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Synthetic method for tazobactam chiral isomer

A technology of chiral isomers and tazobactam, which is applied in the field of synthesis of tazobactam chiral isomers, can solve problems such as surplus raw materials and no product formation, and achieve low raw material costs and convenient post-processing , the effect of high yield

Active Publication Date: 2019-03-22
山东安信制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] But when we repeat the patent JP 63066187 route and synthesize compound II according to the conditions described, no product is generated, and most of the raw materials remain

Method used

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  • Synthetic method for tazobactam chiral isomer
  • Synthetic method for tazobactam chiral isomer
  • Synthetic method for tazobactam chiral isomer

Examples

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Effect test

Embodiment 1

[0034] Example 1: Preparation of (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

[0035] Add 100g of 6-APA to 366g of 50% dilute sulfuric acid, and cool to -5°C. Control the temperature at -10 to 0°C and add dropwise 123g sodium nitrite solution (43g sodium nitrite dissolved in 80g water). After the addition, the temperature was kept at -5-5°C for 1 hour. Control the temperature at -5°C to 5°C, add 177g sodium hypophosphite solution (57g sodium hypophosphite dissolved in 120g water) dropwise, and heat up to 20-30°C for 2 hours. After adding 1.2L of dichloromethane and stirring for 0.5 hour, stand still and separate into layers. The organic phase was washed with 80g saturated sodium bicarbonate solution and distilled to dryness under reduced pressure. Then methanol was added, stirred at 20-30°C for 3 hours, and filtered to obtain 82g of white solid (2S,5R)-3,3-dimethyl-7- Oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (compound 1), yield...

Embodiment 2

[0036] Example 2: (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid-4 oxide preparation

[0037] Add 45g (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid and 800g two Chloromethane, cooling to -10~-5℃. Add sodium tungstate solution (0.03g sodium tungstate dissolved in 750g water), and then add 19g 50% hydrogen peroxide dropwise at -12~5°C. After dripping, keep the temperature at -10~5℃ for 2 hours. Filter, wash the filter cake with 42g of water, and dry under reduced pressure to obtain 44g of white solid (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] Heptane-2-carboxylic acid-4 oxide (compound 2), yield 91%.

Embodiment 3

[0038] Example 3: (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid methyl ester-4 oxidation Preparation

[0039] Add 60g (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid-4 to the reaction flask Add 52 g of methyl iodide and 500 g of DMF, and stir at 20-30°C for 2 hours. The reaction solution was slowly poured into 1.5Kg of water, filtered, the filter cake was washed with 60g of water, and dried under reduced pressure to obtain 63g of off-white solid (2S,5R)-3,3-dimethyl-7-oxo-4-thia- 1-Azabicyclo[3.2.0]heptane-2-carboxylic acid methyl ester-4 oxide (Compound 3), the yield was 98%.

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Abstract

The invention discloses a synthetic method for a tazobactam chiral isomer. The method comprises the following steps of: using 6-APA as a raw material, through diazotization, deaminizing by using sodium hypophosphite to obtain a compound 1, and performing mono-oxidation through a hydrogen peroxide solution, reacting with iodomethane, and reacting with 2-mercaptobenzothiazole, so as to obtain a compound 4; in hydrochloric acid, enabling the compound 4 to react with sodium nitrite to obtain a compound 5; enabling the compound 5 to react with triazole, after oxidizing by using potassium permanganate, performing column chromatography to obtain a compound 7-1; performing hydrolysis and de-protection on the compound 7-1 to obtain the tazobactam chiral isomer. According to the method, a carboxyl is ptotected by using a methyl with smaller steric hindrance, thereby generating more R configurations while constructing a No. 2 carbon atom, and the three configurations of compounds are separated byusing the column chromatography. The method has the advantages of low raw material cost, convenient and rapid post-treatment, and high yield. Reaction reagents in each step are easily obtained. The compounds are shown in the description.

Description

Technical field [0001] The invention relates to a method for synthesizing tazobactam chiral isomers, and belongs to the technical field of medicine. Background technique [0002] Tazobactam is a new synthetic chemical entity used as an inhibitor of drug-resistant β-lactamase in clinical medicine. This product has the characteristics of strong inhibitory activity, wide inhibitory spectrum, good stability, and low toxic and side effects. It is more than 10 times stronger than the currently used sulbactam sodium. It is evaluated as the most promising β- by the International Chemotherapy Conference. Lactamase inhibitors. A compound preparation composed of this product and a semi-synthetic antibiotic drug can inhibit the chromosomes or plasmids produced by G+ bacteria and G- bacteria to inactivate β-lactamase, thereby exerting excellent antibacterial properties. According to research, because piperacillin sodium’s effects and metabolic processes in the body are consistent with tazob...

Claims

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Application Information

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IPC IPC(8): C07D499/87C07D499/04
CPCC07B2200/07C07D499/04C07D499/87
Inventor 李志锋郑长胜吴兆申杨庆坤李卓华
Owner 山东安信制药有限公司
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