Abstract:
A novel process for the preparation of compounds of formula I  
                         
 
by employing novel halo-substituted active methylene compounds of formula III and process of preparation thereof.

Description:
TECHNICAL FIELD  
       [0001]     The present invention relates to a novel halo-substituted active methylene compounds and a process for preparation of the same. More particularly, the present invention relates to a process for preparation of compounds of formula I by employing novel halo-substituted active methylene compounds of formula III.  
       BACKGROUND  
       [0002]     U.S. Pat. No. 5,124,482 and U.S. Pat. No. 5,216,174 discloses the manufacture and use of 4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzenebutane amide for preparation of [R-(R*,R*)]-2-(4-Fluorophenyl)-B,D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino) Carbonyl]-1h-Pyrrole-1-Heptanoic Acid. [R-(R*,R*)]-2-(4-Fluorophenyl)-B,D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)Carbonyl]-1h-Pyrrole-1-Heptanoic Acid is inhibitor of HMG CoA reductase and thus is used as antihypercholesterolemic agent. Hitherto unknown compounds of the formula III  
                         
 
 are extremely useful novel intermediates for an improved process for the preparation of 4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzenebutaneamide (Scheme 1). 
 
       SUMMARY OF THE INVENTION  
       [0003]     The present invention also relates to a process for preparation of novel intermediates of formula III.  
                         
 
         [0004]     The present invention also relates to novel process for preparation compounds of formula I.  
                         
 
         [0005]     As mentioned earlier the compounds of formula I can be prepared by a novel process comprising, 
        a) a) halogenation of compound of formula II to afford a compounds of formula III,     b) reaction of compounds of formula III with compounds of formula IV.  
                         
       
 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0008]     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.  
                         
 
       FORMULA I  
       [0009]     The process of the present invention is new, economical, and commercially feasible method for preparing intermediates used for the preparation of HMG CoA reductase inhibitors.  
         [0010]     The reaction between compounds of formula II and III is carried out in the presence of reagents selected from Bromine, N-bromosuccinimide, thionyl chloride, Br 2 (CN) 2 , 4-(dimethylamino)pyridinium bromide or any such suitable halogenating agent.  
         [0011]     The compounds of formula III can be further used for preparation of 4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzene butane amide which is key intermediate for manufacture of [R-(R*,R*)]-2-(4-Fluorophenyl)-B,D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenyl amino) Carbonyl]-1h-Pyrrole-1-Heptanoic Acid, by reacting with compound of formula IV.  
         [0012]     The reaction between compounds of formula III and 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.  
         [0013]     The following non-limiting examples illustrate the inventors&#39; preferred method for preparing the compounds of the invention.  
       EXAMPLES  
     Example 1  
     Preparation of 2-Bromo-4-methyl-3-oxo-pentanoic Acid Phenylamide  
       [0014]     To a solution of 4-Methyl-3-oxo-pentanoic acid phenylamide (10 g, 0.048 mol) in chloroform (100 mL), liquid bromine (7.8 g, 0.048 mol) was added. After stirring for 30 minutes, the reaction mixture was concentrated and product was isolated by column chromatography (silica gel: 60-120 mesh, eluent: Pet. Ether/ethyl acetate-60:40).  
         [0015]     Yield: 11.0 g, 80%  
       Example 2  
     Preparation of 2-Bromo-4-methyl-3-oxo-pentanoic Acid Phenylamide  
       [0016]     To a solution of 4-Methyl-3-oxo-pentanoic acid phenylamide (10 g, 0.048 mol) in acetone 100 mL), N-bromosuccinimide (8.5 g, 0.048 mol) was added. After stirring for 3 hours, the reaction mixture was concentrated and product was isolated by crystallization from Pet. Ether/ethyl acetate.  
         [0017]     Yield: 12.5 g, 92%  
       Example 3  
     Preparation of 4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzene Butane Amide  
       [0018]     To a chilled solution of diisopropylamine (8 mL, 0.056 mol) in dry THF(50 mL), n-butyl lithium (35 mL, 1.6 M, 0.056 mol) in hexane was added dropwise under nitrogen atmosphere, maintaining the temperature between −10° C. and −25° C. and 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 to the reaction mixture dropwise, maintaining the temperature between −60° C. and −78° C. and stirred for 1 hour at the same temperature. 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. and stirred for 30 minutes. The reaction mixture was 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) brine (2×50 mL) and concentrated to obtain title compound.  
         [0019]     Yield: 16 g, 85%.  
       Example 4  
     Preparation of 4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzene Butane Amide  
       [0020]     To a chilled solution of diisopropylamine (8 mL, 0.056 mol) in dry THF (50 mL), n-butyl lithium (35 mL, 1.6 M, 0.056 mol) in hexane was added dropwise under nitrogen atmosphere, maintaining the temperature between −10° C. and −25° C. and 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 to the reaction mixture dropwise, maintaining the temperature between −60° C. and −78° C. and stirred for 1 hour at the same temperature. 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. and stirred for 30 minutes. The reaction mixture was 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) brine (2×50 mL) and concentrated to obtain title compound.  
         [0021]     Yield: 15 g, 87%.