2,5-difluorobenzenecarbothioamide

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of ethyl 3-bromo-2-oxo-4-phenylbutanoate (13.8 g, 48.4 mmol) in MeOH (161 mL) was slowly added 2,5-difluorobenzothioamide (8.38 g, 48.4 mmol) at room temperature. The reaction mixture was then refluxed for overnight. After cooled down, white precipitate was filtered, washed by cold ethanol and dried. A mixture of methyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate and ethyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate (10.5 g, 61%) was obtained as white solid. LC/MS (uplc): MW 346.1, 1.21 min for methyl ester; 360.1, 1.27 min for ethyl ester. at room temperature The reaction mixture was then refluxed for overnight After cooled down white precipitate was filtered washed by cold ethanol dried A mixture of methyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate

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

Procedure: To a stirred solution of 2,5-difluorobenzothioamide (22.5 g, 129.7 mmol) in EtOH (150 mL) was added hydrazine (6.1 mL, 194.5 mmol). After stirring at room temperature for 30 min, reaction was complete by LC/MS and white solid precipitated. The precipitate was filtered and washed with Hexanes to afford 2,5-difluorobenzimidohydrazide (5.52 g, 94%). reaction precipitated The precipitate was filtered washed with Hexanes

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of 2,5-difluorobenzonitrile (25 g, 180 mmol) in pyridine (90 mL) was treated with 20 wt % ammonium sulfide in water (67.4 mL, 198 mmol) and triethylamine (27.4 mL, 198 mmol). The reaction mixture was stirred at 50° C. for 5 hr until the reaction was complete. After cooling to room temperature, the mixture was diluted with cold water and extracted with EtOAc. The organic layer was separated, then washed with H2O (×3), brine (×3), then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the crude product. Purification on silica gel column (20% EtOAc in hexanes) to afford 2,5-difluorobenzothioamide as yellow solid (31.0 g, 99%). 1H NMR (CDCl3, 300 MHz): δ 7.12 (m, 2H), 7.90 (br, 2H), 8.08 (m, 1H). LC/MS (uplc): MH+174.0, 0.64 min. After cooling to room temperature extracted with EtOAc The organic layer was separated washed with H2O (×3), brine (×3) dried over anhydrous Na2SO4 filtered evaporated under reduced pressure to give the crude product Purification on silica gel column (20% EtOAc in hexanes)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of 2,5-difluorobenzonitrile (25 g, 180 mmol) in pyridine (90 mL) was treated with 20 wt % ammonium sulfide in water (67.4 mL, 198 mmol) and triethylamine (27.4 mL, 198 mmol). The reaction mixture was stirred at 50° C. for 5 hr until the reaction was complete. After cooling to room temperature, the mixture was diluted with cold water and extracted with EtOAc. The organic layer was separated, then washed with H2O (×3), brine (×3), then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the crude product. Purification on silica gel column (20% EtOAc in hexanes) to afford 2,5-difluorobenzothioamide as yellow solid (31.0 g, 99%). 1H NMR (CDCl3, 300 MHz): δ 7.12 (m, 2H), 7.90 (br, 2H), 8.08 (m, 1H). LC/MS (uplc): MH+174.0, 0.64 min. After cooling to room temperature extracted with EtOAc The organic layer was separated washed with H2O (×3), brine (×3) dried over anhydrous Na2SO4 filtered evaporated under reduced pressure to give the crude product Purification on silica gel column (20% EtOAc in hexanes)

