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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

Inactive Publication Date: 2009-10-21
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] 2. Non-protection law
[0018] In the prior art, the synthesis of argatroban adopts a liquid phase method. The problem is that the liquid phase synthesis method requires a large amount of post-reaction treatment work, and it is also difficult to purify and separate the intermediates and target products.
In addition, the yield of argatroban prepared by liquid phase method is low

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: Preparation of (2R, 4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid-2-chlorochloro resin

[0043] Add 200.0 g of 2-chlorochloro resin (substitution degree: 0.5 mmol / g) into a 1000 ml round bottom flask, add DMF 600 ml, and stir vigorously. In an ice-water bath, 36.5g (2R, 4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid and equal molar ratios of DIC, HOBt and DIPEA were added to the above-mentioned round-bottomed flask filled with resin and reacted for 2 hours . After the reaction is completed, filter, wash 3 times with DMF, and wash 3 times with DCM, then shrink with methanol for 30 minutes to obtain (2R, 4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid-2-chlorochloro resin, and detect The degree of substitution is 0.48mmol / g, and the yield is 96%.

Embodiment 2

[0044] Example 2: Preparation of (2R, 4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid-2-chlorochloro resin

[0045] Add 450.0 g of 2-chlorochloro resin (substitution degree: 0.8 mmol / g) into a 2000 ml round bottom flask, add DMF1000 ml and stir vigorously. In an ice-water bath, 262.8g (2R, 4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid and equal molar ratios of DIC, HOBt and DIPEA were added to the above-mentioned round-bottomed flask with resin and reacted for 2 hours . After the reaction is completed, filter, wash 3 times with DMF, and wash 3 times with DCM, then shrink with methanol for 30 minutes to obtain (2R, 4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid-2-chlorochloro resin, and detect The degree of substitution is 0.72mmol / g, and the yield is 90%.

Embodiment 3

[0046] Embodiment 3: Preparation of (2R, 4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid-2-chlorochloro resin

[0047] Add 300.0 g of 2-chlorochloro resin (substitution degree: 0.3 mmol / g) into a 2000 ml round bottom flask, add 800 ml of DMF and stir vigorously. In an ice-water bath, 65.7g (2R, 4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid and equal molar ratios of DIC, HOBt and DIPEA were added to the above-mentioned round-bottomed flask filled with resin and reacted for 2 hours . After the reaction is completed, filter, wash 3 times with DMF, and wash 3 times with DCM, then shrink with methanol for 30 minutes to obtain (2R, 4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid-2-chlorochloro resin, and detect The degree of substitution is 0.29mmol / g, and the yield is 97%.

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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.

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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Application Information

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IPC IPC(8): C07K5/078C07K1/04C07K1/02A61P7/02
Inventor 刘建李红玲马亚平袁建成
Owner HYBIO PHARMA
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