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Preparation and refining method of repaglinide

A refining method and technology of repaglinide glutamate, which is applied in the field of preparation and refining of repaglinide, a drug for treating diabetes, can solve the problems of long reaction time, low yield, high cost, etc., and achieve simple operation and improved Purity and yield, reduced production costs and pollution effects

Inactive Publication Date: 2012-10-17
双鹤药业(海南)有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is reported in US5312924 and CN1571769 that compound IV and compound III are condensed in the presence of carbonyldiimidazole, DCC or triphenylphosphine, triethylamine, carbon tetrachloride, and carried out at -80 ° C, and the product needs to be purified by chromatographic column , high cost, low yield, not suitable for industrial production
And report in US2005 / 0107614 is to condense under the condition of tert-butyl acetyl chloride and alkali, and this process operation is simple, and product is easy to purify, but reaction time is longer, and yield is not high
In the document WO2001035900 report, dangerous and expensive reagents such as lithium diisopropylamide and DMPU need to be used in the reaction, and the above-mentioned various methods have all increased the difficulty of industrial production, increased the cost, thereby increased the production cost of repaglinide. The cost is not conducive to the promotion of industrialization

Method used

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  • Preparation and refining method of repaglinide
  • Preparation and refining method of repaglinide
  • Preparation and refining method of repaglinide

Examples

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Embodiment 1

[0032] According to the preparation method of repaglinide of this embodiment, it comprises successively

[0033] Include the following steps:

[0034] Preparation of Regigamide (III) in Dichloromethane Solution

[0035] Stir to dissolve 19.6g of Regigamine glutamate and 80ml of dichloromethane, add dropwise the lye prepared by 6.37g of sodium hydroxide and 200ml of water; after the addition, stir at room temperature for 1-2 hours. Separate the layers, and extract the aqueous layer with 40ml of dichloromethane×2, combine the organic layers, and dry over anhydrous sodium sulfate; filter, remove about half of the solvent from the filtrate under reduced pressure at 30-35°C, and proceed directly to the next step. (TLC condition-chloroform:methanol=10:1);

[0036] Preparation of Ricolate (V)

[0037] Add 10g of Regalic acid (IV), 75ml of anhydrous dichloromethane, stir to dissolve, cool down to 2-6°C, add 0.1g of DMF, slowly add 9g of thionyl chloride dropwise, the dropwise addit...

Embodiment 2

[0044] According to the preparation method of repaglinide of the present embodiment, it comprises the following steps in sequence:

[0045] Preparation of Regigamide (III) in Dichloromethane Solution

[0046] 3.92kg of Regigamine glutamate and 16L of dichloromethane were stirred and dissolved, and the lye prepared by 1.28kg of sodium hydroxide and 40L of water was added dropwise; after the addition, stirred at room temperature for 1 to 2 hours. The layers were separated, and the aqueous layer was decompressed with 8 L x 2 dichloromethane filtrate at 30-35°C to remove about half of the solvent, and directly proceeded to the next step. (TLC conditions - chloroform: methanol = 10:1).

[0047] Preparation of Ricolate (V)

[0048] Add 2kg of Regalic acid (IV), 15L of anhydrous dichloromethane, stir to dissolve, cool down to 2-6°C, add 20g of DMF, slowly add 1.8kg of thionyl chloride dropwise, about 0.5-1h to complete the dropwise addition, and the dropwise addition is complete ,...

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Abstract

The invention relates to a preparation and refining method of repaglinide. The preparation method comprises the steps that: (S)-3-Methyl-1-(2-piperidinophenyl)butylamine glutamate (II) is adopted as a raw material, and is subjected to hydrolysis and an acylation reaction; an obtained material is subjected to an amidation reaction with 4-ethoxycabonyl-3-ethoxyphenylacetic acid (IV) under the existence of a condensing agent, such that 4-ethoxycabonyl-3-ethoxyphenylacetic ester (V) is obtained; the material V is hydrolyzed under an alkaline condition, such that a repaglinide crude product is obtained; the repaglinide crude product is subjected to ethanol-water solvent crystallization, such that repaglinide (I) is obtained. According to the invention, (S)-3-Methyl-1-(2-piperidinophenyl)butylamine glutamate is adopted as an initial raw material; the reaction conditions are optimized; the yield is improved; and good safety is ensured. An ethanol-water refining method is adopted, such that the product quality is improved, and environment pollution is reduced. Therefore, the method is suitable for industrialized productions.

Description

technical field [0001] The invention relates to the field of organic synthesis of medicines, in particular to a method for preparing and refining repaglinide, a medicine for treating diabetes. Background technique [0002] The chemical name of repaglinide is S(+)-2-ethoxy-4-[N-{1-(2-piperidinylphenyl)-3-methyl-1-butyl}aminocarbonylmethyl ] Benzoic acid is a new type of oral hypoglycemic drug that can promote insulin secretion and has the characteristics of fast absorption and short action time. It can simulate physiological insulin secretion in patients with type II diabetes and effectively control postprandial hyperglycemia. Higher protein binding rate, no accumulation in tissues, good safety. Repaglinide can be used alone as a first-line antidiabetic drug, or it can be used in combination with other hypoglycemic drugs to increase the efficacy. [0003] The synthetic route of repaglinide reported in the literature in the prior art is mainly to obtain compound V through co...

Claims

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Application Information

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IPC IPC(8): C07D295/135
Inventor 魏雪纹李强
Owner 双鹤药业(海南)有限责任公司
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