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Method for synthesizing deuterated tazobactam

A technology of tazobactam and its synthesis method, which is applied in the field of drug synthesis, can solve the problems of easy combustion, decomposition and explosion, harsh reaction conditions, and generally low yield, and achieve long action time, short synthesis steps, and excellent effect Effect

Active Publication Date: 2013-04-03
SUZHOU ROEING BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Generally, acetylene and organic azide are used as raw materials to synthesize the target product tazobactam, but the reactant acetylene is a chemically very active gas, which is prone to combustion, decomposition and explosion.
During the production, transportation and use of acetylene, major vicious fire and explosion accidents are prone to occur, causing heavy casualties and property losses
The use of acetylene for cycloaddition reaction not only has greater risk, but also harsh reaction conditions, and the general yield is low

Method used

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  • Method for synthesizing deuterated tazobactam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Add 2ml deuterated dimethyl sulfoxide to the reactor, and add 0.4mmol 2β-azidomethylpenicillanic acid-1β-oxide, 0.57mmol propiolic acid, 0.07mmol cuprous iodide and Add 0.14 mmol of sodium ascorbate to the solvent, stir and react at room temperature for 16 hours, extract with ethyl acetate after the reaction is completed, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and filter, evaporate the solvent under reduced pressure to obtain the crude product , using ethyl acetate and petroleum ether at a volume of 1:2 to perform column chromatography to obtain deuterated tazobactam with a yield of 85%. The H NMR spectrum of deuterated tazobactam is: 1 H-NMR (500 MHz, CDCl 3 ): δ = 1.32(3H,s), 3.29(1H,dd), 3.70(1H,dd), 4.76(1H,s), 4.9(1H,dd), 5.16(1H,m), 5.25(1H, dd), 7.78(0.01H, s), 8.08(0.01H, s).

Embodiment 2

[0020] Add 2ml of deuterated dimethyl sulfoxide to the reactor, and add 0.37mmol 2β-azidomethylpenicillanic acid-1β-oxide, 0.55mmol propiolic acid, 0.07mmol cuprous iodide, 0.14mmol sodium ascorbate and 0.19mmol triethylamine were added to the solvent, stirred and reacted at 60°C for 3 hours, extracted with ethyl acetate after the reaction was completed, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and decompressed The crude product was obtained by distilling off the solvent, which was filtered and subjected to column chromatography with ethyl acetate and petroleum ether at a volume of 1:5-1:3 to obtain deuterated tazobactam with a yield of 82%.

Embodiment 3

[0022] Add 2ml of deuterated dimethyl sulfoxide to the reactor, and add 0.34mmol 2β-azidomethylpenicillanic acid-1β-oxide, 0.50mmol propiolic acid, 0.02mmol cuprous iodide, 0.04mmol of sodium ascorbate and 0.17mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added to the solvent, stirred and reacted at 80°C for 5 hours, after the reaction was completed, rinse with acetic acid Ethyl extraction, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, which was filtered and column layered with ethyl acetate and petroleum ether with a volume of 1:5-1:2 Analysis obtained deuterated tazobactam, and the yield was 86%.

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Abstract

The invention discloses a method for synthesizing deuterated tazobactam. The method comprises the following steps: adding 2beta-azomethylpenicillanic acid-1beta-oxide, propiolic acid, a catalyst containing copper or cuprous ion and sodium ascorbate in a deuterated solvent in turn, stirring at 25-200 DEG C for reaction for 1 to 48 hours, and after the reaction, performing extraction, filtering and column chromatography to obtain the deuterated tazobactam. Through the method, according to the method for synthesizing the deuterated tazobactam, the deuterated tazobactam is a novel beta-lactamase inhibitor of the penicillanic sulfone type and can be used for treating various bacterial infections; the method has the characteristics of mild reaction condition, short synthesis procedure, simple process and high yield, the safety during the reaction is effectively improved by using propiolic acid as the raw material, and the carbon-deuterium chain in the obtained deuterated tazobactam molecule is so stable that the medicine decomposition process can be effectively retained, therefore, the deuterated tazobactam has a longer action time in the body and is better than the normal tazobactam.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing deuterated tazobactam. Background technique [0002] Tazobactam is white or off-white powder, odorless, slightly bitter taste, chemical name is [2S-(2a, 3b, 5a)]-3-methyl-7-oxo-3-(1H-1, 2,3-Triazol-1-ylmethyl)-4-thio-1-azabicyclo[3,2,0]heptane-2-carboxylic acid 4,4-dioxide, the molecular weight is 322.27 , the molecular formula is C 10 h 12 N 4 o 5 S, the structural formula is as follows: [0003] [0004] Tazobactam is very soluble in dimethylformamide, can be dissolved in methanol, ethanol and acetone, slightly soluble in water, has the advantages of low toxicity, good stability, strong enzyme inhibitory activity, etc., and can be combined with piperacillin The combined application of antibiotics such as , amoxicillin and ampicillin can achieve extremely effective synergistic effects, and it is an important pharmaceutical intermediate. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/87C07D499/04
Inventor 匡春香
Owner SUZHOU ROEING BIOPHARMACEUTICALS CO LTD
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