Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 25℃; Inert atmosphere
Step 1 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine (Compound 4-2) Sodium hydride (720 mg, 30 mmol) was added into a 100 ml reaction flask, and anhydrous THF (40 mL) was added to the reaction flask. After stirring at 0° C. for 5 min, the reaction substrate 5-bromo-1H-pyrazolo[3,4-b]pyridine (4.0 g, 20 mmol, commercially available) was dissolved in THF (20 ml), and the resulting solution was slowly added dropwise to the reaction flask through the constant pressure funnel, and stirred for 30 min. Afterwards, iodomethane (1.6 ml, 26 mmol) was added dropwise to the reaction system. After completion of the addition, the reaction solution was slowly warmed to room temperature and stirred overnight. The reaction progress was monitored by TLC. After completion of the reaction, 10 ml of ice water was added to the reaction system to quench the reaction, THF was removed by concentration under reduced pressure, and the residue was extracted with dichloromethane (60 ml) and water (20 ml*3). The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 4.1 g brown solid, which was separated and purified by Combi-flash chromatography [PE:EA=10:90-40:60] to give the title compound 4-2 (3.1 g, 73percent). MS m/z (ESI): 211.9 [M+H]+.
Preparation 9; 5-Bromo- 1 -methyl- lH-pyrazolo[3,4-b]pyridine; EPO <DP n="26"/> Dissolve l-methyl-5-aminopyrazole (Butt Park LTD; 1.0 g, 10.3 mmol) and 2- bromomalonaldehyde (Aldrich; 1.55 g, 10.3 mmol) in glacial acetic acid (160 niL) and reflux under nitrogen for 48 h. Concentrate under reduced pressure and purify via chromatography (silica gel, 90percent dichloromethane/10percent diethyl ether) to obtain 610 mg (27percent) of the title compound as an off-white solid. TOF MS ES+ exact mass calculated for C7H7N3Br (p+H): m/z = 21 1.9823, Found: 211.9838.
Preparation 9; 5-Bromo- 1 -methyl- lH-pyrazolo[3,4-b]pyridine; EPO <DP n="26"/> Dissolve l-methyl-5-aminopyrazole (Butt Park LTD; 1.0 g, 10.3 mmol) and 2- bromomalonaldehyde (Aldrich; 1.55 g, 10.3 mmol) in glacial acetic acid (160 niL) and reflux under nitrogen for 48 h. Concentrate under reduced pressure and purify via chromatography (silica gel, 90% dichloromethane/10% diethyl ether) to obtain 610 mg (27%) of the title compound as an off-white solid. TOF MS ES+ exact mass calculated for C7H7N3Br (p+H): m/z = 21 1.9823, Found: 211.9838.
Step 1 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine (Compound 4-2) Sodium hydride (720 mg, 30 mmol) was added into a 100 ml reaction flask, and anhydrous THF (40 mL) was added to the reaction flask. After stirring at 0 C. for 5 min, the reaction substrate 5-bromo-1H-pyrazolo[3,4-b]pyridine (4.0 g, 20 mmol, commercially available) was dissolved in THF (20 ml), and the resulting solution was slowly added dropwise to the reaction flask through the constant pressure funnel, and stirred for 30 min. Afterwards, iodomethane (1.6 ml, 26 mmol) was added dropwise to the reaction system. After completion of the addition, the reaction solution was slowly warmed to room temperature and stirred overnight. The reaction progress was monitored by TLC. After completion of the reaction, 10 ml of ice water was added to the reaction system to quench the reaction, THF was removed by concentration under reduced pressure, and the residue was extracted with dichloromethane (60 ml) and water (20 ml*3). The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 4.1 g brown solid, which was separated and purified by Combi-flash chromatography [PE:EA=10:90-40:60] to give the title compound 4-2 (3.1 g, 73%). MS m/z (ESI): 211.9 [M+H]+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 90℃; for 8h;Inert atmosphere;
Step 2 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (compound 4-3) Compound 4-2 (3.1 g, 14.6 mmol) and bis(pinacolato) borate (11.1 g, 43.8 mmol) were added into a 250 ml reaction flask, and DMF (150 ml) and potassium acetate (4.3 g, 43.8 mmol) was added. After the air of reaction system was replaced by argon for three times, Pd(dppf)Cl2 (0.55 g, 0.73 mmol) was added, and then the air was replaced with nitrogen for another three times. The reaction system was heated to 90 C., and stirred for 8 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction solution was filtered, the filter cake was washed with EA (30 ml*3), and the filtrate was concentrated under reduced pressure to remove DMF and give compound 4-3 (13.5 g) as brown solid which was used directly in next reaction. MS m/z (ESI): 260.2 [M+H]+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 1h;
A mixture of <strong>[887115-56-2]5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine</strong> (3.04 g, 14.0 mmol), bis(pinacolato)diboron (4.37 g, 17.0 mmol), PdCl2(dppf) (0.992 g, 1 mmol), and potassium acetate (3.52 g, 36 mmol) in dioxane was heated at 100 C. for 1 hour. Reaction mixture was portioned between ethyl acetate and saturated sodium bicarbonate solution, organic layer dried (MgSO4), filtered, concentrated and purified by CombiFlash (ethyl acetate/hexanes) to give desired product. LCMS-ESI+: calc'd for C13H19BN3O2: 260.2 (M+H)+; found: 260.2 (M+H)+.
ethyl (S)-2-(2-(3-(1-(azetidin-3-yl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-(tert-butoxy)acetate[ No CAS ]
methyl (S)-3-(4-(5-(6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidin-1-yl)azetidine-1-carboxylate[ No CAS ]
ethyl (S)-2-(tert-butoxy)-2-(7-(4-chlorophenyl)-2-(3-(4-isopropylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetate[ No CAS ]
(S)-2-(tert-butoxy)-2-(7-(4-chlorophenyl)-2-(3-(4-isopropylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid[ No CAS ]
tert-butyl (S)-4-(5-(6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)carboxylate[ No CAS ]
tert-butyl (S)-4-(5-(6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-1-carboxylate[ No CAS ]
ethyl (S)-2-(tert-butoxy)-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate[ No CAS ]
ethyl (S)-2-(tert-butoxy)-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate[ No CAS ]
(S)-2-(tert-butoxy)-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetic acid[ No CAS ]
tert-butyl (S)-3-(4-(5-(6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidin-1-yl)azetidine-1-carboxylate[ No CAS ]
(S)-2-(tert-butoxy)-2-(7-(4-chlorophenyl)-2-(3-(1-(1-(methoxycarbonyl)azetidin-3-yl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid[ No CAS ]
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