2,6-difluorobenzenecarbothioamide

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

実験手順: A solution of 2,6-difluorobenzothioamide (1.0 eq) and ethylbromopyruvate (1.0 eq.) in ethanol (1.0 M) was heated in the microwave at 130° C. for 30 minutes. Upon removal of volatiles in vacuo, ethyl acetate was added and the solution was washed with Na2CO3(sat.), with NaCl(sat.), was dried over MgSO4, filtered and concentrated yielding ethyl 2-(2,6-difluorophenyl)thiazole-4-carboxylate (84%). LCMS (m/z): 270.1 (MH+); LC Rt=3.79 min. Upon removal of volatiles in vacuo, ethyl acetate was added the solution was washed with Na2CO3(sat.), with NaCl(sat.) was dried over MgSO4 filtered concentrated

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

実験手順: Into a 3 L three necked round bottom flask equipped with a mechanical stirrer, dry ice condenser, dropping funnel, and outlet to a trap filled with bleach was added pyridine (550 mL), 2,6-difluorobenzonitrile (208 g, 1.50 mol), triethylamine (202 g, 279 mL, 2.0 mol), and sodium sulfide hydrate (521 g, 2.17 mol-broken into pieces small enough to fit into the flask). The temperature of the stirred mixture was lowered to approximately 5° C. and to the slurry was added dropwise concentrated hydrochloric acid (143 g, 288 mL, 3.99 mol). An exotherm was noted and the rate of addition of the hydrochloric acid was such that the temperature of the reaction mixture did not exceed 25° C. for a total addition time of 75 min. The cooling bath was removed and the slurry was allowed to warm to RT and to stir over night. The mixture was poured into water (2 L) and was extracted with ether (3×500 mL). The ether layer was washed with dilute sulfuric acid, water, brine, dried (MgSO4), and the solvent removed in vacuo to give 232 grams of crude product. The starting material was removed from the product via kugelrohr distillation to give 197 g (76%) of 2,6-difluorobenzenethioamide. This material was used without further purification. filled with bleach was lowered to approximately 5° C. and to the slurry did not exceed 25° C. for a total addition time of 75 min The cooling bath was removed The mixture was poured into water (2 L) was extracted with ether (3×500 mL) The ether layer was washed with dilute sulfuric acid, water, brine dried (MgSO4) the solvent removed in vacuo to give 232 grams of crude product The starting material was removed from the product via kugelrohr distillation

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

実験手順: Into a 3 L three necked round bottom flask equipped with a mechanical stirrer, dry ice condenser, dropping funnel, and outlet to a trap filled with bleach was added pyridine (550 mL), 2,6-difluorobenzonitrile (208 g, 1.50 mol), triethylamine (202 g, 279 mL, 2.0 mol), and sodium sulfide hydrate (521 g, 2.17 mol-broken into pieces small enough to fit into the flask). The temperature of the stirred mixture was lowered to approximately 5° C. and to the slurry was added dropwise concentrated hydrochloric acid (143 g, 288 mL, 3.99 mol). An exotherm was noted and the rate of addition of the hydrochloric acid was such that the temperature of the reaction mixture did not exceed 25° C. for a total addition time of 75 min. The cooling bath was removed and the slurry was allowed to warm to RT and to stir over night. The mixture was poured into water (2 L) and was extracted with ether (3×500 mL). The ether layer was washed with dilute sulfuric acid, water, brine, dried (MgSO4), and the solvent removed in vacuo to give 232 grams of crude product. The starting material was removed from the product via kugelrohr distillation to give 197 g (76%) of 2,6-difluorobenzenethioamide. This material was used without further purification. filled with bleach was lowered to approximately 5° C. and to the slurry did not exceed 25° C. for a total addition time of 75 min The cooling bath was removed The mixture was poured into water (2 L) was extracted with ether (3×500 mL) The ether layer was washed with dilute sulfuric acid, water, brine dried (MgSO4) the solvent removed in vacuo to give 232 grams of crude product The starting material was removed from the product via kugelrohr distillation

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

実験手順: As illustrated in step a of Scheme III, 2,6-difluorobenzonitrile is reacted with triethylamine, sodium sulfide hydrate, and hydrochloric acid in pyridine at room temperature to give 2,6-difluorobenzenethioamide.

