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Synthesis of pharmaceutical

A technology for esters and compounds, which is applied to the field of one-pot synthesis of nateglinide, can solve the problems of complex processing, increased difficulty in industrialization, trouble, and the like, and achieves the effect of saving costs

Inactive Publication Date: 2008-06-04
TIANJIN PHARMA GROUP CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the one-pot reaction process is more complicated to deal with, and the post-treatment of the hydrochloride of the first step product D-phenylalanine ester is cumbersome, requiring alkali neutralization treatment, using a large amount of triethylamine or ammonia water, which needs to be processed after using ammonia water. Using lysozyme layered extraction method is extremely troublesome
And the reaction time of this step is very long, more than 24 hours
These factors make the industrialization of the product more difficult

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0035] Add 100ml of methanol to the reaction flask, cool to 0-5°C, keep the temperature below 10°C, add 10ml of thionyl chloride dropwise, add 10g of D-phenylalanine, raise the temperature, keep at 40±2°C for 15 hours, After the reaction, distill off the methanol and precipitate the solid, add 25ml of dichloromethane, stir until the solid is completely dissolved, add 3.5g of 1-hydroxybenzotriazole, cool down to 0-5°C, add 9.5g of p-isopropylcyclohexanecarboxylic acid , keep the temperature below 5°C, add 25ml of dichloromethane dissolved with 12.5g N,N'-dicyclohexylcarbodiimide dropwise into the reaction solution in 1 hour, after the addition is completed, keep it at 10-15°C for 3 hours After the reaction is complete, use a funnel covered with celite to filter, use 25ml of 5% NaOH washing solution to wash the reaction solution twice, and then wash to neutrality. Evaporate dichloromethane, use 65ml of methanol for phase change, lower the temperature to 20-25°C, keep the tempera...

Embodiment 2

[0038] Add 100ml of ethanol to the reaction bottle, cool to 0-5°C, keep the temperature below 10°C, add 10ml of thionyl chloride dropwise, add 10g of D-phenylalanine, raise the temperature, keep at 40±2°C for 15 hours, After the reaction, the ethanol was evaporated and the solid was precipitated, and 25ml of chloroform was added, stirred until the solid was completely dissolved, then 3.5g of 1-hydroxybenzotriazole was added, the temperature was lowered to 0-5°C, 9.5g of p-isopropylcyclohexanecarboxylic acid was added, and kept When the temperature is lower than 5°C, 12.5g of N,N′-dicyclohexylcarbodiimide dissolved in 25ml of chloroform is added dropwise to the reaction solution in 1 hour. After the dropwise addition is completed, the reaction is kept at 10-15°C for 3 hours, and the reaction is completed. Use a funnel covered with celite to filter, wash the reaction solution twice with 25 ml of 5% NaOH washing solution, and then wash with water until neutral. Evaporate chlorofo...

Embodiment 3

[0041]Add 100ml of methanol to the reaction flask, cool to 0-5°C, keep the temperature below 10°C, add 10ml of thionyl chloride dropwise, add 10g of D-phenylalanine, raise the temperature, keep at 40±2°C for 15 hours, After the reaction, the ethanol was evaporated and the solid was precipitated. Add 25ml of tetrahydrofuran, stir until the solid was completely dissolved, add 3.5g of 1-hydroxybenzotriazole, lower the temperature to 0-5°C, add 9.5g of p-isopropylcyclohexanecarboxylic acid, and keep When the temperature is lower than 5°C, 25ml tetrahydrofuran dissolved with 12.5g N,N′-dicyclohexylcarbodiimide is added dropwise into the reaction solution in 1 hour. After the dropwise addition is completed, the reaction is kept at 10-15°C for 3 hours, and the reaction is completed. Evaporate tetrahydrofuran, use 65ml of methanol for phase change, lower the temperature to 20-25°C, keep the temperature below 30°C, add 23ml of 10% NaOH solution dropwise within 30 minutes, keep warm at 2...

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Abstract

The invention relates to a synthesis method of a nateglinide, in particular to the synthesis of the nateglinide by a one-pot method. Original material D-phenylalanine is used as raw material in the method, D-phenylalanine esterified substance (II) is obtained through esterification, a compound (IV) is obtained through acylation of isopropylcyclohexanecarboxylic acid (III), and then the compound (IV) is ester hydrolyzed so as to obtain the nateglinide. The technique of the method has simple technique process and easy and convenient post-treatment; meanwhile, the method has the advantages of strong operability, being easy to be industrialized and cost saving.

Description

technical field [0001] The present invention relates to a synthesis method of nateglinide, in particular to a one-pot method for synthesizing nateglinide. Background technique [0002] Nateglinide was originally developed by Ajinomoto Co., Ltd. and launched in Japan in 1999. It was launched in the United States by Novartis in 2000. It belongs to D-phenylalanine derivatives and is a powerful and rapid insulin secretagogue. Its pharmacological action is to lower blood glucose levels by stimulating insulin secretion from the pancreas. The extent of insulin release is glucose dependent and the effect disappears at low glucose levels. Its characteristics are: it is used as a mealtime blood sugar regulator, and the drug is flexible; it is the first-line treatment drug for patients with early and mild diabetes; it has a fast onset, short duration of action, and good safety; it has synergy with metformin or thiazolidinone drugs. effect. [0003] The synthesis and development of...

Claims

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Application Information

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IPC IPC(8): C07C233/63C07C231/02
Inventor 李建发罗洋李金禄
Owner TIANJIN PHARMA GROUP CORP
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