Preparation method and application of repaglinide

A reaction and post-reaction technology, applied in the field of drug synthesis, can solve problems such as unsuitable for large-scale industrial production, unfavorable for large-scale industrial production, harsh reaction conditions, etc., and achieve the effects of low cost, high yield and mild reaction conditions

Inactive Publication Date: 2015-04-29
蔡伦
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction conditions are harsh, and the yield is low, which is not conducive to large-scale industrial production; synthetic route 2 uses Grignard reaction, NaOCl oxidation, NaBH 4 Reduction reaction, condensation reaction in carbon tetrachloride, in which carbon tetrachloride is a kind of toxic solvent, not suitable for large-scale industrial production
Moreover, there are many reaction steps, the reaction time is relatively long, and the yield is not high.

Method used

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  • Preparation method and application of repaglinide
  • Preparation method and application of repaglinide
  • Preparation method and application of repaglinide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] figure 1 The schematic flow chart of the preparation method of repaglinide provided by the embodiment of the present invention, combined with figure 1 , the embodiment of the present invention provides a kind of preparation method of repaglinide, the small test comprises the following steps:

[0058] Step 1: Preparation of compound B (HHRG-1)

[0059]

[0060] Add 250ml of water to a 1L three-necked round-bottomed flask, add 22g of compound A (regigamine-N-acetyl-L-glutamic acid) under stirring conditions, stir to form a suspension, add 20ml of ammonia water, stir until completely dissolved, and then Stir for 1 hour, add 300ml of dichloromethane and stir for 30 minutes, pour into a 1L separating funnel and let stand to separate layers, then extract the water layer with 200ml of dichloromethane, combine the organic layers, add anhydrous sodium sulfate to dry, filter, and the filtrate Concentrate under reduced pressure at 40°C to obtain 12g of light yellow oily liqui...

Embodiment 2

[0074] figure 1 The schematic flow chart of the preparation method of repaglinide provided by the embodiment of the present invention, combined with figure 1 , the embodiment of the present invention provides a kind of preparation method of repaglinide, pilot test comprises the following steps:

[0075] Step 1: Preparation of HHRG-1

[0076]

[0077] Add 2500ml of water to a 10L reaction kettle, add 220g of Regigamine-N-acetyl-L-glutamic acid under stirring conditions, stir to form a suspension, add 200ml of ammonia water, stir until completely dissolved, stir for another hour, add 3000ml Dichloromethane was stirred for 30 minutes, poured into a 10L separatory funnel and allowed to stand for stratification, the aqueous layer was extracted with 2000ml of dichloromethane, the organic layers were combined, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the The concentration temperature was 40°C, and about 121 g of HHR...

Embodiment 3

[0088] For further illustrating the beneficial effect of the present invention, the embodiment of the present invention has studied by different experimental conditions:

[0089] 1) The preparation conditions of HHRG-1;

[0090] 2) the impact of the acylation reaction temperature on the compound shown in formula D;

[0091] 3) The impact of hydrolysis time on the hydrolysis of the compound shown in formula D, including the following steps;

[0092] First, do the following comparison test:

[0093] Step 1: Preparation of HHRG-1

[0094]

[0095]

[0096] Add 250ml of water to a 1L three-neck round-bottom flask, add 22g of Regigamine-N-acetyl-L-glutamic acid under stirring conditions, stir to form a suspension, add 20ml of ammonia water, stir until completely dissolved, add 300ml of dichloromethane Stir for 30 minutes, pour into a 1L separatory funnel and let stand to separate layers, then extract the water layer with 200ml of dichloromethane, combine the organic layers...

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Abstract

The invention provides a preparation method and application of repaglinide. The preparation method comprises the following steps of neutralizing repagamine.N-acetyl-L-glutamic acid and alkali to obtain repagamine, acylating repagamine, condensing acylated repagamine and ethoxy-4-ethoxycarbonyl phenyl acetic acid to obtain an intermediate and hydrolyzing the intermediate to obtain the repaglinide. The preparation method has the advantages of low cost, high yield, simple process and the like and is more suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method and application of repaglinide. Background technique [0002] The chemical name of repaglinide is (S)-2-ethoxy-4-[2-[[methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2 -Oxoethyl]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 High blood sugar, high protein binding rate, no accumulation in tissues, and good safety. Repaglinide can be used alone as a first-line anti-diabetic drug, or it can be used in combination with other hypoglycemic drugs to increase the efficacy, providing a new method for the treatment of type Ⅱ diabetes. [0003] The preparation method of repaglinide has been reported in many documents. [0004] Synthetic route 1: ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/135A61P3/10
CPCC07D295/135
Inventor 李仁祥丁长龙杨世聪夏可标
Owner 蔡伦
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