(3S,4S,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol -Drug Synthesis Database

【结构式】

【分子编号】43107

【品名】(3S,4S,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol

【CA登记号】3458-28-4

【分子式】C₆H₁₂O₆

【分子量】180.15768

【元素组成】C 40% H 6.71% O 53.28%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

Peracetylation of (I) to yield (II), followed by treatment with thiophenol and boron trifluoride, afforded the mannopyranoside (III). After methanolysis of the acetate esters of (III) in the presence of NaOMe, the resultant tetrahydroxy derivative (IV) was protected as the bis-acetonide (V) by treatment with 2,2-dimethoxypropane and 10-camphorsulfonic acid. The phenylsulfanyl group of (V) was reductively removed by means of lithium and a catalytic amount of naphthalene, yielding the dihydropyran derivative (VI). The free hydroxyl group of (VI) was then esterified with Ac2O in pyridine to give (VII). Addition of sodium azide to dihydropyran (VII) in the presence of cerium ammonium nitrate furnished the azido nitrate (VIII). The nitrate ester of (VIII) was then selectively cleaved by means of sodium nitrite, giving alcohol (IX), which was further protected by silylation with tert-butyldimethylsilyl chloride and imidazole to provide silyl ether (X). Subsequent alcoholysis of the acetate ester group of (X) in the presence of NaOMe provided the key intermediate (XI).

参考文献中间体

合成目标

【1】 Christ, W.J.; Kawata, T.; Hawkins, L.D.; Kobayashi, S.; Asano, O.; Rossignol, D.P. (Eisai Co., Ltd.); Anti-endotoxin cpds.. EP 0536969; JP 1993194470; US 5530113 .

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)	43107	(3S,4S,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol	3458-28-4	C₆H₁₂O₆	详情	详情
(II)	54319	[(2R,3R,4S,5S,6R)-3,4,5,6-tetrakis(acetyloxy)tetrahydro-2H-pyran-2-yl]methyl acetate	n/a	C₁₆H₂₂O₁₁	详情	详情
(III)	59072	(2R,3S,4S,5S)-3,5-bis(acetyloxy)-2-[(acetyloxy)methyl]-6-(phenylsulfanyl)tetrahydro-2H-pyran-4-yl acetate		C₂₀H₂₄O₉S	详情	详情
(IV)	59073	(2R,3S,4S,5S)-2-(hydroxymethyl)-6-(phenylsulfanyl)tetrahydro-2H-pyran-3,4,5-triol		C₁₂H₁₆O₅S	详情	详情
(V)	59074	(3aS,4S,5aR,9aS,9bR)-2,2,8,8-tetramethyl-4-(phenylsulfanyl)hexahydro[1,3]dioxolo[4',5':4,5]pyrano[3,2-d][1,3]dioxine; (3aS,4S,5aR,9aS,9bR)-2,2,8,8-tetramethylhexahydro[1,3]dioxolo[4',5':4,5]pyrano[3,2-d][1,3]dioxin-4-yl phenyl sulfide		C₁₈H₂₄O₅S	详情	详情
(VI)	59075	(4aR,8R,8aS)-2,2-dimethyl-4,4a,8,8a-tetrahydropyrano[3,2-d][1,3]dioxin-8-ol		C₉H₁₄O₄	详情	详情
(VII)	59076	(4aR,8R,8aR)-2,2-dimethyl-4,4a,8,8a-tetrahydropyrano[3,2-d][1,3]dioxin-8-yl acetate		C₁₁H₁₆O₅	详情	详情
(VIII)	59077	(4aR,7R,8R,8aR)-7-azido-2,2-dimethyl-6-(nitrooxy)hexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate		C₁₁H₁₆N₄O₈	详情	详情
(IX)	59078	(4aR,7R,8R,8aR)-7-azido-6-hydroxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate		C₁₁H₁₇N₃O₆	详情	详情
(X)	59079	(4aR,6S,7R,8R,8aR)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate		C₁₇H₃₁N₃O₆Si	详情	详情
(XI)	59080	(4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-ol		C₁₅H₂₉N₃O₅Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The selective tosylation of D-mannose (I) with Ts-Cl in pyridine gives 6-O-tosyl-D-mannose (II), which is cyclized by means of NaOH in pyridine/water, yielding 1,6-anhydro-D-mannose (III) (1). The protection of (III) with 2,2-dimethoxypropane (IV) and TsOH in acetone gives the isopropylidene ketal (V), which is acylated with benzoyl chloride in pyridine, yielding benzoate (VI). The deprotection of (VI) with H2SO4 in dioxane affords 4-O-benzoyl-1,6-anhydro-D-mannose (VII), which is treated first with NaIO4 and then reduced with NaBH4, providing the dioxolane (VIII). This compound without isolation is rearranged in basic medium to the dioxolane (IX), which is selectively silylated with Tbdps-Cl to give the silyl ether (X). The hydrolysis of (X) with NaOMe in methanol yields the diol (XI), which is oxidized with NaIO4 and RuO2 in acetonitrile, affording the carboxylic acid (XII). The modified Hunsdiecker reaction of (XII) with Pb(OAc)4 in ethyl acetate yields the acetoxydioxolane (XIII) (2-4), which is condensed with 6-chloro-2-fluoro-9-(trimethylsilyl)purine (XIV) by means of Tms-OTf in dichloromethane to afford the nucleoside (XV). The reaction of (XV) with NH3 in dimethoxyethane gives the 2-amino-6-chloronucleoside (XVI), which is treated with NH3 in methanol to yield the 2,6-diaminonucleoside (XVII). Finally, this compound is desilylated with TBAF in THF.

