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Details for Patent: 5,674,470

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Details for Patent: 5,674,470

Title: Method for imaging mammalian tissue using 1-substituted- 4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs
Abstract:A method for imaging mammalian tissue utilizing a non-ionic complex of a paramagnetic ion of lanthanide element and a macrocyclic chelating agent.
Inventor(s): Tweedle; Michael F. (Princeton, NJ), Gaughan; Glen T. (Oxford, GB2), Hagan; James J. (Holmdel, NJ)
Assignee: Bracco Diagnostics Inc. (Princeton, NJ)
Filing Date:Jun 06, 1995
Application Number:08/469,546
Claims:1. A method for the preparation of a tetraazacyclo compound, comprising:

reacting 1,4.7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane, and

reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester.

2. The method of claim 1, wherein the ester groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester are removed with strong acid.

3. A method for the preparation of 1-substituted-4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane analogs, comprising:

reacting 1,4,7,10-tetraazacyclododecane with dimethylformamidedimethylacatal in the presence of benzene to yield 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane.

reacting the 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,

reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester,

removing the ester groups of 1-formyl, 4,7,10-triscarboxymethyl- 1,4,7, 10-tetraazacyclododecane tris-t-butylester with strong acid.

4. A method for the preparation of a tetraazacyclo compound having formula I: ##STR22## or a pharmaceutically acceptable salt thereof, wherein Y is ##STR23## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, or alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR24## wherein G is ##STR25## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR26## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy, carbamoyl or carboxyl groups, comprising:

reacting 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane, and

reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester.

5. The method of claim 4, wherein the ester groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester are removed with strong acid.

6. The method of claim 4, wherein R.sub.1 and R.sub.2 are hydrogen.

7. The method of claim 4, wherein R.sub.1 is hydroxyalkyl.

8. The method of claim 4, wherein R.sub.1 is hydroxyalkyl or ##STR27## wherein n is 1, m is 0, G is NHR.sub.4,

wherein R.sub.4 is alkyl.

9. 1-formyl-1,4,7,10-tetraazacyclododecane.

10. 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester.

11. A method of preparing compounds having formula I ##STR28## or a pharmaceutically acceptable salt thereof. wherein Y is ##STR29## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, phenylalkyl or substituted phenylalkyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups ##STR30## wherein G is ##STR31## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR32## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the ten substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups, comprising:

reacting a compound having formula II: ##STR33## with a reactive acid derivative having formula III: ##STR34## wherein X is a readily displaceable group such as chlorine, bromine or iodine, and

displacing X.

12. In the method of claim 11, wherein Y is ##STR35## R.sub.1 is hydrogen, the compounds of formula II are prepared by,

reacting 1,4,7-tritosylate of diethanolamine with 1,7-ditosylate of a 4-substituted 1,4,5-triazaheptane to yield ##STR36## removing the p-toluenesulfonyl groups by acid hydrolysis or by reductive cleavage.

13. In the method of claim 11, wherein Y is ##STR37## the compounds of formula II are prepared by, cylcocondensation of diethylenetriamine with a compound of formula IV: ##STR38## to yield a compound of formula V: ##STR39## reducing the compound of formula V to yield a compound of formula II.

14. The method of claim 11, wherein Y is ##STR40## and R.sub.1 is alkyl, arylalkyl, hydxoxyalkyl or aryl.

15. In the method of claim 11, whereto Y is --NH-- and R.sub.2 is hydrogen,

reacting 1,4,7,10-tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7, 10-tetraazatricyclo(5.5.1.0)tridecane,

reacting 1,4,7,10-tetraazatricyclo(5.5.1.0)tridecane, with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,

reacting 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl-1,4,7,10-triscarboxy-methyl-1,4,7,10-tetraazacyclododecane tris-t-butylester, and

removing the ester and amide groups in the presence of strong acid.

16. The method of claim 11, wherein Y is ##STR41## and Y is not --NH-- and the reaction of compounds of formula II and formula III is carried out at a pH of about 9 to 10.

17. The method of claim 11, wherein the pH of the reaction is maintained by adding alkali metal hydroxide or a tetraakylammonium hydroxide.

18. The method of claim 11, wherein the reaction of compounds of formula II and formula III is carried out at a temperature of between 50.degree.-80.degree. C.

19. The method of claim 11, wherein Y is --NH-- and the reaction of a compound of formula II with a compound of formula III is carried out in an aqueous solution at a pH of about 8.5 to 9 and the temperature of the reaction is maintained at about 45.degree.-55.degree. C.

