* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With potassium acetate; acetic anhydride; acetic acid In chloroform at 20℃; for 0.25 h; Stage #2: With isopentyl nitrite In chloroform at 40 - 60℃; Stage #3: With sodium hydroxide In methanol; water at 0 - 20℃;
To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40° C. IsoamyInitrite was then added dropwise. The reaction was then stirred at 60° C. for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0° C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0° C. and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3*500 mL). The combined organics dried over magnesium sulfate, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 27.9 mmol, 77percent). 1HNMR (400, CD3OD): δ ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H).
77%
With potassium acetate; acetic anhydride; isopentyl nitrite In chloroform; acetic acid at 20 - 60℃;
To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 °C. Isoamylnitrite was then added dropwise. The reaction was then stirred at 60 °C for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 °C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 °C and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3 x 500 mL). The combined organics dried over magnesium sulfate, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 27.9 mmol, 77 percent). 1HNMR (400, CD3OD): ppm 8.55 (s, 1 H), 8.24 (s, 1 H), 8.21 (s, 1 H).
77%
Stage #1: With potassium acetate; acetic anhydride; acetic acid In chloroform at 20 - 60℃; for 48.25 h; Stage #2: With water; sodium hydroxide In methanol at 0 - 20℃;
To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40° C. Isoamylnitrite was then added dropwise. The reaction was then stirred at 60° C. for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0° C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0° C. and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3.x.500 mL). The combined organics were dried over magnesium sulfate, filtered, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 77percent). 1HNMR (400 MHz, CD3OD, δ): 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H).
77%
Stage #1: With potassium acetate; acetic anhydride; acetic acid In chloroform at 20 - 40℃; Stage #2: With tert.-butylnitrite In chloroform at 60℃; for 48 h; Stage #3: With water; sodium hydroxide In methanol at 0 - 20℃;
To a solution of N-(5- bromo-2-methylpyridin-3-yl)acetamide (M-3) (8.3 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.3 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.9 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 °C. Jert-butyl nitrite (6.5 mL, 54 mmol) was then added dropwise. The reaction was then stirred at 60 °C for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 °C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 °C and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3 χ 500 mL). The combined organics dried over magnesium sulfate, and the solvent removed in vacuo to give the title compound as a light brown solid (5.5 g, 27.9 mmol, 77percent). 1HNMR (400, CD3OD): δ ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H). LCMS (ESI) calc'd for C6H4BrN3 [M+H]+: 197.96, found: 198, 199.
77%
Stage #1: With potassium acetate; acetic anhydride; acetic acid In chloroform at 20℃; for 0.25 h; Stage #2: With tert.-butylnitrite In chloroform at 40 - 60℃; for 48 h;
To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (M-3) (8.3 g, 36 mmol) in chloroform (550 mL) atambient temperature was added potassium acetate (4.3 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.9 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 °C. Tert-butyl nitrite (6.5 mL, 54 mmol) was then added dropwise. The reaction was then stirred at 60 °C for 48 hours.The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 °C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 °C and the mixture stirred at ambient temperature for 1 hour before the methanolwas removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3 x 500 mL). The combined organics were dried over magnesium sulfate, and the solvent removed in vacuo to give the title compound as a light brown solid (5.5 g, 27.9 mmol, 77percent). ‘HNMR (400, CD3OD): ö ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H). LCMS (ESI) calc’d for C6H4BrN3 [M+H]: 197.96, found: 198, 199.
With water; sodium hydroxide In tetrahydrofuran; methanol at 27℃; for 5 h;
To a solution of 1 -(6-bromo- 1 H-pyrazolo [4,3-b]pyridin- 1 -yl)ethanone (1.4 g, 5.9 mmol) in tetrahydrofuran (20 mL) and methanol (15 mL) was added a solution of sodium hydroxide (0.71 g, 18 mmol) in water (5 mL) at 27 °C. After 5 h, the reaction was neutralized with hydrogen chloride acid (2 mol/L, 10 mL), and the resulting mixture was extracted withethyl acetate (3 x 50 mL). The collected organic extracts were concentrated in vacuo. Purification by flash column chromatography (1 5—30percent ethyl acetate in petroleum ether) afforded 6-bromo-1H-pyrazolo[4,3-b]pyridine (1.0 g, 86percent yield). 1H NMR (400 MHz, Chloroform-d) ö: 10.46 (brs, 1 H), 8.58 (s, 1 H), 8.25 (s, 1 H), 7.98 (s, 1 H).
