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【结 构 式】 
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【分子编号】32679 【品名】(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid; Retinoic acid 【CA登记号】302-79-4 |
【 分 子 式 】C20H28O2 【 分 子 量 】300.44112 【元素组成】C 79.96% H 9.39% O 10.65% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of retinoic acid (I) with PCl3 in dry benzene gives the corresponding retinoyl chloride (II), which is then condensed with 4-aminophenol (III) in DMF - ether.
| 【1】 Gander, R.J.; Gurney, J.A.; Esters of retinoic acid. BE 0847942; CA 1062700; GB 1543824; NL 7612201; US 4108880 . |
| 【2】 Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaner, J.; 4-Hydroxyphenylretinamide. Drugs Fut 1980, 5, 3, 132. |
| 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) | 32679 | (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid; Retinoic acid | 302-79-4 | C20H28O2 | 详情 | 详情 |
| (II) | 32680 | Retinoyl chloride; (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoyl chloride | C20H27ClO | 详情 | 详情 | |
| (III) | 15715 | 4-Aminophenol | 123-30-8 | C6H7NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The reaction of vinyl-beta-ionol (I) with triphenylphosphonium bromide (II) in ethanol gives the corresponding phosphonium salt (III), which is condensed through a Wittig reaction with cis-beta-formylcrotonic acid (IV) by means of sodium ethoxide in ethanol to afford a mixture of cis-2-cis-4-vitamin A acid (V) and the desired product. Finally, compound (V) is isomerized bv irradiation with diffuse light in ether in the presence of iodine.
| 【1】 Garbers, C.F.; et al.; Synthesis of cis-2, cis-4-vitamin A by a Wittig condensation. J Chem Soc 1968, 16, 1982-83. |
| 【2】 Castaner, J.; Serradell, M.N.; Hillier, K.; Blancafort, P.; Isotretinoin. Drugs Fut 1979, 4, 9, 651. |
| 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) | 33333 | (2E,4E)-3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadien-1-ol | 3917-39-3 | C15H24O | 详情 | 详情 |
| (III) | 33334 | [(2E,4E)-3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienyl](triphenyl)phosphonium bromide | C33H38BrP | 详情 | 详情 | |
| (IV) | 33335 | (Z)-3-methyl-4-oxo-2-butenoic acid | C5H6O3 | 详情 | 详情 | |
| (V) | 32679 | (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid; Retinoic acid | 302-79-4 | C20H28O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The photoisomerization of trans-retinoic acid (I) in hot acetonitrile using a tungsten lamp produces an equilibrium mixture containing the target 9-cis-retinoic acid, which can be isolated by recrystallization from EtOH (1, 2). A number of methods are based on the preparation of the ethyl (IIa) and methyl (IIb) esters of alitretinoin, which can be hydrolyzed to the corresponding carboxylic acid under alkaline conditions (3-11). In an alternative procedure, Wittig reaction of the 9-cis-phosphonium salts (IIIa) or (IIIb) (which can be isolated as byproducts in the production of the analogous all-trans derivatives) with 3-methyl-4-oxocrotonate esters (IVa/b), with concomitant ester group hydrolysis in the reaction medium, provides directly the target 9-cis-retinoic acid (12, 13). A different strategy consists of the condensation of the β-ionylideneacetaldehyde (V) with dimethyl β-methylglutaconate (VI) under strongly alkaline conditions to provide the diacid adduct (VII), which is mono-decarboxylated to 9,13-di-cis-retinoic acid (VIII) in the presence of copper acetate in hot 2,4-lutidine. Subsequent isomerization of (VIII) to the title 9-cis-tretinoin is accomplished by light irradiation in the presence of a trace of iodine (14). In a further synthetic route to the title compound, rearrangement of the propargylic alcohol (IX) with phenylsulfenyl chloride and triethylamine results in the conjugated sulfoxide (X) which, after desulfuration with t-BuLi and MeLi and desilylation with TBAF, gives 9-cis-retinol (XI). Finally, oxidation of alcohol (XI) utilizing MnO2 and AgO in MeOH furnishes the target carboxylic acid (15). Scheme 1.
