Repaglinide synthesis process

A process and compound technology, applied in the field of synthesizing repaglinide, can solve the problems of long reaction time, low yield, high price, etc., and achieve the effect of simple operation, easy-to-obtain raw materials, and low price

Inactive Publication Date: 2006-11-22
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the process mentioned in the patent, N,N'-dicyclohexylcarbodiimide is used to synthesize, and the product needs to be recrystallized multiple times to remove the by-product N,N'-dicyclohexylurea, which increases the production cost; Utilize the product yield that carbonyldiimidazole catalyzes synthesis to obtain low, only have 50~55%, and carbonyldiimidazole is relatively more expensive; And utilize triphenylphosphine, triethylamine, carbon tetrachloride to synthesize, this method Although the yield has increased, the purity of the product can only be achieved by column chromatography
[0006] Subsequently, a new process for the synthesis of repaglinide reported in US2005/0107614 is obtained by condensation of

Method used

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  • Repaglinide synthesis process

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Effect test

Embodiment 1

[0032] Ethyl S(+)-2-ethoxy-4-[N-{1-(2-piperidinylphenyl)-3-methyl-1-butyl}aminocarbonylmethyl]benzoate preparation

[0033] Add ethyl benzoate compound (2) (2.31g, 9.13mmol) into 20ml of dichloromethane, stir at 25°C, slowly add thionyl chloride (1.36g, 11.4mmol), and drop it at 40°C Heated to reflux for 1 hour, cooled to 0-5°C, added triethylamine (1.15g, 11.4mmol), then slowly added a solution of compound 3 (2.25g, 9.13mmol) in dichloromethane (10ml), dropwise After completion, the temperature was raised to 25°C, and the stirring reaction was continued for 3 hours, then 10×2ml of water was added to wash, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and 3.82g of the product was obtained by recrystallization in toluene-n-hexane, with a yield of 87%. .

Embodiment 2

[0035] Preparation of repaglinide

[0036] Add ethyl benzoate compound 4 (2.15g, 4.47mmol) into methanol 25ml, stir and reflux at 65°C, then slowly add 0.9mol / L sodium hydroxide solution (9.94ml, 8.94mmol) and react for 3 hours, Cool to 40-45°C, then add 0.6mol / L hydrochloric acid solution to pH ≈ 5, cool and stir in an ice bath for 0.5h, filter, wash with water, and dry 1.88g of the product, with a yield of 93%.

Embodiment 3

[0038] Methyl S(+)-2-ethoxy-4-[N-{1-(2-piperidinylphenyl)-3-methyl-1-butyl}aminocarbonylmethyl]benzoate preparation

[0039] Add methyl benzoate compound (2) (1.42g, 5.95mmol) into chloroform (12ml), stir, cool to -10°C, slowly add oxalyl chloride (0.38g, 2.98mmol), continue to React at this temperature for 3 hours, then add potassium carbonate (0.81g, 5.95mmol), heat up to 60°C, slowly add 8ml of a chloroform solution of compound 3 (1.47g, 5.95mmol), and continue to stir after the dropwise addition. hours, then add 10×2ml of water to wash, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and recrystallize in toluene-n-hexane to obtain 1.49 g of the product, with a yield of 53.6%.

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Abstract

This invention discloses a process for synthesizing repaglinide by using 4-carboxymethyl-3-ethoxybenzoate as raw material to produce acyl chloride. Compared to other process, this invention is characterized of high efficiency, low toxicity, easy obtained and cheap raw material, simple operation, and high yield with 80.9% total yield rate in two-step reaction, which makes it a good repaglinide systhesis process with good industrialization future.

Description

technical field [0001] The invention relates to the field of organic synthesis of medicines, in particular to a process for synthesizing repaglinide Background technique [0002] The chemical name of repaglinide is S(+)-2-ethoxy-4-[N-{1-(2-piperidinylphenyl)-3-methyl-1-butyl}amine Cylcarbonylmethyl]benzoic acid, a new type of oral hypoglycemic drug belonging to the methylbenzylamine benzoic acid (CBMA) family, can promote insulin secretion. It is different from the binding site of β cells and sulfonylureas, and has With the characteristics of fast absorption, fast onset and short action time, it can simulate physiological insulin secretion in patients with type II diabetes, effectively control postprandial hyperglycemia, has a high protein binding rate, and will not accumulate in tissues. Good safety, and synergistic effect with biguanides. It can be used alone as a first-line antidiabetic drug, and can also be used in combination with other hypoglycemic drugs to increase ...

Claims

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Application Information

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IPC IPC(8): C07D295/135
Inventor 杨健许惠钢
Owner ZHEJIANG UNIV
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