86%
With water; sodium hydroxide In tetrahydrofuran; methanol at 27℃; for 5 h; Inert atmosphere
To a solution of 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanone (1.4 g, 5.9 mmol) in tetrahydrofuran (20 mL) and methanol (15 mL) was added a solution of sodium hydroxide (0.71 g, 18 mmol) in water (5 mL) at 27° C. After 5 h, the reaction was neutralized with hydrogen chloride acid (2 mol/L, 10 mL), and the resulting mixture was extracted with ethyl acetate (3*50 mL). The collected organic extracts were concentrated in vacuo. Purification by flash column chromatography (15→30percent ethyl acetate in petroleum ether) afforded 6-bromo-1H-pyrazolo[4,3-b]pyridine (1.0 g, 86percent yield). 1H NMR (400 MHz, Chloroform-d) δ 10.46 (brs, 1H), 8.58 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H).
With hydrazine hydrate In ethylene glycol at 140℃; for 23 h;
To a solution of the compound [172-1] obtained in the process (1) (426 mg) in ethylene glycol (2.1 mL) was added hydrazine monohydrate (197 µL) at room temperature, and then the reaction mixture was stirred at 140°C for 23 hours. After cooling to room temperature, to the reaction mixture was added water, and extracted with a mixed solution of chloroform/isopropanol (volume ratio 10/1). The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (275 mg) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 10.17 (1H, br), 8.65 (1H, d, J = 1.7 Hz), 8.31 (1H, s), 8.04 (1H, s). ESI-MS found: 198 [M+H]+
275 mg
With hydrazine hydrate In ethylene glycol at 140℃; for 23 h;
(2) Synthesis of 6-bromo-1H-pyrazolo[4,3-b]pyridine [47-2] (hereinafter referred to as a compound [47-2]) To a solution of the compound [47-1] (426 mg) in ethylene glycol (2.1 mL) was added hydrazine monohydrate (197 µL) at room temperature, and the mixture was stirred at 140°C for 23 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with a mixed solution of chloroform/isopropanol (volume ratio 10/1). The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (275 mg) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 10.17 (1H, br), 8.65 (1H, d, J = 1.7 Hz), 8.31 (1H, s), 8.04 (1H, s). ESI-MS found: 198 [M + H]+
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5 h; Stage #2: at 20℃; for 0.5 h;
To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (400 mg, 2.02 mmol) in DMF (10 mL) at 0 oC was added 60percent NaH in mineral oil (80.8 mg, 2.02 mmol) and the mixture was stirred at rt for 30 mm. A solution of Mel (287 mg, 2.02 mmol) in DMF (5 mL) was added and the mixture was stirred at rt for 30 mm. Then the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2504, filtered and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC to give 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine as a white solid (150 mg, 35percent). 1HNMR (300 MHz, DMSO-d6) 8.58-8.60 (m, 2H), 8.30-8.3 1 (m, 1H), 4.06 (s, 3H).
A solution of n-butyllithium in hexane (2.2 molar equivalent) was added at low temperature to a solution of <strong>[1150617-54-1]6-bromo-1H-pyrazolo[4,3-b]pyridine</strong> (0.5 g) in dry THF (20 mL) cooled with a dry ice actone bath. After stirring the mixture at low temperature for 90 minutes, iodine was added (703 mg, 1.1 molar equivalent) and the mixture stirred for another hour before let rise to around 5 C. and quenched with a saturated solution of ammonium chloride. The mixture was extracted with EA and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford 6-iodo-1H-pyrazolo[4,3-b]pyridine. MS (ES): M/Z [M+H]=246. The synthesis of <strong>[1150617-54-1]6-bromo-1H-pyrazolo[4,3-b]pyridine</strong> is described in Example 182 part f.
With potassium carbonate; In acetone; at 20℃; for 4h;Reflux;
To a mixture of <strong>[1150617-54-1]6-bromo-1H-pyrazolo[4,3-b]pyridine</strong> (1.6 g) and potassium carbonate (637 mg) in acetone was added chloroacetone at room temperature. After heating the mixture to reflux for 4 hours, the mixture was concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford 1-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (0.43 g, 21%) along with 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-one (1.46 g, 71%).
