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【结 构 式】 
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【分子编号】68716 【品名】(E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylic acid 【CA登记号】 |
【 分 子 式 】C11H14O4 【 分 子 量 】210.22976 【元素组成】C 62.85% H 6.71% O 30.44% |
合成路线1
该中间体在本合成路线中的序号：(XVI)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：(XVI)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：(XVI)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4
该中间体在本合成路线中的序号：(XVI)Conjugate addition of acrolein (LVIII) to nitromethane in the presence of KOH in MeOH followed by treatment with Na2S2O5 in H2O gives the nitrodisulfonate (LIX), which is hydrolyzed with glyoxylic acid by means of NaHCO3 to yield 4-nitroheptanedial (LX). Compound (LX) is cyclized in the presence of pyrrolidine and PhCOOH in CH2Cl2, providing 5-nitro-1-cyclohexenecarbaldehyde (LXI). Wittig reaction of aldehyde (LXI) with (methoxycarbonylmethylene)triphenylphosphorane (LXII) leads to conjugated ester (LXIII), which is finally saponified with NaOH .
Acid (XXXVII) can be alternatively prepared by Knoevenagel condensation of aldehyde (LXI) with malonic acid (LXIV) .
Hydrolysis of ethylene ketal (XVI) with aqueous p-toluenesulfonic acid gives ketone (LXV), which, without isolation, is converted to oxime (LXVI) by addition of hydroxylamine hydrochloride. Subsequent oxidation of oxime (LXVI) using sodium molybdate and H2O2 leads to compound (XXXVII) .
| 【1】 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. |
| 【2】 Thiruvengadam, T.K., Wang, T., Chiu, J.S., Liao, J. (Schering Corp.). Synthesis of 3-(5-nitrocyclohex-1-enyl)acrylic acid and esters thereof. EP 2035364, JP 2009542675, US 2008009651, WO 2008005344. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 68716 | (E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylic acid | C11H14O4 | 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 | |
| (LVIII) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (LIX) | 68754 | sodium 1,7-dihydroxy-4-nitroheptane-1,7-disulfonate | C7H13NNa2O10S2 | 详情 | 详情 | |
| (LX) | 68755 | 4-nitroheptanedial | C7H11NO4 | 详情 | 详情 | |
| (LXI) | 68756 | 5-nitro-1-cyclohexenecarbaldehyde | C7H9NO3 | 详情 | 详情 | |
| (LXII) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (LXIII) | 68757 | (E)-methyl 3-(5-nitrocyclohex-1-en-1-yl)acrylate | C10H13NO4 | 详情 | 详情 | |
| (LXIV) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
| (LXV) | 68758 | (E)-3-(5-oxocyclohex-1-en-1-yl)acrylic acid | C9H10O3 | 详情 | 详情 | |
| (LXVI) | 68759 | (E)-3-((E)-5-(hydroxyimino)cyclohex-1-en-1-yl)acrylic acid | C9H11NO3 | 详情 | 详情 |