3-chloro-1-(4-fluorophenyl)propan-1-one

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: A solution of 3-chloro-1-(4-fluorophenyl)-propan-1-one (18.6 g, 0.1 mol) in THF (50 mL) was added to a well-stirred suspension of zinc power (13 g, 0.2 mol) in a mixture of aqueous saturated NH4Cl solution (260 mL) and THF (65 mL). A solution of 3-iodo-2-methylprop-1-ene (36.4 g, 0.2 mol) in THF (50 mL) was added dropwise. The reaction mixture was mildly exothermic, and began to reflux spontaneously. After the refluxing had ceased, the mixture was stirred for 1 h. TLC showed the 3-chloro-1-(4-fluorophenyl)propan-1-one not reacted completely. A solution of 3-iodo-2-methylprop-1-ene (18.2 g, 0.1 mol) in THF (30 mL) was added, and the mixture was stirred at rt overnight. The mixture was extracted with EtOAc (2×500 mL). The combined organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc 50:1→30:1→5:1, to give 1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (17 g, yield 76%) as an oil. to reflux spontaneously reacted completely the mixture was stirred at rt overnight The mixture was extracted with EtOAc (2×500 mL) The combined organic layer was dried concentrated The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc 50:1→30:1→5:1

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

Procedure: A 250-mL flask was charged with anhydrous CeCl3 (5.58 g, 22.6 mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C. and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8° C. while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 tR=1.79 min, m/z 213, 211 (M-OH)+; 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5 Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −116.52 (m). The suspension was then cooled to −78° C. After stirring for 2 h at −78° C. to slowly warm to 8° C. while stirring overnight (18 h) The reaction was then quenched with satd aq NaHCO3 extracted with EtOAc dried over Na2SO4 After the solvents were evaporated the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc

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

Procedure: To a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (5.0 g, 0.027 mol) and K2CO3 (7.45 g, 0.054 mol) in acetonitrile (100 mL) was added (S)-3,3-dimethylbutan-2-amine (3.24 g, 0.032 mol), and the reaction mixture was stirred at rt overnight. The solution was filtered, and the filtrate was concentrated to give (S)-3-(3,3-dimethylbutan-2-ylamino)-1-(4-fluorophenyl)propan-1-one (6.40 g, 94%), which was used for the next step without further purification. 1H NMR (CDCl3): 0.82 (s, 9H), 0.91-0.96 (d, 3H), 2.14-2.22 (m, 1H), 2.73-2.82 (m, 1H), 3.01-3.11 (m, 3H), 7.01-7.09 (m, 2H), 7.88-7.96 (m, 2H). The solution was filtered the filtrate was concentrated

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

Procedure: To a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (5.0 g, 0.027 mol) and K2CO3 (7.45 g, 0.054 mol) in acetonitrile (100 mL) was added (S)-3,3-dimethylbutan-2-amine (3.24 g, 0.032 mol), and the reaction mixture was stirred at rt overnight. The solution was filtered, and the filtrate was concentrated to give (S)-3-(3,3-dimethylbutan-2-ylamino)-1-(4-fluorophenyl)propan-1-one (6.40 g, 94%). 1H NMR (CDCl3): 0.82 (s, 9H), 0.91-0.96 (d, 3H), 2.14-2.22 (m, 1H), 2.73-2.82 (m, 1H), 3.01-3.11 (m, 3H), 7.01-7.09 (m, 2H), 7.88-7.96 (m, 2H). The solution was filtered the filtrate was concentrated

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

Procedure: A 1000-mL flask was charged with anhydrous CeCl3 (50 g, 0.2 mol) and THF (360 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C., and a solution of allylmagnesium bromide (1.0 M in THF, 188.2 mL, 188 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (22.6 g, 120 mmol) in THF (269 mL) was added dropwise. The reaction mixture was allowed to slowly warm to rt while stirring overnight. The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (23.8 g, 87%) as an oil. 1H NMR (CDCl3): 2.27 (m, 1H), 2.31 (m, 2H), 2.50 (m, 1H), 2.69 (m, 1H), 3.19 (m, 1H), 3.52 (m, 1H), 5.16 (m, 2H), 5.51 (m, 1H), 7.04 (m, 2H), 7.35 (m, 2H). The suspension was then cooled to −78° C. After stirring for 2 h at −78° C. to slowly warm to rt while stirring overnight The reaction was then quenched with satd aq NaHCO3 extracted with EtOAc dried over Na2SO4 After the solvents were evaporated the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc

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

Procedure: Triethylamine (0.9 ml; 0.0063 mol) was added to a solution of 3-chloro-4'-fluoropropiophenone (1.2 g; 0.0063 mol) in diethyl ether (10 ml). The resulting mixture was stirred for 3 hours at room temperature. Then the mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken up with a mixture of compound of Description 5 [5-methoxy-3-(1,2,5,6-tetrahydro-pyridin-3-ylmethyl)-1H-indole] (0.79 g; 0.0028 mol), triethylamine (0.8 ml; 0.0057 mol) in methylene chloride (20 ml). The reaction mixture was refluxed for 4 hours. Then the reaction was concentrated under vacuum and the residue was triturated with 1N hydrochloric acid. The aqueous phase was decanted, and the guming solid was twice washed with water and triturated with diethyl ether. The title compound hydrochloride was collected by filtration, washed with diethyl ether and recrystallized with a mixture (1/2) of ethyl acetate/acetone. 0.86 g of the desired compound were obtained. Then the mixture was filtered the filtrate was concentrated under vacuum The reaction mixture was refluxed for 4 hours Then the reaction was concentrated under vacuum the residue was triturated with 1N hydrochloric acid The aqueous phase was decanted the guming solid was twice washed with water triturated with diethyl ether The title compound hydrochloride was collected by filtration washed with diethyl ether recrystallized with a mixture (1/2) of ethyl acetate/acetone

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

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

Procedure: The procedure given in Example 135 was followed using 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 3-chloro-4′-fluoropropiophenone as a reactant, instead of 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 3-chloropropiophenone, to give the title compound.

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

Procedure: A solution of 3-chloro-1-(4-fluorophenyl)-propan-1-one (18.6 g, 0.1 mol) in THF (50 mL) was added to a well-stirred suspension of zinc power (13 g, 0.2 mol) in a mixture of aqueous saturated NH4Cl solution (260 mL) and THF (65 mL). A solution of 3-iodo-2-methylprop-1-ene (36.4 g, 0.2 mol) in THF (50 mL) was added dropwise. The reaction mixture was mildly exothermic, and began to reflux spontaneously. After the refluxing had ceased, the mixture was stirred for 1 h. TLC showed the 3-chloro-1-(4-fluorophenyl)propan-1-one not reacted completely. A solution of 3-iodo-2-methylprop-1-ene (18.2 g, 0.1 mol) in THF (30 mL) was added, and the mixture was stirred at rt overnight. The mixture was extracted with EtOAc (2×500 mL). The combined organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc 50:1→30:1→5:1, to give 1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (17 g, yield 76%) as an oil. to reflux spontaneously reacted completely the mixture was stirred at rt overnight The mixture was extracted with EtOAc (2×500 mL) The combined organic layer was dried concentrated The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc 50:1→30:1→5:1