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【结 构 式】 
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【分子编号】11171 【品名】(1R,2R,6S,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione 【CA登记号】 |
【 分 子 式 】C9H8O3 【 分 子 量 】164.16072 【元素组成】C 65.85% H 4.91% O 29.24% |
合成路线1
该中间体在本合成路线中的序号：(XXXVII)The reaction of 5-norbornen-2,3-dicarboxylic anhydride (XXXVII) with hot H2SO4 gives the lactone (XXXVIII), which is reduced with diborane in THF yielding the hydroxylactone (XXXIX). The mesylation of (XXXIX) as usual gives the ester (XL), which by reaction with NaCN in DMSO is converted into the cyanolactone (XLI). The reduction of the lactone ring with LiBH4 in diglyme affords the dihydroxynitrile (XLII), which by benzoylation and oxidation with Jones reagent yields the benzoylated cyanoketone (XLIII). The oxidation of (XLIII) with peracetic acid gives the benzoylated cyanolactone (XLIV), which by methanolysis with H2SO4 and methanol is converted into the cyanoester (XLV). The protection of the free alcohol of (XLV) with dihydropyran and debenzoylation of the resulting product affords the hydroxymethyl cyanoester (XLVI), which by oxidation with pyridinium chlorochromate is converted into the aldehyde (XLVII). The Wittig reaction of (XLVII) with the phosphonate (IX) yields the ketonic cyanoester (XLVIII), which is reduced with NaBH4 to the corresponding alcohol (XLIX). The reaction of (II) with dihydropyran affords the corresponding bis(tetrahydropyranyl) derivative (L).
| 【1】 Sugie, A.; Katsube, J.; Shimomura, H.; Yamamoto, H.; Synthetic studies on cyclopentane derivatives. Part 10. Stereocontrolled approaches to 9(O)-methanoprostacyclin. Tetrahedron Lett 1979, 28, 2607-10. |
| 【2】 Castaner, J.; Hillier, K.; Carbacyclin. Drugs Fut 1981, 6, 12, 753. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 37544 | methyl 2-[(1R,2S,3S,4R)-3-[(E,3S)-3-hydroxy-1-octenyl]-2-(2-nitriloethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]acetate | C24H39NO5 | 详情 | 详情 | |
| (IX) | 13738 | dimethyl 2-oxoheptylphosphonate; Dimethyl (2-oxoheptyl)phosphonate | 36969-89-8 | C9H19O4P | 详情 | 详情 |
| (XXXVII) | 11171 | (1R,2R,6S,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H8O3 | 详情 | 详情 | |
| (XXXVIII) | 37533 | (3R,6R,9S)-5-oxo-4-oxatricyclo[4.2.1.0(3,7)]nonane-9-carboxylic acid | C9H10O4 | 详情 | 详情 | |
| (XXXIX) | 37534 | (3R,6S,9S)-9-(hydroxymethyl)-4-oxatricyclo[4.2.1.0(3,7)]nonan-5-one | C9H12O3 | 详情 | 详情 | |
| (XL) | 37535 | (3R,6S,9S)-9-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-4-oxatricyclo[4.2.1.0(3,7)]nonan-5-one | C12H18O3S | 详情 | 详情 | |
| (XLI) | 37536 | 2-[(3R,6S,9S)-5-oxo-4-oxatricyclo[4.2.1.0(3,7)]non-9-yl]acetonitrile | C10H11NO2 | 详情 | 详情 | |
| (XLII) | 37537 | 2-[(2S,3S,5R)-5-hydroxy-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]acetonitrile | C10H15NO2 | 详情 | 详情 | |
| (XLIII) | 37538 | [(2S,3S)-3-(cyanomethyl)-6-oxobicyclo[2.2.1]hept-2-yl]methyl benzoate | C17H17NO3 | 详情 | 详情 | |
| (XLIV) | 37539 | [(6S,7R)-6-(cyanomethyl)-3-oxo-2-oxabicyclo[3.2.1]oct-7-yl]methyl benzoate | C17H17NO4 | 详情 | 详情 | |
| (XLV) | 37540 | [(1S,2S,3R,5R)-2-(cyanomethyl)-5-hydroxy-3-(2-methoxy-2-oxoethyl)cyclopentyl]methyl benzoate | C18H21NO5 | 详情 | 详情 | |
| (XLVI) | 37541 | methyl 2-[(1R,2S,3R,4R)-3-(hydroxymethyl)-2-(2-nitriloethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]acetate | C17H27NO5 | 详情 | 详情 | |
| (XLVII) | 37542 | methyl 2-[(1R,2S,3R,4R)-3-formyl-2-(2-nitriloethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]acetate | C17H25NO5 | 详情 | 详情 | |
| (XLVIII) | 37543 | methyl 2-[(1R,2S,3S,4R)-2-(2-nitriloethyl)-3-[(E)-3-oxo-1-octenyl]-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]acetate | C24H37NO5 | 详情 | 详情 | |
| (L) | 37545 | methyl 2-((1R,2S,3S,4R)-2-(2-nitriloethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-3-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]cyclopentyl)acetate | C30H49NO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)New syntheses of tandospirone have been described: 1) The hydrogenation of bicyclo[2.2.1]hept-5-ene-2,3-di-exo-carboxylic acid anhydride (I) with H2 over Pd/C in THF-water gives bicyclo[2.2.1]heptane-2,3-di-exo-carboxylic acid anhydride (II), which by reaction with ammonia in THF-water is converted into the imide (III). The reaction of (III) with 1,4-dibromobutane by means of K2CO3 in refluxing acetone yields N-(4-bromobutyl)bicyclo[2.2.1]heptane-2,3-di-exo-carboximide (IV), which is finally condensed with 1-(2-pyrimidinyl)piperazine (V) by means of K2CO3 and KI in hot DMF. 2) Imide (III) is condensed with propargyl bromide (VI) by means of K2CO3 in refluxing acetone affording N-propargylbicyclo[2.2.1]heptane-2,3-di-exo-carboximide (VII), which is allowed to react with piperazine (V) and formaldehyde by means of CuSO4 in dioxane to give N-[4-[4-(2-pyrimidinyl)piperazin-1-yl]-2-butynyl]bicyclo[2.2.1]heptane-2,3-di-exo-carboximide (VIII). Finally, this compound is reduced with H2 over Pd/C. 3) The condensation of piperazine (V) with 4-chlorobutyronitrile (IX) by means of NaOH in acetone gives 4-[4-(2-pyrimidinyl)piperazin-1-yl]butyronitrile (X), which is reduced with LiAlH4 in ether yielding 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (XI). Finally, this compound is condensed with anhydride (II) in refluxing pyridine.