To a mixture of 3-amino-5-bromo-2-methylpyridine (8.3 g) and potassium acetate (5.2 g) in chloroform (200 mL) was added acetic anhydride (16.7 mL) at room temperature and the mixture let stirred at room temperature for 3 hours and then heated to reflux for an additional 2 hours, After cooling the mixture to room temperature, was added isoamylnitrite (11.9 mL) and 18-crown-6-ether (1 g) and the mixture heated to reflux for 26 hours. After cooling to room temperature, the mixture was filtered through a plug of Celite. The filtrate was concentrated under reduced pressure to yield a residue that was treated with a suspension of potassium carbonate (10 g) in a mixture of methanol (150 mL) and water (10 mL) at 0 C. for 2 hours. The mixture was concentrated under reduced pressure to yield a residue that was extracted with EA and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was triturated with a mixture of DCM and heptane to give 6-bromo-1H-pyrazolo[4,3-b]pyridine (6.85 g, 75% overall yield from 10 g of 5-bromo-2-methyl-3-nitropyridine). MS (ES): M/Z [M+H]=198. 1H NMR: (400 MHz, DMSO-d6): 8.33 (br. s, 2H), 8.57 (d, J=1.7 Hz, 1H), 13.47 (br. s, 1H)
To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 C. IsoamyInitrite was then added dropwise. The reaction was then stirred at 60 C. for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 C. and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3*500 mL). The combined organics dried over magnesium sulfate, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 27.9 mmol, 77%). 1HNMR (400, CD3OD): delta ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H).
77%
With potassium acetate; acetic anhydride; isopentyl nitrite; In chloroform; acetic acid; at 20 - 60℃;
To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 C. Isoamylnitrite was then added dropwise. The reaction was then stirred at 60 C for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 C and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3 x 500 mL). The combined organics dried over magnesium sulfate, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 27.9 mmol, 77 %). 1HNMR (400, CD3OD): ppm 8.55 (s, 1 H), 8.24 (s, 1 H), 8.21 (s, 1 H).
77%
To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 C. Isoamylnitrite was then added dropwise. The reaction was then stirred at 60 C. for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 C. and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3×500 mL). The combined organics were dried over magnesium sulfate, filtered, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 77%). 1HNMR (400 MHz, CD3OD, delta): 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H).
77%
To a solution of N-(5- bromo-2-methylpyridin-3-yl)acetamide (M-3) (8.3 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.3 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.9 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 C. Jert-butyl nitrite (6.5 mL, 54 mmol) was then added dropwise. The reaction was then stirred at 60 C for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 C and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3 chi 500 mL). The combined organics dried over magnesium sulfate, and the solvent removed in vacuo to give the title compound as a light brown solid (5.5 g, 27.9 mmol, 77%). 1HNMR (400, CD3OD): delta ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H). LCMS (ESI) calc'd for C6H4BrN3 [M+H]+: 197.96, found: 198, 199.
77%
To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (M-3) (8.3 g, 36 mmol) in chloroform (550 mL) atambient temperature was added potassium acetate (4.3 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.9 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 C. Tert-butyl nitrite (6.5 mL, 54 mmol) was then added dropwise. The reaction was then stirred at 60 C for 48 hours.The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 C and the mixture stirred at ambient temperature for 1 hour before the methanolwas removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3 x 500 mL). The combined organics were dried over magnesium sulfate, and the solvent removed in vacuo to give the title compound as a light brown solid (5.5 g, 27.9 mmol, 77%). ?HNMR (400, CD3OD): oe ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H). LCMS (ESI) calc?d for C6H4BrN3 [M+H]: 197.96, found: 198, 199.
