US 8,802,830 B2Granted

Synthesis of epirubicin from 13-dihydrodaunorubicine

AssigneeSolux Corporation

InventorsAlexander F. Zabudkin, Victor Matvienko, Aleksandr M. Itkin, Alexey Matveev

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Abstract

A method of preparing an anthracyclin such as epirubicin from a starting material comprising 13-dihydrodaunorubicine (13-daunorubicinol). The method comprises producing N-Trifluoroacetyl-13-daunorubicinol from 13-daunorubicinol by acylation. The N-Trifluoroacetyl-13-daunorubicinol is reacted with an aprotic solvent and an acylating agent to produce an intermediate sulfoxy salt which is treated with a strong base to produce 4′-keto-N-Trifluoroacetyldaunorubicin. The 4′-keto-N-Trifluoroacetyldaunorubicin is reacted with a reducing agent, such as borohydride of an alkaline metal, to produce N-Trifluoroacetyl-4′-epi-daunorubicin. The N-Trifluoroacetyl-4′-epi-daunorubicin is hydrolyzed in a basic solution to produce an intermediate compound. The intermediate compound is reacted with a halogenizing agent to produce a 14-Hal-derivative. The 14-Hal derivative is hydrolized in the presence of a formate of an alkaline metal to produce the desired final compound.

Claims32

Dependent claims

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

comprising:
(a) providing N-Trifluoroacetyl-13-daunorubicinol represented by Formula (4);
(b) reacting the N-Trifluoroacetyl-13-daunorubicinol with dimethylsulfoxide (DMSO) activated by an acylating agent, in an aprotic solvent, to produce an intermediate sulfoxy salt and treating the intermediate sulfoxy salt with a strong base to produce 4-′-keto-N-Trifluoroacetyldaunorubicin of Formula (5);
wherein the aprotic solvent is selected from the group consisting of DMSO, DMAA, HMPA, Acetonitrile, DCM, halogenalkanes, aromatic hydrocarbons, and mixtures thereof;
wherein the acylating agent is represented by AcX, wherein:
AcX=PySO3, SOCl2, PHal3, POHal3, wherein Hal=Cl, Br;
or
AcX is defined by the combination of Ac and X, wherein Ac=AlkCO, OC—(CH2)—CO, n=0-4;
AlkSO2, ArCO, or ArSO2;
wherein Alk=alkyl of halogenalkyl radical;
and Ar=phenyl or substituted phenyl radical;
and X═Cl, Br, I, OAc;
wherein the strong base is a cyclic or polycyclic tertiary amine represented by NR7R8R9, wherein R7, R8, and R9=alkyl or cycloalkyl, and wherein, if R8, R9=cycloalkyl, then R8 together with R9 simultaneously=—(CH2) where n=3-6;
(c) reacting the 4′-keto-N-Trifluoroacetyldaunorubicin with a borohydride of an alkaline metal to produce N-Trifluoroacetyl-4′-epi-daunorubicin represented by Formula (6);
(d) hydrolyzing N-Trifluoroacetyl-4′-epi-daunorubicin in a basic solution to produce a compound represented by Formula (7);
wherein An− is an anion of a strong acid;
(e) reacting the compound represented by Formula (7) with a halogenizing agent represented by Formula (8),
wherein R1 through R6 are defined as at least one of H or a hydrocarbon radical of 1 to 4 carbon chains (C1-C4) and Hal is Cl, Br, or I, to form a compound represented by Formula (9),
wherein Hal is Cl, Br, or I, and An− is an anion of strong acid;
and
(f) hydrolyzing the compound represented by Formula (9) in the presence of a formate of an alkaline metal to produce an anthracyclin having a formula represented by Formula (1),

18 more elements

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

comprising:
(a) providing N-Trifluoroacetyl-13-daunorubicinol represented by Formula (4);
(b) reacting the N-Trifluoroacetyl-13-daunorubicinol with dimethylsulfoxide (DMSO) activated by an acylating agent, in an aprotic solvent, to produce an intermediate sulfoxy salt and treating the intermediate sulfoxy salt with a strong base to produce 4′-keto-N-Trifluoroacetyldaunorubicin of Formula (5);
wherein the acylating agent is represented by AcX, wherein:
AcX=PySO3, SOCl2, PHal3, POHal3, wherein Hal=Cl, Br;
or
AcX is defined by the combination of Ac and X, wherein Ac=AlkCO, OC—(CH2)n—CO, n=0-4;
AlkSO2, ArCO, or ArSO2;
wherein Alk=alkyl of halogenalkyl radical;
and Ar=phenyl or substituted phenyl radical;
and X═Cl, Br, I, OAc;
wherein the strong base is a cyclic or polycyclic tertiary amine represented by NR7R8R9, wherein R7, R8, and R9=alkyl or cycloalkyl, and wherein, if R8, R9=cycloalkyl, then R8 together with R9 simultaneously=—(CH2)n where n=3-6;
(c) reacting the 4′-keto-N-Trifluoroacetyldaunorubicin with a borohydride of an alkaline metal to produce N-Trifluoroacetyl-4′-epi-daunorubicin represented by Formula (6);
(d) hydrolyzing N-Trifluoroacetyl-4′-epi-daunorubicin in a basic solution to produce a compound represented by Formula (7);
wherein An− is an anion of a strong acid;
(e) reacting the compound represented by Formula (7) with a halogenizing agent represented by Formula (8),
wherein R1 through R6 are defined as at least one of H or a hydrocarbon radical of 1 to 4 carbon chains (C1-C4) and Hal is Cl, Br, or I, to form a compound represented by Formula (9),
wherein Hal is Cl, Br, or I, and An− is an anion of strong acid;
and
(f) hydrolyzing the compound represented by Formula (9) in the presence of a formate of an alkaline metal to produce an anthracyclin having a formula represented by Formula (1),

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/612,322Filed 18 Dec 2006 · us provisional application
Priority: 20 Dec 2005
Published: US 2007/0142309 A121 Jun 2007
Granted: 12 Aug 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07H 1/00
Processes for the preparation of sugar derivatives
C07H 15/24
Carbocyclic rings: condensed ring systems having three or more rings
C07H 15/252
Condensed ring systems having three or more rings: naphthacene radicals, e.g. daunomycins, adriamycins
C07H
Sugars