-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】2-Deoxy-6-O-[2-deoxy-4-O-phosphono-3-O-[3(R)-(tetradecanoyloxy)tetradecanoyl]-2-[3(R)-(tetradecanoyloxy)tetradecanamido-beta-D-glucopyranosyl]-2-[3(R)-(tetradecanoyloxy)tetradecanamido]-D-glucopyranose triethylammonium salt

【CA登记号】220048-50-0, 220048-49-7 (free acid)

【分子式】C₁₀₂H₁₉₆N₃O₂₁P

【分子量】1831.68072

【开发单位】Corixa (Originator)

【药理作用】IMMUNOMODULATING AGENTS, Immunostimulants, Vaccine adjuvants

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

Acylation of amino alcohol (I) with (R)-3-(n-tetradecanoyloxy)tetradecanoic acid (II) employing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (EDC.MeI) provided amide (III). After hydroxyl group protection with 2,2,2-trichloroethyl chloroformate (A), the resulting acetonide (IV) was hydrolyzed with aqueous AcOH to give (V).

参考文献中间体

【1】 Sowell, C.G.; Johnson, D.A.; Keegan, D.S.; et al.; 3-O-Desacyl monophosphoryl lipid A derivatives: Synthesis and immunostimulant activities. J Med Chem 1999, 42, 22, 4640.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	13664	1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate	17341-93-4	C₃H₂Cl₄O₂	详情	详情
(I)	16046	(4aR,6R,7R,8R,8aS)-7-amino-6-(benzyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-ol		C₁₆H₂₃NO₅	详情	详情
(II)	40612	(3R)-3-(tetradecanoyloxy)tetradecanoic acid		C₂₈H₅₄O₄	详情	详情
(III)	40613	(1R)-1-(2-[[(4aR,6R,7R,8R,8aS)-6-(benzyloxy)-8-hydroxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]amino]-2-oxoethyl)dodecyl myristate		C₄₄H₇₅NO₈	详情	详情
(IV)	40614	(1R)-1-[2-[((4aR,6R,7R,8R,8aR)-6-(benzyloxy)-2,2-dimethyl-8-[[(2,2,2-trichloroethoxy)carbonyl]oxy]hexahydropyrano[3,2-d][1,3]dioxin-7-yl)amino]-2-oxoethyl]dodecyl myristate		C₄₇H₇₆Cl₃NO₁₀	详情	详情
(V)	40615	(1R)-1-[2-[((2R,3R,4R,5R,6R)-2-(benzyloxy)-5-hydroxy-6-(hydroxymethyl)-4-[[(2,2,2-trichloroethoxy)carbonyl]oxy]tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl]dodecyl myristate		C₄₄H₇₂Cl₃NO₁₀	详情	详情

合成路线2

N-Protection of amino alcohol (VI) under Schotten-Baumann conditions with 2,2,2-trichloroethyl chloroformate (B) aforded carbamate (VII). Subsequent esterification of (VII) with acid (II) provided (VIII), which was followed by acetonide hydrolysis to give diol (IX). Selective protection of the primary hydroxyl of (IX) with 1,1-dimethyl-2,2,2-trichloroethyl chloroformate (C) furnished carbonate (X). Further phosphorylation of the free secondary hydroxyl of (X) with diphenylphosphoryl chloride (D) produced phosphate ester (XI). Conversion of the trimethylsily-ethyl glycoside (XI) into the desired glycosyl chloride (XII) was then accomplished by treatment with alpha,alpha-dichloromethyl methyl ether and ZnCl2.

参考文献中间体

【1】 Sowell, C.G.; Johnson, D.A.; Keegan, D.S.; et al.; 3-O-Desacyl monophosphoryl lipid A derivatives: Synthesis and immunostimulant activities. J Med Chem 1999, 42, 22, 4640.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	13664	1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate	17341-93-4	C₃H₂Cl₄O₂	详情	详情
(D)	16074	Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate	2524-64-3	C₁₂H₁₀ClO₃P	详情	详情
(II)	40612	(3R)-3-(tetradecanoyloxy)tetradecanoic acid		C₂₈H₅₄O₄	详情	详情
(VI)	39769	(4aR,6R,7R,8R,8aS)-7-amino-2,2-dimethyl-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-8-ol		C₁₄H₂₉NO₅Si	详情	详情
(VII)	39770	2,2,2-trichloroethyl (4aR,6R,7R,8R,8aS)-8-hydroxy-2,2-dimethyl-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-7-ylcarbamate		C₁₇H₃₀Cl₃NO₇Si	详情	详情
(VIII)	39772	(4aR,6R,7R,8R,8aR)-2,2-dimethyl-7-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl (3R)-3-(tetradecanoyloxy)tetradecanoate		C₄₅H₈₂Cl₃NO₁₀Si	详情	详情
(IX)	39773	(2R,3R,4R,5R,6R)-3-hydroxy-2-(hydroxymethyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate		C₄₂H₇₈Cl₃NO₁₀Si	详情	详情
(X)	39774	(2R,3R,4R,5R,6R)-3-hydroxy-2-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate		C₄₇H₈₃Cl₆NO₁₂Si	详情	详情
(XI)	39775	(2R,3R,4R,5R,6R)-3-[(diphenoxyphosphoryl)oxy]-2-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate		C₅₉H₉₂Cl₆NO₁₅PSi	详情	详情
(XII)	40616	(2R,3R,4R,5S,6R)-2-chloro-5-[(diphenoxyphosphoryl)oxy]-6-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate		C₅₄H₇₉Cl₇NO₁₄P	详情	详情
(C)	38221	1,1,1-trichloro-2-[(chlorocarbonyl)oxy]-2-methylpropane		C₅H₆Cl₄O₂	详情	详情

