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Method for splitting argatroban isomer impurity

A technology for argatroban and isomers, which is applied in the field of separation of argatroban isomer impurities, can solve the problems of low resolution yield, low chiral purity, and no strict control of reaction conditions, and achieves Easy-to-use effects

Active Publication Date: 2019-05-17
BEIJING YUEKANGKECHUANG PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The use of tartaric acid disclosed in the prior art to resolve the racemate of ethyl 4-methyl-2-piperidinecarboxylate, because the reaction conditions are not strictly controlled, the resolution yield is low, and the chiral purity after resolution is also relatively low. lower

Method used

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  • Method for splitting argatroban isomer impurity
  • Method for splitting argatroban isomer impurity
  • Method for splitting argatroban isomer impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] A kind of resolution method of argatroban isomer impurity, this resolution method comprises the steps: S1:(2S,4S)-4-methyl-2-piperidinecarboxylic acid ethyl ester-D-tartrate (compound Ⅰ) preparation feed ratio:

[0029]

[0030] crafting process:

[0031] Add 8.55g of 4-methyl-2-piperidinecarboxylic acid ethyl ester racemate and 7.5g of D-tartaric acid into 150mL of isopropanol and 100mL of acetonitrile, stir, then add 2.16g of 1-butylpyridinium bromide, at 65℃ Heat the reaction, after the reaction is completed, cool to room temperature, add 0.229g pyridinium D-tartrate, stand for crystallization for 12h, and filter to obtain 7.64g white crystals with a yield of 47.6%. S2: Preparation of (2S,4S)-4-methyl-2-piperidinecarboxylic acid ethyl ester (compound Ⅱ)

[0032] Feeding ratio:

[0033]

[0034] crafting process:

[0035] Add 3.21g of compound I into 25mL of methanol, heat to dissolve at 50°C, add 10% sodium hydroxide solution dropwise with stirring, adjust ...

Embodiment 2

[0037] A kind of resolution method of argatroban isomer impurity, this resolution method comprises the steps: S1:(2S,4S)-4-methyl-2-piperidinecarboxylic acid ethyl ester-D-tartrate (compound Ⅰ) Preparation

[0038] Feeding ratio:

[0039]

[0040]

[0041] crafting process:

[0042] Add 8.55g of 4-methyl-2-piperidinecarboxylic acid ethyl ester racemate and 7.5g of D-tartaric acid into 144mL of isopropanol and 90mL of acetonitrile, stir, then add 2.376g of 1-butylpyridinium bromide, at 68℃ Heat the reaction, after the reaction is completed, cool to room temperature, add 0.1145g pyridinium D-tartrate, stand for crystallization for 12h, and filter to obtain 7.59g white crystals with a yield of 47.2%. S2: Preparation of (2S,4S)-4-methyl-2-piperidinecarboxylic acid ethyl ester (compound Ⅱ)

[0043] Feeding ratio:

[0044]

[0045] crafting process:

[0046] Add 3.21g of compound I into 30mL of methanol, heat to dissolve at 48°C, add 10% sodium hydroxide solution dropw...

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Abstract

The invention provides a method for splitting an argatroban isomer impurity. The method comprises the following steps: performing salt formation by taking 4-methyl-2-piperidinecarboxylate racemate asa raw material and taking D-tartaric acid as a splitting agent to obtain (2S,4S)-4-methyl-2-piperidinecarboxylate-D-tartrate shown by a compound I; dissociating the compound I under an alkaline condition to obtain (2S,4S)-4-methyl-2-piperidinecarboxylate shown by a compound II. The splitting method provided by the invention is easy and convenient to operate, the total yield of splitting reaches 46.5 percent, and the chiral purity after splitting can reach 99.2 percent.

Description

technical field [0001] The invention belongs to the field of racemate resolution, in particular to a method for resolution of argatroban isomer impurities. Background technique [0002] Argatroban (Argatroban), chemical name: (2R,4R)-4-methyl-1-[N-[(3-methyl-1,2,3,4-tetrahydro-8-quinoline Base) sulfonyl]-L-arginyl]-2-piperidinecarboxylic acid, the structural formula is as follows: [0003] [0004] Argatroban is an anticoagulant drug that was first launched in Japan in 1990, approved by the US FDA in 2000, and launched in my country in 2005. Argatroban can be used as drugs for treating and preventing thrombosis and platelet aggregation inhibitors, treating chronic arterial blockage and treating cerebral thrombosis. Argatroban contains an important isomeric impurity derived from the enantiomer (2S,4S)-4-carboxylate of the starting material (2R,4R)-4-methylpiperidine-2-carboxylic acid Base-2-piperidinecarboxylic acid ethyl ester, its structural formula is as follows: ...

Claims

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Application Information

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IPC IPC(8): C07D211/60
Inventor 宋更申梁文军肖佳普张婷婷
Owner BEIJING YUEKANGKECHUANG PHARM TECH CO LTD