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

実験手順: A solution of 2,6-difluorobenzothioamide (1.0 eq) and ethylbromopyruvate (1.0 eq.) in ethanol (1.0 M) was heated in the microwave at 130° C. for 30 minutes. Upon removal of volatiles in vacuo, ethyl acetate was added and the solution was washed with Na2CO3(sat.), with NaCl(sat), was dried over MgSO4, filtered and concentrated yielding ethyl 2-(2,6-difluorophenyl)thiazole-4-carboxylate (84%). LCMS (m/z): 270.1 (MH+); LC Rt=3.79 min. Upon removal of volatiles in vacuo, ethyl acetate was added the solution was washed with Na2CO3(sat.), with NaCl(sat) was dried over MgSO4 filtered concentrated

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

実験手順: To a solution of the compound prepared in Example 344 (50 g) in ethanol (250 mL) was added ethyl 2-chloroacetoacetate (42 mL) at room temperature. The mixture was heated to reflux for 12 hours, cooled and concentrated. The residue was stirred with hexane (250 mL) for 30 minutes, filtered and then washed with hexane (50 mL). The solid was dried to obtain the title compound (48.6 g) having the following physical data. The mixture was heated to reflux for 12 hours cooled concentrated filtered washed with hexane (50 mL) The solid was dried

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

実験手順: Into a 3 L three necked round bottom flask equipped with a mechanical stirrer, dry ice condenser, dropping funnel, and outlet to a trap filled with bleach was added pyridine (550 mL), 2,6-difluorobenzonitrile (208 g, 1.50 mol), triethylamine (202 g, 279 mL, 2.0 mol), and sodium sulfide hydrate (521 g, 2.17 mol-broken into pieces small enough to fit into the flask). The temperature of the stirred mixture was lowered to approximately 5° C. and to the slurry was added dropwise concentrated hydrochloric acid (143 g, 288 mL, 3.99 mol). An exotherm was noted and the rate of addition of the hydrochloric acid was such that the temperature of the reaction mixture did not exceed 25° C. for a total addition time of 75 min. The cooling bath was removed and the slurry was allowed to warm to RT and to stir over night. The mixture was poured into water (2 L) and was extracted with ether (3×500 mL). The ether layer was washed with dilute sulfuric acid, water, brine, dried (MgSO4), and the solvent removed in vacuo to give 232 grams of crude product. The starting material was removed from the product via kugelrohr distillation to give 197 g (76%) of 2,6-difluorobenzenethioamide. This material was used without further purification. filled with bleach was lowered to approximately 5° C. and to the slurry did not exceed 25° C. for a total addition time of 75 min The cooling bath was removed The mixture was poured into water (2 L) was extracted with ether (3×500 mL) The ether layer was washed with dilute sulfuric acid, water, brine dried (MgSO4) the solvent removed in vacuo to give 232 grams of crude product The starting material was removed from the product via kugelrohr distillation

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

実験手順: Into a 3 L three necked round bottom flask equipped with a mechanical stirrer, dry ice condenser, dropping funnel, and outlet to a trap filled with bleach was added pyridine (550 mL), 2,6-difluorobenzonitrile (208 g, 1.50 mol), triethylamine (202 g, 279 mL, 2.0 mol), and sodium sulfide hydrate (521 g, 2.17 mol-broken into pieces small enough to fit into the flask). The temperature of the stirred mixture was lowered to approximately 5° C. and to the slurry was added dropwise concentrated hydrochloric acid (143 g, 288 mL, 3.99 mol). An exotherm was noted and the rate of addition of the hydrochloric acid was such that the temperature of the reaction mixture did not exceed 25° C. for a total addition time of 75 min. The cooling bath was removed and the slurry was allowed to warm to RT and to stir over night. The mixture was poured into water (2 L) and was extracted with ether (3×500 mL). The ether layer was washed with dilute sulfuric acid, water, brine, dried (MgSO4), and the solvent removed in vacuo to give 232 grams of crude product. The starting material was removed from the product via kugelrohr distillation to give 197 g (76%) of 2,6-difluorobenzenethioamide. This material was used without further purification. filled with bleach was lowered to approximately 5° C. and to the slurry did not exceed 25° C. for a total addition time of 75 min The cooling bath was removed The mixture was poured into water (2 L) was extracted with ether (3×500 mL) The ether layer was washed with dilute sulfuric acid, water, brine dried (MgSO4) the solvent removed in vacuo to give 232 grams of crude product The starting material was removed from the product via kugelrohr distillation

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

実験手順: Into a 3 L three necked round bottom flask equipped with a mechanical stirrer, dry ice condenser, dropping funnel, and outlet to a trap filled with bleach was added pyridine (550 mL), 2,6-difluorobenzonitrile (208 g, 1.50 mol), triethylamine (202 g, 279 mL, 2.0 mol), and sodium sulfide hydrate (521 g, 2.17 mol, broken into pieces small enough to fit into the flask). The temperature of the stirred mixture was lowered to approximately 5° C. and to the slurry was added dropwise concentrated hydrochloric acid (143 g, 288 mL, 3.99 mol). An exotherm was noted and the rate of addition of the hydrochloric acid was such that the temperature of the reaction mixture did not exceed 25° C. for a total addition time of 75 min. The cooling bath was removed and the slurry was allowed to warm to RT and to stir over night. The mixture was poured into water (2 L) and was extracted with ether (3×500 mL). The ether layer was washed with dilute sulfuric acid, water, brine, dried (MgSO4), and the solvent removed in vacuo to give 232 grams of crude product. The starting material was removed from the product via bulb-to bulb distillation to give 197 g (76%) of 2,6-difluorobenzenethioamide. This material was used without further purification. filled with bleach was lowered to approximately 5° C. and to the slurry did not exceed 25° C. for a total addition time of 75 min The cooling bath was removed The mixture was poured into water (2 L) was extracted with ether (3×500 mL) The ether layer was washed with dilute sulfuric acid, water, brine dried (MgSO4) the solvent removed in vacuo to give 232 grams of crude product The starting material was removed from the product via bulb-to bulb distillation

