METHODS OF MAKING LUBIPROSTONE AND INTERMEDIATES THEREOF

• US 20120065409A1
• Filed: 01/22/2010
• Published: 03/15/2012
• Est. Priority Date: 01/22/2009
• Status: Active Grant

• Current Assignee: Apotex Pharmachem India PVT Limited (Apotex Holdings Incorporated)
• Original Assignee: Apotex Pharmachem India PVT Limited (Apotex Holdings Incorporated)
• Inventors: Wang, Fan, Guntoori, Bhaskar Reddy, Ceccarelli, Alfredo Paul, Zhao, Yajun, Kotipalli, Uma, Duncan, Sammy Chris, Montemayor, Laura Kaye, Kothakonda, Kiran Kumar, Nguyen, Minh T. N., Milnes, Kaarina K., Kells, Kevin Wade
• Granted Patent: US 9,382,272 B2
• Time in Patent Office: Days
• US Class Current: 549/214
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 405/00 Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
• CPC Class Codes: C07C 69/734 Ethers
• CPC Class Codes: C07C 69/738 Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• CPC Class Codes: C07D 307/935 Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
• CPC Class Codes: C07F 7/1892 by reactions not provided for in C07F7/1876 - C07F7/1888

Abstract

There is provided processes for preparing Lubiprostone and intermediates thereof. Also provided are compounds, including intermediates for preparing Lubiprostone as well compositions comprising Lubiprostone and other compounds, including intermediates for preparing Lubiprostone and other compounds. (I)

Claims

1. A process for preparation of Lubiprostone comprising hydrogenation, in the presence of a catalyst, of a compound of Formula 10:

2. The process of claim 1 wherein the hydrogenation is performed using hydrogen gas.

3. The process of claim 1 wherein the catalyst is selected from the group consisting of palladium, platinum, rhodium, ruthenium, and Raney-nickel.

6. The process of claim 1 wherein the catalyst is palladium on carbon.

7. The process of claim 6 wherein the catalyst is 10 wt % palladium on carbon (dry basis), 50 wt % (wet support).

8. The process of claim 1 wherein the S/D is a double bond.

9. The process of claim 1 wherein the compound of Formula 10 is a compound of Formula 18:

10. The process of claim 9 wherein the compound of Formula 18 is a compound of Formula 18a:

11. The process of claim 10 wherein the compound of Formula 18a is prepared by reacting, in the presence of a fifth base, a compound of having a structure of R⁷-G, wherein G is a leaving group and R⁷ is C(R^1′

)(R^2′

)(R^3′

), with a compound of Formula 18;

12. The process of claim 11 wherein the compound of Formula 18 is prepared by reacting, in the presence of a sixth base, a compound of Formula 17:

13. The process of claim 12 wherein the sixth base is selected from the group consisting of:

lithium hydroxide, zinc hydroxide, Zn(OH)₂ prepared from ZnCl₂ and sodium hydroxide, mixtures of ammonia and alkali hydroxides, and mixtures thereof.

15. The process of claim 13 wherein the reacting comprises using a sixth solvent selected from the group consisting of:

acyclic and cyclic aliphatic ethers and lower alkyl halides.

16. The process of claim 15 wherein the sixth solvent comprises a mixture of methyl t-butyl ether and dichloromethane.

18. The process of claim 12 wherein the compound of Formula 17 is prepared by oxidizing a compound of Formula 16:

19. The process of claim 18 wherein the oxidizing comprises using an oxidizing agent selected from the group consisting of:

Dess-Martin periodinane, CrO₃, MnO₂, TEMPO/sodium hypochlorite, SO₃/pyridine and oxalyl chloride/DMSO/triethylamine.

22. The process of claim 19 wherein the oxidizing comprises using a seventh solvent selected from the group consisting of:

dichloromethane, DMSO, and mixtures thereof

24. The process of claim 18 wherein the compound of Formula 16 is prepared by deprotecting a compound of Formula 14:

25. The process of claim 24 wherein the deprotecting comprises using tetra-n-butylammonium fluoride.

26. The process of claim 10 wherein the compound of Formula 18a is prepared by reacting, in the presence of a seventh base, a compound of Formula 17a:

27. The process of claim 26 wherein the compound of Formula 17a is prepared by oxidizing a compound of Formula 16a:

28. The compound of claim 27 wherein the compound of Formula 16a is prepared by deprotection of a compound of Formula 15:

29. The process of claim 10 wherein the compound of Formula 18a is prepared by oxidizing a compound of Formula 23:

30. The process of claim 29 wherein oxidizing comprises using an oxidizing agent selected from the group consisting of:

Dess-Martin periodinane, CrO₃, MnO₂, TEMPO/sodium hypochlorite, SO₃/pyridine and oxalyl chloride/DMSO/triethylamine.

