-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】P1-[2-Acetamido-3-O-[(2-carboxypropyl)(hydroxy)phosphorylmethyl]-2-deoxy-alpha-D-glucopyranosyl]-P2-(uridin-5'-yl)diphosphate

【CA登记号】356785-78-9

【分子式】C₂₂H₃₆N₃O₂₁P₃

【分子量】771.46112

【开发单位】AstraZeneca (Originator)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY

合成路线1 合成路线2

合成路线1

Mesylate (II), prepared from the (hydroxymethyl)phosphinic acid derivative (I), was condensed with the protected glucosamine (III) in the presence of NaH to produce the phosphinate adduct (IV) as a diastereomeric mixture. Selective removal of the P-acetyl ketal group of (IV) with chlorotrimethylsilane and a trace of water gave rise to the deprotected phosphinate (V). This was subjected to Arbuzov reaction with methyl (bromomethyl)acrylate (VI) under silylating conditions to afford the substituted phosphinate (VII). Concomitant double-bond hydrogenation and hydrogenolysis of the benzyl and benzylidene groups of (VII) was effected by hydrogenation over Pd/C. The resulting product (VIII) was then peracetylated with acetic anhydride/pyridine to give the triacetate (IX). Treatment of (IX) with aminoethanol in THF selectively removed the anomeric acetate to produce (X) as a complex diastereomeric mixture.

参考文献中间体

【1】 Reck, F.; et al.; Inhibitors of the bacterial cell wall biosynthesis enzyme MurC. Bioorg Med Chem Lett 2001, 11, 11, 1451.

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)	53154	ethyl 1,1-diethoxyethyl(hydroxymethyl)phosphinate	n/a	C₉H₂₁O₅P	详情	详情
(II)	53155	[(1,1-diethoxyethyl)(ethoxy)phosphoryl]methyl methanesulfonate	n/a	C₁₀H₂₃O₇PS	详情	详情
(III)	53156	N-[(2R,4aR,6S,7R,8R,8aS)-6-(benzyloxy)-8-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]acetamide	n/a	C₂₂H₂₅NO₆	详情	详情
(IV)	53157	ethyl {[(2R,4aR,6S,7R,8R,8aR)-7-(acetylamino)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy}methyl(1,1-diethoxyethyl)phosphinate	n/a	C₃₁H₄₄NO₁₀P	详情	详情
(V)	53158	ethyl {[(2R,4aR,6S,7R,8R,8aR)-7-(acetylamino)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy}methylphosphinate	n/a	C₂₅H₃₂NO₈P	详情	详情
(VI)	32407	methyl 2-(bromomethyl)acrylate		C₅H₇BrO₂	详情	详情
(VII)	53159	methyl 2-{[({[(2R,4aR,6S,7R,8R,8aR)-7-(acetylamino)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy}methyl)(ethoxy)phosphoryl]methyl}acrylate	n/a	C₃₀H₃₈NO₁₀P	详情	详情
(VIII)	53160	methyl 3-[({[(2S,3R,4R,5R,6R)-3-(acetylamino)-2,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy}methyl)(ethoxy)phosphoryl]-2-methylpropanoate	n/a	C₁₆H₃₀NO₁₀P	详情	详情
(IX)	53161	methyl 3-[[({(2R,3R,4R,5R,6R)-3-(acetylamino)-2,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)methyl](ethoxy)phosphoryl]-2-methylpropanoate	n/a	C₂₂H₃₆NO₁₃P	详情	详情
(X)	53162	methyl 3-[[({(3R,4R,5R,6R)-3-(acetylamino)-5-(acetyloxy)-6-[(acetyloxy)methyl]-2-hydroxytetrahydro-2H-pyran-4-yl}oxy)methyl](ethoxy)phosphoryl]-2-methylpropanoate	n/a	C₂₀H₃₄NO₁₂P	详情	详情

合成路线2

Treatment of (X) with BuLi and diphenyl chlorophosphate led to stereoselective formation of the alpha phosphate ester (XI). The phenyl phosphate ester groups of (XI) were then deprotected by catalytic hydrogenation over PtO2 to afford (XII), isolated as a mixture of two major diastereomers. Coupling of (XII) with uridine monophosphate morpholidate (XIII) led to the uridine diphosphate-containing derivative (XIV). Finally, saponification of the ester groups of (XIV) with aqueous NaOH furnished the title compound.

参考文献中间体

【1】 Reck, F.; et al.; Inhibitors of the bacterial cell wall biosynthesis enzyme MurC. Bioorg Med Chem Lett 2001, 11, 11, 1451.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	53162	methyl 3-[[({(3R,4R,5R,6R)-3-(acetylamino)-5-(acetyloxy)-6-[(acetyloxy)methyl]-2-hydroxytetrahydro-2H-pyran-4-yl}oxy)methyl](ethoxy)phosphoryl]-2-methylpropanoate	n/a	C₂₀H₃₄NO₁₂P	详情	详情
(XI)	53163	methyl 3-[[({(2R,3R,4R,5R,6R)-3-(acetylamino)-5-(acetyloxy)-6-[(acetyloxy)methyl]-2-[(diphenoxyphosphoryl)oxy]tetrahydro-2H-pyran-4-yl}oxy)methyl](ethoxy)phosphoryl]-2-methylpropanoate	n/a	C₃₂H₄₃NO₁₅P₂	详情	详情
(XII)	53164	methyl 3-[({[(2R,3R,4R,5R,6R)-3-(acetylamino)-5-(acetyloxy)-6-[(acetyloxy)methyl]-2-(phosphonooxy)tetrahydro-2H-pyran-4-yl]oxy}methyl)(ethoxy)phosphoryl]-2-methylpropanoate	n/a	C₂₀H₃₅NO₁₅P₂	详情	详情
(XIII)	53165	{(2R,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl hydrogen 4-morpholinylphosphonate	n/a	C₁₃H₂₀N₃O₉P	详情	详情
(XIV)	53166		n/a	C₂₉H₄₆N₃O₂₃P₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)