Improvement Of The Synthesis Process Of Tazobactam

Tazobactam is a novelβ-lactamase inhibitor.Since it comes into the market,it has the advantages of low toxicity,good stability and strong enzyme inhibition compared with the other twoβ-lactamase inhibitors,clavulanic acid and sulbactam.The synergistic effect of tazobactam with a variety ofβ-lactam antibiotics can effectively increase its antibacterial activity and broaden its antibacterial spectrum.So far,the market prospect of the drug is still good,worldwide,with annual sales of more than one billion dollars.The long and complex synthesis route,high raw material cost,low yield and high pollution of tazobactam have been the limiting factors for the development of this industry.In view of the problems in the synthesis process,the process conditions of three key intermediates in the synthesis process of tazobactam were optimized in this paper.(1)An improvement was made to the synthesis process conditions of the pyrolysis open-ring.The process conditions were investigated by the mixed solvent method of toluene and cyclohexane.By experiment exploration,the suitable conditions were as follows,n(benzhydryl 6,6-dihydropenicillanate-1-oxide):n(2-mercaptobenzothiazole)1.1:1.0,solvent mass ratio 8.0:1,reaction temperature 100°C,reaction time 2.5h,yield 98.1%.Compared with the conventional method,the mixed solvent method has lower reaction temperature,lower energy consumption,less by-products,less environmental pollution,and both yield and purity of the product were improved.(2)Anewmethodforthesynthesisofbenzhydryl2α-methyl-2β-bromomethyl-penicillanate with hydrobromic acid/sodium nitrite as a halogenated cyclization reagent was proposed.Compared with copper bromide,anhydrous copper chloride and hydrochloric acid/sodium nitrite as halogenated cyclization reagents,the results show that the highest yield was obtained when hydrobromic acid/sodium nitrite was used as a halogenated cyclization reagent.The reaction conditions with hydrobromic acid/sodium nitrite as the halogenated cyclization reagent were optimized by orthogonal test.The experimental results show that the suitable conditions were as follows,the catalyst mass fraction 3.5%,n(thermal cracking open-loop product):n(hydrobromic acid):n(sodium nitrite)1:3:6,reaction time 2.5h,m(dichloromethane):m(thermal cracking open-loop product)7.5:1,reaction temperature-5°C,the yield 85.9%.Hydrobromic acid/sodium nitrite as a cyclization reagent itself is cheap and easy to obtain,especially in the reaction temperature and reaction time it has the biggest advantage,such as short reaction time,mild reaction conditions,and high yield,which is more suitable for industrial production.(3)Benzhydryl 2α-methyl-2β-(1H-1,2,3-triazole)-penicillanate was synthesized by direct introduction of triazole.Using acetone/water as the reaction solvent,by experiment exploration,the suitable conditions were as follows,the reaction time 15h,n(bromo cyclate):n(1H-1,2,3-triazole)1:20,the reaction temperature 40°C,V(acetone):V(water)3.5:1,the catalyst 15g,and the yield 65.8%.Compared with the existing production process,the direct introduction method of triazole reduces the synthesis process steps,optimizes the reaction conditions,overcomes the flammable and explosive production safety problems,which is more in line with the safety principle of industrial production.The product was characterized by melting point measurement,IR,~1HNMR,MS and the like to identify the synthesis of three target products.