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【结 构 式】

【药物名称】B-1287, E-5564

【化学名称】3-O-Decyl-2-deoxy-6-O-[2-deoxy-3-O-[3(R)-methoxydecyl]-6-O-methyl-2-[11(Z)-octadecenamido]-4-O-phosphono-beta-D-glucopyranosyl]-2-(3-oxotetradecanamido)-1-O-phosphono-alpha-D-glucopyranose

【CA登记号】185955-34-4, 261504-30-7 (deleted CAS)

【 分 子 式 】C66H126N2O19P2

【 分 子 量 】1313.68972

【开发单位】Eisai (Originator)

【药理作用】ANTIINFECTIVE THERAPY, Treatment of Septic Shock, Lipid A Analogs, TLR4 (LPS) Receptor Antagonists

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11

合成路线1

Saponification of (R)-methyl 3-hydroxydecanoate (I) gave hydroxy acid (II), which was reduced to diol (III) using LiAlH4. Selective sulfonylation of the primary hydroxyl group of (III) provided tosylate (IV). The secondary hydroxyl group of (IV) was subsequently alkylated with iodomethane in the presence of NaH to furnish the methyl ether (V).

参考文献 中间体
【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 .
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) 59083 methyl (3R)-3-hydroxydecanoate C11H22O3 详情 详情
(II) 64140 (3R)-3-hydroxydecanoic acid C10H20O3 详情 详情
(III) 59084 (3R)-1,3-decanediol C10H22O2 详情 详情
(IV) 49121 (3R)-3-hydroxydecyl 4-methylbenzenesulfonate C17H28O4S 详情 详情
(V) 64141 (3R)-3-methoxydecyl 4-methylbenzenesulfonate C18H30O4S 详情 详情

合成路线2

Treatment of D-glucosamine•HCl (VI) with ethyl trifluoroacetate and NaOMe produced the trifluoroacetamide (VII), which was subsequently acetylated with Ac2O yielding the tetraacetate (VIII). Displacement of the anomeric acetoxy group of (VIII) by allyl alcohol (IX) in the presence of SnCl4 furnished the allyl glucoside (X). After methanolysis of the acetate ester groups of (X), the resultant triol (XI) was protected as the acetonide (XII) by treatment with 2,2-dimethoxypropane and camphorsulfonic acid. Alkylation of the free hydroxyl group of (XII) with tosylate (V) under Williamson's ether synthesis conditions produced adduct (XIII). Selective hydrolysis of the acetonide moiety of (XIII) was accomplished by treatment with hydrofluoric acid to give diol (XIV). The primary hydroxyl of (XIV) was then converted to tosylate (XV) upon treatment with p-toluenesulfonyl chloride and DMAP.

参考文献 中间体
【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 .
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) 64141 (3R)-3-methoxydecyl 4-methylbenzenesulfonate C18H30O4S 详情 详情
(VI) 24036 (3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol; Glucosamine 3416-24-8 C6H13NO5 详情 详情
(VII) 64142 2,2,2-trifluoro-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]acetamide C8H12F3NO6 详情 详情
(VIII) 64143 (2R,3R,4R,5R)-4,6-bis(acetyloxy)-2-[(acetyloxy)methyl]-5-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl acetate C16H20F3NO10 详情 详情
(IX) 12234 2-Propen-1-ol; Allyl alcohol 107-18-6 C3H6O 详情 详情
(X) 64144 (2R,3R,4R,5R)-3-(acetyloxy)-2-[(acetyloxy)methyl]-6-(allyloxy)-5-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-4-yl acetate C17H22F3NO9 详情 详情
(XI) 64145 N-[(3R,4R,5S,6R)-2-(allyloxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-2,2,2-trifluoroacetamide C11H16F3NO6 详情 详情
(XII) 57540 N-[(4aR,6S,7R,8R,8aS)-6-(allyloxy)-8-hydroxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]-2,2,2-trifluoroacetamide C14H20F3NO6 详情 详情
(XIII) 64146 N-((4aR,7R,8R,8aS)-6-(allyloxy)-8-{[(3R)-3-methoxydecyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)-2,2,2-trifluoroacetamide C25H42F3NO7 详情 详情
(XIV) 64147 N-((3R,4R,5S,6R)-2-(allyloxy)-5-hydroxy-6-(hydroxymethyl)-4-{[(3R)-3-methoxydecyl]oxy}tetrahydro-2H-pyran-3-yl)-2,2,2-trifluoroacetamide C22H38F3NO7 详情 详情
(XV) 64148 {(2R,3S,4R,5R)-6-(allyloxy)-3-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-5-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-2-yl}methyl 4-methylbenzenesulfonate C29H44F3NO9S 详情 详情

