Eritoran tetrasodium, B-1287, E-5564

a-D-葡萄糖吡喃糖,3-O-癸基-2-脱氧-6-O-[2-脱氧-3-O-[(3R)-3-甲氧基脱氧]-6-O-甲基-2-[[(11Z)-1-氧基-1-辛克-1-基]氨基]-4-O-磷酸-b-D-葡萄糖吡喃基]-2-[(1,3-二氧乙-手环)氨基]-,1-(二氢磷酸盐),钠盐(1:4)间氯苯基哌嗪盐酸盐Chemical Name: 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 tetrasodium salt
CAS No. 185954-98-7, 261504-30-7 (deleted CAS), 185955-34-4 (free acid)
项目整合开发状态: Phase II
项目研究机构: Eisai (Originator)
合成路线: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).

合成路线:Treatment of D-glucosamine旽Cl (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.

合成路线: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).

合成路线: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.

合成路线: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).

合成路线: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).