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【结 构 式】 
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【分子编号】68747 【品名】(3S,3aS,4R,4aS,7S,9aS)-benzyl 7-((ethoxycarbonyl)amino)-3-methyl-1-oxo-1,3,3a,4,4a,5,6,7,8,9a-decahydronaphtho[2,3-c]furan-4-carboxylate 【CA登记号】 |
【 分 子 式 】C24H29NO6 【 分 子 量 】427.497 【元素组成】C 67.43% H 6.84% N 3.28% O 22.46% |
合成路线1
该中间体在本合成路线中的序号：(LI)Hydrolysis of (5,5-ethylenedioxy-1-cyclohexenyl)acrylic acid (XVI) with p-TsOH followed by reductive amination with NH4OAc and NaBH3CN and N-acylation of the obtained amine with ethyl chloroformate (VIII) gives carbamate (XLI) as a racemic mixture, which is resolved by means of chiral HPLC, providing the (R)-enantiomer (XLII). Esterification of acid (XLII) with allylic alcohol (XXXII) in the presence of EDC and DMAP in CH2Cl2 yields the corresponding ester (XLIII), which by intramolecular Diels–Alder cyclization in xylene at 147 °C followed by epimerization in the presence of DBU furnishes the tricyclic intermediate (XLIV). Catalytic hydrogenation of alkene (XLIV) over Pt/C affords the saturated compound (XLV) , which is finally hydrolyzed with NaOH . Alternatively, condensation of nitro acid (XXXVII) with the hydroxypentynamide (XXX) by means of pivaloyl chloride, NMP and DMAP yields ester (XLVI), which is submitted to partial hydrogenation over Lindlar catalyst poisoned with quinoline to afford triene (XLVII). Thermal Diels–Alder cyclization of compound (XLVII) followed by epimerization in the presence of DBU provides the tricyclic carbamide (XLVIII). Simultaneous nitro group and olefin reduction in compound (XLVIII) by means of H2 and Pt/C or by transfer hydrogenation with HCOOH and Pd/C leads to the tricyclic amine (XLIX), which is finally acylated with ethyl chloroformate (VIII) to afford the corresponding carbamate (XLV) .
Other synthetic approaches to intermediate (X) include alkaline cleavage of benzothiazolyl ketone (L) (4) and hydrogenation/debenzylation of the unsaturated precursor (LI) over Pt/C .
| 【1】 Sudhakar, A., Kwok, D.-I., Wu, G.G., Green, M.D., Thiruvengadam, T.K., Lim, N.K., Wang, T., Huang, M. (Schering Corp.). An exo-selective synthesis of himbacine analogs. EP 1846385, JP 2008526974, US 2006217422, US 7772276, WO 2006076452. |
| 【2】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (X) | 68707 | (3S,3aS,4R,4aS,7S,8aS,9aS)-7-((ethoxycarbonyl)amino)-3-methyl-1-oxododecahydronaphtho[2,3-c]furan-4-carboxylic acid | C17H25NO6 | 详情 | 详情 | |
| (XVI) | 68716 | (E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylic acid | C11H14O4 | 详情 | 详情 | |
| (XXXII) | 68728 | (R,E)-4-hydroxy-N,N-diphenylpent-2-enamide;4(R)-hydroxy-N,Ndiphenyl-2-pentenamide | C17H17NO2 | 详情 | 详情 | |
| (XLI) | 68737 | (E)-3-(5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acrylic acid | C12H17NO4 | 详情 | 详情 | |
| (XLII) | 68738 | (R,E)-3-(5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acrylic acid | C12H17NO4 | 详情 | 详情 | |
| (XLIII) | 68739 | (E)-(R,Z)-5-(diphenylamino)-5-oxopent-3-en-2-yl 3-((R)-5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acrylate | C29H32N2O5 | 详情 | 详情 | |
| (XLIV) | 68745 | ethyl ((1R,3aR,6S,8aR,9S,9aS)-9-(diphenylcarbamoyl)-1-methyl-3-oxo-1,3,3a,5,6,7,8,8a,9,9a-decahydronaphtho[2,3-c]furan-6-yl)carbamate | C29H32N2O5 | 详情 | 详情 | |
| (XLV) | 68744 | ethyl ((1R,3aR,4aR,6S,8aS,9S,9aS)-9-(diphenylcarbamoyl)-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl)carbamate | C29H34N2O5 | 详情 | 详情 | |
| (XLVI) | 68740 | (E)-(R)-5-(diphenylamino)-5-oxopent-3-yn-2-yl 3-(5-nitrocyclohex-1-en-1-yl)acrylate | C26H24N2O5 | 详情 | 详情 | |