| 【1】 Kojima, A.; Ishizumi, K.; Antoku, F.; Synthesis and anxiolytic activity of N-substituted cyclic imides (1R*,2S*,3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3-bicyclo[2.2.1]heptanedicarboximide (tandospirone) and related compounds. Chem Pharm Bull 1991, 39, 9, 2288. |
| 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) | 11171 | (1R,2R,6S,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H8O3 | 详情 | 详情 | |
| (II) | 11172 | (1R,2S,6R,7S)-4-Oxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | 6004-79-1 | C9H10O3 | 详情 | 详情 |
| (III) | 11173 | (1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C9H11NO2 | 详情 | 详情 | |
| (IV) | 11174 | (1R,2S,6R,7S)-4-(4-Bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C13H18BrNO2 | 详情 | 详情 | |
| (V) | 11175 | 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine | 20980-22-7 | C8H12N4 | 详情 | 详情 |
| (VI) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (VII) | 11177 | (1R,2S,6R,7S)-4-(2-Propynyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C12H13NO2 | 详情 | 详情 | |
| (VIII) | 11178 | (1R,2S,6R,7S)-4-[4-[4-(2-Pyrimidinyl)piperazino]-2-butynyl]-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C21H25N5O2 | 详情 | 详情 | |
| (IX) | 11179 | 4-Chlorobutanenitrile; 4-Chlorobutyronitrile | 628-20-6 | C4H6ClN | 详情 | 详情 |
| (X) | 11180 | 4-[4-(2-Pyrimidinyl)piperazino]butanenitrile | C12H17N5 | 详情 | 详情 | |
| (XI) | 11181 | 4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine | 33386-20-8 | C12H21N5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXVIII)Intermediate (XIb) can also be prepared by the following route. Desymmetrization of cis-5-norbornene-exo-2,3-dicarboxylic anhydride (XXVIII) with MeOH in the presence of quinine in toluene/CCl4 at –55 °C affords (1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]-hept-5-ene-2-carboxylic acid (XXIX). Activation of carboxylic acid (XXIX) with ClCOOEt in the presence of Et3N in THF followed by reaction of the resulting mixed anhydride with NaN3 results in the corresponding acyl azide, which then undergoes Curtius rearrangement in refluxing benzene to produce isocyanate (XXX). Without isolation, isocyanate (XXX) is treated with benzyl alcohol in the presence of Et3N in refluxing CH2Cl2 to give the Cbz-protected amine (XXXI). Reduction and deprotection of norbornene derivative (XXXI) with H2 over Pd/C in EtOAc followed by treatment with HCl in Et2O/dioxane gives the saturated amino ester (Vb), which is submitted to reductive alkylation with 4-fluorobenzaldehyde (IX) by means of NaBH3CN and NaOAc in MeOH .
| 【1】 Tran, C.V., Ruebsam, F., Murphy, D.E. et al. (Anadys Pharmaceuticals, Inc.). 5,6-Dihydro-1H-pyridin-2-one compounds. CA 2682584, EP 2129224, JP 2010523586, US 2010034773, US 7939524, US 8101800, US 2012130068, US 8236948, WO 2008124450. |
| 【2】 Dragovich, P.S., Thompson, P.A., Ruebsam, F. (Anadys Pharmaceuticals, Inc.). A method of inhibiting hepatitis C virus by combination of a 5,6-dihydro-1H-pyridin-2-one and one or more additional antiviral compounds. EP 2346329, US 2011229438, WO 2010042834. |
| 【3】 Ruebsam, F., Murphy, D.E., Tran, C.V. et al. Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase. Bioorg Med Chem Lett 2009, 19(22): 6404-12. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Vb) | 68658 | (±)-(1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride | C9H15NO2.HCl | 详情 | 详情 | |
| (XIb) | 68661 | (1S,2R,3S,4R)-methyl 3-((4-fluorobenzyl)amino)bicyclo[2.2.1]heptane-2-carboxylate | C16H20FNO2 | 详情 | 详情 | |
| (IX) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (XXVIII) | 11171 | (1R,2R,6S,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H8O3 | 详情 | 详情 | |
| (XXIX) | 68674 | (1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]-hept-5-ene-2-carboxylic acid | C10H12O4 | 详情 | 详情 | |
| (XXX) | 68675 | C10H11NO3 | 详情 | 详情 | ||
| (XXXI) | 68676 | (1S,2S,3R,4R)-methyl 3-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate | C17H19NO4 | 详情 | 详情 |