Oriented synthesis and crystal structure of 21(S) argatroban, and preparation for monohydrate thereof

A technology of argatroban and monohydrate, which is applied in the field of directional synthesis of 21 argatroban and the preparation of crystal structure and monohydrate, which can solve the problems of low efficiency, undiscovered, complicated operation, etc.
CN101235031AInactive Publication Date: 2008-08-06TIANJIN WEIJIE TECH
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
TIANJIN WEIJIE TECH
Publication Date
2008-08-06
Estimated Expiration
Not applicable · inactive patent

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Abstract

The invention relates to a 21(S) argatroban rational synthesis method, a corresponding crystal structure and a hydrate preparation method, wherein the rational synthesis uses (3S)-1, 2, 3, 4-tetrahydrochysene-3-methyl-8-quinolinesulfonyl chloride as raw material to prepare single diastereoisomer 21(S) argatroban, and uses single crystal and polycrystalline powder X diffraction method to determine the absolute configuration as 21(S) and the crystal systems I, II, and the 21(S) argatroban is soluble in hot water, via controlling the cooling speed, a 21(S) argatroban hydrate is prepared. Animal tests prove that the anticoagulant function of the 21(S) argatroban hydrate is 2-3 powers of 21(R) argatroban hydrate.
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Description

technical field

[0001] The invention belongs to the technical field of medicine, in particular to a directional synthesis of 21(S) argatroban, its crystal structure and the preparation of monohydrate. Background technique

[0002] Argatroban was first reported as a thrombin inhibitor in 1978 by S.Okamoto of Japan Misubishi Chemical Company [US4101653]. In 1992, Japan approved the drug as a thrombin inhibitor for parenteral use [Hijikata-Okunomiya, A., et al., Thromb. Hemostasis, 1992, 18, 135]. Argatroban-(2R,4R)-1-[(2S)-5-[(aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl- 8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid——its chemical composition is a mixture of 21(R) and 21(S) argatroban, usually in a ratio of 64 to 65 : 36~35 [US 6 440 417, Cossy.J., et al, Bioorganic & Medicine Chemistry Letters, 11(2001), 1989-1992, Journal of Pharmaceutical Sciences, Vol.82, No.6, 672(1993)] .

[0003]

[0004] X=CH3, Y=H, 21(S) Arga...

Claims

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