[4-(chloromethyl)phenyl] acetate

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

実験手順: Acetic acid 4-(3-iodo-pyrrolo[2,3-c]pyridin-1-ylmethyl)-phenyl ester was prepared by substituting acetic acid 4-chloromethyl-phenyl ester and Example 717A for benzyl bromide and Example 695J, respectively, in Example 696A. Acetic acid 4-(3-iodo-pyrrolo[2,3-c]pyridin-1-ylmethyl)-phenyl ester was then slurried in a mixture of THF and water, and treated with LiOH to provide the desired product. MS (ESI) m/e 351 (M+H)+, 1H NMR (300 MHz, DMSO-d6): □ 9.44 (s, 1H), 8.87 (s, 1H), 8.20 (d, J=5.43 Hz, 1H), 7.93 (s, 1H), 7.24 (dd, J=5.43, 1.02 Hz, 1H), 7.18 (d, J=8.48 Hz, 2H), 6.68-6.72 (m, 2H), 5.40 (s, 2H).

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

実験手順: Acetic acid 4-(3-iodo-pyrrolo[2,3-c]pyridin-1-ylmethyl)-phenyl ester was prepared by substituting acetic acid 4-chloromethyl-phenyl ester and Example 717A for benzyl bromide and Example 695J, respectively, in Example 696A. Acetic acid 4-(3-iodo-pyrrolo[2,3-c]pyridin-1-ylmethyl)-phenyl ester was then slurried in a mixture of THF and water, and treated with LiOH to provide the desired product. MS (ESI) m/e 351 (M+H)+, 1H NMR (300 MHz, DMSO-d6): □ 9.44 (s, 1H), 8.87 (s, 1H), 8.20 (d, J=5.43 Hz, 1H), 7.93 (s, 1H), 7.24 (dd, J=5.43, 1.02 Hz, 1H), 7.18 (d, J=8.48 Hz, 2H), 6.68-6.72 (m, 2H), 5.40 (s, 2H).

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

実験手順: Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 4-(chloromethyl)phenyl acetate to give 6-(4-acetoxybenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a white solid. similar to the Preparation 177

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

実験手順: To a solution of the product of Example 11 (460 mg) in DMF (10 mL) was added 60% sodium hydride (38 mg) and the reaction stirred at room temperature for 30 minutes before the addition of 4-(chloromethyl)phenyl acetate (280 mg). The reaction mixture was then stirred at room temperature for 17 hrs. Additional 60% sodium hydride (38 mg) was added and the reaction was stirred for a further 2 hours. NaOH (5N, 2 mL) was added and the reaction was stirred at room temperature for 90 minutes. The reaction mixture was acidified with HCl (2N) and extracted into ethyl acetate. The organics were washed with water and brine, dried over magnesium sulphate and evaporated to yield the sub-titled compound (500 mg). the reaction was stirred for a further 2 hours the reaction was stirred at room temperature for 90 minutes extracted into ethyl acetate The organics were washed with water and brine dried over magnesium sulphate evaporated

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-1H-pyrazole (500 mg, 3.40 mmol), 4-(chloromethyl)phenyl acetate (659 mg, 3.57 mmol), and potassium carbonate (1.18 g, 8.50 mmol) was diluted with DMF (5 mL) at ambient temperature. The reaction mixture was heated to 40° C. for 4 hours. The reaction mixture was then diluted with sodium hydroxide (2.0 M in water, 3.40 mL, 6.80 mmol) and stirred for an additional 30 minutes at 40° C. The reaction mixture was then cooled to ambient temperature and diluted with ethyl acetate (200 mL) and saturated aqueous ammonium chloride solution (50 mL). The organic layer was separated and washed with water (50 mL) and then brine (25 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% ethyl acetate/hexanes) to afford 4-((4-bromo-1H-pyrazol-1-yl)methyl)phenol. MS ESI calc'd. for C10H10BrN2O [M+H]+ 253 and 255. found 253 and 255. 1H NMR (500 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.98 (s, 1H), 7.51 (s, 1H), 7.08 (d, J=8.5 Hz, 2H), 6.69 (dd, J=7.0 Hz, 2.0 Hz, 2H), 5.14 (s, 2H). The reaction mixture was then cooled to ambient temperature The organic layer was separated washed with water (50 mL) The organic layer was separated dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure to afford the crude product residue The crude product residue was purified by column chromatography on silica (0-100% ethyl acetate/hexanes)