合成路线3

Displacement of the tosylate group of (XV) by sodium methoxide produced the methyl ether (XVI). Hydrolysis of the trifluoroacetamide function of (XVI) using potassium tert-butoxide in hot DMSO took place with simultaneous allylic double bond isomerization, leading to enol ether (XVII). After protection of the amino group of (XVII) as the trichloroethyl carbamate (XVIII), phosphitylation of the secondary hydroxyl group of (XVIII) with diallyl N,N-diisopropylphosphoramidite in the presence of tetrazole-generated phosphite (XIX), which was further oxidized to phosphate (XX) employing Oxone (R). The O-propenyl group of (XX) was then hydrolyzed by means of HF to provide the monosaccharide building block (XXI).

参考文献 中间体
【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 64148 {(2R,3S,4R,5R)-6-(allyloxy)-3-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-5-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-2-yl}methyl 4-methylbenzenesulfonate C29H44F3NO9S 详情 详情
(XVI) 64149 N-[(3R,4R,5S,6R)-2-(allyloxy)-5-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl]-2,2,2-trifluoroacetamide C23H40F3NO7 详情 详情
(XVII) 64150 (2R,3S,4R,5R)-5-amino-4-{[(3R)-3-methoxydecyl]oxy}-2-(methoxymethyl)-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ol C21H41NO6 详情 详情
(XVIII) 64151 2,2,2-trichloroethyl (3R,4R,5S,6R)-5-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-2-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ylcarbamate C24H42Cl3NO8 详情 详情
(XIX) 64152 2,2,2-trichloroethyl (3R,4R,5S,6R)-5-{[bis(allyloxy)phosphino]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-2-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ylcarbamate C30H51Cl3NO10P 详情 详情
(XX) 64153 2,2,2-trichloroethyl (3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-2-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ylcarbamate C30H51Cl3NO11P 详情 详情
(XXI) 64154 2,2,2-trichloroethyl (3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-2-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-3-ylcarbamate C27H47Cl3NO11P 详情 详情

合成路线4

The other monosaccharide building block (XXXIII) was also synthesized from the common intermediate (XII). Alkylation of (XII) with mesylate (XXIII), prepared from 1-decanol (XXII), gave the decyl ether (XXIV). After acidic acetonide hydrolysis of (XXIV) to yield (XXV), removal of the trifluoroacetamide by means of potassium tert-butoxide, with concomitant O-allyl group isomerization, furnished (XXVI). Imine (XXVII) was then obtained by exchange reaction of amine (XXVI) with benzophenone imine at 45 C. After silylation of the primary hydroxyl of (XXVII) with tert-butyldimethylsilyl chloride affording(XXVIII), the secondary hydroxyl group was protected as the allyl carbonate (XXIX) by sequential treatment with phosgene and then with allyl alcohol. Imine (XXIX) hydrolysis, followed by coupling of the resultant amine (XXX) with 3-oxotetradecanoic acid (XXXI) led to keto amide (XXXII). Precursor (XXXIII) was then obtained by desilylation of (XXXII) with HF.

