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【结 构 式】 
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【分子编号】11528 【品名】(1R,4R,5R)-4-Hydroxy-6-oxabicyclo[3.2.1]octan-7-one 【CA登记号】 |
【 分 子 式 】C7H10O3 【 分 子 量 】142.1546 【元素组成】C 59.14% H 7.09% O 33.76% |
合成路线1
该中间体在本合成路线中的序号：(XXIX)2) [2S,3S,5S,6R,7S,8E,9(1'R,3'R,4'R)]-2-Allyl-3-(tert-butyldimethylsilylox y)-6,8-dimethyl-7-(triethylsilyloxy)-5-(triisopropylsilyloxy)-9-[3-meth oxy-4-(triisopropylsilyloxy)cyclohexyl]-8-nonenal (LI). Quinic acid (XXV) is converted into the lactone (XXVI) by known methods. Then this lactone is treated with thiocarbonyldiimidazole in refluxing dichloroethane yielding the bis(thiocarbonyl)lactone (XXVII), which by reaction with tributyltin hydride and AIBN in refluxing xylene is converted into the lactone (XXIX), either directly or through the intermediate thiocarbonyl-lactone (XXVIII). The silylation of (XXIX) with TIPS-SO3CF3 as usual affords the protected lactone (XXX). Opening of the lactone ring with methylchloroaluminum N-methoxy-N-methylamide gives the methoxyamide (XXXI), which is methylated with methyl trifluoromethylsulfonate to the methoxy-N-methoxyamide (XXXII). The reduction of (XXXII) with diisobutylaluminum hydride gives the aldehyde (XXXIII), which is condensed with 2-lithio-2-(triethylsilyl)propanal (XXXIV), yielding unsaturated aldehyde (XXXV). The condensation of (XXXV) with the boron enolate of oxazolidone (XXVI) affords the oxazolidone derivative (XXXVII), which is treated with methylchloroaluminum N-methoxy-N-methylamide to give the methoxyamide (XXXVIII). The silylation of (XXXVIII) with TES-SO3CF3 as usual yields the silylated amide (XXXIX), which is reduced with diisobutylaluminum hydride to the aldehyde (XL). The condensation of (XL) with chiral acetate (XLI) by means of lithium diisopropylamide in THF affords the hydroxy ester (XLII). Transesterification of (XLII) with NaOCH3 and methanol gives methyl ester (XLIII).
| 【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 63305 | di(1H-imidazol-2-yl)methanethione | C7H6N4S | 详情 | 详情 | ||
| 63306 | C3H9AlClNO | 详情 | 详情 | |||
| (XXV) | 11524 | D-Quinic acid; D-(-)-Chinic acid; D-(-)-Quinic acid; (3R,5R)-1,3,4,5-Tetrahydroxycyclohexanecarboxylic acid | 77-95-2 | C7H12O6 | 详情 | 详情 |
| (XXVI) | 11525 | (1S,3R,4R,5R)-1,3,4-Trihydroxy-6-oxabicyclo[3.2.1]octan-7-one | C7H10O5 | 详情 | 详情 | |
| (XXVII) | 11526 | O-[(1R,2S,6R)-9-oxo-4-thioxo-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undec-8-yl] 1H-imidazole-1-carbothioate | C12H10N2O5S2 | 详情 | 详情 | |
| (XXVIII) | 11527 | (1R,2S,6R,8S)-4-Thioxo-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undecan-9-one | C8H8O4S | 详情 | 详情 | |
| (XXIX) | 11528 | (1R,4R,5R)-4-Hydroxy-6-oxabicyclo[3.2.1]octan-7-one | C7H10O3 | 详情 | 详情 | |
| (XXX) | 11529 | (1R,4R,5R)-4-[(Triisopropylsilyl)oxy]-6-oxabicyclo[3.2.1]octan-7-one | C16H30O3Si | 详情 | 详情 | |
| (XXXI) | 11530 | (1R,3R,4R)-3-Hydroxy-N-methoxy-N-methyl-4-[(triisopropylsilyl)oxy]cyclohexanecarboxamide | C18H37NO4Si | 详情 | 详情 | |
| (XXXII) | 11531 | (1R,3R,4R)-N,3-Dimethoxy-N-methyl-4-[(triisopropylsilyl)oxy]cyclohexanecarboxamide | C19H39NO4Si | 详情 | 详情 | |
| (XXXIII) | 11532 | (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde | C17H34O3Si | 详情 | 详情 | |
| (XXXIV) | 11533 | [1-Methyl-1-[(4-methylphenyl)sulfonyl]-2-oxoethyl]lithium | C10H11LiO3S | 详情 | 详情 | |
| (XXXV) | 11534 | (E)-3-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2-methyl-2-propenal | C20H38O3Si | 详情 | 详情 | |
| (XXXVI) | 11535 | (4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one | 77877-19-1 | C9H15NO3 | 详情 | 详情 |
