Development of Preparation for Key Intermediates of Medicines Using Rearrangements as Key Reactions.

近年来，头孢菌素类药物(Z)-7β-[2-(5-氨基-1，2，4-噻二唑-3-基)-2-(烷氧亚氨基)乙酰氨基]头孢菌素如SCE2787、E1040和E1077等已被报道为具有良好抗菌活性的临床常用抗生素。它们在C-7位的共同酰基部分对应于2-(5-氨基-1，2，4-噻二唑-3-基)-2-(烷氧亚氨基)乙酸的Z-异构体(1)。到目前为止，已知E异构体对有用的β-内酰胺类抗生素没有价值。因此，我们打算通过自己的策略成功地开发一种进入Z-异构体的通用方法，尽管已经有几种方法被报道用于生产1。以氨基异恶唑为原料，通过几条路线的骨架重排制备了Z-异构体(1)。3-氨基-5-甲氧基异恶唑与烷氧羰基异硫氰酸酯反应生成2-(5-烷氧基甲酰氨基-1，2，4-噻二唑-3-基)乙酸甲酯，再与邻甲基羟胺反应生成目标化合物1。化合物1类似于由3-氨基异恶唑合成。2-羟亚氨基-2-(5-甲氧基甲酰氨基-1，2，4-噻唑-3-基)乙酸酯在八水氧化钡和八水氢氧化钡存在下与甲基碘或硫酸二甲酯的O-甲基化反应得到了所需的Z-异构体，得到了1。另一方面，雷尼酚类化合物具有很强的抗菌活性，特别是对牙龈假单胞菌有很强的抗菌活性，而且在结构上以2-苯基苯并呋喃为骨架。本文以邻甲酚为原料，通过对甲氧基苯甲酸酯的邻甲苯甲酸-碳负离子重排反应，有效地合成了碱性化合物2-对羟基苯基苯并呋喃。

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.