31. The process of claim 30 wherein the oxidizing agent is Dess-Martin periodinane.

32. The process of claim 29 wherein oxidizing comprises using a eighth solvent selected from the group consisting of:

dichloromethane, DMSO, and mixtures thereof.

34. The process of claim 29 wherein the compound of Formula 23 is prepared by deprotecting a compound of Formula 22:

35. The process of claim 34 wherein the deprotecting comprises using pyridinium p-toluenesulfonate.

36. The process of claim 34 wherein the compound of Formula 22 is prepared by reacting, in the presence of an eighth base, a compound of Formula 21:

37. The process of claim 36 wherein the eighth base is selected from the group consisting of:

lithium hydroxide, zinc hydroxide, Zn(OH)₂ prepared from ZnCl₂ and sodium hydroxide, mixtures of ammonia and alkali hydroxides, and mixtures thereof.

39. The process of claim 36 wherein the reacting of the compound of Formula 21 with the compound of Formula 12 comprises using a ninth solvent selected from the group consisting of:

acyclic aliphatic ethers, cyclic aliphatic ethers and lower alkyl halides.

40. The process of claim 39 wherein the ninth solvent comprises a mixture of methyl t-butyl ether and dichloromethane.

41. The process of claim 40 wherein the ninth solvent further comprises water.

42. The process of claim 36 wherein the compound of Formula 21 is prepared by oxidizing a compound of Formula 20:

43. The process of claim 42 wherein oxidizing comprises using an oxidizing agent selected from the group consisting of:

Dess-Martin periodinane, CrO₃, MnO₂, TEMPO/sodium hypochlorite, SO₃/pyridine and oxalyl chloride/DMSO/triethylamine.

46. The process of claim 42 wherein oxidizing comprises using a tenth solvent selected from the group consisting of:

dichloromethane, DMSO and mixtures thereof.

48. The process of claim 42 wherein the compound of Formula 20 is prepared by deprotecting a compound of Formula 19:

49. The process of claim 48 wherein deprotecting comprises using TBAF.

50. The process of claim 48 wherein the compound of Formula 19 is prepared by protecting a compound of Formula 15:

51. The process of claim 50 wherein the protecting comprises using dihydropyran.

52. The process of claim 28 wherein the compound of Formula 15 is prepared by reacting, in the presence of a ninth base, a compound of having a structure of R⁷-G, wherein G is a leaving group and R⁷ is C(R^1′

)(R^2′

)(R^3′

), with a compound of Formula 14;

54. The process of claim 52 wherein G is selected from the group consisting of:

chlorine, bromine, iodine, methansulfonyloxy, trifluoromethansulfonyloxy and p-toluenesulfonyloxy.

56. The process of claim 52 wherein R⁷-G is a benzyl halide.

59. The process of claim 52 wherein the ninth base is selected from the group consisting of:

triethylamine, diisopropylamine, pyridine and DBU.

61. The process of any one of claims 24, 52 and 228 wherein the compound of Formula 14 is prepared by reacting, in the presence of a tenth base, a compound of Formula 13:

62. The process of claim 61 wherein the tenth base is selected from the group consisting of:

sodium hydroxide, sodium methoxide, potassium t-butoxide, sodium t-butoxide and lithium t-butoxide.

64. The process of claim 61 wherein the reaction of the compound of Formula 13 with the compound of Formula 11 comprises using an eleventh solvent selected from the group consisting of:

1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, tetrahydrofuran, 1,4-dioxane and anisole.

66. The process of claim 61 wherein the compound of Formula 13 is prepared by reducing a compound of Formula 4:

67. The process of claim 66 wherein the reducing of the compound of Formula 4 comprises using a reducing agent selected from the group consisting of:

DIBAL-H, Red-Al and lithium-tri-tert-butoxy aluminum hydride.

69. The process of claim 66 wherein the reduction of the compound of Formula 4 comprises using a twelfth solvent selected from the group consisting of:

toluene, xylene, dichloromethane and mixtures thereof.

71. The process of claim 1 wherein the compound of Formula 10 is prepared by oxidation of a compound of Formula 9:

72. The process of claim 71 wherein oxidation is performed using an oxidizing agent selected from the group consisting of Dess-Martin periodinane, IBX, CrO₃, MnO₂, TEMPO/sodium hypochlorite and SO₃/pyridine.

