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Preparation method for argatroban intermediate

A technology for argatroban and intermediates, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of unfavorable large-scale production, hydrogen flammability and explosion, unfavorable safety production, etc., and achieves low price, easy control of reaction conditions, and easy operation. easy effect

Inactive Publication Date: 2018-10-16
天津同华生物科技有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, this drug is favored clinically, but the synthetic route of this drug is long and the cost is high. In the prior art, the reaction process involves a reduction reaction, and the hydrogenation pressure in the method is 4-10 MPa, which is harmful to the production site and production equipment. There are strict requirements, which is not conducive to large-scale industrial production, and hydrogen is flammable and explosive, which is not conducive to safe production, so its synthesis method still needs further research and improvement

Method used

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  • Preparation method for argatroban intermediate
  • Preparation method for argatroban intermediate
  • Preparation method for argatroban intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The biocatalyst is a genetically engineered bacterium derived from the transaminase of Vibrio fluvialis. The specific preparation method is: select the gene sequence of the transaminase derived from Vibrio fluvialis and carry out artificial design. The designed gene sequence is shown in SEQ ID NO: 1 in the sequence table shown in the nucleotide sequence; the sequence is synthesized through the whole gene, cloned into the Nde I and Xho I restriction sites of the expression vector pET28a, and transformed into the competent cell of the host bacteria E.coli BL21 (DE3); pick the positive transformation After sequencing and identification, the recombinant expression vector was obtained; the recombinant expression vector was transferred into the E. coli BL21 (DE3) strain, and the recombinant transaminase genetically engineered bacteria capable of inducing the expression of the recombinant transaminase was obtained.

[0032] Inoculate recombinant transaminase genetically enginee...

Embodiment 2

[0034] Formula II compound (R)-4methyldihydrofuran-2(3H)-one ring-opens and then reacts with sodium methoxide to generate formula III compound R-3-methyl-4-hydroxybutyric acid methyl ester.

[0035] The specific reaction process is as follows: the formula II compound (R)-4 methyl dihydrofuran-2 (3H)-one (30g, 0.3mol) was dissolved in methanol (300ml), and sodium methoxide (19.44g, 0.36 mol), and then heated to 80 ° C for 5 h. Cool down after the reaction, concentrate the methanol, adjust the pH to about 7 with ammonium chloride solution, and extract with ether. After drying and concentrating, the compound of formula III R-3-methyl-4-hydroxybutyric acid methyl ester (36.8 g, 0.279 mol) was obtained.

[0036] The reaction formula is as follows:

[0037]

Embodiment 3

[0039] Formula III compound R-3-methyl-4-hydroxybutyric acid methyl ester is oxidized to generate formula IV compound (3R)-3-methyl-4-formyl butyric acid methyl ester.

[0040]The specific reaction process is as follows, under the protection of nitrogen, dissolve oxalyl chloride (10ml, 0.11mol) in dichloromethane (250ml), cool to -60°C, add dropwise dimethyl sulfoxide solution [dimethyl sulfoxide (17ml , 0.22mol) was dissolved in 50ml dichloromethane], dropwise reacted at -60°C for half an hour, and then added dropwise R-3-methyl-4-hydroxybutyrate methyl ester solution [the formula III compound R-3 -Methyl-4-hydroxybutyrate (13.2 g, 0.1 mol) was dissolved in 100 ml of dichloromethane], and stirred for another 1 hour after dropping. Then triethylamine (70ml, 0.5mol) was added dropwise at -60°C, reacted at -60°C for half an hour after the dropwise completion, and then warmed up to room temperature for reaction. After monitoring that the reaction is complete, add water, then ext...

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Abstract

The invention discloses a preparation method for an argatroban intermediate. The preparation method comprises the following steps: subjecting (R)-4-methyldihydrofuran-2(3H)-one to ring opening and then to a reaction with sodium methoxide or potassium methoxide to form R-3-methyl-4-methyl-3-hydroxybutyrate; oxidizing R-3-methyl-4-methyl-3-hydroxybutyrate to form methyl (3R)-3-methyl-4-formylbutyrate; then reacting (3R)-3-methyl-4-formylbutyrate with hydantoin to form (3R)-3-methylene-butyric acid carbomethoxyhydantoin; successively carrying out purification, heating reflux and purification so as to obtain (4S)-4-methyl-2-oxoadipate; reacting (4S)-4-methyl-2-oxoadipate with an amino donor under the action of a catalyst, and carrying out purification so as to obtain (2R,4S)-2-amino-4-methyladipate; reacting (2R,4S)-2-amino-4-methyladipate with methanol, and carrying out purification so as to obtain (2R,4S)-2-amino-6-methoxy-4-methyl-6-oxohexanoic acid; and reacting (2R,4S)-2-amino-6-methoxy-4-methyl-6-oxohexanoic acid with a reducing agent, and carrying out purification so as to obtain the argatroban intermediate. The preparation method of the invention is mild in reaction conditions, low in cost and suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a drug intermediate, in particular to a preparation method of an argatroban intermediate. Background technique [0002] Argatroban is the first antithrombotic drug 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 it was used in the treatment of acute cerebral thrombosis. In 2000, the U.S. Food and Drug Administration approved the injectable antithrombotic small molecule drug argatroban of SmithKline and Texas Biotechnology Company for the treatment and prevention of thrombosis and heparin-induced immune diseases, Thrombocytopenia and for the treatment of patients requiring coronary intervention. In 2005, a new drug "Darbe Argatroban" for the treatment of acute cerebral thrombosis was approved by the State Food and Drug Administration, and was included in the National 863 Project an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
CPCC07D211/60C07B2200/07
Inventor 胡磊吴克婕黄小明
Owner 天津同华生物科技有限责任公司
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