Synthetic method of argatroban and intermediate thereof

A technology of argatroban and intermediates, applied in the field of drug synthesis, which can solve the problems of difficult removal of water

Active Publication Date: 2009-01-21
天津药物研究院药业有限责任公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Feed directly to carry out the next reaction, thus solving the thorny problem of difficult removal of moisture encountered in production, and meeting the needs of large-scale industrial production

Method used

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  • Synthetic method of argatroban and intermediate thereof
  • Synthetic method of argatroban and intermediate thereof
  • Synthetic method of argatroban and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 27g of anhydrous sodium carbonate to the reaction flask, add water to dissolve it, add 47g N G -Nitro-L-arginine 0.214mol), stirred and heated to about 60°C to dissolve, cooled to 25°C, added dropwise 50g (0.206mol) of tetrahydrofuran solution of 3-methyl-8-quinolinesulfonyl chloride, 15 Complete the addition in 1 minute, react at room temperature for 5 hours, evaporate the tetrahydrofuran after the reaction is completed, wash the cooled water phase with 100ml×2 chloroform, add 300ml tetrahydrofuran to the water phase, adjust the pH to about 2.5 with 10% hydrochloric acid, add sodium chloride solid saturated water layer, the tetrahydrofuran layer was separated, and the aqueous layer was extracted and combined with tetrahydrofuran (400ml×3), dried over anhydrous sodium sulfate, overnight. The desiccant was removed by filtration, and 120 g of 4A molecular sieves were added to the filtrate to dry overnight, and then placed to be tested and used.

[0030] Intermediate ...

Embodiment 2

[0033] Add 1.62kg of anhydrous sodium carbonate to a 300L reaction kettle, add water and stir to dissolve, add N G -Nitro-L-arginine 2.72kg (12.4mol), stirred and heated to about 60°C, the solution was clear. Cool down to 25°C, inhale 3.0kg (12.4mol) of tetrahydrofuran solution of 3-methyl-8-quinolinesulfonyl chloride, and 31.8kg of tetrahydrofuran into a 20L dropping bottle, slowly drop into the reaction kettle, and complete the addition in about 40 minutes . The temperature was controlled at 25°C for 5 hours. After the reaction was completed, tetrahydrofuran was distilled off under reduced pressure (control internal temperature < 50°C). Cool the reaction solution below 30°C, wash it with chloroform 6L×2, then add 16kg tetrahydrofuran to the water, adjust the pH to about 2.5 with 10% hydrochloric acid while stirring, add 7.5kg sodium chloride and stir evenly, and let it stand for stratification. The tetrahydrofuran layer was separated, and the water layer was extracted wit...

Embodiment 3

[0036]Add 1.62kg of anhydrous sodium carbonate to a 300L reaction kettle, add water and stir to dissolve, add N G -Nitro-L-arginine 3.5kg (15.9mol), stirred and heated to about 60°C, the solution was clear. Cool down to 25°C, inhale 3.6kg of a tetrahydrofuran solution of 3-methyl-8-quinolinesulfonyl chloride (14.9mol), and 98kg of tetrahydrofuran into a 20L dropping bottle, slowly drop them into the reaction kettle, and complete the addition in about 40 minutes. The temperature was controlled at 25°C for 5 hours. After the reaction was completed, tetrahydrofuran was distilled off under reduced pressure (control internal temperature < 50°C). Cool the reaction solution below 30°C, wash it with 12L×2 chloroform, then add 32kg tetrahydrofuran to the water, adjust the pH to about 2.5 with 10% hydrochloric acid while stirring, add 10kg ammonium chloride and stir evenly, let stand to separate layers, and separate The tetrahydrofuran layer was removed, and the aqueous layer was extr...

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Abstract

The invention relates to a method for preparing N<2>-(3-methyl-8-quinoline sulfonyl)- N-nitryl-L-arginine as the intermediate of argatroban. The method comprises the following steps that the reaction of N-nitryl-L-arginine and a 3-methyl-8-quinoline sulfonyl chloride-THF solution is carried out in an aqueous solution of sodium carbonate ; after the reaction ends, THP is collected through evaporation, and the water layer is extracted with an organic solvent, then THF is added with pH adjusted to 2-3, and then a solid saturated water layer of inorganic salt is added; THF is separated and a desiccant is added and stirred for 10-24 hours, with water content of THF measured to be less than 1 percent, then a molecular sift is added for drying, with the water content of THF controlled within 0.2 percent, and then THF reacts with (2R, 4R) 4MPE directly. The invention solves well the control on the water content of N<2>-(3-methyl-8 quinoline sulfonyl)-N N-nitryl-L-arginine, ensures the successful implementation of amide acylation, and satisfies the requirement of the large-scale industrial production.

Description

technical field [0001] The present invention relates to the technical field of medicine synthesis, more specifically, argatroban intermediate N 2 -(3-Methyl-8-quinolinesulfonyl)-N G - Process for the preparation of nitro-L-arginine. 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, such as common language, sensory or motor dysfunction, requiring long-term hospitalization and family care, which brings serious economic problems to society and families, and is even more serious patients can be life-threatening. In my country, about 3 million people suffer from stroke every year, and it is on the rise in recent years, and there is a lack of acute treatment drugs. [0003] Argatroban (Argatroban) is the only synthetic drug approved for the treatment of acute ischemic st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/36C07D401/12
Inventor 田青松赵健朱建强周学福张殿镇瞿虹吴民义杨胜利马克胡雅萍刘秀颖
Owner 天津药物研究院药业有限责任公司
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