大麻二酚的合成工艺优化

Improved Synthetic Process of Cannabidiol

用3-壬烯-2-酮(2)与丙二酸二乙酯(3)经Michael加成、羟醛缩合反应生成3-氧代-4-(乙氧羰基)-5-戊基-1-环己烯-1-醇钠(4),4经溴代制得2,4-二羟基-3,5-二溴-6-戊基苯甲酸乙酯(5)。5再经催化氢化生成2,4-二羟基-6-戊基苯甲酸乙酯(6),采用Zn(OTf)_(2)作为路易斯酸,6与(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇(7)经亲电取代反应生成2,4-二羟基-3-[(1R,6R)-3-甲基-6-(1-甲基乙烯基)-2-环己烯-1-基]-6-戊基苯甲酸乙酯(8),8经乙二醇/KOH回流脱羧制得大麻二酚(1)粗品,柱色谱纯化后用8%乙醇重结晶得1。优化后的工艺操作简便,1纯度可达99.5%,总收率为26.7%。

In this report,the synthetic process of cannabidiol(1)was improved.Sodium 3-oxo-4-(ethoxycarbonyl)-5-pentylcyclohex-1-en-1-olate(4)was prepared from non-3-en-2-one(2)and diethyl malonate(3)by Michael addition reaction and aldol condensation reaction.Then,the compound 4 was brominated to give ethyl 2,4-dihydroxy-3,5-dibromo-6-pentylbenzoate(5).Next,ethyl 2,4-dihydroxy-6-pentylbenzoate(6)was prepared by catalytic hydrogenation of 5.Then,the electrophilic substitution reaction of compound 6 with(1S,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol(7)gave ethyl 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-6-pentylbenzoate(8).Crude 1 was obtained by decarboxylation of compound 8 in ethylene glycol/KOH under reflux conditions.The final product was obtained by purification with column chromatograply and recrystallization in 8%ethanol.This improved process was easy to operate with an overall yield of 26.7%and purity of 99.5%,which was suitable for industrial production.