5-氯-2-甲基苯甲醛

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: To 2-bromo-4-chloro toluene (20.0 g; 97.3 mmol) in 300 mL of THF at −78° C. was added n-BuLi 2.5M (40.8 mL) dropwise. After 20 min. 1-formylpiperidine (11.4 mL; 103.0 mmol) in 10 mL of THF was added dropwise. After 30 min the reaction mixture was brought to 0° C. and quenched with HCl (10%) and diluted with EtOAc. The organic phase was collected, dry and the solvent evaporated to yield 13.3 g (89%) of 5-chloro-2-methylbenzaldehyde. This crude aldehyde was mixed with 1.1 equivalent of triethyl phosphonoacetate in THF. Sodium hydride 80% (1.3 equivalent ) was added portionwise and 1 h later the reaction was quenched with 25% NH4Cl. The reaction mixture was diluted with EtOAc and the organic phase collected, dried and the solvent removed. The crude oil was purified on a short pad of silica gel using 5% EtOAc in hexane to afford 16.67 g of the title compound. After 30 min the reaction mixture was brought to 0° C. quenched with HCl (10%) diluted with EtOAc The organic phase was collected dry the solvent evaporated

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

实验步骤: To a solution of 2-bromo-4-chlorotoluene (20.0 g; 97.3 mmol) in 300 mL of THF at −78° C. was added dropwise a 2.5 M solution of n-BuLi (102.2 mmol). After 30 min of stirring at that temperature, 1-formylpiperidine (11.4 mL) in 10 mL of THF was added and the solution left for 1 h. It was brought to 0° C. , quenched with NH4OAc (25%) and diluted with EtOAc. The organic phase was dried over Na2SO4, filtered and the solvent removed to yield 13.3 g of the title compound. was added was brought to 0° C. quenched with NH4OAc (25%) diluted with EtOAc The organic phase was dried over Na2SO4 filtered the solvent removed

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

实验步骤: To a solution of 2-bromo-4-chlorotoluene (20.0 g; 97.3 mmol) in 300 mL of THF at −78° C. was added dropwise a 2.5 M solution of n-BuLi (102.2 mmol). After 30 min of stirring at that temperature, 1-formylpiperidine (11.4 mL) in 10 mL of THF was added and the solution left for 1 h. It was brought to 0° C. , quenched with NH4OAc (25%) and diluted with EtOAc. The organic phase was dried over Na2SO4, filtered and the solvent removed to yield 13.3 g of the title compound. was added was brought to 0° C. quenched with NH4OAc (25%) diluted with EtOAc The organic phase was dried over Na2SO4 filtered the solvent removed

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

实验步骤: A mixture of paraformaldehyde (11.5 g, 0.38 mol) and hydroxylamine hydrochloride (26.3 g, 0.38 mol) in water (170 mL) was heated until a clear solution was obtained. Then there was added hydrated sodium acetate (51 g, 0.38 mol), and the mixture was boiled gently under reflux for 15 minutes to give a 10% solution of formaldoxime. A mixture of 2-choro-4-methylaniline (35.5 g, 0.25 mol) and water (50 mL) was stirred, and concentrated hydrochloric acid (57 mL) was added slowly. The mixture was cooled to room temperature, 100 g of ice was added, and the temperature of the mixture was maintained at −5° C. to +5° C. by means of an ice-salt bath. To the stirred mixture there was added a solution of sodium nitrite (17.5 g, 0.25 mol) in water (25 mL). After completion of the addition, the stirring was continued for a period of 15 minutes. The stirred solution of the diazonium salt was made neutral to Congo red by the addition of a solution of hydrated sodium acetate in water (35 mL). The aqueous 10% formaldoxime was added hydrated cupric sulfate (6.5 g, 0.026 mol), sodium sulfite (1.0 g, 0.0079 mole), and a solution of hydrated sodium acetate (160 g) in water (180 mL). The solution was maintained at 10-15° C. by means of a cold-water bath and stirred vigorously. The neutral diazonium salt solution was slowly introduced below the surface of the formaldoxime. After the addition of the diazonium salt solution was complete, the stirring was continued for an additional hour and then the mixture was treated with concentrated hydrochloric acid (230 mL). The mixture was gently heated under reflux for 2 hours. The mixture was extracted with three portions of ether (150 mL), and the ethereal extracts were washed with a saturated NaCl solution, Then the organic layer was dried over anhydrous Na2SO4 and concentrated to obtain yellow solid (Yield: 21 g, 36%). the temperature of the mixture was maintained at −5° C. to +5° C. by means of an ice-salt bath After completion of the addition The solution was maintained at 10-15° C. by means of a cold-water bath stirred vigorously the stirring was continued for an additional hour The mixture was gently heated under reflux for 2 hours The mixture was extracted with three portions of ether (150 mL) the ethereal extracts were washed with a saturated NaCl solution the organic layer was dried over anhydrous Na2SO4 concentrated

