Methods of synthesizing heteroatom-bearing ligands and intermediate used therefor

1. A method of synthesizing a compound of Formula I having the structure:

where all R and R* groups are independently:

(i) R 2 ;

(ii) halogen;

(iii) —OR 2 ;

(iv) —C(O)—OR 2 ;

(v) —C(O)—N(R 2 ) 2 ;

(vi) —N(R 2 ) 2 ;

(vii) -alkyl-C(O)—OR 2 ;

(viii) -alkyl-C(O)—N(R 2 ) 2 ;

(ix) -alkyl-N(R 2 ) 2 ;

(x) -aryl-C(O)—OR 2 ;

(xi) -aryl-C(O)—N(R 2 ) 2 ;

(xii) -aryl-N(R 2 ) 2 ;

(xiii) acyl;

(xiv) acyloxy;

(xv) heterocyclo;

(xvi) hydroxyalkyl;

(xvii) —SO 2 —R 2 ;

(xviii) -alkyl-SO 2 —R 2 ;

(xix) -(A) p -R 3 , where A is a linking group, p is 0 or a positive integer, and R 3 is a bioactive moiety; or

(xx) two R groups, or an R group and an R* group, taken together with the one or more atoms to which they are bonded, form a saturated or unsaturated, spiro or fused, carbocyclic (such as fused 1,2-phenyl) or heterocyclic ring which may be unsubstituted or substituted by one or more groups selected from the groups (i) to (xix) above;

with the proviso that a carbon atom bearing an R group is not directly bonded to more than one heteroatom; and

R 2 is independently hydrogen, alkyl, alkenyl, alkynyl, or aryl, the method comprising the steps of:

(i) contacting 2-{2-(1,3-dioxoisoindolin-2-yl)-1-[(2-nitroimidazolyl)methyl]ethoxy}isoindoline- 1,3-dione:

 with hydrazine, to obtain 1-(3-amino-2-(aminooxy)propyl)-2-nitro-1H-imidazole dihydrochioride; and

(ii) contacting the product of (i) with a compound having the structure IIIa or IIIb or a mixture thereof:

where X is halogen and R and R* are defined above.

2. The method of claim 1 , wherein R is methyl.

3. The method of claim 1 , wherein R* is methyl.

4. The method of claim 1 , wherein R is methyl and R* is methyl.

5. The method of claim 1 , wherein X is selected from Cl, Br, and I.

6. The method of claim 1 , wherein the compound having the structure IIIa or IIIb is 3-chloro-3-methyl-2-nitrosobutane.

7. The method of claim 1 , further comprising the step of contacting 2-[2-hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione with N-hydroxyphthalimide to obtain the 2-{2-(1,3-dioxoisoindolin-2-yl)-1-[(2-nitroimidazolyl)methyl] ethoxy}isoindoline-1,3-dione.

8. The method of claim 7 , further comprising the step of contacting N-(2,3-epoxypropyl)phthalimide with 2-nitroimidazole to obtain the 2-[2-hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione.

9. The method of claim 8 , wherein R is methyl.

10. The method of claim 8 , wherein R* is methyl.

11. The method of claim 8 , wherein R is methyl and R* is methyl.

12. The method of claim 8 , wherein X is selected from Cl, Br, and I.

13. The method of claim 8 , wherein the compound having the structure IIIa or IIIb is 3-chloro-3-methyl-2-nitrosobutane.

14. The method of claim 1 , further comprising the step of contacting 2-[(2S)-2-hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3 (2H)-dione:

with N-hydroxyphthalimide to obtain 2-{(1R)-2-(1,3-dioxoisoindolin-2-yl)-1-[(2-nitroimidazolyl)methyl] ethoxy}isoindoline-1,3-dione:

15. The method of claim 14 , further comprising the step of contacting (R)-2-Oxyranylmethyl-1-H-isoindole-1,3-(2H)-dione with 2-nitroimidazole to obtain 2-[(2S)-hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione:

16. The method of claim 15 , wherein R is methyl.

17. The method of claim 15 , wherein R* is methyl.

18. The method of claim 15 , wherein R is methyl and R* is methyl.

19. The method of claim 15 , wherein X is selected from Cl, Br, and I.

20. The method of claim 15 , wherein the compound having the structure IIIa or IIIb is 3-chloro-3-methyl-2-nitrosobutane.

