ethyl 2,2-difluoroacetate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This procedure is based on literature, see: Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 2958. Thiazole (5.7 mL, 80 mmol) in THF (100 mL) was added to a stirred, cooled (0° C.) solution of isopropylmagnesium chloride-lithium chloride (1.18 M in THF, 74.9 mL, 88 mmol) in THF (75 mL) then the mixture was stirred at room temperature for 1 hour. Then the solution was cooled to −20° C. and ethyl difluoroacetate (9.29 ml, 88 mmol) was added. The mixture was stirred for 10 minutes at −20° C., then 10 minutes at room temperature. The mixture was diluted with ethyl acetate (200 mL), washed with aqueous ammonium chloride (saturated, 200 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chromatography on silica gel, 0-90% ethyl acetate in hexanes) to give 2,2-difluoro-1-(1,3-thiazol-2-yl)ethanone (12 g, 73.6 mmol, 92% yield) as a yellow oil. MS ESI: [M+H]+ m/z 164.0. Then the solution was cooled to −20° C. The mixture was stirred for 10 minutes at −20° C. 10 minutes at room temperature washed with aqueous ammonium chloride (saturated, 200 mL) dried (MgSO4) filtered the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel (chromatography on silica gel, 0-90% ethyl acetate in hexanes)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl difluoroacetate (4.06 g, 32.7 mmol) was dissolved in methyl tert-butyl ether (50 mL). To the stirred solution was added 25 weight % sodium methoxide (7.07 g, 32.7 mmol) followed by 3'-fluoro-4'-methoxyacetophenone (5.0 g, 29.7 mmol). After stirring for 16 hours, 1N HCl (50 mL) was added. The organic layer was collected and washed with water (2×50 mL), dried over anhydrous MgSO4, filtered, and added to hexanes to precipitate a tan solid (7.0 g, 96%): mp 70-72° C. The organic layer was collected washed with water (2×50 mL) dried over anhydrous MgSO4 filtered added to hexanes to precipitate a tan solid (7.0 g, 96%)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(4-Methylphenyl)-2-(4-aminosulfonylphenyl-ethan-1-one oxime from Step 3 (2.0 g, 6.6 mmol), tetrahydrofuran (100 mL), and triethylamine (0.67 g, 6.6 mmol) were stirred at room temperature and treated with bis(1,2-chlorodimethylsilyl)ethane (1.42 g, 6.6 mmol). The solution was cooled to -78° C. under nitrogen. Lithium diisopropylamide (2.0M solution in heptane/tetrahydrofuran/ethylbenzene, 10.9 mL, 21.8 mmol) was added dropwise, and the cooling bath was removed. When the temperature reached -15° C., ethyl difluoroacetate (0.82 g, 6.6 mmol) was added all at once. After stirring for 0.5 hour, trifluoroacetic acid (30 mL) and water (10 mL) were added. The resulting dark mixture was heated to reflux for 20 hours, concentrated, dissolved in ethyl acetate (100 mL), washed with brine, saturated aqueous NaHCO3, and water, dried over MgSO4, and concentrated. A dark oily solid was purified by flash column chromatography eluting with ethyl acetate:hexane (1:1). The appropriate fractions were concentrated and crystallized from ethyl acetate/hexane to yield a white solid (0.23 g, 10%): mp 169.0°-172.3° C. 1H NMR (acetone-d6 /300 MHz) 8.0 (d, J=8.4 Hz, 2H), 7.5 (d, J=8.1 Hz, 2H), 7.3 (d, J=8.1 Hz, 2H), 7.2 (d, J=8.1 Hz, 2H), 7.1 (t, J=51.9 Hz, 1H), 6.7 (bs, 2H), 2.4 (s, 3H). High resolution mass spectrum calc'd. for C17H15F2N2O3S(M+H): 365.0771. Found: 365.0779. the cooling bath was removed reached -15° C. The resulting dark mixture was heated to reflux for 20 hours concentrated dissolved in ethyl acetate (100 mL) washed with brine, saturated aqueous NaHCO3, and water dried over MgSO4 concentrated A dark oily solid was purified by flash column chromatography eluting with ethyl acetate:hexane (1:1) The appropriate fractions were concentrated crystallized from ethyl acetate/hexane

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(4-Methoxyphenyl)-2-(4-aminosulfonylphenyl-ethan-1-one oxime from Step 3 (1.2 g, 3.7 mmol), tetrahydrofuran (100 mL), and triethylamine (0.37 g, 3.7 mmol) were stirred at room temperature and treated with bis(1,2-chlorodimethylsilyl)ethane (0.80 g, 3.7 mmol). The solution was cooled to -78° C. under nitrogen. Lithium diisopropylamide (2.0M solution in heptane/tetrahydrofuran/ethylbenzene, 6.1 mL, 12.2 mmol) was added dropwise, and the cooling bath was removed. When the temperature reached -15° C., ethyl difluoroacetate (0.51 g, 4.1 mmol) was added. After stirring 0.5 hour, trifluoroacetic acid (30 mL) and water (10 mL) were added. The resulting dark mixture was heated to reflux for 20 hours, concentrated, dissolved in ethyl acetate (100 mL), washed with brine, saturated NaHCO3, and water, dried over MgSO4, and concentrated. A dark oily solid was purified by flash column chromatography, eluting with ethyl acetate:hexane (1:1). The appropriate fractions were concentrated and crystallized from ethyl acetate/hexane to yield a white solid (0.21 g, 15%): mp 181.6°-182.6° C. 1H NMR (acetone-d6 /300 MHz) 8.0 (d, J=8.4 Hz, 2H), 7.6 (d, J=8.1 Hz, 2H), 7.5 (d, J=8.1 Hz, 2H), 7.4 (d, J=9.0 Hz, 2H), 7.1 (t, J=51.9 Hz, 1H), 6.7 (bs, 2H), 3.8 (s, 3H). Anal. Calc'd. for C17H14F2N2O4S: C, 53.68; H, 3.71; N, 7.36. Found: C, 53.71; H, 3.74; N, 7.27. the cooling bath was removed reached -15° C. The resulting dark mixture was heated to reflux for 20 hours concentrated dissolved in ethyl acetate (100 mL) washed with brine, saturated NaHCO3, and water dried over MgSO4 concentrated A dark oily solid was purified by flash column chromatography eluting with ethyl acetate:hexane (1:1) The appropriate fractions were concentrated crystallized from ethyl acetate/hexane