ethyl 2,2-difluoropropanoate

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

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

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

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

Procedure: Ethyl 2,2-difluoropropanoate (400 μl) and (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 135 mg, 0.34 mmol) was heated to 150° C. for 30 min. Then it was diluted with acetonitrile and purified by semiprep HPLC followed by flash chromatography on silica gel (n-heptane/ethyl acetate, 4:1) Yield 60 mg (36%). purified by semiprep HPLC

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

Procedure: Ethyl 2,2-difluoropropanoate (400 μl) and (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 135 mg, 0.34 mmol) was heated to 150° C. for 30 min. Then it was diluted with acetonitrile and purified by semiprep HPLC followed by flash chromatography on silica gel (n-heptane/ethyl acetate, 4:1) Yield 60 mg (36%). purified by semiprep HPLC

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a round bottomed flask flushed with argon, a suspension of sodium hydride 60% in mineral oil (1.30 g, 34 mmoles) was rinsed twice with hexane, and suspended in 20 mL of dry THF. The solution was heated to 75° C., and ethyl difluoropropionate (3.00 g, 22 mmoles) and acetonitrile (1.78 mL) in 5 ml of dry THF was added dropwise over 30 minutes. The temperature of the reaction was lowered to 65° C. and stirred overnight. The mixture was then concentrated to an oil and partitioned between water and ether, and extracted twice to remove any mineral oil and other impurities. The aqueous layer was acidified to pH=1 with 10% HCl, and the solution extracted twice. These extracts were dried over magnesium sulfate, filtered and concentrated to a crude oil. The crude product was purified using silica gel chromatography using a gradient of 10-40% ethyl acetate/hexane to afford 4,4-difluoro-3-oxo-pentanenitrile 1H (300 MHz, CDCl3) δ 3.95 (s, 2H), 1.86 (m, 3H). In a round bottomed flask flushed with argon was rinsed twice with hexane was lowered to 65° C. The mixture was then concentrated to an oil partitioned between water and ether extracted twice to remove any mineral oil and other impurities the solution extracted twice These extracts were dried over magnesium sulfate filtered concentrated to a crude oil The crude product was purified

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

Procedure: 2,2-Difluoro-propionic acid ethyl ester I-3a (10.1 g, 70 mmol) was added dropwise to stirred, cooled (0° C.) ethanolamine (4.4 ml, 70 mmol) and the resulting solution was allowed to stir at ambient temperature for 4 hours. Concentration of the reaction mixture in vacuo afforded the title compound (I-3b) as a solid, 11.2 g. to stir at ambient temperature for 4 hours

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

Procedure: 2,2-Difluoro-propionic acid ethyl ester I-3a (10.1 g, 70 mmol) was added dropwise to stirred, cooled (0° C.) ethanolamine (4.4 ml, 70 mmol) and the resulting solution was allowed to stir at ambient temperature for 4 hours. Concentration of the reaction mixture in vacuo afforded the title compound (I-3b) as a solid, 11.2 g. to stir at ambient temperature for 4 hours

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

Procedure: Lithium hexamethyldisilazide (150 ml of a 1M solution in THF, 0.15 mol) was cooled in an argon athmosphere to −78° C. and ethyl acetate (15 ml, 0.14 mol) was added dropwise with stirring. Stirring was continued for one hour at −78° C., then ethyl 2,2-difluoropropionate (12 g, 0.089 mol) was added dropwise with stirring. Stirring was continued for four hours at −78° C., then a saturated solution of ammonium chloride (175 ml) was added dropwise. The mixture was allowed to reach room temperature, acidified with 1M HCl (50 ml) and left standing overnight. The phases were separated. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with 1M HCl, brine, dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by vacuum distillation (54 mbar, 130° C.) to yield 12.4 g (0.068 mmol, 77%) of a colourless liquid that was used directly in the next step. Stirring with stirring Stirring was continued for four hours at −78° C. to reach room temperature left standing overnight The phases were separated The aqueous phase was extracted with ethyl acetate the combined organic phases were washed with 1M HCl, brine dried over sodium sulfate The solvent was removed under reduced pressure the residue was purified by vacuum distillation (54 mbar, 130° C.)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a round bottomed flask flushed with argon, a suspension of sodium hydride 60% in mineral oil (1.30 g, 34 mmoles) was rinsed twice with hexane, and suspended in 20 mL of dry THF. The solution was heated to 75° C., and ethyl difluoropropionate (3.00 g, 22 mmoles) and acetonitrile (1.78 mL) in 5 ml of dry THF was added dropwise over 30 minutes. The temperature of the reaction was lowered to 65° C. and stirred overnight. The mixture was then concentrated to an oil and partitioned between water and ether, and extracted twice to remove any mineral oil and other impurities. The aqueous layer was acidified to pH=1 with 10% HCl, and the solution extracted twice. These extracts were dried over magnesium sulfate, filtered and concentrated to a crude oil. The crude product was purified using silica gel chromatography using a gradient of 10-40% ethyl acetate/hexane to afford 4,4-difluoro-3-oxo-pentanenitrile 1H(300 MHz, CDCl3) δ 3.95 (s, 2H), 1.86 (m, 3H). In a round bottomed flask flushed with argon was rinsed twice with hexane was lowered to 65° C. The mixture was then concentrated to an oil partitioned between water and ether extracted twice to remove any mineral oil and other impurities the solution extracted twice These extracts were dried over magnesium sulfate filtered concentrated to a crude oil The crude product was purified

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Intermediate 1 was added to a stirring solution of NaOEt prepared from sodium (FLUKA, 3.28 g, 143 mmol) and ethanol (150 ml) and the mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled down to room temperature and ethyl 2,2-difluoropropanoate (FLUOROCHEM, 11.83 g, 86 mmol) was added. The mixture was stirred at room temperature for 30 min before being heated to 80° C. for 1.5 h. The reaction mixture was concentrated to dryness and water (200 mL) was added. The reaction mixture pH was adjusted to 4 by addition of 2N HCl solution while a white solid precipitated. The solid was filtered, washed with water and dried under vacuum to afford Intermediate 2. The mother liquors were extracted with DCM (5×35 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give more Intermediate 2 as a white solid. The reaction mixture was cooled down to room temperature before being heated to 80° C. for 1.5 h The reaction mixture was concentrated to dryness and water (200 mL) was added The reaction mixture pH was adjusted to 4 by addition of 2N HCl solution while a white solid precipitated The solid was filtered washed with water dried under vacuum

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Intermediate 1 was added to a stirring solution of NaOEt prepared from sodium (FLUKA, 3.28 g, 143 mmol) and ethanol (150 ml) and the mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled down to room temperature and ethyl 2,2-difluoropropanoate (FLUOROCHEM, 11.83 g, 86 mmol) was added. The mixture was stirred at room temperature for 30 min before being heated to 80° C. for 1.5 h. The reaction mixture was concentrated to dryness and water (200 mL) was added. The reaction mixture pH was adjusted to 4 by addition of 2N HCl solution while a white solid precipitated. The solid was filtered, washed with water and dried under vacuum to afford Intermediate 2. The mother liquors were extracted with DCM (5×35 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give more Intermediate 2 as a white solid. The reaction mixture was cooled down to room temperature before being heated to 80° C. for 1.5 h The reaction mixture was concentrated to dryness and water (200 mL) was added The reaction mixture pH was adjusted to 4 by addition of 2N HCl solution while a white solid precipitated The solid was filtered washed with water dried under vacuum