合成路线1

The phenylhydrazone of benzaldehyde (I) is obtained in the usual way, phenylhydrazine (A) with benzaldehyde (B), which by reaction with benzoyl chloride (II) gives (C) and further treatment with HCl in an organic solvent results in the substituted hydrazine hydrochloride (III). Finally, this compound is condensed with levulinic acid (IV) at high temperature.

合成路线2

In a related strategy, the bromination of levulinic acid (XLII) in MeOH yielded the 3-bromo (XLIV) and 5-bromo (XLIII) esters, which could be separated by distillation. Condensation of methyl 5-bromolevulinate (XLIII) with potassium phthalimide (XXVII) provided methyl phthalimido levulinate (XLV), which was finally hydrolyzed under the same conditions as above for analogous the ethyl ester.

合成路线3

In a variation of the earlier methods, methyl 5-bromolevulinate (XLIII) was prepared by bromination of levulinic acid (XLII) in methanol. Reaction of bromo ketone (XLIII) with NaN3 in cold DMF provided azide (LXXV). Simultaneous azide reduction and methyl ester hydrolysis was then accomplished by catalytic hydrogenation in the presence of HCl. A further related method consisted in the alkylation of sodium diformylamide (LXXVI) with methyl 5-bromolevulinate (XLIII) in several different solvents to afford the N,N-diformylamino ester (LXXVII), which was finally hydrolyzed under acidic conditions.

合成路线4

The reaction of phenol (I) with 4-oxopentanoic acid (II) by means of H2SO4 gives 4,4-bis(4-hydroxyphenyl)pentanoic acid (III), which is esterified with MeOH and H2SO4 to yield the methyl pentanoate (IV). The condensation of (IV) with 2-(chloromethyl)quinoline (V) by means of K2CO3 in DMF affords the adduct (VI), which is finally hydrolyzed with NaOH in methanol/dioxane to provide the target sodium salt. Alternatively, the intermediate methyl pentanoate (IV) can also be obtained by direct condensation of phenol (I) with methyl 4-oxopentanoate (VII) by means of H2SO4 as before.

合成路线5

Glycosylation of sugar (I) with the idopyranosyl fluoride (II) by means of BF3.Et2O and molecular sieves in dichloromethane gives the disaccharide fragment (III), which is then converted into acetonide (V) by saponification of the ester functions with t-BuOK, followed by reaction with 2,2-dimethoxypropane (IV) in DMF and acidification with p-toluensulfonic acid. Methylation of acetonide (V) with MeI and NaH in DMF/MeOH provides the disaccharide (VI), which is then treated with HOAc to yield the 4',6'-diol (VII). Selective silylation of the diol (VII) with tert-butyldimethylsilyl chloride (TBDMSCl) in pyridine leads to the 6'-O-TBDMS derivative (VIII), which is condensed with levulinic acid (IX) by means of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) in dioxane to give the ester (X). Compound (X) is then submitted to simultaneous Jones oxidation and TBDMS removal with CrO3 and H2SO4/H2O in acetone to provide the iduronic acid derivative (XI), which is converted into the key intermediate (XII), first by esterification with MeI and KHCO3 in DMF and then by removal of the 4'-O-levulinoyl protecting group with HOAc and hydrazine hydrate in pyridine.

合成路线6

The L-ioduronic acid methyl ester derivative (XII) is then converted into its D-glucuronic acid methyl ester counterpart (XIII) by epimerization with NaOMe in refluxing MeOH, followed by esterification with MeI and KHCO3 in DMF. Protection of the ester (XIII) with levulinic acid (IX) by means of DCC and DMAP in dioxane, followed by acetolysis of the anomeric center with sulfuric acid in acetic anhydride furnishes the disaccharide (XIV), which is then saponified with piperidine and subjected to reaction with trichloroacetonitrile and Cs2CO3 in THF to yield the imidate (XV). Glycosylation of the disaccharide (XII) with the imidate (XV) by means of trimethylsilyl triflate in CH2Cl2, followed by removal of the levulinoyl group by means of hydrazine acetate, furnishes the tetrasaccharide (XVI), which is coupled with the glucosyl trichloroacetimidate (XVIII) by means of trimethylsilyl trifluoromethanesulfonate in CH2Cl2 providing the pentasaccharide (XVII). Glucosyl imidate (XVIII) is prepared by methylation of 1,6-anhydroglucose (XIX) with MeI and NaH in DMF, followed by acetolysis with Ac2O/TFA to give compound (XX), which is treated with piperidine in THF and finally with trichloroacetonitrile in dichloromethane in the presence of Cs2CO3. The pentasaccharide (XVII) is deprotected by saponification with LiOH in THF/H2O2, and then hydrogenated over Pd/C in tert-butanol/water to provide a fully deprotected pentamer, which is finally subjected to sulfation with triethylamine sulfur trioxide complex in DMF and converted into the corresponding sodium salt by elution in a Dowex 50 XW4-Na+ or a Mono-Q anion-exchange column.

合成路线7

The nonasaccharide (XX) is transformed into (XXI) by the sequence of benzoate esters hydrolysis, O-methylation, acetal hydrolysis, and selective mono-benzoylation, following the same methods as above. The free hydroxyl group of (XXI) is subsequently protected by esterification with levulinic acid (XXII) to give levulinate ester (XXIII). Opening of the 1,6-anhydroglucose unit of (XXIII) is then accomplished by treatment with acetic anhydride in the presence of acetic acid and trifluoroacetic acid, producing (XXIV).

合成路线8