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Preparation method of (2R, 4R)-4-pipecolines-2-ethyl formate compound

A technology of ethyl formate and methylpiperidine, which is applied in the field of preparation of ethyl-4-methylpiperidine-2-carboxylate, can solve the problems of low yield, long synthetic route, poor reaction selectivity, etc. Easy to obtain, high yield and high product purity

Active Publication Date: 2014-03-19
北京成宇化工有限公司
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  • Abstract
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Problems solved by technology

[0019] In summary, the method for the synthesis of the argatroban intermediate (2R, 4R)-4-methylpiperidine-2-ethyl carboxylate reported in the above literature has obvious shortcomings: either the source of raw materials is difficult, or the price of the catalyst is low. Expensive, or the reaction selectivity is poor, the yield is low, or the synthetic route is long, etc.

Method used

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  • Preparation method of (2R, 4R)-4-pipecolines-2-ethyl formate compound
  • Preparation method of (2R, 4R)-4-pipecolines-2-ethyl formate compound
  • Preparation method of (2R, 4R)-4-pipecolines-2-ethyl formate compound

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Experimental program
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Effect test

Embodiment 1

[0045] 1. Preparation of ethyl (2R, 4R)-4-methyl-1-((S)-1-phenethyl)tetrahydropyridine-2-carboxylate

[0046] Combine (2R)-4-methyl-1-((S)-1-phenethyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid ethyl ester (328g, 1.2mol) and ethanol ( 2500mL) into a 5L autoclave, add rhodium-alumina catalyst (10% rhodium loading, 60g), and pass H 2 , React at 35℃, 1MPa for 12h, filter, and recover the catalyst. The reaction solution was concentrated under reduced pressure, ethyl acetate (1000 mL) was added, washed with saturated brine (250 mL x 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless and transparent liquid product (310 g).

[0047] Liquid chromatography determination: (2R, 4R)-4-methyl-1-((S)-1-phenethyl)-2-piperidine ethyl ester content is 73.2%.

[0048] 2. Preparation of (2R, 4R) ethyl-4-methylpiperidine-2-carboxylate

[0049] Put the crude product (200g) and ethanol (1000mL) obtained in the above steps...

Embodiment 2

[0055] 1. Preparation of ethyl (2R, 4R)-4-methyl-1-((S)-1-phenethyl)tetrahydropyridine-2-carboxylate

[0056] Combine (2R)-4-methyl-1-((S)-1-phenethyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid ethyl ester (328.1g, 1.2mol) and ethanol (2500mL) into a 5L autoclave, add rhodium-carbon catalyst (5% rhodium loading, 50g), pass H 2 , React at 40℃, 1Mpa for 12h. Filter and recover the catalyst. The reaction solution was concentrated under reduced pressure, ethyl acetate (1000mL) was added, washed with saturated brine (250mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was decolorized by adding silica gel and filtered. The filtrate was concentrated under reduced pressure to obtain colorless and transparent Liquid product (315g).

[0057] Determination by liquid chromatography: (2R, 4R)-4-methyl-1-((S)-1-phenethyl)-2-piperidine ethyl ester content is 68.5%.

[0058] 2. Preparation of (2R, 4R) ethyl-4-methylpiperidine-2-carboxylate

[0059] Put the crude product (1...

Embodiment 3

[0065] 1. Preparation of ethyl (2R, 4R)-4-methyl-1-((S)-1-phenethyl)tetrahydropyridine-2-carboxylate

[0066] Combine (2R)-4-methyl-1-((S)-1-phenethyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid ethyl ester (273g, 1.0mol) and ethanol ( 2000mL) into a 5L autoclave, add rhodium-alumina catalyst (5% rhodium loading, 75g), pass H 2 , React at 25℃, 0.5Mpa for 12h. Filter and recover the catalyst. The reaction solution was concentrated under reduced pressure, ethyl acetate (1000mL) was added, washed with saturated brine (250mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was decolorized by adding silica gel and filtered. The filtrate was concentrated under reduced pressure to obtain colorless and transparent Liquid product (250g).

[0067] Liquid chromatography determination: (2R, 4R)-4-methyl-1-((S)-1-phenethyl)-2-piperidine ethyl ester content is 62.3%.

[0068] 2. Preparation of (2R, 4R) ethyl-4-methylpiperidine-2-carboxylate

[0069] Put the crude product (25...

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Abstract

The invention relates to a method for preparing (2R, 4R)-4-pipecolines-2-ethyl formate by using 4-methly tetrahydropyridine-2-ethyl formate as a starting material. The synthesis method comprises the following steps: 1) catalytically hydrogenating 4-methyl (1-methylic benzyl) tetrahydropyridine-2-ethyl formate under the effect of a rhodium catalyst to obtain 4-methyl (1-methylic benzyl) piperidine-2-ethyl formate; 2) removing benzyl through a palladium catalyst to obtain 4-pipecolines-2-ethyl formate; and 3) rectifying, separating and purifying to obtain the synthesized (2R, 4R)-4-pipecolines-2-ethyl formate. The preparation method has the advantages that the reaction conditions are easily controlled, the cost is low, the yield is high, the operation process is simple and convenient, and the mass production can be carried out conveniently.

Description

Technical field [0001] The invention belongs to the field of medicine and chemical industry, and more specifically relates to a method for preparing ethyl (2R, 4R)-4-methylpiperidine-2-carboxylate. Background technique [0002] Argatroban is a chemically synthesized drug (chemical name: (2R,4R)-4-methyl-1-[N~2-(3-methyl-1,2,3,4-tetrahydro -8-quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid monohydrate, (Ⅰ). The structural formula is as follows: [0003] [0004] Since the Japanese company Mitsubishi first reported the anticoagulant activity of Argatroban in 1978, scientists have conducted in-depth research on its chemical synthesis, biological activity and clinical application. It was first listed in Japan in 1990, approved by the US FDA in 2000, and listed in my country in 2002. Argatroban can be used as drugs for the treatment and prevention of thrombosis, platelet aggregation inhibitors, treatment of chronic arterial blockage and treatment of cerebral thrombosis. The...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
CPCC07D211/60
Inventor 宋也王道林王玉平
Owner 北京成宇化工有限公司
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