N-(1-phenylethylidene)hydroxylamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a magnetically stirred mixture of 4-amino-2-chloro-5-fluoropyrimidine (0.10 g, 0.68 mmol) and acetophenone oxime (0.092 g, 0.68 mmol) in dry DMF (3 mL) in a 5 mL Biotage Iniator microwave vessel was added NaH (0.027 g of a 60 wt. % suspension, 0.68 mmol) under a N2 atmosphere. After gas evolution ceased, the resulting mixture was sealed with a Biotage Initiator microwave septa cap and heated to 100° C. in a Biotage Initiator microwave for 60 min. The contents were poured into a vial with water (5 mL) and CH2Cl2 (5 mL), and neutralized with a few drops of 2NHCl. The phases were separated and the organic extract was dried over MgSO4, filtered, and evaporated under a stream of nitrogen. The crude contents were purified on silica (EtOAc/hexanes gradient) and evaporation of the product fractions gave 0.057 g (34%) of 1-Phenyl-ethanone-O-(4-amino-5-fluoro-pyrimidin-2-yl)oxime as an off-white solid: mp 163-165° C.; 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.6 Hz, 1H), 7.75 (m, 2H), 7.42 (m, 3H), 5.25 (bs, 2H), 2.51 (s, 3H); HPLC-MS (ESI) m/z 247 (M+H)+. the resulting mixture was sealed with a Biotage Initiator microwave septa cap The phases were separated the organic extract was dried over MgSO4 filtered evaporated under a stream of nitrogen The crude contents were purified on silica (EtOAc/hexanes gradient) and evaporation of the product fractions

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a magnetically stirred mixture of 4-amino-2-chloro-5-fluoropyrimidine (0.10 g, 0.68 mmol) and acetophenone oxime (0.092 g, 0.68 mmol) in dry DMF (3 mL) in a 5 mL Biotage Iniator microwave vessel was added NaH (0.027 g of a 60 wt. % suspension, 0.68 mmol) under a N2 atmosphere. After gas evolution ceased, the resulting mixture was sealed with a Biotage Initiator microwave septa cap and heated to 100° C. in a Biotage Initiator microwave for 60 min. The contents were poured into a vial with water (5 mL) and CH2Cl2 (5 mL), and neutralized with a few drops of 2NHCl. The phases were separated and the organic extract was dried over MgSO4, filtered, and evaporated under a stream of nitrogen. The crude contents were purified on silica (EtOAc/hexanes gradient) and evaporation of the product fractions gave 0.057 g (34%) of 1-Phenyl-ethanone-O-(4-amino-5-fluoro-pyrimidin-2-yl)oxime as an off-white solid: mp 163-165° C.; 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.6 Hz, 1H), 7.75 (m, 2H), 7.42 (m, 3H), 5.25 (bs, 2H), 2.51 (s, 3H); HPLC-MS (ESI) m/z 247 (M+H)+. the resulting mixture was sealed with a Biotage Initiator microwave septa cap The phases were separated the organic extract was dried over MgSO4 filtered evaporated under a stream of nitrogen The crude contents were purified on silica (EtOAc/hexanes gradient) and evaporation of the product fractions

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-methylamino-4-trifluoromethylsulfinylpyrazole (0.5 g, 1.1 mmol), acetophenone-oxime (0.165 g, 1.2 mmol), diisopropylethylamine (0.43 g, 3.3 mmol) and 4-dimethylaminopyridine (41 mg, 0.3 mmol) in tetrahydrofuran (15 ml) was added a toluene solution of phosgene (0.66 g, 20%, 1.2 mmol) at 0-5° C. The mixture was stirred at reflux for 2 hours. Extractive workup (heptane-ethyl acetate, water) and chromatography gave the title product (Compound 3-02, 0.14 g) as a solid; 1H-NMR: 2.25 (3H), 3.21 (3H), 7.42 and 7.68 (5H), 7.82 (2H); 19F-NMR: −64.3 (PhCF3); −72.9 (SO—CF3). at reflux for 2 hours

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-methylamino-4-trifluoromethylsulfinylpyrazole (0.5 g, 1.1 mmol), acetophenone-oxime (0.165 g, 1.2 mmol), diisopropylethylamine (0.43 g, 3.3 mmol) and 4-dimethylaminopyridine (41 mg, 0.3 mmol) in tetrahydrofuran (15 ml) was added a toluene solution of phosgene (0.66 g, 20%, 1.2 mmol) at 0-5° C. The mixture was stirred at reflux for 2 hours. Extractive workup (heptane-ethyl acetate, water) and chromatography gave the title product (Compound 3-02, 0.14 g) as a solid; 1H-NMR: 2.25 (3H), 3.21 (3H), 7.42 and 7.68 (5H), 7.82 (2H); 19F-NMR: −64.3 (PhCF3); −72.9 (SO—CF3). at reflux for 2 hours

