methyl 1-methylcyclopropane-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add acetonitrile (87 mL, 1.6 mol) to a suspension of sodium hydride (66 g, 1.6 mol) in THF (700 mL) at room temperature and stir 10 minutes. Then add 1-methyl-cyclopropanecarboxylic acid methyl ester (90.0 g, 0.78 mol) and reflux the white slurry for 3 hours. Cool the mixture, then add methanol (200 mL) and pour the mixture over water (500 mL). Separate the phases and reduce the pH of the aqueous phase with 1.0N HCl until pH 3-4. Extract the aqueous phase with diethyl ether (2×350 mL), combine the organic layers and wash with aqueous sodium chloride. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile as yellow oil. 1H NMR (CDCl3): 3.59 (s, 2H), 1.37 (s, 3H), 1.30 (q, J=4 Hz, 2H), 0.86 (q, J=4 Hz, 2H). Cool the mixture Separate the phases Extract the aqueous phase with diethyl ether (2×350 mL) wash with aqueous sodium chloride Dry over sodium sulfate filter concentrate under reduced pressure

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of diisopropylamine (7.43 mL, 52.6 mmol) in 60 mL of THF was added n-BuLi (2.5M) (21.03 mL, 52.6 mmol) at −78° C. The reaction was stirred at −78° C. for 30 min, then acetononitrile (2.76 mL, 52.6 mmol) was added at −78° C. and the reaction was stirred for 30 min, then methyl 1-methylcyclopropanecarboxylate (3 g, 52.6 mmol) was added at −78° C. The reaction was stirred at −78° C. for 1 h and then allowed to warm up at rt overnight. The solvent was evaporated and the solid dissolved in water. The aqueous layer was washed with ether and then acidified with 6N HCl to pH 2-3. The aqueous layer was extracted with ether. The organic layer was dried with MgSO4 and concentrated to afford the title compound (2.89 g, 89%). MS (DCI/NH3) m/z 124 (M+H)+. was added at −78° C. the reaction was stirred for 30 min The reaction was stirred at −78° C. for 1 h to warm up at rt overnight The solvent was evaporated the solid dissolved in water The aqueous layer was washed with ether The aqueous layer was extracted with ether The organic layer was dried with MgSO4 concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 61.1 g of acetonitrile and 108.3 g of methyl 1-methylcyclopropanecarboxylate was added drop-by-drop over a one-hour period to a stirred, refluxing mixture of 35.8 g of sodium hydride and 650 ml of tetrahydrofuran. The resulting mixture was stirred and refluxed for a further 18 hours, then most of the solvent was evaporated in a rotary evaporator. The residue was dissolved in 1 liter of water, and the solution was acidified with hydrochloric acid and extracted with ether. The extract was dried (MgSO4) and concentrated. The residue, a liquid, was fractionally distilled to give (1-methylcyclopropylcarbonyl)acetonitrile (D) as a colorless oil which crystallized on standing, m.p.: 32°-33° C. was added drop-by-drop over a one-hour period to a stirred refluxing refluxed for a further 18 hours most of the solvent was evaporated in a rotary evaporator The residue was dissolved in 1 liter of water extracted with ether The extract was dried (MgSO4) concentrated The residue, a liquid, was fractionally distilled

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of diisopropylamine (7.43 ml, 52.6 mmol) in 60 mL of THF at −78° C. was added a solution of n-BuLi in hexanes (2.5M, 21.0 mL, 52.6 mmol). The mixture was stirred at −78° C. for 30 min then acetononitrile (2.76 ml, 52.6 mmol) was added. After 30 min, methyl 1-methylcyclopropanecarboxylate (3.0 g, 52.6 mmol) was added and the reaction mixture was stirred at −78° C. for 1 hour then allowed to warm to room temperature and stirred overnight. The mixture was concentrated and the residue was diluted with water and extracted with ether. The aqueous phase was acidified with 6N aqueous HCl to pH 2-3 and extracted with ether. The combined organic extracts were dried over MgSO4, filtered, and concentrated to afford the title compound 2.89 g (89%). MS (DCI/NH3) m/z 124 (M+H)+. was added After 30 min the reaction mixture was stirred at −78° C. for 1 hour to warm to room temperature stirred overnight The mixture was concentrated the residue was diluted with water extracted with ether extracted with ether The combined organic extracts were dried over MgSO4 filtered concentrated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of diisopropylamine (7.43 mL, 52.6 mmol) in 60 mL of THF was added n-BuLi (2.5M) (21.03 mL, 52.6 mmol) at −78° C. The reaction was stirred at −78° C. for 30 min, then acetononitrile (2.76 mL, 52.6 mmol) was added at −78° C. and the reaction was stirred for 30 min, then methyl 1-methylcyclopropanecarboxylate (3 g, 52.6 mmol) was added at −78° C. The reaction was stirred at −78° C. for 1 hour and then allowed to warm up at room temperature overnight. The solvent was evaporated and the solid dissolved in water. The aqueous layer was washed with ether and then acidified with 6N HCl to pH 2-3. The aqueous layer was extracted with ether. The organic layer was dried with MgSO4 and concentrated to afford the title compound (2.89 g, 89%). MS (DCI/NH3) m/z 124 (M+H)+. was added at −78° C. the reaction was stirred for 30 min The reaction was stirred at −78° C. for 1 hour to warm up at room temperature overnight The solvent was evaporated the solid dissolved in water The aqueous layer was washed with ether The aqueous layer was extracted with ether The organic layer was dried with MgSO4 concentrated

