US 2006/0223766 A1 · Epimerization of 4'-C bond and modification of 14-CH3-(CO)-fragment in anthracyclin antibiotics

Abstract

A method of synthesizing R1, R2-substituted-4′ (ax. or eq.)-OH anthracyclines and their corresponding salts of Formula (1) from daunorubicin or N-Trifluoroacetyl-4-R1-derivatives of daunorubicin, wherein R1 is defined as H, OH, and 4′-HO is defined as ax[ial]. The method includes producing N-Trifluoroacetyl daunorubicin and treating the N-Trifluoroacetyldaunorubicin or N-Trifluoroacetyl-4-R1-derivatives of daunorubicin, wherein R1 is defined as H, OH, with dimethylsulfoxide activated by different acylating agents. The attained intermediate product is then treated with a strong base (ex. tertiary amines) resulting in the 4′-keto-N-Trifluoroacetyl-4-R1 daunorubicin wherein R1 is defined as H, OH, OMe. The 4′-keto-N-Trifluoroacetyl-4-R1-daunorubicin is reacted with a reducing agent, a derivative of a borohydride of an alkaline metal MHBL3 , to produce N-Trifluoroacetyl-4′-epi-4-R1-daunorubicin. The N-Trifluoroacetyl-4′-epi-4-R1-daunorubicin undergoes hydrolysis in a basic solution to produce a derivate of an anthoacyclin which is halogenized [by complex halogenides] to form a 14-Hal-derivative. This result is then hydrolyzed by well-known methods in the presence of a formate of an alkaline metal to form the desired final compound.

Claims8

Dependent claims

A method of preparing an anthracyclin of having a formula represented by Formula (1) comprising:

(a) providing N-Trifluoroacetyl daunorubicin represented by Formula (2), wherein R1 is H, OH, or OMe and R2 is H;
(b) reacting the N-Trifluoroacetyl daunorubicin with an aprotic solvent and an acylating agent to produce an intermediate sulfoxy salt represented by Formula (8), wherein R2 is H;
(c) treating the intermediate sulfoxy salt with a strong base to produce 4′-keto-N-Trifluoroacetyl-4-R1daunorubicin of Formula (3), wherein R1 is H, OH, or OMe;
(d) reacting the 4′-keto-N-Trifluoroacetyl-4-R1daunorubicin with a borohydride of an alkaline metal to produce N-Trifluoroacetyl-4′-epi-4-R1-daunorubicin represented by Formula (4), wherein R1 is defined as H, OH, OMe;
(e) hydrolyzing N-Trifluoroacetyl-4′-epi-4-R1-daunorubicin in a basic solution to produce Formula (5), wherein R1 is defined as H, OH, OMe, R2 is H, and An− is an anion of a strong acid;
(f) reacting Formula (5) with a halogenizing agent represented by Formula (6), wherein R3 through R8 are defined as H or a hydrocarbon radical of 1 to 4 carbon chains (C1-C4) and Hal is Cl, Br, or I to form Formula (7), wherein R1 is H, OH, or OMe and Hal is Cal, Br, or I, and An− is an anion of strong acid;
and
(g) hydrolyzing Formula (7) in the presence of a formate of an alkaline metal to produce an anthracyclin having a formula represented by Formula (1).

5 more elements

Dependencies are inferred from the claim text.

Epimerization of 4'-C bond and modification of 14-CH3-(CO)-fragment in anthracyclin antibiotics

Life of this patent

Epimerization of 4'-C bond and modification of 14-CH3-(CO)-fragment in anthracyclin antibiotics

Life of this patent

Abstract

Claims8