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Preparation method of argatroban intermediate

A technology for argatroban and intermediates, which is applied in the field of preparation of argatroban intermediates, can solve the problems of being unsuitable for large-scale industrial production, difficult to purify products, unfriendly to the environment, etc., and achieves low production cost and good precision. , Environmentally friendly effect

Active Publication Date: 2014-02-12
SHANGHAI SYNCORES TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] In summary, the existing preparation methods of argatroban intermediates all have defects such as difficult product purification, high cost, low production efficiency, unfriendly to the environment, and unsuitable for large-scale industrial production.

Method used

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  • Preparation method of argatroban intermediate
  • Preparation method of argatroban intermediate
  • Preparation method of argatroban intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Add 20.0g of compound A, 24.0g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 200mL of tetrahydrofuran into a dried 500mL four-neck flask under nitrogen protection, and control the temperature at 20~ 30°C, add 11.0g of compound B in batches, and stir at 20~30°C for 2h. Concentrate the reaction solution to dryness, add 200mL of toluene to dissolve the material, wash once with 150mL of saturated brine, separate the liquid, concentrate the organic phase to 50mL, stir at 10~15°C for 8h, filter the material liquid, and wash the filter cake with 10mL of toluene. Dry the filter cake to obtain an off-white solid, which is the intermediate of argatroban. Yield: 80.0%, HPLC purity: 98.0%, content 98.6%, impurity formula III 1.20%, impurity formula IV not detected.

Embodiment 2

[0058] Add 20.0g compound A, 20.0g 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 20mL dichloromethane to the dried 500mL four-necked bottle under nitrogen protection, control Temperature -10~0°C, add 11.0g of compound B in batches, stir at -10~0°C for 8h. Wash once with 150 mL of saturated brine, separate the liquid, concentrate the organic phase to dryness, add 50 mL of methyl tert-butyl ether, stir at 10~15°C for 8 hours, filter the feed liquid, wash the filter cake with 10 mL of methyl tert-butyl ether, and dry The off-white solid obtained from the filter cake is the intermediate of argatroban. Yield: 82.0%, HPLC purity: 97.0%, content 98.1%, impurity formula III 1.26%, impurity formula IV not detected.

Embodiment 3

[0060] Add 20.0g of compound A, 60.0g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 1000mL of acetonitrile to a dried 3000mL four-neck flask under nitrogen protection, and control the temperature from 0 to 10°C, add 11.0g of compound B in batches, and stir at 0~10°C for 6h. Concentrate the reaction solution to dryness, add 200mL of toluene to dissolve the material, wash once with 150mL of saturated brine, separate the liquid, concentrate the organic phase to 50mL, stir at 10~15°C for 8h, filter the material liquid, and wash the filter cake with 10mL of toluene. Dry the filter cake to obtain an off-white solid, which is the intermediate of argatroban. Yield: 80.0%, HPLC purity: 98.2%, content 98.6%, impurity formula III 1.14%, impurity formula IV not detected.

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Abstract

The invention relates to a preparation method of argatroban intermediate (2R,4R)-ethyl-1-((S)-2-(tert-butoxy amido)-5-(3-nitroguanidine)valery)-4-methylpiperidine-2-ethyl carboxylate. The method comprises the following steps: enabling NG-nitro-N2-t-Boc-L-arginine and (2R,4R)-4-methyl-2-ethyl nipecotate to perform condensation reaction in the presence of a condensing agent selected from 1-ethyl-3-(3-dimethylamine propyl)carbodiimide hydrochloride, N,N-diisopropyl carbodiimide and N,N'-carbonyl diimidazole and an aprotic solvent to generate the argatroban intermediate. The raw material for the method is wide in source, cheap and easily-available; the method is mild in reaction condition, short in step, simple in operation, easy to purify the product, low in production cost and environment-friendly, not only suitable for laboratory synthesis, but also suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of an argatroban intermediate. Background technique [0002] Argatroban (Argatroban), chemical name (2R,4R)-4-methyl-1-[N-((R,S)-3-methyl-1,2,3,4-tetrahydro- 8-quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid, structural formula (I): [0003] [0004] Argatroban is an antithrombin drug developed by Mitsubishi, Japan, and has been approved by Japan for the treatment of peripheral thrombosis and acute ischemic stroke. On June 30, 2000, the US FDA approved it for heparin-induced thrombocytopenia and thrombosis syndrome. It is the only synthetic drug approved for the treatment of acute ischemic stroke in the world so far. On October 15, 2004, it was approved for marketing in Sweden, Europe, and the State Food and Drug Administration of China approved the import of Mitsubishi argatroban injection from Japan on August 2, 2002...

Claims

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Application Information

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IPC IPC(8): C07K5/068
Inventor 张席妮杜争鸣郑杰龚义吴江黄鲁宁
Owner SHANGHAI SYNCORES TECH INC
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