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【结 构 式】 
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【分子编号】33481 【品名】4-methoxy-2,3,6-trimethylbenzaldehyde 【CA登记号】 |
【 分 子 式 】C11H14O2 【 分 子 量 】178.23096 【元素组成】C 74.13% H 7.92% O 17.95% |
合成路线1
该中间体在本合成路线中的序号：(VI)By condensation of 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (I) with 3-formylcrotonic acid butyl ester (II) by means of NaH in DMF to yield 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraen-1-oic acid butyl ester (III), which is then hydrolyzed with KOH in refluxing ethanol - water. The starting products (I) and (II) are obtained as follows: 1) The methylation of 2,3,5-trimethylphenol (IV) with KOH and methyl iodide in refluxing aqueous ethanol gives 2,3,5-trimethylanisole (V), which is then carbonylated with POCl3 and DMF (A) to afford 4-methoxy-2,3,6-trimethylbenzaldehyde (VI). The condensation of (VI) with acetone (B) by means of NaOH gives 4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one (VII), which by a Grignard reaction with ethynylmagnesium bromide (C) in THF is converted into 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-4-penten-1-yne (VIII). The controlled hydrogenation of (VIII) with H2 over a Pd catalyst in hexane yields 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-1,4-pentadiene (IX), which is finally treated with triphenylphosphonium bromide in benzene at 60 C to give the phosphonium salt (I). 2) The oxidation of dibutyl L-(+)-tartrate (X) with lead tetraacetate in benzene gives butyl glyoxalate (XI), which is then condensed with propionic aldehyde (D) by means of dibutylamine (E) to afford ester (II).
| 【1】 Bollag, W.; et al.; Polyene derivatives. BE 0813002; DE 2414619; FR 2223037; GB 1468401; GB 1468402; JP 49126637 . |
| 【2】 Castaner, J.; Hillier, K.; RO 10-1670. Drugs Fut 1977, 2, 11, 763. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (B) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (A) | 33491 | Dimethylformamide | 68-12-2 | C3H7NO | 详情 | 详情 |
| (E) | 33492 | N,N-dibutylamine; N-butyl-1-butanamine | 111-92-2 | C8H19N | 详情 | 详情 |
| (I) | 33485 | [(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl](triphenyl)phosphonium bromide | C34H36BrOP | 详情 | 详情 | |
| (II) | 33486 | butyl (E)-3-methyl-4-oxo-2-butenoate | C9H14O3 | 详情 | 详情 | |
| (III) | 33487 | butyl (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate | C25H34O3 | 详情 | 详情 | |
| (IV) | 33479 | 2,3,5-trimethylphenol | 697-82-5 | C9H12O | 详情 | 详情 |
| (V) | 33480 | 1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether | 20469-61-8 | C10H14O | 详情 | 详情 |
| (VI) | 33481 | 4-methoxy-2,3,6-trimethylbenzaldehyde | C11H14O2 | 详情 | 详情 | |
| (VII) | 33482 | (E)-4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one | 54757-47-0 | C14H18O2 | 详情 | 详情 |
| (VIII) | 33483 | (E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1-penten-4-yn-3-ol | C16H20O2 | 详情 | 详情 | |
| (IX) | 33484 | (1E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1,4-pentadien-3-ol | C16H22O2 | 详情 | 详情 | |
| (X) | 33490 | Dibutyl tartrate | 87-92-3 | C12H22O6 | 详情 | 详情 |
| (XI) | 30937 | butyl 2-oxoacetate | C6H10O3 | 详情 | 详情 | |
| (C) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The methylation of 2,3,5-trimethylphenol (I) with NaH and Me-I in DMSO gives 1-methoxy-2,3,5-trimethylbenzene (II), which is condensed with DMF by means of POCl3 and NaOH to yield 4-methoxy-2,3,6-trimethylbenzaldehyde (III). The condensation of benzaldehyde (III) with acetone (IV) by means of NaOH affords the butenone (V). The condensation of (V) with methyl formate by means of NaOMe in ethyl ether provides the sodium enolate (VI), which is treated with MeOH and H2SO4 to obtain the dimethylacetal (VII). The condensation of (VII) with the phosphonium bromide (VIII) by means of tBu-OK in cyclohexane gives the methylene derivative (IX), which is hydrolyzed with formic acid to yield the aldehyde (X). The isomerization of (X) by means of TEA in ethyl ether affords the 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienal as a mixture of (E,E) and (Z,E)-isomers that is separated by chromatography. The desired (E,E)-isomer (XI) is condensed with dimethyl isopropylidenemalonate (XII) by means of Triton B in methanol and hydrolyzed with HCl to provide the monoester (XIII), which is saponified with NaOH in methanol/water to give the malonic acid derivative (XIV). Finally, this compound is monodecarboxylated by means of pyridine in dichloromethane to yield the target Acitretin (Etretin).
