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Preparation method of ceftobiprole ester intermediate (R)-1-tert-butyloxycarbonyl-3-aminopyrrolidine

A technology of tert-butoxycarbonyl and aminopyrrolidine, which is applied in the field of preparation of cefepirox intermediates, can solve problems such as being unsuitable for industrialized production, and achieve the effects of being beneficial to industrialized production, low in cost, and easy to operate

Active Publication Date: 2020-08-28
山西千岫制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This route also involves noble metal catalytic hydrogenation deN-CBZ protection under high temperature and pressure, which is not suitable for industrial production

Method used

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  • Preparation method of ceftobiprole ester intermediate (R)-1-tert-butyloxycarbonyl-3-aminopyrrolidine
  • Preparation method of ceftobiprole ester intermediate (R)-1-tert-butyloxycarbonyl-3-aminopyrrolidine
  • Preparation method of ceftobiprole ester intermediate (R)-1-tert-butyloxycarbonyl-3-aminopyrrolidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The preparation of D-asparagine methyl ester hydrochloride in the step (A)

[0037] Protect the three-necked flask with 2g of methanol and nitrogen gas, cool down to 0°C, slowly drop in 0.27g of thionyl chloride, keep it warm for 1 hour, add 0.5g of D-asparagine, and raise the temperature to 25°C for 5 hours, then complete the reaction.

[0038] Then adjust to acidity with dilute hydrochloric acid, filter, the filter cake is beaten with ether for 1 h, and filter to obtain a white powder with a molar yield of 80%-85%, and LC>95%.

[0039] Preparation of (tert-butoxycarbonyl) asparagine methyl ester in step (B)

[0040] A three-neck flask was passed through a solution of 0.75 g of di-tert-butyl dicarbonate in 7 g of tetrahydrofuran under nitrogen protection, and 0.5 g of D-asparagine methyl ester hydrochloride was added into the flask and suspended in 5 g of tetrahydrofuran and 0.55 g of triethylamine. Cool the resulting white suspension to 0°C, and add di-tert-butyl dic...

Embodiment 2

[0058] The preparation of D-asparagine methyl ester hydrochloride in the step (A)

[0059] Protect the three-necked flask with 2g of methanol and nitrogen gas, cool down to 0°C, slowly drop in 0.29g of thionyl chloride, keep it warm for 1 hour, add 0.5g of D-asparagine, and raise the temperature to 25°C for 5 hours to complete the reaction.

[0060] Then adjust to acidity with dilute hydrochloric acid, filter, the filter cake is beaten with ether for 1 h, and filter to obtain a white powder with a molar yield of 80%-85%, and LC>95%.

[0061] Preparation of (tert-butoxycarbonyl) asparagine methyl ester in step (B)

[0062] A three-neck flask was passed through a solution of 0.78 g of di-tert-butyl dicarbonate in 7 g of tetrahydrofuran under nitrogen protection, and 0.5 g of D-asparagine methyl ester hydrochloride was added into the flask and suspended in 5 g of tetrahydrofuran and 0.55 g of triethylamine. Cool the resulting white suspension to 0°C, and add di-tert-butyl dicarb...

Embodiment 3

[0080] The preparation of D-asparagine methyl ester hydrochloride in the step (A)

[0081] Protect the three-necked flask with 2g of methanol and nitrogen gas, lower the temperature to 0°C, slowly drop in 0.35g of thionyl chloride, keep it warm for 1 hour, add 0.5g of D-asparagine, and raise the temperature to 25°C for 5 hours to complete the reaction.

[0082] Then adjust to acidity with dilute hydrochloric acid, filter, the filter cake is beaten with ether for 1 h, and filter to obtain a white powder with a molar yield of 80%-85%, and LC>95%.

[0083] Preparation of (tert-butoxycarbonyl) asparagine methyl ester in step (B)

[0084] A three-neck flask was protected by nitrogen protection with a solution of 0.66 g of di-tert-butyl dicarbonate in 7 g of tetrahydrofuran, and 0.5 g of D-asparagine methyl ester hydrochloride was added into the flask and suspended in 5 g of tetrahydrofuran and 0.55 g of triethylamine. Cool the resulting white suspension to 0°C, and add di-tert-but...

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Abstract

The invention discloses a preparation method of (R)-1-tert-butyloxycarbonyl-3-aminopyrrolidine. The method comprises the following steps: 1, carrying out a reaction on (D) asparagine with thionyl chloride / methanol to generate D-asparagine methyl ester hydrochloride; protecting the amino group of the D-aspartic acid methyl ester hydrochloride by using di-tert-butyl dicarbonate; carrying out a ringclosing reaction by using sodium hydride, removing BOC anhydride protection of 3-amino by using TFA, and then reducing the diketone at the 2 and 5 sites by using sodium borohydride; finally protecting1-imino by using di-tert-butyl dicarbonate to obtain an yellow oily substance, (R)-1-tert-butyloxycarbonyl-3-aminopyrrolidine. The method is low in cost, small in pollution, easy to operate and beneficial to industrial production, the purity of the product can reach 98%, and a guarantee is provided for subsequent synthesis of high-purity cefepime.

Description

technical field [0001] The present invention relates to a kind of preparation method of ceftriproproxil intermediate, in particular to a kind of preparation method of ceftiproproxil intermediate (R)-1-tert-butoxycarbonyl-3-aminopyrrolidine. Background technique [0002] As important fine chemical intermediates, 3-aminopyrrolidine and its derivatives are widely used in the synthesis of pesticides and pharmaceuticals, among which (R)-1-tert-butoxycarbonyl-3-aminopyrrolidine is the fifth generation It is an important intermediate in the synthesis of cephalosporin antibiotic ceftazidime, and has a good market prospect. [0003] At present, the synthesis of such substances mainly has the following routes: [0004] (1) Japanese Patent JP61057579A report, using acrylate as raw material, adding N-ethoxycarbonylglycine ethyl ester, then performing Dieckmann ring closure, followed by selective hydrolysis and decarboxylation to obtain pyrrolidone, followed by oximation, reduction, aci...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/14
CPCC07D207/14C07B2200/07Y02P20/55
Inventor 王作弟
Owner 山西千岫制药有限公司
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