合成路线1

Compound can be prepared in two different ways: 1) The cyclization of ethyl 2-[4-(chloroacetyl)phenyl]propionate (I) with 2-aminopyridine (II) in refluxing ethanol gives ethyl 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionate (III), which is then hydrolyzed with NaOH in refluxing ethanol water. 2) By cyclization of a mixture of pyridine (IV), hydroxylamine (V) and 2-[4-(chloroacetyl)phenyl]propionic acid (VI) by heating at 80-100 C.

合成路线2

A mixture of freshly distilled pyridine (A) and 1-chloro-2,4-dinitrobenzene (I) in dry acetone is allowed to reflux for 15 h. Removal of the solvent in vacuo affords a residue which is washed with ether, recrystallized in absolute ethanol and characterized as N-(2,4-dinitrophenyl)pyridinium chloride (II). To an ice-cooled solution of compound (II) in methanol, a suspension of isonicotinic acid hydrazide in methanol in five aliquots is added with stirring. Triethylamine is then added and the reaction is allowed to stand at room temperature overnight. The solid which precipitates is purified and characterized as compound (III). A suspension of compound (III) in dioxane:water (4:1 v/v) is heated under reflux for 12 h to afford a clear solution. Separation and purification of the products gives a yellowish crystalline solid of N-(4-pyridylcarbonylimino)pyridiniumylide (IV) and 2,4-dinitroaniline (V). A solution of compound (IV) in 95% ethanol is added dropwise to a solution of sodium borohydride in 95% ethanol pre-cooled to 0 C. After stirring for 4 h at 0 C, the reaction mixture is poured onto crushed ice and allowed to come to room temperature. Extraction with chloroform, drying and purification yields N-(4-pyridylcarbonylamino)-1,2,3,6-tetrahydropyridine.

合成路线3

The reaction of ethyl acetoacetate (I) with NaNO2 in acetic acid-water gives ethyl 2-(hydroxyimino)-3-oxobutyrate (II), which is cyclized with thiourea (III) by means of SO2Cl2 in methylene chloride yielding ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate (IV). The treatment of (IV) with trityl chloride (V) and triethylamine in DMF affords ethyl 2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetate (VI), which by condensation with tert-butyl 2-bromo-2-methylpropionate (VII) by means of K2CO3 in DMSO is converted into ethyl 2-(2-tert-butoxycarbonyl-2-propyloxymino)-2-(2-tritylaminothiazol-4-yl)acetate (VIII). The hydrolysis of (VIII) with NaOH in refluxing methanol gives 2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (IX), which by condensation with tert-butyl 7-aminocephalosporanate (X) by means of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide in DMF yields tert-butyl 7-[2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]cephalosporanate (XI). The hydrolysis of (XI) with trifluoroacetic acid in anisole affords 7-[2-(2-aminothiazol-4-yl)-2-(2-carboxy-2-propyloxyimino)acetamido]cephalosporanic acid (XII), which is finally treated with pyridine (A) and NaI.

合成路线4