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【结 构 式】 
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【分子编号】68713 【品名】(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 【CA登记号】 |
【 分 子 式 】C16H22O5 【 分 子 量 】294.34768 【元素组成】C 65.29% H 7.53% O 27.18% |
合成路线1
该中间体在本合成路线中的序号：(I)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：(I)The tetracyclic aldehyde (I) is prepared as follows. Heck coupling of 3-bromo-3-cyclohexen-1-one ethylene ketal (XIII) with methyl acrylate (XIV) in the presence of PdCl2(PPh3)2 and Et3N in DMF at 75 °C gives the dienoate ester (XV), which is hydrolyzed to the corresponding carboxylic acid (XVI) using NaOH in THF/MeOH. Subsequent DCC-mediated coupling of acid (XVI) with alcohol (XVII) in the presence of 4-pyrrolidinopyridine (4-Ppy) in CH2Cl2 affords the triene ester (XVIII). Intramolecular Diels–Alder reaction in triene (XVIII) by heating in xylene at 215 °C results in a tetracyclic intermediate, which undergoes epimerization at C9a by means of DBU in THF to provide the cis-lactone (XIX). The benzyl ester group of (XIX) is then removed by catalytic hydrogenolysis over Pd/C in EtOAc, and subsequent diastereoselective hydrogenation of the internal double bond over PtO2 in EtOAc affords the tetracyclic carboxylic acid (XX). Finally,chlorination of acid (XX) with SOCl2 in toluene at 180 °C followed by reduction of the resulting acid chloride with Bu3SnH in the presence of Pd(PPh3)4 in toluene yields the key aldehyde (I) .
Hydroxy ester (XVII) is obtained by protection of 2(R)-butynol (XXI) as the corresponding tetrahydropyranyl ether (XXII) with DHP in the presence of p-TsOH. Subsequent deprotonation of the terminal alkyne in compound (XXII) by means of BuLi and treatment with PhCH2OCOCl in THF at –78 °C followed by acidic THP group hydrolysis yields benzyl ester (XXIII), which is finally submitted to partial reduction of the triple bond by hydrogenation over Lindlar catalyst in THF .
| 【2】 Chackalamannil, S., Asberom, T., Xia, Y., Doller, D., Clasby, M.C.,Czarniecki, M.F. Thrombin receptor antagonists. US 6063847. |
| 【1】 Clasby, M.C., Chackalamannil, S., Czarniecki, M. et al. Metabolism-based identification of a potent thrombin receptor antagonist. J Med Chem 2007, 50(1): 129-38. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXII) | 68728 | (R,E)-4-hydroxy-N,N-diphenylpent-2-enamide;4(R)-hydroxy-N,Ndiphenyl-2-pentenamide | C17H17NO2 | 详情 | 详情 | |
| (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 | |
| (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 | |
| (XIII) | 68714 | 3-bromo-3-cyclohexen-1-one ethylene ketal；7-bromo-1,4-Dioxaspiro[4.5]dec-7-ene | 81036-84-2 | C8H11BrO2 | 详情 | 详情 |
| (XIV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (XV) | 68715 | (E)-methyl 3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylate | C12H16O4 | 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 | |
| (XVI) | 68716 | (E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylic acid | C11H14O4 | 详情 | 详情 | |
| (XVII) | 68717 | (R,E)-benzyl 4-hydroxypent-2-enoate | C12H14O3 | 详情 | 详情 | |
| (XVIII) | 68718 | (R,Z)-benzyl 4-(((E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acryloyl)oxy)pent-2-enoate | C23H26O6 | 详情 | 详情 | |
| (XIX) | 68721 | (1'R,3a'R,8a'R,9'S,9a'S)-benzyl 1'-methyl-3'-oxo-3',3a',5',7',8',8a',9',9a'-octahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-carboxylate | C23H28O6 | 详情 | 详情 | |
| (XX) | 68722 | (1'R,3a'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'-carboxylic acid | C16H22O6 | 详情 | 详情 | |
| (XXI) | 68719 | 2(R)-butynol;(R)-but-3-yn-2-ol | 42969-65-3 | C4H6O | 详情 | 详情 |
| (XXI) | 68719 | 2(R)-butynol;(R)-but-3-yn-2-ol | 42969-65-3 | C4H6O | 详情 | 详情 |
| (XXII) | 68720 | 2-((R)-but-3-yn-2-yloxy)tetrahydro-2H-pyran | C9H14O2 | 详情 | 详情 | |
| (XXIII) | 68723 | (R)-benzyl 4-hydroxypent-2-ynoate | C12H12O3 | 详情 | 详情 | |
| (XXIII) | 68723 | (R)-benzyl 4-hydroxypent-2-ynoate | C12H12O3 | 详情 | 详情 | |
| (XXVIII) | 68724 | (R)-(but-3-yn-2-yloxy)trimethylsilane | C7H14OSi | 详情 | 详情 | |
| (XXIX) | 68725 | 1-(diphenylcarbamoyl)imidazole;N,N-diphenyl-1H-imidazole-1-carboxamide | C16H13N3O | 详情 | 详情 | |
| (XXX) | 68726 | (R)-4-hydroxy-N,N-diphenylpent-2-ynamide;4(R)-hydroxy-N,N-diphenyl-2-pentynamide;4-hydroxy-N,N-diphenyl-(4R)-2-Pentynamide | 899809-61-1 | C17H15NO2 | 详情 | 详情 |
| (XXXI) | 68727 | 4-hydroxy-N,N-diphenyl-2-pentynamide | C17H15NO2 | 详情 | 详情 | |
| (XXXIII) | 68729 | (E)-(R,Z)-5-(diphenylamino)-5-oxopent-3-en-2-yl 3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylate | C28H29NO5 | 详情 | 详情 | |
| (XXXIV) | 68730 | (1'R,3a'R,8a'R,9'S,9a'S)-1'-methyl-3'-oxo-N,N-diphenyl-3',3a',5',7',8',8a',9',9a'-octahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-carboxamide | C28H29NO5 | 详情 | 详情 | |
| (XXXV) | 68731 | (1'R,3a'R,4a'R,8a'R,9'S,9a'S)-1'-methyl-3'-oxo-N,N-diphenyldecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-carboxamide | C28H31NO5 | 详情 | 详情 | |
| (XXXVI) | 68732 | (3S,3aS,4R,4aS,8aS,9aS)-3-methyl-1,7-dioxododecahydronaphtho[2,3-c]furan-4-carboxylic acid | C14H18O5 | 详情 | 详情 | |
| (XXXVII) | 68733 | (E)-3-(5-nitrocyclohex-1-en-1-yl)acrylic acid;3-(5-nitro-1-cyclohexenyl)-2-propenoic acid | C9H11NO4 | 详情 | 详情 | |
| (XXXVIII) | 68735 | (4R)-benzyl 4-(((E)-3-(5-nitrocyclohex-1-en-1-yl)acryloyl)oxy)pent-2-ynoate | C21H21NO6 | 详情 | 详情 | |
| (XXXIX) | 68734 | (4R)-benzyl 4-(((E)-3-(5-nitrocyclohex-1-en-1-yl)acryloyl)oxy)pent-2-enoate | C21H23NO6 | 详情 | 详情 | |
| (XL) | 68736 | (3S,3aS,4R,4aS,7R,9aS)-benzyl 3-methyl-7-nitro-1-oxo-1,3,3a,4,4a,5,6,7,8,9a-decahydronaphtho[2,3-c]furan-4-carboxylate | C21H23NO6 | 详情 | 详情 |