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A preparation method of argatroban intermediates

A technology for argatroban and intermediates, which is applied in the field of preparing argatroban intermediates, can solve the problems of unsuitability for industrial production, many reaction by-products, and difficult separation, and achieve complete reaction, simple operation, and easy purification Effect

Active Publication Date: 2009-03-04
TIANJIN WEIJIE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] When L-arginine is directly condensed with quinolinesulfonyl chloride, there are many reaction by-products, which are not easy to separate, and are not suitable for industrial production [Patent Bulletin Ping 1-35000]

Method used

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  • A preparation method of argatroban intermediates
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  • A preparation method of argatroban intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1.N G - Preparation of nitro-L-arginine

[0030] Add 165 g of concentrated sulfuric acid into a 300 ml four-necked reaction flask, add 34.8 g (0.2 mol) of L-arginine with stirring, stir until transparent, add 20.0 g (0.4 mol) of ammonium nitrate, and stir at room temperature for 3 hours. After the reaction, the reaction solution was poured into 600 grams of ice water, neutralized with about 370 grams of ammonia (17%), controlled to pH 6.5, and a white solid was precipitated, filtered, washed with water, and recrystallized with 900 grams of water to obtain N G -Nitro-L-arginine 35.7 grams, content 98.5% (HPLC quantitative analysis method), yield 80.3%.

Embodiment 2

[0031] Example 2.N G —Nitro—N 2 - Preparation of tBoc-L-arginine

[0032] Add 100ml of water into a 300ml four-necked reaction flask, add 4.4 grams (1.1mol) of sodium hydroxide under stirring, cool after stirring and dissolving, add 20.0 grams (0.091mol) of NG -Nitro-L-arginine and 52 grams of tert-butanol, stirred for a while to obtain a transparent solution, added 25.9 grams (0.119mol) of di-tert-butyl carbonate at a liquid temperatureG —Nitro—N 2 —tBoc—L—arginine (HPLC quantitative analysis method), content 96.5%, yield 57.8%.

Embodiment 3

[0033] Embodiment 3.(2R, 4R)-1-[N G —Nitro—N 2 -(tert-butyloxycarbonyl)-L-arginine]-4-methyl-2-piperidinecarboxylate ethyl ester

[0034] In a 5000ml four-necked reaction flask, add 3000ml of dichloromethane, under stirring, add 112.8g (0.655mol) of (2R,4R)-4-methyl-2-piperidinecarboxylate ethyl ester, and dissolve it in about 0.5 hours. Under stirring at room temperature, add DCC134.8 g (0.655 mol), continue stirring for 0.5 hours, add N G —Nitro—N 2 —tBoc—L—209.0 g (0.655 mol) of arginine, stirred at room temperature for 2 hours, detected by TLC (solvent system is ethyl acetate), the raw materials basically disappeared, and the reaction ended. Add 600ml of water, stir for 0.5 hours, cool the reaction solution to 0°C, filter to remove the by-product urea, separate the filtrate, remove the water layer, wash the organic layer twice with 950ml of 10% sodium hydroxide solution, wash with 600ml of 10% citric acid The solution was washed to neutrality, then washed with 600 ml o...

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Abstract

The invention discloses a preparing method of Argatroban intermediate, which is characterized by the following: adopting NG-nitro-N2-tBoc -L-arginine and (2R,4R)-4-methyl-2-piperidine ethyl formate to condensate; making DCC as dehydrant; reacting under -5-35deg.c for 1-5h and stirring; cooling reacting liquid; filtering to remove solid; stratifying filtrate; removing water layer; washing organic layer through sodium hydroxide solution, citrate solution and saturated salt water; drying; evaporating dichloromethane; obtaining yellow solid product.

Description

technical field [0001] The invention relates to a method for preparing an argatroban intermediate. technical background: [0002] In 1978, S.Okamoto of Mitsubishi Chemical Company in Japan reported for the first time the antithrombin activity of Argatroban (Argatroban)-hydrate [US 4 101 653]. During the following 20 years, many researchers conducted in-depth research on the biological activity of Argatroban and its value as medicine. In 1981, S.Okamoto compared heparin in animals [Okamoto, S.et al., Biochem.Biophys.Res.Commun.101, 440 (1981)]; T.Kumoto et al. reported its stereoselective activity [ Kumada, T.et al., Thromb.Res.24,285(1981)]; 1984, R.Kumato performed clinical hemodialysis evaluation [Kikumoto, R.et al., Biochemistry 23,85(1984)]; 1986 The author reported that Argatroban inhibits thrombin activity in mammals and can be used as a therapeutic and prophylactic agent for thrombosis and an inhibitor of platelet aggregation. The monohydrate of Argatroban can be u...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/60
Inventor 宋洪海
Owner TIANJIN WEIJIE TECH
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