NOVEL SYNTHESIS ROUTES FOR PROSTAGLANDINS AND PROSTAGLANDIN INTERMEDIATES USING METATHESIS

• US 20160237056A1
• Filed: 09/30/2014
• Published: 08/18/2016
• Est. Priority Date: 09/30/2013
• Status: Active Grant

• Current Assignee: Patheon Api Services Inc. (Thermo Fisher Scientific Incorporated)
• Original Assignee: Patheon Api Services Inc. (Thermo Fisher Scientific Incorporated)
• Inventors: Yiannikouros, George Petros, Kalaritis, Panos, Gamage, Chaminda Priyapushpa, Arefyev, Denis Viktorovich
• Granted Patent: US 10,100,028 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: C07C 41/28 from acetals, e.g. by dealcoholysis
• CPC Class Codes: C07C 43/196 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 45/70 by reaction with functional groups containing oxygen only in singly bound form
• CPC Class Codes: C07C 49/743 having unsaturation outside the rings, e.g. humulones, lupulones
• CPC Class Codes: C07C 49/753 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 67/08 by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
• CPC Class Codes: C07C 69/604 Polycarboxylic acid esters, the acid moiety containing more than two carboxyl groups
• CPC Class Codes: C07D 311/94 condensed with rings other than six-membered or with ring systems containing such rings
• CPC Class Codes: C07D 313/00 Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom

Abstract

Methods of synthesizing prostaglandins, prostaglandin analogs and their synthetic intermediates are described. The methods can comprise metal-catalyzed metathesis reactions. Also provided are synthetic intermediates that can be used in the synthesis of the prostaglandins and prostaglandin analogs.

Claims

1. A compound of Formula (III):

2. The compound of claim 1, wherein each m is 1.

3. The compound of claim 1 or claim 2, wherein both R₁ and/or both R₃ are the same.

4. The compound of any one of claims 1-3, wherein R₃ is H or alkyl.

5. The compound of any one of claims 1-4, wherein the compound is crystalline.

6. A compound of Formula (IV):

7. The compound of claim 6, wherein each m is 1.

8. The compound of claim 6 or claim 7, wherein both R₁ and/or both R₃ are the same.

9. The compound of any one of claims 6-8, wherein both R groups are the same and/or are alkyl or alkenyl of the formula:

10. The compound of claim 9, wherein one or both of A₄ and A₅ are H.

11. The compound of claim 9 or claim 10, wherein A₁, A₂, and A₃ are independently selected from the group consisting of H, hydroxyl, protected hydroxyl, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, substituted aralkoxyl, thiophenyl, benzothiophenyl, and halo.

12. The compound of any one of claims 6-11, wherein the compound is crystalline.

13. A compound of Formula (V):

14. The compound of claim 13, wherein each m is 1.

15. The compound of claim 13 or claim 14, wherein both R₁ and/or both R₃ are the same.

16. The compound of any one of claims 13-15, wherein both R groups are the same and are alkyl or alkenyl of the formula:

17. The compound of claim 16, wherein one or both of A₄ and A₅ are H.

18. The compound of claim 16 or claim 17, wherein A₁, A₂, and A₃ are independently selected from the group consisting of H, hydroxyl, protected hydroxyl, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, substituted aralkoxyl, thiophenyl, benzothiophenyl, and halo.

19. The compound of any one of claims 13-18, wherein the compound is crystalline.

20. A compound of Formula (VI):

21. The compound of claim 20, wherein each n is the same and/or is 2 or 3.

22. The compound of claim 20 or claim 21, wherein each m is 1.

23. The compound of any one of claims 20-22, wherein both R₁ and/or both R₃ are the same.

24. The compound of any one of claims 20-23, wherein both R groups are the same and/or are alkyl or alkenyl of the formula:

25. The compound of any one of claims 20-24, wherein both R₂ and/or R₄ and/or R₅ groups are the same.

26. The compound of claim 25, wherein R₂, R₄, and R₅ are each H or alkyl.

27. The compound of any one of claims 20-26, wherein the compound is crystalline.

28. A method for preparing a prostaglandin, prostaglandin analog, or a synthetic intermediate thereof, the method comprising:

providing a compound of Formula (VI);

29. The method of claim 28, wherein the transition metal catalyst is a transition metal carbene complex catalyst.

30. The method of claim 28 or claim 29, wherein the transition metal catalyst is a ruthenium benzylidene.

31. The method of any one of claims 28-30, wherein the transition metal catalyst is benzylidene-bis(tricyclohexylphosphine) dichlororuthenium.

32. The method of any one of claims 28-31, wherein the ring closing metathesis reaction is performed in an aprotic solvent.

33. The method of claim 32, wherein the aprotic solvent is dichloromethane.

34. The method of any one of claims 28-33, wherein the lactone is a nine- or ten-membered lactone.

35. The method of any one of claims 28-34, wherein the lactone is a compound of Formula (VII):

36. The method of any one of claims 28-35, further comprising opening the lactone ring via acid catalyzed hydrolysis and esterifying the resulting carboxylic acid.

37. The method of any one of claims 28-35, further comprising reacting the lactone with a nucleophile to form a ring-opened product.

38. The method of claim 37, wherein the nucleophile is selected from the group consisting of an amine, an alcohol, an alkoxide, an alkoxide salt, and hydroxide.

39. The method of claim 37 or claim 38, further comprising removing one or more hydroxyl protecting groups.

40. The method of claim 39, wherein removing the one or more hydroxyl protecting groups is performed prior to reacting the lactone with a nucleophile and provides a compound of Formula (VIII):

41. The method of claim 39, wherein removing the one or more hydroxyl protecting groups is performed after reacting the lactone with a nucleophile.

42. The method of claim 41, wherein after reacting the lactone with a nucleophile and prior to removing the one or more hydroxyl protecting groups, a hydroxyl group formed during ring opening of the lactone is oxidized to provide a cyclopentanone ring-opened product.

43. The method of any one of claims 37-42, wherein reacting the lactone with a nucleophile is performed in an aprotic solvent.

44. The method of any one of claims 28-43, wherein the prostaglandin or prostaglandin analog is selected from the group consisting of bimatoprost, latanoprost, travoprost, tafluprost, unoprostone, dinoprost, carboprost, fluprostenol, cloprostenol, 13, 14-dihydro-15-(2-benzothienyl)-15-pentanor PGF1α

, sulprostone, misoprostol, and limaprost.

45. The method of any one of claims 28-44, wherein the compound of Formula (VI) is crystalline.

46. The method of any one of claims 28-45, wherein both m are 1.

47. The method of any one of claims 28-46, wherein both n are 2 or 3.

48. The method of any one of claims 28-47, wherein the compound of Formula (VI) is provided by the esterification of a compound of Formula (V):

49. The method of claim 48, wherein the esterification is performed by contacting the compound of Formula (V) with an alkenoic acid or acid chloride, or a derivative thereof, wherein the derivative thereof is an alkenoic acid or acid chloride comprising one or more alkyl group substituents.

50. The method of claim 49, wherein the esterification is performed in the presence of a carbodiimide and a non-nucleophilic base.

51. The method of claim 49 or claim 50, wherein the compound of Formula (V) is the product of the enantioselective reduction of carbonyl groups of a compound of Formula (IV):

52. The method of claim 51, wherein the enantioselective reduction is performed by contacting the compound of Formula (IV) with borane and a chiral oxazaborolidine catalyst in an aprotic solvent.

53. The method of claim 51 or claim 52, wherein the compound of Formula (IV) is the product of a stereoselective 1,4-double addition of a nucleophile to a compound of Formula (III):

54. The method of claim 53, wherein the nucleophile is selected from the group consisting of a nitroalkyl anion, an alkyl sulphone anion, an acyl anion equivalent, and an organocuprate produced from an alkyl halide, vinyl halide, or vinyl ether.

55. The method of claim 53 or claim 54, wherein the compound of Formula (III) is the product of an intermolecular metathesis reaction of a chiral allylcyclopentenone performed in the presence of a transition metal catalyst.

56. The method of claim 51 or claim 52, wherein the compound of Formula (IV) is the product of the intermolecular metathesis reaction of a compound of Formula (II):

57. A method for preparing a compound of Formula (III):

58. The method of claim 57, wherein the metal catalyzed intermolecular metathesis reaction is performed between two molecules of the same compound of Formula (I).

59. A method for preparing a compound of Formula (IV):

60. The method of claim 59, wherein the 1,4-addition reaction is a 1,4-double addition reaction of two molecules of the same reagent from a).

61. A method for preparing a compound of Formula (IV):

62. A method for preparing a compound of Formula (V):

63. The method of claim 62, wherein the enantioselective reduction is performed using a reducing agent and a chiral ligand.

64. A method of preparing a compound of Formula (VI):

65. A method for preparing a compound of Formula (VII) or Formula (VIII):

66. The method of claim 65, wherein the transition metal catalyst is a transition metal carbene complex catalyst.

67. The method of claim 65 or claim 66, wherein the transition metal catalyst is a ruthenium benzylidene.

68. The method of any one of claims 65-67, wherein the transition metal catalyst is benzylidene-bis(tricyclohexylphosphine) dichlororuthenium.

69. The method of any one of claims 65-68, wherein the ring closing metathesis reaction is performed in an aprotic solvent.

70. The method of claim 69, wherein the aprotic solvent is selected from the group consisting of dichloromethane, toluene, benzene, heptane, and MTBE.

71. The method of any one of claims 65-70, wherein the compound of Formula (VII) or Formula (VIII) comprises a nine- or ten-membered lactone.

72. The method of any one of claims 65-71, wherein the compound of Formula (VII) or Formula (VIII) is a synthetic intermediate of a prostaglandin or prostaglandin analog.

