Synthesis method of single-ring imipenem p-nitro benzyl ester

A technology of p-nitrobenzyl ester and synthesis method, which is applied in the field of synthesis of monocyclopenem p-nitrobenzyl ester, and can solve problems such as poor product quality, complicated operation, and serious pollution

Inactive Publication Date: 2010-06-23
SHANDONG RUNZE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] There are many defects in this process route, the quality of the obtained product is poor, the operation is complicated, and the pollution is serious

Method used

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  • Synthesis method of single-ring imipenem p-nitro benzyl ester
  • Synthesis method of single-ring imipenem p-nitro benzyl ester

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Experimental program
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Effect test

Embodiment 1

[0038] (1) Synthesis of 6α-bromo-penicillanic acid (bromo)

[0039] In a 1000-liter reactor, add 470 kg of water, cool down to 0-5°C, and add 35 kg of 98% sulfuric acid. After the addition, 120.2 kg of potassium bromide, 43.2 kg of 6-APA and 120 kg of toluene were added successively when the temperature dropped below -10°C. After the addition, wait until the reaction temperature drops below -10°C, start adding 100 kg of 20% sodium nitrite aqueous solution dropwise, and control the reaction temperature at -15 to -10°C for 1 hour. After the dropwise addition, the reaction was carried out under temperature control and stirring for 4 hours, and the liquid phase detection of 6-APA was less than 0.5%. Add 150 kg of toluene, stir and react at below 10°C for 30 minutes, filter, separate layers, extract the aqueous phase with 50 kg of toluene, combine the organic phases and wash with 50 kg of saturated saline, and extract the aqueous phase with 20 kg of toluene after the organic phase...

Embodiment 2

[0047] (1) Synthesis of 6α-bromo-penicillanic acid (bromo)

[0048] In a 1000-liter reactor, add 400 kg of water, cool down to 0-5°C, and add 35 kg of 98% sulfuric acid. After the addition, 120.2 kg of potassium bromide, 43.2 kg of 6-APA and 120 kg of toluene were added successively when the temperature dropped below -10°C. After the addition, wait for the reaction temperature to drop below -10°C, start to add 21.2kg of sodium nitrite in 100kg of aqueous solution dropwise, and control the reaction temperature to -13~-15°C for 1.5h. After the dropwise addition, the reaction was carried out under temperature control and stirring for 2 hours, and the liquid phase detection of 6-APA was less than 0.5%. Add 150 kg of toluene, stir for 30 min below 10°C, filter, separate layers, extract the aqueous phase with 30 kg of toluene, combine the organic phases and wash with 50 mg of saturated brine, and extract the aqueous phase with 20 kg of toluene after the organic phases are separated...

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Abstract

The invention belongs to the technical field of medicines and in particular discloses a synthesis method of single-ring imipenem p-nitro benzyl ester. In the method, 6-APA is used as a raw material, and the single-ring imipenem p-nitro benzyl ester is prepared through reactions of nitration, bromination, oxidation, esterification, ring-opening, and the like. The method is characterized in that noval reagents and catalysts are adopted during synthesis, a single aromatic organic solvent is used as a reaction solvent, and an obtained product is easy to recover and convenient to apply. In the synthesis process, a one-pot synthesis method is adopted, thereby simplifying the process flow and shortening the production period.

Description

(1) Technical field [0001] The invention belongs to the technical field of medicine, in particular to a synthesis method of monocyclopenem p-nitrobenzyl ester. (2) Background technology [0002] Monocyclopenem p-nitrobenzyl ester is a new type of β-lactamase inhibitor intermediate. β-lactamase inhibitors belong to the series of β-lactam drugs. Pathogens produce β-lactamase through plasmid transfer, which causes some drugs (penicillins, cephalosporins, etc.) to undergo lactam ring hydrolysis and inactivation. Major modes of resistance to some common β-lactam antibiotics. In order to overcome this resistance, in addition to the development of new antibiotics with enzyme-resistant properties, β-lactamase inhibitors are also needed. [0003] The structural formula of monocyclopenem p-nitrobenzyl ester is: [0004] [0005] Comprehensive literature reports the synthetic route of monocyclopenem p-nitrobenzyl ester, which mainly comes down to the following synthetic route: ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
Inventor 孙鹏韩振玉郭合广王明庆
Owner SHANDONG RUNZE PHARMA
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