| 【1】 Andriamialisoa, Z.; et al.; A new stereoselective synthesis of acitretin (=Soriatane(R), Neotigason(R)). Helv Chim Acta 2002, 85, 9, 2926. |
| 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) | 33479 | 2,3,5-trimethylphenol | 697-82-5 | C9H12O | 详情 | 详情 |
| (II) | 33480 | 1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether | 20469-61-8 | C10H14O | 详情 | 详情 |
| (III) | 33481 | 4-methoxy-2,3,6-trimethylbenzaldehyde | C11H14O2 | 详情 | 详情 | |
| (IV) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (V) | 33482 | (E)-4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one | 54757-47-0 | C14H18O2 | 详情 | 详情 |
| (VI) | 58106 | sodium (1E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-oxo-1,4-pentadien-1-olate | C15H17NaO3 | 详情 | 详情 | |
| (VII) | 58107 | (E)-5,5-dimethoxy-1-(4-methoxy-2,3,6-trimethylphenyl)-1-penten-3-one | C17H24O4 | 详情 | 详情 | |
| (VIII) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (IX) | 58108 | 2-[(1E)-3-(2,2-dimethoxyethyl)-1,3-butadienyl]-5-methoxy-1,3,4-trimethylbenzene; 4-[(1E)-3-(2,2-dimethoxyethyl)-1,3-butadienyl]-2,3,5-trimethylphenyl methyl ether | C18H26O3 | 详情 | 详情 | |
| (X) | 58109 | (E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylene-4-pentenal | C16H20O2 | 详情 | 详情 | |
| (XI) | 58110 | (2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienal | C16H20O2 | 详情 | 详情 | |
| (XII) | 49671 | dimethyl 2-(1-methylethylidene)malonate | 22035-53-6 | C8H12O4 | 详情 | 详情 |
| (XIII) | 58111 | (2E,4E,6E,8E)-2-(methoxycarbonyl)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid | C23H28O5 | 详情 | 详情 | |
| (XIV) | 58112 | 2-[(2E,4E,6E)-7-(4-methoxy-2,3,6-trimethylphenyl)-1,5-dimethyl-2,4,6-heptatrienylidene]malonic acid | C22H26O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The methylation of 2,3,5-trimethylphenol (I) with MeI and KOH in 10% aqueous ethanol gives 2,3,5-trimethylanisole (II), which is formylated with DMF and POCl3 yielding 2,3,6-trimethyl-p-anisylaldehyde (III). The condensation of (III) with acetone (B) by means of NaOH affords 4-(4-methoxy-2,3,6-trimethylphenyl)but-3-en-2-one (IV), which by a Grignard reaction with ethynylmagnesium bromide (C) in THF is converted into the acetylenic alcohol (V). Partial hydrogenation of (V) with H2 over Pd/C in hexane gives dienic alcohol (VI), which is condensed with triphenylphosphine hydrobromide in benzene affording 5-(4-methoxy-2,3,6 trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (VII). A Wittig condensation of (VII) with butyl 3-formylcrotonate (VIII) by means of NaH in DMF gives butyl 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate (IX), which is hydrolyzed with KOH in refluxing ethanol-water yielding the corresponding free acid (X). This acid is converted into the acyl chloride (XI) by treatment with PCl3 in refluxing benzene. Finally, this compound is treated with ethylamine (E) in ether. The butyl 3-formylcrotonate (VIII) is obtained as follows: The oxidation of dibutyl tartrate (XII) with lead tetraacetate in benzene gives butyl glyoxalate (XIII), which is then condensed with propionaldehyde (XIV) by heating at 110 C with dibutyl-amine (D).
