Imipenem intermediate and preparation method thereof

A technology of imipenem and intermediates, applied in the fields of medicinal chemistry and chemical synthesis, can solve the problems of low conversion rate of reactants, poor crystallinity and the like, and achieve the effects of low cost, high yield and high crude product content

Inactive Publication Date: 2018-10-09
重庆天地药业有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] In order to overcome the defects of the prior art, the present invention provides a method for preparing an imipenem intermediate, which can be used to prepare imipenem from the intermediate, so

Method used

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  • Imipenem intermediate and preparation method thereof
  • Imipenem intermediate and preparation method thereof
  • Imipenem intermediate and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0064] A preparation method of an imipenem intermediate, the method comprising the steps of:

[0065] (1) At -70 degrees Celsius, in the presence of an organic base N,N-diisopropylethylamine and under the protection of a nitrogen atmosphere, add compound III and diphenyl chlorophosphate to the organic solvent N-methylpyrrolidone in the reaction kettle Ester, obtains intermediate IV after thin-layer chromatography (TLC) detects that reaction is complete;

[0066] The ratio between the volume of the organic solvent N-methylpyrrolidone and the weight of compound III is 3ml:1g; the molar ratio of the organic base N,N-diisopropylethylamine to compound III is 1:1 ; The molar ratio of diphenyl chlorophosphate to compound III is 1:1;

[0067] The chemical structural formulas of the compound III and the intermediate IV are:

[0068]

[0069] R1 is p-nitrobenzyl or p-methoxybenzyl;

[0070] (2) At -50 degrees Celsius, in the presence of the organic base N,N-diisopropylethylamine, ...

Embodiment 2

[0093] (1) At 0 degrees Celsius, in the presence of an organic base N,N-dimethylaminopyridine and under the protection of a nitrogen atmosphere, compound III and diphenyl chlorophosphate were added to the organic solvent N-methylpyrrolidone in the reaction kettle, and the Intermediate Ⅳ was obtained after the reaction was completed by layer chromatography (TLC);

[0094] The ratio between the volume of the organic solvent N-methylpyrrolidone and the weight of the compound III is 15ml:1g; the molar ratio of the organic base N,N-dimethylaminopyridine to the compound III is 4:1; the The molar ratio of diphenyl chlorophosphate to compound III is 2:1;

[0095] The chemical structural formulas of the compound III and the intermediate IV are:

[0096]

[0097] R1 is p-nitrobenzyl or p-methoxybenzyl;

[0098] (2) At 0 degrees Celsius, in the presence of an organic base N, N-dimethylaminopyridine, add cysteamine hydrochloride to the intermediate IV, heat the reaction for 2.5 hours...

Embodiment 3

[0121] A preparation method of an imipenem intermediate, the method comprising the steps of:

[0122] (1) At -35 degrees Celsius, in the presence of organic base N,N-diisopropylethylamine and N,N-dimethylaminopyridine and under the protection of nitrogen atmosphere, the organic solvent N-methylpyrrolidone in the reaction kettle Add compound III and diphenyl chlorophosphate, and obtain intermediate IV after the reaction is complete by thin layer chromatography (TLC);

[0123] The ratio between the volume of the organic solvent N-methylpyrrolidone and the weight of compound III is 8ml:1g; the organic base N,N-diisopropylethylamine and N,N-dimethylaminopyridine and The molar ratio of compound III is 2:1; the molar ratio of diphenyl chlorophosphate to compound III is 1.2:1;

[0124] The chemical structural formulas of the compound III and the intermediate IV are:

[0125]

[0126] R1 is p-nitrobenzyl or p-methoxybenzyl;

[0127] (2) At -25 degrees Celsius, in the presence of...

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Abstract

The invention provides an imipenem intermediate and a preparation method thereof. The preparation method includes: uner the organic base A, adding a compound III and diphenyl chlorophosphate in an organic solvent A for reaction to obtain an intermediate IV; under the organic base B, adding cysteamine hydrochloride to the intermediate IV, and performing stirring, suction filtration, cleaning and drying after reaction to obtain an imipenem intermediate I. In the method, under the organic base C, the imipenem intermediate I and an imine side chain are added in an organic solvent D for reaction toobtain an intermediate V; the intermediate V is subjected to separation and purification, then an organic solvent E and organic base D are added, hydrogenation is performed after pH is adjusted, andthen filtration, stirring, suction filtration, cleaning and drying are performed to obtain imipenem II; with the method, shortcomings of low conversion rate and poor crystallinity of reactants due toserious accumulation of impurities, by-products and raw materials in the hydrogenation phase in the existing preparation process of the imipenem are overcome.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and chemical synthesis, in particular to an imipenem intermediate and a preparation method of imipenem. Background technique [0002] Imipenem, also known as: 6-(1-hydroxyethyl)-3-[[2-[(iminomethyl)amino]ethyl]sulfur]-7-oxo-1-azabicyclo[ 3.2.0] Hept-2-ene-2-carboxylic acid belongs to carbapenem β-lactam antibiotics, which can inhibit the formation of bacterial cell walls in combination with various penicillins, thereby achieving the elimination of bacteria parasitic in host cells Purpose, and shows strong activity to Gram-positive and negative aerobic organisms and anaerobic organisms, and shows high stability to β-lactamase, so the market potential is large and the clinical application rate is high. [0003] At present, in the prior art, the synthesis methods of imipenem can be summed up, and there are mainly the following synthetic routes: [0004] Synthetic route 1: US4292436 discloses a m...

Claims

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Application Information

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IPC IPC(8): C07D477/20
CPCC07D477/20
Inventor 秦云白智全刘悉承吴建军唐洪
Owner 重庆天地药业有限责任公司
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