Novel process for the synthesis of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide

• US 20070032664A1
• Filed: 10/11/2006
• Published: 02/08/2007
• Est. Priority Date: 01/09/2001
• Status: Active Grant

• Current Assignee: Donald Butler, Jude Nelson, Michael Pamment, Randall Dejong, Timothy Stuk
• Original Assignee: Donald Butler, Jude Nelson, Michael Pamment, Randall Dejong, Timothy Stuk
• Inventors: Dejong, Randall, Stuk, Timothy, Pamment, Michael, Butler, Donald, Nelson, Jude
• Granted Patent: US 7,361,771 B2
• Time in Patent Office: Days
• US Class Current: 548/517
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 207/416 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

An improved process for the preparation of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide by a novel synthesis is described where methyl cyanoacetate is converted in eight operations or fewer to the desired product, as well as other valuable intermediates used in the process.

Claims

1-51. -51. (canceled)

52. A process for the preparation of a compound of Formula (8)

53. A process for the preparation of compound (13)

54. The process according to claim 53, wherein the acid in Step (a) is selected from the group consisting of hydrogen chloride, para-toluenesulfonic acid and pyridinium para-toluenesulfonate.

55. The process according to claim 54, wherein the acid is para-toluenesulfonic acid.

56. The process according to claim 53, wherein the acetal in Step (a) is benzaldehyde dimethyl acetal.

57. The process according to claim 53, wherein the base in Step (a) is a non-nucleophilic strong base.

58. The process according to claim 53, wherein the base is selected from the group consisting of potassium tert butoxide, potassium bis(trimethylsilyl)amide, and 1,-8-diazabicyclo[5.4.0.]undec-7-ene.

59. The process according to claim 58, wherein the base is potassium tertiary butoxide.

60. The process according to claim 53, wherein the solvent in Step (b) is selected from the group consisting of toluene, dichloromethane, and methyl tertiary butyl ether.

61. The process according to claim 60, wherein the solvent is toluene.

62. The process according to claim 53, wherein the acid in Step (b) is selected from the group consisting of hydrogen chloride, pyridinium para-toluenesulfonate and para-toluenesulfonic acid.

63. The process according to claim 62, wherein the acid is para-toluenesulfonic acid.

64. The process according to claim 53, wherein the catalyst in Step (b) is selected from the group consisting of palladium on carbon, and platinum on carbon, in the presence of hydrochloric acid.

65. The process according to claim 53, wherein the solvent in Step (c) is selected from the group consisting of toluene, dichloromethane, acetonitrile, and methyl tertiary butyl ether.

66. The process according to claim 65, wherein the solvent is toluene.

67. The process according to claim 53, wherein the acid in Step (c) is selected from the group consisting of hydrochloric acid, sulfuric acid, pyridinium p-toluenesulfonate, and para-toluenesulfonic acid.

68. The process according to claim 67, wherein the acid is para-toluenesulfonic acid.

69. The process according to claim 53, wherein R¹ is selected from the group consisting of -O-methyl, -O-ethyl, and -O-tert butyl in a compound of Formula (11).

70. The process according to claim 53, wherein R¹ is selected from the group consisting of -O-methyl, -O-ethyl, and -O-tert butyl in a compound of Formula (14).

71. A process for the preparation of a compound of Formula (11b)

72. The process according to claim 71 wherein the catalyst in Step (a) or (b) is a ruthenium catalyst precursor and a chiral non-racemic diphosphine ligand.

73. The process according to claim 72, wherein the ruthenium catalyst precursor is selected from the group consisting of dichloro-(1,5-cyclooctadiene)-ruthenium (II) oligomer, dibromo-(1,5-cyclooctadiene)-ruthenium (II) dimer, [bis-(2-methallyl)cycloocta-1,5-diene] ruthenium (II) complex and dichloro (p-cymene) ruthenium (II) dimer.

74. The process according to claim 72, wherein the chiral diphosphine ligand is selected from the group consisting of 2,2′

-bis(di-p-tolyl-phosphino)-1,1′

-binaphthyl, 2-diphenyl-phosphinomethyl-4-diphenylphosphino-1-tert-butoxy-carbonylpyrrolidine, tricyclo[8.2.2.24,7]hexadeca-4,6,10,12,13,15-hexaene-5,11-diyl-bis(diphenylphosphine) derivatives, 4,4′

-bidibenzofuran-3,3′

-diylbis(diphenylphosphine), 6,6′

-dimethoxy[1,1′

-biphenyl]-2,2′

-diyl]bis-diphenylphosphine, [5,5′

-dichloro-6,6′

-dimethoxy[1,1′

-biphenyl]-2,2′

-diyl]-bis-diphenylphosphine, [6,7-dihydrodibenzo[e,g][1,4]dioxocin-1,12-diyl]-bis-diphenylphosphine, and 1,2-bis(2,5-dimethylphospholano)benzene derivatives.

75. The process according to claim 72, wherein the catalyst is RuCl₂(DMF)_n((R)-(+)-Cl—

MeO-BIPHEP).

76. The process according to claim 71, wherein the solvent in Step (a) or (b) is selected from the group consisting of an alcohol, dichloromethane, tetrahydrofuran, and toluene.

77. The process according to claim 76, wherein the alcohol is selected from the group consisting of methanol, ethanol, and isopropanol.

78. The process according to claim 76, wherein the alcohol is methanol.

79. A process according to claim 71 wherein the acid in Step (a) or (b) is hydrobromic acid.

80-91. -91. (canceled)

92. A compound of Formula (14)

93. A compound which is ((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl}-2-phenyl-[1,3]dioxan-4-yl)-acetic acid methyl ester.

94. A compound which is ((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl}-2-phenyl-[1,3]dioxan-4-yl)-acetic acid ethyl ester.

95. A compound which is ((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl}-2-phenyl-[1,3]dioxan-4-yl)-acetic acid isopropyl ester.

96. A compound which is ((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl}-2-phenyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester.