2-morpholin-4-ylacetonitrile

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: A reaction mixture was prepared from 203 ml. each of triethylamine and pyridine plus 63 g. of morpholinoacetonitrile. Hydrogen sulfide was bubbled through the heated, stirred reaction mixture for about 2.5 hours. Stirring was continued overnight at ambient temperature. The next day, H2S was passed through the heated, stirred reaction mixture for an additional 1.5 hours. At this point, the solvents were evaporated in vacuo and the residue triturated with ether. The ether was discarded and the residue dissolved in ethanol. Crystalline morpholinothioacetamide formed in the above reaction precipitated and was separated by filtration. Treatment of the filtrate with alcoholic hydrogen chloride yielded morpholinothioacetamide hydrochloride melting in the range 64°-80° C. See also J.A.C.S., 72, 2804 (1950). A reaction mixture was prepared from 203 ml Hydrogen sulfide was bubbled through the heated reaction mixture for about 2.5 hours Stirring stirred reaction mixture for an additional 1.5 hours At this point, the solvents were evaporated in vacuo the residue triturated with ether the residue dissolved in ethanol

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-morpholinoacetonitrile (37.7 mg, 0.299 mmol) in DMSO (0.5 mL) was treated with concentrated aqueous KOH (11M; 8.08 μL, 0.095 mmol). The reaction mixture was heated to 80° C. and a solution of N-(4′-amino-3′-formyl-6-methylbiphenyl-2-yl)-N,3,3-trimethylbutanamide (64 mg, 0.189 mmol) in DMSO (1 mL) was added dropwise. After 10 min the reaction mixture was diluted with water and aqueous saturated ammonium chloride solution. The aqueous mixture was extracted with DCM. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by preparative HPLC (10-100% water with 0.1% TFA/CH3CN, 11 min). The titled compound was isolated as a light-yellow foam. MS (ESI, pos. ion) m/z: 447 (M+1). The aqueous mixture was extracted with DCM The organic phase was separated dried over MgSO4 The solvent was removed under reduced pressure the remaining residue was purified by preparative HPLC (10-100% water with 0.1% TFA/CH3CN, 11 min)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-morpholinoacetonitrile (1.29 g, 10.26 mmol) in DMSO (13 mL) was added aqueous KOH (11.7 M, 0.276 mL, 3.23 mmol). The reaction was heated at 80° C., and a solution of 2-amino-5-bromo-4-fluorobenzaldehyde (1.41 g, 6.45 mmol) in DMSO (13 mL) was added dropwise over 2.5 h. The reaction mixture was stirred at 80° C. for 14 h. It was then cooled to RT and diluted with water (200 mL) and saturated NH4Cl (5 mL). The aqueous phase was extracted with DCM (2×200 mL). The organic fractions were combined, washed with half-saturated brine (4×300 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (150 mL) which had been deactivated with TEA (15 mL) eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N to afford 6-bromo-7-fluoro-3-morpholinoquinolin-2-amine. It was then cooled to RT The aqueous phase was extracted with DCM (2×200 mL) washed with half-saturated brine (4×300 mL) dried over sodium sulfate concentrated The residue was purified by column chromatography on silica gel (150 mL) which eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-morpholinoacetonitrile (1.29 g, 10.26 mmol) in DMSO (13 mL) was added aqueous KOH (11.7 M, 0.276 mL, 3.23 mmol). The reaction was heated at 80° C., and a solution of 2-amino-5-bromo-4-fluorobenzaldehyde (1.41 g, 6.45 mmol) in DMSO (13 mL) was added dropwise over 2.5 h. The reaction mixture was stirred at 80° C. for 14 h. It was then cooled to RT and diluted with water (200 mL) and saturated NH4Cl (5 mL). The aqueous phase was extracted with DCM (2×200 mL). The organic fractions were combined, washed with half-saturated brine (4×300 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (150 mL) which had been deactivated with TEA (15 mL) eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N to afford 6-bromo-7-fluoro-3-morpholinoquinolin-2-amine. It was then cooled to RT The aqueous phase was extracted with DCM (2×200 mL) washed with half-saturated brine (4×300 mL) dried over sodium sulfate concentrated The residue was purified by column chromatography on silica gel (150 mL) which eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 30 g of morpholine acetonitrile in 75 ml of ethyl acetate was added 22.5 ml of dimethyl sulfate, corresponding to approximately equivalent molar amounts of the two reagents. The resulting solution was mechanically stirred in an oil bath maintained at 40° C. After 10 minutes of stirring, a semi-solid precipitate having a brownish coloration formed and settled on the bottom of the flask. HPLC (high pressure liquid chromatography) analysis showed at least 4 undesirable side products, which were removed. The remaining solution was again heated to 40° C. and reacted for an additional 16 hours. After this time, the resulting white paste was filtered and washed with ethyl acetate. MMA was isolated after drying this filtrate as a free flowing off-white solid in 79% yield, having a melting point of 99-101° C. The purity of the MMA was determined by HPLC to be greater than 95%. After 10 minutes of stirring formed were removed The remaining solution was again heated to 40° C. reacted for an additional 16 hours After this time, the resulting white paste was filtered washed with ethyl acetate MMA was isolated after drying this filtrate as

