Synthesis of 6-methylthiopenicillins and 7-heteroatom-substituted cephalosporins.
Synthesis of 6-methylthiopenicillins and 7-heteroatom-substituted cephalosporins.
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6-甲基硫代青霉素和7-杂原子取代的头孢菌素的合成。
DOI：
10.1021/jo00945a023
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发表时间：
1973
期刊：
影响因子：
--
通讯作者：
J. E. Dolfini
中科院分区：
文献类型：
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作者：
W. Slusarchyk;H. Applegate;P. Funke;W. Koster;M. Puar;M. Young;J. E. Dolfini
以6-氨基青霉素酸酯和7-氨基头孢菌酸酯的希夫碱甲基硫代化得到的中间体为原料，制备了多种6- A -甲基硫代青霉素和7-甲基硫代头孢菌素。用高氯氟氟化得到7a-氟头孢菌素席夫碱，该碱可溶解为7a-甲氧基和7a-甲基硫代头孢菌素中间体。乙酸汞催化7′-甲基硫代席夫碱的甲醇解可得到相同的7′-甲氧基头孢菌素席夫碱中间体。7a-甲基硫代头孢菌素与醋酸汞在甲醇中反应得到7a-和7/3-甲氧基头孢菌素的混合物，从中得到纯7/3-甲氧基外聚体。可能是孤立的。用二甲氧基乙烷或乙酸代替甲醇进行同样的反应，制得7-乙酰氧基头孢菌素。对7-取代的头孢菌素进行了核Overhauser研究，得到了C-7的构型分配，这得到了7a-甲基硫-7-苯基乙酰氨基脱乙酰氧基头孢菌酸二丁基酯单晶x射线分析的支持。先前的研究表明，在头孢菌素中引入7-甲基和在青霉素中引入6a-甲基都不能提高抗菌活性。当7 (6)-ce-甲基取代基被乙酰基取代时，也有类似的结果。作为具有C-7(6)位取代基的头孢菌素和青霉素类生物研究的一部分，我们检查除乙酰基以外的吸电子取代基的影响似乎是合理的。杂原子substit -
A number of 6a-methylthiopenicilIins and 7-methylthiocephalosporins have been prepared from intermediates obtained by methylthiolation of Schiff bases of 6-aminopenicillanic acid esters and 7-aminocephalosporanic acid esters. Fluorination with perchloryl fluoride gave a 7a-fluorocephalosporin Schiff base that could be solvolyzed to 7a-methoxy-and 7a-methylthiocephalosporin intermediates. The same 7-methoxycephalosporin Schiff base intermediate could be obtained by mercuric acetate catalyzed methanolysis of the corresponding 7 «-methyl-thio Schiff base. Reaction of a 7a-methylthiocephalosporin with mercuric acetate in methanol gave a mixture of 7a-and 7/3-methoxycephalosporins from which pure 7/3-methoxy epimer. could be isolated. The same reac-tion with methanol replaced by dimethoxyethane or acetic acid yielded a 7-acetoxycephalosporin. Nuclear Overhauser studies performed on the 7-substituted cephalosporins led to assignments of configuration at C-7, which were supported by single-crystal X-ray analysis of 7a-methylthio-7-phenylacetamidodeacetoxycephalosporanic acid ieri-butyl ester., Previous investigations have shown that neither the introduction of a 7-methyl group into a cephalosporin nor of a 6a-methyl group into a penicillin results in improved antimicrobial activity. 1· 2 Similar results were found when the 7 (6)-ce-methyl substituents were replaced by-acetyl groups. 3 As part ofthe biological study of cephalosporins and penicillins possessing sub-stituents at the C-7 (6) position, it seemed reasonable for us to examine the effects ofelectron-withdrawing substituents other than acetyl. Heteroatom substit-