Granted Patent B2

US 7,393,954 · App. 10/734,545 · Granted Jul 1, 2008

Abstract

Claims (59)

1. A method for synthesizing pentostatin, a pentostatin analog, pentostatin aglycone, or a pentostatin aglycone analog which method comprises the steps of:

converting a dialkyl tartarate to a succinonitrile derivative having the formula:

wherein Z is OR 15 , wherein R 15 is a protecting group;

reacting the succinonitrile derivative with an iminoether selected from:

(a) an iminoether having the formula

wherein R is a protecting group or

wherein X is O, S, NH, or CH 2 ; or

(b) an iminoether having the formula

wherein R 16 is

wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from OH, H, methyl, alkyl, CH 2 OH, a halogen, a substituted or unsubstituted O—R′ group, a substituted or unsubstituted S—R′ group, or a NR′R″ group, wherein R′ and R″ are independently a straight-chained or substituted alkyl or alkenyl group; or

(c) an iminoether having the formula

wherein R 17 is

wherein R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from OH, H, methyl, alkyl, CH 2 OH, a halogen, a substituted or unsubstituted O—R′″ group, a substituted or unsubstituted S—R″′ group, or a NR″′R″″ group, wherein R′″ or R″″ are independently a straight-chained or substituted alkyl or alkenyl group;

to form a imidazole ring compound, wherein the imidazole ring compound comprises a moiety having a cyano group;

reducing the cyano group on the imidazole ring compound to a primary amino group;

cyclizing the primary amino group with a second amino group on the imidazole ring compound; and

removing any protecting groups to obtain pentostatin, pentostatin aglycone, a pentostatin compound, wherein the pentostatin compound is selected from:

(a) a pentostatin analog in which the oxygen atom in the sugar moiety is replaced with a sulfur atom, a NH group, or a CH 2 group;

(b) a pentostatin analog in which the sugar moiety is based on arabinose, xylose, ribose, lyxose glucose, galactose, manose, gulose, idose, talose, altrose, allose, fructose, sorbose or tagatose instead of deoxyribose; and

(c) a pentostation aglycone analog which does not contain a sugar moiety, and wherein the carbon atom between the two nitrogen atoms on the seven-member ring is altered.

2. The method of claim 1 , wherein the dialkyl tartarate is in either the L or D enantiomeric form.

3. The method of claim 2 , wherein the dialkyl tartarate is L-Diethyl tartarate.

4. The method of claim 2 , wherein the dialkyl tartarate is D-Diethyl tartarate.

5. The method of claim 1 , wherein the iminoether is obtained from a reaction of ammonia or primary amine with a trimethyl orthoester.

6. The method of claim 5 , wherein the primary amine has the formula R 21 —NH 2 , wherein R 21 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkoxyalkyl group, or a substituted or unsubstituted heteroaryl group.

7. The method of claim 6 , wherein the primary amine is benzyl amine, allyl amine, beta-cyanoethyl amine, or p-methoxy benzyl amine.

8. The method of claim 1 , wherein the iminoether has the formula

wherein R is deoxyribose, ribose, arabinose, xylose, ribose, lyxose, glucose, galactose, mannose, gulose, idose, talose, altrose, allose, fructose, sorbose, or tagatose.

9. The method of claim 8 , wherein R is deoxyribose, the dialkyl tartarate is L-diethyl tartarate, and pentostatin is synthesized.

10. The method of claim 1 , wherein the iminoether has the formula

wherein R is

wherein X is O, S, NH, or CH 2 ; or

wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from OH, H, methyl, alkyl, CH 2 OH, a halogen, a substituted or unsubstituted O—R′ group, a substituted or unsubstituted S—R′ group, or a NR′R″ group, wherein R′ and R″ are independently a straight-chained or substituted alkyl or alkenyl group; or

wherein R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from OH, H, methyl, alkyl, CH 2 OH, a halogen, a substituted or unsubstituted O—R″′ group, a substituted or unsubstituted S—R″′ group, or a NR″′R″″ group, wherein R″′ or R″″ are independently a straight-chained or substituted alkyl or alkenyl group.

11. The method of claim 1 , wherein the cyclization is performed with an orthoformate.

12. The method of claim 11 , wherein the orthoformate has the formula HC(OR 18 ) 3 , wherein R 18 is a straight-chained or substituted alkyl group.

13. The method of claim 1 , further comprising the step of glycosylating the pentostatin aglycone or the pentostatin aglycone analog.

14. The method of claim 13 , wherein the pentostatin aglycone is glycosylated with deoxyribose to obtain pentostatin.

15. The method of claim 1 , wherein R 15 is TBDMS, SiPh 2 C(CH 3 ) 3 , an acetyl group, dimethoxytrityl, or Methylthioethyl amine.

16. The method of claim 1 , wherein the primary amino group comprises a protecting group, and the protecting group is removed after cyclization.

17. A method for synthesizing pentostatin or a pentostatin analog, which method comprises the steps of:

converting a L diethyl tartrate to a succinonitrile intermediate, the intermediate having the formula:

wherein Z is OR 19 , wherein R 19 is a protecting group;

reacting the succinonitrile intermediate with an amino sugar intermediate having the formula:

wherein R 20 is

wherein X is O, S, NH, or CH 2 ; or wherein R 20 is

wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from OH, H, methyl, alkyl, CH 2 OH, or a halogen; or wherein R 20 is

wherein R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from OH, H, methyl, alkyl, CH 2 OH, or a halogen,

to form a imidazole ring compound, wherein the imidazole ring compound comprises a moiety having a cyano group;

reducing the cyano group on the imidazole ring compound to a primary amino group; and

adding a orthoformate to cyclize the primary amino group with a second amino group on the imidazole ring compound; and

removing the protecting group to obtain pentostatin or the pentostatin compound, wherein the pentostatin compound is selected from:

(a) a pentostatin analog in which the oxygen atom in the sugar moiety is replaced with a sulfur atom, a NH group, or a CH 2 group; and

(b) a pentostatin analog in which the sugar moiety is based on arabinose, xylose, ribose, lyxose glucose, galactose, manose, gulose, idose, talose, altrose, allose, fructose, sorbose or tagatose instead of deoxyribose.

18. The method of claim 17 , wherein the amino sugar intermediate has the formula

wherein R is deoxyribose, ribose, arabinose, xylose, ribose, lyxose, glucose, galactose, mannose, gulose, idose, talose, altrose, allose, fructose, sorbose, or tagatose.

19. The method of claim 18 , wherein R is deoxyribose.

20. The method of claim 17 wherein R is

wherein X is S, NH, or CH 2 .

Assignments (8)