| (XXXVII) | 11536 | (4S)-3-((2S,3S,4E)-3-Hydroxy-5-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4-dimethyl-4-pentenoyl)-4-isopropyl-1,3-oxazolidin-2-one | C29H53NO6Si | 详情 | 详情 | |
| (XXXVIII) | 11537 | (2S,3S,4E)-3-Hydroxy-N-methoxy-5-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-N,2,4-trimethyl-4-pentenamide | C25H49NO5Si | 详情 | 详情 | |
| (XXXIX) | 11538 | (2S,3S,4E)-N-Methoxy-5-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-N,2,4-trimethyl-3-[(triethylsilyl)oxy]-4-pentenamide | C31H63NO5Si2 | 详情 | 详情 | |
| (XL) | 11539 | (2S,3S,4E)-5-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4-dimethyl-3-[(triethylsilyl)oxy]-4-pentenal | C29H58O4Si2 | 详情 | 详情 | |
| (XLI) | 11540 | (1S)-2-hydroxy-1,2,2-triphenylethyl acetate; (R)-(+)-1,1,2-Triphenyl-1,2-ethanediol 2-acetate | 95061-47-5 | C22H20O3 | 详情 | 详情 |
| (XLII) | 11541 | (1S)-2-hydroxy-1,2,2-triphenylethyl (3S,4R,5S,6E)-3-hydroxy-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-heptenoate | C51H78O7Si2 | 详情 | 详情 | |
| (XLIII) | 11542 | methyl (3S,4R,5S,6E)-3-hydroxy-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-heptenoate | C32H64O6Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The reaction of the labeled acylated (+)-bornane-10,2-sultam (IV) with triethyl phosphite gives the phosphonate (V), which is treated with paraformaldehyde, galvinoxyl and K2CO3 yielding the acrylate derivative (VI). The cyclization of (VI) with butadiene (VII) by means of diethylaluminum chloride and galvinoxyl (as radical scavenger) affords the cyclohexene-carboxamide derivative (VIII), which is hydrolyzed with LiOH in THF/water giving the (1R)-3-cyclohexenecarboxylic acid (IX). The oxidation of (IX) with m-chloroperbenzoic acid and triethylamine in CCl4 yielded regioselectively the hydroxylactone (X), which is finally hydrolyzed with HCl to the labeled intermediate (I).
| 【1】 Moenius, T.; et al.; C-14 labelling of NVP RAD001 - A new rapamycin derivative. J Label Compd Radiopharm 1999, 42, 1, 29. |
| 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) | 32019 | (1R,3R,4R)-3,4-dihydroxycyclohexanecarboxylic acid | C7H12O4 | 详情 | 详情 | |
| (I) | 45302 | (1R,3R,4R)-3,4-dihydroxycyclohexanecarboxylic acid | C7H12O4 | 详情 | 详情 | |
| (IV) | 32020 | (1S,5S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C12H18BrNO3S | 详情 | 详情 | |
| (IV) | 45305 | (1S,5S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C12H18BrNO3S | 详情 | 详情 | |
| (V) | 32021 | diethyl 2-[(1S,5S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]-2-oxoethylphosphonate | C16H28NO6PS | 详情 | 详情 | |
| (V) | 45306 | diethyl 2-[(1S,5S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]-2-oxoethylphosphonate | C16H28NO6PS | 详情 | 详情 | |
| (VI) | 32022 | (1S,5S)-4-acryloyl-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C13H19NO3S | 详情 | 详情 | |
| (VI) | 45307 | (1S,5S)-4-acryloyl-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C13H19NO3S | 详情 | 详情 | |
| (VII) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (VIII) | 32023 | (1S,5S)-4-[(1R)-3-cyclohexen-1-ylcarbonyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C17H25NO3S | 详情 | 详情 | |
| (VIII) | 45308 | (1S,5S)-4-[(1R)-3-cyclohexen-1-ylcarbonyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C17H25NO3S | 详情 | 详情 | |
| (IX) | 11581 | (1R)-3-Cyclohexene-1-carboxylic acid | C7H10O2 | 详情 | 详情 | |
| (IX) | 45309 | (1R)-3-cyclohexene-1-carboxylic acid | C7H10O2 | 详情 | 详情 | |
| (X) | 11528 | (1R,4R,5R)-4-Hydroxy-6-oxabicyclo[3.2.1]octan-7-one | C7H10O3 | 详情 | 详情 | |
| (X) | 45310 | (1R,4R,5R)-4-hydroxy-6-oxabicyclo[3.2.1]octan-7-one | C7H10O3 | 详情 | 详情 |