Preparing method of (2R,4R)-4-methylpiperidine-2-ethyl formate compound

A technology of ethyl piperidinecarboxylate and ethyl piperidinecarboxylate hydrochloride, which is applied in the field of preparation of ethyl-4-methylpiperidine-2-carboxylate, and can solve unfavorable large-scale production and complicated operation of isomers , Catalysts are expensive and other problems, to achieve the effect of easy operation during scale-up, simple recrystallization method, and easy operation

Inactive Publication Date: 2018-05-18
BEIJING VOBAN PHARMA TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] In summary, the method for the synthesis of argatroban intermediate (2R, 4R)-4-methylpiperidine-2-ethyl carboxylate reported in the above bibliographical data has obvious deficiencies, or the catalyst is expensive and the cost is too high. High, or the route is long, contains dangerous reactions such as hydrogenation, there are safety problems, or the operation is complicated when removing isomers, which is not conducive to large-scale production, etc.

Method used

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  • Preparing method of (2R,4R)-4-methylpiperidine-2-ethyl formate compound
  • Preparing method of (2R,4R)-4-methylpiperidine-2-ethyl formate compound
  • Preparing method of (2R,4R)-4-methylpiperidine-2-ethyl formate compound

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Embodiment 1

[0052] 1. Preparation of 4-methylpiperidine-2-carboxylate hydrochloride

[0053] Add 16.0L of 6N hydrochloric acid and 2.0kg of 4-methyl-2-cyanopiperidine to a 50L glass reaction kettle, heat up to 100°C ± 5°C, and reflux for 5h. After the reaction, the system is evaporated under reduced pressure. After the solvent is evaporated, add 20.0L of absolute ethanol to the reaction kettle, reflux and stir for 1 h, drop to room temperature, filter, remove inorganic salts, collect the mother liquor and evaporate it to dryness under reduced pressure to obtain a solid, add 1.5L of absolute ethanol, 15.0L of methyl alcohol 2.1kg of 4-methylpiperidine-2-carboxylate hydrochloride, the molar yield of this step is about 73%.

[0054] Preparation of 4-methylpiperidine-2-carboxylic acid ethyl ester hydrochloride

[0055] In the glass reactor of 20L, add the absolute ethanol of 11.0L, add the 2.1kg of 4-methylpiperidine-2-formic acid hydrochloride obtained in the above steps into the reactor, s...

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Abstract

The invention relates to a preparing method of a (2R,4R)-4-methylpiperidine-2-ethyl formate compound. The method comprises the following steps of 1, regarding 4-methyl-2-cyanopiperidine as an initialraw material to be subjected to a hydrolysis reaction through hydrochloric acid to obtain 4-methyl-2-piperidinecarboxylicacid hydrochloride; 2, using ethyl alcohol to esterify 4-methyl-2-piperidinecarboxylicacid hydrochloride to obtain 4-methyl-2-ethyl nipecotate hydrochloride; 3, adding a mixed solvent of methyl tertiary butyl ether and ethyl alcohol, reacting the mixed liquid for pulping, filtering to remove cis-form 4-methyl-2-ethyl nipecotate hydrochloride solid, and collecting mother liquor to obtain anti-form 4-methyl-2-ethyl nipecotate hydrochloride; 4, using L-tartaric acid to split anti-form 4-methyl-2-ethyl nipecotate to obtain the target product (2R,4R)-4-methylpiperidine-2-ethyl formate.

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] Argatroban (Argatroban), the chemical structure is as follows: [0003] [0004] Argatroban Alias: Argodropan, Argotoban, is a white powder chemical. Its chemical name is: (2R,4R)-4-methyl-1-[N-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]-L -Arginyl]-2-piperidinecarboxylic acid. [0005] Argatroban is an anticoagulant drug, which 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 and other drugs. The structure of argatroban contains an important trans-piperidine acid structural unit: (2R,4R)-4-methylpiperidin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
CPCC07B2200/13C07D211/60
Inventor 张卫锋金祥罗林
Owner BEIJING VOBAN PHARMA TECH CO LTD
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