2,2,2-trifluoro-1-phenylethanone

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon atmosphere, 20 mL (10.7 mmol, 2 equivalents) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 was added dropwise to a solution of 0.75 mL (5.35 mmol) of trifluoroacetophenone in 2.75 mL of THF at 7˜9° C. The mixture was stirred at 4˜5° C. for 4 hours. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 30 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.54 g of the desired product (NMR yield 97%; internal standard dioxane). Then, the layers were separated The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution After washing the organic layer was dried with anhydrous magnesium sulfate Concentration under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of butyllithium in n-hexane (8.5 ml of 1.6 molar) was added, dropwise, at room temperature and under a nitrogen atmosphere over 10 minutes to [3-(3-phenoxyphenyl)propyl]-triphenylphophonium bromide (7.67 g; 13.75 mmol) in absolute tetrahydrofuran (40 ml). After stirring for 2 hours, α,α,α-trifluoroacetophenone (2.18 g; 12.5 mmol) dissolved in absolute tetrahydrofuran (10 ml) was added dropwise. After stirring for 3 hours at room temperature, the mixture was added to ice-water, extracted with ether and the extract dried over sodium sulphate and evaporated. After chromotography on silica gel using hexane-toluene, there was obtained 4-(3-phenoxyphenyl)-1-phenyl-1-trifluoromethyl-1-butene (3.31 g=71.9% of theory). was added dropwise After stirring for 3 hours at room temperature extracted with ether the extract dried over sodium sulphate evaporated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude solid trifluoroacetophenone from Step 1 (11.54 kg) is dissolved in 48 L of ethanol and is charged into a 100 L round-bottom flask. Water (8L) is then added. Hydroxylamine hydrochloride (NH2OH.HCl, 11.05 kg) is added to the stirred mixture, followed by the addition of NaHCO3 (13.36 kg). The heterogeneous solution is stirred at 60° C. overnight. The reaction is complete within 24 hours by LC assay. Work-up consists of the addition of 40L of water and 25L of toluene, followed by transfer to an extractor. The flask is rinsed with an additional 25L of toluene, which is also transferred to the extractor. The layers are separated, and the organic layer is extracted with one washing of 60L of 1N NaOH. The layers are separated, and the NaOH layer is neutralized with 12N HCL to pH=6.1. The aqueous layer is then extracted with 60L of toluene. The layers are separated and the aqueous layer is extracted a second time with toluene. The combined organic layers are washed with 4L of water. The organic layer is concentrated to a crude solid which can be used in the next step without further purification. Alternatively, the product can be crystallized from a toluene/heptane mixture. The product is predominantly the E oxime (shown in the equation above) rather than the Z oxime and is obtained in 85% yield from 2,4-dipropylresorcinol. is charged into a 100 L round-bottom flask The reaction is complete within 24 hours by LC assay The flask is rinsed with an additional 25L of toluene, which The layers are separated the organic layer is extracted with one washing of 60L of 1N NaOH The layers are separated The aqueous layer is then extracted with 60L of toluene The layers are separated the aqueous layer is extracted a second time with toluene The combined organic layers are washed with 4L of water The organic layer is concentrated to a crude solid which can be used in the next step without further purification Alternatively, the product can be crystallized from a toluene/heptane mixture

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-5-cyclopropyl-4,4-difluoro-1-methoxy-1-oxopentan-2-amine hydrochloride (250 mg, 10 mmol), trifluoroacetophenone (179 mg, 10 mmol), potassium carbonate (426 mg, 30 mmol) was charged in isopropanol (10 mL) under nitrogen. The reaction mixture stirred for 20 h at 60° C. When TLC showed an absence of starting material, is the mixture was filtered under hot and the solids were washed with isopropanol (20 mL) and the filtrates were combined and concentrated under reduced pressure. The residue (400 mg, 10 mmol) was dissolved in acetonitrile (5 mL) and methanol (1 mL) and transferred to a dropping funnel under nitrogen. The zinc borohydride suspension prepared as described above was cooled to −45° C. and treated with the imine solution which was added drop-wise and the reaction was stirred at same temperature for 1 h. Once the staring material was consumed, is the reaction mixture was quenched with 1N HCl solution (10 mL) at 0° C. and then allowed to warm to room temperature. The mixture was extracted with ethyl acetate (3×40 mL) and the combined organic extracts washed with water (50 mL) and brine (50 mL). The organic extracts were evaporated under reduced pressure, and the residue re-dissolved in ethyl acetate (20 mL) and washed with water (20 mL) and brine (50 mL). The solution was dried (MgSO4) and the solvent evaporated under reduced pressure to give (S)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanoic acid as a pale oil (265 mg, 71.3%). was filtered under hot and the solids were washed with isopropanol (20 mL) concentrated under reduced pressure above was cooled to −45° C. was added drop-wise the reaction was stirred at same temperature for 1 h Once the staring material was consumed was quenched with 1N HCl solution (10 mL) at 0° C. to warm to room temperature The mixture was extracted with ethyl acetate (3×40 mL) the combined organic extracts washed with water (50 mL) and brine (50 mL) The organic extracts were evaporated under reduced pressure the residue re-dissolved in ethyl acetate (20 mL) washed with water (20 mL) and brine (50 mL) The solution was dried (MgSO4) the solvent evaporated under reduced pressure

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-5-cyclopropyl-4,4-difluoro-1-methoxy-1-oxopentan-2-amine hydrochloride (250 mg, 10 mmol), trifluoroacetophenone (179 mg, 10 mmol), potassium carbonate (426 mg, 30 mmol) was charged in isopropanol (10 mL) under nitrogen. The reaction mixture stirred for 20 h at 60° C. When TLC showed an absence of starting material, is the mixture was filtered under hot and the solids were washed with isopropanol (20 mL) and the filtrates were combined and concentrated under reduced pressure. The residue (400 mg, 10 mmol) was dissolved in acetonitrile (5 mL) and methanol (1 mL) and transferred to a dropping funnel under nitrogen. The zinc borohydride suspension prepared as described above was cooled to −45° C. and treated with the imine solution which was added drop-wise and the reaction was stirred at same temperature for 1 h. Once the staring material was consumed, is the reaction mixture was quenched with 1N HCl solution (10 mL) at 0° C. and then allowed to warm to room temperature. The mixture was extracted with ethyl acetate (3×40 mL) and the combined organic extracts washed with water (50 mL) and brine (50 mL). The organic extracts were evaporated under reduced pressure, and the residue re-dissolved in ethyl acetate (20 mL) and washed with water (20 mL) and brine (50 mL). The solution was dried (MgSO4) and the solvent evaporated under reduced pressure to give (S)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanoic acid as a pale oil (265 mg, 71.3%). was filtered under hot and the solids were washed with isopropanol (20 mL) concentrated under reduced pressure above was cooled to −45° C. was added drop-wise the reaction was stirred at same temperature for 1 h Once the staring material was consumed was quenched with 1N HCl solution (10 mL) at 0° C. to warm to room temperature The mixture was extracted with ethyl acetate (3×40 mL) the combined organic extracts washed with water (50 mL) and brine (50 mL) The organic extracts were evaporated under reduced pressure the residue re-dissolved in ethyl acetate (20 mL) washed with water (20 mL) and brine (50 mL) The solution was dried (MgSO4) the solvent evaporated under reduced pressure