Pyrazolo[1,5-a]pyridine-3-carboxylic acid, 4-bromo-, methyl ester

In contrast to the other examples, only the cyclisation reaction was performed in flow. TheVapourtec R-series was equipped with three pumps. MSH 1 (2 g, 71 percent damp solid, 6.60 mmol)1 and 3-bromopyridine 2a (1.04 g, 6.60 mmol) were dissolved together in THF/H2O (1:1, 33 mL, 0.2 M). Triethylamine (0.92mL, 6.60 mmol) dissolved in THF (8.25 mL, 0.8 M) was mixed with the first inlet via a Y-piece with flow rates of2.86 mL/min and 1.07 mL/min respectively (1.5 eq of triethylamine). Methyl propiolate 4a (0.56 g, 6.60 mmol) wasdissolved in THF (8.25 mL, 0.8 M) and introduced in a second Y-piece at flow rate 1.07 mL/min (1.5 eq of methylpropiolate). The system solvent was THF. The PFA reactor coils, with volumes 2 mL and 10 mL respectively, were setto temperatures 30 °C and 90 °C respectively. The reaction mixture from the first two inlet streams spent 31 secondsresidency time in the first reactor and then 2 minutes residency time in the second reactor. The operating pressure was7.5 bar with 3 pumps. The reaction set-up was flushed afterwards with 33 percent HCl (conc.) in MeOH followed by IPA.The total flow rate at the outlet was 5 mL/min. The outlet stream (40 mL, collected over 8 minutes) was concentratedin vacuo to remove the THF and then diluted with EtOAc (250 mL) and brine (100 mL). The organic layer wasseparated and the aqueous phase washed twice more with EtOAc (2 x 200 mL). The combined organic layers weredried over anhydrous sodium sulfate and concentrated in vacuo to give a dark red oil.The crude material was purified by column chromatography on a 100 g silica column using the Biotage machine anda gradient from 7 to 60 percent EtOAc/heptane. 5a eluted first from the column. Pale red solid (0.43 g, 8 min collectiontime, 42 percent). 1H NMR (400 MHz, d6-DMSO) 4.10 (3H, s, CH3), 7.79 (1H, d, J = 8 Hz, ArH), 8.26 (1H, d, J = 8 Hz, ArH), 8.73 (1H, s, ArH), 9.56 (1H, s, ArH) ppm. 13C NMR (101 MHz, d6-DMSO) 51.2, 103.3, 108.1, 118.8, 130.3, 131.4, 138.7, 144.6, 162.6 ppm. HRMS (FAB) calcd for C9H8O2N2Br 254.97637, found 254.97636/256.97421.5b eluted second from the column. Pale yellow solid. (0.14 g, 8 min collection time, 14 percent). 1H NMR (400 MHz, d6-DMSO) 3.82 (3H, s, CH3), 7.06 (1H, dd, J = 4 and 4 Hz, ArH), 7.87 (1H, d, J = 4 Hz, ArH), 8.50 (1H, s, ArH), 8.93(1H, d, J = 4 Hz, ArH) ppm. 13C NMR (101 MHz, d6-DMSO) 51.3, 104.7, 109.8, 114.4, 129.8, 132.8, 137.6, 145.6, 161.9 ppm. HRMS (FAB) calcd for C9H8O2N2Br 254.97637, found 254.97638/256.97424In contrast to the other examples, only the cyclisation reaction was performed in flow. TheVapourtec R-series was equipped with three pumps. MSH 1 (2 g, 71 percent damp solid, 6.60 mmol)1 and 3-bromopyridine 2a (1.04 g, 6.60 mmol) were dissolved together in THF/H2O (1:1, 33 mL, 0.2 M). Triethylamine (0.92mL, 6.60 mmol) dissolved in THF (8.25 mL, 0.8 M) was mixed with the first inlet via a Y-piece with flow rates of2.86 mL/min and 1.07 mL/min respectively (1.5 eq of triethylamine). Methyl propiolate 4a (0.56 g, 6.60 mmol) wasdissolved in THF (8.25 mL, 0.8 M) and introduced in a second Y-piece at flow rate 1.07 mL/min (1.5 eq of methylpropiolate). The system solvent was THF. The PFA reactor coils, with volumes 2 mL and 10 mL respectively, were setto temperatures 30 °C and 90 °C respectively. The reaction mixture from the first two inlet streams spent 31 secondsresidency time in the first reactor and then 2 minutes residency time in the second reactor. The operating pressure was7.5 bar with 3 pumps. The reaction set-up was flushed afterwards with 33 percent HCl (conc.) in MeOH followed by IPA.The total flow rate at the outlet was 5 mL/min. The outlet stream (40 mL, collected over 8 minutes) was concentratedin vacuo to remove the THF and then diluted with EtOAc (250 mL) and brine (100 mL). The organic layer wasseparated and the aqueous phase washed twice more with EtOAc (2 x 200 mL). The combined organic layers weredried over anhydrous sodium sulfate and concentrated in vacuo to give a dark red oil.The crude material was purified by column chromatography on a 100 g silica column using the Biotage machine anda gradient from 7 to 60 percent EtOAc/heptane. 5a eluted first from the column. Pale red solid (0.43 g, 8 min collectiontime, 42 percent). 1H NMR (400 MHz, d6-DMSO) 4.10 (3H, s, CH3), 7.79 (1H, d, J = 8 Hz, ArH), 8.26 (1H, d, J = 8 Hz, ArH), 8.73 (1H, s, ArH), 9.56 (1H, s, ArH) ppm. 13C NMR (101 MHz, d6-DMSO) 51.2, 103.3, 108.1, 118.8, 130.3, 131.4, 138.7, 144.6, 162.6 ppm. HRMS (FAB) calcd for C9H8O2N2Br 254.97637, found 254.97636/256.97421.5b eluted second from the column. Pale yellow solid. (0.14 g, 8 min collection time, 14 percent). 1H NMR (400 MHz, d6-DMSO) 3.82 (3H, s, CH3), 7.06 (1H, dd, J = 4 and 4 Hz, ArH), 7.87 (1H, d, J = 4 Hz, ArH), 8.50 (1H, s, ArH), 8.93(1H, d, J = 4 Hz, ArH) ppm. 13C NMR (101 MHz, d6-DMSO) 51.3, 104.7, 109.8, 114.4, 129.8, 132.8, 137.6, 145.6, 161.9 ppm. HRMS (FAB) calcd for C9H8O2N2Br 254.97637, found 254.97638/256.97424n-Butyllithium (0.251 g, 3.92 mmol, 2.5 M in tetrahydrofuran) and dibutylmagnesium (1.629 g, 11.76 mmol, 1.0 M in heptane) were charged into a nitrogen filled three-necked flask at room temperature. A solution of In contrast to the other examples, only the cyclisation reaction was performed in flow. TheVapourtec R-series was equipped with three pumps. MSH 1 (2 g, 71 % damp solid, 6.60 mmol)1 and 3-bromopyridine 2a (1.04 g, 6.60 mmol) were dissolved together in THF/H2O (1:1, 33 mL, 0.2 M). Triethylamine (0.92mL, 6.60 mmol) dissolved in THF (8.25 mL, 0.8 M) was mixed with the first inlet via a Y-piece with flow rates of2.86 mL/min and 1.07 mL/min respectively (1.5 eq of triethylamine). Methyl propiolate 4a (0.56 g, 6.60 mmol) wasdissolved in THF (8.25 mL, 0.8 M) and introduced in a second Y-piece at flow rate 1.07 mL/min (1.5 eq of methylpropiolate). The system solvent was THF. The PFA reactor coils, with volumes 2 mL and 10 mL respectively, were setto temperatures 30 C and 90 C respectively. The reaction mixture from the first two inlet streams spent 31 secondsresidency time in the first reactor and then 2 minutes residency time in the second reactor. The operating pressure was7.5 bar with 3 pumps. The reaction set-up was flushed afterwards with 33 % HCl (conc.) in MeOH followed by IPA.The total flow rate at the outlet was 5 mL/min. The outlet stream (40 mL, collected over 8 minutes) was concentratedin vacuo to remove the THF and then diluted with EtOAc (250 mL) and brine (100 mL). The organic layer wasseparated and the aqueous phase washed twice more with EtOAc (2 x 200 mL). The combined organic layers weredried over anhydrous sodium sulfate and concentrated in vacuo to give a dark red oil.The crude material was purified by column chromatography on a 100 g silica column using the Biotage machine anda gradient from 7 to 60 % EtOAc/heptane. 5a eluted first from the column. Pale red solid (0.43 g, 8 min collectiontime, 42 %). 