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

実験手順: Into a 3 L three necked round bottom flask equipped with a mechanical stirrer, dry ice condenser, dropping funnel, and outlet to a trap filled with bleach was added pyridine (550 mL), 2,6-difluorobenzonitrile (208 g, 1.50 mol), triethylamine (202 g, 279 mL, 2.0 mol), and sodium sulfide hydrate (521 g, 2.17 mol, broken into pieces small enough to fit into the flask). The temperature of the stirred mixture was lowered to approximately 5° C. and to the slurry was added dropwise concentrated hydrochloric acid (143 g, 288 mL, 3.99 mol). An exotherm was noted and the rate of addition of the hydrochloric acid was such that the temperature of the reaction mixture did not exceed 25° C. for a total addition time of 75 min. The cooling bath was removed and the slurry was allowed to warm to RT and to stir over night. The mixture was poured into water (2 L) and was extracted with ether (3×500 mL). The ether layer was washed with dilute sulfuric acid, water, brine, dried (MgSO4), and the solvent removed in vacuo to give 232 grams of crude product. The starting material was removed from the product via bulb-to bulb distillation to give 197 g (76%) of 2,6-difluorobenzenethioamide. This material was used without further purification. filled with bleach was lowered to approximately 5° C. and to the slurry did not exceed 25° C. for a total addition time of 75 min The cooling bath was removed The mixture was poured into water (2 L) was extracted with ether (3×500 mL) The ether layer was washed with dilute sulfuric acid, water, brine dried (MgSO4) the solvent removed in vacuo to give 232 grams of crude product The starting material was removed from the product via bulb-to bulb distillation

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

実験手順: Into a 3 L three necked round bottom flask equipped with a mechanical stirrer, dry ice condenser, dropping funnel, and outlet to a trap filled with bleach was added pyridine (550 mL), 2,6-difluorobenzonitrile (208 g, 1.50 mol), triethylamine (202 g, 279 mL, 2.0 mol), and sodium sulfide hydrate (521 g, 2.17 mol, broken into pieces small enough to fit into the flask). The temperature of the stirred mixture was lowered to approximately 5° C. and to the slurry was added dropwise concentrated hydrochloric acid (143 g, 288 mL, 3.99 mol). An exotherm was noted and the rate of addition of the hydrochloric acid was such that the temperature of the reaction mixture did not exceed 25° C. for a total addition time of 75 min. The cooling bath was removed and the slurry was allowed to warm to RT and to stir over night. The mixture was poured into water (2 L) and was extracted with ether (3×500 mL). The ether layer was washed with dilute sulfuric acid, water, brine, dried (MgSO4), and the solvent removed in vacuo to give 232 grams of crude product. The starting material was removed from the product via bulb-to bulb distillation to give 197 g (76%) of 2,6-difluorobenzenethioamide. This material was used without further purification. filled with bleach was lowered to approximately 5° C. and to the slurry did not exceed 25° C. for a total addition time of 75 min The cooling bath was removed The mixture was poured into water (2 L) was extracted with ether (3×500 mL) The ether layer was washed with dilute sulfuric acid, water, brine dried (MgSO4) the solvent removed in vacuo to give 232 grams of crude product The starting material was removed from the product via bulb-to bulb distillation

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

実験手順: A solution of 2,6-difluorobenzothioamide (1.0 eq) and ethylbromopyruvate (1.0 eq.) in ethanol (1.0 M) was heated in the microwave at 130° C. for 30 minutes. Upon removal of volatiles in vacuo, ethyl acetate was added and the solution was washed with Na2CO3(sat.), with NaCl(sat.), was dried over MgSO4, filtered and concentrated yielding ethyl 2-(2,6-difluorophenyl)thiazole-4-carboxylate (84%). LCMS (m/z): 270.1 (MH+); LC Rt=3.79 min. Upon removal of volatiles in vacuo, ethyl acetate was added the solution was washed with Na2CO3(sat.), with NaCl(sat.) was dried over MgSO4 filtered concentrated