75. The process of claim 71 wherein oxidation is conducted in a fourth solvent, the fourth solvent comprising dichloromethane.

76. The process of claim 71 wherein the compound of Formula 9 is prepared by reaction, in the presence of a second base, of a compound of Formula 8:

77. The process of claim 76 wherein R^6′

is H.

78. The process of claim 77 wherein R⁶ is H.

79. The process of any one of claim 1, 71 or 76 wherein the compound of Formula 10 that is hydrogenated to Lubiprostone is a compound of Formula 10a:

80. The process of claim 79 wherein the compound of Formula 10a is prepared by reacting a compound having a structure of R⁷-G, wherein G is a leaving group and R⁷ is C(R^1′

)(R^2′

)(R^3′

), with a compound of Formula 10;

82. The process of claim 80 wherein G is selected from the group consisting of:

chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, and p-toluenesulfonyloxy.

84. The process of claim 80 wherein R⁷-G is a benzyl halide.

85. The process of claim 80 wherein R⁷-G is benzyl bromide.

86. The process of claim 80 wherein the reaction of R⁷-G with the compound of Formula 10 wherein R⁶ is H is conducted in the presence of a fourth base.

88. The process of claim 86 wherein the fourth base is selected from the group consisting of:

triethylamine, diisopropylamine, diisopropylethylamine, pyridine and DBU.

91. The process of any one of claims 1, 71 and 76 wherein R⁶ is C(R^1′

)(R^2′

)(R^3′

); and

R^1′

is aryl or substituted aryl, and R^2′

and R^3′

are H.

92. The process of any one of claims 1, 71 and 76 wherein R⁶ is C(R^1′

)(R^2′

)(R^3′

) and R^1′

is substituted phenyl.

93. The process of any one of claims 1, 71 and 76 wherein R⁶ is C(R^1′

)(R^2′

)(R^3′

) and R^1′

is substituted phenyl and R^2′

and R^3′

are H.

95. The process of claim 93 wherein R^1′

is substituted with one or more substituents selected from the group consisting of;

(4)-methoxy;

(3,4)-dimethoxy;

(2,6)-dimethoxy;

(2)-nitro;

(4)-nitro;

(4)-phenyl;

(2,6)-dichloro;

(2)-trifluoromethyl;

(4)-trifluoromethyh;

(2,4)-dimethyl and (4)-methyl.

96. The process of any one of claims 1, 71 and 76 wherein R⁶ is C(R^1′

)(R^2′

)(R^3′

) and R^1′

is phenyl and R^2′

and R^3′

are H.

97. The process of claim 78 further comprising reacting the compound of Formula 9 with a compound having a structure of R⁷-G, wherein G is a leaving group and R⁷ is C(R^1′

)(R^2′

)(R^3′

), where R^1′

, R^2′

and R^3′

are independently selected is C(R^1′

)(R^2′

)(R^3′

), where R^1′

, R^2′

and R^3′

are independently selected from the group consisting

99. The process of claim 97 wherein G is chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy.

101. The process of claim 97 wherein R⁷-G is benzyl bromide.

102. The process of claim 97 wherein the reaction of R⁷-G occurs in the presence of a third base.

103. The process claim 102 wherein the third base is selected from the group consisting of triethylamine, diisopropylethylamine, diisopropylamine, pyridine and DBU.

130. The process of any one of claims 1, 9, 10, 11, 12, 18, 24, 26, 27, 28, 29, 34, 36, 42, 48, 50, 71 and 76 wherein hydrogenation comprises using ethyl acetate.

156. The process of any one of claims 1, 76 and 132 wherein the S/D bond between carbon 9b1 and carbon 9b2 of the compound of Formula 10 is a single bond.

157. The process of any one of claims 1, 71, 76 and 132 wherein the S/D bond between carbon 9b1 and carbon 9b2 of the compound of Formula 10 is a double bond.

158. The process of any one of claims 1, 76 and 132 wherein the reaction comprises a mixture of compounds of Formula 10 wherein the mixture comprises compounds in which the S/D bond between carbon 9b1 and carbon 9b2 is a single bond and compounds in which the S/D bond between carbon 9b 1 and carbon 9b2 is a double bond.

