Method for continuously preparing argatroban

A technology of argatroban and dripping, which is applied in the field of medicine, can solve problems such as high temperature and high pressure reaction time, and achieve the effects of reducing the amount of condensing agent, reducing production costs, and shortening reaction time

Pending Publication Date: 2020-07-31
江巨东
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Multiple steps in the reaction process of the present invention almost use the same solvent, which is more conducive to solvent recovery and realizes the purpose of waste liquid reduction; in addition, the method selects a microreactor to carry out palladium carbon hydrogenation reduction, thereby avoiding the high temperature and high pressure in the hydrogenation process. Long response time and other issues, so as to ensure safety in the production process

Method used

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  • Method for continuously preparing argatroban
  • Method for continuously preparing argatroban
  • Method for continuously preparing argatroban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] The method for the continuous preparation of argatroban of embodiment 1

[0053] (1) Sulfonylation reaction

[0054] Add 25.8g (0.645mol) of sodium hydroxide and 400ml of water to a 1000mL three-necked flask, stir to dissolve, then add 50g (0.43mol) N-nitro-L-arginine and stir to dissolve at room temperature; in another 500ml three-necked flask Add 135.1g (0.559mol) of 3-methyl-8-quinolinesulfonyl chloride and 250ml of chloroform, stir to dissolve, and transfer to the above-mentioned 1000ml three-neck flask. After the transfer is complete, add 0.5g TEBA, raise the temperature to 40°C for 2 hours, let stand to separate the layers, and discard the organic phase. Add 400ml of chloroform to the water phase, adjust the pH to 6.0 with concentrated hydrochloric acid, stir, separate layers, and discard the water phase. Add 40 g of anhydrous sodium sulfate to the organic phase, dry for 30 min, filter, and transfer the filtrate to a 1000 ml three-necked flask, and transfer to t...

Embodiment 2

[0063] The method for the continuous preparation of argatroban of embodiment 2

[0064] (1) Sulfonylation reaction

[0065] Add 24.2g (0.43mol) of potassium hydroxide and 250ml of water to a 1000mL three-necked flask, stir to dissolve, then add 50g (0.43mol) N-nitro-L-arginine and stir to dissolve at room temperature; in another 500ml three-necked flask Add 103.9g (0.43mol) of 3-methyl-8-quinolinesulfonyl chloride and 150ml of dichloromethane, stir to dissolve, and transfer to the above-mentioned 1000ml three-necked flask. After the transfer was completed, 0.25 g of tetrabutylammonium bromide was added, the temperature was raised to 30° C. for 3 h, the mixture was allowed to stand and the layers were separated, and the organic phase was discarded. Add 250ml of dichloromethane to the water phase, adjust the pH to 5.0 with concentrated hydrochloric acid, stir, separate layers, and discard the water phase. Add 30 g of anhydrous magnesium sulfate to the organic phase, dry it for...

Embodiment 3

[0074] The method for the continuous preparation of argatroban of embodiment 3

[0075] (1) Sulfonylation reaction

[0076]Add 31.6g (0.559mol) of potassium hydroxide and 300ml of water to a 1000mL three-necked flask, stir to dissolve, then add 50g (0.43mol) N-nitro-L-arginine and stir to dissolve at room temperature; in another 500ml three-necked flask Add 124.7g (0.516mol) of 3-methyl-8-quinolinesulfonyl chloride and 200ml of dichloromethane, stir to dissolve, and transfer to the above-mentioned 1000ml three-necked flask. After the transfer is complete, add 0.4g TEBA, raise the temperature to 40°C for 2 hours, let stand to separate the layers, and discard the organic phase. Add 300ml of dichloromethane to the water phase, adjust the pH to 5.4 with concentrated hydrochloric acid, stir, separate layers, and discard the water phase. Add 35g of anhydrous magnesium sulfate to the organic phase, dry for 30min, filter, transfer the filtrate into a 1000ml three-neck flask, and tra...

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Abstract

The invention belongs to the technical field of medicines and relates to a method for continuously preparing argatroban. The method comprises the specific processes of achieving N-nitro-L-arginine sulfonylation reaction through a phase transfer catalyst in two phases of water and a solvent; after reaction is completed, directly carrying out condensation on an organic phase without concentration treatment and ethyl (2R,4R)-4-methyl-2-piperidinecarboxylate; after reaction is completed, carrying out hydrolysis reaction on a water phase in an alkaline condition; carrying out hydrogenation reduction by using a microreactor; and finally carrying out refining to obtain argatroban. According to the method, tedious treatment and purification steps of various intermediates are reduced, and continuous reaction is achieved, so that the production efficiency is improved. Meanwhile, almost the same solvent is adopted by a plurality of steps in the reaction process, solvent recovery is facilitated, and the target of waste liquid reduction is achieved. In addition, the microreactor is adopted by the method for carrying out palladium carbon hydrogenation reduction, so that high temperature, high pressure, long reaction time and other problems in the hydrogenation process are avoided to ensure the safety in the production process.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for continuously preparing argatroban. Background technique [0002] Argatroban as a thrombin inhibitor was first used in Japan in the early 1980s, and was subsequently approved by the US Food and Drug Administration for clinical use. Argatroban is a small molecule direct thrombin inhibitor derived from L-arginine, which has good selectivity. Its structural formula is composed of arginine, piperidine and quinoline, a total of three functional groups. Forming a tripod structure makes the combination of argatroban and thrombin active site have the characteristics of three-dimensionality, rapidity, selectivity and reversibility. It can reversibly block the catalytic site and non-polar region of thrombin, inhibit the fibrin production, platelet aggregation and vasoconstriction caused by thrombin, and at the same time inhibit the activation of coagulation factor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/068C07K1/02
CPCC07K5/06095
Inventor 江巨东
Owner 江巨东
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