摘要
艾沙康唑为新型氮唑类抗真菌药,具有较高的药效和较低的副作用。以价廉的(R)-乳酸甲酯为原料,先用大孔磺酸型树脂D001在室温和无溶剂的条件下催化二氢吡喃保护(R)-乳酸甲酯上的羟基,接着在甲醇钠催化下用吗啡啉对其进行胺解,然后再通过格氏反应合成了艾沙康唑的前体原料。为降低反应能耗,提高反应的产率,比较了羟基保护和胺解先后顺序对反应产率的影响,优化了羟基保护的反应条件,探讨了引发剂和助剂对格氏反应的影响。研究表明,乳酸甲酯和二氢吡喃物质的量之比为1∶1.05,D001的用量为0.5 g/7.8 g乳酸甲酯,室温下反应1 h后直接滤除树脂,再用0.1 mol的甲醇钠和1.1 mol吗啉室温下胺解2 h,两步反应产率高达88.2%;以LiCl为助剂,碘和异丙基溴协同引发的第3步格氏反应产率高达86.2%。优化后的反应具有更高的经济效益和实际的工业应用价值。
Esaconazole is a new type of azolium antifungal drug with higher efficacy and lower side effects.Using(R)-methyl lactate as raw material,the hydropyrane-protected hydroxyl group on(R)-methyl lactate was catalyzed by macroporous sulfonic acid resin D001 at room temperature and solvent-free,and then aminated with morpholine under the catalysis of sodium methoxide,afterwards the precursor of Esaxconazole was synthesized by Grignoll reaction.The effects of hydroxyl protection and aminolysis sequence on the reaction yield were compared,the reaction conditions of hydroxyl protection were optimized,and the effects of initiator and auxiliaries on Grignard reaction were discussed.The energy consumption of the reaction was reduced and the yield of the reaction was increased.The results showed that the ratio of methyl lactate to dihydropyran was 1∶1.05,the dosage of D001 was 0.5 g/7.8 g methyl lactate,the resin was directly filtered after reaction at room temperature for 1 h,and then aminated with 0.1 mol sodium methoxide and 1.1 mol morpholine at room temperature for 2 h.The two-step reaction yield was as high as 88.2%.With LiCl as auxiliary agent,the yield of the third step reaction induced by iodine and isopropyl bromide was over 86.2%.So the optimized reaction had higher economic benefit and practical industrial application value.
作者
吕新宇
张芬芬
蒋卫华
L Xinyu;ZHANG Fenfen;JIANG Weihua(School of Petrochemical Engineering,Changzhou University,Changzhou 213164,China)
出处
《应用化工》
北大核心
2025年第11期2889-2893,2898,共6页
Applied Chemical Industry
基金
常熟市科技发展计划项目(ST202203)。
