Solid phase method for synchronizing Argatroban

A technology of argatroban and solid-phase method, applied in the field of solid-phase synthesis of argatroban, which can solve the problem of low yield in liquid phase reaction, increased post-reaction treatment work, and difficult purification and separation of intermediates and target products And other problems, to achieve considerable economic and practical value, low cost, wide application prospects

Inactive Publication Date: 2009-09-02
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] 2. Non-protection law
The use of liquid phase method will increase a lot of post-reaction treatment work. At the same time, the purification and separation of intermediates and target products are also very difficult tasks, and the yield of liquid phase reaction is low.

Method used

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  • Solid phase method for synchronizing Argatroban
  • Solid phase method for synchronizing Argatroban
  • Solid phase method for synchronizing Argatroban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: Preparation of (2R, 4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid-chloro resin or hydroxyl resin

[0042] Add 200.0 g of chlorine resin or hydroxyl 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, 36g (2R, 4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid and equal molar ratios of DIC, HOBt, and DIPEA were added to the above round-bottomed flask filled with resin to react for 2 hours. After the reaction is completed, filter, wash 3 times with DMF and 3 times with DCM, then shrink with methanol for 30 minutes to obtain (2R, 4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid-chloro resin or hydroxyl resin, and detect The degree of substitution is 0.48mmol / g, and the yield is 96%.

Embodiment 2

[0043] Embodiment 2: Preparation of (2R, 4R)-4-methyl-2-piperidinecarboxylic acid-chloro resin or hydroxyl resin

[0044]Add (2R,4R)-N-Fmoc-4-methyl-2-piperidinecarboxylic acid and chlorine resin prepared above into a 1000ml round bottom flask, add 600ml of 20% DBLK and stir vigorously for 30min. After the reaction was completed, filter, wash with DMF for 3 times, and DCM for 3 times, and set aside for use.

Embodiment 3

[0045] Embodiment 3: Preparation of Fmoc-Arg (X)-(2R, 4R)-4-methyl-2-piperidinecarboxylic acid-chloro resin or hydroxyl resin

[0046] Put the (2R,4R)-4-methyl-2-piperidinecarboxylic acid-chloro resin or hydroxyl resin to be used into a 1000ml round bottom flask, add 700ml tetrahydrofuran and stir vigorously. In an ice-water bath, 65g of Fmoc-Arg(X)-OH and equal molar ratios of DIC, HOBt, and DIPEA were added to the above round-bottomed flask filled with resin and reacted for 2 hours. After the reaction is completed, filter, wash 3 times with DMF, wash 3 times with DCM, and shrink with methanol for 30 minutes to obtain Fmoc-Arg(X)-(2R,4R)-4-methyl-2-piperidinecarboxylic acid-chloro resin or hydroxyl Resin, the detected substitution degree is 0.45mmol / g, and the yield is 94%.

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Abstract

The invention discloses a solid phase method for synchronizing Argatroban, including the following steps: (1) (2R, 4R)-N-Fmoc-4-methyl-2-nipecotic acid, macromolecule resin, protective amino acid, coupling reagent and organic base are used as starting raw materials to form (2R, 4R)-N-Fmoc-4-methyl-2-nipecotic acid-resin; (2) Fmoc protection is removed, and a solid phase method is adopted to couple Fmoc-Arg(X)-OH so as to obtain Fmoc-Arg(X)-(2R, 4R)-4-methyl-2-nipecotic acid-resin; (3) the Fmoc protection is removed, and after 3-methyl-1,2,3 4-tetrahydroquinoline-sulfonic acid chloride is coupled, complete full protection Argatroban-resin is obtained; (4) complete peptide protection Argatroban-resin is reacted with a side chain separated blocking group so as to gain the crude product of the Argatroban; and (5) after the operation of recrystallization is carried out, the Argatroban with high purity is obtained. The technical process of the invention has the advantages of simple reaction operation, easy post treatment, less raw material, low cost, more than 80 percent of total yield, considerable economic and practical value as well as broad application prospect in the field of designing and synchronizing polypeptide drugs.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to a new method for synthesizing argatroban by a solid-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 began to be used in the treatment of acute cerebral thrombosis and myocardial infarction. Adjuvant therapy of thrombus and anticoagulant treatment in antithrombin (AT) deficient patients undergoing hemodialysis. [0003] In 2000, the U.S. Food and Drug Administration (FDA) approved the injectable antithrombotic small molecule drug argatroban (Novastan) from SmithKlineBeecham and Texas Bitechnology for the treatment of And the prevention of thrombosis and heparin-induced immune disease-thrombocytopenia (HIT), as well as the treatment of patients requiring percu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078C07K1/04A61P7/02
Inventor 李红玲刘建马亚平袁建成
Owner HYBIO PHARMA
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