Study On Functionalizing At C-3 Chain Of Cephalosporin Intermediate GCLE

Cephalosporin antibiotics plays an important role on clinical practice for treating the most bacterial infection which is one of common diseases.Formerly, the drugs or prodrugs were semi-synthesized by chemical or enzymatic remolding of 7-ACA nucleus. Successful research of GCLE [(6R-trans)-5-Thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3-chloromethyl-8-oxo-7-[(phenylacetyl)amino]-diphenylmethyl ester] provides new synthetic route for researching and developing new cephalosporin antibiotics.GCLE which chemically synthesized from penicillin is an important cephalosporin intermediate that has five sites on its cephem nucleus for chemical modification(2-,3-,5-,7a-,7-3-), here we pay main attention on the functionalization at C-3 chain and try to seek synthetic route of ceftazi-dime from GCLE.1, Basing on the review of literature, by chemically modifying GCLE at C-3 chain, three series of cephalosporin derivatives were synthesized, their structures are showed as following:It is these three series of cephalosporin derivatives that were used broadly in clinical. a Cephalosporin derivatives having substituted or unsubstituted vinyl at 3-position. Diphenylmethyl(6R,7R)-8-oxo-7-(phenylacetyl)amino-3-vinyl-5-thia-l-azabicyclo[4.2.0] oct-2-ene-2-carboxylate(8) were synthesized according to Wittig Reaction via fractional step method and one-pot process separately. Each intermediate was purified and their structures were identified.Optimized separately the reaction condition of preparing compound 3 and synthesizing compound 8 from GCLE via one-pot process by means of uniform design, the yield is up to 97% and 82% and the latter is increased by 24.3% than fractional step method; Moreover compounds 10-15 were synthesized.IK Cephalosporin derivatives possessing 3-thiomethyl moiety. Seven such esters' intermediateswere synthesized facilely from GCLE via Williamson Reaction in the presence of sodium bromide.Literature adopted such method to prepare this series derivatives as in presence of sodium iodide and sodium carbonate or bicarbonate. Basing on pre-experiments, alkali was cut off and sodium iodide was replaced by sodium bromide. As a result, not only 3-ene isomer of cephem nucleus producing was avoided, but also the cost was reduced.Adding a little of organic acid into reaction system when mercaptan having imidazole structure condensing with bromo-intermediate of GCLE may reduce proportion of 3-ene isomer in resultant. 3-ene isomer in esters' mixture(20-23) may change into 2-ene configuration during being deblocked C-2 carboxyl-protecting group.c, Cephalosporin derivatives bearing aminomethyl group in the 3-side. Four cephalosporin derivatives taking substituted or unsubstituted pyridiniornethyl group at 3-side were synthesized.Esters' derivatives(8,10,17-23,32-35) were deblocked their C-2 carboxyl-protecting group. Twelve cephalosporin derivatives possessing C-2 carboxyl group were tested against ten trains both of gram-positive and gram-negative bacteria in vitro. The result make clear that all compounds tested exhibited a certain activity against the selected strains. Among them, compounds 16,24-26, 30 showed higher activity against gram-positive bacteria than control.2, The third-generation cephalosporin-type antibiotics-Ceftazidime was synthesized via five steps from GCLE.Forty-one cephalosporin compounds were synthesized from GCLE(intermediates 29), among them, compounds 12,17,19-24,26-31,47,48 have not been reported in literature.Structures of synthesized compounds were elucidated by NMR, MS and related analysis.