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A kind of preparation method of [n-methyl-pyridin-2-yl] carbamic acid-1-chloroethyl ester

A technology of carbamate and picoline, applied in the field of organic synthesis, can solve problems such as unfavorable 2' removal, no description of the purification method of side chain compound 3, etc., and achieves the effects of avoiding side reactions, novel reaction steps, and simple post-processing

Active Publication Date: 2018-09-14
JIANGSU CHIA TAI FENGHAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] It can be seen from formula 1 that in the first step of the reaction, due to the strong acylation ability of the acid chloride, both N-acylation and O-acylation can occur, even if the reaction is carried out at a low temperature according to the patent, the by-product 2' is inevitable The side chain compound 3 is an oil, which is not conducive to the removal of 2', and the purification method of the side chain compound 3 is not described in the patent

Method used

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  • A kind of preparation method of [n-methyl-pyridin-2-yl] carbamic acid-1-chloroethyl ester
  • A kind of preparation method of [n-methyl-pyridin-2-yl] carbamic acid-1-chloroethyl ester
  • A kind of preparation method of [n-methyl-pyridin-2-yl] carbamic acid-1-chloroethyl ester

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Effect test

Embodiment 1

[0026] Dissolve 13.8g (0.1mol) of 2-(N-methylamino)-3-hydroxymethylpyridine and 23.5g (0.125mol) of Boc-sarcosine in 60mL of dichloromethane, and slowly add 24g of (0.125mol) EDCI and 3.66g (0.03mol) dimethylaminopyridine, after stirring for 2h, wash the dichloromethane layer with ammonium chloride aqueous solution, dry after separation, concentrate the white solid, use DCM:PE=1: 10 was recrystallized to obtain 28.5 g of white solid with a yield of 92%.

[0027] 1 H NMR (CDCl 3 ):1.35~1.48(9H),2.93~2.95(3H),3.03~3.04(3H),3.93~4.00(2H),5.07~5.11(2H),6.57~6.58(1H),7.39~7.40(1H) ,8.18~8.20(1H)

Embodiment 2

[0029] Dissolve 13.8g (0.1mol) of 2-(N-methylamino)-3-hydroxymethylpyridine and 22.6g (0.12mol) of Boc-sarcosine in 60mL of dichloromethane, and slowly add 24g of (0.125mol) EDCI and 3.66g (0.03mol) dimethylaminopyridine, after stirring for 2h, wash the dichloromethane layer with 1% hydrochloric acid solution, dry after separation, and concentrate the white solid with DCM:PE=1 :10 for recrystallization to obtain 27.3g white solid, yield 88%.

Embodiment 3

[0031] Dissolve 13.8g (0.1mol) of 2-(N-methylamino)-3-hydroxymethylpyridine and 24.4g (0.13mol) of Boc-sarcosine in 60mL of dichloromethane, and slowly add 24g of (0.125mol) EDCI and 3.66g (0.03mol) dimethylaminopyridine, after stirring for 2h, wash the dichloromethane layer with ammonium chloride aqueous solution, dry after separation, concentrate the white solid, use DCM:PE=1: 10 was recrystallized to obtain 28.6 g of white solid with a yield of 92.3%.

[0032] 2. Synthesis of [N-methyl-N-3-((tert-butoxycarbonylmethylamino)acetoxymethyl)pyridin-2-yl]carbamate-1-chloroethyl ester

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Abstract

The invention relates to a preparation method of [N-methyl-N-3-((tert-butoxycarbonyl methyl amino) acetoxy methyl) pyridine-2-yl] carbamate-1-ethyl chloride. The method is as below: first reacting 2-(N-methyl amino)-3- hydroxymethyl pyridine with Boc-sarcosine at low temperature; and reacting with 1-chloroethyl chloroformate. The invention has the advantages of mild reaction condition and simple process and high purity of products, and meets the basic requirements of industrial enlargement production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to [N-methyl-N-3-((tert-butoxycarbonylmethylamino)acetoxymethyl)pyridin-2-yl]carbamic acid-1-chloro Synthesis of ethyl esters. Background technique [0002] Isavuconazole is an antifungal drug jointly developed by Swiss Baselia Pharmaceutical Co., Ltd. and Japan Astellas. Its water-soluble prodrug is sulfate. As a new broad-spectrum triazole drug, isavuconazole has the following characteristics compared with other similar drugs: [0003] (1) The finished drug component is a water-soluble prodrug, which can be developed for oral and intravenous administration, and the intravenous preparation does not contain cyclodextrin, and there is no potential nephrotoxicity risk of excipients. [0004] (2) The bioavailability is high, and the two administration routes can be conveniently switched. It has the excellent pharmacokinetic characteristics of drugs for the treatment of systemic fung...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/75C07D213/74
Inventor 侯可辉杨杨朱永强于钦策张兵兵刘兆刚
Owner JIANGSU CHIA TAI FENGHAI PHARMA