1,1-二苯肼盐酸盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of N,N-diphenylhydrazine hydrochloride (79.5 g, 0.36 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) was slowly added to a solution of 4-diethylamino-2-hydroxybenzaldehyde (58.0 g, 0.3 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) in the presence of excess sodium carbonate. The reaction mixture was refluxed until all of the aldehyde reacted in about ½ hour. The residue obtained after evaporation of the solvent (800 ml) was treated with ether, and the ether extract was washed with water until the pH of the water reached 7. The organic layer was dried over anhydrous magnesium sulphate, treated with activated charcoal, and filtered. Then, the ether solvent was evaporated. The residue was recrystallized from ethanol. Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off and washed with cold ethanol. The yield was 85 g (78.8%). The melting point was found to be 95.5–96.5° C. (recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume). The 1H NMR spectrum (100 Mhz) of the product in CDCl3 was characterized by the following chemical shifts (in ppm): 11.55 (s, 1H, OH); 7.55–6.95 (m, 11H, CH═N, Ph); 6.7 (d, J=8.6 Hz; 1H, 6-H of 1,2,4-subst. Ph); 6.23 (s, 1H, 3-H of 1,2,4-subst. Ph); 6.1 (d, J=8.6 Hz, 1H, 5-H of 1,2,4-subst. Ph); 3.3 (q, J=8.0 Hz, 4H, CH2); 1.1 (t, J=8.0 Hz, 6H, CH3). An elemental analysis yielded the following results in weight percent: C, 76.68; H, 7.75; N, 11.45, which compared with calculated values for C23H25N3O in weight percent of: C, 76.85; H, 7.01; N, 11.69. reacted in about ½ hour The residue obtained after evaporation of the solvent (800 ml) was treated with ether the ether extract was washed with water until the pH of the water The organic layer was dried over anhydrous magnesium sulphate treated with activated charcoal filtered Then, the ether solvent was evaporated The residue was recrystallized from ethanol Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off washed with cold ethanol to be 95.5–96.5° C. recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume) An elemental analysis yielded the following results in weight percent

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of N,N-diphenylhydrazine hydrochloride (79.5 g, 0.36 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) was slowly added to a solution of 4-diethylamino-2-hydroxybenzaldehyde (58.0 g, 0.3 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) in the presence of excess sodium carbonate. The reaction mixture was refluxed until 4-diethylamino-2-hydroxybenzaldehyde was completely reacted in about 30 minutes. The solvent (800 ml) was removed by evaporation. The residue obtained was extracted with ether and the ether extract was washed with water until the pH of the water reached 7. The organic layer was dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered. The ether solvent was evaporated. The residue was recrystallized from ethanol. Crystals were filtered off and washed with cold ethanol. The product was 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone. The yield was 85 g (78.8%). The melting point was found to be 95.5–96.5° C. (recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume). The 1H-NMR spectrum (100 Mhz) of the product in CDCl3 was characterized by the following chemical shifts (in ppm): 11.55 (s, 1H, OH); 7.55–6.95 (m, 11H, CH═N, Ph); 6.7 (d, J=8.6 Hz; 1H, 6-H of 1,2,4-subst. Ph); 6.23 (s, 1H, 3-H of 1,2,4-subst. Ph); 6.1 (d, J=8.6 Hz, 1H, 5-H of 1,2,4-subst. Ph); 3.3 (q, J=8.0 Hz, 4H, CH2); 1.1 (t, J=8.0 Hz, 6H, CH3). An elemental analysis yielded the following results in weight percent: C, 76.68; H, 7.75; N, 11.45, which compared with calculated values for C23H25N3O in weight percent of: C, 76.85; H, 7.01; N, 11.69. was completely reacted in about 30 minutes The solvent (800 ml) was removed by evaporation The residue obtained was extracted with ether the ether extract was washed with water until the pH of the water The organic layer was dried over anhydrous magnesium sulfate treated with activated charcoal filtered The ether solvent was evaporated The residue was recrystallized from ethanol Crystals were filtered off washed with cold ethanol to be 95.5–96.5° C. recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume) An elemental analysis yielded the following results in weight percent

