|
【结 构 式】 
|
【分子编号】65477 【品名】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 【CA登记号】 |
【 分 子 式 】C21H30O2 【 分 子 量 】314.468 【元素组成】C 80.21% H 9.62% O 10.18% |
合成路线1
该中间体在本合成路线中的序号：(IIb)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 |
合成路线2
该中间体在本合成路线中的序号：(IIb)Alitretinoin esters (IIa) and (IIb) can be prepared by a variety of methods. Horner-Emmons reaction of either the ionylideneacetaldehyde (V) (3, 4) or its tricarbonyl iron complex (XII) (5) with diethyl 3-(ethoxycarbonyl)-2-methylprop-2-enylphosphonate (XIII), optionally followed by decomplexation using CuCl2 in EtOH, provides alitretinoin ethyl ester (IIa). Alternatively, Wittig reaction of aldehyde (V) with iodomethylenetriphenylphosphorane, followed by in situ elimination of HI using an excess of sodium hexamethyldisilazide, and then addition of lithium butyl(tributylstannyl)cyanocuprate to the obtained terminal acetylene, leads to the unstable vinyl stannane (XIV). Subsequent Stille coupling of crude stannane (XIV) with the vinyl triflate (XV) (derived from ethyl acetoacetate) furnishes the target 9-cis-retinoate (IIa) (6). In a different route, the addition of lithium butyl(tributylstannyl)-cyanocuprate (generated from Bu3SnH, BuLi and CuCN) to (Z)-3-methyl-2-penten-4-yn-1-ol (XVI) and MnO2 oxidation of the allyl alcohol function results in the stannyl dienal (XVII). Subsequent Horner-Emmons reaction of aldehyde (XVII) with phosphonate (XIII) followed by iododestannylation of the obtained adduct furnishes the tetraenyl iodide (XVIII). 2,2,6-Trimethylcyclohexanone (XIX) is reacted with hydrazine hydrate and Et3N in boiling EtOH to produce the corresponding hydrazone, which is converted to vinyl iodide upon treatment with iodine and DBN. Metalation of the vinyl iodide with t-BuLi followed by trapping with trimethyl borate generates an unstable intermediate, assumed to be the boronic ester (XX). Then, Suzuki coupling between the in situ-generated boronate (XX) and freshly prepared tetraenyl iodide (XVIII) provides the target cis-retinoate (IIa) in satisfactory yields (7, 8). Two related synthetic strategies, useful for introducing tritium labeling onto the cyclohexenyl ring of (II), are based on the catalytic hydrogenation of the conjugated cyclohexadiene compound (XXIa) or its nonconjugated analogue (XXIb) in the presence of Rh(PPh3)3Cl (9). Compound (IIb), along with some labeled derivatives, can be prepared by the following route. Condensation of 2,2,6-trimethylcyclohexanone (XIX) with the bromomagnesium acetylide of (Z)-3-methyl-2-penten-4-yn-1-ol (XVI) affords the propargylic alcohol adduct (XXII). After reduction of the triple bond of (XXII) with LiAlH4, oxidation of the primary alcohol group using MnO2 in dry CH2Cl2 yields the hydroxy dienal (XXIII). Wittig olefination of aldehyde (XXIII) with (methoxycarbonylmethylene)triphenylphosphorane followed by smooth dehydration of the tertiary alcohol with 80% formic acid in hexane then leads to the tetraenoate ester (XXIV). After reduction of ester (XXIV) with DIBALH and reoxidation of the obtained alcohol to aldehyde with MnO2, the addition of methylmagnesium bromide results in the secondary alcohol (XXV). The deuterium and tritium analogues of (XXV) can be similarly obtained by using the corresponding labeled Grignard reagents. Subsequent oxidation of (XXV) with MnO2 followed by condensation of the resulting methyl ketone with methyl diethylphosphonoacetate leads to the 9-cis-methylretinoate (IIb) (10, 11). Scheme 2.
| 【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. |
| 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 | |
| (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 |
| (XII) | 65488 | complex of (2E,4E)-3-Methyl-5-(2,6,6-Trimethyl-1-Cyclohexenyl)Penta-2,4-Dienal with Fe(CO)3 | C15H22O.Fe(CO)3 | 详情 | 详情 | |
| (XIII) | 44704 | ethyl (E)-4-(diethoxyphosphoryl)-3-methyl-2-butenoate | 41891-54-7 | C11H21O5P | 详情 | 详情 |
| (XIV) | 65489 | C28H50Sn | 详情 | 详情 | ||
| (XV) | 65490 | C7H9F3O5S | 详情 | 详情 | ||
| (XVI) | 65491 | (Z)-3-methylpent-2-en-4-yn-1-ol | 105-29-3 | C6H8O | 详情 | 详情 |
| (XVII) | 65492 | C18H34OSn | 详情 | 详情 | ||
| (XVIII) | 65493 | C13H17IO2 | 详情 | 详情 | ||
| (XIX) | 65494 | 2,2,6-Trimethylcyclohexanone | C9H15O | 详情 | 详情 | |
| (XX) | 65495 | C11H21BO2 | 详情 | 详情 | ||
| (XXI) | 65496 | C22H30O2 | 详情 | 详情 | ||
| (XXII) | 65497 | C15H24O2 | 详情 | 详情 | ||
| (XXIII) | 65498 | C15H24O2 | 详情 | 详情 | ||
| (XXIV) | 65499 | C18H26O2 | 详情 | 详情 | ||
| (XXV) | 65500 | C18H28O | 详情 | 详情 |