JP2006527164A - Novel halogen-substituted active methylene compounds - Google Patents

Abstract

Provided are novel methods for synthesizing Formula I compounds by using novel halogen-substituted active methylene compounds of Formula III and methods for their synthesis.

Description

   The present invention relates to a novel halogen-substituted active methylene compound and a synthesis method thereof. More particularly, the invention relates to a process for the synthesis of compounds of formula I by using novel halogen-substituted active methylene compounds of formula III.

  US5124482 and US5216174 are [R- (R *, R *)]-2- (4-Fluorophenyl) -B, D-Dihydroxy-5- (1-Methylethyl) -3-Phenyl-4-[(Phenylamino) Carbonyl] Disclosed is the preparation and use of 4-Fluoro-α- [2-methyl-1-oxopropyl] γ-oxo-N-β-diphenylbenzenebutane amide for the synthesis of -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 an HMG CoA reductase inhibitor and is therefore used as an anti-high cholesterol drug.

The compound of formula III not known so far is

4-Fluoro-α- [2-methyl-1-oxopropyl] γ-oxo-N-β-diphenylbenzenebutane amide is a novel intermediate that is extremely useful in an improved synthesis method. (Figure 1)

The invention also relates to a process for the synthesis of novel intermediates of formula III.

The invention also relates to a novel method for the synthesis of compounds of formula I.

As mentioned above, the compound of formula I is
a) a) halogenation of a compound of formula II to provide a compound of formula III,
b) reaction of a compound of formula III with a compound of formula IV,
Can be synthesized by novel methods including:

[Detailed Description of the Invention]
Formula I compounds are important intermediates for the synthesis of drug molecules, particularly HMG Co-A reductase inhibitors. HMG Co-A reductase inhibitors are useful as inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG Co-A reductase) and are therefore useful as hypolipidemic or hypocholesterolemic agents. is there.

  The method of the present invention is a new, economical and commercially viable method for synthesizing intermediates used for the synthesis of HMG Co-A reductase inhibitors.

The reaction of the Formula II compound with the Formula III compound is selected from bromine, N-bromosuccinimide, thionyl chloride, Br ₂ (CN) ₂ , 4-dimethylaminopyridinium bromide, or any other such suitable halogenating reagent. Carried out in the presence of a reagent.

  The compound of formula III is further reacted with the compound of formula IV to produce [R- (R *, R *)]-2- (4-Fluorophenyl) -B, D-Dihydroxy-5- (1-Methylethyl) -3-Phenyl 4-Fluoro-α- [2-methyl-1-oxopropyl] γ-oxo-N-, an important intermediate for the production of -4-[(Phenylamino) Carbonyl] -1h-Pyrrole-1-Heptanoic Acid It can be used for the synthesis of β-diphenylbenzenebutane amide.

  The reaction of the Formula III compound with the Formula IV compound is carried out in the presence of a reagent selected from lithium diisopropylamide, N-butyllithium sodium hydride, sodium ethoxide or any other such suitable base.

  The following non-limiting examples illustrate the preferred methods for the synthesis of the compounds of the present inventors.

[Example]

[Synthesis of 2-Bromo-4-methyl-3-oxo-pentanoic acid phenylamide]
To a solution of 4-Methyl-3-oxo-pentanoic acid phenylamide (10 g, 0.048 mol) in chloroform (100 mL) was added liquid bromine (7.8 g, 0.048 mol). After stirring for 30 minutes, the reaction mixture was concentrated and the products were separated by column chromatography (silica gel: 60-120 mesh, eluent: Pet. Ether / ethyl acetate-60: 40).

  Yield: 11.0 g, 80%

[Synthesis of 2-Bromo-4-methyl-3-oxo-pentanoic acid phenylamide]
To a solution of 4-Methyl-3-oxo-pentanoic acid phenylamide (10 g, 0.048 mol) in acetone (100 mL) was added N-bromosuccinimide (8.5 g, 0.048 mol). After stirring for 3 hours, the reaction mixture was concentrated and the product was crystallized and separated from Pet. Ether / ethyl acetate.

  Yield: 12.5 g, 92%

[Synthesis of 4-Fluoro-α- [2-methyl-1-oxopropyl] γ-oxo-N-β-diphenylbenzenebutane amide]
While maintaining a temperature between −10 ° C. and −25 ° C., a cooled solution of diisopropylamine (8 mL, 0.056 mol) in dry THF (50 mL) was added to N-butyllithium in hexane (35 mL, 1.6 M, 0 0.056 mol) was added dropwise under a nitrogen atmosphere and stirred at the same temperature for 30 minutes. A drop of 1- (4-Fluoro-phenyl) -2-phenyl-ethanone (10 g, 0.047 mol) in THF (20 mL) was added to the reaction mixture while maintaining the temperature between −60 ° C. and −78 ° C. Added one by one and stirred at the same temperature for 1 hour. While maintaining the temperature between −60 ° C. and −78 ° C., 2-Bromo-4-methyl-3-oxo-pentanoic acid phenylamide (13.4 g, 0.047 mol) in THF (30 mL) was added to the reaction mixture. It was added dropwise and stirred for 30 minutes. The reaction mixture was slowly warmed to 10-15 ° C. over 1 h and quenched with water (50 mL). The product was extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with water (2 × 50 mL), brine (2 × 50 mL) and concentrated to give the title compound.

  Yield: 16 g, 85%

[Synthesis of 4-Fluoro-α- [2-methyl-1-oxopropyl] γ-oxo-N-β-diphenylbenzenebutane amide]
While maintaining a temperature between −10 ° C. and −25 ° C., a cooled solution of diisopropylamine (8 mL, 0.056 mol) in dry THF (50 mL) was added to N-butyllithium in hexane (35 mL, 1.6 M, 0 0.056 mol) was added dropwise under a nitrogen atmosphere and stirred at the same temperature for 30 minutes. 1- (4-Fluoro-phenyl) -3-methyl-butan-1-one (8.4 g, 0.047 mol) in THF (20 mL) while maintaining the temperature between −60 ° C. and −78 ° C. Was added dropwise to the reaction mixture and stirred at the same temperature for 1 hour. While maintaining the temperature between −60 ° C. and −78 ° C., 2-Bromo-4-methyl-3-oxo-pentanoic acid phenylamide (13.4 g, 0.047 mol) in THF (30 mL) was added to the reaction mixture. It was added dropwise and stirred for 30 minutes. The reaction mixture was slowly warmed to 10-15 ° C. over 1 h and quenched with water (50 mL). The product was extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with water (2 × 50 mL), brine (2 × 50 mL) and concentrated to give the title compound.

  Yield: 15 g, 87%

  Since there is no original text, it cannot be described.

Claims (5)

A method for synthesizing a compound of formula I comprising a reaction step of a compound of formula III and a compound of formula IV to obtain a compound of formula I.

  The reaction between the compound of formula III and the compound of formula IV is carried out in the presence of a reagent selected from lithium diisopropylamide, N-butyllithium sodium hydride, sodium ethoxide or any other such suitable base. The method of claim 1. The method of claim 1, wherein said Formula III compound is synthesized by halogenation of Formula II compound to provide Formula II compound.

Said halogenation is carried out in the presence of a reagent selected from bromine, N-bromosuccinimide, thionyl chloride, Br ₂ (CN) ₂ , 4-dimethylaminopyridinium bromide, or any other such suitable halogenating reagent. 4. The method of claim 3, wherein: Formula III intermediate.

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