Preparation method of repaglinide key intermediate

A technology for intermediates and carbon monoxide, applied in the field of synthesis of repaglinide intermediates, can solve the problems of harsh reaction conditions, difficult operation, unstable process, etc., and achieves simple operation, easy control, and good reaction reproducibility. Effect

Inactive Publication Date: 2019-11-22
HANGZHOU ZHONGMEI HUADONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] In summary, the existing synthetic route has the defects of long route, low total yield, harsh reaction conditions, difficult operation, unstable process, etc., which are not suitable for industrial production. Therefore, a synthetic route with simple route, mild conditions and suitable for industrial production is developed. routes are very important

Method used

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  • Preparation method of repaglinide key intermediate
  • Preparation method of repaglinide key intermediate
  • Preparation method of repaglinide key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Add 4-methyl-2-ethoxy ethyl benzoate (2.08g, 10mmol), ethanol (23g, 0.50mol), tetrahydrofuran (100mL), tert-butyl peroxy ether (1.75g, 10mmol) successively in the reaction kettle , PdCl 2 (54.3mg, 0.3mmol) and 1,2-bis(di-2-pyridylphosphine)ethane (123.3mg, 0.3mmol), charged with 2.0MPa of CO, heated to reflux, and stirred for 20 hours. Cool to room temperature, add 2mol / L sodium hydroxide aqueous solution (30mL) to the reaction solution after pressure relief, stir and react for 6 hours, add cyclohexane (50mL×3) to wash, the reaction solution is neutralized to pH 7 with hydrochloric acid, reduce Concentrate under reduced pressure to about 50 mL, acidify to pH 3 with hydrochloric acid, precipitate a yellow solid, filter, and recrystallize the filter residue with toluene-petroleum ether to obtain white solid intermediate (I) (1.94 g, yield: 76.9%).

Embodiment 2

[0042] In the reaction kettle, add 4-methyl-2-ethoxy ethyl benzoate (2.08g, 10mmol), ethanol (80.0g, 1.74mol), potassium persulfate (7.53g, 12mmol), triruthenium dodecacarbonyl (193.8mg, 0.3mmol), 2-bis(diphenylphosphine)methylenepyridine (82.2mg, 0.3mmol), charged with 2.0MPa of CO, heated to reflux, and stirred for 10 hours. After cooling to room temperature, 2 mol / L potassium hydroxide aqueous solution (10 mL) was added to the reaction solution after the pressure was released, and the reaction was stirred for 6 hours. Wash with cyclohexane (50mL×3), neutralize with hydrochloric acid to pH 7, concentrate under reduced pressure to about 50mL, acidify with hydrochloric acid to pH 3, precipitate a yellow solid, filter, and recrystallize the filter residue with toluene-petroleum ether to obtain a white solid Intermediate (I) (2.06 g, yield: 81.7%).

Embodiment 3

[0044] Add 4-methyl-2-ethoxy ethyl benzoate (2.08g, 10mmol), isopropanol (100mL, 1.33mol), 30% hydrogen peroxide (13.6mL, 12mmol), copper fluoride (24.9mL) in the reaction kettle mg, 0.3mmol), bis-(diphenylphosphine)ethylamine (132.9mg, 0.3mmol), filled with 2.0MPa of CO, heated to reflux, and stirred for 10 hours. Cool to room temperature, add 2mol / L potassium hydroxide aqueous solution (30mL) to the reaction liquid after pressure relief, stir and react at 40°C for 6 hours, add cyclohexane (50mL×3) to wash, and neutralize the reaction liquid with hydrochloric acid until the pH is 7 , concentrated under reduced pressure to about 50 mL, acidified with hydrochloric acid to pH 3, precipitated a yellow solid, filtered, and recrystallized the filter residue with toluene-petroleum ether to obtain white solid intermediate (I) (1.87 g, yield: 74.1%).

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Abstract

The invention discloses a preparation method of a repaglinide key intermediate (I). The preparation method comprises the following steps: reacting ethyl 4-methyl-2-ethoxybenzoate (II) with carbon monoxide and alcohol under the conditions of a catalyst and an oxidant, and selectively hydrolyzing reactants to obtain an intermediate (I). The preparation method is simple, efficient, mild in condition,good in reproducibility, high in yield and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, in particular to a method for synthesizing a repaglinide intermediate (I). Background technique [0002] Repaglinide is a new type of non-sulfonylurea short-acting oral insulin-stimulating hypoglycemic drug developed by Boehringer Ingelheim, Germany. Repaglinide will not accumulate in tissues, has good safety, and has a synergistic effect with biguanides. It can be used alone as a first-line diabetes drug or combined with other hypoglycemic drugs to increase the efficacy. [0003] [0004] Intermediate (I) 2-(3-ethoxy-4-(ethoxyl)phenyl)acetic acid is the key intermediate of repaglinide. In the prior art, the intermediate (I) is mainly prepared from ethyl 4-methyl-2-ethoxybenzoate (II) as a raw material. [0005] [0006] The first reported synthetic route is: ethyl 4-methyl-2-ethoxybenzoate (II) is brominated, cyano-substituted, cyano-hydrolyzed to diacid, esterified, an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/36C07C67/313C07C69/92
CPCC07C67/313C07C67/36C07C69/92
Inventor 余睿洪旭明郑敏邵青凌
Owner HANGZHOU ZHONGMEI HUADONG PHARMA
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