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

Procedure: To a solution of ethyl 3-bromo-2-oxo-4-phenylbutanoate (13.8 g, 48.4 mmol) in MeOH (161 mL) was slowly added 2,5-difluorobenzothioamide (8.38 g, 48.4 mmol) at room temperature. The reaction mixture was then refluxed for overnight. After cooled down, white precipitate was filtered, washed by cold ethanol and dried. A mixture of methyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate and ethyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate (10.5 g, 61%) was obtained as white solid. LC/MS (uplc): MW 346.1, 1.21 min for methyl ester; 360.1, 1.27 min for ethyl ester. at room temperature The reaction mixture was then refluxed for overnight After cooled down white precipitate was filtered washed by cold ethanol dried A mixture of methyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.9 ml (94.2 mmol; 1.5 equivalents) of methyl iodide is added to 10.8 g (62 mmol) of 2,5-difluorobenzenecarbothioamide in solution in 70 ml of acetone. The reaction mixture is maintained under stirring at 25° C. for 24 hours, then the solvent is evaporated off under reduced pressure. Methyl 2,5-difluorobenzene carbimidothioate hydroiodide is obtained (18.4 g; yield=93%), after crystallization from ethyl ether, in the form of beige powder. The reaction mixture is maintained the solvent is evaporated off under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 10 g (71.9 mmol) of 2,5-difluorobenzonitrile and 16.2 g (215.7 mmol; 3 equivalents) of thioacetamide are dissolved in 80 ml of dimethylformamide containing 10% hydrochloric acid. The reaction mixture is maintained under stirring at 100° C. for 48 hours. After returning to ambient temperature, the reaction mixture is poured onto ice and insoluble material is filtered out. The mother liquors are extracted with 3 times 80 ml of ethyl acetate and the organic phases are washed with twice 50 ml of water. The organic phases are combined, dried over sodium sulphate and the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane mixture 1:2) and 10.8 g (yield=87%) of 2,5-difluorobenzenecarbothioamide is obtained. The reaction mixture is maintained After returning to ambient temperature the reaction mixture is poured onto ice and insoluble material is filtered out The mother liquors are extracted with 3 times 80 ml of ethyl acetate the organic phases are washed with twice 50 ml of water dried over sodium sulphate the solvents are evaporated under reduced pressure The residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane mixture 1:2)

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

Procedure: To a stirred solution of 2,5-difluorobenzothioamide (22.5 g, 129.7 mmol) in EtOH (150 mL) was added hydrazine (6.1 mL, 194.5 mmol). After stirring at room temperature for 30 min, reaction was complete by LC/MS and white solid precipitated. The precipitate was filtered and washed with Hexanes to afford 2,5-difluorobenzimidohydrazide (5.52 g, 94%). reaction precipitated The precipitate was filtered washed with Hexanes

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of 2,5-difluorobenzonitrile (25 g, 180 mmol) in pyridine (90 mL) was treated with 20 wt % ammonium sulfide in water (67.4 mL, 198 mmol) and triethylamine (27.4 mL, 198 mmol). The reaction mixture was stirred at 50° C. for 5 hr until the reaction was complete. After cooling to room temperature, the mixture was diluted with cold water and extracted with EtOAc. The organic layer was separated, then washed with H2O (×3), brine (×3), then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the crude product. Purification on silica gel column (20% EtOAc in hexanes) to afford 2,5-difluorobenzothioamide as yellow solid (31.0 g, 99%). 1H NMR (CDCl3, 300 MHz): δ 7.12 (m, 2H), 7.90 (br, 2H), 8.08 (m, 1H). LC/MS (uplc): MH+174.0, 0.64 min. After cooling to room temperature extracted with EtOAc The organic layer was separated washed with H2O (×3), brine (×3) dried over anhydrous Na2SO4 filtered evaporated under reduced pressure to give the crude product Purification on silica gel column (20% EtOAc in hexanes)

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

Procedure: To a solution of ethyl 3-bromo-2-oxo-4-phenylbutanoate (13.8 g, 48.4 mmol) in MeOH (161 mL) was slowly added 2,5-difluorobenzothioamide (8.38 g, 48.4 mmol) at room temperature. The reaction mixture was then refluxed for overnight. After cooled down, white precipitate was filtered, washed by cold ethanol and dried. A mixture of methyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate and ethyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate (10.5 g, 61%) was obtained as white solid. LC/MS (uplc): MW 346.1, 1.21 min for methyl ester; 360.1, 1.27 min for ethyl ester. at room temperature The reaction mixture was then refluxed for overnight After cooled down white precipitate was filtered washed by cold ethanol dried A mixture of methyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate