Preparation method of tebipenem ester

A technology of tipipenem and southern acid, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of high risk and high cost, and achieve the effect of simple operation, short route steps and saving production cost

Inactive Publication Date: 2013-04-24
BEIJING KANGJIANYUAN TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This process is relatively mature, but because it uses palladium carbon to catalyze the hydrogenation reaction, it is dangerous and expensive in industrial production

Method used

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  • Preparation method of tebipenem ester
  • Preparation method of tebipenem ester
  • Preparation method of tebipenem ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1, preparation of tipipenem acid and tipipenem piffate

[0038] Step 1: (1R,5S,6S)-1-Methyl--6-[(R)-1-Hydroxyethyl]-2-[1-(1,3-Dihydrothiazole)azetidinyl -3-] the preparation of thio-carbapenicillin-2-ene-3-carboxylate (formula IV)

[0039]

[0040] Compound (VI) (59.5g) (please indicate the formula) and compound (V) (25.2g) (R=Me) were dissolved in acetonitrile (180mL), acetone (180mL), N,N-dimethylformamide ( 18mL) in a mixed solvent, lower the temperature to 0°C, add diisopropylethylamine (41.8mL) dropwise, after dropping, control the temperature at 0°C, monitor the reaction with TLC until the reaction of the compound of formula (V) disappears, add water to quench the reaction, pump Filter, and the filter cake is washed with acetonitrile and water to obtain an off-white solid with a yield of 98%;

[0041] The structural confirmation data are as follows:

[0042] 1 H-NMRδ (600MHz CDCl3): 5.12-4.99 (2H, m), 4.79-4.73 (1H, m), 4.55-4.49 (4H, m), 4.37 (2...

Embodiment 2

[0054] Embodiment 2, preparation of tipipenem acid and tipipenem piffate

[0055] Step (1), (3) embodiment 1 simultaneously, just replace step (2) with following steps:

[0056] Compound (IV) (10g) was dissolved in a mixed solvent (volume ratio 1:2) of water and n-butanol (volume ratio 1:2) (120mL), adding (sodium dihydrogen phosphate) buffer solution to make the pH of the reaction system be 4.5. Stir at room temperature for 19 hours. After the reaction, add acetone to the aqueous phase for crystallization to obtain the compound of formula (III), tipipenem acid, with a yield of 66%.

[0057] The total yield of tipipenem pivoxil prepared by the method in Example 2 was 52.3%.

Embodiment 3

[0058] Example 3, preparation of tipipenem acid and tipipenem piffate

[0059] Step (1), (3) embodiment 1 simultaneously, just replace step (2) with following steps:

[0060] Compound (IV) (10g) was dissolved in a mixed solvent (120mL) of water and n-butanol with a volume ratio of 1:2, sodium dihydrogen phosphate-sodium hydroxide buffer solution was added to make the pH of the reaction system 11.5, and stirred at room temperature for 8 Hours, after the reaction was completed, acetone was added to the aqueous phase for crystallization to obtain the compound of formula (III), namely tipipenem acid, with a yield of 76%.

[0061] The total yield of tipipenem pivoxil prepared by the method in Example 3 was 60.3%.

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Abstract

The invention discloses a preparation method of tebipenem ester. The method comprises the following steps of: 1), carrying out reaction on the compound of the formula (IV) under acidic or alkaline condition, removing protective groups, so as to obtain tebipenem acid, wherein the pH (potential of hydrogen) value of the acidic condition is 2-6 and the pH value of the alkaline condition is 9-13; and 2), reacting the tebipenem acid with iodomethyl pivalate, so as to obtain the tebipenem ester. The method disclosed by the invention is easy to operate and mild in reaction condition, the noble metal palladium catalyst is not required, and thus the method is more beneficial for industrial production and the cost is greatly reduced. Formula (IV) is shown in the specification.

Description

technical field [0001] The invention relates to a preparation method of tipipenem pivoxil. Background technique [0002] Carbapenem antibiotics (Carbapenems) are atypical β-lactam antibiotics with a new structure. It is used for the treatment of severe nosocomial infections, multidrug-resistant bacterial infections, and mixed infections. In recent years, Merck's Imipenem and Japan's Sankyo's Panipenem have been used clinically in my country. , Meropenem (Meropenem) from Sumitomo, Japan, etc. [0003] Tipipenem pivoxil is the world's first oral carbapenem antibiotic for the treatment of ear, nose, throat and upper respiratory tract infections in pediatric patients. Tipipenem piffate is an oral carbapenem antibiotic developed by Meiji Seika Co., Ltd., which was approved in Japan in 2009 for the first time in the world. It is recommended for the treatment of ear, nose, throat and upper respiratory tract infections in pediatric patients. It is the first product of its class an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/08
CPCY02P20/55
Inventor 沈刚张虹杨凤敏陈友江王恩杰唐亚林
Owner BEIJING KANGJIANYUAN TECH
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