O-(2,2,2-trifluoroethyl)hydroxylamine;hydrochloride

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

Procedure: To an ethanol (6 mL) suspension of 0.20 g of ethyl=4-{3-[4-(3-{4-[ethoxy(imino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzimidate were added 0.61 g of O-(2,2,2-trifluoroethyl)hydroxylamine hydrochloride and 0.84 mL of triethylamine at room temperature, which was then stirred at the same temperature for one week. Chloroform and water were added to the reaction solution. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and then dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:ethanol=30:1), to which hexane was then added, followed by collecting the solid by filtration to provide 0.12 g of 4-{3-[4-(3-{4-[amino(2,2,2-trifluoroethoxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-(2,2,2-trifluoroethyl)oxime as white solid form. The organic layer was separated washed with a saturated sodium chloride aqueous solution dried with anhydrous magnesium sulfate by distilling off the solvent under reduced pressure The resultant residue was purified to which hexane was then added by collecting the solid by filtration

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

Procedure: 2,2,2-Trifluoroethoxyamine hydrochloride (37 mg, 0.24 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (50 mg, 0.16 mmol) in methanol (4 mL). The reaction mixture was stirred at room temperature for 3 hours. After concentration to dryness the residue was diluted by addition of dichloromethane (50 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (1×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using ethyl acetate/methanol (95:5) as eluent to obtain the title product as a white solid (47 mg, 50%). After concentration to dryness the residue was diluted by addition of dichloromethane (50 mL) and saturated sodium bicarbonate solution (10 mL) The aqueous phase was extracted with dichloromethane (2×40 mL) The combined organic phases were washed with a saturated solution of sodium chloride (1×20 mL) dried over sodium sulfate filtered concentrated to dryness The residue was purified by chromatography on silica gel

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

Procedure: 2,2,2-Trifluoroethoxyamine hydrochloride (37 mg, 0.24 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (50 mg, 0.16 mmol) in methanol (4 mL). The reaction mixture was stirred at room temperature for 3 hours. After concentration to dryness the residue was diluted by addition of dichloromethane (50 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (1×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using ethyl acetate/methanol (95:5) as eluent to obtain the title product as a white solid (47 mg, 50%). After concentration to dryness the residue was diluted by addition of dichloromethane (50 mL) and saturated sodium bicarbonate solution (10 mL) The aqueous phase was extracted with dichloromethane (2×40 mL) The combined organic phases were washed with a saturated solution of sodium chloride (1×20 mL) dried over sodium sulfate filtered concentrated to dryness The residue was purified by chromatography on silica gel

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

Procedure: 2,2,2-Trifluoroethoxyamine hydrochloride (37 mg, 0.24 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (50 mg, 0.16 mmol) in methanol (4 mL). The reaction mixture was stirred at room temperature for 3 hours. After concentration to dryness the residue was diluted by addition of dichloromethane (50 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (1×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using ethyl acetate/methanol (95:5) as eluent to obtain the title product as a white solid (47 mg, 50%). After concentration to dryness the residue was diluted by addition of dichloromethane (50 mL) and saturated sodium bicarbonate solution (10 mL) The aqueous phase was extracted with dichloromethane (2×40 mL) The combined organic phases were washed with a saturated solution of sodium chloride (1×20 mL) dried over sodium sulfate filtered concentrated to dryness The residue was purified by chromatography on silica gel

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

Procedure: A suspension of 2-(2-formylaminothiazol-4-yl)-glyoxylic acid (3.0 g) in methanol (60 ml) and water (60 ml) was adjusted to pH 8 with 1 N aqueous solution of sodium hydroxide under stirring. To the solution was added 2,2,2-trifluoroethoxyamine hydrochloride (2.24 g) and then adjusted to pH 2.5 to 3 with 1 N aqueous solution of sodium hydroxide. After the solution was stirred at ambient temperature for 1.5 hours, methanol was removed from the resultant solution under reduced pressure. The remaining aqueous solution was adjusted to pH 7 with 1 N aqueous solution of sodium hydroxide and then washed with ethyl acetate. To the aqueous solution was added ethyl acetate and then adjusted to pH 1.5 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated under reduced pressure to give 2-(2,2,2-trifluoroethoxyimino)-2-(2-formylaminothiazol-4-yl)acetic acid (syn isomer) (2.4 g), mp 162° to 163° C. (dec.). After the solution was stirred at ambient temperature for 1.5 hours methanol was removed from the resultant solution under reduced pressure washed with ethyl acetate To the aqueous solution was added ethyl acetate extracted with ethyl acetate The extract was washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate evaporated under reduced pressure

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

Procedure: To an ethanol (6 mL) suspension of 0.20 g of ethyl=4-{3-[4-(3-{4-[ethoxy(imino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzimidate were added 0.61 g of O-(2,2,2-trifluoroethyl)hydroxylamine hydrochloride and 0.84 mL of triethylamine at room temperature, which was then stirred at the same temperature for one week. Chloroform and water were added to the reaction solution. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and then dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:ethanol=30:1), to which hexane was then added, followed by collecting the solid by filtration to provide 0.12 g of 4-{3-[4-(3-{4-[amino(2,2,2-trifluoroethoxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-(2,2,2-trifluoroethyl)oxime as white solid form. The organic layer was separated washed with a saturated sodium chloride aqueous solution dried with anhydrous magnesium sulfate by distilling off the solvent under reduced pressure The resultant residue was purified to which hexane was then added by collecting the solid by filtration

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

Procedure: 2,2,2-Trifluoroethoxyamine hydrochloride (37 mg, 0.24 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (50 mg, 0.16 mmol) in methanol (4 mL). The reaction mixture was stirred at room temperature for 3 hours. After concentration to dryness the residue was diluted by addition of dichloromethane (50 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (1×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using ethyl acetate/methanol (95:5) as eluent to obtain the title product as a white solid (47 mg, 50%). After concentration to dryness the residue was diluted by addition of dichloromethane (50 mL) and saturated sodium bicarbonate solution (10 mL) The aqueous phase was extracted with dichloromethane (2×40 mL) The combined organic phases were washed with a saturated solution of sodium chloride (1×20 mL) dried over sodium sulfate filtered concentrated to dryness The residue was purified by chromatography on silica gel