[(2R,3R,4S,5S,6R)-3,4,5,6-tetrakis(acetyloxy)tetrahydro-2H-pyran-2-yl]methyl acetate -Drug Synthesis Database

【结构式】

【分子编号】54319

【品名】[(2R,3R,4S,5S,6R)-3,4,5,6-tetrakis(acetyloxy)tetrahydro-2H-pyran-2-yl]methyl acetate

【CA登记号】n/a

【分子式】C₁₆H₂₂O₁₁

【分子量】390.34408

【元素组成】C 49.23% H 5.68% O 45.09%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(II)

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：(V)

The Friedel-Crafts condensation of 2-(2'-methoxybiphenyl-3-yl)acetic acid ethyl ester (I) with adipoyl dichloride (II) by means of AlCl3 gives the adduct (III), which is treated with BBr3 to cleave the methoxy groups and yield the diphenolic compound (IV). The condensation of (IV) with alpha-D-mannose pentaacetate (V) by means of BF3/Et2O affords the bis glycoside (VI), which is hydrolyzed with aq. LiOH aq. or NaOH to provide the dicarboxylic acid (VII). Finally, both ketonic groups of (VII) are reduced with LiOH and N2H4, or with Et3SiH, TFA and BF3/Et2O, or with H2, Pd(OH)2 and BBr3, to furnish the target bis mannopyranoside.

参考文献中间体

合成目标

【1】 Dupré, B.; Beck, P.J.; Vanderslice, P.; Hu, X.; Scott, I.L.; Kassir, J.M.; McAbee, K.L.; Bui, H.; Dixon, R.A.F.; Kogan, T.P.; Novel synthetic inhibitors of selectin-mediated cell adhesion: Synthesis of 1, 6-bis[3-(3-carboxymethylphenyl)-4-(2-alpha-D-mannopyranosyloxy)phenyl]hexane (TBC1269). J Med Chem 1998, 41, 7, 1099.

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)	54316	ethyl 2-(2'-methoxy[1,1'-biphenyl]-3-yl)acetate	n/a	C₁₇H₁₈O₃	详情	详情
(II)	52933	Hexanedioyl dichloride; Adipoyl chloride		C₆H₈Cl₂O₂	详情	详情
(III)	54317	ethyl 2-(5'-{6-[3'-(2-ethoxy-2-oxoethyl)-6-methoxy[1,1'-biphenyl]-3-yl]-6-oxohexanoyl}-2'-methoxy[1,1'-biphenyl]-3-yl)acetate	n/a	C₄₀H₄₂O₈	详情	详情
(IV)	54318	ethyl 2-(5'-{6-[3'-(2-ethoxy-2-oxoethyl)-6-hydroxy[1,1'-biphenyl]-3-yl]-6-oxohexanoyl}-2'-hydroxy[1,1'-biphenyl]-3-yl)acetate	n/a	C₃₈H₃₈O₈	详情	详情
(V)	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
(VI)	54320	ethyl 2-[5'-{6-[3'-(2-ethoxy-2-oxoethyl)-6-({(2R,3S,4S,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)[1,1'-biphenyl]-3-yl]-6-oxohexanoyl}-2'-({(3S,4S,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)[1,1'-biphenyl]-3-yl]acetate	n/a	C₆₆H₇₄O₂₆	详情	详情
(VII)	54321	2-(5'-[6-(3'-(2-hydroxy-2-oxoethyl)-6-{[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}[1,1'-biphenyl]-3-yl)-6-oxohexanoyl]-2'-{[(3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}[1,1'-biphenyl]-3-yl)acetic acid	n/a	C₄₆H₅₀O₁₈	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

The Friedel-Crafts condensation of 2-(2'-methoxybiphenyl-3-yl)acetic acid (VIII) with adipoyl dichloride (II) by means of AlCl3 in dichloromethane gives the adduct (IX), which is submitted to reduction of both carbonyl groups by means of LiOH and N2H4, or with Et3SiH, TFA and BF3/Et2O, or with H2, Pd(OH)2 and BBr3, to yield the hexane-1,6-diyl derivative (X). The cleavage of the methoxy groups of (X) by means of BBr3 in dichloromethane affords the bis phenolic compound (XI), which is condensed with alpha-D-mannose pentaacetate (V) by means of BF3/Et2O in dichloroethane to provide the bis glycoside (XII). Finally, this compound is hydrolyzed with LiOH in water to furnish the target bis mannopyranoside.

