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 a sugar moiety
wherein the sugar moiety is
2. The compound of claim 1 , wherein the compound is a derivative of an anthracycline selected from the group consisting of epirubicin, and annamycin.
3. 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.
4. 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 the solution; and
3) heating the solution to reduce the 13-benzene-, or substituted benzene-, sulfonylhydrazone anthracycline,
wherein the acidic pyridinium salt is pyridinium p-toluenesulfonate and the reducing agent is sodium cyanoborohydride.
5. The process according to claim 4 , further comprising the step of hydrolyzing the reduced 13-benzene-sulfonylhydrazone anthracycline, thereby forming the 13-deoxy anthracycline.
6. The process according to claim 4 wherein the heating is at about 65° C. to about 75° C.
7. The process according to claim 4 wherein the 13-benzene-sulfonylhydrazone anthracycline is a derivative of an anthracycline selected from the group consisting of epirubicin, and annamycin.
8. A process for preparing a 5-imino-13-deoxy anthracyclines, comprising:
1) preparing a 13-deoxy anthracycline according to claim 4 ; and
2) converting the 13-deoxy anthracycline to the corresponding 5-imino-13-deoxy anthracycline with ammonia at less than about 20° C.,
wherein the 13-deoxy anthracycline is synthesized from a corresponding 13-benzenesulfonylhydrazone anthracycline.
9. The process according to claim 8 wherein the step of converting the 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.
10. The process according to claim 8 wherein the 13-deoxy anthracycline is selected from the group consisting of the 13-deoxy forms of epirubicin, and annamycin.
11. The compound of claim 1 , wherein R 6 is
12. The compound of claim 1 , wherein R 6 is