3-Fluoro-5-hydroxybenzonitrile

off-white powder

A mixture of Example 16f(30 mg, 0.09 mmol), Example 2a (15 mg, 0.10 mmol) and K2C03 (36 mg, 0.26 mmol) in DMF (0.6 mL) was stirred at 25C for 2 hours. The reaction was diluted with water (10 mL), extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried over Na2SO4, filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 16g (30 mg, yield 75%) as a white solid. 'H NMR (400 MHz, Chloroform-cl) 7.82 (d, J 8.8 Hz, 1H), 7.21 (d, J 8.7 Hz, 1H), 7.03 (s, 1H), 6.93 (d, J= 2.3 Hz, 1H), 6.90- 6.81 (m, 1H), 6.43 (t, J= 54.0 Hz, 1H), 4.50 (d, J= 6.8 Hz, 2H), 4.27 (q, J= 4.8, 3.9 Hz, 2H).To a 10-mL Schlenk tube were added Example 8f (280 mg, 0.93 mmol), Example 2a (155 mg, 1.12 mmol), K2C03 (386 mg, 2.8 mmol) and DMF (4 mL). The tube was sealed and heated at 120C for 16 hours. The reaction was cooled to room temperature. Water (10 mL) was added, the mixture was extracted by EtOAc (20 mL*3). The combined organic phase was washed with brine, dried over Na2SO4, filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 9a (98 mg, yield 25%) as a white solid. 'H NMR (400 IVIHz, Chloroform-cl) 7.46 (d, J 8.6 Hz, 1H), 7.24 (d, J 8.6 Hz, 1H), 7.17 (ddd, J= 7.6, 2.4, 1.3 Hz, 1H), 7.08 (dt, J = 2.2, 1.1 Hz, 1H), 6.97 (dt, J= 9.3, 2.3 Hz, 1H), 4.43-4.36 (m, 2H), 4.29-4.24 (m, 2H).To a suspension of Example 8e (512 mg, 2.0 mmol) and Na2CO3 (318 mg, 3 mmol) in DMF (8 mL) was added Example 2a (329 mg, 2.4 mmol). The mixture was stirred at 75C for 18 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried over Na2SO4, filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example ha (260 mg, yield 35%) as a yellow solid. MS [M+1] = 374.0. 'H NIVIR (400 MHz, Chloroform-cl) 7.59 (d, J= 8.4 Hz, 1H), 7.51 (d, J= 8.5 Hz, 1H), 7.30 -7.27 (m, 1H), 7.16 (dt, J 2.2, 1.1 Hz, 1H), 7.08 (dt, J8.9, 2.3 Hz, 1H).To a solution of Example 431 (150 mg, 0.63 mmol) in DMF (8 mL) was added Example 43j (214 mg, 1.56 mmol) and Cs2CO3 (509 mg, 1.56 mmol) in sequence. After being purged with N2 in the flask, the reaction was started at 80C with stirring overnight. Then, the reaction solution was poured into water (50 mL) and filtrated. After extraction with EtOAc (10 mL*2), combined organic layer was dried over Na2504, and concentrated under reduced pressure, and purified by doing silica gel chromatography (Petroleum ether/EtOAc = 2/1) to give the desired product (Example 43k, 224 mg, yield 100%) as a pale-yellow solid. LCMS [M+1] = 358.To a solution of Example 42m (910 mg, 2.94 mmol) in 1, 4-Dioxane (13 mL) was added Example 42n (804 mg, 5.87 mmol), CuT (111 mg, 0.59 mmol), 2-(dimethylamino)acetic acid (151 mg, 1.47 mmol) and Cs2CO3 (1.9 g, 5.87 mmol). The mixture was stirred at 110C overnight under N2. The mixture was extracted with EtOAc (50 mL * 2). The combined organic phase was washed with brine, dried over Na2SO4, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by doing silica gel chromatography (Petroleum ether/EtOAc = 10/1) to give the desired product (Example 42o, 150 mg, yield 14%) as a yellow solid. LCMS [M+1] = 366.9.A mixture of Example ii (1.7 g, 5.5 mmol), Example 2a (900 mg, 6.6 mmol) and K2C03 (1.9 g, 13.7 mmol) in DMF (30 mL) was stirred at 80C for 16 hours. The reaction was diluted with water (30 mL), extracted with EtOAc (30 mL*2). The combined organic phase was washed with brine, dried over Na2504, filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 2b (740 mg, yield 32%) as a yellow solid.A solution of Example 22b (400 mg, 1.2 mmol) and Example 2a (197 mg, 1.4 mmol) in DMF (8 mL) was treated with DIEA (1.0 g, 8.0 mmol) and stirred at 70 C for 0.5 hour. The reaction mixture was poured into water (40 mL) and extracted with EtOAc (40 mL*3). The combined organics were rinsed with brine, dried with Na2SO4, filtered, and concentrated to dryness to afford crude product Example 22c (350 mg, crude yield 64%) as a yellow solid, which was used in the next step without purification.?H NIVIR (400 MHz, Chloroform-cl) 8.55 (d, J 8.5 Hz, 1H), 7.58 (d, J 8.6 Hz, 1H), 7.32 (d, J= 7.6 Hz, 1H), 7.20 (s, 1H), 7.14-7.09 (m, 1H).

Molecular Weight:137.11
XLogP3:1.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:137.027691913
Monoisotopic Mass:137.027691913
Topological Polar Surface Area:44
Heavy Atom Count:10
Complexity:162
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes