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Argatroban and preparation thereof

A technology of argatroban and a synthesis method, which is applied in the field of drug synthesis, can solve the problems of complicated operation, low yield, large respiratory tract irritation, etc., and achieves the effects of simplified operation steps, simple synthesis process and shortened reaction time.

Inactive Publication Date: 2009-01-21
TIANJIN TAIPU PHARMA SCI & TECH DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the synthetic route is relatively simple and the raw materials are easy to obtain, it is difficult to obtain in N 2 -(3-Methyl-8-quinolinesulfonyl)-N G -In the condensation reaction of nitro-L-arginine (carboxylate) and (2R, 4R) 4MPE, the method that literature adopts is to first prepare carboxylate into acid chloride and then carry out condensation, the acid chloride reagent used in this method Phosphorus oxychloride, phosphorus trichloride, etc., which have a pungent odor, are easy to absorb moisture, smoke violently in humid air, pollute the environment, and are irritating to the human respiratory tract, which can cause irritation symptoms and eye and skin burns
And adopt this method, complicated operation, lower yield, higher cost, especially not suitable for large-scale industrialized production

Method used

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  • Argatroban and preparation thereof
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  • Argatroban and preparation thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0034] (2R, 4R)-1-[N G -Nitro-N 2 Preparation of -(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid ethyl ester (Z-VIII):

[0035]Add 76.4 g (0.18 mol) of carboxylate and 30.7 g (0.18 mol) of (2R, 4R) 4MPE into the reaction flask, add 1000 ml of THF and stir to dissolve, add 49.5 g (0.18 mol) of DPPA at 0°C, and stir at room temperature for 14 hours. Add 500ml of saturated brine, stir for 10 minutes, separate the organic layer, extract the aqueous layer with THF 200ml×2, combine the organic layers, concentrate to dryness, add 500ml of chloroform to dissolve, wash with sodium bicarbonate aqueous solution and water, and dry, Concentrate to dryness to obtain a yellow solid with a yield of 54%, HPLC≥92% (normalization method).

Embodiment 2

[0037] (2R, 4R)-1-[N G -Nitro-N 2 Preparation of -(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid ethyl ester (Z-VIII):

[0038] Add 100g (0.24 moles) of the carboxylate and 44g (0.26 moles) of (2R, 4R) 4MPE into the reaction flask, add 1000ml of dichloromethane and stir to dissolve, add 72.6g (0.26 moles) of diethyl bromophosphate at -5°C 23.2ml (0.288mol) of pyridine was added dropwise under stirring, stirred at 30°C for 6 hours, 500ml of saturated saline was added, the organic layer was separated, the aqueous layer was extracted with 400ml of dichloromethane, the organic layers were combined, and sodium bicarbonate aqueous solution and Washed with water, dried and concentrated to dryness to obtain a yellow solid with a yield of 84.5%, HPLC≥95% (normalization method).

Embodiment 3

[0040] (2R, 4R)-1-[N G -Nitro-N 2 Preparation of -(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid ethyl ester (Z-VIII):

[0041] Add 76.4g (0.18 moles) of the carboxylate and 30.7 grams (0.18 moles) of (2R, 4R) 4MPE to the reaction flask, add 800ml of DMF, stir to dissolve, add 31.2ml (0.216 moles) of diethyl phosphate chloride at 0°C, Add 26.4 g (0.216 mol) of DMAP under stirring, stir at 25°C for 6 hours, evaporate the solvent to dryness under reduced pressure, add 500 ml of water, extract the aqueous layer three times with 600 ml of dichloromethane, combine the organic layers, and use sodium bicarbonate aqueous solution and water respectively Washed, dried, and concentrated to dryness to obtain a yellow solid with a yield of 88.5%, HPLC≥95% (normalization method).

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Abstract

The invention relates to a method for synthesizing argatroban. The method comprises the following steps that nitryl L-arginie and quinoline sulfonchloride are condensed, and undergo amidation with piperidine ethyl formate, followed by hydrolysis and hydrogenation to obtain argatroban; the amidation is to make carboxylate (c-v) and (2R, 4R) 4MPE (Z-VII) react in an organic solvent in the presence of condensing agent, or the presence of both condensing agent and dehydration promoter, in which the molecular ratio of carboxylate (c-v): (2R, 4R) 4MPE (Z-VII): condensing agent: dehydration promoter is 1: 0.8-1.2: 0.8-1.2: 0-1.2. The condensing agent adopted by the invention is diphenylphosphoryl azide, diethylthiophosphoryl, chlorophosphoric acid diethyl or bromophosphoric acid diethyl. The invention has simplified operation, lowered cost, decreased pollution, increased yielding rate, and is suitable for large-scale industrialized production of argatroban.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a method for preparing chemically synthesized drugs, more specifically, a method for synthesizing argatroban. Background technique [0002] Stroke is the scientific name of cerebral apoplexy, which is a sudden onset of cerebral blood circulation disorders. The clinical manifestations are mainly characterized by sudden fainting, unconsciousness or sudden crooked mouth and eyes, hemiplegia, strong tongue, and mental retardation. Cerebral stroke includes ischemic stroke (transient ischemic attack, atherosclerotic thrombotic cerebral infarction, lacunar infarction, cerebral embolism), hemorrhagic stroke (cerebral hemorrhage, subarachnoid hemorrhage), high Blood pressure encephalopathy and vascular dementia four categories. According to statistics, there are 2 million stroke patients in my country every year. The incidence rate is as high as 120 / 100,000. There are currently 7...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 周学福魏文涛孙继铨赵健张殿镇瞿虹吴民义杨胜利马克胡雅萍刘秀颖
Owner TIANJIN TAIPU PHARMA SCI & TECH DEV
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