4-[(2-methylpropan-2-yl)oxy]benzaldehyde

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

実験手順: In a manner analogous to Preparation 1, tosylmethylisocyanide (0.23 g, 1.20 mmol), 4-(tert-butoxy)benzaldehyde (0.23 g, 1.26 mmol) and NaCN (5.9 mg, 0.12 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 374.4 (M+H+).

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

実験手順: (S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}4-methyl-pentan-1-one (0.500 g, 1.25 mmol, Example 53) and 4-(tert-butoxy)benzaldehyde (0.229 mL, 1.25 mmol, Lancaster) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 25 minutes. The 2 layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. TLC (50% EtOAc in Hexanes as the eluant) showed two spots with Rf values 0.9 and 0.55. The solution was concentrated in vacuo affording a viscous oil. The lower spot on TLC (Rf=0.55) was isolated by flash chromatography (30% EtOAc in hexanes). Forty-four percent (0.311 g) of the pure titled compound was obtained as a white foam: mp 56-61° C. APCI-MS m/z 564.5 (MH+). the solution was cooled to 0° C. in an ice-water bath The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. 12 hours at ambient temperature the resulting mixture was stirred for 25 minutes The 2 layers were separated the aqueous layer was extracted with CH2Cl2 (2×20 mL) The combined organic solution was dried over Na2SO4 The solution was concentrated in vacuo affording a viscous oil

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

実験手順: (S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}4-methyl-pentan-1-one (0.500 g, 1.25 mmol, Example 53) and 4-(tert-butoxy)benzaldehyde (0.229 mL, 1.25 mmol, Lancaster) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 25 minutes. The 2 layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. TLC (50% EtOAc in Hexanes as the eluant) showed two spots with Rf values 0.9 and 0.55. The solution was concentrated in vacuo affording a viscous oil. The lower spot on TLC (Rf=0.55) was isolated by flash chromatography (30% EtOAc in hexanes). Forty-four percent (0.311 g) of the pure titled compound was obtained as a white foam: mp 56-61° C. APCI-MS m/z 564.5 (MH+). the solution was cooled to 0° C. in an ice-water bath The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. 12 hours at ambient temperature the resulting mixture was stirred for 25 minutes The 2 layers were separated the aqueous layer was extracted with CH2Cl2 (2×20 mL) The combined organic solution was dried over Na2SO4 The solution was concentrated in vacuo affording a viscous oil

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

実験手順: In a manner analogous to Preparation 1, tosylmethylisocyanide (0.23 g, 1.20 mmol), 4-(tert-butoxy)benzaldehyde (0.23 g, 1.26 mmol) and NaCN (5.9 mg, 0.12 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 374.4 (M+H+).

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

実験手順: 58 g (1 mole) of acetone and 36 g (0.2 mole) of p-tert.-butoxy-benzaldehyde are introduced into a 300 ml stirred autoclave, 5 g of zinc oxide and 1 g of 1% strength palladium on active charcoal are added and the mixture is heated to 160° C., with vigorous stirring, under 20 bar hydrogen pressure. After a reaction time of 2 hours, the reaction mixture is cooled, freed from catalyst by filtration, and subjected to fractional distillation. 19 g of 1-(4-tert.-butoxy-phenyl)-butan-3-one (yield: 43%) are obtained. are added After a reaction time of 2 hours, the reaction mixture is cooled freed from catalyst by filtration subjected to fractional distillation

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

実験手順: In a manner analogous to Preparation 1, tosylmethylisocyanide (0.23 g, 1.20 mmol), 4-(tert-butoxy)benzaldehyde (0.23 g, 1.26 mmol) and NaCN (5.9 mg, 0.12 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 374.4 (M+H+).

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

実験手順: Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-[(2-methylpropan-2-yl)oxy]benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-[(2-methylpropan-2-yl)oxy]phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine. The crude product was purified by hplc eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents

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

実験手順: 89 g (0.5 mole) of p-tert.-butoxy-benzaldehyde are added dropwise, in the course of 15 minutes, to a mixture of 290 g (5 moles) of acetone and 30 ml of 0.5% strength aqueous sodium hydroxide solution at 20°-25° C., whilst stirring. After all has been added, the pH must be not less than 10; if it is not, sodium hydroxide solution must then be added. The reaction is complete after about 5 hours, as is demonstrable by thin layer chromatography or gas chromatography. Acetic acid is then added to the solution until it is neutral, the excess acetone is distilled off under reduced pressure and the reaction product is taken up in ether. The ether solution is washed salt-free with water, the ether is distilled off and the reaction product is fractionated, giving 88 g of main fraction. This corresponds to a yield of 81% of theory. After all has been added the excess acetone is distilled off under reduced pressure The ether solution is washed salt-free with water the ether is distilled off giving 88 g of main fraction

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

実験手順: (S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}4-methyl-pentan-1-one (0.500 g, 1.25 mmol, Example 53) and 4-(tert-butoxy)benzaldehyde (0.229 mL, 1.25 mmol, Lancaster) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 25 minutes. The 2 layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. TLC (50% EtOAc in Hexanes as the eluant) showed two spots with Rf values 0.9 and 0.55. The solution was concentrated in vacuo affording a viscous oil. The lower spot on TLC (Rf=0.55) was isolated by flash chromatography (30% EtOAc in hexanes). Forty-four percent (0.311 g) of the pure titled compound was obtained as a white foam: mp 56-61° C. APCI-MS m/z 564.5 (MH+). the solution was cooled to 0° C. in an ice-water bath The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. 12 hours at ambient temperature the resulting mixture was stirred for 25 minutes The 2 layers were separated the aqueous layer was extracted with CH2Cl2 (2×20 mL) The combined organic solution was dried over Na2SO4 The solution was concentrated in vacuo affording a viscous oil

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

実験手順: In a manner analogous to Preparation 1, tosylmethylisocyanide (0.23 g, 1.20 mmol), 4-(tert-butoxy)benzaldehyde (0.23 g, 1.26 mmol) and NaCN (5.9 mg, 0.12 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 374.4 (M+H+).