Process for preparation of 4-fluoro-α-[2methyl-l-oxopropyl]-γ-oxo—N—β-diphenylbenzene butane amide
A process for preparation of 4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butane amide also known as a diketone intermediate of atorvastatin, completely devoid of impurities 3,4-difluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-n-β-diphenylbenzene butane amide; methyl, 2{-2[-(4-fluorophenyl)-2-oxo-1-phenylethyl)]}-4-methyl-3-oxo pentanoate; 1,4-bis(4-fluorophenyl)-2,3-diphenylbutane-1,4-dione, 1-(4-fluorophenyl)-2-phenyl ethanone; 1-(4-fluorophenyl)-2-phenyl ethanone and containing about 0.05% or less of 2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butane amide. In that process the said diketone intermediate of formula 1 is obtained by maintaining temperature −25° C. to 50° C. during Friedel-Crafts acylation, in situ halogenation of formula II in presence of a solvent and nucleophilic substitution from a compound of formula III with formula IV in presence of a base.
1. A process for controlling impurities during preparation of a compound of formula (I)
the processing comprising:
performing a Friedel-Crafts condensation of fluorobenzene with phenylacetyl chloride at a reaction temperature ranging from about—10° C. to 0° C. to afford a compound of Formula II;
performing a halogenation of said formula II in at least one inert solvent to afford a compound of formula III wherein X is halogen;
and
performing a nucleophilic substitution of said formula III in a base in a solvent having a compound of formula IV to afford the compound of formula I;
wherein said impurities consist of α-[-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butan amide, 3,4-difluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-n-β-diphenylbenzene butane amide, 1,4-bis(4-fluorophenyl)-2,3-diphenylbutane-1,4-dione, 2{-2[-(4-fluorophenyl)-2-oxo-1-phenylethyl)]}-4-methyl-3-oxo pentanoate and 1-(4-fluorophenyl)-2-phenyl ethanone.
2. The process of claim 1 , wherein said Friedel-Crafts condensation is carried out in presence of Lewis acid catalyst to afford said Formula II.
3. The process of claim 2 , wherein said lewis acid catalyst is selected from the group comprising FeCl3, SbCl5, BF3, TiCl4, ZnC2 or AlCl3.
4. The process of claim 1 , wherein the halogenation of said formula II is carried out in situ in presence of methylene chloride.
5. The process of claim 1 , wherein said halogen is selected from the group consisting of bromine and chlorine.
6. The process of claim 1 , wherein said base for nucleophilic substitution of said formula III is either sodium carbonate, potassium carbonate cesium carbonate, triethyl amine, or diisopropylethylamine.
7. The process of claim 1 , wherein said solvent for nucleophilic substitution of said formula III is selected from the group consisting of tetrahydrofuran, 1,2-dimethoxy ethane, methylene chloride, ethyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, isopropanol, acetonitrile, dimethyl formamide, N-methyl pyyrolidinone, dimethyl sulfoxide, methanol or a mixture there of.
8. The process of claim 7 , wherein said solvent is acetone.
9. The process of claim 1 , wherein said formula I contains less than 0.05% of said α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butane amide.
10. The process of claim 1 , wherein said formula I is completely devoid of said 3,4-difluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-n-β-diphenylbenzene butane amide.
11. The process of claim 1 , wherein said formula I is completely devoid of said methyl, 2{-2[-4-fluorophenyl)-2-oxo-1-phenylethyl)]}-4-methyl-3-oxo pentanoate.
12. The process of claim 1 , wherein said formula I is completely devoid of said 1-(4-fluorophenyl)-2-phenyl ethanone.
13. The process of claim 1 , wherein presence of the impurity in the preparation of formula I is being determined by ultra performance liquid chromatography (UPLC).