With triethylamine;2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; palladium dichloride; In acetonitrile; at 100℃; under 15001.5 Torr; for 18h;
To a solution of <strong>[1150617-54-1]6-bromo-1H-pyrazolo[4,3-b]pyridine</strong> (5.5 g, 27.9 mmol) in methanol (125 mL) and acetonitrile (75 mL) was added triethylamine (22 mL, 156 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.98 g, 3.07 mmol), palladium dichloride (1.23 g, 6.98 mmol). The mixture was placed under 20 bar of carbon monoxide, heated to 100 C., and stirred vigorously for 18 hours. The reaction mixture was cooled to ambient temperature and filtered through Celite before the solvent was removed in vacuo to yield a brown oil. This crude oil was then purified by flash column chromatography (1:1, ethyl acetate:hexane) to give methyl 1H-pyrazolo[4,3-b]pyridine-6-carboxylate as a pale yellow solid (4.52 g, 92% yield). 1HNMR (400, CDCl3) delta ppm 10.56 (s, 1H), 9.23 (s, 1H), 8.35 (s, 1H), 8.40 (s, 1H), 4.01 (s, 3H).
92%
With triethylamine;(S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); palladium dichloride; In acetonitrile; at 100℃; under 15001.5 Torr; for 18h;
To a solution of <strong>[1150617-54-1]6-bromo-1H-pyrazolo[4,3-b]pyridine</strong> (5.5 g, 27.9 mmol) in methanol (125 mL) and acetonitrile (75 mL) was added triethylamine (22 mL, 156 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1 .98 g, 3.07 mmol), palladium dichloride (1.23 g, 6.98 mmol). The mixture was placed under 20 bar of carbon monoxide, heated to 100 C, and stirred vigorously for 18 hours. The reaction mixture was cooled to ambient temperature and filtered through Celite before the solvent was removed in vacuo to yield a brown oil. This crude oil was then purified by flash column chromatography (1:1, ethyl acetate : hexane) to give methyl 1H-pyrazolo[4,3-b]pyridine-6-carboxylate as a pale yellow solid (4.52 g, 92 % yield). 1HNMR (400, CDCIs) ppm 10.56 (s, 1 H), 9.23 (s, 1 H), 8.35 (s, 1 H), 8.40 (s, 1 H), 4.01 (s, 3H).
92%
With triethylamine;2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; palladium dichloride; In acetonitrile; at 100℃; under 15001.5 Torr; for 18h;
To a solution of <strong>[1150617-54-1]6-bromo-1H-pyrazolo[4,3-b]pyridine</strong> (5.5 g, 27.9 mmol) in methanol (125 mL) and acetonitrile (75 mL) was added triethylamine (22 mL, 156 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.98 g, 3.07 mmol), and palladium dichloride (1.23 g, 6.98 mmol). The mixture was placed under 20 bar of carbon monoxide, heated to 100 C., and stirred vigorously for 18 hours. The reaction mixture was cooled to ambient temperature and filtered through Celite before the solvent was removed in vacuo to yield a brown oil. This crude oil was then purified by flash column chromatography (50% ethyl acetate/hexanes) to give methyl 1H-pyrazolo[4,3-b]pyridine-6-carboxylate as a pale yellow solid (4.52 g, 92%). 1HNMR (400 MHz, CDCl3, delta): 10.56 (s, 1H), 9.23 (s, 1H), 8.35 (s, 1H), 8.40 (s, 1H), 4.01 (s, 3H).
69%
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; palladium dichloride; In acetonitrile; at 100℃; under 15001.5 Torr; for 18h;
To a solution of 6-bromo-lH-pyrazolo[4,3-b]pyridine (M-4) ( 0.5 g, 2.5 mmol) in methanol ( 15 ml) and acetonitrile ( 7 ml) was added Et3N ( 2.2 ml, 5.6 mmol ), Binap ( 0.17 g, 0.63 mmol) and palladium dichloride ( 0.17 g, 0.27 mmol). The mixture was placed under 20 bar of carbon monoxide, stirred at 100 C for 18 h. The mixture was cooled, filtered and purified by Pre-TLC to give 310 mg white solid. ( 69 % ). LCMS (ESI) calc'd for [M+H]+: 178.1, found: 178.1.
69%
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; palladium dichloride; In acetonitrile; at 100℃; under 15001.5 Torr; for 18h;
To a solution of <strong>[1150617-54-1]6-bromo-1H-pyrazolo[4,3-b]pyridine</strong> (M-4) (0.5 g, 2.5 mmol) in methanol (15 ml) and acetonitrile (7 ml) was added Et3N (2.2 ml, 5.6 mmol), Binap (0.17 g, 0.63 mmol) and palladium dichloride (0.17 g, 0.27 mmol). The mixture was placed under 20 bar of carbonmonoxide, and stirred at 100 C for 18 h. The mixture was cooled, filtered and purified by Prep-TLC to give 310mg of a white solid. (69 %). LCMS (ESI) calc?d for [M+H]: 178.1, found: 178.1.
