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【结 构 式】 
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【药物名称】Vorapaxar;Sch-530348 【化学名称】N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[2-[5-(3-Fluorophenyl)pyridin-2-yl]vinyl]-1-methyl-3-oxoperhydronaphtho[2,3-c]furan-6-yl]carbamic acid ethyl ester 【CA登记号】618385-01-6；750634-26-5 【 分 子 式 】C29H33FN2O4 【 分 子 量 】492.5817 |
【开发单位】Merck & Co., Inc. (US) 【药理作用】PAR1 Receptor Antagonist；Antiplatelet Therapy |
合成路线1
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
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
Protection of 2(R)-butynol (XXI) with HMDS by means of H2SO4 in refluxing THF gives the corresponding silyl ether (XXVIII), which, after deprotonation with hexyl lithium, undergoes carbamoylation with 1-(diphenylcarbamoyl)imidazole (XXIX) in THF/toluene, yielding 4(R)-hydroxy-N,N-diphenyl-2-pentynamide (XXX) . Alternatively, propargylic alcohol (XXX) is obtained by enzymatic resolution of racemic 4-hydroxy-N,N-diphenyl-2-pentynamide (XXXI) by means of vinyl acetate in the presence of selected lipase enzymes, producing a mixture of ureacted (S)-alcohol and (R)-acetate ester, which, after isolation, is hydrolyzed with KOH or with hydrolase enzyme . Reduction of propargyl derivative (XXX) with H2 over Lindlar catalyst in EtOAc affords 4(R)-hydroxy-N,Ndiphenyl-2-pentenamide (XXXII), which is then coupled with carboxylic acid (XVI) via the mixed anhydride method or with EDC and DMAP, providing ester (XXXIII). Intramolecular Diels–Alder reaction of triene (XXXIII) in refluxing xylene followed by epimerization by treatment with DBU leads to the decahydronaphtho[2,3-c]furan derivative (XXXIV), which by subsequent catalytic hydrogenation over Pt/C in EtOAc yields the saturated compound (XXXV). Finally, hydrolysis of N,N-diphenylamide (XXXV) with NaOH followed by ketal hydrolysis by means of HCl furnishes the keto acid (XXXVI), which is then reductively aminated to afford intermediate (IX) .
Alternatively, esterification of 3-(5-nitro-1-cyclohexenyl)-2-propenoic acid (XXXVII) with benzyl 4(R)-hydroxy-2-pentynoate (XXIII) via the mixed anhydride method gives the corresponding ester (XXXVIII), which by reduction of its alkyne group with H2 over Lindlar catalyst in toluene yields olefin (XXXIX). Diels–Alder cyclization of triene (XXXIX) in xylene at 150 °C followed by treatment with DBU furnishes the tricyclic nitro intermediate (XL), which is finally reduced with H2 over Pt/C in EtOAc .
| 【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. |
| 【3】 Li, T., Tamarez, M.M., Zaks, A. (Schering Corp.). Preparation of chiral propargylic alcohol and ester intermediates of himbacine analogs. CA 2594742, EP 1848683, JP 2008526254, US 2006172397, WO 2006076565. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|
合成路线4
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5
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 |
合成路线6
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 |
合成路线7
Rearrangement of 5-bromo-2-methylpyridine 1-oxide (LXVII) with trifluoroacetic anhydride gives (5-bromopyridin-2-yl)methyl trifluoroacetate (LXVIII), which, without isolation, is hydrolyzed in MeOH solution, yielding (5-bromopyridin-2-yl)methanol trifluoroacetate salt (LXIX). Basification of compound (LXIX) with K2CO3 followed by chlorination with SOCl2 affords 5-bromo-2-(chloromethyl)pyridine (LXX), which is subsequently condensed with diethyl phosphite in the presence of LiHMDS, affording phosphonate (LXXI). Finally, Suzuki coupling of bromopyridine derivative (LXXI) with 3-fluorophenylboronic acid (V) by means of Na2CO3 and Pd/C in H2O at 75 °C provides the phenylpyridine compound (XII) .
O-Protection of 6-methyl-3-pyridinol (LXXII) with TIPSCl in DMF gives the corresponding silyl ether (LXXIII), which is then condensed with diethyl chlorophosphate (LXXIV) in the presence of BuLi and DIEA in THF, yielding diethyl phosphonate (II) .
| 【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】 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 |
|---|---|---|---|---|---|---|
| (II) | 68703 | diethyl ((5-((triisopropylsilyl)oxy)pyridin-2-yl)methyl)phosphonate | C19H36NO4PSi | 详情 | 详情 | |
| (V) | 68704 | 3-fluorophenylboronic acid;3-Fluorobenzeneboronic acid | 768-35-4 | C6H6BFO2 | 详情 | 详情 |
| (XII) | 68705 | diethyl ((5-(3-fluorophenyl)pyridin-2-yl)methyl)phosphonate | C16H19FNO3P | 详情 | 详情 | |
| (LXVII) | 68760 | 5-bromo-2-methylpyridine 1-oxide；5-bromo-2-Picoline-1-oxide；3-Bromo-6-methylpyridine 1-oxide;5-bromo-2-methylpyridine N-oxide;5-Bromo-2-picoline N-oxide | 31181-64-3 | C6H6BrNO | 详情 | 详情 |
| (LXVIII) | 68761 | (5-bromopyridin-2-yl)methyl trifluoroacetate；(5-bromopyridin-2-yl)methyl 2,2,2-trifluoroacetate | C8H5BrF3NO2 | 详情 | 详情 | |
| (LXIX) | 68762 | (5-bromopyridin-2-yl)methanol 2,2,2-trifluoroacetate | C6H6BrNO.C2HF3O2 | 详情 | 详情 | |
| (LXX) | 68763 | 5-bromo-2-(chloromethyl)pyridine | 168823-76-5 | C6H5BrClN | 详情 | 详情 |
| (LXXI) | 68764 | diethyl ((5-bromopyridin-2-yl)methyl)phosphonate | C10H15BrNO3P | 详情 | 详情 | |
| (LXXII) | 25748 | 6-methyl-3-pyridinol; 5-Hydroxy-2-methylpyridine | 1121-78-4 | C6H7NO | 详情 | 详情 |
| (LXXIV) | 68765 | 2-methyl-5-((triisopropylsilyl)oxy)pyridine | C15H27NOSi | 详情 | 详情 | |
| (LXXV) | 23623 | Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate | 814-49-3 | C4H10ClO3P | 详情 | 详情 |