Synthetic Cephalosporins Intermediates

In recent years, a great deal of funds and man powers were threw into thechemical synthetic drugs in the world. It has been arousing the fast fiercedevelopment in the pharmaceutical intermediate research. Especially,cephalosporins becomes the focus that people concern. Cephalosporinsoccupies more and more market quotas in the global anti-infective medicinewith its high growth and good clinic. The plain industry of cephalosporins inChina has got the substantial development from 80's in last century.Thedevelopment of cephalosporins changes with each passing day in recentyears.The market request of each kind of cephalosporins' intermediates alsoincreases quickly, and there are many problems such as defective process,serious pollution and high cost in the intermediates' production in our country.Therefore, there are vast of market foreground for the researches of thecephalosporins' intermediates .The thesis consists of three parts:Part one: The Research for the Synthesis of Ammouium2-Methoxyimino-2-Furylacetate2-Methoxyimino-2-furylacetic acid is synthesized from 2-furanyloxoaceticacid which is prepared from 2-Acetylfuran by oximation andmethoxylaminehydrochloride. And then neutralized with ammoniumhydroxide, the target compound ammouium 2-Methoxyimino-2-furylacetate isobtained. The oxidation process of 2-Furanyloxoacetic acid is reduced fromtwo steps to one step . The temperature of the oxidation reaction is declinedfrom 65℃ to 50℃.The molar ratio of 2-Acetylfuran and sodium nitrite is1:2.5. The yield of 2-Methoxyimino-2-furylacetic acid is 70%.The pH of the oximation for the process of 2-Methoxyimino-2-furylaceticacid is controlled from 5.0~6.0. The molar ratio of 2-Furanyloxoacetic acidand methoxylaminehydrochloride is 1.0:1.2. The temperature of this reactionis raised to 40 ℃ and time is delayed to 8h. The yield of2-Methoxyimino-2-furylacetic acid is 85%. The preparation for Ammouium2-Methoxyimino-2-furylacetate manipulated the neutralization withammonium hydroxide. It's easy to opearate and its yield is 92%.Through optimizing these mentioned conditions, side reactions andpollutions are reduced significantly, its yield is raised obviously. The newprocess consisted of 21 steps is much more simple than the traditional onethat is consisted of 30 steps. The structure of the target compound was testedby IR, 1H-NMR,13C-NMR and element analysis. The total yield is 55% whichis higher than the reported. The HPLC purity of the sample is higher than99.0%. The good results in its yield and quality.was achieved .It is worthmaking industrialization exploration.Part two: The Synthesis of Aminothiazoyl Loximate[2-(2-amino-4-thiazolyl)-2-(z)-methoxy iminoacetic acid ]The target compound is synthesized using methyl acetoacetate as rawmaterial by the step of oximation, methylation, bromination,cyclocondensation and hydrolysis. The research showed that the middleproduct of oximation , methylation and bromination needn't be refined. Thethree reactions could use the same solvent. We used composite phase transfercatalyst in the methylation. Its total yield is 50% that is higher than thereported (46%). The structure of the product is identified with elementanalysis, IR and 13C-NMR. The new process not only simplified the operationand shortened the toal reaction time (from 40 steps to 20 steps), but alsoreduced the initial cost, thus there will be important value in industrialapplication.Part three: Research on a New Synthetic Process of1-Methyl-5-Mercapto-1,2,3,4-TetrazoleA new synthetic process of 1-methyl-5-mercapto-1,2,3,4-tetrazole wasresearched using isothiocyanatomethane and sodium azide as the raw material.The molar ratio of isothiocyanatomethane and sodium azide is 1.05:1.0. Theoptimum temperature of the reaction is 75℃ and its reaction time is 2h afteradding isothiocyanatomethane. The structure of the product is identified withelement analysis, IR and 1H-NMR. The purification process that the researchdetermined has improved the HPLC purity of the compound and its quality isaccording with the standards of many foreign medicine companies.Isothiocyanatomethane was prepared from methylamine, carbon bisulfideand hydrogen peroxide. Its yield was raised from 60% to 68%.Sodium azide was prepared from ethanol, sodium nitrite and hydrochloricacid. Its yield was raised to 82%. The initial cost was reduced with usingethanol instead of n-butanol. The ethyl nitrite and the wet sodium azidewithout the separation and purification can be used in the next reaction stepdirectly.