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【结 构 式】 
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【分子编号】68723 【品名】(R)-benzyl 4-hydroxypent-2-ynoate 【CA登记号】 |
【 分 子 式 】C12H12O3 【 分 子 量 】204.22548 【元素组成】C 70.57% H 5.92% O 23.5% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)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 |
合成路线2
该中间体在本合成路线中的序号：(XXIII)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 |
合成路线3
该中间体在本合成路线中的序号：(XXIII)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 |