3-bromo-1,1,1-trifluoropropan-2-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of N-[4-(methylsulfonyl)phenyl]-4-(2-thienyl)benzenecarboximidamide (0.7 g, 1.96 mmol) and sodium bicarbonate (0.33 g, 3.93 mmol) in 2-propanol (30 mL) was added 3-bromo-1,1,1-trifluoroacetone (0.449 g, 2.35 mmol). After the reaction mixture was heated to 80° C. for 21 hours, the solvent was removed. The residue was redissolved in CH2Cl2 (50 mL) and washed with water (30 mL×2). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (2/1) to give the subtitle compound (0.351 g, 30.1% yield, via 2 steps). the solvent was removed The residue was redissolved in CH2Cl2 (50 mL) washed with water (30 mL×2) dried over Na2SO4 filtered concentrated in vacuo The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (2/1)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of compound 287 (14 g, 1 eq.) in EtOH (140 mL) was added 3-bromo-1,1,1-trifluoroacetone (8.8 mL, 1.2 eq.). The mixture was stirred at 90° C. for 16 hrs and concentrated in vacuo. DCM (20 mL) and water (20 mL) were added. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and flushed on a silica gel column with 5% MeOH/DCM to yield compound 288 as a beige compound in 12% yield. MS (ESI, EI+): m/z=292 (MH+). concentrated in vacuo DCM (20 mL) and water (20 mL) were added Organics were dried over Na2SO4 filtered concentrated under reduced pressure flushed on a silica gel column with 5% MeOH/DCM

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

実験手順: Acetonitrile (0.97 g, 23.7 mmol) is added dropwise to a solution of lithium diisopropylamide (two molar in hydrocarbons, 10.9 mL, 21.8 mmol) in tetrahydrofuran at -78° C. The reaction mixture is stirred at -78° C. for 30 minutes, treated with a solution of 3,4,5-trichloro-2-thiophenecarbonitrile (3.87 g, 18.2 mmol) in tetrahydrofuran, stirred for 30 minutes at -78° C., warmed to room temperature over 45 minutes, quenched with saturated ammonium chloride solution and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to obtain a red solid. A mixture of the red solid and 1-bromo-3,3,3-trifluoroacetone (1.95 mL, 18.7 mmol) in acetic acid is refluxed for three hours and 30 minutes, diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to obtain a red solid. Flash chromatography of the solid using silica gel and a 15% ethyl acetate in hexane solution gives the title product as a white solid (0.49 g, 7.8%, mp 220°-221° C.). stirred for 30 minutes at -78° C. warmed to room temperature over 45 minutes quenched with saturated ammonium chloride solution extracted with ether The combined organic extracts are washed sequentially with water and brine dried over MgSO4 concentrated in vacuo to obtain a red solid is refluxed for three hours and 30 minutes extracted with ether The combined organic extracts are washed sequentially with water and brine dried over MgSO4 concentrated in vacuo to obtain a red solid

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

実験手順: To a solution of 33.9 g 1-bromo-3,3,3-trifluoro-2-propanone in 300 ml of absolute ethanol are added 28.6 g 4-methyl-1-piperazinylthiocarboxamide. The mixture is refluxed for 4 hours, evaporated to dryness and the residue partitioned between ethyl ether and aqueous NaOH. The ether phase is washed, dried and evaporated, whereby the title compound is obtained, m.p. 62° (ethyl acetate/hexane). The mixture is refluxed for 4 hours evaporated to dryness the residue partitioned between ethyl ether and aqueous NaOH The ether phase is washed dried evaporated

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

実験手順: A solution of methyl (2R)-2-[4-(carbamoylamino)phenyl]propanoate (2.7 g, 9.95 mmol) in dioxane (50 ml) was treated at room temperature with 3-bromo-1,1,1-trifluoro-propan-2-one (1.03 ml, 10 mmol) and the resulting mixture was refluxed for 2 h. After cooling at room temperature, the solvent was evaporated under vacuum, the crude diluted with CH2Cl2 (50 ml) and washed with a saturated NaHCO3 aqueous solution (3×30 ml), dried over anhydrous Na2SO4 and evaporated to give pure methyl (2R)-2-(4-{[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl)propanoate (2.5 g, 7.96 mmol) as yellow oil (80%). 1H-NMR (CDCl3): δ 10.05 (bs, 1H, NH), 8.30 (s, 1H), 7.45 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 3.75 (q, 1H, J=7 Hz), 3.65 (s, 3H), 1.50 (d, 3H, J=7 Hz). the resulting mixture was refluxed for 2 h the solvent was evaporated under vacuum the crude diluted with CH2Cl2 (50 ml) washed with a saturated NaHCO3 aqueous solution (3×30 ml) dried over anhydrous Na2SO4 evaporated

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

実験手順: A solution of methyl (2R)-2-[4-(carbamothioylamino)phenyl]propanoate (10.7 g, 0.0484 mol) in dioxane (200 ml) was treated at room temperature with 3-bromo-1,1,1-trifluoro-propan-2-one (5 ml, 0.0484 mol) and the resulting mixture was refluxed for 2 h. After cooling at room temperature, the solvent was evaporated under vacuum, the crude diluted with CH2Cl2 (200 ml) and washed with a saturated NaHCO3 aqueous solution (3×100 ml), dried over anhydrous Na2SO4 and evaporated to give pure methyl (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate (12.8 g, 38.7 mmol) as yellow oil (80%). 1H-NMR (CDCl3): δ 8.65 (bs, 1H, NH), 7.30 (m, 4H), 7.05 (s, 1H), 3.75 (q, 1H, J=7 Hz), 3.65 (s, 3H), 1.50 (d, 3H, J=7 Hz). the resulting mixture was refluxed for 2 h the solvent was evaporated under vacuum the crude diluted with CH2Cl2 (200 ml) washed with a saturated NaHCO3 aqueous solution (3×100 ml) dried over anhydrous Na2SO4 evaporated

