Patent Grant
7179942
The present application claims the benefit under 35 U.S.C. § 371 of International Application No.: PCT/IN03/00216, filed Jun. 9, 2003, the entire contents of this application is hereby incorporated herein by reference.
The present invention relates to novel halo-substituted active methylene compounds and a process for preparation of the same. More particularly, the present invention relates to a process for the preparation of compounds of Formula I by employing novel halo-substituted active methylene compounds of Formula III.
U.S. Pat. Nos. 5,124,482 and 5,216,174 disclose the manufacture and use of 4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzenebutane amide for the preparation of [R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)Carbonyl]-1h-Pyrrole-1-Heptanoic Acid. [R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)Carbonyl]-1[[h]]H-Pyrrole-1-Heptanoic Acid is an inhibitor of HMG CoA reductase and can thus be used as an antihypercholesterolemic agent.
In one aspect, the present invention provides compounds of Formula III
wherein X is halogen, which are useful intermediates for an improved process for the preparation of 4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzenebutaneamide. See Scheme 1.
In another aspect, the present invention relates to a process for preparation of novel intermediates of Formula III
where X is halogen.
In yet another aspect, the present invention relates to a process for preparation of compounds of Formula I
wherein G is alkyl or aryl.
In one embodiment, compounds of Formula I are prepared by a process comprising,
to afford a compound of Formula III
wherein X is halogen; and
reacting the compound of Formula III
wherein X is halogen,
with a compound of Formula IV
wherein G is alkyl or aryl.
Compounds of Formula I are important intermediates for the preparation of drug molecules, especially HMG Co-A reductase inhibitors. The HMG Co-A reductase inhibitors are useful as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) and are thus useful as hypolipidemic or hypocholesterolemic agents.
wherein G is alkyl or aryl.
In one aspect, the process of the present invention is a new, economical, and commercially feasible method for preparing intermediates used for the preparation of HMG CoA reductase inhibitors.
In one embodiment, compounds of Formula I are prepared by a process comprising,
to afford a compound of Formula III
wherein X is halogen; and
reacting the compound of Formula III
wherein X is halogen,
with a compound of Formula IV
wherein G is alkyl or aryl.
In one embodiment, the step of halogenating the compound of Formula II is carried out in the presence of reagents selected from Bromine, N-bromosuccinimide, thionyl chloride, Br2(CN)2, 4-(dimethylamino)pyridinium bromide or any such suitable halogenating agent.
The compounds of Formula III can be further used for the preparation of 4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzene butane amide, which is a key intermediate for the manufacture of [R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenyl amino) Carbonyl]-1h-Pyrrole-1-Heptanoic Acid (e.g., by reacting them with a compound of Formula IV).
In certain embodiments, the step of reacting the compound of Formula III with a compound of Formula IV is carried out in the presence of reagents selected from Lithium diisopropylamide, sodium hydride n-butyllithium, sodium ethoxide or any such suitable base.
The illustrated embodiments have been set forth only for the purposes of example, and should not be taken as limiting the invention. Therefore it should be understood that, within the scope of the appended claims, the invention may be practiced other than specifically described herein.
Liquid bromine (7.8 g, 0.048 mol) was added to a solution of 4-Methyl-3-oxo-pentanoic acid phenylamide (10 g, 0.048 mol) in chloroform (100 mL). After stirring for 30 minutes, the reaction mixture was concentrated and the product was isolated by column chromatography(silica gel: 60–120 mesh, eluent: Pet. Ether/ethyl acetate—60:40)
Yield: 11.0 g, 80%
N-bromosuccinimide (8.5 g, 0.048 mol) was added to a solution of 4-Methyl-3-oxo-pentanoic acid phenylamide (10 g, 0.048 mol) in acetone 100 mL.). After stirring for 3 hours, the reaction mixture was concentrated and product was isolated by crystallization from Pet. Ether/ethyl acetate.
Yield: 12.5 g, 92%
A solution of n-butyl lithium (35 mL, 1.6 M, 0.056 mol) in hexane was added dropwise to a chilled solution of diisopropylamine (8 mL, 0.056 mol) in dry THF(50 mL), under nitrogen atmosphere, maintaining the temperature between −10° C. and −25° C. The resulting mixture was stirred for 30 minutes at the same temperature. A solution of 1-(4-Fluoro-phenyl)-2-phenyl-ethanone (10 g, 0.047 mol) in THF (20 mL) was added dropwise to the reaction mixture, maintaining the temperature between −60° C. and −78° C. The resulting mixture was stirred for 1 hour at the same temperature. A solution of 2-Bromo-4-methyl-3-oxo-pentanoic acid phenylamide (13.4 g, 0.047 mol) in THF (30 mL) was added dropwise to the reaction mixture, maintaining the temperature between −60° C. and −78° C. The resulting mixture was stirred for 30 minutes, was slowly warmed to 10–15° C. over a period of 1 hour, and was quenched with water (50 mL). The product was extracted with ethyl acetate (2×50 mL). The combined organic extract was washed with water (2×50 mL) and brine (2×50 mL), and concentrated to obtain title compound.
Yield: 16 g, 85%.
A solution of n-butyl lithium (35 mL, 1.6 M, 0.056 mol) in hexane was added dropwise to a chilled solution of diisopropylamine (8 mL, 0.056 mol) in dry THF (50 mL), under nitrogen atmosphere, maintaining the temperature between −10° C. and −25° C. The resulting reaction mixture was stirred for 30 minutes at the same temperature. A solution of 1-(4-Fluoro-phenyl)-3-methyl-butan-1-one (8.4 g, 0.047 mol) in THF (20 mL) was added dropwise to the reaction mixture, maintaining the temperature between −60° C. and −78° C. The resulting reaction mixture was stirred for 1 hour at the same temperature. A solution of 2-Bromo-4-4-methyl-3-oxo-pentanoic acid phenylamide (13.4 g, 0.047 mol) in THF (30 mL) was added dropwise to the reaction mixture, maintaining the temperature between −60° C. and −78° C. The resulting mixture was stirred for 30 minutes, slowly warmed 10–15° C. over a period of 1 hour, and quenched with water (50 mL). The product was extracted with ethyl acetate (2×50 mL). Combined organic extract was washed with water (2×50 mL) and brine (2×50 mL), and concentrated to obtain title compound.
Yield: 15 g, 87%.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IN03/00216 | 6/9/2003 | WO | 00 | 12/8/2004 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2004/108660 | 12/16/2004 | WO | A |
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| Number | Date | Country | |
|---|---|---|---|
| 20050113607 A1 | May 2005 | US |