With N-ethyl-N,N-diisopropylamine;1,1'-bis-(diphenylphosphino)ferrocene; bis(benzonitrile)palladium(II) dichloride; at 135℃; under 11251.1 Torr; for 4h;
A mixture of T-7 (1.60 g, 8.08 mmol), DIPEA (2.00 mL, 11.5 mmol), dichlorobis(benzonitrile)palladium (II) (100.0 mg, 0.26 mmol), and 1,1- bis(diphenylphosphino)ferrocene (dppf) (200.0 mg, 0.36 mmol) in absolute EtOH (35 mL) in a pressure reactor is placed under 15 bars of carbon monoxide and warmed at 135C. After 4 hours, the mixture is cooled to room temperature, returned to atmospheric pressure and opened. The reaction is concentrated and then diluted with brine (100 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers are washed with brine (3 x 50 mL), dried over magnesium sulfate, treated with decolorizing carbon, filtered through filter agent and silica gel and concentrated. The residue is dissolved in DCM and passed through silica gel eluting with Et2O to provide T-8.
With water; sodium hydroxide; In tetrahydrofuran; methanol; at 27℃; for 5h;
To a solution of 1 -(6-bromo- 1 H-pyrazolo [4,3-b]pyridin- 1 -yl)ethanone (1.4 g, 5.9 mmol) in tetrahydrofuran (20 mL) and methanol (15 mL) was added a solution of sodium hydroxide (0.71 g, 18 mmol) in water (5 mL) at 27 C. After 5 h, the reaction was neutralized with hydrogen chloride acid (2 mol/L, 10 mL), and the resulting mixture was extracted withethyl acetate (3 x 50 mL). The collected organic extracts were concentrated in vacuo. Purification by flash column chromatography (1 5-30% ethyl acetate in petroleum ether) afforded 6-bromo-1H-pyrazolo[4,3-b]pyridine (1.0 g, 86% yield). 1H NMR (400 MHz, Chloroform-d) oe: 10.46 (brs, 1 H), 8.58 (s, 1 H), 8.25 (s, 1 H), 7.98 (s, 1 H).
86%
With water; sodium hydroxide; In tetrahydrofuran; methanol; at 27℃; for 5h;Inert atmosphere;
To a solution of 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanone (1.4 g, 5.9 mmol) in tetrahydrofuran (20 mL) and methanol (15 mL) was added a solution of sodium hydroxide (0.71 g, 18 mmol) in water (5 mL) at 27 C. After 5 h, the reaction was neutralized with hydrogen chloride acid (2 mol/L, 10 mL), and the resulting mixture was extracted with ethyl acetate (3*50 mL). The collected organic extracts were concentrated in vacuo. Purification by flash column chromatography (15?30% ethyl acetate in petroleum ether) afforded 6-bromo-1H-pyrazolo[4,3-b]pyridine (1.0 g, 86% yield). 1H NMR (400 MHz, Chloroform-d) delta 10.46 (brs, 1H), 8.58 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H).
With methanol; potassium carbonate; for 1h;Reflux;
To a solution of T-5 (13.14 g, 57.36 mmol) in toluene (200 mL) is added acetic anhydride (16.50 mL, 174.5 mmol), acetic acid (16.50 mL, 288.2 mmol) and potassium acetate (12.30 g, 125.3 mmol). The mixture is warmed at reflux and isoamyl nitrite (10.0 mL, 71.5 mmol) is added. After 3 hours, the reaction is concentrated to provide without isolation T-6. The residue is diluted with methanol (250 mL) and K2CO3 (32.0 g, 188 mmol) is added and the mixture is warmed at reflux. After 1 hour, the reaction is poured into water and extracted with EtOAc (3 x 150 mL). The combined organic layers are washed with brine (2 x 50 mL), dried over magnesium sulfate, filtered through a pad of silica gel and filter agent and concentrated. The solid is triturated with Et2O to provide T-7. The filtrate is purified on silica gel using a gradient of 25-100% EtOAc in hexanes and then 5% methanol in ethyl acetate. The material from the column is triturated with ether-heptane to provide T-7.