参考文献 中间体
【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 57540 N-[(4aR,6S,7R,8R,8aS)-6-(allyloxy)-8-hydroxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]-2,2,2-trifluoroacetamide C14H20F3NO6 详情 详情
(XXII) 40729 1-decanol 112-30-1 C10H22O 详情 详情
(XXIII) 64156 decyl methanesulfonate C11H24O3S 详情 详情
(XXIV) 64157 N-[(4aR,7R,8R,8aS)-6-(allyloxy)-8-(decyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]-2,2,2-trifluoroacetamide C24H40F3NO6 详情 详情
(XXV) 64158 N-[(3R,4R,5S,6R)-2-(allyloxy)-4-(decyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-2,2,2-trifluoroacetamide C21H36F3NO6 详情 详情
(XXVI) 64159 (2R,3S,4R,5R)-5-amino-4-(decyloxy)-2-(hydroxymethyl)-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ol C19H37NO5 详情 详情
(XXVII) 64160 (2R,3S,4R,5R)-4-(decyloxy)-5-[(diphenylmethylene)amino]-2-(hydroxymethyl)-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ol C32H45NO5 详情 详情
(XXVIII) 64151 2,2,2-trichloroethyl (3R,4R,5S,6R)-5-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-2-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ylcarbamate C24H42Cl3NO8 详情 详情
(XXIX) 64162 allyl (2R,3S,4R,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(decyloxy)-5-[(diphenylmethylene)amino]-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate C42H63NO7Si 详情 详情
(XXX) 64163 allyl (2R,3S,4R,5R)-5-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(decyloxy)-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate C29H55NO7Si 详情 详情
(XXXI) 59107 3-oxotetradecanoic acid C14H26O3 详情 详情
(XXXII) 64164 allyl (2R,3S,4R,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate C43H79NO9Si 详情 详情
(XXXIII) 64165 allyl (2R,3S,4R,5R)-4-(decyloxy)-2-(hydroxymethyl)-5-[(3-oxotetradecanoyl)amino]-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate C37H65NO9 详情 详情

合成路线5

Monosaccharide (XXI) was activated as the trichloroacetimidate (XXXIV) upon treatment with trichloracetonitrile. Coupling between the protected monosaccharide (XXXIII) and imidate (XXXIV) using silver triflate as the coupling promoter produced the protected disaccharide adduct (XXXV). After reductive cleavage of the trichloroethyl carbamate protecting group of (XXXV), the resultant amine (XXXVI) was acylated with vaccenoyl chloride (XXXVII) giving amide (XXXVIII).

参考文献 中间体
【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXI) 64154 2,2,2-trichloroethyl (3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-2-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-3-ylcarbamate C27H47Cl3NO11P 详情 详情
(XXXIII) 64165 allyl (2R,3S,4R,5R)-4-(decyloxy)-2-(hydroxymethyl)-5-[(3-oxotetradecanoyl)amino]-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate C37H65NO9 详情 详情
(XXXIV) 64166 (3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-2-yl 2,2,2-trichloroethanimidoate C29H47Cl6N2O11P 详情 详情
(XXXV) 64167 allyl (2R,3S,4R,5R)-2-{[((2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-2-yl)oxy]methyl}-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate C64H110Cl3N2O19P 详情 详情
(XXXVI) 64168 allyl (2R,3S,4R,5R)-2-({[(2R,3R,4R,5S,6R)-3-amino-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-2-yl]oxy}methyl)-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate C61H109N2O17P 详情 详情
(XXXVII) 64169 (Z)-11-octadecenoyl chloride C18H33ClO 详情 详情
(XXXVIII) 64170 allyl (2R,3S,4R,5R)-2-[({(2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-[(Z)-11-octadecenoylamino]tetrahydro-2H-pyran-2-yl}oxy)methyl]-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate C79H141N2O18P 详情 详情

合成路线6

Hydrolysis of the enol ether group of (XXXVIII) with HF yielded (XXXIX), which was converted to phosphate (XL) by sequential phosphitylation with diallyl N,N-diisopropylphosphoramidite, followed by oxidation with m-chloroperbenzoic acid. The title disaccharide was finally obtained by palladium-catalyzed deprotection of the allyl phosphate and carbonate ester groups of (XL).