参考文献中间体

合成目标

【1】 Mukherjee, A.K.; Dasgupta, F.; Novel synthetic inhibitors of selection-mediated cell adhesion: Synthesis of 1,6-bis [3-(3-carboxymethylphenyl)-4-(O-alpha-D-mannopyranosyl)phenyl]hexane (TBC 1269). Chemtracts - Org Chem 2000, 13, 9, 1431.
【2】 Kogan, T.P.; Dupre, B.; Scott, I.L.; Bui, H.; Wheeler, K.L.; Keller, K.M.; Kassir, J.M. (Texas Biotechnology Corp.); Di- and trivalent small molecule selectin inhibitors. JP 1999508885; WO 9701335 .

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)	52933	Hexanedioyl dichloride; Adipoyl chloride		C₆H₈Cl₂O₂	详情	详情
(V)	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
(VIII)	54322	2-(2'-methoxy[1,1'-biphenyl]-3-yl)acetic acid	187269-42-7	C₁₅H₁₄O₃	详情	详情
(IX)	54323	2-(5'-{6-[3'-(2-hydroxy-2-oxoethyl)-6-methoxy[1,1'-biphenyl]-3-yl]-6-oxohexanoyl}-2'-methoxy[1,1'-biphenyl]-3-yl)acetic acid	n/a	C₃₆H₃₄O₈	详情	详情
(X)	54324	2-(5'-{6-[3'-(2-hydroxy-2-oxoethyl)-6-methoxy[1,1'-biphenyl]-3-yl]hexyl}-2'-methoxy[1,1'-biphenyl]-3-yl)acetic acid	n/a	C₃₆H₃₈O₆	详情	详情
(XI)	54325	2-(2'-hydroxy-5'-{6-[6-hydroxy-3'-(2-hydroxy-2-oxoethyl)[1,1'-biphenyl]-3-yl]hexyl}[1,1'-biphenyl]-3-yl)acetic acid	n/a	C₃₄H₃₄O₆	详情	详情
(XII)	54326	2-[5'-{6-[3'-(2-hydroxy-2-oxoethyl)-6-({(2R,3S,4S,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)[1,1'-biphenyl]-3-yl]hexyl}-2'-({(3S,4S,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)[1,1'-biphenyl]-3-yl]acetic acid	n/a	C₆₂H₇₀O₂₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(V)

Treatment of alpha-D-mannose pentaacetate (V) with HF and pyridine in dichloromethane furnishes 2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl fluoride (XIII), which is saponified with K2CO3 in MeOH and then submited to reesterification with pivaloyl chloride and DMAP in pyridine to yield the tetra-O-pivaloyl derivative (XIV). Mannosylation of compound (XV) with the pivaloyl protected compound (XIV) affords the bis glycoside derivative (XVI), which is finally converted into the desired product by first removal of the pivaloyl groups with NaOMe in MeOH/THF, followed by saponification of the ethyl ester groups with aqueous NaOH.

参考文献中间体

合成目标

【1】 Scott, I.L.; et al.; Stereospecific alpha-D-mannosylation. Carbohydr Res 1999, 317, 1-4, 210.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	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
(XIII)	54329	(2R,3S,4S,5S,6R)-3,5-bis(acetyloxy)-2-[(acetyloxy)methyl]-6-fluorotetrahydro-2H-pyran-4-yl acetate	n/a	C₁₄H₁₉FO₉	详情	详情
(XIV)	54328	(2R,3S,4S,5S,6R)-3,5-bis[(2,2-dimethylpropanoyl)oxy]-2-{[(2,2-dimethylpropanoyl)oxy]methyl}-6-fluorotetrahydro-2H-pyran-4-yl pivalate	n/a	C₂₆H₄₃FO₉	详情	详情
(XV)	54327	ethyl 2-(5'-{6-[3'-(2-ethoxy-2-oxoethyl)-6-hydroxy[1,1'-biphenyl]-3-yl]hexyl}-2'-hydroxy[1,1'-biphenyl]-3-yl)acetate	n/a	C₃₈H₄₂O₆	详情	详情
(XVI)	54330	(2R,3R,4S,5S)-3,5-bis[(2,2-dimethylpropanoyl)oxy]-2-{[(2,2-dimethylpropanoyl)oxy]methyl}-6-{[3'-(2-ethoxy-2-oxoethyl)-5-(6-{3'-(2-ethoxy-2-oxoethyl)-6-[((2R,3S,4S,5R,6R)-3,4,5-tris[(2,2-dimethylpropanoyl)oxy]-6-{[(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-pyran-2-yl)oxy][1,1'-biphenyl]-3-yl}-6-oxohexanoyl)[1,1'-biphenyl]-2-yl]oxy}tetrahydro-2H-pyran-4-yl 2,2-dimethylpropanoate	n/a	C₉₀H₁₂₂O₂₆	详情	详情

Extended Information