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CN-122010712-A - Synthesis method of bevacizidine and intermediate thereof

CN122010712ACN 122010712 ACN122010712 ACN 122010712ACN-122010712-A

Abstract

The invention provides a preparation method of bevacizidine and an intermediate thereof, which comprises the steps of reacting a compound 4 with a compound 5 in the presence of alkali to obtain a compound 6, and hydrolyzing and dehydroxylating the compound 6 to obtain the bevacizidine. The preparation method of the beipezic acid has the advantages of short route, low cost, higher yield of each step of reaction and less byproducts, and is suitable for industrialized mass production.

Inventors

  • ZHAI NING
  • WANG GUOPING
  • YU ZHENPENG
  • ZHAO MIN
  • YANG YANG

Assignees

  • 扬州奥锐特药业有限公司

Dates

Publication Date
20260512
Application Date
20241111

Claims (10)

  1. 1. A method for preparing bevacizidine, comprising the steps of: Reacting compound 4 with compound 5 in the presence of a base to give compound 6, and Hydrolyzing the compound 6 and removing the hydroxyl protecting group to obtain the bepaigesic acid, The reaction formula is as follows: Wherein R 1 is selected from silicon-based, benzyl, C 1 -C 6 alkyl or allyl, said silicon-based, benzyl, C 1 -C 6 alkyl or allyl being optionally further substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 5 -C 6 cycloalkyl, aryl, and R 2 is selected from C 1 -C 6 alkyl.
  2. 2. The method for preparing bevacizine according to claim 1, wherein R 1 is selected from the group consisting of trimethylsilyl, t-butylsilyl, t-butyldiphenylsilyl, methoxymethyl, and R 2 is selected from methyl or ethyl.
  3. 3. The process for the preparation of bevacizidine acid according to claim 1 or 2, characterized in that the base is chosen from among organic non-nucleophilic strong bases, Preferably, the organic non-nucleophilic strong base is selected from lithium diisopropylamide or sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, or a combination thereof, more preferably lithium diisopropylamide.
  4. 4. The method for preparing bevacizidine according to claim 1 or 2, wherein the method for preparing the compound 4 comprises the steps of: The compound 3 reacts with a hydroxyl protecting agent to obtain a compound 4, and the reaction formula is as follows: Preferably, the hydroxyl protecting agent is selected from the group consisting of trimethylchlorosilane, t-butyldimethylsilyl chloride, t-butyldiphenylchlorosilane, benzyl chloride, 2-tetrahydropyran, methoxymethyl chloride, allyl chloride, or a combination thereof, more preferably trimethylchlorosilane, and/or Preferably, the reaction of compound 3 with the hydroxyl protecting agent is carried out in the presence of an acid-binding agent, preferably selected from pyridine, imidazole, triethylamine, or a combination thereof, more preferably triethylamine.
  5. 5. The method for preparing bevacizidine according to claim 4, wherein the method for preparing the compound 3 comprises the steps of: reacting compound 1 with a brominating agent to give compound 2, and Reducing the compound 2 to give a compound 3, The reaction formula is as follows:
  6. 6. The process for preparing bevacizine according to claim 5, wherein said brominating agent is selected from the group consisting of hydrogen bromide, hydrobromic acid, phosphine tribromide, or a combination thereof, more preferably hydrogen bromide, and/or The reducing agent used is selected from sodium borohydride, lithium aluminum hydride, potassium borohydride, aluminum isopropoxide, more preferably sodium borohydride.
  7. 7. A method for preparing bevacizidine, comprising the steps of: the compound 3 reacts with a hydroxyl protecting agent to obtain a compound 4, Reacting compound 4 with compound 5 in the presence of a base to give compound 6, and Hydrolyzing the compound 6 and removing the hydroxyl protecting group to obtain the bepaigesic acid, The reaction formula is as follows: Wherein R 1 is selected from the group consisting of silicon, benzyl, C 1 -C 6 alkyl, or allyl, said silicon, benzyl, C 1 -C 6 alkyl, or allyl being optionally further substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 5 -C 6 cycloalkyl, aryl, and R 2 is selected from C 1 -C 6 alkyl.
  8. 8. A method for preparing bevacizidine, comprising the steps of: (1) The compound 1 reacts with a brominating agent to obtain a compound 2, (2) Reducing the compound 2 to obtain a compound 3; (3) Reacting the compound 3 with a hydroxyl protecting agent to obtain a compound 4; (4) Reacting compound 4 with compound 5 in the presence of a base to give compound 6, and (5) Hydrolyzing the compound 6 and removing the hydroxyl protecting group to obtain the bepaigesic acid, The reaction formula is as follows: Wherein R 1 is selected from the group consisting of silicon, benzyl, C 1 -C 6 alkyl, or allyl, said silicon, benzyl, C 1 -C 6 alkyl, or allyl being optionally further substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 5 -C 6 cycloalkyl, aryl, and R 2 is selected from C 1 -C 6 alkyl.
  9. 9. A method for preparing bevacizidine, comprising the steps of: (1) The compound 1 reacts with a brominating agent to obtain a compound 2, (2) The compound 2 is reduced to obtain a compound 3, (3) The compound 3 reacts with trimethylchlorosilane to obtain a compound 4-1, (4) Reacting compound 4-1 with compound 5-1 in the presence of a base to give compound 6, and (5) Hydrolyzing the compound 6 to obtain the bevacizidine, The reaction formula is as follows: 。
  10. 10. A process for the preparation of compound 6, comprising the steps of: the compound 4 and the compound 5 are reacted in the presence of a base to obtain a compound 6, wherein the reaction formula is as follows: Wherein R 1 is selected from the group consisting of silicon, benzyl, C 1 -C 6 alkyl, or allyl, said silicon, benzyl, C 1 -C 6 alkyl, or allyl being optionally further substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 5 -C 6 cycloalkyl, aryl, and R 2 is selected from the group consisting of C 1 -C 6 alkyl, More preferably, R 1 is selected from trimethylsilyl, t-butylsilyl, t-butyldiphenylsilyl, methoxymethyl, and R 2 is selected from methyl or ethyl.

