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1. WO2009073147 - PROCÉDÉ DE PRÉPARATION DE BIS(THIOHYDRAZIDE AMIDES)

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CLAIMS
What is claimed is:

1. A method of regioselectively preparing a hydrazide represented by formula (I):



(I)
wherein:
Ri is H, an optionally substituted aliphatic group, or an optionally substituted aryl group; and
R3 is an optionally substituted aliphatic group or an optionally
substituted aryl group; comprising the steps of:
a) dissolving a thioglycolic acid represented by formula (II):



(II)
in an aqueous solution, wherein the aqueous solution comprises at
least about 1 equivalent of Mn+(0H')n in relation to the thioglycolic acid; and wherein n is 1 or 2; and when n is 1, Mn+ is selected from
Li+, Na+, K+, Rb+ or Cs+; and when n is 2, Mn+ is selected from Be2+, Mg2+, Sr2+ or Ba2+.
b) dissolving in water at least about 1 equivalent of a hydrazine in
relation to the thioglycolic acid used in step a), wherein the hydrazine is represented by formula (III):

HN NH2

R3
(III) ; and c) adding the thioglycolic acid solution to the hydrazine solution,
thereby regioselectively preparing a hydrazide represented by
formula (I).

2. The method of Claim 1, wherein the thioglycolic acid solution comprises between about 0.9 and about 1.1 equivalents of Mn+(0H')n in relation the thioglycolic acid.

3. The method of Claim 1 or 2, wherein the hydrazine solution comprise
between about 1 equivalent and about 1.75 equivalents of a hydrazine in relation to the thioglycolic acid.

4. The method of any one of Claims 1 through 3, wherein hydrazine solution is maintained at between about -10 0C and about 15 0C during addition of the thioglycolic acid solution.

5. The method of any one of Claims 1 through 4, wherein Mn+(0H")n is NaOH.

6. The method of any one of Claims 1 through 5, wherein Ri is an optionally substituted phenyl.

7. The method of any one Claims 1 through 6, wherein Rj is an unsubstituted phenyl.

8. The method of any one of Claims 1 through 7, wherein R3 is a lower alkyl group.

9. The method of any one of Claims 1 through 8, wherein R3 is methyl.

10. The method of any one of Claims 1 through 9, wherein about 1.01
equivalents of Mn+(0H")n in relation to the thioglycolic acid is present in the thioglycolic acid solution.

11. The method of any one of Claims 1 through 10, wherein the thioglycolic acid solution prepared in step a) comprises between about 0.9 L and about 1.15 L of water per mole of the thioglycolic acid.

12. The method of any one of Claims 1 through 1 1 , wherein about 1.3
equivalents of the hydrazine in relation to the thioglycolic acid is present in the hydrazine solution.

13. The method of any one Claims 1 through 12, wherein the hydrazine solution prepared in step b) comprises between about 0.9 L and about 1.15 L of water per mole of the thioglycolic acid.

14. The method of any one of Claims 1 through 13 , further comprising the step of extracting the hydrazide represented by formula (I) into a water
immiscible organic solvent and separating the organic layer from the water layer.

15. The method of Claim 14, wherein the organic solvent is isopropyl acetate, butyl acetate, methylene chloride, chloroform, diethyl ether, petroleum ether, toluene, or combinations thereof.

16. The method of Claim 15, wherein the organic solvent is methylene chloride.

17. The method of any one of Claims 14, 15 or 16, wherein between about 0.75 L and about 1.0 L of organic solvent is used for the extraction per mole of thioglycolic acid.

18. The method of any one of Claims 14 through 17, further comprising the step of washing the organic layer with an aqueous basic solution, wherein the base is selected from the group consisting of LiOH, NaOH or KOH.

19. The method of Claim 18, wherein the aqueous basic solution is a NaOH
solution having a normality of between about 0.5 N and about 0.05 N.

20. The method of Claim 19, wherein the NaOH solution has a normality of about 0.1 N.

21. The method of any one of Claims 18, 19 or 20, wherein between about 0.75 L and about 1.0 L of basic solution is used for the wash per mole of
thiolglycolic acid.

22. The method of any one of Claims 18, 19, 20, or 21, wherein the basic wash is repeated one or more times.

23. The method of any one of Claims 18 through 22, further comprising the step of washing the organic layer with water one or more times following the last basic wash, wherein the water from the last water wash has a pH of about 8 or less than 8.

24. The method of Claim 22 or 23, wherein between about 0.75 L and about 1.0 L of water per mole of thioglycolic acid is used in each wash.

