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The preparation method of tipipenem ester

A technology of tipipenem ester and volume ratio, which is applied in the field of preparation of tipipenem ester, can solve problems such as unfavorable product performance, and achieve the effects of precise control of raw materials and processes, efficient synthesis process, and stable market supply

Active Publication Date: 2018-02-06
HENAN QUANYU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the invention uses the finished product tibipenem as the raw material to directly react, and external factors (such as: storage, transportation, purchase of manufacturers) are more likely to be affected, which is unfavorable for the maintenance of product performance

Method used

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  • The preparation method of tipipenem ester
  • The preparation method of tipipenem ester
  • The preparation method of tipipenem ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Preparation of Intermediate I:

[0061] Weigh 252.9 g (1.2 mol) of 1-(4,5-dihydro-2-thiazolyl) azetidine-3-thiol hydrochloride and 594.5 g of 1β-methylcarbapenem bicyclic nucleus (1mol) was added to 1189ml of diisopropylethylamine, stirred and reacted at -25°C for 4 hours, after the reaction was completed, 600ml of pure water was added, the temperature was raised to 2°C within 30 minutes, suction filtered, and the filter cake was washed with acetonitrile water (V acetonitrile: V water = 2:3) 297ml of the solution was washed and dried to obtain 457.4g of intermediate I with a calculated yield of 88.3% and a measured purity of 99.0%.

Embodiment 2

[0063] Preparation of Intermediate I:

[0064] Weigh 274.0 g (1.3 mol) of 1-(4,5-dihydro-2-thiazolyl) azetidine-3-thiol hydrochloride and 594.5 g of 1β-methyl carbapenem bicyclic nucleus (1mol) was added to 1783ml of diisopropylethylamine, stirred and reacted at -20°C for 3.5 hours, after the reaction was completed, 900ml of pure water was added, the temperature was raised to 0°C within 30 minutes, suction filtered, and the filter cake was washed with acetonitrile water (V acetonitrile: V water = 2:3) 297ml of the solution was washed and dried to obtain 458.4g of intermediate I with a calculated yield of 88.5% and a measured purity of 99.2%.

Embodiment 3

[0066] Preparation of Intermediate II:

[0067] The 228.7g intermediate I obtained in Example 1 was mixed with the volume ratio of n-butanol aqueous solution (the volume ratio of n-butanol and water is 3:1) 1150ml, palladium carbon catalyst (0.5% palladium) 18.3g and sodium bicarbonate 274.5g Mix and react for 4 hours under the conditions of hydrogen pressure 1MPa, 25~30°C, and rotation speed 500r / min. After the reaction, filter with suction, adjust the pH of the filtrate to 5.5 with 4mol / l hydrochloric acid, and separate the liquids to obtain the aqueous phase and n-butanol Phase; lower the temperature to 5~6°C, slowly add acetone 6 times its volume while stirring the water phase, crystallize the solution, filter with suction, and dry to obtain 150.3g of intermediate II, the calculated yield is 88.9%, and the purity is determined 99.6%.

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Abstract

The invention provides a preparation method of tebipenem pivoxil, and relates to the technical field of pesticide synthesis. The preparation method of the tebipenem pivoxil comprises the following steps that 1-(4,5-dihydro-2-thiazolyl) azetidine-3-thiol hydrochloride and 1 beta-methyl vinyl phosphate are used as raw materials to take a reaction under the existence of diisopropylethylamine, and an acetonitrile water solution is used for washing to obtain an intermediate I; the intermediate I, an n-butyl alcohol water solution, a palladium-carbon catalyst and sodium bicarbonate take a mixed reaction, and treatment is performed to obtain an intermediate II; the intermediate II and chloromethyl pivalate take a reaction through phase transfer catalyst catalysis under the existence of diisopropylethylamine and dimethylformamide to obtain an intermediate III; the intermediate III and a sodium bicarbonate water solution are mixed, ethyl acetate is added, and reaction and refining are performed to prepare the tebipenem pivoxil. The preparation method has the advantages that the purity and the yield of the intermediates are obviously improved; the purity of the final product of the tebipenem pivoxil reaches 99.21 to 99.78 percent; the yield reaches 88.7 to 92.1 percent.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of tipipenem axetil. Background technique [0002] Tipipenem ( Tebipenempivoxil ) is a new type of broad-spectrum antibiotic for oral administration of penem, which was originally developed by Wyeth Rieter Company of Japan, and then transferred to Meiji Seika Pharmaceutical Company in Japan in March 2002. First listed in Japan on 26th. Tipipenem ester, chemical name (1R,5S,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[1-(2-thiazolin-2-yl) Azetidin-3-ylthio]-1-carbapillin-2-ene-3-carboxylic acid pivaloyloxymethyl ester, its chemical structural formula is: , the molecular formula is: C 22 h 31 N 3 o 6 S 2 . [0003] The structural feature of tipipenem is that the side chain at the C3 position is a thiazolyl-substituted azetidine group, and at the same time, the prodrug is formed by forming pivalate from the carboxylic acid at the C2 position, which imp...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D477/06C07D477/20
CPCC07D477/06C07D477/20
Inventor 李健王峰周小旭朱俊丽徐冰陈军
Owner HENAN QUANYU PHARMA CO LTD
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