Practical Preparation of (Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic Acid: A Side-Chain of the Fourth Generation of Cephem Antibiotics

Abstract

A Z-isomer (4) of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid, which is the common acyl moiety of clinically useful cephem antibiotics, has been prepared from the aminoisoxazoles through the skeletal rearrangement in several routes. Reaction of 3-amino-5-methoxyisoxazole (7) with alkoxycarbonyl isothiocyanates gave methyl 2-(5-alkoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetates (8), which were converted into the target compound 4 through the reaction of the corresponding keto ester with O-methylhydroxylamime. Compound 4 was prepared similarly from 3-aminoisoxazole (10). Also, O-methylation of 2-hydroxyimino-2-(5-methoxycarbonylamino-1,2,4-thiazol-3-yl)acetate (15) 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 (14a) of methyl 2-(5-methoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetate, which was led to 4.

New Procedure for the Preparation of (Z)-2-(5-Amino-1,2,4-thiadiazole-3-yl)-2-trityloxyiminoacetic Acid

“…Then, how to efficiently convert compound 13 into 1,2,4-thiadiazoles 15 via a skeleton rearrangement of the thiourea intermediate 14 was one of our main tasks. Initially, treatment of compound 13 with ethoxycarbonyl isothiocyanate under various condition to afford ethyl 3-(2-acetamido-2-oxoethyl)-1,2,4-thiadiazol-5-ylcarbamate ( 15a ) was investigated. , The results in Table reveal that Lewis acids (zinc chloride) or bases (pyridine, triethyl amine, and N , N , N′ , N′ -tetramethylethylenediamine) could not increase the yields of 15a , and the highest yield was 64% under acid- or base-free condition (Table , entry 5). HPLC analysis revealed that the main byproduct was the unrearranged thiourea 14a , and the crude product was purified by recrystallization from acetone to yield a white crystalline.…”

“…However, there were the two following problems regarding Scheme in the reported method, namely: (1) the overall yield of 2 was low (11% yield); (2) toxic and hazardous agents such as bromine and peracetic acid were used. Alternatively, the key intermediate 6 could be prepared from the 3-amino-5-methoxyisoxaole ( 11 ) directly through the skeletal rearrangement in several routes. , As shown in Scheme , the starting compound 11 was prepared from the malononitrile ( 9 ) through 3,3-dimethoxyacrylonitrile ( 10 ). Reaction of 11 with methoxycarbonyl isothiocyanate afforded 6 in 86% yield.…”

“…To improve the quality and the yield of product 2 , as well as to reduce the cost and make the process more environmentally suitable for a commercial production, we developed a new and efficient procedure for the preparation of 2 outlined in Scheme . Initially, an efficient one-pot synthesis of N -(3-aminoisoxazol-5-yl)acetamide ( 13 ) from malononitrile under mild conditions was described. , Important intermediates N -(3-(2-acetamido-2-oxoethyl)-1,2,4-thiadiazol-5-yl)benzamide ( 15b) were prepared from compound 13 and benzoyl isothiocyanate through the skeletal rearrangement of thiourea intermediate 14 with good yield and purity. ,, The target compound 2 was formed and isolated as a white solid, and a purity of 98.5% was obtained by HPLC analysis after being recrystallized with ethanol. In this new procedure, up to 19% overall isolated yield was achieved from malononitrile …”

Patent Review of Manufacturing Routes to Fifth-Generation Cephalosporin Drugs. Part 1, Ceftolozane

“…The synthesis of the thiadiazolyl-oximinoacetic acid side chain is not described in the Medicinal Chemistry patents nor publication, but similar type compounds were published in a 1993 European patent application (Scheme ). The disadvantages of this route include the length (eight linear steps), relatively low overall yield of 12%, and the high temperature (>200 °C) required to convert the trimethoxy nitrile 25 to the vinyl nitrile 26 .…”

Total synthesis and development of bioactive natural products

“…We devised a novel and concise preparation directed toward the mass production of the ( Z )-methoxyimino compound: ( Z )-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid ( 88 ) based on the skeletal rearrangement of the aminoisoxazoles 81 or 84 , and stereoselective formation of 88 (Scheme 8 ). 33 ) 3-Amino-5-methoxyisoxazole ( 81 ) was subjected to the skeletal rearrangement in question. A suspension of methyl chloroformate and KSCN in acetonitrile was stirred at 70°C for 30 min to give methoxycarbonyl isothiocyanate in situ , which in turn reacted with 81 to afford methyl 2-(5-methoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetate ( 83 ) in 86% yield, through skeletal rearrangement of the intermediary thiourea derivative 82 .…”