3-BROMOISONICOTINIC ACID METHYL ESTER

A mixture of 3.98 g of the acid obtained in the previous step (20 mmol, 1 eq.) in 50 ml of methanol is reflux heated in the presence of 4 ml of concentrated sulfuric acid. The mixture is allowed to return to ambient temperature and extracted 3 times with ethyl acetate. The organic phase is dried on NaTo a stirred solution of 3-bromoisonicotinic acid 1 (2 g, 9.90 mmol) in MeOH: THF(2: 1, 30 mL) under argon atmosphere was added CH2N2 (2 g, 49.50 mmol) at 0 °C; warmed toRT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20percent EtOAc/ hexanes to afford compound 2 (1.4 g, 66percent) as brown oil. TLC: 20percent EtOAc/ hexanes (R 0.7); ‘H-NMR (CDC13, 400 MHz): ö 8.87 (s, 1H), 8.62 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 5.6 Hz, 1H), 3.97 (s, 3H).Compound 119a. Aqueous layer was separated and freeze dried on lyophilyzer to obtain 3-(quinolin-4-ylamino)isonicotinic acid (Quant. Yield) as a white solid. LCMS 266.1 [M+H]+ 1H NMR (400 MHz, DMSO-d6) delta 13.66 (s, 1H), 8.93 (s, 1H), 8.58 (d, J=5.3 Hz, 1H), 8.28-8.18 (m, 1H), 8.14 (d, J=4.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.79 (d, J=4.8 Hz, 1H), 7.72 (t, J=7.0 Hz, 1H), 7.58 (t, J=7.2 Hz, 1H), 7.45-7.33 (m, 1H), 6.76 (br. s., 1H).Compound 117a. To a solution of Compound 115a. To a solution of LCMS 266.1 [M+H]+Compound 51a. To a solution of ethyl 3-bromoisonicotinate (0.3 g, 1.38 mmol, 1.0 equiv) in Toluene (15 mL) and water (2 mL) was added quinolin-4-ylboronic acid (0.288 g, 1.66 mmol, 1.2 equiv), K3PO4.3H2O (0.887 g, 4.14 mmol, 3.0 equiv) and resulting reaction mixture purged with N2 gas for 10 minute, followed by the addition of Pd(OAc) (0.032 g, 0.139 mmol. 0.1 equiv) and tricyclohexylphosphine (0.053 g, 0.139 mmol. 0.1 equiv). The resulting reaction mixture was heated at 100 C. for overnight. Product formation was confirmed by LCMS. After the completion of reaction, the mixture was filtered through celite bed, washed with ethyl acetate (100 mL). Filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash chromatography (100% ethyl acetate as an eluent) to obtain methyl 3-(quinolin-4-yl)isonicotinate (0.230 g, 62.7% Yield) as white solid. (0873) LCMS 265.3 [M+H]+Example 53 Synthesis of N-(2-((2R)-2-cyano-4, 4-difluorocyclopentyl)-2-oxoethyl)-3-(phenylamino)isonicotinamide Compound 102a. To a stirred solution of Compound 104a. To a solution of ethyl 3-bromoisonicotinate (0.2 g, 0.922 mmol, 1.0 equiv) in toluene (8 mL) and water (2 mL) was added tert-butyl 5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)indoline-1-carboxylate (0.381 g, 1.106 mmol, 1.2 equiv), K2CO3 (0.38 g, 2.764 mmol, 3.0 equiv) and resulting reaction mixture purged with N2 gas for 10 min, followed by the addition of Pd(PPh3)4 (0.033 g, 0.046 mmol. 0.05 equiv). The resulting reaction mixture was heated at 100 C. for overnight. Product formation was confirmed by LCMS. After the completion of reaction, the mixture was filtered through Celite bed, washed with ethyl acetate (100 mL). Filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash chromatography (0-20% ethyl acetate in hexane as an eluent) to obtain compound of tert-butyl 5-(4-(methoxycarbonyl)pyridin-3-yl)indoline-1-carboxylate (0.200 g, 61.34%) as a yellow oil. (0782) LCMS 355.4 [M+H]+Compound 64a. To a solution of ethyl 3-bromoisonicotinate (0.3 g, 1.38 mmol, 1.0 equiv) in Toluene (15 mL) and water (2 mL) was added o-tolylboronic acid (0.288 g, 1.66 mmol, 1.2 equiv), K2CO3 (0.571 g, 4.14 mmol, 3.0 equiv) and resulting reaction mixture purged with N2 gas for 10 minute, followed by the addition of Pd(PPh3)4 (0.08 g, 0.007 mmol. 0.05 equiv). The resulting reaction mixture was heated at 90 C. for overnight. Product formation was confirmed by LCMS. After the completion of reaction, the mixture was filtered through celite bed, washed with ethyl acetate (100 mL). Filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash chromatography (0-20% ethyl acetate in hexane as an eluent) to obtain methyl 3-(o-tolyl)isonicotinate (0.300 g, 95%) as yellow liquid. (0813) LCMS 228.3 [M+H]+ (0814) 1H NMR (400 MHz, DMSO-d6) delta 8.76 (d, J=5.3 Hz, 1H), 8.55 (s, 1H), 7.77 (d, J=4.8 Hz, 1H), 7.39-7.14 (m, 3H), 7.08 (d, J=7.5 Hz, 1H), 3.33 (s, 3H), 2.02 (s, 3H)Compound 66a. To a solution of ethyl 3-bromoisonicotinate (0.2 g, 0.93 mmol, 1.0 equiv) in mixture of toluene (16 mL) & water (4 mL) was added 1-methyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-indole (0.48 g, 1.85 mmol, 2.0 equiv), K2CO3 (0.382 g, 2.78 mmol, 3.0 equiv) and resulting reaction mixture purged with N2 gas for 10 min. followed by the addition of Pd(PPh3)2Cl2 (0.033 g, 0.046 mmol. 0.05 equiv). The resulting reaction mixture was heated at 100 C. for overnight. Product formation was confirmed by LCMS. After the completion of reaction, the mixture was filtered through celite bed, washed with ethyl acetate (100 mL). Filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash chromatography (0-20% ethyl acetate in hexane as an eluent) to obtain methyl 3-(1-methyl-1H-indol-4-yl)isonicotinate (0.180 g, 73.4%) as a yellow oil. (0773) LCMS 267.2 [M+H]+ (0774) 1H NMR (400 MHz, DMSO-d6) delta 8.74 (s, 1H), 8.67 (d, J=4.8 Hz, 1H), 7.67-7.49 (m, 3H), 7.40 (d, J=3.1 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 6.49 (d, J=3.1 Hz, 1H), 3.92 (s, 3H), 3.63 (s, 3H).

Molecular Weight:216.03
XLogP3:1.4
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:214.95819
Monoisotopic Mass:214.95819
Topological Polar Surface Area:39.2
Heavy Atom Count:11
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes