2-bromo-2,2-difluoroacetyl chloride

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

Procedure: Bromodifluoroacetyl chloride (0.800 g, 4.1 mmol) was added dropwise to a cooled (0° C.) solution of 4-(2-Iodophenylamino)piperidine-1-carboxylic acid tert-butyl ester (1.500 g, 3.7 mmol) and triethylamine (1.0 mL, 7.1 mmol) in dichloromethane (20 mL). The cooling bath was removed 30 minutes after the addition of all reagents. The reaction mixture was stirred at ambient temperature for 1 hour, then diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4 and concentrated. Purification of the residue by flash chromatography to afford 4-[(2-bromo-2,2-difluoroacetyl)-(2-iodophenyl)amino]piperidine-1-carboxylic acid tert-butyl ester (1.730 g, 83%). 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, J=1.2 and 7.8 Hz, 1H), 7.41-7.06 (m, 3H), 4.45-4.37 (m, 1H), 4.17-4.03 (m, 2H), 2.81-2.64 (m, 2H), 2.18-2.12 (m, 1H), 1.89-1.84 (m, 1H), 1.59-1.52 (m, 1H), 1.40 (s, 9H), 1.25-0.98 (m, 1H). The cooling bath was removed 30 minutes after the addition of all reagents diluted with ethyl acetate washed with water and brine dried over anhydrous Na2SO4 concentrated Purification of the residue by flash chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 200 mL, three-necked flask was charged with 4.76 g (31.8 mmol, 1.11 equivalents) of 1-adamantane methanol and 55 g of diethyl ether, followed by stirring to obtain a suspension. Then, 6.15 g (28.6 mmol, 1.0 equivalent) of bromodifluoroacetic chloride were added thereto. The resulting suspension was cooled down to 0° C. by using an iced bath, followed by adding 5.78 g (57.2 mmol, 2.0 equivalents) of triethylamine in a slow dropwise manner. This reaction liquid was allowed to stand with stirring to reach room temperature, followed by stirring at room temperature for 1 hour. Then, 50 g of water were added to wash the reaction liquid. The resulting organic layer was washed with 50 g of saturated sodium hydrogencarbonate, 50 g of saturated brine, and 50 g of water in sequence. Then, it was dried with magnesium sulfate, followed by distilling the solvent off, thereby obtaining 8.78 g of the target adamantane-1-ylmethyl bromodifluoroacetate (yield: 95%, purity: 100%). to obtain a suspension This reaction liquid with stirring to reach room temperature by stirring at room temperature for 1 hour to wash the reaction liquid The resulting organic layer was washed with 50 g of saturated sodium hydrogencarbonate, 50 g of saturated brine, and 50 g of water in sequence Then, it was dried with magnesium sulfate by distilling the solvent off,

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 200 mL, three-necked flask was charged with 4.76 g (31.8 mmol, 1.11 equivalents) of 1-adamantane methanol and 55 g of diethyl ether, followed by stirring to obtain a suspension. Then, 6.15 g (28.6 mmol, 1.0 equivalent) of bromodifluoroacetic chloride were added thereto. The resulting suspension was cooled down to 0° C. by using an iced bath, followed by adding 5.78 g (57.2 mmol, 2.0 equivalents) of triethylamine in a slow dropwise manner. This reaction liquid was allowed to stand with stirring to reach room temperature, followed by stirring at room temperature for 1 hour. Then, 50 g of water were added to wash the reaction liquid. The resulting organic layer was washed with 50 g of saturated sodium hydrogencarbonate, 50 g of saturated brine, and 50 g of water in sequence. Then, it was dried with magnesium sulfate, followed by distilling the solvent off, thereby obtaining 8.78 g of the target adamantane-1-ylmethyl bromodifluoroacetate (yield: 95%, purity: 100%). to obtain a suspension This reaction liquid with stirring to reach room temperature by stirring at room temperature for 1 hour to wash the reaction liquid The resulting organic layer was washed with 50 g of saturated sodium hydrogencarbonate, 50 g of saturated brine, and 50 g of water in sequence Then, it was dried with magnesium sulfate by distilling the solvent off,

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 200 mL, three-necked flask was charged with 4.76 g (31.8 mmol, 1.11 equivalents) of 1-adamantane methanol and 55 g of diethyl ether, followed by stirring to obtain a suspension. Then, 6.15 g (28.6 mmol, 1.0 equivalent) of bromodifluoroacetic chloride were added thereto. The resulting suspension was cooled down to 0° C. by using an iced bath, followed by adding 5.78 g (57.2 mmol, 2.0 equivalents) of triethylamine in a slow dropwise manner. This reaction liquid was allowed to stand with stirring to reach room temperature, followed by stirring at room temperature for 1 hour. Then, 50 g of water were added to wash the reaction liquid. The resulting organic layer was washed with 50 g of saturated sodium hydrogencarbonate, 50 g of saturated brine, and 50 g of water in sequence. Then, it was dried with magnesium sulfate, followed by distilling the solvent off, thereby obtaining 8.78 g of the target adamantane-1-ylmethyl bromodifluoroacetate (yield: 95%, purity: 100%). to obtain a suspension This reaction liquid with stirring to reach room temperature by stirring at room temperature for 1 hour to wash the reaction liquid The resulting organic layer was washed with 50 g of saturated sodium hydrogencarbonate, 50 g of saturated brine, and 50 g of water in sequence Then, it was dried with magnesium sulfate by distilling the solvent off,

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 50-L reaction vessel, 476 g (3.18 mol, 1.11 eq) of 1-adamantanemethanol and 5.5 kg of diethyl ether were added. The resulting solution was suspended by stirring, followed by adding thereto 615 g (2.86 mol, 1.0 eq) of bromodifluoroacetyl chloride. The suspended solution was cooled down to 0° C. Then, 578 g (5.72 mol, 2.0 eq) of triethylamine was slowly dropped to the cooled suspended solution. This reaction solution was left, while stirring, until it reached room temperature. The reaction solution was further stirred for 1 hour at room temperature. Subsequently, the reaction solution was washed with 5 kg of water. The thus-obtained organic layer was washed with 5 kg of saturated sodium hydrogencarbonate solution, with 5 kg of saturated sodium chloride solution, and then, with 5 kg of water. The washed organic layer was dried with magnesium sulfate and subjected to solvent distillation. With this, 878 g of target bromodifluoroacetic acid adamantane-1-ylmethyl ester was obtained (yield: 95%, purity: 100%). were added by adding This reaction solution was left while stirring, until it reached room temperature The reaction solution was further stirred for 1 hour at room temperature Subsequently, the reaction solution was washed with 5 kg of water The thus-obtained organic layer was washed with 5 kg of saturated sodium hydrogencarbonate solution, with 5 kg of saturated sodium chloride solution The washed organic layer was dried with magnesium sulfate subjected to solvent distillation

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

Procedure: Bromodifluoroacetyl chloride (0.800 g, 4.1 mmol) was added dropwise to a cooled (0° C.) solution of 4-(2-Iodophenylamino)piperidine-1-carboxylic acid tert-butyl ester (1.500 g, 3.7 mmol) and triethylamine (1.0 mL, 7.1 mmol) in dichloromethane (20 mL). The cooling bath was removed 30 minutes after the addition of all reagents. The reaction mixture was stirred at ambient temperature for 1 hour, then diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4 and concentrated. Purification of the residue by flash chromatography to afford 4-[(2-bromo-2,2-difluoroacetyl)-(2-iodophenyl)amino]piperidine-1-carboxylic acid tert-butyl ester (1.730 g, 83%). 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, J=1.2 and 7.8 Hz, 1H), 7.41-7.06 (m, 3H), 4.45-4.37 (m, 1H), 4.17-4.03 (m, 2H), 2.81-2.64 (m, 2H), 2.18-2.12 (m, 1H), 1.89-1.84 (m, 1H), 1.59-1.52 (m, 1H), 1.40 (s, 9H), 1.25-0.98 (m, 1H). The cooling bath was removed 30 minutes after the addition of all reagents diluted with ethyl acetate washed with water and brine dried over anhydrous Na2SO4 concentrated Purification of the residue by flash chromatography