| For the past few years,there will still be a large demand for antibiotics in the pharmaceutical industry in the coming years with the growing problem of bacterial infections.Penicillins,quinolones,cephalosporins and tetracyclines are main antibiotics commonly used in clinical practice,cephalosporins are widely used in the diseases which were caused by Staphylococcus aureus,S.pneumoniae,Corynebacterium diphtheriae,Corynebacterium pneumoniae and Streptococcus pyogenes,due to their broad antibacterial spectrum,high antibacterial efficiency,low adverse effects and low cytotoxicity.At present,the development of cephalosporin antibiotics has a broad prospect and potential market.（6R,7R）-3-Hydroxy-8-oxo-7-[（phenylacetyl）amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenyl methyl ester（CBG）is a key intermediate in the synthesis of cephalosporin antibiotics and an important intermediate in the research and development of its new derivatives.To address the problems of high raw material cost,high toxicity,complex production process,harsh reaction conditions,many by-products and difficult to isolate,this paper optimizes the synthetic route of CBG,aiming to develop a low-cost and high yield process route.In this paper,penicillin G potassium salt（PGK）which is industrially availa ble as the starting material and benzophenone hydrazone（BPH）as the esterifyin g agent instead of diphenylmethanol,p-methoxybenzyl chloride and trichloroethy l chloroformate in the traditional process,peroxyacetic acid（PAA）as the oxidiz ing agent instead of 3-chloroperoxybenzoic acid,periodate and sodium periodate,ozone and hydrogen peroxide to achieve the esterification-oxidation one-pot to synthese 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,3,3-dimethyl-7-oxo-6-[（2-phenylacetyl）amino]-diphenylmethylester-4-oxide（I）,which not only reduces the production cost and avoids the anhydrous operation process,but also has mi ld reaction conditions and simple post-treatment.Compound I was subjected to ring-opening reaction in the presence of trimethyl phosphite to give diphenylmet hyl-2-（3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl）-3-methylbut-3-en oate（II）,toluene and 1,2-dichloroethane（DCE）was used as a mixture solution to replace the single solvent toluene during the reaction,which not only reduce reaction temperature,but also avoided the decomposition of compound II at hig h temperature,which can improve the yield of the ring-opening reaction.Then compound II underwent a series of ozonation,reduction,sulfonation and enamin ation to give diphenylmethyl 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,3,3-morpholinyl-7-oxo-6-[（2-phenylacetyl）amino]-diphenylmethylester-4-oxide（III）.In the ozonation process,a mixture of methanol（Me OH）and dichloromethane（DCM）was selected instead of a single alkane solvent,and Me OH could inhibit the formation of polymorphous ozone compounds.In the reduction reaction proc ess,trimethyl phosphite which is less toxic,was selected instead of dimethyl su lfide which is highly toxic,as the reducing agent to reduce the production dang ers and control cost In the sulfonylation reaction process,p-toluenesulfonyl chlo ride was selected as the amidation reaction,N-methylmorpholine was used as th e acid binding agent and morpholine was used as amidation reagen.Finally,the target product CBG was obtained by the bromination reaction and hydrolytic c yclization of compound III.During the bromination reaction,the bromine was d iluted with DCM to reduce the concentration of bromine to reduce side reaction,quinoline was chosen as the binding acid agent instead of 2,4-dimethylpyridine which has a high price,to reduce the production cost of CBG.In this improving process route,the effects of factors such as the substance ratio of reactants,reaction temperature,time,solvent ratio,reaction concentration,type of reducing agent and acid binding agent on the yields of I-III and CBG were investigated,and the optimal process conditions were finally determined as follows:（1）The effects of the substance ratios of PGK,BPH and PAA,reaction time and temperature on the yield of I were investigated.The results showed that the highest yield of compound I was 93.2%,which was obtained when n（PGK）:n（BPH）:n（PAA）=1:1.15:2.5,after reacted at 5℃for 3 h.（2）The effects of the substance ratio of compound I and trimethyl phosphite,solvent ratio and reaction time on the yield of compound II were investigated.When n（I）:n（trimethyl phosphite）=1:1.4 and V（toluene）:V（DCE）=1:1.5,the highest yield of compound II was achieved at 90.8%after 6 h of reflux reaction.（3）The effects of reaction temperature,solvent ratio,type and amount of r educing agent,amount of sulfonylation reagent and enaminylation reagent and t he type of acid binding agent on the yield of compound III were investigated.When V（Me OH）:V（DCM）=1:5,compound II reacted with ozone for 40 min at-60℃,trimethyl phosphite was added as reducing agent and n（II）:n（phosphite tr imethyl phosphite）=1:1.2,reacted at 0°C after 20 min,then extracted,p-toluene sulfonyl chloride was added as sulfonylation and n（II）:n（p-toluenesulfonyl chlori de）=1:1.1,after reacted 20 min at-5°C,N-methylmorpholine was added as aci d binding agent and morpholine used as enaminizing reagent and n（II）:n（N-meth ylmorpholine）:n（morpholine）=1:2.1:1.1,after reacted at 0℃for 3 h,the high est yield of compound III was obtained which could reached 79.1%.（4）The effects of bromine reagent type and dosage,reaction concentration and temperature,and the type of acid binding agent on the yield of CBG were investigated.When bromine was used as the bromine reagent,diluted to 0.035 g/m L by DCM,quinoline was used as the acid binding agent,and n（III）:n（quinoline）:n（bromine）=1:1:1.1,the reaction was carried out at-15℃for 1 h,and Me OH and 8%sulphuric acid solution were added directly and n（III）:n（8%H2SO4）=1:0.68,the highest yield of CBG was obtained after reacted 20 h at 25°C,which could reach 90.3%.The total yield of CBG was 60.4%,higher than the current industrial production55.7%.After process was optimizated,the use of the one-pot method for the esterification and oxidation reactions to give compound I which can shorten the reaction time,avoid the anhydrous conditions of the esterification reaction,avoid the use of more expensive oxidising agents and catalysts,making post-processing simple and less costly.Compound II was obtained by the ring-opening reaction from compound I,a mixed solvent was chosen to lower the reaction temperature and increase the yield.The use of mixed solvents for the ozonation reaction of compound II can inhibit side reactions.Trimethyl phosphite was used as a reducing agent to reduce production danger and cut down costs.The use of p-toluenesulfonyl chloride for the sulfonylation reaction can greatly improve the efficiency and selectivity of the reaction and reduce the side reactions.Quinoline was used as the acid binding agent for the compound III in bromination reaction to reduce costs.Bromine was diluted with DCM to reduce the concentration of bromine to reduce side reactions.This thesis provides a research and experimental basis for the optimisation of the CBG in industrial production. |
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