泊沙康唑关键中间体的合成工艺研究

Study on the Synthesis of Key Intermediate of Posaconazol

N′-(2S,3S)-2-(苄氧基)-3-戊基甲酰肼(1)为制备泊沙康唑的关键中间体。对化合物1的合成工艺进行了改进和优化。以L-乳酸为起始原料,与氯苄发生取代反应制得L-苄氧基丙酸,L-苄氧基丙酸与N-甲基-N-甲氧基亚磷酰胺(4)在微波催化下发生酰胺化反应,制得(S)-2-苄氧基-N-甲基-N-氧甲基丙酰胺(5),化合物5再与LiAlH_(4)发生还原反应,制得(S)-2苄氧基丙醛(6)。甲酸乙酯与水合肼反应制得甲酰肼后直接与化合物6发生成腙反应,制得(E,S)-N′-(2-(苄氧基)亚丙基)甲酰肼(7),化合物7再与乙基溴化镁发生格氏反应,即制得化合物1。对影响收率的微波功率、反应温度、反应时间、还原剂的量等因素进行了考察,结果表明在优化条件下总收率达到36.3%,产品纯度达到98.4%,ee值99.1%。化合物1及中间体的结构通过IR,^(1)H NMR和ESI-MS进行了确证。该工艺原料价廉,操作简单,反应条件温和,收率较高,适合工业化生产。

L-benzyloxy propionic acid was prepared from L-lactic acid by substitution reaction with chlorobenzyl.Then it was amidated with N-methyl-N-methoxyphosphoramidite(4) under microwave catalysis to prepare(S)-2-benzyloxy-N-methyl-N-methoxypropanamide(5).Compound 5 was reduced with LiAlH_(4) to prepare(S)-2-benzyloxypropionaldehyde(6).After ethyl formate reacted with hydrazine hydrate to produce formyl hydrazide,it directly reacted with compound 6 to produce(E,S)-N′-(2-(benzyloxy)propylidene)formylhydrazine(7).Compound 7 reacted with ethyl magnesium bromide to produce N′-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine(1).The factors affecting the yield such as microwave power,reaction temperature,reaction time and the amount of reducing agent were investigated.Under the optimized conditions,the total yield was 36.3%,the purity of the product was 98.4% and the ee value was 99.1%.The structures of compound 1 and its intermediates were confirmed by IR,^(1)H NMR and ESI-MS.The process has the advantages of cheap raw materials,simple operation,mild reaction conditions and high yield,which is suitable for industrial production.