酮康唑杂质16

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: Stir a mixture of (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (10.4 g, 55.7 mmol) and 2,4-dichloroacetophenone (10.5 g, 55 mmol) in dry toluene (400 mL) at 110° C. for 48 h. Concentrate and dissolve the residue in methanol (160 mL), add sodium borohydride (3.37 g, 89 mmol) slowly and stir for 20 min. Add 1 N sodium hydroxide (200 mL) and extract with diethyl ether. Combine the organic layers, wash with water, dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with 0:100 to 40:60 ethyl acetate:2-methylpentane to give (S)-3-[1-(2,4-dichlorophenyl)-ethylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (5.6 g, 28%). 1H NMR (300 MHz, CDCl3) δ 7.41-7.51 (1H, m), 7.34 (1H, s), 7.24 (1H, dd, J=8.38, 1.98 Hz), 4.21-4.36 (1H, m), 3.42-3.57 (2H, m), 3.21-3.33 (1H, m), 3.04-3.15 (1H, m), 2.88-3.03 (1H, m), 1.96-2.05 (1H, m), 1.63-1.72 (1H, m), 1.37-1.47 (9H, m), 1.30 (3H, dd, J=6.59, 1.51 Hz), MS (ES): m/z=359[M+]. Concentrate dissolve the residue in methanol (160 mL) stir for 20 min extract with diethyl ether wash with water dry (magnesium sulfate) concentrate chromatograph on silica gel, eluting with 0:100 to 40:60 ethyl acetate

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

实验步骤: Stir a mixture of (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (10.4 g, 55.7 mmol) and 2,4-dichloroacetophenone (10.5 g, 55 mmol) in dry toluene (400 mL) at 110° C. for 48 h. Concentrate and dissolve the residue in methanol (160 mL), add sodium borohydride (3.37 g, 89 mmol) slowly and stir for 20 min. Add 1 N sodium hydroxide (200 mL) and extract with diethyl ether. Combine the organic layers, wash with water, dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with 0:100 to 40:60 ethyl acetate:2-methylpentane to give (S)-3-[1-(2,4-dichlorophenyl)-ethylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (5.6 g, 28%). 1H NMR (300 MHz, CDCl3) δ 7.41-7.51 (1H, m), 7.34 (1H, s), 7.24 (1H, dd, J=8.38, 1.98 Hz), 4.21-4.36 (1H, m), 3.42-3.57 (2H, m), 3.21-3.33 (1H, m), 3.04-3.15 (1H, m), 2.88-3.03 (1H, m), 1.96-2.05 (1H, m), 1.63-1.72 (1H, m), 1.37-1.47 (9H, m), 1.30 (3H, dd, J=6.59, 1.51 Hz), MS (ES): m/z=359[M+]. Concentrate dissolve the residue in methanol (160 mL) stir for 20 min extract with diethyl ether wash with water dry (magnesium sulfate) concentrate chromatograph on silica gel, eluting with 0:100 to 40:60 ethyl acetate

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

实验步骤: Diisopropylamine (16.2 g) was dissolved in tetrahydrofuran (133 ml), and 1.6N n-butyl lithium (100 ml) was dropwise added thereto under ice-cooling. The reaction mixture was stirred at the same temperature for 10 min, and a solution of 2,4-dichloroacetophenone (25.2 g) in tetrahydrofuran (133 ml) was dropwise added under cooling in a dry ice-acetone bath. Hexamethylphosphoramide (26.7 ml) was added little by little. The mixture was stirred at the same temperature for 5 min, and chlorotrimethylsilane (20.3 ml) was dropwise added, which was followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between ice-cooled n-hexane and ice-cooled water. The organic layer was washed twice with ice-cooling water and then once with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to dryness to give a crude product (37.5 g) of the objective compound as a pale-yellow oil. under ice-cooling under cooling in a dry ice-acetone bath The mixture was stirred at the same temperature for 5 min by stirring at room temperature for 30 min The reaction mixture was partitioned between ice- cooled n-hexane and ice- cooled water The organic layer was washed twice with ice- cooling water once with saturated brine, dried over sodium sulfate concentrated under reduced pressure to dryness

