|Budget Amount *help
¥14,300,000 (Direct Cost : ¥14,300,000)
Fiscal Year 1995 : ¥2,500,000 (Direct Cost : ¥2,500,000)
Fiscal Year 1994 : ¥4,600,000 (Direct Cost : ¥4,600,000)
Fiscal Year 1993 : ¥7,200,000 (Direct Cost : ¥7,200,000)
Recently, (Z) -7beta- [2- (5-amino-1,2,4-thiadiazol-3-yl)-2- (alkoxyimino) acetamido] cephalosporins such as SCE2787 (cephazopran), E1040 and E1077 have been reported as clinically useful antibiotics having excellent antimicrobial activities. Their common acyl moiety at the C-7 position is corresponding to the Z-isomer (1) of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (alkoxyimino) acetic acid. The E isomer is known to be not valuable for useful beta-lactam antibiotics, so far. Consequentyl, it was our intention to successfully develop a general method of entry into the Z-isomer by our own strategy, although several methods have been reported for the production of 1. The Z-isomer (1) has been prepared from the aminoisoxazoles through the skeletal rearrangement in several routes. Reaction of 3-amino-5-methoxyisoxazole with alkoxycarbonyl isothiocyanates gave methyl 2- (5-alkoxy carbonylamino-1,2,4-thiadiazol-3-yl) accetates, which were converted into the target compound 1 through the reaction of the corresponding keto ester with O-methylhydroxylamime. Compound 1 was prepared similarly from 3-aminoisoxa-zole. Also, O-methylation of 2-hydroxyimino-2- (5-methoxycarbonyl amino-1,2,4-thiazol-3-yl) acetate with methyl iodide or dimethyl sulfate in the presence of barium oxide and barium hydroxide octahydrate was found to afford exclusively the desired Z-isomer, which was led to 1.
On the other hand, rataniaphenols are known to show strong antibiotic activities especially against B.gingivalis, and structurally, have a 2-phenylbenzofuran unit as their skeletons. Herein, the basic compound, 2-p-hydroxyphenylbenzofuran has been effectively synthesized from o-cresol through an ortho-toluate-carbanion rearrangement of the p-methoxybenzoate.