20. A method for the preparation of 1,4,7-triscarboxymethyl-10-(2'-hydroxypropyl)-1,4,7,10-tetraazacyelododeca ne comprising:

reacting 1,4,7,10-tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane,

reacting the 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,

reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester,

removing the ester and amide groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester with strong acid to yield 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane

reacting 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane with propylene oxide, acidify the product, apply to a carbon exchange resin and elute with ammonia.

21. A method for the preparation of gadolinium (III), comprising:

reacting 1,4,7,10-tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane,

reacting the 1,4,7,10-tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,

reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7.10-tetraazacyclododecane tris-t-butylester,

removing the ester and amide groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester with strong acid to yield 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane,

reacting the 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane with propylene oxide, acidify the product, apply to a carbon exchange resin, elute with ammonia, and reacting with Gd(OAC).sub.3.4H.sub.2 O.

22. A method for the preparation of a tetraazacyclo compound that forms a stable, charge neutral, complex when combined with a paramagnetic ion of a lanthanide element, comprising:

reacting 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane, and

reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester.

23. The method of claim 22 wherein the ester and amide groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester are removed with strong acid.

24. A method for the preparation of 1-substituted-4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane analogs which forms a stable, charge neutral, complex when combined with a paramagnetic ion of a lanthanide element, comprising:

reacting 1,4,7,10 tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane,

reacting the 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,

reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester,

removing the ester and amide groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester with strong acid.

25. A method for the preparation of a tetraazacyclo compound which forms a stable, charge neutral, complex when combined with a paramagnetic ion of a lanthanide element, having formula I: ##STR42## or a pharmaceutically acceptable salt thereof, wherein Y is ##STR43## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, or alkoxy having from one to five carbon atom, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR44## wherein G is ##STR45## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR46## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chow, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups, comprising;

reacting 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane, and

reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 1,4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester.

26. The method of claim 25, wherein the ester and amide groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester are removed with strong acid.

27. The method of claim 25, wherein R.sub.1 and R.sub.2 are hydrogen.

28. The method of claim 25, wherein R.sub.1 is hydroxyalkyl.

29. The method of claim 25, wherein R.sub.1 is hydroxyalkyl or ##STR47## wherein n is 1, m is 0, G is NHR.sub.4,

wherein R.sub.4 is alkyl.

30. A method of preparing compounds having formula I: ##STR48## or a pharmaceutically acceptable salt thereof, said compounds form a stable, charge neutral, complex when combined with a paramagnetic ion of a lanthanide element,

wherein Y is ##STR49## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, phenylalkyl or substituted phenylalkyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR50## ##STR51## wherein G is ##STR52## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR53## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups, comprising:

reacting a compound having formula II: ##STR54## with a reactive acid derivative having formula III: ##STR55## whereto X is a readily displaceable group such as chlorine, bromine or iodine and

displacing X.

31. In the method of claim 30, wherein Y is ##STR56## R.sub.1 is hydrogen, the compounds of formula II are prepared by,

reacting 1,4,7-tritosylate of diethanolamine with 1,7-ditosylate of a 4-substituted 1,4.5-triazaheptane to yield ##STR57## removing the p-toluenesulfonyl groups by acid hydrolysis or by reductive cleavage.

32. In the method of claim 30, wherein Y is ##STR58## the compounds of formula II are prepared by: cylcocondensation of diethylenetriamine with a compound of formula IV: ##STR59## to yield a compound of formula V: ##STR60## reducing the compound of formula V to yield a compound of formula II.

33. The method of claim 30, wherein ##STR61## is --N--, and R.sub.1 is alkyl, arylalkyl, hydroxyalkyl or aryl.

34. In the method of claim 30, wherein Y is --NH-- and R.sub.2 is hydrogen,

reacting 1,4,7,10-tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10-tetraazatricyclo(5.5.1.0)tridecane,

reacting 1,4,7,10-tetraazatricyclo(5.5.1.0)tridecane, with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,

reacting 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxy-methyl-1,4,7,10-tetraazacyclododecane tris-t-butylester , and

removing the ester and amide groups in the presence of strong acid.

35. The method of claim 30, wherein Y is ##STR62## and Y is not --H-- and the reaction of compounds of formula II and formula III is carried out at a pH of about 9 to 10.

36. The method of claim 30, wherein the pH of the reaction is maintained by adding alkali metal hydroxide or a tetraalkylammonium hydroxide.