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a methylene chloride solution (1 ml) of phosgene dimer (0.027 ml) was added a methylene chloride solution (2 ml) of (5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-1-naphthyl)methanol (0.12 g) and pyridine (0.1 ml) at -5° C., and the solution was stirred at room temperature for two hours. To the reaction mixture was added a solution of 1,1-diphenylhydrazine hydrochloride (0.10 g) and pyridine (0.05 ml) in methylene chloride (2 ml). The solution was stirred at room temperature for 3 hours, washed with 5% hydrochloric acid, water, and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (n-hexane-ethyl acetate) over silica gel to afford 2-[(5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-1-naphthyl)methoxycarbonyl]-1,1-diphenyihydrazine (0.13 g) as colorless solids. The solution was stirred at room temperature for 3 hours washed with 5% hydrochloric acid, water, and brine dried over sodium sulfate evaporated in vacuo The residue was chromatographed (n-hexane-ethyl acetate) over silica gel

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1,1-diphenylhydrazine hydrochloride (0.365 g, 1.65 mmol) and 4-oxo-1-piperidinecarboxylic acid tert-butyl ester (0.329 g, 1.65 mmol) in pyridine (3 mL) was heated in a sealed tube at 120° C. with stirring for 3 h. The reaction mixture was subsequently cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed (SiO2/hexanes:ethyl acetate, 3:2) to give the title compound (0.214 g, 37%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 2H), 7.40 (m, 1H), 7.35 (m, 2H), 7.26 (m, 2H), 7.14 (m, 2H), 4.72 (s, 2H), 3.78 (s, 2H), 2.71 (s, 2H), 1.51 (s, 9H); LCMS: m/e 349 (M+H)+. The reaction mixture was subsequently cooled to room temperature partitioned between ethyl acetate and water The organic layer was separated dried (MgSO4) filtered evaporated to dryness The residue was chromatographed (SiO2/hexanes:ethyl acetate, 3:2)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1,1-diphenylhydrazine hydrochloride (0.365 g, 1.65 mmol) and 4-oxo-1-piperidinecarboxylic acid tert-butyl ester (0.329 g, 1.65 mmol) in pyridine (3 mL) was heated in a sealed tube at 120° C. with stirring for 3 h. The reaction mixture was subsequently cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed (SiO2/hexanes:ethyl acetate, 3:2) to give the title compound (0.214 g, 37%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 2H), 7.40 (m, 1H), 7.35 (m, 2H), 7.26 (m, 2H), 7.14 (m, 2H), 4.72 (s, 2H), 3.78 (s, 2H), 2.71 (s, 2H), 1.51 (s, 9H); LCMS: m/e 349 (M+H)+. The reaction mixture was subsequently cooled to room temperature partitioned between ethyl acetate and water The organic layer was separated dried (MgSO4) filtered evaporated to dryness The residue was chromatographed (SiO2/hexanes:ethyl acetate, 3:2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of N,N-diphenylhydrazine hydrochloride (79.5 g, 0.36 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) was slowly added to a solution of 4-diethylamino-2-hydroxybenzaldehyde (58.0 g, 0.3 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) in the presence of excess sodium carbonate. The reaction mixture was refluxed until all of the aldehyde reacted in about ½ hour. The residue obtained after evaporation of the solvent (800 ml) was treated with ether and the ether extract was washed with water until the pH of the water reached 7. The organic layer was dried over anhydrous magnesium sulphate, treated with activated charcoal, and filtered. Next, the ether solvent was evaporated. The residue was recrystallized from ethanol. Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off and washed with cold ethanol. The yield was 85 g (78.8%). The melting point was found to be 95.5-96.5° C. (recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume). The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 11.55 (s, 1H, OH); 7.55-6.95 (m, 11H, CH═N, Ph); 6.7 (d, J=8.6 Hz; 1H, 6-H of 1,2,4-subst. Ph); 6.23 (s, 1H, 3-H of 1,2,4-subst. Ph); 6.1 (d, J=8.6 Hz, 1H, 5-H of 1,2,4-subst. Ph); 3.3 (q, J=8.0 Hz, 4H, CH2); 1.1 (t, J=8.0 Hz, 6H, CH3). An elemental analysis yielded the following results in weight percent: C, 76.68; H, 7.75; N, 11.45, which compared with calculated values for C23H25N3O in weight percent of: C, 76.85; H, 7.01; N, 11.69. reacted in about ½ hour The residue obtained after evaporation of the solvent (800 ml) was treated with ether the ether extract was washed with water until the pH of the water The organic layer was dried over anhydrous magnesium sulphate treated with activated charcoal filtered Next, the ether solvent was evaporated The residue was recrystallized from ethanol Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off washed with cold ethanol to be 95.5-96.5° C. recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume) An elemental analysis yielded the following results in weight percent