21. The method of claim 1 , further comprising the step of contacting 2-[(2R)-2-hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione:

with N-hydroxyphthalimide to obtain 2-{(1S)-2-(1,3-dioxoisoindolin-2-yl)-1-[(2-nitroimidazolyl)methyl] ethoxy}isoindoline-1,3-dione:

22. The method of claim 21 , further comprising the step of contacting (S)-2-Oxyranylmethyl-1-H-isoindole-1,3-(2H)-dione with 2-nitroimidazole to obtain 2-[(2R)-2-hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione:

23. The method of claim 22 , wherein R is methyl.

24. The method of claim 22 , wherein R* is methyl.

25. The method of claim 22 , wherein R is methyl and R* is methyl.

26. The method of claim 22 , wherein X is selected from Cl, Br, and I.

27. The method of claim 22 , wherein the compound having the structure IIIa or IIIb is 3-chloro-3-methyl-2-nitrosobutane.

28. A method of synthesizing a compound having the structure:

where all R and R* groups are independently:

(i) R 2 ;

(ii) halogen;

(iii) —OR 2 ;

(iv) —C(O)—OR 2 ;

(v) —C(O)—N(R 2 ) 2 ;

(vi) —N(R 2 ) 2 ;

(vii) -alkyl-C(O)—OR 2 ;

(viii) -alkyl-C(O)—N(R 2 ) 2 ;

(ix) -alkyl-N(R 2 ) 2 ;

(x) -aryl-C(O)—OR 2 ;

(xi) -aryl-C(O)—N(R 2 ) 2 ;

(xii) -aryl-N(R 2 ) 2 ;

(xiii) acyl;

(xiv) acyloxy;

(xv) heterocyclo;

(xvi) hydroxyalkyl;

(xvii) —SO 2 —R 2 ;

(xviii) -alkyl-SO 2 —R 2 ;

(xix) -(A) p -R 3 , where A is a linking group, p is 0 or a positive integer, and R 3 is a bioactive moiety; or

(xx) two R groups, or an R group and an R* group, taken together with the one or more atoms to which they are bonded, form a saturated or unsaturated, spiro or fused, carbocyclic (such as fused 1,2-phenyl) or heterocyclic ring which may be unsubstituted or substituted by one or more groups selected from the groups (i) to (xix) above;

with the proviso that a carbon atom bearing an R group is not directly bonded to more than one heteroatom; and

R 2 is independently hydrogen, alkyl, alkenyl, alkynyl, or aryl, the method comprising the steps of:

(i) contacting 2-{(1R)-2-(1,3-dioxoisoindolin-2-yl)-1-[(2-nitroimidazolyl)methyl]ethoxy}isoindoline-1,3-dione:

 with hydrazine, to obtain 1-(3-amino-2-(aminooxy)propyl)-2-nitro-1H-imidazole dihydrochloride; and

(ii) contacting the product of (i) with a compound having the structure IIIa or IIIb or a mixture thereof:

where X is halogen and R and R* are defined above.

29. A method of synthesizing a compound having the structure:

wherein all R and R* groups are independently:

(i) R 2 ;

(ii) halogen;

(iii) —OR 2 ;

(iv) —C(O)—OR 2 ;

(v) —C(O)—N(R 2 ) 2 ;

(vi) —N(R 2 ) 2 ;

(vii) -alkyl-C(O)—OR 2 ;

(viii) -alkyl-C(O)—N(R 2 ) 2 ;

(ix) -alkyl-N(R 2 ) 2 ;

(x) -aryl-C(O)—OR 2 ;

(xi) -aryl-C(O)—N(R 2 ) 2 ;

(xii) -aryl-N(R 2 ) 2 ;

(xiii) acyl;

(xiv) acyloxy;

(xv) heterocyclo;

(xvi) hydroxyalkyl;

(xvii) —SO 2 —R 2 ;

(xviii) -alkyl-SO 2 —R 2 ;

(xix) -(A) p -R 3 , where A is a linking group, p is 0 or a positive integer, and R 3 a bioactive moiety; or

(xx) two R groups, or an R group and an R* group, taken together with the one or more atoms to which they are bonded, form a saturated or unsaturated, spiro or fused, carbocyclic (such as fused 1,2-phenyl) or heterocyclic ring which may be unsubstituted or substituted by one or more groups selected from the groups (i) to (xix) above;

with the proviso that a carbon atom bearing an R group is not directly bonded to more than one heteroatom; and

R 2 is independently hydrogen, alkyl, alkenyl, alkynyl, or aryl, the method comprising the steps of:

(i) contacting 2-{(1S)-2-(1,3-dioxoisoindolin-2-yl)-1-[(2-nitroimidazolyl) methyl]ethoxy}isoindoline-1,3-dione;

 with hydrazine, to obtain 1-(3-amino-2-(aminooxy)propyl)-2-nitro-1H-imidazole dihydrochloride; and

(ii) contacting the product of(i) with a compound having the structure IIIa or IIIb or a mixture thereof:

where X is halogen and R and R* are defined above.