With methanol; potassium carbonate; for 1h;Reflux;
[0005731 To a stirred solution of compound 6 (1.25 g, 1 eq) in methanol (15 mL), K2C03 (2.15 g, 3 eq) was added and heated to reflux for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was dissolved in water and extracted with ethyl acetate (2 X 25 mE). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 7. LCMS (mlz): 199.90 (M+ 1).
With hydrazine hydrate; In ethylene glycol; at 140℃; for 23h;
To a solution of the compound [172-1] obtained in the process (1) (426 mg) in ethylene glycol (2.1 mL) was added hydrazine monohydrate (197 muL) at room temperature, and then the reaction mixture was stirred at 140C for 23 hours. After cooling to room temperature, to the reaction mixture was added water, and extracted with a mixed solution of chloroform/isopropanol (volume ratio 10/1). The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (275 mg) as a yellow solid. 1H-NMR (400 MHz, CDCl3) delta: 10.17 (1H, br), 8.65 (1H, d, J = 1.7 Hz), 8.31 (1H, s), 8.04 (1H, s). ESI-MS found: 198 [M+H]+
275 mg
With hydrazine hydrate; In ethylene glycol; at 140℃; for 23h;
(2) Synthesis of 6-bromo-1H-pyrazolo[4,3-b]pyridine [47-2] (hereinafter referred to as a compound [47-2]) To a solution of the compound [47-1] (426 mg) in ethylene glycol (2.1 mL) was added hydrazine monohydrate (197 muL) at room temperature, and the mixture was stirred at 140C for 23 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with a mixed solution of chloroform/isopropanol (volume ratio 10/1). The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (275 mg) as a yellow solid. 1H-NMR (400 MHz, CDCl3) delta: 10.17 (1H, br), 8.65 (1H, d, J = 1.7 Hz), 8.31 (1H, s), 8.04 (1H, s). ESI-MS found: 198 [M + H]+
6-bromo-3-chloro-1H-pyrazolo[4,3-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
140 mg
With N-chloro-succinimide; In acetonitrile; at 60℃; for 5h;
The compound [172-2] obtained in the process (2) (123 mg) in acetonitrile (4.1 mL) was added N-chlorosuccinimide (91 mg) at room temperature, and then the reaction mixture was stirred at 60C for 3 hours. Furthermore, N-chlorosuccinimide (91 mg) was added at 60C and the reaction mixture was stirred for 2 hours. After cooling to room temperature, to the reaction mixture was added an aqueous solution of 1N-sodium hydroxide, and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the titled compound (140 mg) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) delta: 9.99 (1H, br), 8.69 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J = 2.0 Hz). ESI-MS found: 232 [M+H]+
140 mg
With N-chloro-succinimide; In acetonitrile; at 60℃; for 5h;
(3) Synthesis of 6-bromo-3-chloro-1H-pyrazolo[4,3-b]pyridine [47-3] (hereinafter referred to as a compound [47-3]) To a solution of the compound [47-2] (123 mg) in acetonitrile (4.1 mL) was added N-chlorosuccinimide (91 mg) at room temperature, and the mixture was stirred at 60C for 3 hours. N-Chlorosuccinimide (91 mg) was added again to the reaction mixture at 60C, and stirred at 60C for 2 hours. After cooling, an aqueous solution of 1N-sodium hydroxide was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the titled compound (140 mg) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) delta: 9.99 (1H, br), 8.69 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J = 2.0 Hz). ESI-MS found: 232 [M + H]+
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 85℃;Sealed tube;
A mixture of <strong>[1150617-54-1]6-bromo-1H-pyrazolo[4,3-b]pyridine</strong> (0.3 g, 2 mmol;)(Annova Chem Cat. No. L05238), (3,5-dimethoxyphenyl)boronic acid (0.33 g, 1.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (100 mg, 0.1 mmol), and potassium phosphate (0.64 g, 3.0 mmol) in 1,4-dioxane (1 mL) and water (0.12 mL) was degassed and sealed. It was stirred at 85 C. overnight. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.38 g). LCMS (M+H)+=256.2.