| (XLVII) | 68741 | (E)-(R,Z)-5-(diphenylamino)-5-oxopent-3-en-2-yl 3-(5-nitrocyclohex-1-en-1-yl)acrylate | C26H26N2O5 | 详情 | 详情 | |
| (XLVIII) | 68743 | (3R,3aS,4R,4aR,7S,9aS)-3-methyl-7-nitro-1-oxo-N,N-diphenyl-1,3,3a,4,4a,5,6,7,8,9a-decahydronaphtho[2,3-c]furan-4-carboxamide | C26H26N2O5 | 详情 | 详情 | |
| (XLIX) | 68742 | (3R,3aS,4R,4aR,7S,8aS,9aS)-7-amino-3-methyl-1-oxo-N,N-diphenyldodecahydronaphtho[2,3-c]furan-4-carboxamide | C26H30N2O3 | 详情 | 详情 | |
| (L) | 68746 | ethyl ((1R,3aR,4aR,6R,8aR,9S,9aS)-9-(benzo[d]thiazole-2-carbonyl)-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl)carbamate | C24H28N2O5S | 详情 | 详情 | |
| (LI) | 68747 | (3S,3aS,4R,4aS,7S,9aS)-benzyl 7-((ethoxycarbonyl)amino)-3-methyl-1-oxo-1,3,3a,4,4a,5,6,7,8,9a-decahydronaphtho[2,3-c]furan-4-carboxylate | C24H29NO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(LI)Partial hydrogenation of propargylic ester (LII) over Lindlar catalyst deactivated with quinoline in toluene gives the triene compound (LIII), which by intramolecular Diels–Alder reaction in NMP at 145 °C followed by epimerization with DBU yields the tricyclic adduct (LIV). Reduction of the nitro group of intermediate (LIV) by means of H2 and Pd/C yields amine (LV), which is finally N-acylated with ethyl chloroformate (VIII) to afford intermediate (L) .
The condensation of acid (XLII) with benzyl hydroxypentynoate (XXIII) by means of pivaloyl chloride, Et3N and DMAP yields ester adduct (LVI), which is submitted to partial hydrogenation in the presence of Lindlar catalyst and quinoline to afford trienoate (LVII). Finally, Diels–Alder cyclization of (LVII) and subsequent epimerization with DBU provides the tricyclic lactone (LI) .
| 【1】 Sudhakar, A., Kwok, D.-I., Wu, G.G., Green, M.D., Thiruvengadam, T.K., Lim, N.K., Wang, T., Huang, M. (Schering Corp.). An exo-selective synthesis of himbacine analogs. EP 1846385, JP 2008526974, US 2006217422, US 7772276, WO 2006076452. |
| 【2】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (L) | 68746 | ethyl ((1R,3aR,4aR,6R,8aR,9S,9aS)-9-(benzo[d]thiazole-2-carbonyl)-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl)carbamate | C24H28N2O5S | 详情 | 详情 | |
| (VIII) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (XXIII) | 68723 | (R)-benzyl 4-hydroxypent-2-ynoate | C12H12O3 | 详情 | 详情 | |
| (XLII) | 68738 | (R,E)-3-(5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acrylic acid | C12H17NO4 | 详情 | 详情 | |
| (LI) | 68747 | (3S,3aS,4R,4aS,7S,9aS)-benzyl 7-((ethoxycarbonyl)amino)-3-methyl-1-oxo-1,3,3a,4,4a,5,6,7,8,9a-decahydronaphtho[2,3-c]furan-4-carboxylate | C24H29NO6 | 详情 | 详情 | |
| (LII) | 68749 | (E)-(R)-5-(benzo[d]thiazol-2-yl)-5-oxopent-3-yn-2-yl 3-(5-nitrocyclohex-1-en-1-yl)acrylate | C21H18N2O5S | 详情 | 详情 | |
| (LIII) | 68748 | (E)-(R,Z)-5-(benzo[d]thiazol-2-yl)-5-oxopent-3-en-2-yl 3-(5-nitrocyclohex-1-en-1-yl)acrylate | C21H20N2O5S | 详情 | 详情 | |
| (LIV) | 68751 | (3R,3aS,4R,4aS,7S,9aS)-4-(benzo[d]thiazole-2-carbonyl)-3-methyl-7-nitro-3,3a,4,4a,5,6,7,8-octahydronaphtho[2,3-c]furan-1(9aH)-one | C21H20N2O5S | 详情 | 详情 | |
| (LV) | 68750 | (3R,3aS,4R,4aS,7S,8aR,9aS)-7-amino-4-(benzo[d]thiazole-2-carbonyl)-3-methyldecahydronaphtho[2,3-c]furan-1(3H)-one | C21H24N2O3S | 详情 | 详情 | |
| (LVI) | 68753 | (R)-benzyl 4-(((E)-3-((R)-5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acryloyl)oxy)pent-2-ynoate | C24H27NO6 | 详情 | 详情 | |
| (LVII) | 68752 | (R,Z)-benzyl 4-(((E)-3-((S)-5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acryloyl)oxy)pent-2-enoate | C24H29NO6 | 详情 | 详情 |