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The synthetic intermediate 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-5-(1-methyl-cyclopropyl)-4-phenyl -4,5-dihydro-isoxazol-5-ol (0.833 g) is prepared from Example 1, Compound B and 1-methyl-cyclopropanecarboxylic acid methyl ester by the general method described in Step A of Example 35.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The synthetic intermediate 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-5-(1-methyl-cyclopropyl)-4-phenyl -4,5-dihydro-isoxazol-5-ol (0.833 g) is prepared from Example 1, Compound B and 1-methyl-cyclopropanecarboxylic acid methyl ester by the general method described in Step A of Example 35.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The synthetic intermediate 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-5-(1-methyl-cyclopropyl)-4-phenyl -4,5-dihydro-isoxazol-5-ol (0.833 g) is prepared from Example 1, Compound B and 1-methyl-cyclopropanecarboxylic acid methyl ester by the general method described in Step A of Example 35.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Combine lithium diisopropylamide (LDA, 2.0 M/heptanes; Aldrich; 2.2 eq, 88 mmol, 44 mL) with THF (1.5 mL/mmol; 60 mL) and cool to −78° C. Combine methyl 1-methylcyclopropane carboxylate (TCI US; 4.56 g, 40 mmol) and CH3CN (4.20 mL, 80 mmol) in THF (10 mL) and add slowly with stirring. Stir the mixture at −65 to −78° C. for 1 hour, then remove the bath and warm the mixture to room temperature. Concentrate the reaction mixture to a slurry under reduced pressure. Add hexanes (150 mL) to form a precipitate from the slurry. Collect the solid by vacuum filtration and wash with hexanes (2×50 mL). Replace the catch flask with a clean one, and dissolve the solid on the frit in 50 mL 2.5 M HCl and collect in the flask. Rinse with 20 mL 2.5 M HCl followed by 200 mL Et2O. Separate the layers in the filtrate and extract the acidic phase with Et2O (150 mL). Combine the Et2O organic phases, dry with MgSO4, filter and concentrate under reduced pressure to yield 3-(1-Methyl-cyclopropyl)-3-oxo-propionitrile as a clear amber oil (3.58 g, 29.1 mmol, 73%). Use without purification in reaction with tolylhydrazine hydrochloride (5.23 g, 33.0 mmol) and ethanol (2 mL/mmol) at reflux for 20 hr. Cool the reaction mixture to room temperature and concentrate under reduced pressure. Dilute the residue with ethyl acetate (250 mL) and wash with water (2×60 mL), saturated aq. NaHCO3 (60 mL) and saturated aq. sodium chloride (60 mL). Dry the organic phase with MgSO4, filter and concentrate by rotary evaporation. Subject residue to silica gel chromatography eluting with a gradient of ethyl acetate and hexane to provide 5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (4.2238 g, 18.5 mmol, 46%). LCMS (ES+): m/z=228.2 [M+H]. Stir the mixture at −65 to −78° C. for 1 hour remove the bath Concentrate the reaction mixture to a slurry under reduced pressure Add hexanes (150 mL) to form a precipitate from the slurry Collect the solid by vacuum filtration wash with hexanes (2×50 mL) Replace the catch flask with a clean one, and dissolve the solid on the frit in 50 mL 2.5 M HCl collect in the flask Rinse with 20 mL 2.5 M HCl Separate the layers in the filtrate extract the acidic phase with Et2O (150 mL) Combine the Et2O organic phases, dry with MgSO4 filter concentrate under reduced pressure

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of diisopropylamine (7.43 ml, 52.6 mmol) in 60 mL of THF at −78° C. was added a solution of n-BuLi in hexanes (2.5M, 21.0 mL, 52.6 mmol). The mixture was stirred at −78° C. for 30 min then acetononitrile (2.76 ml, 52.6 mmol) was added. After 30 min, methyl 1-methylcyclopropanecarboxylate (3.0 g, 52.6 mmol) was added and the reaction mixture was stirred at −78° C. for 1 hour then allowed to warm to room temperature and stirred overnight. The mixture was concentrated and the residue was diluted with water and extracted with ether. The aqueous phase was acidified with 6N aqueous HCl to pH 2-3 and extracted with ether. The combined organic extracts were dried over MgSO4, filtered, and concentrated to afford the title compound 2.89 g (89%). MS (DCI/NH3) m/z 124 (M+H)+. was added After 30 min the reaction mixture was stirred at −78° C. for 1 hour to warm to room temperature stirred overnight The mixture was concentrated the residue was diluted with water extracted with ether extracted with ether The combined organic extracts were dried over MgSO4 filtered concentrated