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 30 g of morpholine acetonitrile in 75 ml of ethyl acetate was added 22.5 ml of dimethyl sulfate, corresponding to approximately equivalent molar amounts of the two reagents. The resulting solution was mechanically stirred in an oil bath maintained at 40° C. After 10 minutes of stirring, a semi-solid precipitate having a brownish coloration formed and settled on the bottom of the flask. HPLC (high pressure liquid chromatography) analysis showed at least 4 undesirable side products, which were removed. The remaining solution was again heated to 40° C. and reacted for an additional 16 hours. After this time, the resulting white paste was filtered and washed with ethyl acetate. MMA was isolated after drying this filtrate as a free flowing off-white solid in 79% yield, having a melting point of 99-101° C. The purity of the MMA was determined by HPLC to be greater than 95%. After 10 minutes of stirring formed were removed The remaining solution was again heated to 40° C. reacted for an additional 16 hours After this time, the resulting white paste was filtered washed with ethyl acetate MMA was isolated after drying this filtrate as

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 30 g of morpholine acetonitrile in 75 ml of ethyl acetate was added 22.5 ml of dimethyl sulfate, corresponding to approximately equivalent molar amounts of the two reagents. The resulting solution was mechanically stirred in an oil bath maintained at 40° C. After 10 minutes of stirring, a semi-solid precipitate having a brownish coloration formed and settled on the bottom of the flask. HPLC (high pressure liquid chromatography) analysis showed at least 4 undesirable side products, which were removed. The remaining solution was again heated to 40° C. and reacted for an additional 16 hours. After this time, the resulting white paste was filtered and washed with ethyl acetate. MMA was isolated after drying this filtrate as a free flowing off-white solid in 79% yield, having a melting point of 99°-101° C. The purity of the MMA was determined by HPLC to be greater than 95%. After 10 minutes of stirring formed were removed The remaining solution was again heated to 40° C. reacted for an additional 16 hours After this time, the resulting white paste was filtered washed with ethyl acetate MMA was isolated after drying this filtrate as

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 30 g of morpholine acetonitrile in 75 ml of ethyl acetate was added 22.5 ml of dimethyl sulfate, corresponding to approximately equivalent molar amounts of the two reagents. The resulting solution was mechanically stirred in an oil bath maintained at 40° C. After 10 minutes of stirring, a semi-solid precipitate having a brownish coloration formed and settled on the bottom of the flask. HPLC (high pressure liquid chromatography) analysis showed at least 4 undesirable side products, which were removed. The remaining solution was again heated to 40° C. and reacted for an additional 16 hours. After this time, the resulting white paste was filtered and washed with ethyl acetate. MMA was isolated after drying this filtrate as a free flowing off-white solid in 79% yield, having a melting point of 99°-101° C. The purity of the MMA was determined by HPLC to be greater than 95%. After 10 minutes of stirring formed were removed The remaining solution was again heated to 40° C. reacted for an additional 16 hours After this time, the resulting white paste was filtered washed with ethyl acetate MMA was isolated after drying this filtrate as

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

実験手順: A reaction mixture was prepared from 203 ml. each of triethylamine and pyridine plus 63 g. of morpholinoacetonitrile. Hydrogen sulfide was bubbled through the heated, stirred reaction mixture for about 2.5 hours. Stirring was continued overnight at ambient temperature. The next day, H2S was passed through the heated, stirred reaction mixture for an additional 1.5 hours. At this point, the solvents were evaporated in vacuo and the residue triturated with ether. The ether was discarded and the residue dissolved in ethanol. Crystalline morpholinothioacetamide formed in the above reaction precipitated and was separated by filtration. Treatment of the filtrate with alcoholic hydrogen chloride yielded morpholinothioacetamide hydrochloride melting in the range 64°-80° C. See also J.A.C.S., 72, 2804 (1950). A reaction mixture was prepared from 203 ml Hydrogen sulfide was bubbled through the heated reaction mixture for about 2.5 hours Stirring stirred reaction mixture for an additional 1.5 hours At this point, the solvents were evaporated in vacuo the residue triturated with ether the residue dissolved in ethanol

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To anhydrous THF (35 mL) was added LiAlH4 (3.19 g, 84 mmol) in one portion in an ice bath. The mixture was stirred at 0° C. for 20 min, and a solution of 2-morpholinoacetonitrile (3.50 g, 28 mmol) in anhydrous THF (10 mL) was added dropwise. Upon the end of addition the mixture was refluxed for 3 h, then cooled to rt, diluted with water (20 mL), filtered and concentrated in vacuo to give the title compound as yellow oil (2.62 g, 72%). Upon the end of addition the mixture was refluxed for 3 h cooled to rt filtered concentrated in vacuo

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

実験手順: To a suspension of K2CO3 (6.50 g, 47 mmol) and morpholine (3.75 g, 43 mmol) in acetonitrile (30 mL) was added 2-bromoacetonitrile (5.16 g, 43 mmol) in one portion under the protection of N2 in an ice bath. The mixture was stirred at rt for 2 h, then filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (5.41 g, 100%). filtered The filtrate was concentrated in vacuo