Cepharanthine

合成路线:The condensation of 3,4-methylenedioxy-5-[2-methoxy-4-(N-carbobenzoxyaminoethyl)phenoxy]phenylethylamine (I) with 4-[2-methoxy-5-(methoxycarbonylmethyl)phenoxyphenylacetic acid (II) by means of dicyclohexylcarbodiimide in methylene chloride gives the amide (III),which is hydrolyzed with aqueous Na2CO3 to the corresponding free acid (IV).The cyclization of (IV) by the p-nitrophenyl ester method yields the cyclobisamide (V),which by a Bischler-Napieralski reaction with POCl3 in chloroform is converted into the bis(3,4-dihydroisoquinoline) (VI).The hydrogenation of (VI) with H2 over Pt affords the bis(tetrahydroisoquinoline) derivative (VII),which without isolation is finally methylated with formalin and NaBH4.

合成路线:The starting phenylethylamine (I) is prepared by condensation of N-formyl-5-bromo-3,4-methylenedioxyphenylethylamine (VIII) with N-carbobenzoxy-3-methoxy-4-hydroxyphenylethylamine (IX) through an Ullman condensation catalysed by CuO,followed by elimination of the formyl group with HCl in methanol.Compound (VIII) is prepared as follows: 3,4-dihydroxy-5-bromobenzaldehyde (X) is methylenated with methylene bromide (A) and CuO in DMF giving 3,4-methylenedioxy-5-bromobenzaldehyde (XI),which is condensed with nitromethane (B) in acetic acid containing ammonium acetate affording 3,4-methylenedioxy-5-bromo-beta-nitrostyrene (XII).The reduction of (XII) under Clemensen conditions yields 3,4-methylenedioxy-5-bromophenylethylamine (XIII),which is finally formylated with formic acid in decalin.Compound (IX) is prepared as follows: 3-methoxy-4-hydroxy-beta-nitrostyrene (XIV) is treated with ethyl chloroformate (C) in pyridine yielding the corresponding ethoxycarbonyl derivative (XV),which is reduced under Clemensen conditions to 3-methoxy-4-ethoxycarbonyloxyphenylethylamine (XVI).Finally,this compound is treated first with benzyloxycarbonyl chloride and then with aqueous NaHCO3.

合成路线:The starting phenylacetic acid (II) is prepared by an Ullman condensation between tert-butyl-4-hydroxyphenylacetate (XVII) and methyl 3-bromo-4-methoxyphenylacetate (XVIII) catalysed by CuO,followed by treatment with p-toluenesulfonic acid in benzene.Compound (XVII) is prepared by esterification of 4-benzyloxyphenylacetic acid (XIX) to the corresponding tart butyl ester (XX),followed by hydrogenolysis with H2 over Pd/C.Compound (XVIII) is prepared by methylation of methyl 3-bromo-4-hydroxyphenylacetate (XXI) with dimethyl sulfate and K2CO3 in DMF.

参考文献标题:Synthesis of di-cepharanthine
文献作者:Tomita,M.; et al.
参考来源:Tetrahedron Lett 1967,1201-06


合成路线:The condensation of 3,4-methylenedioxy-5-[2-methoxy-4-(N-carbobenzoxyaminoethyl)phenoxy]phenylethylamine (I) with 4-[2-methoxy-5-(methoxycarbonylmethyl)phenoxyphenylacetic acid (II) by means of dicyclohexylcarbodiimide in methylene chloride gives the amide (III),which is hydrolyzed with aqueous Na2CO3 to the corresponding free acid (IV).The cyclization of (IV) by the p-nitrophenyl ester method yields the cyclobisamide (V),which by a Bischler-Napieralski reaction with POCl3 in chloroform is converted into the bis(3,4-dihydroisoquinoline) (VI).The hydrogenation of (VI) with H2 over Pt affords the bis(tetrahydroisoquinoline) derivative (VII),which without isolation is finally methylated with formalin and NaBH4.

合成路线:The starting phenylethylamine (I) is prepared by condensation of N-formyl-5-bromo-3,4-methylenedioxyphenylethylamine (VIII) with N-carbobenzoxy-3-methoxy-4-hydroxyphenylethylamine (IX) through an Ullman condensation catalysed by CuO,followed by elimination of the formyl group with HCl in methanol.Compound (VIII) is prepared as follows: 3,4-dihydroxy-5-bromobenzaldehyde (X) is methylenated with methylene bromide (A) and CuO in DMF giving 3,4-methylenedioxy-5-bromobenzaldehyde (XI),which is condensed with nitromethane (B) in acetic acid containing ammonium acetate affording 3,4-methylenedioxy-5-bromo-beta-nitrostyrene (XII).The reduction of (XII) under Clemensen conditions yields 3,4-methylenedioxy-5-bromophenylethylamine (XIII),which is finally formylated with formic acid in decalin.Compound (IX) is prepared as follows: 3-methoxy-4-hydroxy-beta-nitrostyrene (XIV) is treated with ethyl chloroformate (C) in pyridine yielding the corresponding ethoxycarbonyl derivative (XV),which is reduced under Clemensen conditions to 3-methoxy-4-ethoxycarbonyloxyphenylethylamine (XVI).Finally,this compound is treated first with benzyloxycarbonyl chloride and then with aqueous NaHCO3.

合成路线:The starting phenylacetic acid (II) is prepared by an Ullman condensation between tert-butyl-4-hydroxyphenylacetate (XVII) and methyl 3-bromo-4-methoxyphenylacetate (XVIII) catalysed by CuO,followed by treatment with p-toluenesulfonic acid in benzene.Compound (XVII) is prepared by esterification of 4-benzyloxyphenylacetic acid (XIX) to the corresponding tart butyl ester (XX),followed by hydrogenolysis with H2 over Pd/C.Compound (XVIII) is prepared by methylation of methyl 3-bromo-4-hydroxyphenylacetate (XXI) with dimethyl sulfate and K2CO3 in DMF.
参考文献标题:Cepharanthine
文献作者:Serradell,M.N.; Blancafort,P.; Mealy,N.; Casta馿r,J.
参考来源:Drugs Fut 1979,4(7),481