Synthetic Process Study Of (2-Formamido-1,3-Thiazol-4-Yl) Glyoxylic Acid

Cephalosporin antibiotics have a variety of advantages, including strong antibacterial activity, wide antimicrobial spectrum, resistance to β-lactamase, acid and alkali, as well as low toxicity. They have been commonly used for the treatment of bacterial infectious diseases.Both Cefixime and Cefazidime are very important third generation semi-synthesis cephalosporins which have a strong bactericidal and anti-bacterial broad spectrum of characteristics,and had been widely used in clinical.Azetreonam is the first clinic used drug of a new class of β-lactam antibiotics known as monobactams. The drug is actuvely against the majority of infections caused by aerobic Gram-negative bacteria.2-(formamido-1,3-thiazol-4-yl) glyoxylic acid is used for intermediates of cephalosporin,such as Cefixime, Ceftazidime and Aztreonam, et al. The exploration and discovery a mature and feasible synthesis process of which can not only obtain great social benefits but also generate considerable economic benefits. Thus to explore a route with a high purity and high yield is of great significance. In this paper, based on analysis of existing synthetic route and several experiments, we adopted a synthetic process which is suitable for industrial production: Ethyl-demethylaminothiazolyloximate reacts with sodium bisulfite in ethanol-water mixtures to reduce oxime to carbonyl group; Then the product reacts with formic acid and acetic anhydride to the formylation product; After that, the formylation product is hydrolyzed under the condition of alkaline solution to 2-(formamido-1,3-thiazol-4-yl)glyoxylic acid which is the target product。And the experimental conditions are discussed in this paper, here are completed work:(1) About the synthesis of intermediates of I, Feed ratio was determined through the experiment to MEthyl-demethylaminothiazolyloximate: MNa HSO3 = 1:3.5, Ethanol: H2O(V: V = 1:1) as the best solvent, 60 ~ 70℃ as the best reaction temperature, 20 h as the optimum reaction time,pH of 4.5~5 as the optimum.Under the condition of which, crude products I yield was the highest.(2) About the synthesis of intermediates II, which determined through the experiment were Mformic acid : Mproduct I = 4:1 and Mformic acid : Macetic anhydride = 1:1 as the best of Feed ratio, the optimum reaction temperature 15℃, the optimum reaction time 6 h. Under the condition ofwhich, crude products II yield was the highest.(3) In the synthesis of the target product 2-(formamido-1,3-thiazol-4-yl)glyoxylic acid,we determined that Mintermediates II: MNaOH = 1:2.5 is the best weight ratio, and the optimum reaction temperature is about 20 ~ 30℃, and the optimum reaction time si 5 h. Under the condition of which, crude products III yield was the highest.(4) We carryed on the amplification experiments, and designed the flow chart and operation procedures of pilot process.(5) We made study of Zinc-Induced Deoximation and the regeneration of carbonyl compounds from oximes by using cupric chloride dihydrate as a recoverable promoter for hydrolysis of 2-(2-Aminothiazole-4-yl)-2-methoxyiminoacetic acid, 2-(2-Aminothiazole-4-yl)-2-hydroxyiminoacetic acid, Ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate and2-(formamido-1,3-thiazol-4-yl)glyoxylic acid to be applied to industrial production.The process route in this paper had made development in the process, the raw material cost, the product yield and purity, and the environmental protection.