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of N,N-diphenylhydrazine hydrochloride (79.5 g, 0.36 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) was slowly added to a solution of 4-diethylamino-2-hydroxybenzaldehyde (58.0 g, 0.3 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) in the presence of excess sodium carbonate. The reaction mixture was refluxed until all of the aldehyde reacted in about ½ hour. The residue obtained after evaporation of the solvent (800 ml) was treated with ether and the ether extract was washed with water until the pH of the water reached 7. The organic layer was dried over anhydrous magnesium sulphate, treated with activated charcoal, and filtered. Next, the ether solvent was evaporated. The residue was recrystallized from ethanol. Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off and washed with cold ethanol. The yield was 85 g (78.8%). The melting point was found to be 95.5-96.5° C. (recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume). The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 11.55 (s, 1H, OH); 7.55-6.95 (m, 11H, CH═N, Ph); 6.7 (d, J=8.6 Hz; 1H, 6-H of 1,2,4-subst. Ph); 6.23 (s, 1H, 3-H of 1,2,4-subst. Ph); 6.1 (d, J=8.6 Hz, 1H, 5-H of 1,2,4-subst. Ph); 3.3 (q, J=8.0 Hz, 4H, CH2); 1.1 (t, J=8.0 Hz, 6H, CH3). An elemental analysis yielded the following results in weight percent: C, 76.68; H, 7.75; N, 11.45, which compared with calculated values for C23H25N3O in weight percent of: C, 76.85; H, 7.01; N, 11.69. reacted in about ½ hour The residue obtained after evaporation of the solvent (800 ml) was treated with ether the ether extract was washed with water until the pH of the water The organic layer was dried over anhydrous magnesium sulphate treated with activated charcoal filtered Next, the ether solvent was evaporated The residue was recrystallized from ethanol Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off washed with cold ethanol to be 95.5-96.5° C. recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume) An elemental analysis yielded the following results in weight percent

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of the carboxylic acid (prepared in reference example 5, 150 mg), 2-chloro-N-methylpyridinum iodide (197 mg). 1,1-diphenylhydrazine hydrochloride (147 mg) and triethylamine (0.216 ml) in methylene chloride (6 ml) was stirred overnight at room temperature. The mixture was poured into 1N hydrochloric acid, and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue was crystallized from crystallized ethyl acetate to give the title compound (as pale yellow powder; 167 mg) having the following physical data. extracted with methylene chloride The extract was washed with a saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate evaporated The residue was crystallized from crystallized ethyl acetate

