3-bromo-2,2-dimethylpropanoic acid

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

実験手順: 3-Bromo-2,2-dimethylpropanoic acid (200 mg) was dissolved in EtOH (5 ml) and treated with concentrated H2SO4 (0.4 ml). This mixture was heated at reflux overnight then evaporated. The residue was extracted from H2O with EtOAc (×2) and the combined organic solutions dried and evaporated to give the title compound (316 mg) as a clear oil. δH (CDCl3, 400 MHz) 1.20 (3H, t), 1.32 (6H, s), 3.51 (2H, s), 4.18 (2H, q). This mixture was heated at reflux overnight then evaporated The residue was extracted from H2O with EtOAc (×2) the combined organic solutions dried evaporated

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

実験手順: 3-Bromo-2,2-dimethylpropionic acid (5.03 g, 27.8 mmol) was dissolved in DCM (60 mL). Oxalyl chloride (3.64 mL, 41.67 mmol) was added slowly over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was dissolved in DCM (40 mL) and added to a solution of 4-fluorophenyl-piperazine (5.00 g, 27.8 mmol) and DIPEA (7.24 mL, 41.67 mmol) in DCM (30 mL) at 0° C. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred at room temperature for 16 hours. The reaction mixture was washed with 10% citric acid solution (2×100 mL), dried (MgSO4) and concentrated in vacuo to give 3-bromo-1-(4-fluorophenyl)piperazine-2,2-dimethylpropan-1-one (8.04 g, 84%) as a yellow solid which was used without further purification. concentrated in vacuo The residue was dissolved in DCM (40 mL) to warm to room temperature over 1 hour stirred at room temperature for 16 hours The reaction mixture was washed with 10% citric acid solution (2×100 mL) dried (MgSO4) concentrated in vacuo

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

実験手順: 3-Bromo-2,2-dimethylpropionic acid (10.0 g, 55.3 mmol) was dissolved in DCM (60 mL). Oxalyl chloride (7.20 mL, 82.9 mmol) was added slowly over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was dissolved in DCM (40 mL) and added to a solution of 4-methylphenyl-piperazine dihydrochloride (13.76 g, 55.3 mmol) and DIPEA (33.0 mL, 193.4 mmol) in DCM (100 mL) at 0° C. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred at room temperature for 16 hours. The reaction mixture was washed with 10% citric acid solution (2×100 mL), dried (MgSO4) and concentrated in vacuo to give 3-bromo-1-(4-methylphenyl)piperazine-2,2-dimethylpropan-1-one (9.62 g, 52%) as a white solid which was used without further purification. concentrated in vacuo The residue was dissolved in DCM (40 mL) to warm to room temperature over 1 hour stirred at room temperature for 16 hours The reaction mixture was washed with 10% citric acid solution (2×100 mL) dried (MgSO4) concentrated in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Bromo-2,2-dimethylpropionic acid (1.50 g, 8.29 mmol) was dissolved in thionyl chloride (10 mL) and DMF (0.1 mL). The reaction mixture was heated at reflux for 1.5 hours and then concentrated in vacuo, The residue was dissolved in DCM (10 mL) and added to a solution of 4-chlorophenyl piperazine dihydrochloride (2.35 g, 8.70 mmol) and DIPEA (5.05 mL, 29.0 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and then concentrated in vacuo. The residue was dissolved in DCM (100 mL) and washed with 10% citric acid solution (50 mL), sat aq NaHCO3 solution (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was purified using normal phase column chromatography (eluting with heptane, followed by a 1:1 mixture of EtOAc:heptane) to give 3-bromo-1-(4-chlorophenyl)piperazine-2,2-dimethyl-propan-1-one (0.87 g, 29.3%) as a yellow solid. The reaction mixture was heated at reflux for 1.5 hours concentrated in vacuo The residue was dissolved in DCM (10 mL) concentrated in vacuo The residue was dissolved in DCM (100 mL) washed with 10% citric acid solution (50 mL) dried (MgSO4) concentrated in vacuo The resulting residue was purified eluting with heptane followed by a 1:1 mixture of EtOAc