Description

Synthesis method of bevacizidine and intermediate thereof Technical Field The invention belongs to the field of organic compound preparation, and in particular relates to a synthesis method of bevacizidine and an intermediate thereof. Background Bevacizidine (Bempedoic acid) is an adenosine triphosphate citrate lyase (ACL) inhibitor that reduces low density lipoprotein cholesterol (LDL-C) by inhibiting cholesterol synthesis in the liver. The drug was marketed in the united states by the U.S. Food and Drug Administration (FDA) 2 months in 2020, and was the first non-statin oral cholesterol-lowering drug approved by the FDA for the last 20 years, for the treatment of heterozygous familial hypercholesterolemia adult patients, or adult patients in need of further lowering LDL-C atherosclerosis cardiovascular disease. The molecular structural formula is shown as follows: At present, a plurality of reported synthetic routes exist for synthesizing bepaigesic acid at home and abroad, and the problems of complicated process route, high production cost and the like exist. The synthetic route for bevacizidine reported in prior art WO2004067489 is shown in scheme 1 below: According to the method, ethyl isobutyrate and 1, 5-dibromopentane are used as starting materials, lithium Diisopropylamide (LDA) is condensed at low temperature to obtain 7-bromo-2, 2-dimethylheptanoic acid ethyl ester (compound 1), the compound 1 is used as an alkylating reagent to be catalyzed by tetrabutylammonium iodide (TBAI) under a strong alkaline condition with methyl isonitrile p-toluenesulfonate (TosMIC) to prepare a compound 2, then the compound 2 is hydrolyzed under an acidic condition to obtain a compound 3, the compound 3 is hydrolyzed in an ethanol system to obtain a compound 4, and then the compound 4 is reduced by NaBH 4 to obtain the target product bepric acid. The process has the advantages that alpha position alkylation is poor in selectivity, disubstituted impurities cannot be avoided, p-toluenesulfonyl methyl isonitrile used in the second step is high in toxicity and difficult to obtain, atom economy is poor, dangerous material sodium hydride is used, industrial production operation is not facilitated, selectivity is improved by using excessive 1, 5-dibromopentane, and related impurities such as 1, 5-dibromopentane are large in residue, and rectification purification is needed. And potential genotoxic impurities (p-toluenesulfonyl derivatives) can be generated after the third step of hydrolysis, which is unfavorable for quality control of bulk drugs. In conclusion, the route has large loss and high potential risk, and is not suitable for industrial production. The synthetic route reported by prior art CN116396158 for bepaigesic acid is shown in scheme 2 below: Caprolactone is used as a starting material, key intermediates 1, 11-dibromoundecane-6-oxo-trimethylsilyl ether is obtained through ring-opening methylation, titanium tetrachloride catalyzed claisen condensation, alkaline hydrolysis decarboxylation, bromination, sodium borohydride reduction and trimethylsilane protection (6 steps), then the key intermediates are coupled with (1-ethoxy-2-methyl-1-oxo-propane-2-yl) zinc bromide to obtain 2,2,14,14-tetramethyl-8- (trimethylsiloxy) pentadecane diethyl dicarboxylic acid, and finally hydrolysis and deprotection are carried out under acidic conditions to obtain the bevacizide. The route uses cheap caprolactone as a starting material, but the route is longer, and meanwhile, the price of the used ethyl 2-bromoisobutyrate is higher, so that the production cost is greatly increased. The synthetic route reported by prior art CN114907204 for bepaigesic acid is shown in scheme 3 below: The method takes valerolactone as a starting material, and obtains the target compound bevacizumab through claisen condensation, bromination, glycol protection, copper-catalyzed format coupling and sodium borohydride reduction. The route has ingenious design and simple route, but the 3, 3-dimethyl oxetan-2-one used is high in price and not easy to obtain, and meanwhile, the Grignard coupling reaction is difficult to control, the yield is low, so that the industrialized application of the route is limited. The synthetic route reported by prior art CN114907204 for bepaigesic acid is shown in the following scheme 4: Caprolactone is used as a starting material, key intermediates 1, 11-dibromoundecane-6-oxo-trimethylsilyl ether is obtained through ring-opening methylation, dieckmann condensation catalyzed by titanium tetrachloride, alkaline hydrolysis decarboxylation, bromination, sodium borohydride reduction and trimethylsilane protection (6 steps), then the key intermediates are coupled with (1-ethoxy-2-methyl-1-oxo-propane-2-yl) zinc bromide to obtain 2,2,14,14-tetramethyl-8- (trimethylsiloxy) pentadecane diethyl dicarboxylic acid, and finally the intermediate is hydrolyzed and deprotected under an acidic condition to obtain bevacizine. This route, although