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-1H-pyrazole (500 mg, 3.40 mmol), 4-(chloromethyl)phenyl acetate (659 mg, 3.57 mmol), and potassium carbonate (1.18 g, 8.50 mmol) was diluted with DMF (5 mL) at ambient temperature. The reaction mixture was heated to 40° C. for 4 hours. The reaction mixture was then diluted with sodium hydroxide (2.0 M in water, 3.40 mL, 6.80 mmol) and stirred for an additional 30 minutes at 40° C. The reaction mixture was then cooled to ambient temperature and diluted with ethyl acetate (200 mL) and saturated aqueous ammonium chloride solution (50 mL). The organic layer was separated and washed with water (50 mL) and then brine (25 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% ethyl acetate/hexanes) to afford 4-((4-bromo-1H-pyrazol-1-yl)methyl)phenol. MS ESI calc'd. for C10H10BrN2O [M+H]+ 253 and 255. found 253 and 255. 1H NMR (500 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.98 (s, 1H), 7.51 (s, 1H), 7.08 (d, J=8.5 Hz, 2H), 6.69 (dd, J=7.0 Hz, 2.0 Hz, 2H), 5.14 (s, 2H). The reaction mixture was then cooled to ambient temperature The organic layer was separated washed with water (50 mL) The organic layer was separated dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure to afford the crude product residue The crude product residue was purified by column chromatography on silica (0-100% ethyl acetate/hexanes)

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

実験手順: Acetic acid 4-(3-iodo-pyrrolo[2,3-c]pyridin-1-ylmethyl)-phenyl ester was prepared by substituting acetic acid 4-chloromethyl-phenyl ester and Example 717A for benzyl bromide and Example 695J, respectively, in Example 696A. Acetic acid 4-(3-iodo-pyrrolo[2,3-c]pyridin-1-ylmethyl)-phenyl ester was then slurried in a mixture of THF and water, and treated with LiOH to provide the desired product. MS (ESI) m/e 351 (M+H)+, 1H NMR (300 MHz, DMSO-d6): □ 9.44 (s, 1H), 8.87 (s, 1H), 8.20 (d, J=5.43 Hz, 1H), 7.93 (s, 1H), 7.24 (dd, J=5.43, 1.02 Hz, 1H), 7.18 (d, J=8.48 Hz, 2H), 6.68-6.72 (m, 2H), 5.40 (s, 2H).

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

実験手順: Acetic acid 4-(3-iodo-pyrrolo[2,3-c]pyridin-1-ylmethyl)-phenyl ester was prepared by substituting acetic acid 4-chloromethyl-phenyl ester and Example 717A for benzyl bromide and Example 695J, respectively, in Example 696A. Acetic acid 4-(3-iodo-pyrrolo[2,3-c]pyridin-1-ylmethyl)-phenyl ester was then slurried in a mixture of THF and water, and treated with LiOH to provide the desired product. MS (ESI) m/e 351 (M+H)+, 1H NMR (300 MHz, DMSO-d6): □ 9.44 (s, 1H), 8.87 (s, 1H), 8.20 (d, J=5.43 Hz, 1H), 7.93 (s, 1H), 7.24 (dd, J=5.43, 1.02 Hz, 1H), 7.18 (d, J=8.48 Hz, 2H), 6.68-6.72 (m, 2H), 5.40 (s, 2H).

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

実験手順: Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (68 mg) in anhydrous DMF (1.0 ml) was added dropwise to a solution of sodium hydride (16 mg) in anhydrous DMF (1.0 ml), and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 4-acetoxybenzyl chloride (0.04 ml) in anhydrous DMF (0.5 ml) was added, and the resulting mixture was stirred at room temperature overnight. Saturated brine was added to the reaction solution and the resulting mixture was extracted with chloroform. Organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=6/1) to obtain (4-acetoxybenzyl)-(4-iodophenyl)pyrimidin-2-ylamine (67 mg). NMR (HL, CDCl3): δ 2.28(3H, s), 5.22 (2H, s), 6.63 (1H, t, J=4.6 Hz), 6.98-7.02 (4H, m), 7.26 (2H, d, J=8.1 Hz), 7.64-7.67 (2H, m), 8.34 (2H, d, J=4.6 Hz) the resulting mixture was stirred at room temperature overnight the resulting mixture was extracted with chloroform Organic layer was dried over anhydrous sodium sulfate After removing anhydrous sodium sulfate by filtration the filtrate was concentrated The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=6/1)