37. The method of claim 30, wherein the reaction of compounds of formula II and formula III is carried out at a temperature of between 50.degree.-80.degree. C.

38. The method of claim 30, wherein Y is --NH-- and the reaction of a compound of formula II with a compound of formula III is carried out in an aqueous solution at a pH of about 8.5 to 9 and the temperature of the reaction is maintained at about 45.degree.-55.degree. C.

39. A method for the preparation of an asymmetric tetraazacyclo compound comprising:

reacting 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane, and

reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraacyclododecane tris-t-butylester.

40. The method of claim 39 wherein the ester and amide groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester are removed with strong acid.

41. A method for the preparation of asymmetric 1-substituted-4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane analogs, comprising:

reacting 1,4,7,10 tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10tetraazatricyclo(5.5.1.0)tridecane,

reacting the 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,

reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 1,4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester,

removing the ester and amide groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester with strong acid.

42. A method for the preparation of an asymmetric tetraazacyclo compound having formula I: ##STR63## or a pharmaceutically acceptable salt thereof, wherein Y is ##STR64## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, or alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR65## wherein G is ##STR66## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR67## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups, comprising:

reacting 1,4,7,10 tetraazatricyclo(5.5,1.0)tridecane with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane, and

reacting the 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester.

43. The method of claim 42, wherein the ester and amide groups of 1-formyl, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane tris-t-butylester are removed with strong acid.

44. The method of claim 42, wherein R.sub.1 and R.sub.2 are hydrogen.

45. The method of claim 42, wherein R.sub.1 is hydroxyalkyl.

46. The method of claim 42, wherein R.sub.1 is hydroxyalkyl or ##STR68## wherein n is 1, m is 0, G is NHR.sub.4,

wherein R.sub.4 is alkyl.

47. A method of preparing asymmetric compounds having formula I: ##STR69## or a pharmaceutically acceptable salt thereof, said compounds form, wherein Y is ##STR70## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, phenylalkyl or substituted phenylalkyl alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups ##STR71## wherein G is ##STR72## wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR73## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups, comprising:

reacting a compound having formula II: ##STR74## with a reactive acid derivative having formula III: ##STR75## wherein X is a readily displaceable group such as chlorine, bromine or iodine and

displacing X.

48. In the method of claim 47, wherein Y is ##STR76## R.sub.1 is hydrogen, the compounds of formula II are prepared by,

reacting 1,4,7-tritosylate of diethanolamine with 1,7-ditosylate of a 4-substituted 1,4,5-triazaheptane to yield ##STR77## removing the p-toluenesulfonyl groups by acid hydrolysis or by reductive cleavage.

49. In the method of claim 47, wherein Y is ##STR78## compounds of formula II are prepared by: cylcocondensation of diethylenetriamine with a compound of formula IV: ##STR79## to yield a compound of formula V: ##STR80## reducing the compound of formula V to yield a compound of formula II.

50. The method of claim 47, wherein ##STR81## is --N--, and R.sub.1 is alkyl, arylalkyl, hydroxyalkyl or aryl.

51. In the method of claim 47, wherein Y is --NH-- and R.sub.2 is hydrogen,

reacting 1,4,7,10-tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10-tetraazatricyclo(5.5.1.0)tridecane,

reacting 1,4,7,10-tetraazatricyclo(5.5.1.0)tridecane, with an ethanol/water mixture to yield 1-formyl-1,4,7,10-tetraazacyclododecane,

reacting 1-formyl-1,4,7,10-tetraazacyclododecane with t-butyl bromoacetate to yield 1-formyl, 4,7,10-triscarboxy-methyl-1,4,7,10-tetraazacyclododecane tris-t-butylester , and

removing the ester and amide groups in the presence of strong acid.

52. The method of 47, wherein Y is ##STR82## and Y is not --NH-- and the reaction of compounds of formula II and formula III is carried out at a pH of about 9 to 10.

53. The method of claim 47, wherein the pH of the reaction is maintained by adding alkali metal hydroxide or a tetraalkylammonium hydroxide.

54. The method of claim 47, wherein the reaction of compounds of formula II and formula III is carried out at a temperature of between 50.degree.-80.degree. C.

55. The method of claim 47, wherein the Y is --NH-- and the reaction of a compound of formula II with a compound of formula III is carried out in an aqueous solution at a pH of about 8.5 to 9 and the temperature of the reaction is maintained at about 45.degree.-55.degree. C.
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