2-(bromomethyl)-5-chlorobenzonitrile

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

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

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

Procedure: DIEA (3.57 mL, 20.50 mmol) was added to a stirred mixture of 3-hydroxyazetidine hydrochloride (1.00 g, 9.11 mmol) and 2-bromomethyl-5-chlorobenzonitrile (2.10 g, 9.11 mmol) in CH2Cl2 (75 mL). After 16 h the reaction mixture was concentrated and the residue was partitioned between ether and 1N HCl. The aqueous layer was washed with ether, made neutral with NaHCO3, saturated with NaCl and extracted into CH2Cl2. The organic layer was dried (Na2SO4) and evaporated to give 5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzonitrile (1.67 g) as a gum: 1H NMR (CDCl3, 400 MHz) δ 3.03 (m, 2H), 3.68 (m, 2H), 4.49 (t, J=6.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.53 (d,d, J=2.2, 6.2 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H). After 16 h the reaction mixture was concentrated the residue was partitioned between ether and 1N HCl The aqueous layer was washed with ether extracted into CH2Cl2 The organic layer was dried (Na2SO4) evaporated

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

Procedure: DIEA (0.196 mL, 1.12 mmol) was added to a stirred mixture of 3,3-difluoroazetidine hydrochloride (64.8 mg, 0.50 mmol) and 2-bromomethyl-5-chlorobenzonitrile (121.0 mg, 0.52 mmol) in CH2Cl2 (7 mL). After 16 h the reaction was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was partitioned between 1N HCl and ether. The aqueous layer was made neutral with NaHCO3 and was extracted with CH2Cl2. The organic layer was dried with Na2SO4 and then evaporated to give 5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzonitrile (67.8 mg) as a glass: 1H NMR (CDCl3, 400 MHz) δ 3.68 (t, J=11.9 Hz. 4H), 3.93 (s, 2H), 7.54 (m, 2H), 7.63 (d, J=2.2 Hz, 1H). After 16 h the reaction was partitioned between EtOAc and water The organic layer was washed with water and brine dried (Na2SO4) evaporated The residue was partitioned between 1N HCl and ether was extracted with CH2Cl2 The organic layer was dried with Na2SO4 evaporated

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

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

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

Procedure: To a solution of 2-amino-5-chloronicotinamide (0.16 g) in N,N-dimethylformamide (3 ml) was added 2-(bromomethyl)-5-chlorobenzonitrile (0.32 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:2-4:1). 2N Hydrochloric acid-methanol solution (1 ml) was added to the obtained yellow oil at room temperature, and the obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (3 mg). The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:2-4:1) 2N Hydrochloric acid-methanol solution (1 ml) was added to the obtained yellow oil at room temperature the obtained precipitate was recrystallized from methanol-ethyl acetate

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

Procedure: The specific operation referred to the step (5) described in Example 1 for details. 347 mg (R)-1-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)piperidin-3-yl carbamic acid ter.-butyl ester (1 mmol) and 251 mg 2-(bromomethyl)-5-chlorobenzonitrile (1.1 mmol) were charged. A column chromatography was performed to afford 300 mg titled product with a yield of 60.5%.

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

Procedure: DIEA (3.57 mL, 20.50 mmol) was added to a stirred mixture of 3-hydroxyazetidine hydrochloride (1.00 g, 9.11 mmol) and 2-bromomethyl-5-chlorobenzonitrile (2.10 g, 9.11 mmol) in CH2Cl2 (75 mL). After 16 h the reaction mixture was concentrated and the residue was partitioned between ether and 1N HCl. The aqueous layer was washed with ether, made neutral with NaHCO3, saturated with NaCl and extracted into CH2Cl2. The organic layer was dried (Na2SO4) and evaporated to give 5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzonitrile (1.67 g) as a gum: 1H NMR (CDCl3, 400 MHz) δ 3.03 (m, 2H), 3.68 (m, 2H), 4.49 (t, J=6.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.53 (d,d, J=2.2, 6.2 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H). After 16 h the reaction mixture was concentrated the residue was partitioned between ether and 1N HCl The aqueous layer was washed with ether extracted into CH2Cl2 The organic layer was dried (Na2SO4) evaporated

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

Procedure: DIEA (0.196 mL, 1.12 mmol) was added to a stirred mixture of 3,3-difluoroazetidine hydrochloride (64.8 mg, 0.50 mmol) and 2-bromomethyl-5-chlorobenzonitrile (121.0 mg, 0.52 mmol) in CH2Cl2 (7 mL). After 16 h the reaction was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was partitioned between 1N HCl and ether. The aqueous layer was made neutral with NaHCO3 and was extracted with CH2Cl2. The organic layer was dried with Na2SO4 and then evaporated to give 5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzonitrile (67.8 mg) as a glass: 1H NMR (CDCl3, 400 MHz) δ 3.68 (t, J=11.9 Hz. 4H), 3.93 (s, 2H), 7.54 (m, 2H), 7.63 (d, J=2.2 Hz, 1H). After 16 h the reaction was partitioned between EtOAc and water The organic layer was washed with water and brine dried (Na2SO4) evaporated The residue was partitioned between 1N HCl and ether was extracted with CH2Cl2 The organic layer was dried with Na2SO4 evaporated

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