25. The method of Claim 23 or 24, further comprising the steps of:
concentrating the organic layer to between about 0.2 L and about 0.5 L per mole of thioglycolic acid;
adding between about 0.75 L and about 1.25 L of hexane(s) or
heptane(s) to the concentrated organic layer to form a slurry;
stirring the slurry for about 1 hour to about 24 hours; and
collecting the solid hydrazide.

26. The method of any one of Claims 1 through 25, wherein the yield of the hydrazide is about 80% or greater and the purity is about 98 % or greater.

27. A method of preparing a bis(thio-hydrazide amide) represented by formula (IV):



(IV)
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:
Ri is H, an optionally substituted aliphatic group, or an optionally substituted aryl group;
R3 is an optionally substituted aliphatic group or an optionally
substituted aryl group; and
Y is a covalent bond or a methylene which is optionally substituted with one or two independently selected methyl or ethyl group, comprising the steps of:
a) dissolving a hydrazide represented by formula (I):



(I)
in a solution comprising an organic solvent and optionally at least
about 1 equivalent in relation to the hydrazide of a non-nucleophilic base;
b) a bis(acid chloride) represented by formula (V):

(V)
c) dissolving between about 0.4 and 0.65 equivalents of the bis(acid
chloride) in an organic solvent; and
d) adding the bis(acid chloride) solution to the hydrazide solution,
thereby preparing a bis(thio-hydrazide amide) represented by formula (IV).

28. The method of Claim 27, wherein the hydrazide solution is cooled to
between about -10 0C and about 15 0C before addition of the bis(acid
chloride) and the temperature is maintained in this range during addition of the bis(acid chloride) and formation of the bis(thio-hydrazide amide).

29. The method of Claim 27 or 28, wherein the non-nucleophilic base is
triethylamine.

30. The method of Claim 27, 28, or 29, wherein between about 1 equivalent and about 1.1 equivalents of the non-nucleophilic base is used in relation to the hydrazide.

31. The method of any one of Claims 27 through 30, wherein between about 0.5 equivalents and about 0.6 equivalents of the bis(acid chloride) is used in relation to the hydrazide.

32. The method of Claim 31 , wherein the bis(acid chloride) is malonyl
dichloride.

33. The method of any one of Claims 27 through 32, further comprising the step of adding water to the reaction mixture prepared in step d) to quench the reaction.

34. The method of Claim 33, wherein the water is added to the reaction mixture after the reaction mixture has been allowed to react for between about 5
minutes and about 2 hours.

35. The method of Claim 33 or 34, wherein between about 0.75 L and about 1.25 L of water per gram of hydrazide is used to quench the reaction.

36. The method of any one of Claims 27 through 35, wherein the organic solvent used in steps a) and c) is a water immiscible organic solvent.

37. The method of Claim 36, wherein the water immiscible organic solvent is ethyl acetate.

38. The method of any one of Claims 36 through 37, further comprising the steps of:
separating the organic layer from the water layer; and
reducing the volume of the organic layer until the bis(thio-hydrazide amide) precipitates out.

39. The method of Claim 38, wherein the volume of the organic layer is reduced by about one-third.

40. The method of any one of Claims 27 through 39, wherein Ri is an
unsubstituted phenyl.

41. The method of any one of Claims 27 through 40, wherein R3 is methyl.

42. A method of preparing a bis(thio-hydrazide amide) represented by formula
(IV):

(IV)
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:
R1 is H, an optionally substituted aliphatic group, or an optionally substituted aryl group;
R3 is an optionally substituted aliphatic group or an optionally
substituted aryl group; and
Y is a covalent bond or a methylene which is optionally substituted with one or two independently selected methyl or ethyl group, comprising the step of combining 1-ethy 1-3 -(3 -dimethyl aminopropyl)carbodiimide
(EDC), a hydrazide represented by formula (I):



(I)
and a bis(carboxylic acid) represented by formula (VI):



(VI)
in an organic solvent selected from the group consisting of DMF and
methylene chloride, thereby forming a compound represented by formula
(IV).

43. The method of Claim 44, wherein between about 0.5 and about 0.6
equivalents of bis(carboxylic acid) in relation to the hydrazide is used.

44. The method of Claim 43, wherein the bis(carboxylic aid) is malonic acid.

45. The method of Claim 43 or 44, wherein between about 1 and about 1.5
equivalents of EDC in relation to the hydrazide is used.

