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Preparation method of chiral dimethyl cyclopropyl carboxamide

A technology of dimethyl cyclopropanecarboxamide and dimethyl cyclopropanecarboxylate is applied in the preparation of chiral dimethyl cyclopropanecarboxamide compounds, in the field of dimethyl cyclopropanecarboxamide, and can solve the problem of high cost, Problems such as low yield of preparation method

Inactive Publication Date: 2014-12-10
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In view of the defects in the above-mentioned prior art, the technical problem to be solved by the present invention is to provide a preparation method of chiral dimethylcyclopropylcarboxamide compound, said chiral dimethylcyclopropylcarboxamide compound The preparation method should solve the technical problems of low yield and high cost of the preparation method in the prior art

Method used

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  • Preparation method of chiral dimethyl cyclopropyl carboxamide
  • Preparation method of chiral dimethyl cyclopropyl carboxamide
  • Preparation method of chiral dimethyl cyclopropyl carboxamide

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Embodiment 1

[0026]

[0027] The preparation method of above-mentioned a kind of (S)-ethyl dimethylcyclopropanecarboxylate specifically comprises the steps:

[0028] In a 1000 mL three-necked flask equipped with a thermometer and a dropping funnel, add (R,R)-(+)-2,2'-isopropylidenebis(4-tert-butyl-2-oxazoline) ( 1.74 g, 5.94 mmol), cuprous trifluoromethanesulfonate (1.14 g, 5.4 mmol) and dichloromethane (250 mL) were stirred at room temperature (25~30 ℃) for 2 h. Cool the reaction system to -5~0°C, add isobutylene to saturation, then slowly add ethyl diazoacetate (114 g, 1 mol) dropwise, control the temperature of the reaction system at 0°C, and slowly warm up to room temperature (25 ℃), continue to stir and react for 1 h; after the completion of the EDA reaction by TLC, the system is concentrated under reduced pressure (T 98 %, e.e. >95%.

Embodiment 2

[0030]

[0031] Above-mentioned a kind of (S)-dimethyl cyclopropanecarboxylate preparation method specifically comprises the steps:

[0032] In a 1000 mL three-necked flask equipped with a thermometer and a dropping funnel, add (R,R)-(+)-2,2'-isopropylidenebis(4-tert-butyl-2-oxazoline) ( 1.74 g, 5.94 mmol), cuprous trifluoromethanesulfonate (1.14 g, 5.4 mmol) and dichloromethane (250 mL) were stirred at room temperature (25~30 ℃) for 2 h. Cool the reaction system to -5~0°C, add isobutylene to saturation, then slowly add isopropyl diazoacetate (129 g, 1 mol) dropwise, control the temperature of the reaction system at 0°C, and slowly warm up to room temperature after the addition ( 25 ℃), continue to stir the reaction for 1 h; after the completion of the EDA reaction by TLC, the system is concentrated under reduced pressure (T 98 %, e.e. Value >95%.

Embodiment 3

[0034]

[0035] The preparation method of above-mentioned a kind of (S)-dimethylcyclopropanecarboxylate, specifically comprises the steps:

[0036] In a 1000 mL three-necked flask equipped with a thermometer and a dropping funnel, add (R,R)-(+)-2,2'-isopropylidenebis(4-tert-butyl-2-oxazoline) ( 1.74 g, 5.94 mmol), cuprous trifluoromethanesulfonate (1.14 g, 5.4 mmol) and dichloromethane (250 mL) were stirred at room temperature (25~30 ℃) for 2 h. Cool the reaction system to -5~0°C, add isobutylene to saturation, then slowly add the above-prepared methyl diazoacetate (101 g, 1 mol) dropwise, control the temperature of the reaction system to 0°C, and slowly heat up the system after the addition After reaching room temperature (25 ℃), continue to stir and react for 1 h; after the EDA reaction is complete by TLC, the system is concentrated under reduced pressure (T 98 %, e.e. values ​​>95%.

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Abstract

The invention discloses a preparation method of chiral dimethyl cyclopropyl carboxamide. The method comprises a step of asymmetric cyclopropyl alkylation and a step of catalytic amidation of cyclopropyl formic ether, wherein in the step of asymmetric cyclopropyl alkylation, a cyclopropyl alkylation reaction is carried out on ethyl diazoacetate and isobutene under the catalysis of a chiral ligand complex of a cuprous salt so as to obtain (S)-dimethyl cyclopropyl formate; and in the step of catalytic amidation of cyclopropyl formic ether, an ammonolysis reaction is carried out on the (S)-dimethyl cyclopropyl formate by one step so as to directly obtain (S)-2,2-dimethyl cyclopropyl carboxamide, and refining the carboxamide with an alcohol so as to obtain the chiral dimethyl cyclopropyl carboxamide with chemical purity being greater than 99.5% and an e.e. value being greater than 99.5%. Thus, the method used for synthesizing the (S)-2,2-dimethyl cyclopropyl carboxamide is environment-friendly, simple, rapid and efficient.

Description

technical field [0001] The invention belongs to the field of chemical industry, in particular to a kind of dimethylcyclopropylcarboxamide, in particular to a preparation method of chiral dimethylcyclopropylcarboxamide compound. Background technique [0002] Cilastatin is an inhibitor of renal dehydropeptidase, which can improve the stability of imipenem (Imipenem) in vivo. Clinical experiments have shown that the compound preparation of cilastatin and imipenem, Taineng, is particularly It is suitable for the treatment of combined infection of multiple bacteria and mixed infection of aerobic bacteria and anaerobic bacteria. (S)-2,2-dimethylcyclopropanamide with molecular formula shown in 1 is one of the key intermediates for the synthesis of cilastatin (Cilastatin), (S)-2,2-dimethylcyclopropane The preparation methods of formamide mainly include: 1) dimethyl malonate is used as starting material, and it is prepared through cyclopropanation, saponification, hydrolysis, he...

Claims

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Application Information

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IPC IPC(8): C07C233/58C07C231/02C07C231/24
Inventor 刘烽潘仙华唐鹤于万盛潘丽陈彦宇
Owner SHANGHAI INST OF TECH
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