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

実験手順: 5-thiocyanato-thiazol-2-ylamine (15.7 g) was dissolved in degassed methanol and sodium borohydride (4.5 g) in MeOH was added in one portion. The reaction was stirred for 30 min and 3-bromo-2,2-dimethyl-propionic acid (27 g) (prepared in the same manner as described by Greene at al, J Am Chem Soc 1955, 77, 3016) and diisopropylethylamine (17 mL) was added and the reaction stirred overnight at room temperature. The reaction was diluted with water, partially concentrated in vacuo and 5% citric acid was added until pH 4. The brown precipitate was filtered, washed with water and acetonitrile, and dried over night at room temperature to give 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid as light brown crystals. was added the reaction stirred overnight at room temperature partially concentrated in vacuo and 5% citric acid was added until pH 4 The brown precipitate was filtered washed with water and acetonitrile dried over night at room temperature

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

実験手順: At room temperature under shielded light, to N,N′-diisopropylcarbodiimide (99.75 g) was added copper(I) chloride (1.57 g), and then tert-butanol (83 ml) was added dropwise over 20 minutes, followed by stirring for 4 days. The supernatant (78 ml) was added dropwise to a dichloromethane suspension (270 ml) of 3-bromo-2,2-dimethylpropanoic acid (49.4 g) at room temperature over 30 minutes, followed by stirring for 18 hours. Acetic acid (18.8 ml) was added, and stirred for 1 hour. The reaction suspension was filtered, and ice water and sodium hydrogen carbonate were added to the filtrate for neutralization. After the precipitate was filtered off, the organic layer separated from the filtrate was washed with saturated sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After pentane was added to the residue, insolubles were filtered off, and the filtrate was concentrated under reduced pressure to afford tert-butyl 3-bromo-2,2-dimethylpropanoic acid (18.81 g). by stirring for 18 hours stirred for 1 hour The reaction suspension was filtered ice water and sodium hydrogen carbonate were added to the filtrate for neutralization After the precipitate was filtered off the organic layer separated from the filtrate was washed with saturated sodium hydrogen carbonate dried over anhydrous sodium sulfate concentrated under reduced pressure After pentane was added to the residue, insolubles were filtered off the filtrate was concentrated under reduced pressure

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

実験手順: Bromopivalic acid (Example 10(a)) (59.4 g, 328 mmol) was reacted with 2-aminothiophenol (41 g, 328 mmol, freshly distilled) according to the procedure for Example 1(d). Column chromatography yielded the title compound (52.3 g, 232 mmol, 71%). 1H NMR (DMSO-d6) δ 12.44 (br s, 1H); 7.22 (d, 1H); 6.99 (t, 1H); 6.63 (d, 1H); 6.47 (t, 1H); 5.27 (br s, 2H); 2.88 (s, 2H); 1.14 (s, 6H). MS Da/e=226 (MH+), 208 (M-H2O), 180 (M-CO2). Calcd for C11H15NSO2 : C, 58.64; H, 6.71; N, 6.22; S, 14.23. Found: C, 58.41; H, 6.78; N, 6.13; S, 14.29. freshly distilled)

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

実験手順: Bromopivalic acid (Example 10(a)) (59.4 g, 328 mmol) was reacted with 2-aminothiophenol (41 g, 328 mmol, freshly distilled) according to the procedure for Example 1(d). Column chromatography yielded the title compound (52.3 g, 232 mmol, 71%). 1H NMR (DMSO-d6) δ 12.44 (br s, 1H); 7.22 (d, 1H); 6.99 (t, 1H); 6.63 (d, 1H); 6.47 (t, 1H); 5.27 (br s, 2H); 2.88 (s, 2H); 1.14 (s, 6H). MS Da/e=226 (MH+), 208 (M-H2O), 180 (M-CO2). Calcd for C11H15NSO2 : C, 58.64; H, 6.71; N, 6.22; S, 14.23. Found: C, 58.41; H, 6.78; N, 6.13; S, 14.29. freshly distilled)

