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在降压药物研究中,血管紧张素转化酶(ACE)抑制剂是进展最快的一类药物。Spirapril是不含巯基的ACE抑制剂enalapril衍生物。合成本品有二条合成路线: 1)在回流的乙酸中用对-甲苯磺酸,使1-苄氧碳酰基-4-氧脯氨酸甲酯(Ⅰ)与乙二硫醇(Ⅱ)环化生成7-苄氧碳酰基-1,4-二硫杂-7-氮杂螺[4,4]壬烷-8-羧酸甲酯(Ⅲ),Ⅲ与20%氢滇酸脱去保护基团,得1,4-二硫杂-7-氮杂螺[4,4]壬烷-8-羧酸甲酯(Ⅳ)。Ⅳ与N-苄氧碳酰基丙氨酸N-羟基琥珀酰亚胺酯(Ⅴ)缩合成相应的二肽甲酯(Ⅵ),Ⅵ由氢氧化钠水解成游离酸(Ⅶ),Ⅶ与20%氢溴酸脱去保护基团,得7-丙氨酰-1,4-二硫杂-
In the study of antihypertensive drugs, angiotensin-converting enzyme (ACE) inhibitors are among the most rapidly evolving classes of drugs. Spirapril is a thiol-free ACE inhibitor enalapril derivative. Synthesis of the product has two synthetic routes: 1) the reflux of acetic acid with p-toluenesulfonic acid, 1-benzyloxycarbonyl-4-oxoproline methyl ester (Ⅰ) and ethanedithiol (Ⅱ) ring Methyl 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro [4,4] nonane-8-carboxylate (III) was deprotected with 20% , To give methyl 1,4-dithia-7-azaspiro [4,4] nonane-8-carboxylate (IV). IV is condensed with the N-hydroxysuccinimide ester (V) of N-benzyloxycarbonylalanine to the corresponding dipeptide methyl ester (VI), and VI is hydrolyzed from sodium hydroxide to the free acid (VII), VII and 20 Deprotection of the hydrobromic acid gave 7-alanyl-1,4-dithia-