159. The process of any one of claims 1, 71, 76 and 132 wherein R¹ is aryl or substituted aryl.

160. The process of any one of claims 1, 71, 76 and 132 wherein R¹ is substituted phenyl.

161. The process of any one of claims 1, 71, 76 and 132 wherein R¹ is substituted phenyl and R² and R³ are H.

162. The process of any one of claims 1, 71, 76 and 132 wherein R¹ is substituted with one or more substituents selected from the group consisting of:

methoxy, nitro, phenyl, chloro, trifluoromethyl and C₁-C₆ alkyl.

163. The process of any one of claims 1, 71, 76 and 132 wherein R¹ is substituted with one or more substituents selected from the group consisting of:

(4)-methoxy;

(3,4)-dimethoxy;

(2,6)-dimethoxy;

(2)-nitro;

(4)-nitro;

(4)-phenyl;

(2,6)-dichloro;

(2)-trifluoromethyl;

(4)-trifluoromethyh;

(2,4)-dimethyl and (4)-methyl.

164. The process of any one of claims 1, 71, 76 and 132 wherein R¹ is phenyl and R² and R³ are H.

228. The process of claim 50 wherein the compound of Formula 15 is prepared by reacting, in the presence of a ninth base, a compound of having a structure of R⁷-G, wherein G is a leaving group and R⁷ is C(R^1′

)(R^2′

)(R^3′

), with a compound of Formula 14;

229. The process of claim 228 wherein G is selected from the group consisting of:

chlorine, bromine, iodine, methansulfonyloxy, trifluoromethansulfonyloxy and p-toluenesulfonyloxy.

230. The process of claim 228 wherein R⁷-G is a benzyl halide.

4-5. -5. (canceled)

14. (canceled)

17. (canceled)

20-21. -21. (canceled)

23. (canceled)

33. (canceled)

38. (canceled)

44-45. -45. (canceled)

47. (canceled)

53. (canceled)

55. (canceled)

57-58. -58. (canceled)

60. (canceled)

63. (canceled)

65. (canceled)

68. (canceled)

70. (canceled)

73-74. -74. (canceled)

81. (canceled)

83. (canceled)

87. (canceled)

89-90. -90. (canceled)

94. (canceled)

98. (canceled)

100. (canceled)

106. The process of any one of claims 76 to 105 wherein the second base is selected from the group consisting of metal alkoxides and metal hydrides.

107. The process of any one of claims 76 to 105 wherein the second base is potassium t-butoxide.

108. The process of any one of claims 76 to 105 wherein reaction of the compounds of Formula 8 and Formula 11 occurs in the presence of a third solvent.

109. The process of claim 108 wherein the third solvent comprises THF.

110. The process of any one of claims 76 to 105 wherein the compound of Formula 8 is obtained by reduction, using a reducing agent, of a compound of Formula 7:

111. The process of claim 110 wherein the reducing agent is selected from the group consisting of DIBAL-H, Red-Al (vitride®

), lithium-tri-tert-butoxy aluminium hydride.

113. The process of claim 110 wherein reduction occurs in the presence of a second solvent.

114. The process of claim 113 wherein the second solvent is toluene.

115. The process of claim 110 wherein the reduction of the compound of Formula 7 to Formula 8 is conducted at a temperature of from about −

100°

C. to about 0°

C.

116. The process of claim 110 wherein the S/D bond between carbon 8b1 and carbon 8b2 of the compound of Formula 8 is a single bond, the S/D bond between carbon 8b3 and group X of the compound of Formula 8 is a single bond and X is OH.

117. The process of claim 110 wherein the compound of Formula 7 is obtained by reaction, in the presence of a first base, of a compound of Formula 6:

118. The process of claim 117 wherein R⁴ and R⁵ independently ndependently selected from the group consisting of:

methyl, ethyl and propyl.

120. The process of claim 117 wherein the reaction of the compound of Formula 6 with the compound of Formula 12 is conducted in a first solvent selected from the group consisting of cyclic and acyclic aliphatic ethers, lower alkyl halides and mixtures thereof.

121. The process of claim 120 wherein the first solvent comprises a mixture of methyl t-butyl ether and dichloromethane.

123. The process of claim 117 wherein the first base is a mixture of lithium hydroxide and ammonia.

126. The process of claim 117 wherein the first base is Zn(OH)₂ or Zn(OH)₂ prepared from ZnCl₂ and sodium hydroxide.

127. The process of claim 117 wherein the first base is a mixture of lithium hydroxide and triethylamine.

129. The process of claim 127 wherein the source of triethylamine is triethylamine hydrochloride.

104-105. -105. (canceled)

112. (canceled)

119. (canceled)

122. (canceled)

124-125. -125. (canceled)

128. (canceled)

131. A process for preparation of Lubiprostone comprising:

reducing a compound of Formula 4;

145. The process of claim 131 or 132 wherein R⁶ and R^6′

are C(R^1′

)(R^2′

)(R^3′

); and

R^1′

is aryl or substituted aryl, and R^2′

and R^3′

are H.

