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Stage #1: for 2 h; Reflux Stage #2: With potassium carbonate In tetrahydrofuran at 20℃; for 24 h;
A solution of isonicotinic acid (14, 5.0 g, 40.6 mmol) in thionyl chloride (40 mL) was heated at reflux for 2 h. After completion of the reaction, thionyl chloride was removed under reduced pressure. THF (50 mL), K2CO3 (16.8 g, 121.9 mmol) and aniline (3.78 g, 40.6 mmol) were added to the residue and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was concentrated and the residue was recrystallized from EtOAc-hexanes (60:40) to afford the product 15 (8.0 g, 99percent) as a light yellow solid: mp 166-168 °C. IR (KBr) 1344, 1653, 1465, 665 cm 1; *H NMR (DMSO-ifc, 300 MHz) δ 10.49 (s, 1 H), 8.78 (m, 2 H), 7.86 (m, 2 H), 7.78 (m, 2 H), 7.39 (t, = 8.0 Hz, 2 H), 7.15 (t, = 6.5 Hz, 1 H).
Reference：
[1] Patent: WO2017/160898, 2017, A1, . Location in patent: Paragraph 00105; 00125
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1370 - 1387
[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 11, p. 6027 - 6033
[4] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1981, vol. 20, # 11, p. 1007 - 1008
3
[ 55-22-1 ]
[ 62-53-3 ]
[ 3034-31-9 ]
[ 1126-46-1 ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 40℃; for 2.5 h; Stage #2: for 20 h;
A solution of 1,10-carbonyldiimidazole (130 g,0.81 mol), isonicotinic acid (100 g, 0.81 mol) and DMF (300 mL) was heated at 40 C for 2.5 h before aniline (100 g, 0.81 mol) was added in a single portion. After 20 h, water (1.2 L) was added. The resulting suspension was filtered andthe solids dried under vacuum to afford isonicotinanilide (39) (142.6 g, 89percent).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 4, p. 976 - 981
4
[ 100-48-1 ]
[ 98-80-6 ]
[ 3034-31-9 ]
Yield
Reaction Conditions
Operation in experiment
73%
With potassium <i>tert</i>-butylate; copper(ll) bromide In <i>tert</i>-butyl alcohol at 20℃; for 37 h;
General procedure: A 10 mL round-bottomed flask was charged with the appropriate nitrile 2 (0.50 mmol), arylboronic acid 1(0.60 mmol), CuBr2 (6 mg, 5molpercent), t-BuOK (168 mg, 1.50 mmol), and t-BuOH (3.0 mL), and the mixture was stirred at r.t. until the reaction was complete (TLC). H2O (4.0 mL) was added, and the mixture was extracted with EtOAc (3 ×10 mL). The combined organic layers were washed twice with H2O,dried (Na2SO4), and concentrated to give a residue that was purified by column chromatography (silica gel, PE–EtOAc).
A solution of isonicotinic acid (14, 5.0 g, 40.6 mmol) in thionyl chloride (40 mL) was heated at reflux for 2 h. After completion of the reaction, thionyl chloride was removed under reduced pressure. THF (50 mL), K2CO3 (16.8 g, 121.9 mmol) and aniline (3.78 g, 40.6 mmol) were added to the residue and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was concentrated and the residue was recrystallized from EtOAc-hexanes (60:40) to afford the product 15 (8.0 g, 99%) as a light yellow solid: mp 166-168 C. IR (KBr) 1344, 1653, 1465, 665 cm 1; *H NMR (DMSO-ifc, 300 MHz) delta 10.49 (s, 1 H), 8.78 (m, 2 H), 7.86 (m, 2 H), 7.78 (m, 2 H), 7.39 (t, = 8.0 Hz, 2 H), 7.15 (t, = 6.5 Hz, 1 H).
A 2.5 M n-BuLi solution in hexanes (17.8 mL, 44.4 mmol) was added to a solution of 15 (4.0 g, 20 mmol) in dry THF (120 mL) at -78 C. The solution was held at -78 C for 0.5 h and then allowed to rise to 0 C and kept at 0 C for 6 min. The mixture was cooled to -78 C and DMF (2.94 mL, 40.4 mmol) was added. After 1 h at -78 C, the reaction mixture was warmed to 0 C and kept at 0 C for 1 h. H20 (40 mL) was added, the organic layer was separated, and the water layer was extracted with CHCI3 (2 x 40 mL). The combined organic layer was dried over Na2S04, concentrated, and purified by silica gel flash column chromatography (60:40 EtOAc- hexanes) to afford compound 16 (3.0 g, 67%) as an off-white solid: mp 209-211 C. IR (KBr) 3356, 1721, 776 cm ; lH NMR (DMSC fc, 300 MHz) delta 8.97 (s, 1 H), 8.86 (d, = 4.9 Hz, 1 H), 7.77 (m, 3 H), 7.48 (t, = 6.1 Hz, 2 H), 7.28 (t, = 7.5 Hz, 1 H), 7.10 (br s, 1 H), 6.69 (s, 1 H).
PREPARATION A Preparation of 4-(N-phenylcarbamoyl)piperidine <strong>[3034-31-9]4-(N-phenylcarbamoyl)pyridine</strong> [75.0 g, prepared as in Chem. Abs., 2013h (1958)] was hydrogenated in acetic acid (800 ml) using a platinum oxide catalyst at 50 p.s.i./30. The catalyst was then removed by filtration, the solution evaporated, the residue basified to about pH 12 with sodium hydroxide, extracted with chloroform, and the organic extract discarded. The aqueous phase was evaporated to dryness, the residue boiled with chloroform, filtered and evaporated to leave 4-(N-phenylcarbamoyl)piperidine (17.0 g), m.p. 121-127. The hydrochloride salt, m.p. 231-233, was prepared in isopropanol from the free base and hydrogen chloride, and was recrystallized from isopropanol/ethyl acetate. Analysis %: Found: C, 60.1; H, 7.2; N, 11.7. Calculated for C12 H16 N2 O.HCl: C, 59.9; H, 7.1; N, 11.6.
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