1H NMR (400 MHz, d6-DMSO) 4.10 (3H, s, CH3), 7.79 (1H, d, J = 8 Hz, ArH), 8.26 (1H, d, J = 8 Hz, ArH), 8.73 (1H, s, ArH), 9.56 (1H, s, ArH) ppm. 13C NMR (101 MHz, d6-DMSO) 51.2, 103.3, 108.1, 118.8, 130.3, 131.4, 138.7, 144.6, 162.6 ppm. HRMS (FAB) calcd for C9H8O2N2Br 254.97637, found 254.97636/256.97421.5b eluted second from the column. Pale yellow solid. (0.14 g, 8 min collection time, 14 %). 1H NMR (400 MHz, d6-DMSO) 3.82 (3H, s, CH3), 7.06 (1H, dd, J = 4 and 4 Hz, ArH), 7.87 (1H, d, J = 4 Hz, ArH), 8.50 (1H, s, ArH), 8.93(1H, d, J = 4 Hz, ArH) ppm. 13C NMR (101 MHz, d6-DMSO) 51.3, 104.7, 109.8, 114.4, 129.8, 132.8, 137.6, 145.6, 161.9 ppm. HRMS (FAB) calcd for C9H8O2N2Br 254.97637, found 254.97638/256.97424A solution of methyl 4-bromopyrazolo [1 , 5-ajpyridine-3-carboxylate (500 mg, 1.97 mmol), potassium trifluoro(2-methoxyethyl)borate (490 mg, 1.28 mmol), RuPhos (734 mg, 1.58 mmol), Pd(OAc)2(177 mg, 0.79 mmol) and C52CO3(1.92 g, 5.91 mmol) in CPME (8 mL) and water (2 mL) was stirred for 5 hours at 100 C under N2. The mixture was diluted with water, extracted with EA(x3), the organic layer was dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to give desired compound as yellow solid (140 mg, 30%). ESI MS m/z = 235.3 [M+Hf.A solution of Methyl 4-bromopyrazolo [1, 5 -a]pyridine-3 -carboxylate (100 mg, 0.39 mmol), Pd(OAc)2 (5.3 mg, 0.024 mmol), BNAP (22 mg, 0.035 mmol) and Cs2CO3 (192 mg, 0.59 mmol) were placed in a pressure vial. The reaction mixture was degassed (3x vacuum and argon), then toluene (2 mL) and morpholine (0.044 mL, 0.51 mmol) were added. Thereaction mixture was degassed again, and then was stirred at 120 C for 3 h. After cooled to rt, the reaction was filtered through a pad of CELITE, and the solvent was removed. The crude product was purified by reverse phase chromatography to provide Intermediate 109 (74 mg, 72%) as a light tan solid. 'H NMR (400MHz, CDC13) oe 8.46 (s, 1H), 8.43 (d, J=6.6 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.05 (t, J7.2 Hz, 1H), 4.11 - 4.04(m, 4H), 3.94 (s, 3H), 3.40 - 3.27 (m, 4H). LC-MS(ESI) m/z: 262.0 [M+H].Preparation 26-Bromo-pyrazolo[1 , 5-a]pyridine[00118] To a freshly prepared solution of hydroxylamine-O-sulfonic acid (8g, 70.7 mmol) in 50 ml_ of ice water 3-bromopyridine (6.9 ml_, 70.7 mmol) is added. The mixture is heated at 90 0C for 30 min, then cooled to room temperature and K2CO3 (9.7 g, 70.7 mmol) is added. The water is evaporated (bath temperature 30-40 0C) and the crude product is treated with EtOH (100 imL). The precipitate is filtered and the filtrate is concentrated to small volume (2OmL) and HI (5.4 mL) is added. The reaction mixture is then evaporated to dryness in vacuo. The residue is dissolved in dry DMF (50 mL) and anhydrous K2CO3 (11.7 g, 84.8 mmol) is added. Methyl propiolate (7 ml, 84.8 mmol) is then added dropwise. The mixture is stirred in open flask for 24 h, then diluted with water (50 mL) and extracted with EtOAc (2x150 mL). The organic layers are combined, washed with brine (2x100ml), dried over Na2SO4. The residue is purified by column chromatography (hexane : EtOAc 8:1 ) to give 6-bromo-pyrazolo[1 , 5-a]pyridine-3- carboxylic acid methyl ester and 4-bromo-pyrazolo[1 , 5-a]pyridine-3-carboxylic acid methyl ester in ca. 1 :1 ratio.

Molecular Weight:255.07
XLogP3:1.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:253.96909
Monoisotopic Mass:253.96909
Topological Polar Surface Area:43.6
Heavy Atom Count:14
Complexity:237
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes