恶烷-4-腈

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Obtained by operating as in example 87a, from 6.3 g (62.2 mmoles) of diisopropylamine in 104 ml of tetrahydrofuran, 38.7 ml (62.0 mmoles) of a 1.6M solution of n-butyllithium in hexane, 9.3 g of 1,3-dimethylimidazolidin-2-one, 8.8 g (56.7 mmoles) of 2,3,5,6-tetrahydro-4H-pyran-4-carbonitrile (prepared according to Gibson C. S. and Johnson J. D. A., J. Chem. Soc. (1930), 2525-30) in 93 ml tetrahydrofuran and 17.7 g (62 mmoles) of the compound prepared in example 26a. After purification by chromatography on a column of silica in a hexane-ethyl acetate (1:1) mixture, there is obtained 10.5 g (yield=75.5%) oil. Obtained prepared After purification by chromatography on a column of silica in a hexane-ethyl acetate (1:1) mixture

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Obtained by operating as in example 87a, from 6.3 g (62.2 mmoles) of diisopropylamine in 104 ml of tetrahydrofuran, 38.7 ml (62.0 mmoles) of a 1.6M solution of n-butyllithium in hexane, 9.3 g of 1,3-dimethylimidazolidin-2-one, 8.8 g (56.7 mmoles) of 2,3,5,6-tetrahydro-4H-pyran-4-carbonitrile (prepared according to Gibson C. S. and Johnson J. D. A., J. Chem. Soc. (1930), 2525-30) in 93 ml tetrahydrofuran and 17.7 g (62 mmoles) of the compound prepared in example 26a. After purification by chromatography on a column of silica in a hexane-ethyl acetate (1:1) mixture, there is obtained 10.5 g (yield=75.5%) oil. Obtained prepared After purification by chromatography on a column of silica in a hexane-ethyl acetate (1:1) mixture

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirring solution of 2,4,6-trichloropyridine (4.65 g, 24.7 mmol) and tetrahydropyran-4-carbonitrile (2.29 g, 20.6 mmol) in THF (100 mL, 0.2 M) and under nitrogen at −78° C. was added lithium bis(trimethylsilyl)amide (29 mL, 29 mmol, 1.0 M in THF) and after 5 min, the cooling bath was removed. After stirring a further 40 min, the reaction was quenched by the addition of sat. aq. NH4Cl and then concentrated. The mixture was extracted with CH2Cl2 and organics dried over MgSO4. Following concentration, the residue was purified by flash column chromatography (100:0-70:30 heptanes/EtOAc) but care needed to be taken to prevent compound precipitation on the column. After purification, 4-(2,6-dichloro-4-pyridyl)tetrahydropyran-4-carbonitrile was obtained a white solid (3.75 g, 71%); 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=0.6 Hz, 2H), 4.17-4.05 (m, 2H), 3.93-3.84 (m, 2H), 2.15-1.99 (m, 4H). the cooling bath was removed the reaction was quenched by the addition of sat. aq. NH4Cl concentrated The mixture was extracted with CH2Cl2 organics dried over MgSO4 concentration the residue was purified by flash column chromatography (100:0-70:30 heptanes/EtOAc) compound precipitation on the column After purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of tetrahydropyran-4-carbonitrile (5.00 g) and THF (50 ml) was admixed at 0° C. with lithium hexamethyldisilazide (1 M, 63 ml) and, after 90 minutes, methyl iodide (4.26 ml) was added dropwise with good cooling. After 12 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was dissolved in THF (200 ml), and lithium aluminum hydride (3.79 g) was added. The mixture was boiled at reflux for 6 hours. Water (3.8 ml) and then sodium hydroxide solution (40%; 3.8 ml) were cautiously added dropwise to the cooled suspension. The precipitate was filtered off and the filtrate was concentrated. This afforded the product with the molecular weight of 129.20 (C7H15NO); MS (ESI): 130 (M+H+). the reaction mixture was partitioned between water and ethyl acetate The organic phase was dried over sodium sulfate concentrated The residue was dissolved in THF (200 ml) lithium aluminum hydride (3.79 g) was added at reflux for 6 hours Water (3.8 ml) and then sodium hydroxide solution (40%; 3.8 ml) were cautiously added dropwise to the cooled suspension The precipitate was filtered off the filtrate was concentrated This afforded the product with the molecular weight of 129.20 (C7H15NO)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2,3-dichloropyrazine (1.219 g, 8.18 mmol) and tetrahydro-2H-pyran-4-carbonitrile (1 g, 9.00 mmol) in Toluene (16.36 mL) at room temperature was added LiHMDS (18.00 mL, 18.00 mmol) dropwise. The reaction mixture was stirred overnight at room temperature. Reaction was quenched with saturated NH4Cl and extracted with EtOAc. Two purifications with Biotage (0-10% MeOH/DCM & 0-100% EtOAc/Hexane) were conducted to isolate product. Reaction was quenched with saturated NH4Cl extracted with EtOAc to isolate product

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2,3-dichloropyrazine (1.219 g, 8.18 mmol) and tetrahydro-2H-pyran-4-carbonitrile (1 g, 9.00 mmol) in Toluene (16.36 mL) at room temperature was added LiHMDS (18.00 mL, 18.00 mmol) dropwise. The reaction mixture was stirred overnight at room temperature. Reaction was quenched with saturated NH4Cl and extracted with EtOAc. Two purifications with Biotage (0-10% MeOH/DCM & 0-100% EtOAc/Hexane) were conducted to isolate product. Reaction was quenched with saturated NH4Cl extracted with EtOAc to isolate product

反应条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: KHMDS 1 M in THF (0.758 mL) was added dropwise to a mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 100 mg, 0.253 mmol) and tetrahydro-2h-pyran-4-carbonitrile (42.1 mg, 0.379 mmol) in THF (2.5 mL), under a nitrogen atmosphere. The RM was stirred at −70° C. for 1 h, and allowed to warm to RT overnight. The RM was quenched with water and the solvent was evaporated off under reduced pressure to afford 5-bromo-6-(4-cyanotetrahydro-2h-pyran-4-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, of which (50 mg, 0.106 mmol), Pd(Ph3P)4 (18 mg, 0.016 mmol), pyrimidin-5-ylboronic acid (20 mg, 0.159 mmol), K3PO4 (68 mg, 0.319 mmol) and toluene (1.3 mL) were added to a vial, which was sealed, evacuated/purged with argon. The RM was stirred at 110° C. for 3 h, diluted with MeOH, filtered through a cartridge PL-Thiol MP-Resin and concentrated the combined filtrates were evaporated to dryness under reduced pressure. The crude product was purified by preparative SFC (Column 2-EP, gradient: 6% to 11% in 6 min) and lyophilized to afford an off-white powder. UPLC-MS (Condition 2) tR=1.2 min, m/z=469.9 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 2.00 (d, J=13.55 Hz, 2H) 2.40 (td, J=13.08, 3.95 Hz, 2H) 3.52 (t, J=12.14 Hz, 2H) 3.94 (d, J=8.66 Hz, 2H) 7.39 (d, J=8.66 Hz, 2H) 7.86 (d, J=8.85 Hz, 2H) 8.30 (s, 1H) 8.96 (s, 2H) 9.23 (d, J=1.13 Hz, 1H) 9.32 (s, 1H) 10.67 (s, 1H). to warm to RT overnight The RM was quenched with water the solvent was evaporated off under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Combined tetrahydro-2H-pyran-4-carbonitrile (1.000 g, 9.00 mmol) and titanium (IV)isopropoxide (2.90 mL, 9.90 mmol) in ether (45.0 mL), then ethylmagnesium bromide (6.60 mL, 19.79 mmol) was added and the reaction was allowed to warm to room temperature for 1 hour. The reaction was stirred for an additional 30 minutes and boron trifluoride etherate (2.280 mL, 18.0 mmol) was added and the reaction was stirred for 2 hours. The reaction was then diluted with 10 mL water and 20 mL 1 N HCl and extracted twice with 200 mL EtOAc. The organic layers were combined and concentrated to afford the title compound (850 mg, 53.5%) as a yellow oil. the reaction was stirred for 2 hours extracted twice with 200 mL EtOAc concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Combined tetrahydro-2H-pyran-4-carbonitrile (1.000 g, 9.00 mmol) and titanium (IV)isopropoxide (2.90 mL, 9.90 mmol) in ether (45.0 mL), then ethylmagnesium bromide (6.60 mL, 19.79 mmol) was added and the reaction was allowed to warm to room temperature for 1 hour. The reaction was stirred for an additional 30 minutes and boron trifluoride etherate (2.280 mL, 18.0 mmol) was added and the reaction was stirred for 2 hours. The reaction was then diluted with 10 mL water and 20 mL 1 N HCl and extracted twice with 200 mL EtOAc. The organic layers were combined and concentrated to afford the title compound (850 mg, 53.5%) as a yellow oil. the reaction was stirred for 2 hours extracted twice with 200 mL EtOAc concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2,3-dichloropyrazine (1.219 g, 8.18 mmol) and tetrahydro-2H-pyran-4-carbonitrile (1 g, 9.00 mmol) in Toluene (16.36 mL) at room temperature was added LiHMDS (18.00 mL, 18.00 mmol) dropwise. The reaction mixture was stirred overnight at room temperature. Reaction was quenched with saturated NH4Cl and extracted with EtOAc. Two purifications with Biotage (0-10% MeOH/DCM & 0-100% EtOAc/Hexane) were conducted to isolate product. Reaction was quenched with saturated NH4Cl extracted with EtOAc to isolate product

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2,3-dichloropyrazine (1.219 g, 8.18 mmol) and tetrahydro-2H-pyran-4-carbonitrile (1 g, 9.00 mmol) in Toluene (16.36 mL) at room temperature was added LiHMDS (18.00 mL, 18.00 mmol) dropwise. The reaction mixture was stirred overnight at room temperature. Reaction was quenched with saturated NH4Cl and extracted with EtOAc. Two purifications with Biotage (0-10% MeOH/DCM & 0-100% EtOAc/Hexane) were conducted to isolate product. Reaction was quenched with saturated NH4Cl extracted with EtOAc to isolate product

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Combined tetrahydro-2H-pyran-4-carbonitrile (1.000 g, 9.00 mmol) and titanium (IV)isopropoxide (2.90 mL, 9.90 mmol) in ether (45.0 mL), then ethylmagnesium bromide (6.60 mL, 19.79 mmol) was added and the reaction was allowed to warm to room temperature for 1 hour. The reaction was stirred for an additional 30 minutes and boron trifluoride etherate (2.280 mL, 18.0 mmol) was added and the reaction was stirred for 2 hours. The reaction was then diluted with 10 mL water and 20 mL 1 N HCl and extracted twice with 200 mL EtOAc. The organic layers were combined and concentrated to afford the title compound (850 mg, 53.5%) as a yellow oil. the reaction was stirred for 2 hours extracted twice with 200 mL EtOAc concentrated