合成路线1

The alkylation of isovanillin (I) with cyclopentyl bromide (II) and K2CO3 in DMF gives 3-(cyclopentyloxy)-4-methoxybenzaldehyde (III), which is methylated with MeLi in THF yielding the 1-phenylethanol (IV). The oxidation of (IV) with pyridinium dichromate (PDC) in dichloromethane affords the corresponding acetophenone (V), which is treated with NH2OH in pyridine to afford the oxime (VI). Finally, this oxime is treated with NaOCN and TFA in dichloromethane, or with chlorosulfonyl isocyanate in THF.

合成路线2

The alkylation of isovanillin (I) with cyclopentyl bromide (II) by means of K2CO3 in refluxing ethanol (or hot DMF) gives the 4-cyclopentyloxy-3-methoxybenzaldehyde (III), which is oxidized with H2O2 and NaOH (or NaClO2 in AcOH/water) yielding the carboxylic acid (IV). The reaction of (IV) with SOCl2 and DMF in refluxing toluene affords the acyl chloride (V), which is finally condensed with 3,5-dichloropyridine-4-amine (VI) by means of potassium tert-butoxide in toluene or NaH in THF or by heating at the melting point. The intermediate 3,5-dichloropyridine-4-amine (VI) is obtained by chlorination of pyridine-4-amine (VII) with HCl and H2O2 at 70 C.

合成路线3

Isovanillin (I) was alkylated with phenethyl bromide (II) in the presence of K2CO3 to afford phenethyl ether (III). The aldehyde function of (III) was then reduced with NaBH4, and the resulting alcohol (IV) was converted to chloride (V) by means of SOCl2 in THF-DMF. Subsequent displacement of the chlorine atom of (V) by KCN afforded nitrile (VI), which was hydrolyzed to acid (VII) with KOH in aqueous EtOH. Further conversion of (VII) to acid chloride (VIII), followed by condensation with dipropyl amine (IX) in toluene provided amide (X). Finally, reduction with LiAlH4 gave the corresponding amine, that was isolated as the hydrochloride salt.

合成路线4

Isovanillin (I) is an available starting material to obtain 3-cyclopentyloxy-4-methoxybenzaldehyde (II), which is converted into the corresponding oxime (III) by treatment with hydroxylamine hydrochloride / sodium acetate trihydrate and NaHCO3. The oxime (III) is reduced to benzylamine (IV) by means hydrogen gas and catalyzed by Raney-Nickel. The reaction of benzylamine (IV) with carbon disulfide and ethyl chloroformate gives the corresponding benzyl isothiocyanate (V), which is converted into thiourea (VI) by means ammonia solution. The cyclization of thiourea (VI) with potasium tert-butoxide and ethyl cyanoacetate yields the corresponding 2-thiouracil (VII), which is converted into 5-nitroso derivative (VIII) by treatment with acetic acid and sodium nitrite solution. The hydrogenation of 5-nitroso-uracil (VIII) with hydrogen gas and neutral Raney-nickel gives diaminouracil compound (IX), which is converted into the isobutyrilaminouracil derivative (XI) by means NaHCO3 and isobutyric anhydride (X). Compound (XI) is refluxed in NaOH to afford 2-thioxantine (XII), which is converted into 2,6-dithioxantine (XIII) by means phosphorus pentasulfide in pyridine. Finally, the reaction of compound (XIII) with ethylamine gives the 2-thioisoguanine (XIV), which is desulfurized by neutral Raney-Nickel and converted into the desired purine hydrochloride by means hydrochloric acid.

合成路线5

The reaction of isovanillin with hydroxylamine sulfate and NaOH in refluxing ethanol/water gives the corresponding oxime (II), which is reduced with Raney-Ni and NaOH in the same solvent yielding the benzylamine (III). The protection of the amino group of (III) with benzyloxycarbonyl chloride affords the carbamate (IV), which is condensed with ethyl bromoacetate (IV) by means of K2CO3 in refluxing 2-butanone to give the ester (VI). The hydrolysis of (VI) with NaOH in hot methanol/water yields the corresponding acid (VII), which is condensed with 1-benzylpiperazine (VIII) by means of ethyl chloroformate in THF to afford the piperazide (IX). The deprotection of the amino group of (IX) with H2 over Pd/C in hot ethanol gives the benzylamine (X), which is finally condensed with 4,5-dichloropyridazin-3(2H)-one (XI) by means of triethylamine in refluxing ethanol/water.

合成路线6

In a different synthetic strategy, the required dibromostyrene (XIV) was prepared in low yield by Wittig-like condensation of 3-hydroxy-4-methoxybenzaldehyde (XII) with carbon tetrabromide in the presence of PPh-3. In an improved process, the phenolic hydroxyl of (XII) was first protected as the silyl ether (X), which was then condensed with CBr4/PPh3 to give (XIII). Subsequent desilylation of (XIII) with tetrabutylammonium fluoride provided (XIV). Stereoselective debromination of the dibromostyrene (XIV) with tributyltin hydride and tetrakis(triphenylphosphine)palladium(0) led to the Z-bromostyrene (XV). This was finally subjected to a palladium-catalyzed Suzuki coupling with 3,4,5-trimethoxybenzeneboronic acid (XVI) to furnish the title Z-olefin as the major isomer

合成路线7

A further synthetic strategy was based on the Perkin condensation between 3,4,5-trimethoxyphenylacetic acid (XVII) and 3-hydroxy-4-methoxybenzaldehyde (XII). Decarboxylation of the resultant phenylcinnamic acid (XVIII) by heating with copper powder in quinoline furnished the desired stilbene, accompanied by only minor amounts of the corresponding E-isomer

合成路线8

Addition of ethylmagnesium bromide to 3,4,5-trimethoxybenzaldehyde (I) gave secondary alcohol (II), which was converted into ketone (III) by Swern oxidation with DMSO and oxalyl chloride. Piperidinium acetate-catalyzed aldol condensation of propiophenone (III) with 3-hydroxy-4-methoxybenzaldehyde (IV), with water removal over 4 Å molecular sieves, gave the corresponding chalcone, obtained as a mixture of geometric isomers, from which the major E-isomer was separated by column chromatography.

合成路线9

Coupling of isovanillin (I) with 3-hydroxytetrahyrofuran (II) in the presence of triphenyl phosphine and diisopropyl azodicarboxylate yielded the tetrahydrofuryl ether (III). Subsequent oxidation of the aldehyde using sodium chlorite and sulfamic acid gave carboxylic acid (IV), which was further converted to acid chloride (V) upon treatment with SOCl2 in toluene. Finally, condensation of (V) with 4-amino-3,5-dimethylisoxazole (VI) provided the title compound.

合成路线10

Isovanillin (I) was protected as the silyl ether (II) and subsequently reduced to the benzyl alcohol (III). After conversion of (III) to bromide (IV), its reaction with triphenylphosphine gave phosphonium bromide (V). The ylide resulting from deprotonation of (V) with n-butyllithium was then condensed with 3,4,5-trimethoxybenzaldehyde (VI) to afford the required E-stilbene (VII) along with the corresponding Z-isomer, which were separated by column chromatography. Asymmetric Sharpless dihydroxylation of (VII) by means of AD mix-alpha provided the (1S,2S)-diol (VIII). Finally, desilylation of (VIII) using tetrabutylammonium fluoride afforded the target phenol.

合成路线11

3-Hydroxy-4-methoxy-2-nitrobenzaldehyde (II) was prepared by nitration of isovanillin (I) with fuming nitric acid in cold HOAc. Subsequent alkylation of the phenolic hydroxyl of (II) with n-pentyl bromide yielded the corresponding pentyl ether (III). The nitro group of (III) was then reduced to amine (IV) employing tin chloride in EtOH. Condensation of amino aldehyde (IV) with dimethyl malonate under Knoevenagel conditions furnished the quinolinone derivative (V). Saponification of the ester group of (V), followed by activation of the resultant carboxylic acid (VI) with SOCl2, gave rise to the acid chloride (VII). This was then coupled with 3,4-(methylenedioxy)benzylamine (VIII) to provide the target amide.

合成路线12

Isovanillin (I) was protected as the allyl ether (III) by treatment with allyl bromide (II) and K2CO3. Aldehyde reduction of (III) with NaBH4 gave alcohol (IV), which was converted to chloride (V) using SOCl2. Condensation of chloride (V) with the sodium salt of 3,4,5-trimethoxyphenol (VI) produced the corresponding ether (VII). Finally, deprotection of the allyl group of (VII) was achieved by treatment with Wilkinson’s catalyst and DABCO.

合成路线13

In an alternative procedure, isovanillin (XI) was protected by O-benzylation, giving (XII), and its aldehyde group was subsequently reduced to alcohol (XIII) with NaBH4. The benzylic alcohol (XIII) was chlorinated to (XIV), which was converted to nitrile (XV) by chloride displacement with tetraethylammonium cyanide. Nitrile (XV) was subjected to Claisen condensation with ethyl formate, yielding (XVI), followed by sulfonylation with benzenesulfonyl chloride to afford (XVII), which was cyclized to the amino thiophene (XVIII) by treatment with ethyl thioglycolate (IV) as above. Condensation of (XVIII) with 2,5-dimethoxytetrahydrofuran (VI) produced the corresponding pyrrole derivative (XIX). After conversion of the ester group of (XIX) to amide (XX) upon heating with pyrrolidine (VIII), its cyclization with POCl3 furnished the thienopyrrolizinone (XXI). The O-benzyl protecting group of (XXI) was finally cleaved by treatment with HBr in HOAc.

合成路线14

Alkylation of isovanillin (I) with 2-indanyl tosylate (II) produces the corresponding indanyl ether (III). Subsequent reduction of the aldehyde function of (III) with NaBH4 yields the benzylic alcohol (IV), which is converted to chloride (V) by treatment with SOCl2. Displacement of chloride (V) by KCN in hot DMF gives nitrile (VI). The phenylacetonitrile (VI) is then converted to the homologous phenylpropionitrile derivative (VII) by alkylation with iodomethane in the presence of LDA. Further cyano group reduction in (VII) by hydrogenation over Raney Ni provides amine (VIII). Condensation of amine (VIII) with diphenyl N-cyanocarbonimidate affords the N-cyano isourea (IX) which, after reaction with 2,2-dimethoxyethylamine (X), yields the cyano guanidine (XI). Finally, cyclization of (XI) under acidic conditions gives rise to the target 2-(cyanoimino)imidazole derivative.

合成路线15

In a related strategy, the precursor di-tert-butyl combretastatin A-4 phosphate (Va) is prepared by protection of isovanillin (XI) as the corresponding imine (XII) with butylamine and p-toluenesulfonic acid, followed by phosphitylation with di-tert-butyl N,N-diethylphosphoramidite in the presence of tetrazole, and oxidation to phosphate (XIII) with m-chloroperbenzoic acid. Subsequent Wittig reaction of aldehyde (XIII) with 3,4,5-trimethoxybenzyl triphenylphosphonium bromide (VIII) produces the target stilbene phosphate derivative (Va) (6). Scheme 3.

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