New method for synthesizing argatroban by combining solid phase method and liquid phase method

A technology of argatroban and methyl, which is applied in the field of synthesis of polypeptide compounds, can solve the problems of difficult purification and separation of intermediates and target products, low yield of argatroban, etc., and achieve considerable economic and practical value. Ease of handling and simple operation of the response
CN101560244AInactive Publication Date: 2009-10-21HYBIO PHARMA
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Patent Information

Authority / Receiving Office
CN · China
Current Assignee / Owner
HYBIO PHARMA
Publication Date
2009-10-21
Estimated Expiration
Not applicable · inactive patent

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Abstract

The invention discloses a method for synthesizing argatroban. The method comprises the following steps: the (2R, 4R)-N-Fmoc-4-methyl-2-nipecotic acid reacts with high polymer resin to obtain (2R, 4R)-N-Fmoc-4-methyl-2-nipecotic acid-resin; deprotection is carried out, Fmoc-arginyl (nitryl)-OH is coupled by a solid phase synthesis method to obtain Fmoc-arginyl (nitryl)-(2R, 4R)-4-methyl-2-nipecotic acid-resin; the deprotection is carried out again, the 3-methyl-8-quinolinesulfonyl chloride is coupled by the solid phase synthesis method to obtain 3-methyl-8-quinolinesulfonyl-arginyl (nitryl)-(2R, 4R)-4-methyl-2-nipecotic acid-resin; cracking cutting reaction is performed to the obtained resin to obtain 3-methyl-8-quinolinesulfonyl-arginyl (nitryl)-(2R, 4R)-4-methyl-2-nipecotic acid; the argatroban crude product is obtained through catalytic hydrogenation; and the argatroban is obtained through recrystallization. The method is suitable for the large-scale production and is simple and easy in operation, stable in process and low in production cost, and the total yield is up to 60 percent.
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Description

technical field

[0001] The invention relates to a synthesis method of polypeptide compounds, in particular to a synthesis method of argatroban which combines a solid-phase method and a liquid-phase method. Background technique

[0002] 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 in the treatment of acute cerebral thrombosis and as an adjunct to thrombolysis in myocardial infarction. Treatment, and for anticoagulant treatment in patients with antithrombin (AT) deficiency during hemodialysis.

[0003] In 2000, the U.S. Food and Drug Administration (FDA) approved the injectable antithrombotic small-molecule drug argatroban (Novastan) from SmithKline Beecham and Texas Biotechnology. Treatment and prevention of thrombosis and heparin-induced immune disease - thrombocytopenia (HIT), and for the treatment of pat...

Claims

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