Method for synthesizing meropenem intermediate

A synthesis method, the technology of meropenem, applied in the field of synthesis of meropenem intermediates, can solve the problems of labor-intensive step-by-step operation, uncontrollable yield, increased production cost, etc., to achieve complete reaction of raw materials, high product yield, The effect of easy operation

Active Publication Date: 2010-11-24
XINXIANG HAIBIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Such a step-by-step operation is labor-intensive and time-consuming, occupies equipment, reduces the final yield of the product, and increases production costs. At the same time, it will inevitably produce "three wastes" such as waste water, waste residue,

Method used

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  • Method for synthesizing meropenem intermediate
  • Method for synthesizing meropenem intermediate
  • Method for synthesizing meropenem intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Into a reactor equipped with a reflux device, nitrogen gas was preliminarily exhausted to exhaust the air in the reactor, and 20.0 g of compound II (prepared according to patent ZL200610083362.7), 200 ml of dichloromethane, 10 mg of rhodium octanoate, 60 mg of Zinc chloride, heat up to reflux reaction, HPLC monitors the reaction, the reaction is completed, the normalized content of the intermediate product is 93.62%, the obtained reaction solution is cooled to about -20°C, and 150ml of acetonitrile and 10.0g of diisopropyl Diethylethylamine, 30.0g of DPC, react at about -25°C, monitor the reaction by HPLC, after the reaction is completed, cool the obtained reaction solution to about -35°C, add 7.0g of diisopropylethylamine, add 20g of the compound III. Control the temperature and react at about -35°C, monitor by HPLC. After the reaction is completed, add 10% formic acid to wash 8 times, discard the water phase, add 20g of anhydrous magnesium sulfate to the organic phase,...

Embodiment 2

[0049]In the reactor equipped with reflux device, feed nitrogen in advance to exhaust the air in the reactor, add 20.0g of compound II, 200ml of dichloromethane, 10mg of rhodium octanoate, 60mg of zinc bromide, and heat up to reflux reaction, HPLC monitors the reaction. After the reaction is completed, cool the obtained reaction solution to about -20°C, add 150ml of acetonitrile, add 10.0g of diisopropylethylamine, and 30.0g of DPC, react at about -25°C, and monitor by HPLC Reaction, after the reaction is completed, cool down the obtained reaction solution to about -35°C, add 7.0g of diisopropylethylamine, add 20g of compound III, control the temperature to react at about -35°C, monitor by HPLC, after the reaction is complete, add Wash 8 times with 10% sodium dihydrogen phosphate, discard the water phase, add 20 g of anhydrous magnesium sulfate to the organic phase to dry, filter, concentrate the filtrate under reduced pressure, add 200 ml of ethyl acetate to the concentrate to...

Embodiment 3

[0052] In the reactor equipped with a reflux device, feed nitrogen to exhaust the air in the reactor in advance, add 20.0g of compound II, 180ml of methylene chloride, 20mg of rhodium octanoate, 70mg of zinc bromide, and heat up to reflux reaction, HPLC monitors the reaction. After the reaction is completed, cool the obtained reaction solution to about -20°C, add 150ml of acetonitrile, add 7.0g of diisopropylethylamine, 15.0g of DPC, and 30mg of DMAP. The reaction was monitored by HPLC. After the reaction is completed, cool down the obtained reaction solution to about -35°C, add 7.0g of diisopropylethylamine, add 20g of compound III, control the temperature at about -35°C, monitor by HPLC, and add 10% Wash with sodium dihydrogen phosphate 8 times, discard the water phase, add 20 g of anhydrous magnesium sulfate to the organic phase, dry, filter, concentrate the filtrate under reduced pressure, add 200 ml of ethyl acetate to the concentrate to crystallize, filter, and dry the f...

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Abstract

The invention relates to a method for synthesizing a meropenem intermediate, which comprises the following steps: (1) in an inert gas atmosphere, adding an organic solvent, a compound II, a noble metal catalyst and auxiliary catalysts into a reactor, heating the materials to perform a reaction, and monitoring the reaction by TLC or HPLC; (2) at the end of the reaction, adding the organic solvent, cooling the reaction solution, adding an organic alkali or DPC, and monitoring a reaction by the TLC or HPLC; (3) at the end of the reaction, cooling the reaction solution, adding the organic alkali and a compound III, performing a reaction at a controlled temperature, and monitoring the reaction by the TLC or HPLC; and (4) washing, removing a water phase, dehydrating an organic phase, filtering to remove solid, concentrating the organic phase, adding the organic solvent for crystallization, filtering the solution, washing the crystals, and drying the crystals to obtain the target compound I. Compared with the techniques of the same kind, the method, which is simple and convenient in operation, of the invention has the advantages of adding two auxiliary catalysts at the same time, greatly reducing the consumption of noble metal catalyst, making raw materials react more completely, producing less impurities and improving product yield.

Description

technical field [0001] The present invention relates to a method for synthesizing meropenem, in particular to a method for synthesizing a meropenem intermediate. Background technique [0002] Carbapenem antibiotics are a new type of fully synthetic β-lactam antibiotics, which have strong antibacterial activity against Gram-positive and negative bacteria, aerobic bacteria, and anaerobic bacteria. Since the discovery of thiamycin in 1976, the research on carbapenem antibiotics has made great progress. In particular, 1β-methyl carbapenem antibiotics have good chemical stability and are stable to β-lactamase and renal dehydropeptide-I enzymes. They are currently one of the first-choice drugs for the treatment of severe and multidrug-resistant bacterial infections. It has been more and more widely used in clinical practice. [0003] Currently commercialized 1β-methyl carbapenem antibiotics include meropenem, biapenem, doripenem, and ertapenem. Meropenem is the first 1β-methyl ...

Claims

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Application Information

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IPC IPC(8): C07D477/20C07D477/06
Inventor 赵鹏任鹏傅秀强徐银峰田伟豹
Owner XINXIANG HAIBIN PHARMA
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