| 【1】 Bollag, W.; et al.; Polyene derivatives. BE 0813002; FR 2223037; GB 1468401; GB 1468402 . |
| 【2】 Bollag, W.; et al.; Antidandruff compositions containing 9-(4-lower alkoxy-2,3,6-trilower-alkylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid lower alkyl amides. DE 2542366; ES 441173; FR 2330381; GB 1504350; JP 51057840; US 4021574 . |
| 【3】 Castaner, J.; Hillier, K.; Motretinide. Drugs Fut 1978, 3, 2, 126. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (E) | 10928 | Ethanamine | 75-04-7 | C2H7N | 详情 | 详情 |
| (B) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (A) | 33491 | Dimethylformamide | 68-12-2 | C3H7NO | 详情 | 详情 |
| (D) | 33492 | N,N-dibutylamine; N-butyl-1-butanamine | 111-92-2 | C8H19N | 详情 | 详情 |
| (I) | 33479 | 2,3,5-trimethylphenol | 697-82-5 | C9H12O | 详情 | 详情 |
| (II) | 33480 | 1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether | 20469-61-8 | C10H14O | 详情 | 详情 |
| (III) | 33481 | 4-methoxy-2,3,6-trimethylbenzaldehyde | C11H14O2 | 详情 | 详情 | |
| (IV) | 33482 | (E)-4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one | 54757-47-0 | C14H18O2 | 详情 | 详情 |
| (V) | 33483 | (E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1-penten-4-yn-3-ol | C16H20O2 | 详情 | 详情 | |
| (VI) | 33484 | (1E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1,4-pentadien-3-ol | C16H22O2 | 详情 | 详情 | |
| (VII) | 33485 | [(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl](triphenyl)phosphonium bromide | C34H36BrOP | 详情 | 详情 | |
| (VIII) | 33486 | butyl (E)-3-methyl-4-oxo-2-butenoate | C9H14O3 | 详情 | 详情 | |
| (IX) | 33487 | butyl (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate | C25H34O3 | 详情 | 详情 | |
| (X) | 33488 | (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid | C21H26O3 | 详情 | 详情 | |
| (XI) | 33489 | (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoyl chloride | C21H25ClO2 | 详情 | 详情 | |
| (XII) | 33490 | Dibutyl tartrate | 87-92-3 | C12H22O6 | 详情 | 详情 |
| (XIII) | 30937 | butyl 2-oxoacetate | C6H10O3 | 详情 | 详情 | |
| (XIV) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (C) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(B)The reaction of 2,3,5-trimethylanisole (II) [prepared by alkylation of 2,3,5-trimethylphenol (I) with methyl iodide] with DMF and POCl3 affords 4-(4-methoxy-2,3,6-trimethylbenzaldehyde (V), which is condensed with propanone (B) in aqueous NaOH giving 4-(4-methoxy-2,3,6-trimethylphenyl)-but-3-en-2-one (VI). The Grignard reaction of (VI) with ethynylmagnesium bromide (C) in THF yields 5-(4-methoxy-2,3,6-trimethylphe-nyl)-3-methyl-3-hydroxypenta-4-en-1-yne (VII), which is partially hydrogenated with H2 over deactivated Pd in hexane to give 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxypenta-1,4-diene (VIII). The reaction of (VIII) with triphenylphosphonium hydrobromide in benzene affords 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (IX). Finally, this compound is submitted to a Wittig reaction with ethyl 3,4-formylcrotonate (D) in DMF (NaH is used as base).
| 【1】 Bollag, W. et al.; Polyene derivatives. DE 2414619; ES 424750; FR 2223037; GB 1468401; GB 1468402 . |
| 【2】 Castaner, J.; Thorpe, P.; RO 10/9359. Drugs Fut 1977, 2, 3, 199. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 33481 | 4-methoxy-2,3,6-trimethylbenzaldehyde | C11H14O2 | 详情 | 详情 | |
| (D) | 40061 | ethyl (E)-3-methyl-4-oxo-2-butenoate | 62054-49-3 | C7H10O3 | 详情 | 详情 |
| (I) | 33479 | 2,3,5-trimethylphenol | 697-82-5 | C9H12O | 详情 | 详情 |
| (II) | 33480 | 1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether | 20469-61-8 | C10H14O | 详情 | 详情 |
| (V) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (VI) | 33482 | (E)-4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one | 54757-47-0 | C14H18O2 | 详情 | 详情 |
| (VII) | 33483 | (E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1-penten-4-yn-3-ol | C16H20O2 | 详情 | 详情 | |
| (VIII) | 33484 | (1E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1,4-pentadien-3-ol | C16H22O2 | 详情 | 详情 | |
| (IX) | 33485 | [(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl](triphenyl)phosphonium bromide | C34H36BrOP | 详情 | 详情 | |
| (C) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |