合成路线1

Synthesis of curcumin was first described by Lampe et al. In our laboratory curcumin has been synthesized by condensing vanillin (I) and acetyl acetone (II) in a medium of ethyl acetate using tributylborate as boron complex to avoid Knoevenagel condensation at C-3 of acetyl acetone. Curcumin is isolated from the reaction mixture by acidification and extraction with ethyl acetate. The organic layers are washed until neutral, dried and the solvent is removed. purified by chromatography over silica gel using ether/petroleum ether as the solvent.

合成路线2

The protection of 4-bromo-2-methoxyphenol (I) with ethyl vinyl ether (II) and TsOH in dichloromethane gives the ethoxyethyl ether (III), which is treated with n-BuLi in THF to yield the phenyl lithium compound (IV). The reaction of (IV) with 2H-labeled DMF (V), followed by hydrolysis with HCl, affords the labeled 4-hydroxy-3-methoxybenzaldehyde (VI), which is finally condensed with pentane-2,4-dione (VII) by means of B2O3 and tetrahydroquinoline in DMF.

合成路线3

The protection of 4-bromo-2-methoxyphenol (I) with ethyl vinyl ether (II) and TsOH in dichloromethane gives the ethoxyethyl ether (III), which is treated with n-BuLi in THF to yield the phenyl lithium compound (IV). The reaction of (IV) with 14C-labeled DMF (V), followed by hydrolysis with HCl, affords the labeled 4-hydroxy-3-methoxybenzaldehyde (VI), which is finally condensed with pentane-2,4-dione (VII) by means of B2O3 and tetrahydroquinoline in DMF.

合成路线4

TMK 688 is derived trom the condensation ot 5-(3'-methoxy-4'-hydroxyphenyl)-2,4-pentadienoic acid (IV) and N-aminoethyl 4-diphenylmethoxypiperidine (X) in the presence of ethyl chloroformate in dichloromethane. Synthesis of intermediate (IV): Vanillin (I) is protected with ethyl chloroformate to give (II), which is then treated with triethyl 4-phosphonocrotonate and followed by alkali hydrolysis to produce (IV).

合成路线5

The condensation of 4-hydroxy-3-methoxybenzaldehyde (I) with ethyl cyanoacetate (II) by means of NaOH in ethanol gives the 2-cyanopropenoate (III), which is then alkylated at the OH group with ethyl 2-bromoacetate (IV) by means of K2CO3 and tetrabutylammonium bromide in THF.

合成路线6

Protection of vanillin (I) as the benzyl ether (II), followed by reaction with benzylmagnesium bromide, furnished alcohol (III). Oxidation of alcohol (III) to the corresponding ketone (IV) was achieved by means of chromium trioxide or, in an improved procedure, by Oppenauer oxidation with cyclohexanone and sodium tert-butoxide. Benzyl group cleavage in (IV) either with HBr, or by transfer hydrogenolysis, yielded phenol (V). Regioselective nitration of (V) gave the ortho-nitrophenol (VI). The title compound was finally obtained by methyl ether cleavage in (VI) with boiling HBr or with AlCl3 in pyridine.

合成路线7

The condensation of vanillin (I) with epichlorohydrin (II) in ethanolic NaOH produced the glycidyl ether (III). Epoxide ring opening in (III) by means of tert-butylamine (IV) in EtOH furnished amino alcohol (V). The title dihydropyridine derivative was then obtained by reaction between aldehyde (V), methyl acetoacetate (VI), ammonia under Hantzsch condensation conditions, and was isolated after conversion to the hydrochloride salt.

合成路线8

Vanillin (I) was protected as the tetrahydropyranyl ether (II) by treatment with dihydropyran in the presence of pyridinium p-toluenesulfonate. Similarly, hydroxyacetone (III) was converted to the corresponding tetrahydropyranyl ether (IV). Aldol condensation between aldehyde (II) and ketone (IV) using LDA in cold THF furnished the hydroxy ketone (V). Removal of the tetrahydropyranyl protecting groups of (V) under acidic conditions caused the dehydration of the beta-hydroxyl group, affording the unsaturated ketone (VI). The phenolic hydroxyl group of (VI) was then protected as the trimethylsilyl ether (VII). After protection of the phenolic hydroxyl group of ferulic acid (VIII) as the silyl ether (IX), coupling between (IX) and (VII) by means of DCC and DMAP provided the silyl-protected ester (X). This was finally desilylated by treatment with HOAc in aqueous THF.

合成路线9

The condensation of vanillin (VII) with epichlorohydrin (VIII) in ethanolic NaOH produced the glycidyl ether (IX). Epoxide ring opening in (IX) by means of amine (VI) in EtOH furnished amino alcohol (X). The title dihydropyridine derivative was then obtained by reaction between aldehyde (X), methyl acetoacetate (XI), and ammonia under Hantzsch condensation conditions.

合成路线10