Synthesis method of new cephalosporin side-chain intermediate compound

Abstract

The invention discloses a synthesis method of a new cephalosporin side-chain intermediate compound, which comprises the following steps: by taking isobutyric acid and element bromine as raw materials, dropwisely adding the element bromine more than once, reacting to obtain alpha-bromoisobutyric acid, wherein after the element bromine is dropwisely added each time, chlorine gas is introduced to further react, so that the HBr byproduct is converted into element bromine which can be used for reaction with the isobutyric acid; reacting the obtained alpha-bromoisobutyric acid and isobutylene under the action of a protonic acid strong catalyst, and performing direct distillation to obtain tert-butyl alpha-bromoisobutyrate; performing alkylation reaction on the tert-butyl alpha-bromoisobutyrate and ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate under the catalytic action of a phase-transfer catalyst by taking acetone as solvent; and hydrolyzing to obtain (Z)-2-amino-alpha-[[2-(tert-butoxy)-1,1-demethyl-2-oxoethoxy]imino]-4-thiazol acetic acid. The production process disclosed by the invention has the advantages of simple process, high raw material conversion rate and yield, environment friendliness and low cost.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to the key intermediate (Z)-2-amino-α-[[2-(tert-butoxy)-1,1- Dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid synthesis technology. Background technique [0002] The current synthesis technology of (Z)-2-amino-α-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid There have been reports in domestic and foreign literature, generally demethylaminothiaxamic acid (Z)-2-(2-amino-4thiazole)-hydroxyimine ethyl acetate (compound 2) and tert-butyl α-bromoisobutyrate (Compound 6) is used as a raw material through alkanization, hydrolysis and acidification to obtain (Z)-2-amino-α-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy base]imino]-4-thiazoleacetic acid (compound 1). [0003] synthetic route: [0004] 1) [0005] [0006] 2) [0007] [0008] Among them, α-tert-butyl bromoisobutyrate is one of the important intermediates fo...

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Problems solved by technology

[0041] The applicant found that the shortcoming of the above method is that the yield of the last step of the esterification reaction is relatively low, about 60%; the catalyst pyridine used has a special odor, and is not easy to fully recycle, causing serious environmental pollution. It affects the application of tert-butyl α-bromoisobutyrate

There are also people who used triethylamine instead of pyridine as a catalyst to make the yield of esterification reach 88.1%, but the yield is still unsatisfactory, which is not conducive to large-scale industrial production

[0042] The alkylation reaction of histidine side-chain acid reacts with α-bromoisobutyrate tert-butyl ester and desmethylaminothioxamic acid ethyl ester, by compound 6 and compound 2, solvent adopts DMF or DMSO, condensation reaction obtains compound 3, because These solvents are highly polar and have a high boiling point. Although the production process is beneficial to the ionization of the inorganic salt potassium carbonate and the promotion of the reaction, it is necessary to dilute the reactants after the reaction with water so that the product can be precipitated from the solvent, resulting in solvent recovery. Difficult to carry out, the difficulty of solvent recovery is increased, and the cost is high

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