E-5531

Chemical Name: 2-Deoxy-6-O-[2-deoxy-3-O-[3(R)-[5(Z)-dodecenoyloxy]decyl]-6-O-methyl-2-(3-oxotetradecanamido)-4-O-phosphono-beta-D-glucopyranosyl]-3-O-[3(R)-hydroxydecyl]-2-(3-oxotetradecanamido)-alpha-D-glucopyranose-1-O-phosphate
CAS No. 151663-12-6 (tetrasodium salt)
项目整合开发状态: Phase II
项目研究机构: Eisai (Originator)
合成路线: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).

合成路线:Reformatskii condensation of the organozinc reagent derived from methyl bromoacetate (XIII) with n-heptyl cyanide (XII) gave rise to the keto ester adduct (XIV).Catalytic hydrogenation of (XIV) in the presence of the chiral catalyst generated from dichloro(cycloocta-1,5-diene)ruthenium and (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl furnished the (R)-hydroxyester (XV) in high enantiomeric excess.Ester group reduction in (XV) by means of LiAlH4 afforded diol (XVI),which was further converted to the primary tosylate (XVII) with p-toluenesulfonyl chloride in pyridine.Then,alkylation of the intermediate alcohol (XI) with tosylate (XVII) under Williamson's ether synthesis conditions provided the common precursor (XVIII).

合成路线:Protection of the free hydroxyl of (XVIII) as the allyloxycarbonyl derivative (XIX) was achieved by sequential treatment with phosgene and then with allyl alcohol.Acetonide group hydrolysis in (XIX) under acidic conditions gave diol (XX),which was selectively silylated at the primary hydroxyl group with tert-butyldimethylsilyl chloride and imidazole to afford (XXI).The remaining hydroxyl group of (XXI) was subsequently protected as the allyl carbonate (XXII) with phosgene and allyl alcohol as above.Then,regioselective mono-desilylation of (XXII) with HF provided the desired building block (XXIII).

合成路线:The precursor cis-dodec-5-enoic acid (XXIX) was prepared as shown in Scheme 4.The lithium acetylide of 1-octyne (XXIV) was alkylated with 1,3-diiodopropane (XXV) to give the iodoalkyne (XXVI).Displacement of the iodide of (XXVI) with KCN in hot DMSO provided nitrile (XXVII),which was hydrolyzed to the corresponding carboxylic acid (XXVIII) employing KOH in ethylene glycol at 140 C.Partial hydrogenation of the triple bond in the presence of poisoned Lindlar catalyst furnished the (Z)-olefin (XXIX).

合成路线:The common precursor (XVIII) was converted into building block (XXXV) as follows.Esterification of (XVIII) with the unsaturated fatty acid (XXIX) by means of DCC and DMAP gave ester (XXX).The acetonide group of (XXX) was then hydrolyzed to diol (XXXI) under acidic conditions.Methylation of (XXXI) with iodomethane in the presence of silver oxide produced a mixture of two regioisomeric methyl ethers.In this mixture,the undesired 4-methoxy compound (XXXIII) was then selectively silylated at the free primary 6-hydroxyl group,which allowed chromatographic separation from the target 6-methoxy compound (XXXII).Phosphitylation of (XXXII),followed by oxidation of the intermediate phosphite with m-chloroperbenzoic acid,furnished phosphate (XXXIV).Desilylation of (XXXIV) to the required intermediate (XXXV) was accomplished by treatment with HF in acetonitrile.

合成路线:The hydroxyl group of (XXXV) was activated by treatment with trichloroacetonitrile to produce the corresponding trichloroacetimidate (XXXVI) as a diastereomeric mixture,which was used without separation.Coupling between imidates (XXXVI) and building block (XXIII) was accomplished by means of trimethylsilyl triflate,producing the disaccharide derivative (XXXVII).The azido groups of (XXXVII) were then reduced employing tin(II)tris-benzenethiolate triethylamine complex to afford diamine (XXXVIII).