Compositions and processes for preparing 13-deoxy-anthracyclines
13-benzenesulfonylhydrazone anthracyclines useful in producing improved yields in the synthesis 13-deoxyanthrcyclines, and an improved method of reducing 13-benzene-sulfonylhydrazone anthracyclines to 13-deoxyanthrcyclines wherein the reduction reaction is maintained at temperatures of about 55° C. to 64° C. without stirring or agitation. The reaction is completed with the addition of aqueous bicarbonate which forms the 13-deoxyanthracycline and precipitates. The precipitates are filtered and the precipitate and filtrate are extracted separately with organic solvents. The crude 13-deoxy anthracycline can be converted to 5-imino-13-deoxy anthracycline by reaction with methanolic ammonia. The reaction can also be performed with an acidic pyridinium salt instead of a strong acid so that neutralization of the reaction or extraction of the product is not necessary, thereby facilitating purification.
1. A compound represented by the formula:
wherein:
R 1 , R 2 and R 3 are H or OH;
R 4 is H, OH, alkyl, or O-alkyl;
R 5 is O or NH; and
R 6 is H, OH, or a sugar moiety;
wherein said sugar moiety is
2. The compound of claim 1 , wherein said compound is a derivative of an anthracycline selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin, annamycin, and carminomycin.
3. The compound of claim 1 , wherein R 6 is
4. The compound of claim 2 , wherein R 6 is
5. A method for producing a compound according to claim 1 which comprises reacting a 13-keto anthracycline or acid salt thereof with benzene-sulfonylhydrazide in an alcohol solvent at about 35 to 50° C. for about 10 to 24 hours.
6. A process for preparing 13-deoxy anthracyclines, comprising:
1) forming an alcohol solution of a 13-benzene sulfonylhydrazone anthracycline;
2) adding a reducing agent and an acid to said solution;
3) heating said solution, without agitation or stirring, to reduce said 13-benzene sulfonylhydrazone anthracycline; and
4) neutralizing said solution with aqueous base, thereby forming said 13-deoxy anthracycline and precipitates.
7. The process according to claim 6 further comprising the step of filtering said precipitate, extracting said 13-deoxy anthracycline from said precipitate, and extracting said 13-deoxy anthracycline from the filtrate.
8. The process according to claim 6 wherein said heating is at about 55° C. to about 64° C., said reducing agent is cyanoborohydride, and said acid is p-toluenesulfonic acid.
9. The process according to claim 8 wherein said heating is at about 59° C. to about 60° C.
10. The process according to claim 6 wherein said 13-benzene sulfonylhydrazone anthracycline is a derivative of an anthracycline selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin, annamycin, and carminomycin.
11. A process for preparing 5-imino-13-deoxy anthracyclines comprising:
1) preparing a 13-deoxy anthracycline according to claim 6 ;
2) dissolving said 13-deoxy anthracycline in an alcohol; and
3) converting said 13-deoxy anthracycline to the corresponding 5-imino-13-deoxy anthracycline with ammonia at less than about 20° C.; and
wherein said 13-deoxy anthracycline is synthesized from a corresponding 13-benzenesulfonylhydrazone anthracycline.
12. The process according to claim 11 wherein the step of converting said 13-deoxy anthracycline to the corresponding 5-imino-13-deoxy anthracycline with ammonia is at about 1° C. to about 4° C. for 1 to 4 days.
13. The process according to claim 11 wherein said 13-deoxy anthracycline is selected from the group consisting of the 13-deoxy forms of doxorubicin, daunorubicin, epirubicin, idarubicin, annamycin and carminomycin.
14. A process for preparing 13-deoxy anthracyclines, comprising:
1) forming an alcohol solution of a 13-benzene-, or substituted benzene-, sulfonylhydrazone anthracycline;
2) adding a reducing agent and an acidic pyridinium salt to said solution; and
3) heating said solution to reduce said 13-benzene-, or substituted benzene-, sulfonylhydrazone anthracycline;
and wherein said acidic pyridinium salt is pyridinium-p-toluenesulfonate and said reducing agent is cyanoborohydride.
15. The process according to claim 14 , further comprising the step of hydrolyzing said reduced 13-benzene-, or substituted benzene-, sulfonylhydrazone anthracycline, thereby forming said 13-deoxy anthracycline.
16. The process according to claim 14 wherein said heating is at about 65° C. to about 75° C.
17. The process according to claim 14 wherein said 13-benzene-, or substituted benzene-, sulfonylhydrazone anthracycline is a derivative of an anthracycline selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin, annamycin, and carminomycin.
18. A process for preparing 5-imino-13-deoxy anthracyclines comprising:
1) preparing a 13-deoxy anthracycline according to claim 14 ; and
2) converting said 13-deoxy anthracycline to the corresponding 5-imino-13-deoxy anthracycline with ammonia at less than about 20° C.
19. The process according to claim 18 wherein the step of converting said 13-deoxy anthracycline to the corresponding 5-imino-13-deoxy anthracycline with ammonia is at about 1° C. to about 4° C. for 1 to 4 days.
20. The process according to claim 18 wherein said 13-deoxy anthracycline is selected from the group consisting of the 13-deoxy forms of doxorubicin, daunorubicin, epirubicin, idarubicin, annamycin and carminomycin.
21. The process according to claim 18 wherein said 13-deoxy anthracycline is synthesized from a corresponding 13-benzenesulfonylhydrazone anthracycline.