46. The method of Claim 45, wherein the EDC is added portionwise such that the reaction temperature is maintained at less than about 300C.

47. The method of any one of Claims 42 through 46, wherein the organic solvent is DMF.

48. The method of Claim 47, wherein between about 4.5 L and about 5.5 L of
DMF per kilogram of hydrazide is used.

49. The method of Claim 47 or 48, wherein after the reaction is substantially complete, the reaction is diluted by addition of an alcohol.

50. The method of Claim 49, wherein the alcohol is ethanol.

51. The method of Claim 50, wherein between about 3.5 L and about 4.5 L of ethanol per kilogram of hydrazide is used to dilute the reaction mixture.

52. The method of Claim 51 , wherein between about 18 L and about 22 L of water is added to the mixture to precipitate out the compound represented by formula (IV).

53. The method of any one of Claims 42 through 52, wherein Rj is phenyl.

54. The method of any one of Claims 42 through 53, wherein R3 is methyl.

55. A method of preparing a crystalline bis(thio-hydrazide amide) represented by represented by formula (IV):

(IV)
or a tautomer thereof,, wherein:
Ri is H, an optionally substituted aliphatic group, or an optionally substituted aryl group;
R3 is an optionally substituted aliphatic group or an optionally
substituted aryl group; and
Y is a covalent bond or a methylene which is optionally substituted with one or two independently selected methyl or ethyl group, comprising the steps of:
a) dissolving the bis(thio-hydrazide amide) in acetone, wherein the
acetone optionally comprises up to about 15 % water;
b) adding the solution of bis(thio-hydrazide amide) to water; and
c) collecting the precipitated bis(thio-hydrazide amide).

56. The method of Claim 55, wherein between about 12 kg and about 15 kg of acetone is used for each kilogram of bis(thio-hydrazide amide).

57. The method of Claim 56, wherein the acetone is maintained at between about 15 0C and about 25 0C during dissolution of the bis(thio-hydrazide amide).

58. The method of Claim 56 or 57, wherein between about 30 kg and about 35 kg of water is used per kilogram of bis(thio-hydrazide amide).

59. The method of any one of Claims 55 through 58, wherein the mixture of bis(thio-hydrazide amide) in acetone and water is cooled to between about -5 0C and 15 0C before collecting the precipitated bis(thio-hydrazide amide).

60. The method of any one of Claims 55 through 59, further comprising washing the precipitated bis(thio-hydrazide amide) with a mixture of acetone and water.

61. The method of any one of Claims 55 through 60, wherein the bis(thio- hydrazide amide) is N-malonyl-bis(N'-methyl-N'-thiobenzoylhydrazide) represented by the following structural formula:



or a tautomer thereof.

62. Crystalline N-malonyl-bis(N'-methyl-N'-thiobenzoylhydrazide), or a
tautomer thereof, which is prepared by the method of Claim 61.

63. A pharmaceutical composition comprising crystalline N-malonyl-bis(N'- methyl-N'-thiobenzoylhydrazide) of Claim 62 and a pharmaceutically
acceptable diluent or a pharmaceutically acceptable carrier.

64. N-malonyl-bis(N'-methyl-N'-thiobenzoylhydrazide) represented by the following structural formula:



or a tautomer thereof, wherein at least about 90 % of the N-malonyl-bis(N'- methyl-N'-thiobenzoylhydrazide) has a particle size of less than about 150 μm.

65. The N-malonyl-bisCN'-methyl-N'-thiobenzoylhydrazide) of Claim 64, wherein the N-malonyl-bis(N'-methyl-N'-thiobenzoylhydrazide) is
crystalline.

66. A method of preparing the N-malonyl-bis(N'-methyl-N'- thiobenzoylhydrazide) of Claim 64, comprising the steps of:
a) milling N-malonyl-bisCN'-methyl-N'-thiobenzoylhydrazide) through a 500 μm screen, thereby forming N-malonyl-bis(N'-methyl-N'- thiobenzoylhydrazide) having a particle size of less than about 500 μm; and
b) milling the N-malonyl-bis(N ' -methyl -N ' -thiobenzoylhydrazide)
having a particle size of 500 μm through a 150 μm screen, thereby
forming N-malonyl-bis(N'-methyl-N'-thiobenzoylhydrazide) having a particle size of less than about 150 μm.

67. A pharmaceutical composition comprising an N-malonyl-bis(N'-methyl-N'- thiobenzoylhydrazide) of Claim 64 and a pharmaceutically acceptable
diluent or a pharmaceutically acceptable carrier.