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

实验步骤: A mixture of paraformaldehyde (11.5 g, 0.38 mol) and hydroxylamine hydrochloride (26.3 g, 0.38 mol) in water (170 mL) was heated until a clear solution was obtained. Then there was added hydrated sodium acetate (51 g, 0.38 mol), and the mixture was boiled gently under reflux for 15 minutes to give a 10% solution of formaldoxime. A mixture of 2-choro-4-methylaniline (35.5 g, 0.25 mol) and water (50 mL) was stirred, and concentrated hydrochloric acid (57 mL) was added slowly. The mixture was cooled to room temperature, 100 g of ice was added, and the temperature of the mixture was maintained at −5° C. to +5° C. by means of an ice-salt bath. To the stirred mixture there was added a solution of sodium nitrite (17.5 g, 0.25 mol) in water (25 mL). After completion of the addition, the stirring was continued for a period of 15 minutes. The stirred solution of the diazonium salt was made neutral to Congo red by the addition of a solution of hydrated sodium acetate in water (35 mL). The aqueous 10% formaldoxime was added hydrated cupric sulfate (6.5 g, 0.026 mol), sodium sulfite (1.0 g, 0.0079 mole), and a solution of hydrated sodium acetate (160 g) in water (180 mL). The solution was maintained at 10-15° C. by means of a cold-water bath and stirred vigorously. The neutral diazonium salt solution was slowly introduced below the surface of the formaldoxime. After the addition of the diazonium salt solution was complete, the stirring was continued for an additional hour and then the mixture was treated with concentrated hydrochloric acid (230 mL). The mixture was gently heated under reflux for 2 hours. The mixture was extracted with three portions of ether (150 mL), and the ethereal extracts were washed with a saturated NaCl solution, Then the organic layer was dried over anhydrous Na2SO4 and concentrated to obtain yellow solid (Yield: 21 g, 36%). the temperature of the mixture was maintained at −5° C. to +5° C. by means of an ice-salt bath After completion of the addition The solution was maintained at 10-15° C. by means of a cold-water bath stirred vigorously the stirring was continued for an additional hour The mixture was gently heated under reflux for 2 hours The mixture was extracted with three portions of ether (150 mL) the ethereal extracts were washed with a saturated NaCl solution the organic layer was dried over anhydrous Na2SO4 concentrated

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under N2 was added 2-bromo-4-chlorotoluene (10.0 mL, 75.0 mmol) in anhydrous THF (150 mL). The clear sol. was cooled to −78° C. and BuLi (36.6 mL, 82.4 mmol, 2.25 M sol. in hexanes) was added dropwise over 20 min. The resulting light orange sol. was stirred at −78° C. for 1 h, and DMF (30 mL, 375 mmol) was added in a single addition. The resulting mixture was allowed to warm to rt over 4 h. The reaction was quenched by addition of aq. 1M HCl (20 mL), and stirred at rt overnight. The reaction mixture was poured into a 500 mL separatory funnel containing aq. 1M HCl (200 mL). The mixture was extracted with Et2O (3×100 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to a yellow oil. Purification by short-path distillation under reduced pressure (≈1 mm Hg) yielded the title compound as a light yellow oil (7.99 g, 69%). bp=70-72° C. at 1 mm Hg. Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under N2 to warm to rt over 4 h The reaction was quenched by addition of aq. 1M HCl (20 mL) stirred at rt overnight The reaction mixture was poured into a 500 mL separatory funnel containing aq. 1M HCl (200 mL) The mixture was extracted with Et2O (3×100 mL) layers were washed with brine dried over MgSO4 filtered concentrated under reduced pressure to a yellow oil Purification by short-path distillation under reduced pressure (≈1 mm Hg)

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

实验步骤: As described in Example 35, 2-methyl-5-chlorobenzaldehyde is converted to 3-chloro-6-(2-methyl-5-chlorophenyl)pyridazine. A mixture of the preceding compound and formylhydrazine in n-butanol is refluxed for 24 hours to give the product of the example. is refluxed for 24 hours to give the product of the example

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 5-Chloro-2-methyl-benzaldehyde (4 g, 16 mmol) and 6-chlorooxindole (2.5 g, 16 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (1.32 mL, 16 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as yellow solid (Yield: 4.5 g). cooled to room temperature The precipitate was collected by filtration