参考文献 中间体
【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXVIII) 64170 allyl (2R,3S,4R,5R)-2-[({(2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-[(Z)-11-octadecenoylamino]tetrahydro-2H-pyran-2-yl}oxy)methyl]-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate C79H141N2O18P 详情 详情
(XXXIX) 64171 allyl (2R,3S,4R,5R)-2-[({(2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-[(Z)-11-octadecenoylamino]tetrahydro-2H-pyran-2-yl}oxy)methyl]-4-(decyloxy)-6-hydroxy-5-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-3-yl carbonate C76H137N2O18P 详情 详情
(XL) 64172 allyl (2R,3S,4R,5R,6R)-6-{[bis(allyloxy)phosphoryl]oxy}-2-[({(2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-[(Z)-11-octadecenoylamino]tetrahydro-2H-pyran-2-yl}oxy)methyl]-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-3-yl carbonate C82H146N2O21P2 详情 详情

合成路线7

Hydroxy acid (II) was converted to methyl ether (XLI) by treatment with trimethylsilyl diazomethane. Reduction of acid (XLI) to alcohol (XLII) was accomplished by treatment with DIBAL in cold dichloromethane. Alcohol (XLII) was transformed to alkyl iodide (XLIII) via tosylation to (V), followed by displacement of tosylate (V) with NaI in acetone. Alkylation of the known azido sugar (XLIV) with the alkyl iodide (XLIII) in the presence of Ag2O provided ether (XLV). Then, acidic acetonide (XLV) hydrolysis led to diol (XLVI). Selective alkylation of the primary hydroxyl group of (XLVI) using iodomethane in the presence of Ag2O, followed by reprotection of some desilylated product, furnished the methyl ether (XLVII). The secondary hydroxyl group of (XLVII) was then converted to phosphate ester (XLVIII) employing the same phosphitylation/oxidation sequence as above.

参考文献 中间体
【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 .
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) 64140 (3R)-3-hydroxydecanoic acid C10H20O3 详情 详情
(V) 64141 (3R)-3-methoxydecyl 4-methylbenzenesulfonate C18H30O4S 详情 详情
(XLI) 64173 (3R)-3-methoxydecanoic acid C11H22O3 详情 详情
(XLII) 64174 (3R)-3-methoxy-1-decanol C11H24O2 详情 详情
(XLIII) 64175 (3R)-1-iodo-3-methoxydecane; (1R)-1-(2-iodoethyl)octyl methyl ether C11H23IO 详情 详情
(XLIV) 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
(XLV) 64176 [((4aR,6S,7R,8R,8aS)-7-azido-8-{[(3R)-3-methoxydecyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)oxy](tert-butyl)dimethylsilane; (4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl (3R)-3-methoxydecyl ether C26H51N3O6Si 详情 详情
(XLVI) 64177 (2R,3S,4R,5R,6S)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)-4-{[(3R)-3-methoxydecyl]oxy}tetrahydro-2H-pyran-3-ol C23H47N3O6Si 详情 详情
(XLVII) 64178 (2R,3S,4R,5R,6S)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-2-(methoxymethyl)tetrahydro-2H-pyran-3-ol C24H49N3O6Si 详情 详情
(XLVIII) 64179 diallyl (2R,3S,4R,5R,6S)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl phosphate C30H58N3O9PSi 详情 详情

合成路线8

Azido sugar (XLVIII) was reduced to the corresponding amine (XLIX) employing the in situ generated tin tris(benzenthiolate) triethylamine complex. Amine (XLIX) was then protected as the trichloethyl carbamate (L) by treatment with Troc-chloride and pyridine. After desilylation of (L) with HF, the resultant alcohol was activated as the trichloroacetimidate (XXXIV) as in Scheme 27814501e.

参考文献 中间体
【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXIV) 64166 (3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-2-yl 2,2,2-trichloroethanimidoate C29H47Cl6N2O11P 详情 详情
(XLVIII) 64179 diallyl (2R,3S,4R,5R,6S)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl phosphate C30H58N3O9PSi 详情 详情
(XLIX) 64180 diallyl (2R,3S,4R,5R,6S)-5-amino-6-{[tert-butyl(dimethyl)silyl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl phosphate C30H60NO9PSi 详情 详情
(L) 64181 2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-3-ylcarbamate C33H61Cl3NO11PSi 详情 详情

合成路线9

Alkylation of azido sugar (XLIV) with 1-iododecane (LI) in the presence of Ag2O provided decyl ether (LII). Then, selective acetonide hydrolysis in (LII) to (LIII), followed by silylation with tert-butyldimethylsilyl chloride provided the bis-silyl ether (LIV). Alcohol (LIV) was then protected as the allyl carbonate (LV) by treatment with phosgene, followed by allyl alcohol. The primary silyl ether group of (LV) was selectively removed by treatment with HF giving the monosaccharide (LVI), which was coupled with imidate (XXXIV) yielding disaccharide (LVII).