146. The process of claim 131 or 132 wherein R⁶ and R^6′

are C(R^1′

)(R^2′

)(R^3′

) and R^1′

is substituted phenyl.

147. The process of claim 131 or 132 wherein R⁶ and R^6′

are C(R^1′

)(R^2′

)(R^3′

) and R^1′

is substituted phenyl and R^2′

and R^3′

are H.

148. The process of claim 131 or 132 wherein R^1′

is substituted with one or more substituents selected from the group consisting of;

methoxy, nitro, phenyl, chloro, trifluoromethyl and C₁-C₆ alkyl.

149. The process of claim 131 or 132 wherein R^1′

is substituted with one or more substituents selected from the group consisting of;

(4)-methoxy;

(3,4)-dimethoxy;

(2,6)-dimethoxy;

(2)-nitro;

(4)-nitro;

(4)-phenyl;

(2,6)-dichloro;

(2)-trifluoromethyl;

(4)-trifluoromethyh;

(2,4)-dimethyl and (4)-methyl.

150. The process of claim 131 or 132 wherein R⁶ and R^6′

are C(R^1′

)(R^2′

)(R^3′

) and R^1′

is phenyl and R^2′

and R^3′

are H.

132. A process for preparation of Lubiprostone comprising:

reacting, in the presence of a first base, a compound of Formula 6

133. The process of claim 132 wherein R⁶ and R^6′

are H.

134. The process of claim 133 wherein the compound of Formula 10 that is hydrogenated to Lubiprostone is a compound of Formula 10a:

136. The process of claim 134 wherein G is selected from the group consisting of:

chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, and p-toluenesulfonyloxy.

137. The process of claim 134 wherein G is bromine.

138. The process of claim 134 wherein R⁷-G is a benzyl halide.

139. The process of claim 134 wherein R⁷-G is benzyl bromide.

140. The process of any one of claims 134 to 139 wherein the reaction of R⁷-G with the compound of Formula 10 is conducted in the presence of a fourth base.

141. The process of claim 140 wherein the fourth base is an organic base or an inorganic base.

142. The process of claim 140 wherein the fourth base is selected from the group consisting of:

triethylamine, diisopropylamine, diisopropylethylamine, pyridine and DBU.

143. The process of claim 140 wherein the fourth base is diisopropylamine.

144. The process of claim 140 wherein the fourth base is pyridine.

151. The process of claim 132 further comprising reacting the compound of Formula 9 with a compound having a structure R⁷-G, wherein G is a leaving group and R⁷ is C(R^1′

)(R^2′

)(R^3′

), where R^1′

, R^2′

and R^3′

are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl.

153. The process of claim 151 wherein G is chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, or p-toluenesulfonyloxy.

154. The process of claim 151 wherein G is bromine.

155. The process of claim 151 wherein R⁷-G is benzyl bromide.

135. (canceled)

152. (canceled)

165. A compound of Formula 13:

166. A compound of Formula 14:

167. A compound of Formula 15:

168. A compound of Formula 16:

169. A compound of Formula 16a:

170. A compound of Formula 17:

171. A compound of Formula 17a:

172. A compound of Formula 18a:

173. A compound of Formula 19:

174. A compound of Formula 20:

175. A compound of Formula 21:

176. A compound of Formula 22:

177. A compound of Formula 23:

178. A compound selected from the group consisting of:

(3aR,4S,5R,6aS)-5-(phenylmethoxy)-4-(triisopropylsilyloxymethyl)hexahydrocyclopenta[b]furan-2-ol;

(5Z)-7-[(1R,2S,3R,5S)-3-Benzyloxy-5-hydroxy-2-[(triisopropylsilyloxy)methyl]cyclopentyl]hept-5-enoic acid;

Benzyl(Z)-7-[(1R,2S,3R,5S)-5-hydroxy-3-(2-phenylmethoxy)-2-(triisopropylsilyloxymethyl)cyclopentyl]-5-heptanoate;

(5Z)-Benzyl 7-[(1R,2S,3R,5S)-3-benzyloxy-5-hydroxy-2-(hydroxymethyl)cyclopentyl]hept-5-enoate;

(5Z)-Benzyl 7-[(1R,2R,3R)-3-benzyloxy-2-formyl-5-oxocyclopentyl]hept-5-enoate;

Benzyl (Z)-7-[(1R,2S,3R,5S)-2-(triisopropylsilyloxymethyl)-3-(2-phenylmethoxy)-5-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptanoate;

Benzyl(Z)-7-[(1R,2S,3R,5S)-2-hydroxymethyl-3-(2-phenylmethoxy)-5-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptanoate;

Benzyl(Z)-7-[(1R,2S,3R,5S)-2-formyl-3-(2-phenylmethoxy)-5-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptanoate;

Benzyl(Z)-7-[(1R,2R,3R,5S)-5-(2-tetrahydropyranyloxy)-2-((E)-3-oxo-1octenyl)-3-(phenylmethoxy)cyclopentyl]heptanoate; and

Benzyl(Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-((E)-3-oxo-1octenyl)-3-(phenylmethoxy)cyclopentyl]heptanoate.

179-187. -187. (canceled)

188. A compound of Formula 7:

198. The compound or composition of any one of claims 188 to 190 wherein R⁶ is H.

199. The compound or composition of any one of claims 188 to 190 wherein R⁶ is C(R^1′

)(R^2′

)(R^3′

) and R^1′

is substituted phenyl.

200. The compound or composition of any one of claims 188 to 190 wherein R⁶ is C(R^1′

)(R^2′

)(R^3′

) and R^1′

is substituted phenyl and R^2′

and R^3′

are H.

203. The compound or composition of any one of claims 188 to 190 wherein R⁶ is C(R^1′

)(R^2′

)(R^3′

) and R^1′

is phenyl and R^2′

and R^3′

are H.

204. The compound or composition of any one of claims 188 to 190 wherein R^1′

is phenyl substituted with one or more substituents selected from the group consisting of;

methoxy, nitro, phenyl, chloro, trifluoromethyl and C₁-C₆ alkyl.

205. The compound or composition of any one of claims 188 to 190 wherein R^1′

is substituted phenyl substituted with one or more substituents selected from the group consisting of;

methoxy, nitro, phenyl, chloro, trifluoromethyl and C₁-C₆ alkyl; and

R² and R³ are H.

208. The compound or composition of any one of claims 188 to 190 wherein R¹ is phenyl and R² and R³ are H.

189. A compound of Formula 8:

191. The compound of claim 189 or 190 wherein the S/D bond between a carbon and group X is a single bond and X is OH.

192. The compound of claim 189 or 190 wherein the S/D bond between a carbon and group X is a double bond and X is O.

193. A composition comprising a mixture of compounds of claim 189 or 190 wherein the mixture comprises

i) a compound in which the S/D bond between a carbon and group X is a single bond and X is OH;

and

ii) a compound in which the S/D bond between a carbon and group X is a double bond and X is O.

190. A compound of Formula 9:

194. A compound of Formula 10:

195-197. -197. (canceled)

201-202. -202. (canceled)

206-207. -207. (canceled)

209. A compound selected from the group consisting of:

(3aR,4R,5R,6aS)-hexahydro-2-oxo-5-(phenylmethoxy)-2H-cyclopenta[b]furan-4-carboxaldehyde;

(3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-l-octenyl)-2-oxo-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan;

(3aR,4R,5R,6aS)-4-(4,4-difluoro-3-oxo-octyl)-2-oxo-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan;

(3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-hydroxy-1-octenyl)-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan-2-ol;

(3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan-2-ol;

(3aR,4R,5R,6aS)-4-(4,4-difluoro-3-hydroxy-1-octyl)-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan-2-ol;

(3aR,4R,5R,6aS)-4-(4,4-difluoro-3-oxo-1-octyl)-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan-2-ol;

(Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-hydroxy-1-octenyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoic acid;

(Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoic acid;

(Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxy-1-octyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoic acid;

(Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-oxo-1-octyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoic acid;

Benzyl (Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-hydroxy-1-octenyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoate;

Benzyl(Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoate;

Benzyl(Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxy-1-octyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoate;

Benzyl(Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-oxo-1-octyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoate;

(Z)-7-[(1R,2R,3R)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoic acid;

(Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxo-1-octyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoic acid;

Benzyl(Z)-7-[(1R,2R,3R)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoate; and

Benzyl(Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxo-1-octyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoate.

210-227. -227. (canceled)

231. The process of 228 wherein the ninth base is selected from the group consisting of:

triethylamine, diisopropylamine, pyridine and DBU.