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Synthetic method for tazobactam

A synthetic method, the technology of tazobactam, applied in the field of drug synthesis, can solve the problems of long synthetic route, increased risk, difficult industrialization, etc., and achieve the effects of mild reaction conditions, improved safety, and good compatibility

Active Publication Date: 2013-04-17
SUZHOU ROEING BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

One uses 6-aminopenicillanic acid as a raw material to obtain tazobactam through reactions such as esterification, oxidation, chlorination, ring formation, oxidation, and hydrolysis. The synthetic route is long and the use of acetylene gas in the raw material is increased. dangerous
The second is to use sulbactam as a raw material to obtain tazobactam through reactions such as azidation, protection, cyclization and deprotection. This synthetic route has low yield and is difficult to industrialize
The third is to synthesize tazobactam from penicillin G potassium salt. Although penicillin G potassium salt is cheap, it is easy to produce isomerized by-products and the total yield is low.

Method used

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  • Synthetic method for tazobactam

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] 2ml of dimethylsulfoxide was contained in the reactor, and 0.57mmol of propiolic acid, 0.4mmol of 2β-azidomethylpenicillanic acid-1β-oxide, 0.14mmol of sodium ascorbate and 0.07mmol of Cuprous iodide, stirred and reacted at room temperature for 16 hours, extracted with ethyl acetate after the reaction, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain the crude product, the crude product was used Ethyl acetate and petroleum ether at a volume ratio of 1:2 were used as the eluent for column chromatography to obtain tazobactam with a yield of 87%. The H NMR spectrum of tazobactam is: 1 H-NMR (400 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(1H, s), 8.08(1H, s).

Embodiment 2

[0019] 2ml of dimethyl sulfoxide was contained in the reactor, and 0.55mmol of propiolic acid, 0.37mmol of 2β-azidomethylpenicillanic acid-1β-oxide, 0.14mmol of sodium ascorbate, 0.07mmol of Cuprous iodide and 0.19 mmol triethylamine were stirred and reacted at a temperature of 60°C for 3 hours, extracted with ethyl acetate after the reaction, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and The crude product was obtained by distillation under reduced pressure, and the crude product was subjected to column chromatography with ethyl acetate and petroleum ether at a volume ratio of 1:5-1:3 as the eluent to obtain tazobactam with a yield of 80%.

Embodiment 3

[0021] 2ml of dimethyl sulfoxide was contained in the reactor, and 0.50mmol of propiolic acid, 0.34mmol of 2β-azidomethylpenicillanic acid-1β-oxide, 0.04mmol of sodium ascorbate, 0.02mmol of Cuprous iodide and 0.17mmol 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), stirred and reacted for 5 hours at a temperature of 80°C, and reacted with acetic acid after the reaction ethyl acetate for extraction, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain the crude product, and the crude product was washed with ethyl acetate and petroleum ether at a volume ratio of 1:5-1:2. The liquid was removed and column chromatography was carried out to obtain tazobactam with a yield of 84%.

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Abstract

The invention discloses a synthetic method for tazobactam. The method comprises the following steps: adding propiolic acid, 2 beta-azidomethyl penicillanic acid-1 beta-oxide, sodium ascorbate and a catalyst containing cuprous ions or copper ions to a solvent in sequence; stirring and reacting these materials for 0.5-72 h at 20-180 DEG C; and after the reaction is finished, extracting a reactant and carrying out column chromatography on the reactant so as to obtain the tazobactam. Through the method, the synthetic method for the tazobactam, disclosed by the invention, has the advantages as follows: the tazobactam is a novel sulbactam type beta-lactamase inhibitor and can be used for treating a plurality of bacterial infections; and compared with a method with acetylene as raw material, the method has the advantages as follows: through using the propiolic acid as the raw material, the safety in the reaction process is enhanced and an electricity absorbing carboxyls on a molecule is beneficial for carrying out cycloaddition reaction and preferably compatible with a reaction substrate; the reaction condition is mild; the reaction can be conducted at normal temperature; the operation process is convenient and simple; the yield of obtained products is high; and industrial production can be carried out on a large scale.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing tazobactam. Background technique [0002] The chemical name of tazobactam 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, and the molecular formula is C 10 h 12 N 4 o 5 S, the structural formula is: [0003] [0004] Tazobactam is white or off-white powder, odorless, slightly bitter taste. Tazobactam is a new type of penicillane sulfone β-lactamase inhibitor developed by Dapeng Pharmaceutical Company of Japan. It is one of the best β-lactamase inhibitors in clinical application at present, with high stability, It is characterized by low toxicity and strong enzyme inhibitory activity, and is used to treat various bacterial infections. [0005] According to the different starting materials used, generally, the synthesis route...

Claims

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Application Information

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IPC IPC(8): C07D499/87C07D499/04
Inventor 匡春香
Owner SUZHOU ROEING BIOPHARMACEUTICALS CO LTD
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