参考文献 中间体
【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXIV) 64166 (3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-2-yl 2,2,2-trichloroethanimidoate C29H47Cl6N2O11P 详情 详情
(XLIV) 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
(LI) 64182 1-iododecane C10H21I 详情 详情
(LII) 64183 {[(4aR,7R,8R,8aS)-7-azido-8-(decyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy}(tert-butyl)dimethylsilane; (4aR,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl decyl ether C25H49N3O5Si 详情 详情
(LIII) 64184 (2R,3S,4R,5R)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol C22H45N3O5Si 详情 详情
(LIV) 64185 (2R,3S,4R,5R)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(decyloxy)tetrahydro-2H-pyran-3-ol C28H59N3O5Si2 详情 详情
(LV) 64186 allyl (2R,3S,4R,5R)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(decyloxy)tetrahydro-2H-pyran-3-yl carbonate C32H63N3O7Si2 详情 详情
(LVI) 64187 allyl (2R,3S,4R,5R)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl carbonate C26H49N3O7Si 详情 详情
(LVII) 64188 allyl (2R,3S,4R,5R)-5-azido-2-{[((2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-2-yl)oxy]methyl}-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)tetrahydro-2H-pyran-3-yl carbonate C53H94Cl3N4O17PSi 详情 详情

合成路线10

Reduction of the azido group of disaccharide (LVII), followed by acylation of the resultant amine (LVIII) with keto acid (XXXI) produced keto amide (LIX). The Troc protecting group of (LIX) was then removed by reductive treatment with zinc-copper couple in AcOH yielding amine (LX).

参考文献 中间体
【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXI) 59107 3-oxotetradecanoic acid C14H26O3 详情 详情
(LVII) 64188 allyl (2R,3S,4R,5R)-5-azido-2-{[((2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-2-yl)oxy]methyl}-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)tetrahydro-2H-pyran-3-yl carbonate C53H94Cl3N4O17PSi 详情 详情
(LVIII) 64189 allyl (2R,3S,4R,5R)-5-amino-2-{[((2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-2-yl)oxy]methyl}-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)tetrahydro-2H-pyran-3-yl carbonate C53H96Cl3N2O17PSi 详情 详情
(LIX) 64190 allyl (2R,3S,4R,5R)-2-{[((2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-2-yl)oxy]methyl}-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-3-yl carbonate C67H120Cl3N2O19PSi 详情 详情
(LX) 64191 allyl (2R,3S,4R,5R)-2-({[(2R,3R,4R,5S,6R)-3-amino-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-2-yl]oxy}methyl)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-3-yl carbonate C64H119N2O17PSi 详情 详情

合成路线11

Amine (LX) was acylated with cis-vaccenic acid (LXI) to produce amide (LXII). This was desilylated by means of HF yielding alcohol (XXXIX), which was finally converted to the title compound using the same sequence as in Scheme 27814501f.

参考文献 中间体
【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXIX) 64171 allyl (2R,3S,4R,5R)-2-[({(2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-[(Z)-11-octadecenoylamino]tetrahydro-2H-pyran-2-yl}oxy)methyl]-4-(decyloxy)-6-hydroxy-5-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-3-yl carbonate C76H137N2O18P 详情 详情
(LX) 64191 allyl (2R,3S,4R,5R)-2-({[(2R,3R,4R,5S,6R)-3-amino-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-2-yl]oxy}methyl)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-3-yl carbonate C64H119N2O17PSi 详情 详情
(LXI) 64192 (Z)-11-octadecenoic acid C18H34O2 详情 详情
(LXIII) 64193 allyl (2R,3S,4R,5R)-2-[({(2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-[(Z)-11-octadecenoylamino]tetrahydro-2H-pyran-2-yl}oxy)methyl]-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-3-yl carbonate C82H151N2O18PSi 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)