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【结 构 式】 
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【分子编号】49671 【品名】dimethyl 2-(1-methylethylidene)malonate 【CA登记号】22035-53-6 |
【 分 子 式 】C8H12O4 【 分 子 量 】172.18088 【元素组成】C 55.81% H 7.02% O 37.17% |
合成路线1
该中间体在本合成路线中的序号：(XII)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2
该中间体在本合成路线中的序号：(VII)The formylation of the beta-ionone (I) with methyl formate and NaOMe gives the enol (II), which by reaction with methanol and H2SO4 yields the dimethylacetal (III). The reaction of (III) with methylenetriphenylphosphorane (IV) affords the methylene compound (V), which is treated with formic acid to provide the aldehyde (VI). The condensation of (VI) with isopropylidenemalonic acid dimethyl ester (VII) by means of NaOH gives the polyenic malonic acid (VIII) as a mixture of isomers that is separated by crystallization in ethyl ether to yield the desired all-trans-isomer (IX). Finally, this malonic acid is selectively monodecarboxylated by means of refluxing 2,6-dimethylpyridine to afford the target (E,E,E,Z)-isomer.
| 【1】 Valia, A.; et al.; Stereoselective synthesis of 13 E retinoic and 13 Z retinoic acids via a new intermediate compound, C-15 beta-methylenealdehyde. Tetrahedron 2000, 56, 37, 7211. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa),(IX) | 49672 | 2-[(2E,4E,6E)-1,5-dimethyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6-heptatrienylidene]malonic acid | C21H28O4 | 详情 | 详情 | |
| (VIIb) | 49673 | 2-[(2E,4Z,6E)-1,5-dimethyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6-heptatrienylidene]malonic acid | C21H28O4 | 详情 | 详情 | |
| (I) | 39584 | (E)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one | 14901-07-6 | C13H20O | 详情 | 详情 |
| (II) | 49667 | (1E,4E)-1-hydroxy-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,4-pentadien-3-one | C14H20O2 | 详情 | 详情 | |
| (III) | 49668 | (E)-5,5-dimethoxy-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-penten-3-one | C16H26O3 | 详情 | 详情 | |
| (IV) | 27301 | methylene(triphenyl)phosphorane | C19H17P | 详情 | 详情 | |
| (V) | 49669 | (E)-1-methoxy-3-methylene-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-pentenyl methyl ether; 2-[(1E)-3-(2,2-dimethoxyethyl)-1,3-butadienyl]-1,3,3-trimethyl-1-cyclohexene | C17H28O2 | 详情 | 详情 | |
| (VI) | 49670 | (E)-3-methylene-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-pentenal | C15H22O | 详情 | 详情 | |
| (VII) | 49671 | dimethyl 2-(1-methylethylidene)malonate | 22035-53-6 | C8H12O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号： (I)
| 【1】 Cartier D, Valla A, Le Guillou R, et al. 2003. New, regiaselective, one-pot synthesis of (all-E) -retinoic acid and analogues from enaminodiester synthons. Eur J Org Chem, (12). 2250～2253 |
| 【2】 Cartier D, Valla A, Labia R, et al. 2003. A new one-pot synthesis of all E-retinoic acid via a new enamin odiester synthon. Tetrahedrcm Lett, 44 (31): 5789～5790 |
| 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) | 49671 | dimethyl 2-(1-methylethylidene)malonate | 22035-53-6 | C8H12O4 | 详情 | 详情 |
| (V) | 66904 | dimethyl 2-((2E,4E,6E,8Z)-6-methyl-8-(2,6,6-trimethylcyclohex-2-en-1-ylidene)octa-2,4,6-trien-2-yl)malonate | C23H32O4 | 详情 | 详情 | |
| (II) | 66902 | (E)-dimethyl 2-(4-(dimethylamino)but-3-en-2-ylidene)malonate | C11H17NO4 | 详情 | 详情 | |
| (III) | 39584 | (E)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one | 14901-07-6 | C13H20O | 详情 | 详情 |
| (IV) | 66903 | dimethyl 2-((2E,4E,7E)-6-oxo-8-(2,6,6-trimethylcyclohex-1-en-1-yl)octa-2,4,7-trien-2-yl)malonate | C22H30O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号： (IV)
| 【1】 Valla A, Andriamialisoa Z, Prat V, et aL. 2000. Stereoselective synthesis of 13E and 132 retinoic acids via a novelintermediate-methylenealdehyde at 0-15. Tetrahedron, 56 (37): 7211～7215 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 49671 | dimethyl 2-(1-methylethylidene)malonate | 22035-53-6 | C8H12O4 | 详情 | 详情 |
| (I) | 66905 | (E)-5,5-dimethoxy-1-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-1-en-3-one | C16H26O3 | 详情 | 详情 | |
| (II) | 66906 | (E)-2-(5,5-dimethoxy-3-methylenepent-1-en-1-yl)-1,3,3-trimethylcyclohex-1-ene | C17H28O2 | 详情 | 详情 | |
| (III) | 66907 | (E)-3-methylene-5-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-4-enal | C15H22O | 详情 | 详情 |