问题：求头孢克洛化学合成方法
类型：求助 (悬赏分:3分)
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版块：化工工艺设计(wanghong,)
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时间：2006-02-21 10:52:52 编辑加入/取消收藏订制/取消短消息举报该贴

各位老师,近期刚刚接触药物合成,急需头孢克洛的合成方法及工艺资料.
我打算从7-acca经一步合成，请帮我一下。谢谢

回复人：tangyyer,★★★★★ (有空来逛逛my blog: http://tangyyer.blog.hexun.com) 时间：2006-02-21 12:06:52 编辑

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见专利DE 2408698; ES 423531; FR 2218877; GB 1461323; JP 49110689; JP 56138190；J Med Chem 1975, 18 (4): 403-8。具体的合成是：
The ozonolysis of p-nitrobenzyl ester of 7-amino-3-methylenecephem-4-carboxylic acid (I) in CH2Cl2 gives the p-nitrobenzyl ester of 7-amino-3-hydroxy-3-cephem-4-carboxylic acid (II), which is then condensed with thiophene-2-acetyl chloride (A) in aqueous THF to afford p-nitrobenzyl ester of 7-(thiophene-2-acetamido)-3-hydroxy-3-cephem-4-carboxylic acid (III). The chlorination of (III) with SOCl2, PCl3, POCl3, (COCl)2 or COCl2 in DMF yields p-nitrobenzyl ester of 7-(thiophene-2-acetamido)-3-chloro-3-cephem-4-carboxylic acid (IV), which is then partially hydrolized with dry pyridine and PCl5 giving p-nitrobenzyl ester of 7-amino-3-chloro-3-cephem-4-carboxylic acid (V). This compound can be acylated easily to p-nitrobenzyl ester of 7-(D-alpha-phenylglycylamido)-3-chloro-3-cephem-4-carboxylic acid (VI), which is finally hydrogenolyzed with Zn and conc. HCl (1).

An alternative way starting also from (V) is its hydrogenolysis with H2 over Pd/C in THF-MeOH giving the 7-amino-3-chloro-3-cephem-4-carboxylic acid (VII), which is then acylated as usual (2).

Manufacturer
Eli Lilly and Co.

References

1. Chauvette, R.R. and Pennington, P.A.; Chemistry of cephalosporin antibiotics. 30. 3-Methoxy- and 3-halo-3-cephems; J Med Chem 1975, 18(4), 403-408

2. Chauvette, R.R. (Lilly, Eli and Co.); DE 2408698

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