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1,1-Diphenylhydrazine hydrochloride (1.2 equiv., 0.6 mmol, 135 mg), 2-chlorobromobenzene (1.0 equiv., 0.5 mmol, 0.06 mL), Pd(OAC)2 (0.05 equiv, 0.025 mmol, 6 mg), BINAP (0.05 equiv., 0.025 mmol, 16 mg), and NaOtBu (1.4 equiv., 0.7 mmol, 67 mg) and diisopropylamine (2 mL) were added to an oven dried test tube which was capped with a septum and purged briefly with argon (˜1 min.) and then heated to 80° C. for 5 hours. The reaction was then cooled to room temperature, diluted with Et2O (2 mL), filtered through Celite and concentrated under vacuum. The crude mixture was purified by flash column chromatography (2% EtOAc/Hex) to give the title product as a white solid (109 mg, 0.37 mmol, 74% yield). dried test tube which was capped with a septum purged briefly with argon (˜1 min.) The reaction was then cooled to room temperature diluted with Et2O (2 mL) filtered through Celite concentrated under vacuum The crude mixture was purified by flash column chromatography (2% EtOAc/Hex)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1,1-Diphenylhydrazine hydrochloride (1.2 equiv., 0.6 mmol, 135 mg), bromobenzene (1.0 equiv., 0.5 mmol, 0.05 mL), Pd(OAc)2 (0.01 equiv, 0.005 mmol, 2 mg), BINAP (0.01 equiv., 0.005 mmol, 3 mg), and NaOtBu (2.8 equiv., 1.4 mmol, 134 mg) and toluene (3 mL) were added to an oven dried test tube which was capped with a septum and purged briefly with argon (˜1 min.) and then heated to 80° C. for 4 hours. The reaction was then cooled to room temperature, diluted with Et2O (2 mL), filtered through Celite and concentrated under vacuum. The crude mixture was purified by flash column chromatography (5% EtOAc/Hex) to give the title product as a white solid (123 mg, 0.47 mmol, 95% yield). dried test tube which was capped with a septum purged briefly with argon (˜1 min.) The reaction was then cooled to room temperature diluted with Et2O (2 mL) filtered through Celite concentrated under vacuum The crude mixture was purified by flash column chromatography (5% EtOAc/Hex)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a methylene chloride solution (1 ml) of phosgene dimer (0.027 ml) was added a methylene chloride solution (2 ml) of (5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-1-naphthyl)methanol (0.12 g) and pyridine (0.1 ml) at -5° C., and the solution was stirred at room temperature for two hours. To the reaction mixture was added a solution of 1,1-diphenylhydrazine hydrochloride (0.10 g) and pyridine (0.05 ml) in methylene chloride (2 ml). The solution was stirred at room temperature for 3 hours, washed with 5% hydrochloric acid, water, and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (n-hexane-ethyl acetate) over silica gel to afford 2-[(5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-1-naphthyl)methoxycarbonyl]-1,1-diphenylhydrazine (0.13 g) as colorless solids. The solution was stirred at room temperature for 3 hours washed with 5% hydrochloric acid, water, and brine dried over sodium sulfate evaporated in vacuo The residue was chromatographed (n-hexane-ethyl acetate) over silica gel

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of N,N-diphenylhydrazine hydrochloride (79.5 g, 0.36 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) was slowly added to a solution of 4-diethylamino-2-hydroxybenzaldehyde (58.0 g, 0.3 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) in the presence of excess sodium carbonate. The reaction mixture was refluxed until all of the aldehyde reacted in about ½ hour. The residue obtained after evaporation of the solvent (800 ml) was treated with ether, and the ether extract was washed with water until the pH of the water reached 7. The organic layer was dried over anhydrous magnesium sulphate, treated with activated charcoal, and filtered. Then, the ether solvent was evaporated. The residue was recrystallized from ethanol. Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off and washed with cold ethanol. The yield was 85 g (78.8%). The melting point was found to be 95.5–96.5° C. (recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume). The 1H NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 11.55 (s, 1H, OH); 7.55–6.95 (m, 11H, CH═N, Ph); 6.7 (d, J=8.6 Hz; 1H, 6-H of 1,2,4-subst. Ph); 6.23 (s, 1H, 3-H of 1,2,4-subst. Ph); 6.1 (d, J=8.6 Hz, 1H, 5-H of 1,2,4-subst. Ph); 3.3 (q, J=8.0 Hz, 4H, CH2); 1.1 (t, J=8.0 Hz, 6H, CH3). An elemental analysis yielded the following results in weight percent C, 76.68; H, 7.75; and N, 11.45; which compared with calculated values for C23H25N3O in weight percent of C, 76.85; H, 7.01; and N, 11.69. reacted in about ½ hour The residue obtained after evaporation of the solvent (800 ml) was treated with ether the ether extract was washed with water until the pH of the water The organic layer was dried over anhydrous magnesium sulphate treated with activated charcoal filtered Then, the ether solvent was evaporated The residue was recrystallized from ethanol Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off washed with cold ethanol to be 95.5–96.5° C. recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume) An elemental analysis yielded the following results in weight percent C, 76.68