泊沙康唑杂质114

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:

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

实验步骤: In a sealed flask were combined 12.99 g (83.2 mmol) 2,4-Difluoroacetophenone, 8.80 g (274 mmol, 3.3 equiv) Hydrazine and 8.7 mL EtOH and heated at 150° C. for 18 h. The resultant solid is dissolved in 150 mL EtOH, precipitated with 500 mL H2O, cooled, filtered, air and pump dried to give 8.56 g (57.0 mmol) 6-Fluoro-3-methyl-1H-indazole which is used without characterization. The material thus obtained is combined with 6.35 g (62.7 mmol, 1.1 equiv) Et3N and 1.39 g (11.4 mmol, 0.2 equiv) DMAP in 110 mL CH3CN cooled to 0° C. 14.93 g (68.4 mmol, 1.2 equiv) (BOC)2O in 80 mL CH3CN is added dropwise with stirring at 0° C. and the resultant reaction mixture stirred 2 h at 0° C. followed by 18 h at ambient temperature. The solvent is removed in vacuo and the crude material partitioned between EtOAc (200 mL) and H2O (100 mL). The pH is adjusted to 2.0 with 1N HCl, the organic phase separated, dried (MgSO4), filtered and concentrated in vacuo to an orange solid which is purified by filtration through a pad of 60 g silica gel eluted with 1.2 L DCM. The filtrate is concentrated in vacuo to give 12.68 g (50.7 mmol) of 6-Fluoro-3-methyl-indazole-1-carboxylic acid tert-butyl ester as a tan crystalline solid: 1H NMR (CDCl3, 300 MHz) δ7.78 (d, 1H, J=9.8), 7.57 (m, 1H), 7.07 (m, 1H), 2.57 (s, 3H), 1.72 (s, 9H); TLC Rf =0.52 (DCM). In a sealed flask were combined precipitated with 500 mL H2O cooled filtered air and pump dried

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:

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 40.0 g (0.256 moles) 2', 4'-difluoroacetophenone (commercially available) in 400 mL diethyl ether at 0° C. was added 40 mL (0.405 moles) ethyl trifluoroacetate. At 5° C., 80 mL of a 25% wt. sodium methoxide in methanol (0.37 moles) were added over 15 minutes. The reaction mixture was stirred overnight at 25° C. The mixture was poured over 300 mL ice water and 21.3 mL (0.37 moles) acetic acid were added. The organic layer was washed two times with water, dried over anhydrous MgSO4, and concentrated in vacuo to give 62.85 g (97%) 4-(2,4-difluorophenyl)-1,1,1-trifluoro-4-hydroxy-3-buten-2-one as a yellow oil; 1HNMR (CDCl3) ppm: 6.61 (s,1H), 6.87 (m, 1H), 6.97 (m, 1H), 7.97 (m, 1H). were added The organic layer was washed two times with water dried over anhydrous MgSO4 concentrated in vacuo

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 40.0 g (0.256 moles) 2', 4'-difluoroacetophenone (commercially available) in 400 mL diethyl ether at 0° C. was added 40 mL (0.405 moles) ethyl trifluoroacetate. At 5° C., 80 mL of a 25% wt. sodium methoxide in methanol (0.37 moles) were added over 15 minutes. The reaction mixture was stirred overnight at 25° C. The mixture was poured over 300 mL ice water and 21.3 mL (0.37 moles) acetic acid were added. The organic layer was washed two times with water, dried over anhydrous MgSO4, and concentrated in vacuo to give 62.85 g (97%) 4-(2,4-difluorophenyl)-1,1,1-trifluoro-4-hydroxy-3-buten-2-one as a yellow oil; 1HNMR (CDCl3) ppm: 6.61 (s,1H), 6.87 (m, 1H), 6.97 (m, 1H), 7.97 (m, 1H). were added The organic layer was washed two times with water dried over anhydrous MgSO4 concentrated in vacuo

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 stirred for 10 min. after which the solution of 1-(2,4-difluorophenyl)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 (4×50mL), 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 (4×50mL) 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: The title compound was prepared in 82% yield from 1-(2,4-difluorophenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.90 (3H, s), 3.11(3H, s), 5.59-5.62 (1H, m), 6.77-6.83 (1H, m), 6.88-6.93 (m, 1H), 7.75-7.83 (2H, m).

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

实验步骤: 2′,4′-difluoroacetophenone (5 g, 32 mmol) was reacted with sodium borohydride (1.21 g) in THF (20 mL) and methanol (10 mL) for 1 hr. The resultant mixture was evaporated to dryness and partitioned between methylene chloride and water. The organic layer was separated, dried, and evaporated to give 1-(2′,4′-difluorophenyl)-ethanol as a colorless oil (4.86 g, 96%). 1H NMR (300 MHz, CDCl3) δ 7.48 (m, 1H), 6.85 (m, 1H), 6.75 (m, 1H), 5.15 (q, 1H), 2.0 (s, 1H), 1.5 (d, 3H). 1-(2′,4′-difluorophenyl)-ethanol (5.384 g, 34 mmol), t-butyltrimethylsilyl chloride (6.148 g, 40.8 mmol) and imidazole (5.567 g, 81.8 mmol) in DMF (60 mL) were combined and stirred at rt overnight. The resultant mixture was evaporated to dryness in vacuo, and then the residue was partitioned between methylene chloride and water. The organic layer was separated, dried and evaporated to give 1-(2′,4′-difluorophenyl)-ethyl t-butyltrimethylsilyl ether as a white solid (6.88 g, 74%). 1H NMR (300 MHz, CDCl3) δ 7.45 (q, 1H), 6.75 (m, 1H), 6.62 (m, 1H), 5.05 (q, 1H), 1.32 (d, 3H), 0.88 (s, 9H), 0.05 and 0.01 (each s, each 3H). A 1.6 M solution of n-butyl lithium in hexane (3.75 mL, 6 mmol) was added dropwise to a solution of 1-(2′,4′-difluorophenyl)-ethyl t-butyltrimethylsilyl ether (1.362 g, 5 mmol) in THF (60 mL) at −50° C. and was stirred at the same temperature for 3 h. The reaction mixture was poured to dry ice; and then was evaporated to dryness. The residue was partitioned between methylene chloride and water, acidified with acetic acid. The organic layer was separated, dried, and evaporated to give 2,6-difluoro-3-(1-t-butyltrimethylsilyloxyethyl)-benzoic acid Compound 5A as white solid (1.57 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.70 (q, 1H), 7.00 (t, 1H), 6.00 (br, 1H), 5.15 (q, 1H), 1.40 (d, 3H), 0.90 (s, 9H), 0.12 and 0.05 (each s, each 3H). The resultant mixture was evaporated to dryness partitioned between methylene chloride and water The organic layer was separated dried evaporated