2-chloro-6-fluorobenzoyl chloride

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

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

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

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

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: Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.18 g, 0.85 mmol), 2-chloro-6-fluoro-benzoyl chloride (0.318 g, 1.65 mmol), and 1,4-dioxane (10 mL). Stir and heat the mixture at reflux. After 2 hr., cool the reaction mixture to ambient temperature and concentrate. Load the mixture onto an SCX column (10 g), wash with methanol, and elute with 2M ammonia/methanol. Concentrate the eluent to obtain the free base of the title compound (0.30 g, 94%) as an oil. Dissolve the oil in methanol (5 mL) and treat with ammonium chloride (0.045 g, 0.85 mmol). Concentrate the mixture and dry under vacuum to obtain the title compound. HRMS Obs. m/z 376.1237; Calc. m/z 376.1228; m.p. 155° C. (dec). heat the mixture at reflux concentrate Load the mixture onto an SCX column (10 g), wash with methanol elute with 2M ammonia/methanol Concentrate the eluent

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

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: Using a method similar to example 1, using 2-chloro-6-fluoro-benzoyl chloride (134 mg, 0.69 mmol) and 6-(4-dimethylamino-cyclohex-1-enyl)-pyridin-2-ylamine, isomer 2 (preparation 11, 100 mg, 0.46 mmol) provides the free amine of the title compound as an oil (82 mg, 48%): MS (ES): m/z=374 (M+H)+; 1H NMR (CD3OD): δ 8.15 (t, 1H), 7.57 (m, 3H), 7.34 (d, 1H), 7.20 (t, 1H), 6.71 (m, 1H), 3.52 (m, 1H), 2.86 (s, 6H), 2.69 (m, 4H), 2.35 (m, 1H), 1.87 (m, 1H). Using a salt formation method similar to that in example 1 gives the dihydrochloride salt.

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

Procedure: Using a method similar to example 1, using 2-chloro-6-fluoro-benzoyl chloride (116 mg, 0.60 mmol) and 6-(4-dimethylamino-cyclohex-1-enyl)-pyridin-2-ylamine, isomer 1 (preparation 10, 100 mg, 0.46 mmol) provides the free amine of the title compound as a colorless oil (78 mg, 45%): MS (ES): m/z=374.1 (M+H)+; 1H NMR (CDCl3): δ 9.03 (s, br, 1H), 8.26 (d, 1H), 7.73 (t, 1H), 7.30 (m, 1H), 7.19 (d, 1H), 7.09 (d, 1H), 6.98 (dt, 1H), 6.62 (m, 1H), 2.58 (m, 1H), 2.38 (m, 3H), 2.34 (s, 6H), 2.15 (m, 2H), 1.53 (m, 1H). Using a salt formation method similar to that in example 1 provides the di-hydrochloride salt.