Processes for Preparing Substituted N-Aryl-N'-[3-(1H-Pyrazol-5-Yl) Phenyl] Ureas and Intermediates Thereof

• US 20070293685A1
• Filed: 07/21/2004
• Published: 12/20/2007
• Est. Priority Date: 03/23/2004
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated
• Original Assignee: Arena Pharmaceuticals Incorporated
• Inventors: Li, Hongmei, Teegarden, Bradley, Carleton, Fiona, Fritch, John, Lally, Edward
• Granted Patent: US 7,812,176 B2
• Time in Patent Office: Days
• US Class Current: 548/375.1
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: C07C 233/43 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/16 Halogen atoms or nitro radicals

Abstract

The present invention is directed to processes for the preparation of substituted phenylpyrazole ureas of Formula (I), that are useful as 5-HT_2A serotonin receptor modulators for the treatment of disease.

Claims

1. A process for preparing a compound of Formula (I):

26. The process of claim 1 wherein:

R^1a is F;

R^1b is H;

R^1c is F;

R^1d is H;

R^1e is H;

R² is methyl;

R³ is Br;

R⁴ is methoxy; and

R⁵, at each occurrence, is H.

27. The process of claim 1 wherein:

R^1a is H;

R^1b is H;

R^1c is Cl;

R^1d is H;

R^1e is H;

R² is methyl;

R³ is Br;

R⁴ is methoxy; and

R⁵, at each occurrence, is H.

32. The process of claim 1 wherein the process comprises reacting a compound of Formula (II):

33. The process of claim 32 wherein said reacting is carried out in an organic solvent.

34. The process of claim 33 wherein said organic solvent comprises an aromatic solvent.

35. The process of claim 33 wherein said organic solvent comprises toluene.

40. The process of claim 33 wherein said reacting is carried out at a reduced temperature.

41. The process of claim 40 wherein said reduced temperature is about 10 to about 20°

C.

45. The process of claim 33 wherein said compound of Formula (III) is added in molar excess relative to the amount of Formula (II).

46. The process of claim 1 wherein said compound of Formula (II) is prepared by the process comprising deprotecting a compound of Formula (IV):

59. The process of claim 46 wherein said compound of Formula (IV) is prepared by the process comprising halogenating a compound of Formula (V):

67. The process of claim 59 wherein said compound of Formula (V) is prepared by the process comprising cyclizing a compound of Formula (VI):

80. The process of claim 67 wherein said compound of Formula (VI) is prepared by the processes comprising condensing a compound of Formula (VII):

2-25. -25. (canceled)

28-31. -31. (canceled)

36-39. -39. (canceled)

42-44. -44. (canceled)

47-58. -58. (canceled)

60-66. -66. (canceled)

68-79. -79. (canceled)

81-90. -90. (canceled)

91. A process for preparing a compound of Formula (II):

92. The process of claim 91 wherein Pr is an acyl group.

94. The process of claim 91 wherein Pr is —

C(O)Me.

95. The process of claim 91 wherein said base is sodium hydroxide.

96. The process of claim 91 wherein said reacting is carried out in an organic solvent.

97. The process of claim 96 wherein said organic solvent comprises an alcohol.

98. The process of claim 97 wherein said organic solvent comprises methanol.

160. The process of claim 96 wherein said reacting is carried out at about 0 to about 100°

C.

93. (canceled)

99. (canceled)

100. (canceled)

101. A process for the preparation of a compound of Formula (IV):

103. The process of claim 101 wherein said halogenating reagent is a brominating reagent.

104. The process of claim 103 wherein said halogenating reagent comprises N-bromosuccinimide.

105. The process of claim 104 wherein said reacting is carried out in an organic solvent.

106. The process of claim 105 wherein said organic solvent comprises an alcohol.

107. The process of claim 106 wherein said organic solvent comprises methanol.

102. (canceled)

108. A process for preparing a compound of Formula (V):

109. The process of claim 108 wherein R² is methyl.

110. The process of claim 108 wherein said reacting is carried out in the presence of an organic solvent.

111. The process of claim 110 wherein said organic solvent comprises an alcohol.

112. The process of claim 110 wherein said organic solvent comprises methanol.

113. The process of claim 108 wherein said reacting is carried out in the presence of an acid.

115. The process of claim 113 wherein said acid comprises HCl.

114. (canceled)

116-119. -119. (canceled)

120. A process for preparing a compound of Formula (VI):

122. The process of claim 120 wherein said R and R′

are both methyl.

123. The process of claim 120 wherein said R^2a and R^2b are both methyl.

124. The process of claim 120 wherein said reacting with an acetal of Formula (VIII) is carried out in a solvent.

125. The process of claim 124 wherein said solvent comprises an alcohol.

126. The process of claim 124 wherein said solvent comprises ethanol.

127. The process of claim 120 wherein said reacting with an acetal of Formula (VIII) is carried out at about reflux temperature.

121. (canceled)

128-130. -130. (canceled)

131. A compound of Formula (II), (IV), (V) or (VI):

155. The compound of claim 131 wherein said compound has Formula (II) and R² is methyl;

R³ is Cl or Br;

R⁴ is methoxy; and

R⁵, at each occurrence, is H.

156. The compound of claim 131 wherein said compound has Formula (IV) and R² is methyl;

R³ is Br;

R⁴ is methoxy;

R⁵, at each occurrence, is H; and

Pr is —

C(O)Me.

158. The compound of claim 131 wherein said compound has Formula (V) and R² is methyl;

R⁴ is methoxy;

R⁵, at each occurrence, is H; and

Pr is —

C(O)Me.

159. The compound of claim 131 wherein said compound has Formula (VI) and R^2a is methyl;

R^2b is methyl;

R⁴ is methoxy;

R⁵, at each occurrence, is H; and

Pr is —

C(O)Me.

132-154. -154. (canceled)

157. (canceled)