富马酸卢帕他定的合成

Synthesis of Rupatadine Fumarate

以烟酸乙酯(4)和间氯苯乙腈(5)为原料,经克莱森缩合、酸水解脱羧反应,得2-(3-氯苯基)-1-(吡啶-3-基)-1-乙酮(6)。6与水合肼经黄鸣龙还原反应,得3-(3-氯苯乙基)吡啶(7),7在钨酸钠催化下经过氧化氢氧化后,再经Reissert-Henze吡啶氰基化反应,得3-(3-氯苯乙基)-2-氰基吡啶(8),水解后闭环得8-氯-10,11-二氢-4-氮杂-5H-二苯并[a,d]-5-环庚酮(3),再与1-[(5-甲基吡啶-3-基)甲基]-4-哌啶酮(12)经McMurry偶联反应,并与富马酸成盐,得到富马酸卢帕他定(1),总收率28.0%(以4计),纯度99.7%。该路线避免格氏试剂的使用,且环合反应使用“一锅法”,操作方便,适合工业化生产。

Starting with ethyl nicotinate(4)and 3-chlorobenzyl cyanide(5)as raw materials,through the Claisen condensation,acid hydrolysis and decarboxylation,2-(3-chlorophenyl)-1-(pyridin-3-yl)-1-ethanone(6)was obtained.Compound 3-(3-chlorophenethyl)pyridine(7)was generated by Huang Minglong reduction with hydrazine hydrate.After sodium tungstate catalysis and subsequent oxidation with hydrogen peroxide,followed by the Reissert-Henze pyridine cyanation reaction,3-(3-chlorophenethyl)-2-cyanopyridine(8)was obtained.After hydrolysis and ring closure,8-chloro-10,11-dihydro-4-aza-5H-dibenzo[a,d]cyclohept-5-one(3)was obtained.Then compound 3 reacted with 1-[(5-methylpyridin-3-yl)methyl]-4-piperidone(12)by McMurry coupling reaction and salted with fumaric acid,resulting in rupatadine fumarate(1).The overall yield was 28.0%(based on 4),with a purity of 99.7%.This synthetic route avoids the use of Grignard reagents.Additionally,the cyclization employs a one-pot"method,providing convenient operation and suitability for industrial production.