A kind of synthetic method of argatroban

A synthetic method, the technology of argatroban, applied in the field of drug synthesis, can solve the problems of flammability and explosion of hydrogen, unfavorable safety production, unfavorable large-scale production, etc., achieve mild and easy-to-control reaction conditions, avoid technical and safety problems problems, risk reduction effects

Active Publication Date: 2019-08-27
河北广祥制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this hydrogenation reduction method, the hydrogenation pressure is 4-10 MPa, which belongs to medium and high pressure reactions, and has strict requirements on production sites and production equipment, which is not conducive to large-scale industrial production; moreover, hydrogen is flammable and explosive, which is not conducive to safe production

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  • A kind of synthetic method of argatroban
  • A kind of synthetic method of argatroban
  • A kind of synthetic method of argatroban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The synthetic method of compound I is as follows:

[0040] 25 g of (2R,4R)-1-[2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methyl-2 at 5°C -Ethyl piperidinecarboxylate hydrochloride (compound A) was dissolved in 200mL of chloroform, and 18.5g of triethylamine and 14.7g of 3-methyl-8-quinolinesulfonyl chloride (compound B) were added successively. The reaction was stirred at low temperature for 3 hours. After the reaction was completed, it was washed twice with 50 mL of water. The chloroform phase was dried with anhydrous sodium sulfate, and the solvent was evaporated to dryness. The residue was chromatographed on a 50 g silica gel column to obtain 32.1 g of compound I with a yield of 91 wt%.

[0041] The mass spectrum ESI-MS(m / z) of the product was detected: 578.0[M+H] + , 600.0[M+Na] + , 576.2[M-H] -

[0042]

[0043] The synthetic method of compound II is as follows:

[0044] Dissolve 30 g of the compound I prepared above in 100 mL of ethanol and ...

Embodiment 2

[0052] The synthesis method of compound I and compound II: refer to Example 1.

[0053] The synthetic method of argatroban: 25g (0.0455mol) compound II of aforementioned preparation is dissolved in 500mL ethanol, add 7.5g palladium loading capacity and be the palladium charcoal catalyst of 10wt% (add in the form of wet palladium charcoal with moisture content 70wt%) ) and 21g (0.456mol) formic acid, stirred and reacted at 40°C for 12h, the reaction was completed, filtered, evaporated to dryness of ethanol, the residue was dissolved in 200mL ethyl acetate, washed twice with 100mL water, separated, and 25g anhydrous sodium sulfate was added to the organic phase Dry for 6 hours, filter, and evaporate the solvent to dryness to obtain 21.2 g of white solid with a yield of 91.8 wt%. Then recrystallized with 425mL of 95wt% ethanol to obtain 18.4g of white powder, and the recrystallization yield was 86.7wt%.

[0054] After testing the proton nuclear magnetic resonance spectrum (1H.NM...

Embodiment 3

[0056] The synthesis method of compound I and compound II: refer to Example 1.

[0057] The synthetic method of argatroban: 30g (0.0546mol) of compound II prepared above was dissolved in 450mL of methanol, and 12g of palladium loading was added as a palladium carbon catalyst (in the form of wet palladium carbon with a moisture content of 70wt%) that was 10wt%. and 44.5g (0.654mol) of sodium formate, stirred and reacted at 30°C for 14h, the reaction was completed, filtered, evaporated to dryness of methanol, the residue was dissolved in 240mL of ethyl acetate, washed twice with 120mL of water, separated, and 30g of anhydrous sodium sulfate was added to the organic phase After drying for 6 hours, filtering, and evaporating the solvent to dryness, 24.4 g of a white solid was obtained, and the yield was 88 wt%. Then recrystallized with 490mL of 95wt% ethanol to obtain 20.3g of white powder, and the recrystallization yield was 83.2wt%.

[0058] After testing the proton nuclear mag...

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Abstract

The invention discloses a synthesis method of argatroban .The method includes the step of making a compound II of a structure shown in the formula II make contact with and react with a hydrogen donor under the catalytic transfer hydrogenation conditions through the catalyst to obtain an argatroban rough product, wherein the hydrogen donor is formic acid or formate, and the formula II can be seen in the description .By means of the method, formic acid or formate serves as the hydrogen donor, the compound II is subjected to hydrogenation and reduction to obtain argatroban .By means of the method, in the hydrogenation and reduction process of the compound II, catalytic transfer hydrogenation reaction replaces catalytic hydrogenation reaction, operation steps are simplified, the problems on the aspects of technology and safety caused by hydrogen application are solved, reaction dangerousness is reduced, reaction conditions are mild and easy to control, and the method is more suitable for industrial application and production of argatroban.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a synthesis method of argatroban. Background technique [0002] Acute and ischemic stroke are the five most common diseases in the world, and stroke mortality accounts for 10.12% of the total death toll. Survivors after stroke account for 75% of stroke patients and most of them have sequelae, which bring serious economic problems to society and family. Argatroban is currently the only synthetic drug approved in the world for the treatment of acute stroke. It has the advantages of high treatment efficiency and low incidence of side effects, and has a broad market prospect. [0003] 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 it was used in the treatment of acute cerebral thrombosis. In 2000, the U.S. Food and Dru...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/068C07K1/36C07K1/34C07K1/30C07K1/02
Inventor 殷殿书董岩曹柳印杰王少鹏刘少倩褚海龙王春发张清江
Owner 河北广祥制药有限公司
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