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【结 构 式】 
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【分子编号】68707 【品名】(3S,3aS,4R,4aS,7S,8aS,9aS)-7-((ethoxycarbonyl)amino)-3-methyl-1-oxododecahydronaphtho[2,3-c]furan-4-carboxylic acid 【CA登记号】 |
【 分 子 式 】C17H25NO6 【 分 子 量 】339.38864 【元素组成】C 60.16% H 7.42% N 4.13% O 28.29% |
合成路线1
该中间体在本合成路线中的序号：(X)In one strategy, Horner–Emmons condensation of tetracyclic aldehyde (I) with pyridylmethyl phosphonate (II) by means of BuLi in THF gives the olefin adduct (III), which, after desilylation to the corresponding hydroxypyridine with TBAF in THF, is treated with Tf2O in pyridine to afford the pyridyl triflate (IV). Suzuki coupling of triflate (IV) with 3-fluorophenylboronic acid (V) by means of Pd(PPh3)4 and K2CO3 in toluene/EtOH/H2O at 100 °C gives the phenylpyridine derivative (VI). After hydrolysis of the ethylene ketal group in compound (VI) by means of HCl in acetone at 50 °C, the resulting tricyclic ketone is reductively aminated with NH3 and NaBH3CN in the presence of Ti(O-i-Pr)4 and TiCl4 in EtOH/CH2Cl2 to yield a diastereomeric mixture of primary amines that are separated by preparative TLC, providing the 6(R)-amine (VII). Finally, amine (VII) is acylated with ethyl chloroformate (VIII) in the presence of Et3N in CH2Cl2 .
In another strategy, N-acylation of the tricyclic amino acid (IX) with ethyl chloroformate (VIII) yields the carbamate (X), which, after reduction of the carboxyl group to the corresponding aldehyde (XI), is subjected to Wittig reaction with phosphonate (XII) .
| 【1】 Chackalamannil, S., Wang, Y., Greenlee, W.J. et al. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem 2008, 51(11): 3061-4. |
| 【2】 Chackalamannil, S., Greenlee, W.J., Xia, Y., Chelliah, M., Clasby, M.C., Wang, Y., Veltri, E.P. (Schering Corp.). Tricyclic thrombin receptor antagonists. EP 1495018, EP 1860106, EP 1982984, EP 2062890, EP 2065384, JP 2005528406, JP 2010132710, US 2003216437, US 7304078, WO 200308928. |
| 【3】 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. |
| 【4】 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 |
|---|---|---|---|---|---|---|
| (I) | 68713 | (1'R,3a'R,4a'R,8a'R,9a'S)-1'-methyl-3'- oxodecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho [2,3-c]furan]-9'-carbaldehyde | C16H22O5 | 详情 | 详情 | |
| (II) | 68703 | diethyl ((5-((triisopropylsilyl)oxy)pyridin-2-yl)methyl)phosphonate | C19H36NO4PSi | 详情 | 详情 | |
| (III) | 68712 | (1'R,3a'R,4a'R,8a'R,9'S,9a'S)-1'-methyl-9'-((E)-2-(5-((triisopropylsilyl)oxy)pyridin-2-yl)vinyl)octahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-3'(7'H)-one | C31H47NO5Si | 详情 | 详情 | |
| (IV) | 68711 | 6-((E)-2-((1'R,3a'R,4a'R,8a'R,9'S,9a'S)-1'-methyl-3'-oxodecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-yl)vinyl)pyridin-3-yl trifluoromethanesulfonate | C23H26F3NO7S | 详情 | 详情 | |
| (V) | 68704 | 3-fluorophenylboronic acid;3-Fluorobenzeneboronic acid | 768-35-4 | C6H6BFO2 | 详情 | 详情 |
| (VI) | 68710 | (1'R,3a'R,4a'R,8a'R,9'S,9a'S)-9'-((E)-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-1'-methyloctahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-3'(7'H)-one | C28H30FNO4 | 详情 | 详情 | |
| (VII) | 68709 | 7-amino-4-((E)-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-3-methyldecahydronaphtho[2,3-c]furan-1(3H)-one | C26H29FN2O2 | 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 |
| (IX) | 68708 | (3S,3aS,4R,4aS,7S,8aS,9aS)-7-amino-3-methyl-1-oxododecahydronaphtho[2,3-c]furan-4-carboxylic acid | C14H21NO4 | 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 | |
| (XI) | 68706 | ethyl ((1S,3aS,4aS,6S,8aS,9R,9aR)-9-formyl-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl)carbamate | C17H25NO5 | 详情 | 详情 | |
| (XII) | 68705 | diethyl ((5-(3-fluorophenyl)pyridin-2-yl)methyl)phosphonate | C16H19FNO3P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)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 |