Patent ID: 8357785

Claim:
A method of producing 4′-O-aralkyl derivatives of anthracyclines of Formula 1, wherein R 1 ═H, OH, or OMe; R 2 ═H, OH, or OCOAlk1; Alk1=linear or branch alkyl, alkenyl or alkynyl C 1 -C 12 ; 4′-OCH 2 —R 3 is equatorial or axial; R 3 =Alk1 or Ar An − =anion of a strong acid; by utilizing an alkylating agent R 3 —CH 2 X, wherein X is selected from the group consisting of Cl—, Br—, I—, Ts, CH 3 SO 2 O—CF 3 SO 2 O, comprising the steps of: (a) providing a starting material comprising an anthracycline derivative salt of daunorubicine hydrochloride in alcohol, according to the following formula wherein R 1 is defined as in Formula 1; (b) incubating said starting material with a solution of TfN 3 in dichloromethane until said starting material is completely reacted, to produce 3′-N 3 -daunorubicine according to the following formula wherein R 1 is as defined in Formula 1; (c) dissolving the product of step (b) in an aprotic solvent; (d) reacting the product of step (c) with an excess of an alkylating agent R 3 —CH 2 X and a strong base, to produce 4′-OR 3 —N 3 -daunorubicine, according to the following formula, wherein R 3 and X are as defined in Formula 1; (e) dissolving the product of step (d) in Tetrahydrofuran (THF) and reacting it with triphenylphosphine, to produce 4′-OR 3 -daunorubicin according to the following formula wherein R 3 is as defined in Formula 1; (f) reacting the product of step (e) with a complex halogenide of Formula 2, where R 9 through R 14 are defined as H or a hydrocarbon radical of 1 to 4 carbon chains (C 1 -C 4 ); Hal is Cl, Br, I in a medium basicity aprotic solvent, to produce a 14-halogenated derivative; (g) hydrolyzing the product of step (f), to produce 4′-OR 3 -doxorubicin according to the following formula wherein R 1 and R 2 are as defined in Formula 1,