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

実験手順: A solution of methyl (2R)-2-[4-(carbamothioylamino)phenyl]propanoate (10.7 g, 0.0484 mol) in dioxane (200 ml) was treated at room temperature with 3-bromo-1,1,1-trifluoro-propan-2-one (5 ml, 0.0484 mol) and the resulting mixture was refluxed for 2 h. After cooling at room temperature, the solvent was evaporated under vacuum, the crude diluted with CH2Cl2 (200 ml) and washed with a saturated NaHCO3 aqueous solution (3×100 ml), dried over anhydrous Na2SO4 and evaporated to give pure methyl (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate (12.8 g, 38.7 mmol) as yellow oil (80%). 1H-NMR (CDCl3): δ 8.65 (bs, 1H, NH), 7.30 (m, 4H), 7.05 (s, 1H), 3.75 (q, 1H, J=7 Hz), 3.65 (s, 3H), 1.50 (d, 3H, J=7 Hz). the resulting mixture was refluxed for 2 h the solvent was evaporated under vacuum the crude diluted with CH2Cl2 (200 ml) washed with a saturated NaHCO3 aqueous solution (3×100 ml) dried over anhydrous Na2SO4 evaporated

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

実験手順: Methyl 4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiophene-2-carboxylate: Using a procedure similar to Example 204, step (a), 56 mg (0.21 mmol) of methyl 4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate was allowed to react with 40 mg (0.21 mmol) of bromotrifluoroacetone (Aldrich Chemical Co., Milwaukee, Wis.) to afford 40.3 mg (54%) of methyl 4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C11H11F3N2O3S3, 373.00 (M+H), found 373.0.

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 6, 160 g, 510 mmol), 3-bromo-1,1,1-trifluoroacetone (200 g, 1.02 mol) in acetonitrile (3 L) was heated at 80° C. for 20 h. The solution was then cooled down and concentrated. 2:1 Acetonitrile: methyl tert-butyl ether (2.4 L) was added, and the solution thus obtained was placed on a rotovap, and the volume of solvent was reduced by half. The precipitate that formed was filtered and dried in a vacuum oven at 40° C. After letting the filtrate sit, more solid precipitated out and an additional two crops of precipitate were collected and dried in the vacuum oven at 40° C. resulting in a combined collection of 202.4 g (92%) of 1-(5-bromo-4-(4-hydroxy-4-(trifluoromethyl)-4,5-dihydrothiazol-2-yl)pyridin-2-yl)-3-ethylurea as pale yellow solid. The solution was then cooled down concentrated 2:1 Acetonitrile: methyl tert-butyl ether (2.4 L) was added the solution thus obtained The precipitate that formed was filtered dried in a vacuum oven at 40° C more solid precipitated out an additional two crops of precipitate were collected dried in the vacuum oven at 40° C.

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 6, 160 g, 510 mmol), 3-bromo-1,1,1-trifluoroacetone (200 g, 1.02 mol) in acetonitrile (3 L) was heated at 80° C. for 20 h. The solution was then cooled down and concentrated. 2:1 Acetonitrile: methyl tert-butyl ether (2.4 L) was added, and the solution thus obtained was placed on a rotovap, and the volume of solvent was reduced by half. The precipitate that formed was filtered and dried in a vacuum oven at 40° C. After letting the filtrate sit, more solid precipitated out and an additional two crops of precipitate were collected and dried in the vacuum oven at 40° C. resulting in a combined collection of 202.4 g (92%) of 1-(5-bromo-4-(4-hydroxy-4-(trifluoromethyl)-4,5-dihydrothiazol-2-yl)pyridin-2-yl)-3-ethylurea as pale yellow solid. The solution was then cooled down concentrated 2:1 Acetonitrile: methyl tert-butyl ether (2.4 L) was added the solution thus obtained The precipitate that formed was filtered dried in a vacuum oven at 40° C more solid precipitated out an additional two crops of precipitate were collected dried in the vacuum oven at 40° C.

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of 5-bromo-N-(2,5-dichloro-phenyl)-thiophene-2-carboxamidine (634 mg, 1.8 mmol) and sodium bicarbonate (227 mg, 2.7 mmol) in 8 mL 2-proponal was added 3-bromo-1,1,1-trifluoroacetone (520 mg, 2.7 mmol). The reaction mixture was heated at 50° C. for 1.5 hrs, then at 80° C. for 4 hrs. After cooling to room temperature, the residue was filtered out and washed with dichloromethane. The filtrate and washings were combined together and concentrated under vacuum to give a light pink solid that was used directly for the next step (820 mg, 99% yield). 1H-NMR (400 MHz, DMSO-d6): δ 3.09 (d, 1H), 3.95 (dd, 1H), 6.31 (d, 1H), 6.91 (d, 1H), 7.15 (m, 1H), 7.33 (dd, 1H), 7.44 (m, 2H). After cooling to room temperature the residue was filtered out washed with dichloromethane concentrated under vacuum to give a light pink solid that