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Process for the preparation of carbapenem using cabapenem intermediates and recovery of cabapenem

A technology for compounds and analogs, applied in the field of preparing carbapenem intermediates, can solve the problems of difficult recovery and purification, low concentration and difficult crystallization, product time damage, etc., and achieves shortened reaction process time, long service life, and reduced manufacturing process. cost effect

Inactive Publication Date: 2011-11-23
SAVIOR LIFETEC CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Literature Chromatography A Journal (J.Chromatogr A). 1079, 80-91 (2005) mentions several operating methods such as high pressure column chromatography (HPLC), very low temperature storage environment (-70°C) and long-term distillation , these methods all need high cost and huge manpower technology on a laboratory scale, and it is not easy to carry out a large amount of recovery and purification
[0008] In addition, the recovery and purification of the mother liquor of the ertapenem compound generally encounters low concentration and difficult crystallization (about 2-8mg / ml), high content of impurities (about 50-60% observed from the analysis spectrum), complex solution Difficulties such as composition and product damage over time

Method used

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  • Process for the preparation of carbapenem using cabapenem intermediates and recovery of cabapenem
  • Process for the preparation of carbapenem using cabapenem intermediates and recovery of cabapenem
  • Process for the preparation of carbapenem using cabapenem intermediates and recovery of cabapenem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] A. Preparation of compounds of formula (Ia)

[0060] After 43.2 grams of compounds having the formula (III) structural formula were placed in 777ml of dichloromethane and stirred and dissolved, then 145mg of Rh was added in this solution. 2 October 4 , and after heating the mixture at reflux for 7 hours, 388 ml of dichloromethane were removed by distilling the solution. A dichloromethane (dichloromethane) solution containing a compound of formula (IV) is cooled to a temperature lower than -35°C, and at a temperature lower than -35°C, 71.3 grams of chlorophosphoric acid bis(2, 4-dichlorophenyl) ester (bis(2,4-dichlorophenyl)-chlorophosphate, DDCP) and 17.63 grams of diisopropylethylamine (diisopropylethylamine, DIPEA) dissolved in 43ml of methylene chloride and 40mg of 4 - a mixture of dimethylaminopyridine (4-dimethylamino pyridine), added to the reaction solution, and reacted for 2 hours. Then, at a temperature of 0-5°C, mix 100ml of 1% hydrochloric acid (HCl, liqui...

Embodiment 2

[0064] A. Prepare the compound with formula (VI) structural formula by the compound with formula (Ia) structural formula

[0065] Provide the compound of formula (Ia) obtained in Example 1A at -30°C dissolved in 500 ml of dichloromethane: p-nitrobenzyl (1R, 5S, 6S)-6-[(IR)-1-hydroxyethyl ]-2-[(bis(2,4-dichlorophenyl)phosphoryloxy)]-1-carbapenem-2-ene-3-carboxylic acid (p-nitrobenzyl(1R,5S,6S) -6-[(IR)-1-hydroxyethyl]-2-[(bis(2,4-dichlorophenyl)phosphono)oxy]-1-methylcarbapen-2-en-3-carboxylate), add 44.7 grams of 3-( [[(2S,4S)-sulfhydryl-2-pyrrolidinyl-1-(4-nitrobenzyloxy)formyl]formyl]amino)benzoic acid (3-([[(2S,4S) -mercapto-2-pyrrolidinyl-1-(4-nitrobenzoic acid)carbonyl]carbonyl]amino)benzoic acid). To react the mixture, 41.0 g of diisopropylethylamine (DIPEA) was added and stirred at -30°C. After the reaction was completed, 500ml of water was added to the reacted mixture, stirred and separated, and the organic layer obtained could generate a compound of formula (VI), a...

Embodiment 3

[0071] A. Preparation of Compound (R=H) with Formula (II) Structural Formula

[0072] At 20° C., in the compound having the structural formula (VI) dissolved in dichloromethane prepared by Example 2A, add 648 ml of purified water containing 48 grams of 10% palladium carbon (Palladium on carbon, Pd / C) and 37.2 grams of sodium bicarbonate. The nitrogen in the reactor was replaced twice by introducing hydrogen gas, and then within the first hour under the hydrogen atmosphere, the pressure was adjusted to 25-80 psi, and the reaction temperature was controlled at 20°C and maintained for 4 After ~5 hours, lower the temperature to below 10°C, then adjust the pH value (pH) to about 5.0 with 5% hydrochloric acid (HCl), filter off 10% palladium carbon (Pd / C) and separate the organic layer . Adjust the pH value of the liquid layer to about 6.5, and then add about 1 kg of dichloromethane for extraction. At a temperature of 0-5°C, the liquid solution produced in the above steps was extr...

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Abstract

The present invention aims to prepare carbapenem intermediates which can effectivly produce Ertapenem, Meropenem and Doripenem; and provides an effective process for recovering ertapenem compounds.

Description

technical field [0001] The present invention relates to a novel process for the preparation of carbapenem intermediates for efficient production of Ertapenem, Meropenem and Doripenem, and for efficient purification and recovery of carbon Penem method. Background technique [0002] Carbapenem is a broad-spectrum antibiotic that can effectively treat many species of gram positive and gram negative aerobic and anaerobic bacteria Antibiotics for bacterial infection. Since carbapenems were first isolated from enzyme culture in 1974, this type of antibiotic has encountered problems caused by the emergence of drug resistance and new emerging bacteria. Problem, the development of novel carbapenem compounds is necessary. [0003] Ertapenem among the carbapenem antibiotics is a commercial product developed by Merck & Co. Inc.: Yimanzhi Injection ( ), the chemical name of ertapenem is [4R, 5S, 6S]-3-[[(3S, 5S)-5-[[(3-carboxyphenyl)amino]carbonyl]-3-rolidinyl] Thio]-6-[(1R)-1-hydr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561C07D477/06C07D477/20
CPCC07F9/65611C07D477/06C07D477/20A61P31/00Y02P20/55C07D477/18C07D487/04A61K31/407
Inventor 曾伟宏张文信张家茂叶家玮郭原良
Owner SAVIOR LIFETEC CORP
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