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetophenone oxime (180 mg, 1.3 mmol) was dissolved in tetrahydrofuran (15 mL). Mixture was cooled to 0° C. 2.0M Butyllithium in pentanes (1.35 mL, 2.7 mmol) was added to the mixture drop-wise. Reaction stirred at 0° C. for 1 hour. A solution of tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (360 mg, 1.3 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture drop-wise. Reaction stirred at 0° C. for 1 hour. Reaction was quenched with aqueous ammonium chloride. Mixture was extracted 2× ethyl acetate. Combined extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as clear colorless oil in 71% yield. MS m/e (M−H)−=345.1. Reaction Reaction stirred at 0° C. for 1 hour Reaction was quenched with aqueous ammonium chloride Mixture was extracted 2× ethyl acetate Combined extracts were dried (magnesium sulfate) filtered concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetophenone (5.0 mL, 43 mmol) was dissolved in methanol (50 mL). Hydroxylamine hydrochloride (6.1 g, 88 mmol) was added to the mixture followed by 10N sodium hydroxide (10 mL, 100 mmol). Reaction was stirred at room temperature for 20 minutes. 10N Sodium hydroxide (5 mL, 50 mmol) was added to the mixture. Reaction was heated at reflux for 1 hour. Mixture was cooled to room temperature and stirred for 4 hours. Reaction mixture was concentrated in vacuo. Residue was treated with water. Mixture was extracted 2× diethyl ether. Combined extracts were washed 1× water, 1× brine. Organic layer was dried (magnesium sulfate), filtered and concentrated. Title compound was obtained as white solid in 76% yield. MS m/e (M+H)+=136.0. Reaction Reaction was heated at reflux for 1 hour Mixture was cooled to room temperature stirred for 4 hours Reaction mixture was concentrated in vacuo Residue was treated with water Mixture was extracted 2× diethyl ether Combined extracts were washed 1× water, 1× brine Organic layer was dried (magnesium sulfate) filtered concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetophenone oxime (180 mg, 1.3 mmol) was dissolved in tetrahydrofuran (15 mL). Mixture was cooled to 0° C. 2.0M Butyllithium in pentanes (1.35 mL, 2.7 mmol) was added to the mixture drop-wise. Reaction stirred at 0° C. for 1 hour. A solution of tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (360 mg, 1.3 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture drop-wise. Reaction stirred at 0° C. for 1 hour. Reaction was quenched with aqueous ammonium chloride. Mixture was extracted 2× ethyl acetate. Combined extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as clear colorless oil in 71% yield. Reaction Reaction stirred at 0° C. for 1 hour Reaction was quenched with aqueous ammonium chloride Mixture was extracted 2× ethyl acetate Combined extracts were dried (magnesium sulfate) filtered concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetophenone (5.0 mL, 43 mmol) was dissolved in methanol (50 mL). Hydroxylamine hydrochloride (6.1 g, 88 mmol) was added to the mixture followed by 10N sodium hydroxide (10 mL, 100 mmol). Reaction was stirred at room temperature for 20 minutes. 10N Sodium hydroxide (5 mL, 50 mmol) was added to the mixture. Reaction was heated at reflux for 1 hour. Mixture was cooled to room temperature and stirred for 4 hours. Reaction mixture was concentrated in vacuo. Residue was treated with water. Mixture was extracted 2× diethyl ether. Combined extracts were washed 1× water, 1× brine. Organic layer was dried (magnesium sulfate), filtered and concentrated. Title compound was obtained as white solid in 76% yield. MS m/e (M+H)+=136.0. Reaction Reaction was heated at reflux for 1 hour Mixture was cooled to room temperature stirred for 4 hours Reaction mixture was concentrated in vacuo Residue was treated with water Mixture was extracted 2× diethyl ether Combined extracts were washed 1× water, 1× brine Organic layer was dried (magnesium sulfate) filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Hydroxy-4-[2-({[1-phenylethylidene]amino}oxy)ethoxy]benzoic acid was prepared as a white solid (0.712 g, 27%) from 4-(2-bromo-ethoxy)-2-hydroxy-benzoic acid methyl ester and 1-phenyl-ethanone oxime using a procedure similar to that of step 1 of example 6. 1H NMR (400 MHz, DMSO-d6); δ 13.60 (bs, 1H), 11.50 (bs, 1H), 7.66 (m, 3H), 7.40 (m, 3H), 6.53 (dd, 1H), 6.52 (s, 1H), 4.44 (t, 2H), 4.32 (t, 2H), 2.18 (m, 2H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-phenyl-ethanone oxime (1.156 g, 8.55 mmol) in tetrahydrofuran (75 mL) was added 4-(2-bromo-ethoxy)-2-hydroxy-benzoic acid methyl ester (2.346 g, 8.52 mmol), tetrabutylammonium iodide (0.968 g, 2.62 mmol) and 15% sodium hydroxide solution (30 mL). The reaction was heated at reflux overnight, cooled to room temperature and the layers were separated. The aqueous layer was neutralized to pH 7 by the addition of concentrated hydrochloric acid and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (25/75)+1% formic acid to afford 2-hydroxy-4-[2-(1-phenyl-ethylideneaminooxy)-ethoxy]-benzoic acid (0.712 g, 27%) as a white solid. mp=149.1-150.4° C.; mass spectrum (+APCI, M+H) m/z 316. 1H NMR (400 MHz, DMSO-d6); δ 13.60 (bs, 1H), 11.50 (bs, 1H), 7.66 (m, 3H), 7.39 (m, 3H), 6.53 (m, 2H), 4.44 (t, 2H), 4.31 (t, 2H), 2.17 (s, 3H). Elemental analysis: Calcd. for C17H17NO5: C, 67.7; H, 5.43; N, 4.44, Found: C, 64.45; H, 5.32; N, 4.42. The reaction was heated at reflux overnight the layers were separated The aqueous layer was neutralized to pH 7 by the addition of concentrated hydrochloric acid extracted with ethyl acetate The combined organics were washed with brine dried over anhydrous magnesium sulfate concentrated in vacuo The residue was purified by flash chromatography