Preparation method of argatroban intermediate

A technology for argatroban and intermediates, applied in the field of drug preparation, can solve problems such as cumbersome operations, and achieve the effects of simplifying the process, reducing costs, and reducing the number of crystallization times

Pending Publication Date: 2021-03-23
安庆恩聚生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The object of the present invention is to provide a kind of preparation method of argatroban intermediate, to solve the problem proposed in the above-mentioned background technology: adopt chemical resolution method more in the prior art, obtain qualified product through at least three recrystallizations, operate Complicated, the yield is 10~30%

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Dissolve 15kg of ethyl 4-methylpiperidine-2-carboxylate (cis:trans=5:95) in 60kg of acetone, slowly add 30kg of 10% sodium dihydrogen phosphate aqueous solution under stirring, and heat to 50 -55 degrees, drop 20% sodium hydroxide aqueous solution to adjust the pH to 8.5, then add 210 grams of alkaline protease at one time, keep the reaction temperature at 50~55 degrees for 6 hours, the isomer of 2s configuration detected by HPLC is less than 0.1% (Pre-column derivatization with 2,3,4,6-O-tetraacetyl-beta-D-glucopyranosyl isothiocyanate; column: EclipsePlus C18 Agilent column (5μm, 4.6×250 mm); Column temperature: 40 degrees; mobile phase: acetonitrile: water = 10%~90%, 45 minutes; detection wavelength: 254,; flow rate: 1mL / min). Add 30 kg of water, concentrate most of the acetone, drop to room temperature, add 60 kg of dichloromethane, stir for 30 minutes, filter out insoluble matter, separate the organic layer, extract the water layer once with 15 kg of dichloromethan...

Embodiment 2

[0021] 30 grams of ethyl 4-methylpiperidine-2-carboxylate (cis: trans = 5:95) was dissolved in 150 ml of ethanol, slowly added 60 grams of 10% sodium dihydrogen phosphate aqueous solution under stirring, heated to 50 -55°C, add 20% sodium hydroxide aqueous solution dropwise to adjust the pH to 8.5, then add 1 gram of alkaline protease at one time, keep the reaction temperature at 50-55°C for 12 hours, the isomer of 2s configuration detected by HPLC is less than 0.1% , add 30 grams of water, concentrate most of the ethanol, drop to room temperature, add 100 milliliters of dichloromethane, stir for 10 minutes, filter off the insoluble matter, separate the organic layer, extract the water layer with 30 milliliters of dichloromethane once, and the organic layer Combined, washed once with 5% aqueous sodium carbonate solution, washed once with water, concentrated and dried to obtain a yellow-brown oil, added 60 milliliters of acetone to the oil, stirred to dissolve, then added 60 mil...

Embodiment 3

[0023] 30 grams of ethyl 4-methylpiperidine-2-carboxylate (cis: trans = 5:95) was dissolved in 150 ml of acetone, slowly added 60 grams of 10% sodium dihydrogen phosphate aqueous solution under stirring, heated to 50 -55 degrees, drop 20% sodium hydroxide aqueous solution to adjust the pH to 8.0, then add 1 gram of alkaline protease at one time, keep the reaction temperature at 50-55 degrees for 12 hours, HPLC detects 2.7% of the isomer of the 2s configuration, Add 30 grams of water, concentrate most of the ethanol, lower to room temperature, add 100 milliliters of dichloromethane, stir for 10 minutes, filter off the insoluble matter, separate the organic layer, extract the water layer once with 30 milliliters of dichloromethane, and combine the organic layers , washed once with 5% aqueous sodium carbonate solution, washed once with water, concentrated and dried to obtain a yellow-brown oil, added 60 milliliters of acetone to the oil, stirred and dissolved, then added 60 millil...

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PUM

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Abstract

The invention discloses a preparation method of an argatroban intermediate, belonging to medicine preparation. The invention particularly relates to the field of preparation of medicine intermediates,and especially relates to an enzyme resolution preparation method for an important argatroban intermediate, namely ethyl (2R,4R)-4-methyl-2-piperidinecarboxylate L-tartrate. The invention aims at overcoming the defects of excessive crystallization times and low yield of the existing process, and provides the preparation method, which is simple in research, design and operation, good in selectivity, high in yield and easier for industrial production, for the argatroban intermediate ethyl (2R,4R)-4-methyl-2-piperidinecarboxylate L-tartrate. The preparation method is a brand-new preparation method.

Description

technical field [0001] The present invention relates to the preparation of medicines, in particular to the field of preparation of pharmaceutical intermediates, in particular to the production of (2R,4R)-4-methylpiperidine-2-ethyl carboxylate-L-tartrate, an important intermediate of argatroban Enzymatic resolution preparation method. Background technique [0002] Argatroban is a piperidine carboxylic acid derivative of L-arginine, which belongs to anticoagulant drugs. It is a small molecular substance with high selectivity, can reversibly directly inhibit the activity of thrombin, and quickly bind to thrombin in free blood clots in the circulation to produce anticoagulant effect. For thrombosis associated with heparin-induced thrombocytopenia. [0003] In the preparation method of argatroban, (2R,4R)-4-methylpiperidine-2-carboxylic acid ethyl ester-L-tartrate is an important intermediate for synthesizing the argatroban bulk drug. The raw material 4-methylpiperidine-2-carb...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
CPCC07D211/60
Inventor 王伟强李小鹏邵建勇栾义黄英豪杨宁王慧斌
Owner 安庆恩聚生物医药科技有限公司
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