合成路线3

Coupling of glycosyl chloride (XII) with glycoside (V) in the presence of silver triflate gave rise to the corresponding beta-disaccharide and subsequent reductive cleavage of the trichloro ethyl-based protecting groups with Zn/AcOH yielded disaccharide (XIII). Further N-acylation of (XIII) with acid (II) in the presence of 2-ethoxy-1-(ethoxycarbonyl)-1,2-dihydroquinoline (EEDQ) furnished amide (XIV). Finally, two-step hydrogenolytic deprotection of the benzyl and phenyl groups of (XIV) and lyophilization in the presence of triethylamine provided the title compound.

参考文献中间体

【1】 Sowell, C.G.; Johnson, D.A.; Keegan, D.S.; et al.; 3-O-Desacyl monophosphoryl lipid A derivatives: Synthesis and immunostimulant activities. J Med Chem 1999, 42, 22, 4640.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(II)	40612	(3R)-3-(tetradecanoyloxy)tetradecanoic acid	C₂₈H₅₄O₄	详情	详情
(V)	40615	(1R)-1-[2-[((2R,3R,4R,5R,6R)-2-(benzyloxy)-5-hydroxy-6-(hydroxymethyl)-4-[[(2,2,2-trichloroethoxy)carbonyl]oxy]tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl]dodecyl myristate	C₄₄H₇₂Cl₃NO₁₀	详情	详情
(XII)	40616	(2R,3R,4R,5S,6R)-2-chloro-5-[(diphenoxyphosphoryl)oxy]-6-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate	C₅₄H₇₉Cl₇NO₁₄P	详情	详情
(XIII)	40617		C₈₇H₁₄₃N₂O₁₈P	详情	详情
(XIV)	40618		C₁₁₅H₁₉₅N₂O₂₁P	详情	详情

合成路线4

In a related procedure for the synthesis of the protected precursor (XIV), the known bis(trichloroethoxycarbonyl) derivative (XV) was coupled with glycosyl chloride (XII) to give the corresponding disaccharide which was deprotected to (XVI) upon treatment with Zn/AcOH. Bis N-acylation of (XV) with acid (II) in the presence of EEDQ then provided the target intermediate (XIV).

参考文献中间体

【1】 Sowell, C.G.; Johnson, D.A.; Keegan, D.S.; et al.; 3-O-Desacyl monophosphoryl lipid A derivatives: Synthesis and immunostimulant activities. J Med Chem 1999, 42, 22, 4640.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(II)	40612	(3R)-3-(tetradecanoyloxy)tetradecanoic acid	C₂₈H₅₄O₄	详情	详情
(XII)	40616	(2R,3R,4R,5S,6R)-2-chloro-5-[(diphenoxyphosphoryl)oxy]-6-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate	C₅₄H₇₉Cl₇NO₁₄P	详情	详情
(XIV)	40618		C₁₁₅H₁₉₅N₂O₂₁P	详情	详情
(XV)	40619	(2R,3R,4R,5R,6R)-2-(benzyloxy)-5-hydroxy-6-(hydroxymethyl)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-4-yl 2,2,2-trichloroethyl carbonate	C₁₉H₂₁Cl₆NO₉	详情	详情
(XVI)	40620	(2R,3R,4R,5R,6R)-3-amino-2-[[(2R,3S,4R,5R,6R)-5-amino-6-(benzyloxy)-3,4-dihydroxytetrahydro-2H-pyran-2-yl]methoxy]-5-[(diphenoxyphosphoryl)oxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate	C₅₉H₉₁N₂O₁₅P	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)