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【结 构 式】 
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【分子编号】11524 【品名】D-Quinic acid; D-(-)-Chinic acid; D-(-)-Quinic acid; (3R,5R)-1,3,4,5-Tetrahydroxycyclohexanecarboxylic acid 【CA登记号】77-95-2 |
【 分 子 式 】C7H12O6 【 分 子 量 】192.16868 【元素组成】C 43.75% H 6.29% O 49.95% |
合成路线1
该中间体在本合成路线中的序号：(XXV)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：(XXXVII)10) Albertini et al. reported a formal synthesis of epibatidine utilizing the enantiopure cyclohexanone (XXXVIII) as a convenient starting material which was easily available from D-(-)quinic acid (XXXVII). An important step in this synthesis was the regioselective intramolecular nucleophilic ring opening of the vicinal diol cyclic sulfate (XXXIX). When (XXXIX) was subjected to hydrogenation, the azido group was converted into an amino group and an internal displacement took place spontaneously to form the inner salt (XL). Three standard manipulations furnished the optically pure ketone (VIII), which had already been converted to epibatidine as described by Fletcher and coworkers.
| 【1】 Albertini, E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G.P.; Zanirato, V.; Enantioselective approach to 7-azabicyclo[2.2.1]heptane ring systems using D-(-)-quinic acid as the chiral educt: Application to the formal synthesis of (+)-epibatidine. Tetrahedron Lett 1997, 38, 4, 681-4. |
| 【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXL) | 16406 | (3aR,5S,7aS)-5-azidohexahydro-1,3,2lambda(6)-benzodioxathiole-2,2-dione | C6H9N3O4S | 详情 | 详情 | |
| (VIII) | 16374 | (1R,4S)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptan-2-one | C11H17NO3 | 详情 | 详情 | |
| (XXXVII) | 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 |
| (XXXVIII) | 16405 | (3aR,7aS)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-one | C9H14O3 | 详情 | 详情 | |
| (XL) | 16407 | (1R,2R,4S)-2-(sulfonatooxy)-7-azoniabicyclo[2.2.1]heptane | C6H11NO4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)1) The reaction of (-)-quinic acid (I) with 2,2-dimethoxypropane (II) and p-toluenesulfonic acid in refluxing acetone gives the protected lactone (III), which by treatment with sodium ethoxide in ethanol yields the ethyl ester (IV). The acylation of (IV) with mesyl chloride and TEA in dichloromethane affords the mesylate (V), which is dehydrated with SO2Cl2 in dichloromethane, giving the cyclohexenecarboxylate (VI). The transketalization of (VI) with 3-pentanone and HClO4 affords the 3,4-pentylidene ketal (VII), which is cleaved with borane methyl sulfide complex to the 3-pentyl ether (VIII). The epoxidation of (VIII) by treatment with KHCO3 in hot ethanol affords the epoxide (IX), which is opened with sodium azide and ammonium chloride in ethanol/water, resulting in the the azido alcohol (X). The cyclization of (X) with triphenylphosphine in refluxing THF/acetonitrile or trimethylphosphine in anhydrous acetonitrile yields aziridine (XI), which is opened by means of sodium azide in hot DMF to the azidoamine (XII). The acetylation of (XII) with acetic anhydride provides the azidoacetamide (XIII), which is reduced with H2 over Lindlar catalyst or over RaNi in ethanol and treated with 85% phosphoric acid.
| 【1】 Rohloff, J.C.; Kent, K.M.; Postich, M.J.; et al.; Practical total synthesis of the anti-influenza drug GS-4104. J Org Chem 1998, 63, 13, 4545. |
| 【2】 Castañer, J.; Leeson, P.A.; Graul, A.; Oseltamivir Phosphate. Drugs Fut 1999, 24, 11, 1189. |
| 【3】 McGee, L.R.; Kent, K.M.; Portich, M.J.; Kim, C.U.; Williams, M.A.; Zhang, L.; Prisbe, E.J.; Rohloff, J.C.; Munger, J.D.; St. John, D.E. (Gilead Sciences Inc.); Preparation of cyclohexene carboxylate derivs.. WO 9807685 . |
| 【4】 Postich, M.J.; Williams, M.A.; Rohloff, J.C.; Prisbe, E.J.; McGee, L.R.; Kent, K.M.; Munger, J.D.; Zhang, L.; Kim, C.U.; Kelly, D.E. (Gilead Sciences Inc.); Preparation of carbocyclic cpds.. US 5886213 . |
