, 45, 17, 3569-3572) and the like can be synthesized by using 7-ketolithocholic acid as an intermediate. Most of the current production processes of ursodeoxycholic acid and obeticholic acid are basically based on a method using 7-ketolithocholic acid as a raw material, so that efficient obtaining of 7-ketolithocholic acid becomes very important. From the current literature and patent investigation, the synthesis of 7-ketolithocholic acid is largely divided into the following methods: 1. Cholic acid is used as raw material WO2014020024A1 reports that cholic acid is used as a raw material, acid of a side chain is esterified by methanol hydrochloride, hydroxyl groups at 3,7 positions are protected by acetic anhydride, hydroxyl groups at 12 positions are oxidized by sodium hypochlorite to form ketone, 12-position ketone is reduced by corymbose, and finally 7-position hydroxyl groups are selectively oxidized by sodium hypobromite to form ketone to obtain the target compound 7-ketolithocholic acid. The whole process uses the yellow cronnong reaction with high temperature, the reaction temperature of the step is high, hydrazine hydrate has high toxicity and easy explosion, and the requirement on equipment is high. 2. Chenodeoxycholic acid is used as raw material CN106046095 reports that in acetone and water, NBS oxidation of chenodeoxycholic acid gives 7-ketolithocholic acid, which is expensive and limits its application. 3. Uses hyocholic acid as raw material Patent CN110423261 a reports a preparation method using hyocholic acid as raw material. The scheme has the defects that 1) a chromium reagent such as Jones reagent is used, the pollution is high, the environmental protection pressure is high, 2) part of the reagent such as lithium iodide is high in price, TBSCl is high in overall cost, 3) pyridine is used as a solvent in the third step, and the odor is high and the toxicity is high. In addition to the disadvantages of the three methods, the other major reason is that the methods are all using cholic acid of animal origin, and the animal body is generally provided with a plurality of animal viruses such as swine fever, avian influenza, prion and other various physiologically active substances, so that the animal body has certain biotoxicity to human bodies. Therefore, there is a need to find new, safe and effective 7-ketolithocholic acid intermediates and methods for their synthesis. Disclosure of Invention In order to solve the technical problems, the invention aims to provide a preparation method of 7-ketolithocholic acid or an intermediate thereof, which is simple, high in yield, safe and effective and is prepared by a novel intermediate I-1. It is another object of the present invention to provide a novel intermediate I-1 and a process for its preparation. The aim of the invention is achieved by the following technical scheme: the preparation process of compound of the formula I includes hydrogenating compound I-1 in the presence of catalyst to obtain compound of the formula I; wherein R 1 is H, alkyl, e.g., C 1-6 alkyl, e.g., methyl, ethyl, propyl, or t-butyl; According to an embodiment of the present invention, in the above reaction, the catalyst is selected from Raney Ni catalyst, pd/C catalyst, pt/C catalyst or Ru/C catalyst. According to an embodiment of the invention, in the above reaction, the mass ratio of the compound I-1 to the catalyst is (2-20): 1, for example (5-15): 1, exemplary 10:1; According to an embodiment of the present invention, in the above reaction, the reaction is carried out in the presence of a solvent, which is an amide-based solvent, for example, at least one selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, formamide, N-methylpyrrolidone, N-methylformamide, N-methylacetamide, and N, N-dimethylpropylurea. According to the invention, when R 1 in the compound of formula I is alkyl, the method further comprises the step of