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of p-cresol (108 g., 1.0 mole) and acetic anhydride (16.6 ml., 18.0 g., 0.18 mole) was heated at 130° C. while acetic anhydride (87 ml., 94 g., 0.92 mole) was added over a 30 minute period (a gentle exotherm slowly brought the mixture to reflux). This solution was further heated at reflux (150° C.) for one hour and then acetic acid was distilled off until the pot temperature reached 195° C. Heating of the mixture containing p-cresol acetate was discontinued and acetic anhydride (99 ml., 1.0 mole) was added. The mixture was cooled to 50° C. and anhydrous sodium acetate (131 g., 1.6 mole) was added followed by 3.0 g. of azobisisobutyronitrile (AIBN). After heating to 70° C. chlorine (49 g., 0.69 mole) was added through a gas dispersion tube below the surface of the liquid over a period of 1-2 hours while maintaining the temperature between 70°-75° C. The reaction was mildly exothermic and required some cooling. Upon completion of the chlorine addition, the p-acetoxybenzyl chloride thus obtained was converted to p-acetoxybenzyl acetate by refluxing (150° C.) the reaction mixture for 4 hours. The reaction mixture is cooled to 60°-65° C. and 10 ml. water is added to destroy remaining acetic anhydride. The temperature is controlled at 70°-75° C. while four 10 ml. portions of water are added at 30-minute intervals. The mixture is then cooled to 35° C. and drowned into 300 ml. water. After all salts are dissolved the layers are allowed to separate and the aqueous layer is discarded. Toluene (200 ml.) is added to the organic phase and the resulting solution is washed three times with water. The toluene solution then was distilled to give the following fraction. was added over a 30 minute period (a gentle exotherm to reflux) This solution was further heated acetic acid was distilled off until the pot temperature reached 195° C Heating of the mixture containing p-cresol acetate The mixture was cooled to 50° C. was added through a gas dispersion tube below the surface of the liquid over a period of 1-2 hours while maintaining the temperature between 70°-75° C

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

実験手順: Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (68 mg) in anhydrous DMF (1.0 ml) was added dropwise to a solution of sodium hydride (16 mg) in anhydrous DMF (1.0 ml), and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 4-acetoxybenzyl chloride (0.04 ml) in anhydrous DMF (0.5 ml) was added, and the resulting mixture was stirred at room temperature overnight. Saturated brine was added to the reaction solution and the resulting mixture was extracted with chloroform. Organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=6/1) to obtain (4-acetoxybenzyl)-(4-iodophenyl)pyrimidin-2-ylamine (67 mg). NMR (HL, CDCl3): δ 2.28(3H, s), 5.22 (2H, s), 6.63 (1H, t, J=4.6 Hz), 6.98-7.02 (4H, m), 7.26 (2H, d, J=8.1 Hz), 7.64-7.67 (2H, m), 8.34 (2H, d, J=4.6 Hz) the resulting mixture was stirred at room temperature overnight the resulting mixture was extracted with chloroform Organic layer was dried over anhydrous sodium sulfate After removing anhydrous sodium sulfate by filtration the filtrate was concentrated The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=6/1)

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of p-cresol (108 g., 1.0 mole) and acetic anhydride (16.6 ml., 18.0 g., 0.18 mole) was heated at 130° C. while acetic anhydride (87 ml., 94 g., 0.92 mole) was added over a 30 minute period (a gentle exotherm slowly brought the mixture to reflux). This solution was further heated at reflux (150° C.) for one hour and then acetic acid was distilled off until the pot temperature reached 195° C. Heating of the mixture containing p-cresol acetate was discontinued and acetic anhydride (99 ml., 1.0 mole) was added. The mixture was cooled to 50° C. and anhydrous sodium acetate (131 g., 1.6 mole) was added followed by 3.0 g. of azobisisobutyronitrile (AIBN). After heating to 70° C. chlorine (49 g., 0.69 mole) was added through a gas dispersion tube below the surface of the liquid over a period of 1-2 hours while maintaining the temperature between 70°-75° C. The reaction was mildly exothermic and required some cooling. Upon completion of the chlorine addition, the p-acetoxybenzyl chloride thus obtained was converted to p-acetoxybenzyl acetate by refluxing (150° C.) the reaction mixture for 4 hours. The reaction mixture is cooled to 60°-65° C. and 10 ml. water is added to destroy remaining acetic anhydride. The temperature is controlled at 70°-75° C. while four 10 ml. portions of water are added at 30-minute intervals. The mixture is then cooled to 35° C. and drowned into 300 ml. water. After all salts are dissolved the layers are allowed to separate and the aqueous layer is discarded. Toluene (200 ml.) is added to the organic phase and the resulting solution is washed three times with water. The toluene solution then was distilled to give the following fraction. was added over a 30 minute period (a gentle exotherm to reflux) This solution was further heated acetic acid was distilled off until the pot temperature reached 195° C Heating of the mixture containing p-cresol acetate The mixture was cooled to 50° C. was added through a gas dispersion tube below the surface of the liquid over a period of 1-2 hours while maintaining the temperature between 70°-75° C