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A kind of preparation method of argatroban monohydrate

A technology for argatroban and monohydrate, which is applied in the field of preparation of argatroban monohydrate, and can solve the problems of large changes in the ratio of the 21-position R/S isomer, cumbersome operation, and many solvents

Active Publication Date: 2018-08-24
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses a lot of solvents (water), the operation is cumbersome, the purity of the final product is not high, and the ratio of the 21-position R / S isomer varies greatly

Method used

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  • A kind of preparation method of argatroban monohydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add 20L of ethanol / purified water mixed solvent (ethanol accounted for 97% by volume) to 1019g of crude argatroban, and heat to reflux to dissolve. After complete dissolution, cool down to room temperature, then cool down to 0-5°C and stir for crystallization for 3 hours. Filter with suction and dry under normal pressure at 50°C for 6 hours. Obtained 704 g of white powder.

[0023] Add 14L of ethanol / purified water mixed solvent (volume ratio of ethanol is 97%), heat to reflux to dissolve. After complete dissolution, cool down to room temperature, then cool down to 0-5°C and stir for crystallization for 3 hours. Filter with suction and dry under normal pressure at 50°C for 12 hours. 600.5 g of white powder was obtained.

[0024] Add 7.2L of ethanol / purified water (volume ratio of ethanol is 25%), stir and heat to reflux, add 60g of activated carbon and continue stirring for 0.5h. After filtering, the filtrate was naturally cooled to room temperature with stirring, ...

Embodiment 2

[0026] Add 2L of ethanol / purified water mixed solvent (97% ethanol by volume) to 100g of crude argatroban, and heat to reflux to dissolve. After complete dissolution, cool down to room temperature, then cool down to 0-5°C and stir for crystallization for 3 hours. Filter with suction and dry under normal pressure at 50°C for 8 hours. 71.2 g of white powder were obtained.

[0027] Add 1.4L ethanol / purified water mixed solvent (ethanol accounted for 97% by volume), heat to reflux to dissolve. After complete dissolution, cool down to room temperature, then cool down to 0-5°C and stir for crystallization for 3 hours. Filter with suction and dry under normal pressure at 50°C for 14 hours. 62 g of white powder were obtained.

[0028] Add 740mL of ethanol / purified water (volume ratio of ethanol is 25%), stir and heat to reflux, add 6.2g of activated carbon and continue stirring for 0.5h. After filtering, the filtrate was naturally cooled to room temperature with stirring, and the...

Embodiment 3

[0030] Add 1.2 L of ethanol / purified water mixed solvent (ethanol accounted for 97% by volume) to 60 g of crude argatroban, and heat to reflux to dissolve. After complete dissolution, cool down to room temperature, then cool down to 0-5°C and stir for crystallization for 3 hours. Filter with suction and dry under normal pressure at 50°C for 7 hours. 42.6 g of white powder were obtained.

[0031] Add 850mL ethanol / purified water mixed solvent (ethanol accounted for 97% by volume), heat to reflux to dissolve. After complete dissolution, cool down to room temperature, then cool down to 0-5°C and stir for crystallization for 3 hours. Filter with suction and dry under normal pressure at 50°C for 12 hours. 38 g of white powder were obtained.

[0032] Add 460mL of ethanol / purified water (volume ratio of ethanol is 25%), stir and heat to reflux, add 3.5g of activated carbon and continue stirring for 0.5h. After filtering, the filtrate was naturally cooled to room temperature with...

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Abstract

The invention discloses a preparation method of argatroban monohydrate. The method comprises the following steps: (1) taking a crude product, adding into a 97% (V / V) ethanol aqueous solution, dissolving, cooling to the room temperature, then cooling again to 0-5 DEG C, carrying out stirring crystallization, carrying out suction filtration, drying, and thus obtaining a white powder I; (2) treating the white powder I through repeating the operations of the step (1), and thus obtaining a white powder II; and (3) taking the white powder II, adding into a 25% (V / V) ethanol aqueous solution, dissolving, decoloring, filtering, naturally cooling the filtrate to the room temperature under stirring, continuing to carry out stirring crystallization, carrying out suction filtration, drying, and thus obtaining the argatroban monohydrate. The purity of the final product argatroban monohydrate can reach more than 99.90%, the 21-site R / S isomer ratio is mainly controlled at 65:34, and thus the argatroban biological activity is exerted to a greatest degree.

Description

technical field [0001] The invention belongs to the technical field of medicine refining, and in particular relates to a preparation method of argatroban monohydrate. technical background [0002] Argatroban monohydrate (argatroban monohydrate, 1) is a highly active and highly selective thrombin inhibitor. Its anticoagulant effect does not depend on antithrombin in the body, but directly binds to free Thrombin binds and inactivates it. [0003] In addition, due to the small molecular weight of argatroban, it can directly enter the thrombus, inactivate the thrombin that has been bound to fibrin, and indirectly inhibit the generation of thrombin. platelet aggregation reaction. Because argatroban can greatly reduce the level of thrombin-antithrombin complex in plasma and effectively improve the hypercoagulable state of patients, it has a very good clinical effect in the treatment of chronic thromboembolic diseases. [0004] The chemical name of argatroban monohydrate is (2R,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/068C07K1/14
Inventor 赵志全吴尽陈见见徐冰
Owner SHANDONG NEWTIME PHARMA
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