合成路线1

The sulfonation of methyl N-trifluoroacetyldaunosaminide (I) with mesyl chloride or with 4-bromophenylsulfonyl chloride in pyridine gives the corresponding 4-O-mesyl derivative (II) or 4-O-(4-bromophenylsulfonyl) derivative (IIa); both compounds by reaction with NaI in refluxing butanone yield the 4-iodo compound (III). The hydrogenation of (III) with H2 over Pd/C in methanol, followed by hydrolysis with hot acetic acid yields 4-deoxy-N-trifluoroacetyldaunosaminide (IV), which is esterified with p-nitrobenzoyl chloride in pyridine affording the corresponding p-nitrobenzoyl ester (V). The reaction of (V) with dry HCl in methylene chloride gives 1,4-dideoxy-N-trifluoroacetyldanosaminide (VI), which is condensed with daunomycinone (VII) by means of silver trifluoromethylsulfonate in methylene chloride and hydrolyzed with NaOH to afford 4'-deoxy-daunomycine (VIII). The bromination of (VIII) with Br2 in methanol-dioxane gives 4'-deoxy-14-bromodaunomycine (IX), which is finally hydrolyzed with aqueous sodium formate.

合成路线2

L-Fucose (I) is converted successively to its methyl glucoside (II), the 3,4-O-isopropylidene derivative (III), the 2-O-acetyl derivative (IV), the 2-O-acetyl-L-methylfucoside (V), the tosylate (VI), the 4-O-benzyl derivative (VII) and finally, through various steps, the 3,4-O-diacetyl-2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl bromide (VIII). The condensation of (VIII) with daunomycinone (IX) gives the daunomycin derivative (X), which is converted to the isopropylidene derivative (XI). The bromination of (XI) affords the bromo derivative (XII).

合成路线3

Coupling of daunomycinone (III) with 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl bromide (II), which was obtained from 1,3,4-tri-O-acetyl-derivative (I), was performed by a Koenings-Knorr type of reaction to obtain the daunomycin derivative (IV). Deprotection of (IV) with sodium hydroxide in water gave corresponding derivative (V), which was subsequently treated with bromine in dichloromethane and acetone to afford the bromo derivative (VI). Condensation of (VI) with N-Boc-beta-alanine sodium salt (VII) in acetone/water gave the protected beta-alaninate derivative (VIII), which was finally treated with hydrochloride in ether to obtain DA-125.

合成路线4

Condensation of daunomycinone (I) with aminoglycal (II) in the presence of triphenylphosphine hydrobromide provided the protected hexopyranosyl daunomycinone (III). Deacetylation with K2CO3 in MeOH-CH2Cl2 gave alcohol (IV), and further hydrolysis of the trifluoroacetamide with NaOH yielded amine (V), which was isolated as the hydrochloride. Finally, condensation of two molecules of (V) with a,a'-dibromo-p-xylene (VI) in the presence of Na2CO3 in DMF-CH2Cl2 at room temperature, followed by precipitation of the dihydrochloride from MeOH-Et2O, provided the target compound.

合成路线5

Reduction of ketone (I) with NaBH4 in MeOH at low temperature yielded alcohol (II) as the major product. This was treated with trifluoromethanesulfonic anhydride to provide triflate (III), which was displaced with NaI to form iodide (IV). Acetolysis of the methyl pyranoside (IV) produced the 1-alpha-O-acetyl derivative (V) along with minor amounts of the beta-anomer. The reaction of (V) with dry HCl in benzene gave the corresponding glycosyl chloride, which was subsequently coupled with daunorubicinone (VI) using HgO and HgBr2 to provide the title compound as the major anomer.

合成路线6