| 【5】 Bischofberger, N.W.; Kim, C.U.; Williams, M.A.; Mills, R.G.; Hitchcock, M.J.M.; Dahl, T.C.; Lew, W.; Liu, H. (Gilead Sciences Inc.); Cpds. containing six-membered rings, processes for their preparation, and their use as medicaments. EP 1015417; WO 9914185 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIII) | 29906 | ethyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C16H26N4O4 | 详情 | 详情 | |
| (I) | 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 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 29896 | (1R,2R,6R,8S)-8-hydroxy-4,4-dimethyl-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undecan-9-one | C10H14O5 | 详情 | 详情 | |
| (IV) | 29897 | ethyl (3aR,5R,7R,7aS)-5,7-dihydroxy-2,2-dimethylhexahydro-1,3-benzodioxole-5-carboxylate | C12H20O6 | 详情 | 详情 | |
| (V) | 29898 | ethyl (3aR,5S,7R,7aR)-5-hydroxy-2,2-dimethyl-7-[(methylsulfonyl)oxy]hexahydro-1,3-benzodioxole-5-carboxylate | C13H22O8S | 详情 | 详情 | |
| (VI) | 29899 | ethyl (3aR,7R,7aR)-2,2-dimethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C13H20O7S | 详情 | 详情 | |
| (VII) | 29900 | ethyl (3aR,7R,7aR)-2,2-diethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C15H24O7S | 详情 | 详情 | |
| (VIII) | 29901 | ethyl (3R,4R,5R)-3-(1-ethylpropoxy)-4-hydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate | C15H26O7S | 详情 | 详情 | |
| (IX) | 29902 | ethyl (1S,5R,6S)-5-(1-ethylpropoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C14H22O4 | 详情 | 详情 | |
| (X) | 29903 | ethyl (3R,4S,5R)-5-azido-3-(1-ethylpropoxy)-4-hydroxy-1-cyclohexene-1-carboxylate | C14H23N3O4 | 详情 | 详情 | |
| (XI) | 29904 | ethyl (1R,5R,6R)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate | C14H23NO3 | 详情 | 详情 | |
| (XII) | 29905 | ethyl (3R,4R,5S)-4-amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C14H24N4O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Reaction of quinic acid (I) with boiling cyclohexanone (II) and a trace of H2SO4 under azeotropical removal of water gave lactone-ketal (III). Subsequent alkylation with bromide (IV) and NaH in DMF at r.t. provided ether (V), which was hydrolyzed with NaOH in aqueous dioxan to produce the sodium carboxylate (VI). Protected 4-hydroxycinnamic acid (VII) was converted to the imidazolide (VIII) on treatment with carbonyl diimidazole (CDI) in DMF, and this was subsequently condensed with (VI) in the presence of NaH in DMF to afford ester (IX). Finally, deprotection of acetal and silylethoxymethyl groups with HCl in aqueous dioxan at r.t. provided the target compound.
| 【1】 Hemmerle, H.; Schindler, P.; Herling, A. (Aventis SA); Derivs. of substd. cyclohexane, their process of preparation and their application for the treatment of diseases. EP 0587088; JP 1994211736; US 5463062 . |
| 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) | 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 |
| (II) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (III) | 18750 | (3'aR,4'R,7'S,8'aR)-7'-Hydroxyspiro[cyclohexane-1,2'-[4,7]methanoperhydro[1,3]dioxolo[4,5-c]oxepin]-6'-one | C13H18O5 | 详情 | 详情 | |
| (IV) | 18751 | 1-[(1S,2R)-2-(bromomethyl)cyclopropyl]-4-chlorobenzene | C10H10BrCl | 详情 | 详情 | |
| (V) | 18752 | (3'aR,4'R,7'S,8'aR)-7'-[2(S)-(4-Chlorophenyl)cycloprop-1(R)-ylmethoxy]spiro[cyclohexane-1,2'-[4,7]methanoperhydro[1,3]dioxolo[4,5-c]oxepin]-6'-one | C23H27ClO5 | 详情 | 详情 | |
| (VI) | 18753 | (3'aR,5'S,7'R,7'aR)-5'-[2(S)-(4-Chlorophenyl)cycloprop-1(R)-ylmethoxy]-7'-hydroxyspiro[cyclohexane-1,2'-perhydro[1,3]benzodioxole]-5-carboxylic acid sodium salt | C23H28ClNaO6 | 详情 | 详情 | |
| (VII) | 18754 | (E)-3-(4-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)-2-propenoic acid | C15H22O4Si | 详情 | 详情 | |
| (VIII) | 18755 | (E)-1-(1H-imidazol-1-yl)-3-(4-[[2-(trimethylsilyl)ethoxy]methoxy]phenyl)-2-propen-1-one | C18H24N2O3Si | 详情 | 详情 | |
| (IX) | 18756 | (3'aR,5'S,7'R,7'aR)-5'-[2(S)-(4-Chlorophenyl)cycloprop-1(R)-ylmethoxy]-7'-[3-[4-[2-(trimethylsilyloxy)ethoxymethoxy]phenyl]-2(E)-propeneoyloxy]spiro[cyclohexane-1,2'-perhydro[1,3]benzodioxole]-5-carboxylic acid | C38H49ClO9Si | 详情 | 详情 |