| 【1】 Coe, J.W. (Pfizer, Inc.). Method for the preparation of 9-cis retinoic acid. WO 9422818. |
| 【2】 Coe, J.W., O’Connell, T. Convenient preparation of 9-cis-retinoic acid. Bioorg Med Chem Lett 1994, 4(2): 349-50. |
| 【3】 Boehm, M.F., McClurg, M.R., Pathirana, C. et al. Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties. J Med Chem 1994, 37(3): 408-14. |
| 【4】 Bennani, Y.L. An efficient and stereoselective synthesis of 9-cis-retinoic acid. J Org Chem 1996, 61(10): 3542-4. |
| 【5】 Wada, A., Hiraishi, S., Takamura, N., Date, T., Aoe, K., Ito, M. A novel method for a stereoselective synthesis of trisubstituted olefin using tricarbonyliron complex: A highly stereoselective synthesis of (all-E)- and (9Z)-retinoic acids. J Org Chem 1997, 62(13): 4343-8. |
| 【6】 Wada, A., Fukunaga, K., Ito, M., Mizuguchi, Y., Nakagawa, K., Okano, T. Preparation and biological activity of 13-substituted retinoic acids. Bioorg Med Chem 2004, 12(14): 3931-42. |
| 【7】 Pazos, Y., de Lera, A.R. Stereoselective synthesis of 9-cis-retinoic acid by Suzuki reaction. Tetrahedron Lett 1999, 40(47): 8287-90. |
| 【8】 Pazos, Y., Iglesias, B., de Lera, A.R. The Suzuki coupling reaction in the stereocontrolled synthesis of 9-cis-retinoic acid and its ring-demethylated analogues. J Org Chem 2001, 66(25): 8483-9. |
| 【9】 Bennani, Y.L., Boehm, M.F. Synthesis of high specific activity 2,3- and 3,4-[3H]2-9-cis-retinoic acid. J Org Chem 1995, 60(5): 1195-200. |
| 【10】 Tadikonda, P.K., Lacy, J.M., Rigdon, M.G., DeLuca, H.F. Synthesis of 9-cis-retinoic acid and C-20-[3H3C]-9-cis-retinoic acid with high specific activity. J Label Comp Radiopharm 1997, 34(1): 1-10. |
| 【11】 DeLuca, H.F., Tadikonda, P.K. (Wisconsin Alumni Res. Found.). Method of synthesis of retinoic acid. US 5808120. |
| 【12】 John, M., Paust, J. (BASF AG). Preparation of 9-(Z)-retinoic acid. US 5504230. |
| 【13】 Soukup, M., Thomessen, R. (F. Hoffmann-la Roche AG). Process for the production of 9-cis retinoic acid. CA 2520018, EP 1615879, JP 2006522757, US 2004235951, US 7015353, WO 2004089887. |
| 【14】 Robeson, C.D., Cawley, J.D., Weisler, L., Stern, M.H., Eddinger, C.C., Chechak, A.J. Chemistry of vitamin A. XXIV. The synthesis of geometric isomers of vitamin A via methyl beta-methylglutaconate. J Am Chem Soc 1955, 77(15): 4111. |
| 【15】 de Lera, A.R., Castro, A., Torrado, A., Lopez, S. Stereoselective isomerization of 10-arylsulfenate-11,12-dehydroretinoids to 9-cis-retinoids. Tetrahedron Lett 1998, 39(25): 4575-8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Iia) | 65476 | 9-cis-Retinoic acid ethyl ester; Ethyl (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate | C22H32O2 | 详情 | 详情 | |
| (IIb) | 65477 | 9-cis-Retinoic acid methyl ester; Methyl (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate | C21H30O2 | 详情 | 详情 | |
| (IIIa) | 65478 | (E,E)-[3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexen-1-yl)Penta-2,4-Dienyl]Triphenylphosphonium Chloride | 53282-28-3 | C33H38ClP | 详情 | 详情 |
| (IIIb) | 65479 | (E,E)-[3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexen-1-yl)Penta-2,4-Dienyl]Triphenylphosphonium bisulfate | C33H38P.HSO4 | 详情 | 详情 | |
| (Iva) | 40061 | ethyl (E)-3-methyl-4-oxo-2-butenoate | 62054-49-3 | C7H10O3 | 详情 | 详情 |
| (Ivb) | 65480 | Methyl (E)-3-methyl-4-oxocrotonate | C6H8O3 | 详情 | 详情 | |
| (I) | 32679 | (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid; Retinoic acid | 302-79-4 | C20H28O2 | 详情 | 详情 |
| (V) | 65481 | (2E,4E)-3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexenyl)Penta-2,4-Dienal | 1209-68-3 | C15H22O | 详情 | 详情 |
| (VI) | 65482 | Dimethyl 3-methylpent-2-enedioate | 52313-87-8 | C8H12O4 | 详情 | 详情 |
| (VII) | 65483 | C21H28O4 | 详情 | 详情 | ||
| (VIII) | 65484 | 9-cis-Retinoic acid; (2E,4E,6Z,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoic acid | 5300-03-8 | C20H28O2 | 详情 | 详情 |
| (IX) | 65485 | C27H44O2Si | 详情 | 详情 | ||
| (X) | 65486 | C32H52O2SSi | 详情 | 详情 | ||
| (XI) | 65487 | 9-cis Retinol; 9-Cis-Retinol; Retinol, 9-Cis-; 13-Cis-Retinol | 22737-97-9 | C20H30O | 详情 | 详情 |