4-(chloromethyl)-N-methylbenzamide

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: The title compound is prepared in a manner substantially analogous to Procedure C using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-chloromethyl-N-methyl-benzamide [CAS 220875-88-7]. MS (ES+) 422.2

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

実験手順: To a solution 4-(chloromethyl)benzoyl chloride (1.0 g, 5.29 mmol) and methylamine.HCl (1.0 g, 5.80 mmol) in dichloromethane (40 mL) was added DIPEA (2.01 g, 15.6 mmol) at 0° C. and stirred for 1 h. The reaction mixture was extracted with water (1×50 mL). The organic layer was extracted with brine (1×50 mL), dried over Na2SO4 and the solvent was removed under reduced pressure to afford 1.0 g (quantitative) of 4-(chloromethyl)-N-methylbenzamide (I-30) as an off white solid. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=3.5 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 4.80 (s, 2H), 2.78 (d, J=4.4 Hz, 3H); ESI-LC/MS (m/z): [M+H]+ 184.2, RT 2.46 min. The reaction mixture was extracted with water (1×50 mL) The organic layer was extracted with brine (1×50 mL) dried over Na2SO4 the solvent was removed under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a suspension of 4-(chloromethyl)-N-methyl-benzamide (50 mmol) in toluene (200 mL) was added thionyl chloride (29.1 mL, 400 mmol) at room temperature. The resulting suspension was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was azeotroped with toluene and dried under high vacuum. To a suspension of sodium azide (4.55 g, 70 mmol) in acetonitrile (100 mL) was added chlorotrimethylsilane (9.15 mL, 73.4 mmol) at room temperature and the suspension was stirred for 1.5 hours. The reaction mixture was cooled to −10° C. and the above crude imidoyl chloride (50 mmol) in acetonitrile (65 mL) was added over 5 minutes. The mixture was stirred for 2 hours at 0° C. and then stirred at room temperature for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration gave a light yellow solid which was dissolved in hexanes-ethyl acetate (220 mL, 11:9 ratio) at 60-70° C. The resulting solution was stored in the refrigerator overnight and the precipitated solids were collected by filtration and washed with hexanes. After drying in air, 4-(1-methyltetrazol-5-yl)benzyl chloride was isolated as 6.26 g (60%) of a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.76 (d, J=8.2 Hz, 2 H), 7.61 (d, J=8.2 Hz, 2 H), 4.67 (s, 2 H), 4.20 (s, 3 H). HRMS (ES+) cald. for C9H9ClN4 [(M+H)+] 209.0589, obsd. 209.0588. The resulting suspension was heated at reflux for 15 hours concentrated under vacuum The residue was azeotroped with toluene dried under high vacuum The reaction mixture was cooled to −10° C. The mixture was stirred for 2 hours at 0° C. stirred at room temperature for 15 hours extracted with ethyl acetate (2×100 mL) The combined organic extracts were washed with brine dried over anhydrous magnesium sulfate Filtration and concentration gave a light yellow solid which was dissolved in hexanes-ethyl acetate (220 mL, 11:9 ratio) at 60-70° C was stored in the refrigerator overnight the precipitated solids were collected by filtration washed with hexanes After drying in air

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

実験手順: To a solution of 4-(chloromethyl)-benzoic acid (8.53 g, 50 mmol) in toluene (100 mL) was added thionyl chloride (14.5 mL, 200 mmol) at room temperature. The resulting solution was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting oily residue was azeotroped with toluene and dried under high vacuum to obtain the crude acid chloride. To a suspension of the above crude acid chloride (50 mmol) in dichloromethane (110 mL) was added methylamine hydrochloride (3.72 g, 55 mmol) at −5° C. to 0° C. Diisopropylethylamine (19.3 mL, 110 mmol) was added drop-wise over 15-20 minutes at 0° C. After completion of the addition, the mixture was stirred for 45 minutes at 0° C., then warmed to room temperature. After stirring at room temperature for 15 minutes, the reaction mixture was diluted with water and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration gave the crude solid which was dissolved in toluene at ˜60-70° C. The resulting solution was stored in the refrigerator overnight and the precipitated solids were collected by filtration and then washed with hexanes. After drying in air, 4-(chloromethyl)-N-methyl-benzamide was isolated as a light yellow solid. The resulting solution was heated at reflux for 15 hours concentrated under vacuum The resulting oily residue was azeotroped with toluene dried under high vacuum to obtain the crude acid chloride After completion of the addition warmed to room temperature After stirring at room temperature for 15 minutes the aqueous layer was extracted with dichloromethane The combined organic layers were washed with brine dried over anhydrous magnesium sulfate Filtration and concentration gave the crude solid which was stored in the refrigerator overnight the precipitated solids were collected by filtration washed with hexanes After drying in air

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

実験手順: The title compound is prepared in a manner substantially analogous to Procedure C using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-chloromethyl-N-methyl-benzamide [CAS 220875-88-7]. MS (ES+) 422.2

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

実験手順: To a solution 4-(chloromethyl)benzoyl chloride (1.0 g, 5.29 mmol) and methylamine.HCl (1.0 g, 5.80 mmol) in dichloromethane (40 mL) was added DIPEA (2.01 g, 15.6 mmol) at 0° C. and stirred for 1 h. The reaction mixture was extracted with water (1×50 mL). The organic layer was extracted with brine (1×50 mL), dried over Na2SO4 and the solvent was removed under reduced pressure to afford 1.0 g (quantitative) of 4-(chloromethyl)-N-methylbenzamide (I-30) as an off white solid. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=3.5 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 4.80 (s, 2H), 2.78 (d, J=4.4 Hz, 3H); ESI-LC/MS (m/z): [M+H]+ 184.2, RT 2.46 min. The reaction mixture was extracted with water (1×50 mL) The organic layer was extracted with brine (1×50 mL) dried over Na2SO4 the solvent was removed under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir: