Synthetic method of repaglinide

A synthesis method and methyl technology, which are applied in the field of synthesis technology of repaglinide, can solve the problems of large reaction temperature change, great harm to human body, equipment corrosion, etc., and achieve short reaction time, high product yield, and improved yield. Effect

Active Publication Date: 2012-11-07
河北富格药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the condensation process of this process, the reaction temperature changes greatly, the energy consumption is high, and the oxalyl chloride and phosphorus pentachloride used seriously corrode the equipment and are harmful to the human body.

Method used

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  • Synthetic method of repaglinide
  • Synthetic method of repaglinide
  • Synthetic method of repaglinide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: a, ( S Preparation of )-3-methyl-1-[2-(1-piperidinyl)phenyl]butylamine

[0028] Add 0.01mol (4.35g) of ( S )-3-methyl-1-[2-(1-piperidinyl)phenyl]butylamine N - Dissolve acetylglutamate in 50ml of dichloromethane, stir and cool down to 15°C, then add 2.5ml of 4M NaOH solution dropwise, when the material is clear, extract three times with 25ml of dichloromethane, combine the extracts, add Anhydrous NaSO 4 dry to get ( S )-3-Methyl-1-[2-(1-piperidinyl)phenyl]butylamine in dichloromethane;

[0029] b, 2-ethoxy-4-[2-[[( S )-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]ethyl benzoate

[0030] The above 75ml ( S )-3-Methyl-1-[2-(1-piperidinyl)phenyl]butylamine in dichloromethane was stirred and cooled to 15°C, and then 0.015mol (3.78g) of 3-ethoxy- 4-ethoxycarbonylphenylacetic acid, 0.015mol (2.03g) of HOBT, 0.015mol (5.55g) of DIEA and 0.015mol (1.94g) of EDC·HCl, and monitor the reaction process by thin-layer chromatography (TLC), 4-6 hou...

Embodiment 2

[0033] Embodiment 2: the difference between this embodiment and embodiment 1 is that

[0034] a.( S Preparation of )-3-methyl-1-[2-(1-piperidinyl)phenyl]butylamine

[0035] 0.015mol (6.53g) of ( S )-3-methyl-1-[2-(1-piperidinyl)phenyl]butylamine N - Dissolve acetylglutamate in 70ml of dichloromethane, stir and cool down to 20°C, then add 7.5ml of 2M KOH aqueous solution dropwise, when the feed liquid is clear, extract three times with 30ml of dichloromethane, combine the extracts, add Anhydrous NaSO 4 dry to get ( S )-3-Methyl-1-[2-(1-piperidinyl)phenyl]butylamine in dichloromethane;

[0036] b, 2-ethoxy-4-[2-[[( S )-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]ethyl benzoate

[0037] The above 80ml ( S )-3-Methyl-1-[2-(1-piperidinyl)phenyl]butylamine in dichloromethane was stirred and cooled to 20°C, then 0.02mol (5.05g) of 3-ethoxy- 4-ethoxycarbonylphenylacetic acid, 0.02mol (2.70g) of HOBT, 0.02mol (2.58g) of DIEA and 0.02mol (3.83g) of EDC·HCl, TLC ...

Embodiment 3

[0040] Embodiment 3: the difference between this embodiment and embodiment 1 is,

[0041] a.( S Preparation of )-3-methyl-1-[2-(1-piperidinyl)phenyl]butylamine

[0042] 0.015mol (6.53g) of ( S )-3-methyl-1-[2-(1-piperidinyl)phenyl]butylamine N - Dissolve acetylglutamate in 60ml of dichloromethane, stir and cool down to 0°C, then add 4M NH 3 ·H 2 O solution 3.75ml, when the material liquid is clarified, extract three times with 30ml dichloromethane, after combining the extracts, add anhydrous NaSO 4 dry to get ( S )-3-Methyl-1-[2-(1-piperidinyl)phenyl]butylamine in dichloromethane;

[0043] b, 2-ethoxy-4-[2-[[( S )-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]ethyl benzoate

[0044] The above 80ml ( S )-3-Methyl-1-[2-(1-piperidinyl)phenyl]butylamine in dichloromethane was stirred and cooled to 20°C, then 0.02mol (5.05g) of 3-ethoxy- 4-ethoxycarbonylphenylacetic acid, 0.02mol (2.70g) of HOBT, 0.02mol (2.58g) of DIEA and 0.02mol (3.83g) of EDC·HCl, TLC mo...

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Abstract

The invention discloses a synthetic method of repaglinide, comprising the steps of dissolving N-acetyl glutamate of (S)-3-methyl-1-[2-(1-piperidyl)phenyl] butyl amine into dichloromethane, stirring, cooling, alkalifying, extracting and drying to obtain (S)-3-methyl-1-[2-(1-piperidyl)phenyl] butyl amine dichloromethane solution; cooling the solution, adding 3-ethyoxyl-4-carbethoxy phenylacetic acid, HOBT (N-hydroxybenzotriazole), DIEA (N,N-diisopropyl ethylamine) and EDC.HCl (1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride) in turn and reacting; washing, drying and distilling to obtain repaglinide ethyl ester; adding ethanol, dropping alkali liquid, heating and reacting; and acidizing, growing crystals and performing suction filtration to obtain a product. The synthetic method has the advantages that EDC.HC1 is used as an acylation reagent, so that the reaction by-product urea is easy to elute; due to combination with HOBT, the condensation yield can be improved; the condensation condition is mild; the reaction time is short; the yield is 96%; the purity can reach more than 98%; recrystallization is not needed and the next hydrolytic reaction can be preformed directly; and the process is simple, so that the synthetic method is suitable for commercial production.

Description

technical field [0001] The invention relates to a synthesis process of repaglinide. Background technique [0002] The chemical name of repaglinide is ( S )-(+)-2-ethoxy-4-[2-[3-methyl-1-[2-(1-piperidinyl)phenyl]butanyl]-amino]-2-carbonyl ethyl Benzoic acid is an oral hypoglycemic agent that regulates postprandial blood sugar by stimulating the release of insulin from the pancreas. [0003] US5216167 and subsequent patents US5312924 and US6143769 were the first to report the synthesis method of phenylacetyl benzylamine compounds, especially repaglinide, and their hypoglycemic pharmacological activity. The key step in the synthesis of this compound is the condensation step involved in the formation of the amide bond, namely ( S )-3-methyl-1-[2-(1-piperidinyl)phenyl]butylamine is condensed with 3-ethoxy-4-ethoxycarbonylphenylacetic acid to obtain 2-ethoxy-4-[ 2-[ [( S )-3-methyl-1-[2-(1-piperidinyl) phenyl] butyl] amino]-2-oxoethyl] ethyl benzoate, then remove the protecti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/135
Inventor 岳振路
Owner 河北富格药业有限公司
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