Argatroban byproduct and its synthesis, separation and identification method

A technology for argatroban and by-products, which is applied in the fields of argatroban by-products and synthesis and separation and identification, can solve the problems of difficult separation, difficult purification, and difficulty in reaching the standard of impurity content of product Argatroban, and achieves mild conditions and steps. Reasonable design and simple operation

Active Publication Date: 2007-09-12
TIANJIN WEIJIE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Any of the above routes must go through the intermediate 2 [(2R, 4R)-1-[N G -Nitro-N 2 -(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid], hydrogenation reduction to obtain Argatroban, meanwhile, all generate an identical main by-product, Because the nature of the main by-product is similar to that of Argatroban, it is not easy to separate, and the purification is difficult, so that the impurity content of the product Argatroban is difficult to reach the standard

Method used

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  • Argatroban byproduct and its synthesis, separation and identification method
  • Argatroban byproduct and its synthesis, separation and identification method
  • Argatroban byproduct and its synthesis, separation and identification method

Examples

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example 1

[0033] See (US 4 258 192) for the preparation example of intermediate 2 (compound 2), and see accompanying drawing 1 for the reaction formula.

example 2

[0034] Example 2, palladium carbon catalytic hydrogenation method:

[0035] 1 g of compound 2 prepared in Example 1, 0.02 g of triphenylphosphine, 0.2 g of 5% palladium on carbon, 13 ml of absolute ethanol and 4 ml of glacial acetic acid were successively added into a 100 ml autoclave. Control the external temperature of the autoclave at 65-70°C, feed hydrogen gas, keep the pressure at 10 MPa, follow the reaction by HPLC (high performance liquid chromatography), react for 24 hours, and stop the reaction. Remove palladium carbon by filtration, desolventize, dissolve with 20ml of dichloromethane, adjust pH=7 with saturated sodium bicarbonate. The organic layer was separated, washed with 10 ml of saturated sodium chloride, left to stand, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and dichloromethane was removed to obtain 0.75 g of a white solid, which was compound 3, with a yield of 82%. .

[0036] Compound 3 structure identification:

[0...

example 3

[0052] Example 3. stannous chloride method:

[0053] Add 1g of compound 2 prepared in Example 1, 2.4g of stannous chloride and 40ml of absolute ethanol into a 100ml four-neck flask, stir and react at 20-25°C for 24 hours, follow the reaction by HPLC, the content of compound 2 no longer decreases, stop the reaction. Ethanol was removed in vacuo, water and dichloromethane were added, the aqueous layer was extracted with dichloromethane, the organic layers were combined, washed with water, washed with saturated sodium chloride, washed with water, dried over anhydrous magnesium sulfate, filtered, and precipitated to obtain 0.6 g of compound 3 . Yield 65%. HPLC retention time was 8.5 minutes.

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Abstract

This invention relates to an outgrowth of argatroban and a method for synthesization and separation and authentication, in which, when preparing argatroban by catalysis and hydrogenation, it makes an outgrowth with difficult separation to determine that said outgrowth is a compound by separation, authentication and synthesization, which is hydrolyzed further to get argatroban, and when testifying the hydrolyzed intermediate, it first of all recovers nitro delinking, then hydrolyzes quinoline 1, 2, 3 and 4 to get 1, and the content of compound 3 can be reduced to the allowance sphere by following the hydrogenation reactin of the intermediate.

Description

technical field [0001] The invention relates to a by-product of argatroban and its synthesis, separation and identification method. technical background [0002] In 1978, the antithrombin activity of argatroban (Argatroban, 1) hydrate [US 4 101 653] was first reported by S.Okamoto of Mitsubishi Chemical Company in Japan. During the following 20 years, many researchers conducted in-depth research on the biological activity of Argatroban and its value as medicine. In 1981, S.Okamoto compared heparin in animals [Okamoto, S.et al., Biochem.Biophys.Res.Commun.101, 440 (1981)]; T.Kumoto et al. Report [Kumada, T.et al., Thromb.Res.24, 285 (1981)]; In 1984, R.Kumao carried out clinical hemodialysis evaluation [Kikumoto, R.et al., Biochemistry 23, 85 (1984) ]; In 1986, the author reported that Argatroban inhibited thrombin activity in mammals, which can be used as a treatment and prevention agent for thrombosis and platelet aggregation inhibitor. Argatroban monohydrate can be used...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12G01N30/00
Inventor 宋洪海
Owner TIANJIN WEIJIE TECH
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