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

实验步骤: Diisopropylamine (16.2 g) was dissolved in tetrahydrofuran (133 ml), and 1.6N n-butyl lithium (100 ml) was dropwise added thereto under ice-cooling. The reaction mixture was stirred at the same temperature for 10 min, and a solution of 2,4-dichloroacetophenone (25.2 g) in tetrahydrofuran (133 ml) was dropwise added under cooling in a dry ice-acetone bath. Hexamethylphosphoramide (26.7 ml) was added little by little. The mixture was stirred at the same temperature for 5 min, and chlorotrimethylsilane (20.3 ml) was dropwise added, which was followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between ice-cooled n-hexane and ice-cooled water. The organic layer was washed twice with ice-cooling water and then once with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to dryness to give a crude product (37.5 g) of the objective compound as a pale-yellow oil. under ice-cooling under cooling in a dry ice-acetone bath The mixture was stirred at the same temperature for 5 min by stirring at room temperature for 30 min The reaction mixture was partitioned between ice- cooled n-hexane and ice- cooled water The organic layer was washed twice with ice- cooling water once with saturated brine, dried over sodium sulfate concentrated under reduced pressure to dryness

反应条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and the reaction mixture was stirred for 10 min. after which the solution of 1-(2,4-dichlorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product. heated for another 10 min the reaction mixture was cooled to 0° C was added dropwise After complete addition extracted in diethyl ether (4×50 mL) dried over Na2SO4 concentrated at 25° C. to obtain the product

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

实验步骤: Part D. A mixture of 2,4-dichloroacetophenone (10.0 g, 52.9 mmol) and dimethylformamide diethyl acetal (10.0 mL, 58.3 mmol) was heated to reflux for 12 hours, then cooled and evaporated under high vacuum. The residual oil was separated by column chromatography (silica gel, 1:1 ethyl acetate-hexane) to afford the product, 1-(2,4-dichlorobenzoyl)-2-(N,N-dimethylamino)ethene, as a viscous oil (12.11 g, 49.6 mmol, 94%). TLC RF 0.05 (20:80 ethyl acetate-hexane). Spectral data: 1H NMR (300 MHz, CDCl3): δ 7.40 (1H, d, J=2.2 Hz), 7.38-7.23 (3H, m), 5.33 (1H, d, J=12.4 Hz), 3.11 (3H, br s), 2.89 (3H, br s). MS (NH3—CI): m/e 249 (1), 248 (10), 247 (8), 246 (64), 245 (16), 244 (100). was heated to reflux for 12 hours cooled evaporated under high vacuum The residual oil was separated by column chromatography (silica gel, 1:1 ethyl acetate-hexane)

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2,4-dichloroacetophenone (378 mg, 2.0 mmol), p-chloro-phenylhydrazine (358 mg, 2.0 mmol and polyphosphoric acid (PPA) (0.5 mL) is heated at 100° C. for 8 h, cooled to room temperature, diluted with water, stirred briefly, allowed to stand at room temperature for 16 h and filtered. The filtercake is washed with water and air-dried to afford the title compound, 320 mg (54% yield), identified by NMR and mass spectral analyses. cooled to room temperature filtered The filtercake is washed with water air-dried

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

实验步骤: Using 2′,4′-dichloroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.

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

实验步骤: Stir a mixture of (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (10.4 g, 55.7 mmol) and 2,4-dichloroacetophenone (10.5 g, 55 mmol) in dry toluene (400 mL) at 110° C. for 48 h. Concentrate and dissolve the residue in methanol (160 mL), add sodium borohydride (3.37 g, 89 mmol) slowly and stir for 20 min. Add 1 N sodium hydroxide (200 mL) and extract with diethyl ether. Combine the organic layers, wash with water, dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with 0:100 to 40:60 ethyl acetate:2-methylpentane to give (S)-3-[1-(2,4-dichlorophenyl)-ethylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (5.6 g, 28%). 1H NMR (300 MHz, CDCl3) δ 7.41-7.51 (1H, m), 7.34 (1H, s), 7.24 (1H, dd, J=8.38, 1.98 Hz), 4.21-4.36 (1H, m), 3.42-3.57 (2H, m), 3.21-3.33 (1H, m), 3.04-3.15 (1H, m), 2.88-3.03 (1H, m), 1.96-2.05 (1H, m), 1.63-1.72 (1H, m), 1.37-1.47 (9H, m), 1.30 (3H, dd, J=6.59, 1.51 Hz), MS (ES): m/z=359[M+]. Concentrate dissolve the residue in methanol (160 mL) stir for 20 min extract with diethyl ether wash with water dry (magnesium sulfate) concentrate chromatograph on silica gel, eluting with 0:100 to 40:60 ethyl acetate

反应条件: temp:0.00; pressure:0.00; stir: