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Preparation method of optically-pure argatroban

An argatroban and optical technology, applied in the field of medicine, can solve the problems of unfavorable production safety and labor protection, high price of quinoline sulfonyl chloride, complicated separation process, etc., and achieves low production cost, high ee value and simple operation. Effect

Inactive Publication Date: 2014-07-23
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The chemical properties of 21(S) and 21(R) argatroban are similar, and the separation process is complicated, so it is particularly difficult to obtain a single component of 21(S) or 21(R) argatroban
The disadvantage of this method is that the raw material (3S)-1,2,3,4-tetrahydro-3-methyl-8-quinolinesulfonyl chloride is expensive and difficult to obtain, and the catalytic hydrogenation reaction with palladium carbon needs to be carried out under high pressure conditions The operation is highly dangerous, which is not conducive to production safety and labor protection

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1 Preparation of formula A argatroban

[0038] Add 27.5g (0.05mol) of the compound of formula I and 150mL of methanol into a 250mL three-necked flask, stir to dissolve, add 38.6mg (0.05mmol) of the chiral catalyst shown in formula II and 25mL of formic acid, under nitrogen protection, react at 20°C for 3~ 5h, TLC monitors the reaction. After the reaction, the catalyst was removed by filtration, the filter cake was washed with an appropriate amount of methanol, the filtrates were combined, and concentrated to dryness under reduced pressure to obtain about 23.7 g of a yellow solid.

[0039] Add the obtained solid into a 250mL three-necked flask, add 30mL of ethanol and 100mL of purified water, heat to reflux to dissolve, then add 0.2g of activated carbon, continue to reflux for 30min, filter to remove the activated carbon while it is hot, and naturally cool and crystallize the filtrate, filter, wash, 80 After vacuum drying at ℃ for 5 hours, 22.6 g of off-whit...

Embodiment 2

[0040] Embodiment 2 Preparation of formula A argatroban

[0041]Add 27.5g (0.05mol) of the compound of formula I and 150mL of methanol into a 250mL three-necked flask, stir to dissolve, add 19.3mg (0.025mmol) of the chiral catalyst shown in formula II and 25mL of formic acid, under nitrogen protection, react at 30°C for 3~ 5h, TLC monitors the reaction. After the reaction, the catalyst was removed by filtration, the filter cake was washed with an appropriate amount of methanol, the filtrates were combined, and concentrated to dryness under reduced pressure to obtain about 23.0 g of a yellow solid.

[0042] Add the obtained solid into a 250mL three-necked flask, add 30mL of ethanol and 100mL of purified water, heat to reflux to dissolve, then add 0.2g of activated carbon, continue to reflux for 30min, filter to remove the activated carbon while it is hot, and naturally cool and crystallize the filtrate, filter, wash, 80 After vacuum drying at ℃ for 5 hours, 21.6 g of white s...

Embodiment 3

[0043] Embodiment 3 Preparation of formula A argatroban

[0044] Add 27.5g (0.05mol) of the compound of formula I and 150mL of methanol into a 250mL three-necked flask, stir to dissolve, add 45.2mg (0.05mmol) of the chiral catalyst shown in formula III and 2.5g of ammonium formate, nitrogen protection, and react at 30°C 3~5h, TLC monitors the reaction. After the reaction, the catalyst was removed by filtration, the filter cake was washed with an appropriate amount of methanol, the filtrates were combined, and concentrated to dryness under reduced pressure to obtain about 22.8 g of a yellow solid.

[0045] Add the obtained solid into a 250mL three-necked flask, add 35mL of ethanol and 100mL of purified water, heat to reflux to dissolve, then add 0.2g of activated carbon, continue to reflux for 30min, filter while hot to remove the activated carbon, the filtrate is naturally cooled and crystallized, filtered, washed, 80 After vacuum drying at ℃ for 5 hours, 20.9 g of off-whit...

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Abstract

The invention belongs to the technical field of medicine, and provides a preparation method of optically-pure argatroban represented by the formula A. In the preparation method, a compound represented by a formula I is subjected to a transfer hydrogenation reaction in the presence of a chiral catalyst so as to obtain the argatroban represented by the formula A. The preparation method provided by the invention has the advantages of mild conditions, simple operation, high yield, low production cost, and suitability for massive production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of optically pure argatroban. Background technique [0002] Argatroban (Argatroban) is an antithrombotic drug first developed and synthesized by Mitsubishi Chemical Research Institute in Japan. It was first used in the clinical treatment of peripheral arterial occlusive disease, and then it was used to treat acute cerebral thrombosis, and Adjuvant therapy of thrombolysis in myocardial infarction and anticoagulant treatment in antithrombin (AT) deficient patients undergoing hemodialysis. In 2000, the FDA approved the injectable antithrombotic small molecule drug Argatroban (Novastan) of SmithKline Beecham and Texas Bitechnology for the treatment and prevention of thrombosis and heparin-induced immunity Disease-thrombocytopenia (HIT), and for the treatment of patients requiring percutaneous coronary intervention (PCI). On March 5, 2003, at the 28th Internation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/068C07K5/078
Inventor 赵小伟李晓昕张艳阳
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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