73. The method of any one of claims 65-72, wherein the precursor compound is a compound of Formula (VI):

74. The method of claim 73, wherein R₂ is alkyl.

75. The method of any one of claims 65-72, wherein the precursor compound is a compound of Formula (VI-A):

76. A method for preparing a compound of Formula (IX):

77. The method of claim 76, wherein the reaction that cleaves the carbon-carbon double bond is an ozonolysis reaction.

78. A compound of Formula (VII) or Formula (VIII):

79. The compound of claim 78, wherein R is aldehyde, nitroalkyl, —

CH₂NO₂, or —

CH═

CH₂ or wherein R comprises a benzothiophenyl group, optionally wherein R comprises an alkyl or alkenyl group of the formula;

80. The compound of claim 78, wherein R comprises a ketone.

81. The compound of claim 80, wherein R₁ is other than dinitrobenzoyl or trimethylsilyl (TMS).

82. The compound of claim 80 or claim 81, wherein R₁ is H, ethoxyethyl or tert-butyldimethylsilyl (TBDMS).

83. The compound of claim 78, wherein two of A_t A₂, and A₃ are ═

O and the remaining A₁, A₂, and A₃ group is other than a phenoxyalkyl or substituted phenoxyalkyl group.

84. A compound of Formula (II) or Formula (V-A):

85. A compound of Formula (VI-A):

86. A compound of one of Formulae (XI), (XIV), (XV), or (XVI):

87. A compound of claim 86, wherein the compound is a compound of one of Formulas (XI), (XV), and (XVI), wherein one of R₉, R₉′

, and R₉″

is -M₃(R₁₄)(R₁₄′

)(R₁₄″

), wherein M₃ is carbon, nitrogen, oxygen or sulfur; and

each of R₁₄, R₁₄′

, and R₁₄″

is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted alkyl, vinyl, aryl, substituted aryl, aralkyl, substituted aralkyl, acyl, alkoxyl, aralkoxyl, substituted aralkoxyl, furyl, pyranyl, thiophenyl, benzothiophenyl, halogen, hydroxyl, protected hydroxyl, or amino;

wherein R₁₄′ and

/or R₁₄″

can be present or absent and/or further wherein when one of R₁₄, R₁₄′

, and R₁₄″

is hydroxyl or amino, the other two of R₁₄, R₁₄′ and

R₁₄″

is not halogen or amino.

88. A compound selected from the group comprising:

89. A method of preparing a prostaglandin, prostaglandin analog, or a synthetic intermediate thereof, the method comprising:

providing a nitro group-containing compound of the formula;

90. The method of claim 89, wherein the nitro group-containing compound is compound VII-5 or VIII-5 and the aldehyde is compound VII-5A′

or VIII-5A′

;

91. The method of claim 89 or claim 90, further comprising performing a Horner-Emmons reaction between the aldehyde and a phosphonate to provide a compound of Formula (XI):

92. The method of claim 91, wherein one of R₉, R₉′

, and R₉″

has the formula -M₃(R₁₄)(R₁₄′

)(R₁₄″

), wherein;

M₃ is carbon, nitrogen, oxygen or sulfur; and

each of R₁₄, R₁₄′

, and R₁₄″

is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted alkyl, vinyl, aryl, substituted aryl, aralkyl, substituted aralkyl, acyl, alkoxyl, aralkoxyl, substituted aralkoxyl, furyl, pyranyl, thiophenyl, benzothiophenyl, halogen, hydroxyl, protected hydroxyl, or amino;

wherein R₁₄′ and

/or R₁₄″

can be present or absent and/or further wherein when one of R₁₄, R₁₄′

, and R₁₄″

is hydroxyl or amino, the other two of R₁₄, R₁₄′ and

R₁₄″

is not halogen or amino.

93. A method of preparing a prostaglandin, prostaglandin analog, or a synthetic intermediate thereof, the method comprising:

providing a compound of the Formulae (VII-6) or (VIII-6);

94. The method of claim 93, wherein the compound of Formula (VII-6) or (VIII-6) is provided by a method comprising one of:

(a) performing a metal-catalyzed metathesis reaction of a compound of Formula (VI);

95. A method of preparing a prostaglandin, prostaglandin analog, or a synthetic intermediate thereof, the method comprising providing a compound of Formula (X):

96. A method of preparing a prostaglandin, prostaglandin analog, or a synthetic intermediate thereof, the method comprising:

providing a compound of Formula (I);

97. The method of claim 96, wherein the nucleophile is selected from the group consisting of a nitroalkyl anion, an alkyl sulphone anion, an acyl anion equivalent, and an organocuprate produced from an alkyl halide, vinyl halide or vinyl ether.

98. The method of claim 96 or claim 97, further comprising one or more additional steps, optionally wherein the one or more additional steps comprise one or more of:

(a) selectively reducing the ketone of the compound of Formula (II) to provide a compound of Formula (V-A);

99. A compound of Formula (XII) or (XIII):