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

実験手順: 3-Bromo-2,2-dimethylpropanoic acid (200 mg) was dissolved in EtOH (5 ml) and treated with concentrated H2SO4 (0.4 ml). This mixture was heated at reflux overnight then evaporated. The residue was extracted from H2O with EtOAc (×2) and the combined organic solutions dried and evaporated to give the title compound (316 mg) as a clear oil. δH (CDCl3, 400 MHz) 1.20 (3H, t), 1.32 (6H, s), 3.51 (2H, s), 4.18 (2H, q). This mixture was heated at reflux overnight then evaporated The residue was extracted from H2O with EtOAc (×2) the combined organic solutions dried evaporated

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

実験手順: 3-Bromo-2,2-dimethylpropionic acid (5.03 g, 27.8 mmol) was dissolved in DCM (60 mL). Oxalyl chloride (3.64 mL, 41.67 mmol) was added slowly over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was dissolved in DCM (40 mL) and added to a solution of 4-fluorophenyl-piperazine (5.00 g, 27.8 mmol) and DIPEA (7.24 mL, 41.67 mmol) in DCM (30 mL) at 0° C. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred at room temperature for 16 hours. The reaction mixture was washed with 10% citric acid solution (2×100 mL), dried (MgSO4) and concentrated in vacuo to give 3-bromo-1-(4-fluorophenyl)piperazine-2,2-dimethylpropan-1-one (8.04 g, 84%) as a yellow solid which was used without further purification. concentrated in vacuo The residue was dissolved in DCM (40 mL) to warm to room temperature over 1 hour stirred at room temperature for 16 hours The reaction mixture was washed with 10% citric acid solution (2×100 mL) dried (MgSO4) concentrated in vacuo

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

実験手順: 3-Bromo-2,2-dimethylpropionic acid (10.0 g, 55.3 mmol) was dissolved in DCM (60 mL). Oxalyl chloride (7.20 mL, 82.9 mmol) was added slowly over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was dissolved in DCM (40 mL) and added to a solution of 4-methylphenyl-piperazine dihydrochloride (13.76 g, 55.3 mmol) and DIPEA (33.0 mL, 193.4 mmol) in DCM (100 mL) at 0° C. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred at room temperature for 16 hours. The reaction mixture was washed with 10% citric acid solution (2×100 mL), dried (MgSO4) and concentrated in vacuo to give 3-bromo-1-(4-methylphenyl)piperazine-2,2-dimethylpropan-1-one (9.62 g, 52%) as a white solid which was used without further purification. concentrated in vacuo The residue was dissolved in DCM (40 mL) to warm to room temperature over 1 hour stirred at room temperature for 16 hours The reaction mixture was washed with 10% citric acid solution (2×100 mL) dried (MgSO4) concentrated in vacuo

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

実験手順: 3-Bromo-2,2-dimethylpropionic acid (10.0 g, 55.3 mmol) was dissolved in DCM (60 mL). Oxalyl chloride (7.20 mL, 82.9 mmol) was added slowly over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was dissolved in DCM (40 mL) and added to a solution of 4-methylphenyl-piperazine dihydrochloride (13.76 g, 55.3 mmol) and DIPEA (33.0 mL, 193.4 mmol) in DCM (100 mL) at 0° C. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred at room temperature for 16 hours. The reaction mixture was washed with 10% citric acid solution (2×100 mL), dried (MgSO4) and concentrated in vacuo to give 3-bromo-1-(4-methylphenyl)piperazine-2,2-dimethylpropan-1-one (9.62 g, 52%) as a white solid which was used without further purification. concentrated in vacuo The residue was dissolved in DCM (40 mL) to warm to room temperature over 1 hour stirred at room temperature for 16 hours The reaction mixture was washed with 10% citric acid solution (2×100 mL) dried (MgSO4) concentrated in vacuo