参考文献中间体

合成目标

【1】 Zottola, M.A.; Vite, G.D.; Alonso, R.; Fraser-Reid, B.; A practical efficient large-scale synthesis of 1,6-anhydrohexopyranoses. J Org Chem 1989, 54, 26, 6123.
【2】 Ahn, S.K.; Choi, B.G.; Schinazi, R.F.; Alves, A.J.; Kim, H.O.; Chu, C.K.; Van Roey, P.; Beach, J.W.; Jeong, L.S.; Asymetric synthesis of 1,3-dioxolane-pyrimidine nucleosides and their anti-HIV activity. J Med Chem 1992, 35, 11, 1987.
【3】 Chu, C.K.; Schinazi, R.F. (Emory University; University of Georgia); Enantiomerically pure beta-D-dioxolane-nucleosides. US 5925643; WO 9404154 .
【4】 Schinazi, R.P. (Emory University); Enantiomerically pure beta-D-dioxolane nucleosides with selective anti-hepatitis B virus activity. JP 1996507286; US 5444063; WO 9409793 .
【5】 Islam, Q.; Kim, K.O.; Alves, A.J.; Van Roey, P.; Chu, C.K.; Ahn, S.K.; Schinazi, R.F.; Beach, J.W.; Jeong, L.S.; Asymmetric synthesis of enantiomerically pure (-)-(1'R,4'R)-dioxolane-thymine and its anti-HIV activity. Tetrahedron Lett 1991, 32, 31, 3791.
【6】 Schinazi, R.F.; Nampalli, S.; Shanmuganathan, K.; Cannon, D.L.; Alves, A.J.; Jeong, L.S.; Beach, J.W.; Chu, C.K.; Kim, H.O.; 1,3-Dioxolanylpurine nucleosides (2R,4R) and (2R,4S) with selective anti-HIV-1 activity in human lymphocytes. J Med Chem 1993, 36, 1, 30.

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)	43107	(3S,4S,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol	3458-28-4	C₆H₁₂O₆	详情	详情
(II)	43108	[(2R,3S,4S,5S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl]methyl 4-methylbenzenesulfonate		C₁₃H₁₈O₈S	详情	详情
(III)	43109	(1R,2S,3S,4S,5R)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol	498-07-7	C₆H₁₀O₅	详情	详情
(IV)	43110	1,1-dimethoxy-2-methylpropane; 1-methoxy-2-methylpropyl methyl ether	41632-89-7	C₆H₁₄O₂	详情	详情
(V)	43111	(1R,2S,6S,7R,8R)-4,4-dimethyl-3,5,10,11-tetraoxatricyclo[6.2.1.0(2,6)]undecan-7-ol	14440-51-8	C₉H₁₄O₅	详情	详情
(VI)	43112	(1R,2S,6R,7R,8R)-4,4-dimethyl-3,5,10,11-tetraoxatricyclo[6.2.1.0(2,6)]undec-7-yl benzoate		C₁₆H₁₈O₆	详情	详情
(VII)	43113	(1R,2S,3R,4S,5R)-3,4-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-2-yl benzoate		C₁₃H₁₄O₆	详情	详情
(VIII)	43114	(1S)-2-hydroxy-1-[(2R,4R)-2-(hydroxymethyl)-1,3-dioxolan-4-yl]ethyl benzoate		C₁₃H₁₆O₆	详情	详情
(IX)	43115	(2S)-2-hydroxy-2-[(2R,4R)-2-(hydroxymethyl)-1,3-dioxolan-4-yl]ethyl benzoate		C₁₃H₁₆O₆	详情	详情
(X)	43116	(2S)-2-[(2R,4R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1,3-dioxolan-4-yl]-2-hydroxyethyl benzoate		C₂₉H₃₄O₆Si	详情	详情
(XI)	43117	(1S)-1-[(2R,4R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1,3-dioxolan-4-yl]-1,2-ethanediol		C₂₂H₃₀O₅Si	详情	详情
(XII)	43118	(2R,4R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1,3-dioxolane-4-carboxylic acid		C₂₁H₂₆O₅Si	详情	详情
(XIII)	43119	(2R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1,3-dioxolan-4-yl acetate		C₂₂H₂₈O₅Si	详情	详情
(XIV)	43120	6-chloro-2-fluoro-9-(trimethylsilyl)-9H-purine		C₈H₁₀ClFN₄Si	详情	详情
(XV)	43121	9-[(2R,4R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1,3-dioxolan-4-yl]-6-chloro-2-fluoro-9H-purine; tert-butyl(diphenyl)silyl [(2R,4R)-4-(6-chloro-2-fluoro-9H-purin-9-yl)-1,3-dioxolan-2-yl]methyl ether		C₂₅H₂₆ClFN₄O₃Si	详情	详情
(XVI)	43122	9-[(2R,4R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1,3-dioxolan-4-yl]-6-chloro-9H-purin-2-amine; 9-[(2R,4R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1,3-dioxolan-4-yl]-6-chloro-9H-purin-2-ylamine		C₂₅H₂₈ClN₅O₃Si	详情	详情
(XVII)	43123	9-[(2R,4R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1,3-dioxolan-4-yl]-9H-purine-2,6-diamine; 2-amino-9-[(2R,4R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1,3-dioxolan-4-yl]-9H-purin-6-ylamine		C₂₅H₃₀N₆O₃Si	详情	详情

Extended Information