Unlock instant, AI-driven research and patent intelligence for your innovation.

The preparation method of (2r,4r)-4-methylpiperidine-2-ethyl carboxylate compound

A technology of ethyl piperidine carboxylate and ethyl formate, which is applied in the field of medicine and chemical industry, can solve the problems of low yield, long synthetic route, poor reaction selectivity, etc., and achieve the effects of easy availability of raw materials, high yield and high purity of products

Active Publication Date: 2016-08-17
北京成宇化工有限公司
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • The preparation method of (2r,4r)-4-methylpiperidine-2-ethyl carboxylate compound
  • The preparation method of (2r,4r)-4-methylpiperidine-2-ethyl carboxylate compound
  • The preparation method of (2r,4r)-4-methylpiperidine-2-ethyl carboxylate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0046] Combine (2R)-4-methyl-1-((S)-1-phenethyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid ethyl ester (328 g, 1.2 mol) and ethanol ( 2500mL) into the 5L autoclave, add rhodium-alumina catalyst (10% rhodium loading, 60g), feed H 2 , reacted at 35°C and 1MPa for 12h, filtered and recovered 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 transparent liquid product (310 g).

[0047] Determination by liquid chromatography: the content of (2R,4R)-4-methyl-1-((S)-1-phenethyl)-2-piperidinecarboxylic acid ethyl ester was 73.2%.

[0048] 2. Preparation of (2R,4R)-4-methylpiperidine-2-carboxylic acid ethyl ester

[0049] The crude product (...

Embodiment 2

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

[0056] Combine (2R)-4-methyl-1-((S)-1-phenethyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid ethyl ester (328.1 g, 1.2 mol) and ethanol (2500mL) was added to the 5L autoclave, rhodium-carbon catalyst (5% rhodium loading, 50g) was added, and H 2 , at 40 ℃, 1Mpa reaction 12h. Filtration, recovery 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, silica gel was added to the filtrate to decolorize, filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless transparent Liquid product (315g).

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

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

Embodiment 3

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

[0066] Combine (2R)-4-methyl-1-((S)-1-phenethyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid ethyl ester (273 g, 1.0 mol) and ethanol ( 2000mL) in the 5L autoclave, add rhodium-alumina catalyst (5% rhodium loading, 75g), feed H 2 , at 25 ℃, 0.5Mpa reaction for 12h. Filtration, recovery of 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, silica gel was added to the filtrate to decolorize, filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless transparent Liquid product (250 g).

[0067] Determination by liquid chromatography: (2R,4R)-4-methyl-1-((S)-1-phenethyl)-2-piperidinecarboxylic acid ethyl ester content was 62.3%.

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

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 particularly relates to a preparation method of (2R,4R)-4-methylpiperidine-2-ethyl carboxylate. Background technique [0002] Argagtroban 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 anticoagulant activity of argatroban was first reported by Japan's Mitsubishi Company 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 launched in my country in 2002. Argatroban can be used as a treatment and prevention of thrombosis and platelet aggregation inhibitors, treatment of chronic arterial blockage and treatment of cerebral thrombosis...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(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