6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-sulfonyl chloride[ No CAS ]
6-bromo-1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)sulfonyl)-1H-pyrazolo[4,3-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
One hundred milligrams sodium hydride was dissolved in 30 ml anhydrous tetrahydrofuran, stirred for 5 minutes at room temperature. Five hundred and fifty milligrams 6-bromoindazole was dissolved in 30 ml anhydrous tetrahydrofuran, then slowly and dropwisely added into the tetrahydrofuran solution of sodium hydride, stirred for 30 minutes at room temperature after the addition was completed. Nine hundred and seven milligrams 6-[(1-methyl)-4-pyrazolyl]-imidazo[1,2-a]pyridine-3-sulfonyl chloride was dissolved in 30 ml anhydrous tetrahydrofuran, slowly and dropwisely added into the reactant liquid, stirred overnight at room temperature after the addition was done, the reaction was completed. Tetrahydrofuran was removed by evaporation, the remainder was dissolved in dichloromethane, washed three times with water, the organic layer was dried over anhydrous sodium sulfate then concentrated, isolated by flash preparative chromatography to obtain compound 1-{(6-[(1-methyl)-4-pyrazolyl]-imidazo[1,2-a]pyridine)-3-sulfonyl}-6-bromo-1-H-pyrazolo[4,3-b]pyridine(m=968 mg, yield: 76%). ESI (m/z): 460.0, 458.0 [M+H]+.
6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; ethanol; water; at 120℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation;
Into a microwave reaction tube, 300 mg compound a, 473 mg 1-methyl-1H-pyrazolo-4-borate pinacol ester and 628 mg potassium carbonate were disposed, 5 ml dioxane, 2.5 ml ethanol and 2.5 ml water were added into the microwave reaction tube, air was displaced for three times, under a nitrogen atmosphere, 62 mg complex of 1,1?-bis(diphenylphosphino) ferrocene palladium (II) dichloride and dichloromethane was added into the microwave tube, then the microwave tube was sealed, The microwave tube was placed into a microwave reactor, reaction was conducted at a temperature of 120 C. for 30 minutes, till the reaction was completed. The aforementioned reactant liquid was poured into 15 ml water, extracted three times with dichloromethane, the organic layer was dried over anhydrous sodium sulfate then concentrated, isolated by flash preparative chromatography to obtain compound n (m=275 mg, yield: 91%). (0192) 1H NMR (300 MHz, DMSO-d6) delta 13.29 (s, 1H), 8.80 (s, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 8.07 (s, 2H), 3.90 (s, 3H).
86%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere; Sealed tube;
A solution of <strong>[1150617-54-1]6-bromo-1H-pyrazolo[4,3-b]pyridine</strong> (29) (330mg, 1.52 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30) (378 mg, 1.82 mmol), PdCl2(dppf)-CH2Cl2 (61.9 mg, 80 mol) and K2CO3 (628mg, 4.54 mmol) in 1,4-dioxane:water (15 mL, 2:1, v) in a microwave tube was flushed with N2 for 5min then sealed. The tube was heated at 80 C for 2 h. Then the reaction mixture was evaporated todryness. The residue was purified by flash chromatography to give 31 (260 mg, 86% yield); LC-MSm/z (ESI) found (M + H)+ 200.0 (M + H)+; 1H-NMR (400 MHz, DMSO-d6) delta13.29 (s, 1H), 8.80 (s, 1H),8.36 (s, 1H), 8.24 (s, 1H), 8.07 (s, 2H), 3.90 (s, 3 H).
82%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;
<strong>[1150617-54-1]6-bromo-1H-pyrazolo[4,3-b]pyridine</strong> (400 mg, 2.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.4 mmol), K2CO3 (828 mg, 6 mmol), and Pd(dppf)Cl2(81.7 mg, 0.1 mmol) were dissolved in the solvent of 1,4-dioxane/H2O (v/v = 3:1, 20 mL). The resultingmixture was stirred at 80 C under Ar for 2 h. Then, the reaction mixture was evaporated to dryness.The residue was purified by flash chromatography to give compound 39 as a yellow hairy solidwith the yield of 82%. 1H-NMR (300 MHz, DMSO-d6, ppm) 13.29 (s, 1H), 8.80 (s, 1H), 8.36 (s, 1H),8.24 (s, 1H), 8.07 (s, 2H), 3.90 (s, 3H). ESI-MS: C10H10N7O2S, Exact Mass: 199.09, m/z 200.0 (M + 1)+.Retention time 2.51 min, >95% purity.
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