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【结 构 式】 
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【分子编号】12620 【品名】o-Vanillin; 2-Hydroxy-3-methoxybenzaldehyde 【CA登记号】148-53-8 |
【 分 子 式 】C8H8O3 【 分 子 量 】152.14972 【元素组成】C 63.15% H 5.3% O 31.55% |
合成路线1
该中间体在本合成路线中的序号：(I)The demethylation ot o-vanillin (I) with AlCl3 dissolved in pyridine gives 2,3 dihydroxybenzaldehyde (II). Subsequent alkylation by means of hexyl bromide with NaH gives 3-hexyloxy-2-hydroxybenzaldehyde (III), which is then condensed with malononitrile and piperidine, yielding 3-cyano-8-hexyloxycromen-2-one (IV), a needle-like yellow crystalline substance. Finally, compound (IV) is treated with sodium azide and AlCl3 in refluxing THF, yielding the formation of the tetrazole ring.
| 【1】 Tasaka, K.; KP-136. Drugs Fut 1988, 13, 10, 915. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 | |
| 11108 | n-Hexyl bromide; 1-Bromohexane | 111-25-1 | C6H13Br | 详情 | 详情 | |
| (I) | 12620 | o-Vanillin; 2-Hydroxy-3-methoxybenzaldehyde | 148-53-8 | C8H8O3 | 详情 | 详情 |
| (II) | 12380 | 2,3-Dihydroxybenzaldehyde | 24677-78-9 | C7H6O3 | 详情 | 详情 |
| (III) | 23096 | 3-(hexyloxy)-2-hydroxybenzaldehyde | C13H18O3 | 详情 | 详情 | |
| (IV) | 23097 | 8-(hexyloxy)-2-oxo-2H-chromene-3-carbonitrile | C16H17NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIV)2) The esterification of 2-hydroxy-3-methoxybenzaldehyde (XXIV) with methanesulfonyl chloride and triethylamine gives the corresponding mesylate (XXV), which is nitrated with fuming HNO3 to 2-(methanesulfonyloxy)-3-methoxy-6-nitrobenzaldehyde (XXVI). The condensation of (XXVI) or 2-(benzenesulfonyloxy)-3-methoxy-6-nitrobenzaldehyde (XXVIII) with 2-(diethoxyphosphoryl)acetic acid methyl ester by means of NaH in THF yields 3-(2-hydroxy-3-methoxy-6-nitrophenyl)acrylic acid methyl ester (XXVII), which is benzylated with benzyl bromide and K2CO3 to the benzyl derivative (XXIX). The cyclization of (XXIX) with refluxing triethyl phosphite affords 4-benzyloxy-5-methoxy-1H-indole-2-carboxylic acid methyl ester (XXX), which is reduced to the corresponding carbaldehyde (XXXI) according to Tetrahedron Lett 1994, 50: 7657. The methylation of (XXXI) with NaH and methyl iodide in DMF yields the N-methyl derivative (XXXII), which is condensed with 2-(diethoxyphosphoryl)acetic acid methyl ester by means of NaH in THF to afford 3-(4-benzyloxy-5-methoxy-1-methylindol-2-yl)acrylic acid methyl ester (XXXIII). The formylation of (XXXIII) with POCl3 and DMF gives the 4-formyl derivative (XXXIV), which is debenzylated with trimethylsilyl iodide in acetonitrile to the 4-hydroxy compound (XXXV). The oxidation of (XXXV) with Fremy's salt as before yields 3-(3-formyl-5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole-2-yl) acrylic acid methyl ester (XXXVI), which is treated successively with Na2S2O4, DIBAL, and finally with FeCl3, as before, to afford the dihydroxy quinone (XXII), already obtained.
| 【1】 Cotterill, A.S.; Moody, C.J.; Roffey, J.R.; An improved synthesis of the indolequinone anticancer agent EO9. Tetrahedron 1995, 51, 26, 7223-30. |
| 【2】 Bailey, S.M.; Lohmeyer, M.; Dimbleby, R.; Castaner, J.; EO9. Drugs Fut 1996, 21, 2, 143. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 27698 | methyl 2-(diethoxyphosphoryl)acetate | 1067-74-9 | C7H15O5P | 详情 | 详情 | |
| (XXII) | 12618 | 3-(Hydroxymethyl)-2-[(E)-3-hydroxy-1-propenyl]-5-methoxy-1-methyl-1H-indole-4,7-dione | C14H15NO5 | 详情 | 详情 | |
| (XXIII) | 10151 | Ethyleneimine; Aziridine; Azirane | 151-56-4 | C2H5N | 详情 | 详情 |
| (XXIV) | 12620 | o-Vanillin; 2-Hydroxy-3-methoxybenzaldehyde | 148-53-8 | C8H8O3 | 详情 | 详情 |
| (XXV) | 12621 | 2-formyl-6-methoxyphenyl methanesulfonate | C9H10O5S | 详情 | 详情 | |
| (XXVI) | 12622 | 2-formyl-6-methoxy-3-nitrophenyl methanesulfonate | C9H9NO7S | 详情 | 详情 | |
| (XXVII) | 12623 | methyl (E)-3-(2-hydroxy-3-methoxy-6-nitrophenyl)-2-propenoate | C11H11NO6 | 详情 | 详情 | |
| (XXVIII) | 12624 | 2-formyl-6-methoxy-3-nitrophenyl benzenesulfonate | C14H11NO7S | 详情 | 详情 | |
| (XXIX) | 12625 | methyl (E)-3-[2-(benzyloxy)-3-methoxy-6-nitrophenyl]-2-propenoate | C18H17NO6 | 详情 | 详情 | |
| (XXX) | 12626 | methyl 4-(benzyloxy)-5-methoxy-1H-indole-2-carboxylate | C18H17NO4 | 详情 | 详情 | |
| (XXXI) | 12627 | 4-(Benzyloxy)-5-methoxy-1H-indole-2-carbaldehyde | C17H15NO3 | 详情 | 详情 | |
| (XXXII) | 12628 | 4-(Benzyloxy)-5-methoxy-1-methyl-1H-indole-2-carbaldehyde | C18H17NO3 | 详情 | 详情 | |
| (XXXIII) | 12629 | ethyl (E)-3-[4-(benzyloxy)-5-methoxy-1-methyl-1H-indol-2-yl]-2-propenoate | C22H23NO4 | 详情 | 详情 | |
| (XXXIV) | 12630 | ethyl (E)-3-[4-(benzyloxy)-3-formyl-5-methoxy-1-methyl-1H-indol-2-yl]-2-propenoate | C23H23NO5 | 详情 | 详情 | |
| (XXXV) | 12631 | ethyl (E)-3-(3-formyl-4-hydroxy-5-methoxy-1-methyl-1H-indol-2-yl)-2-propenoate | C16H17NO5 | 详情 | 详情 | |
| (XXXVI) | 12632 | ethyl (E)-3-(3-formyl-5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indol-2-yl)-2-propenoate | C16H15NO6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)In a different strategy, 3-methoxysalicylaldehyde (VII) was protected as the silyl ether (VIII) using t-butyldimethylsilyl chloride and Et3N. Wittig reaction of aldehyde (VIII) with (9-hydroxynonyl)triphenylphosphonium bromide (IX) afforded olefin (X). This was alternatively prepared by addition of Grignard reagent (XI) to the aldehyde (VIII) to give carbinol (XII), which was further subjected to dehydration and acetal hydrolysis under acidic conditions to afford (X). Catalytic hydrogenation of olefin (X) furnished the 10-aryl decanol (XIII). The heptadecenyl side chain of (XVI) was then constructed by Swern oxidation of alcohol (XIII) to the corresponding aldehyde (XIV), followed by Wittig reaction with heptyltriphenylphosphonium bromide (XV). Desilylation of (XVI) with tetrabutylammonium fluoride gave the phenol precursor (VI), which was finally oxidized to the desired quinone by the same method as above.
| 【1】 Wu, S.J.; Yang, Q.Z.; Chemical studies of Iris pallasii Fisch. var. chinensis Fisch.. Acta Chim Sin 1980, 38, 2, 156. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 56674 | 2-[(Z)-10-heptadecenyl]-6-methoxyphenol | C24H40O2 | 详情 | 详情 | |
| (VII) | 12620 | o-Vanillin; 2-Hydroxy-3-methoxybenzaldehyde | 148-53-8 | C8H8O3 | 详情 | 详情 |
| (VIII) | 56675 | 2-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxybenzaldehyde | C14H22O3Si | 详情 | 详情 | |
| (IX) | 56676 | (9-hydroxynonyl)(triphenyl)phosphonium bromide | C27H34BrOP | 详情 | 详情 | |
| (X) | 56677 | (Z)-10-(2-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxyphenyl)-9-decen-1-ol | C23H40O3Si | 详情 | 详情 | |
| (XI) | 56678 | bromo[9-(1-ethoxyethoxy)nonyl]magnesium | C13H27BrMgO2 | 详情 | 详情 | |
| (XII) | 56679 | 1-(2-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxyphenyl)-10-(1-ethoxyethoxy)-1-decanol | C27H50O5Si | 详情 | 详情 | |
| (XIII) | 56680 | 10-(2-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxyphenyl)-1-decanol | C23H42O3Si | 详情 | 详情 | |
| (XIV) | 56681 | 10-(2-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxyphenyl)decanal | C23H40O3Si | 详情 | 详情 | |
| (XV) | 56682 | heptyl(triphenyl)phosphonium bromide | 13423-48-8 | C25H30BrP | 详情 | 详情 |
| (XVI) | 56683 | tert-butyl{2-[(Z)-10-heptadecenyl]-6-methoxyphenoxy}dimethylsilane; tert-butyl(dimethyl)silyl 2-[(Z)-10-heptadecenyl]-6-methoxyphenyl ether | C30H54O2Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Condensation of 3-methoxysalicylaldehyde (I) with cyanoacetamide (II) in the presence of piperidine gave rise to the carbamoyl iminochromene (III). Subsequent condensation of (III) with 3,4,5-trimethoxybenzaldehyde furnished the title compound.
| 【1】 Perry, P.J.; McGown, A.T.; Pavlidis, V.H.; Hadfield, J.A.; Synthesis and anticancer activities of 4-oxobenzopyrano[2,3-d]pyrimidines. Anti-Cancer Drugs 1999, 10, 6, 591. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 12620 | o-Vanillin; 2-Hydroxy-3-methoxybenzaldehyde | 148-53-8 | C8H8O3 | 详情 | 详情 |
| (II) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (III) | 38139 | 2-imino-8-methoxy-2H-chromene-3-carboxamide | C11H10N2O3 | 详情 | 详情 | |
| (IV) | 11136 | 3,4,5-Trimethoxybenzaldehyde | 86-81-7 | C10H12O4 | 详情 | 详情 |