Treatment of (20S)-camptothecin (I) with HOAc and H2O2 followed by light irradiation in H2SO4 yields hydroxy derivative (II), which is then nitrated by means of HNO3 and H2SO4 to afford compound (III). Sulfonation of (III) by reaction with p-TsCl (IV) in the presence of Et3N and DMAP in CH2Cl2 provides sulfonate (V), which is then subjected to reduction by treatment with Pd(OAc)2, PPh3 and triethylammoniumformate (HCOOH稥t3N) to give 9-aminocamptothecin (VI). Reaction of (VI) with nitrophenyl chloroformate (VII) in dioxane, followed by treatment with intermediate (VIII) and DMAP in acetonitrile, provides (IX). Alternatively, (IX) can also be obtained by first treatment of (VI) with triphosgene followed by reaction with intermediate (VIII) in pyridine and chromatographic purification. Finally, (IX) is treated with potassium trimethyl silanate (KOSiMe3) for methyl ester cleavage and acidified with HCl.
Intermediate (VIII) can be obtained as follows: Bromination of glucuronate derivative (X) by means of TiBr4 in CH2Cl2 followed by reaction with p-hydroxybenzaldehyde (XI) in acetonitrile in the presence of Ag2O affords derivative (XII), whose aldehyde moiety is then reduced by means of NaBH4 and silica gel in isopropanol/CHCl3 to provide benzyl alcohol (XIII). Finally, O-acetyl groups of (XIII) are cleaved by means of NaOMe in MeOH to furnish intermediate (VIII).
Treatment of glucuronic acid gamma-lactone (I) with sodium methoxide in methanol affords methyl glucuronate (II), which is further acylated by acetic anhydride to form the tetraacetate ester (III). Bromination of (III) with TiBr4, followed by coupling of the resultant bromide (IV) with p hydroxybenzaldehyde (V) in the presence of Ag2O yields the peracetylated glucuronide (VI). Aldehyde (VI) reduction employing NaBH4 in the presence of silica gel leads to the benzyl alcohol (VII). The acetate ester groups of (VII) are then removed with sodium methoxide in methanol to furnish (VIII).
10-Hydroxycamptothecin (IX) is nitrated with HNO3/H2SO4 and the resulting 9-nitro-10-hydroxycamptothecin (X) is treated with tosyl chloride to form the tosylate (XI). Palladium-catalyzed reduction of nitro tosylate (XI) gives rise to 9-aminocapmtothecin (XII). Amine (XII) is activated as the isocyanate (XIII) upon treatment with triphosgene (1) or alternatively as the aryl carbamate (XIV) employing p-nitrophenyl chloroformate. Coupling of either isocyanate (XIII) or carbamate (XIV) with p-hydroxybenzyl alcohol glucuronide (VIII) leads to adduct (XV). The methyl glucuronate ester (XV) is finally hydrolyzed to the target acid under anhydrous conditions by using potassium trimethylsilanolate.
The hydroxylation of camptothecin (I) with H2O2 in HOAc gives 10-hydroxycamptothecin (II), which is nitrated with HNO3/H2SO4 to yield 10-hydroxy-9-nitrocamptothecin (III). The sulfonation of (III) with TsCl, DEA and DMAP affords 9-nitro-10-p-toluenesulfonyloxy)camptothecin (IV), which is finally desulfonated and reduced by means of ammonium formate and a Pd(OAc)3/bidentate phosphine ligand catalyst. Other sulfonates such as 1-naphthyl-, phenyl-, 4-fluorophenyl-, 4-nitrophenyl-, 4-methoxyphenyl- or methylsulfonate can be used instead of the reported p-toluenesulfonate.