* 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 sodium hydroxide; water In methanol for 4 h; Heating / reflux Stage #2: With hydrogenchloride In methanol; water at 20℃;
Compound Ib (3.4 g, 13.2 mmol) in MeOH (50 mL) was refluxed with 2MNaOH (10 mL) for 4 hrs. The mixture was cooled to room temperature and acidified with hydrochloric acid to give Compound Ic (3.22 g, 100percent). 1H NMR (300 MHz,CD3OD) δ 8.62 (s, IH), 8.58 (s, IH);' MS (ESI) m/z: 359 (M+H+).
92%
Stage #1: at 90℃; for 3 h; Stage #2: With hydrogenchloride In water at 0℃;
Step 7[00181] A suspension of methyl 5-bromo-lH-pyrazolo[3,4-.pound.]pyridine-3- carboxylate (VII) (70 mg, 0.27 mmol) in aqueous IN NaOH solution (20 mL) was heated at 90°C for 3 h until the solution became clear. The solution was then cooled to 0°C and acidified with a 10percent> HC1 solution. The solids formed were filtered, washed with cold water and dried at room temperature under vacuum to give 5-bromo-lH-pyrazolo[3,4- .pound.]pyridine-3-carboxylic acid (VIII) as a white solid (60 mg, 0.25 mmol, 92percent yield). 1H NMR (CDCls) δ ppm 8.58 (d, J=3.01 Hz, 1 H), 8.66 (d, J=3.01 Hz, 1 H); ESIMS found for C7H4BrN302 mlz 242.1 (M+H).
92%
Stage #1: With sodium hydroxide In water at 90℃; for 3 h; Stage #2: With hydrogenchloride In water at 0℃;
spension of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) (70 mg, 0.27 mmol) in aqueous 1N NaOH solution (20 mL) was heated at 90° C. for 3 h until the solution became clear. The solution was then cooled to 0° C. and acidified with a 10percent HCl solution. The solids formed were filtered, washed with cold water and dried at room temperature under vacuum to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVIII) as a white solid (60 mg, 0.25 mmol, 92percent yield). 1H NMR (CDCl3) δ ppm 8.58 (d, J=3.01 Hz, 1H), 8.66 (d, J=3.01 Hz, 1H); ESIMS found for C7H4BrN3O2 m/z 242.1 (M+H).
92%
at 90℃; for 3 h;
Step 7 A suspension of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XV) (70 mg, 0.27 mmol) in aqueous 1N NaOH solution (20 mL) was heated at 90° C. for 3 h until the solution became clear. The solution was then cooled to 0° C. and acidified with a 10percent HCl solution. The solids formed were filtered, washed with cold water and dried at room temperature under vacuum to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVI) as a white solid (60 mg, 0.25 mmol, 92percent yield). 1H NMR (CDCl3) δ ppm 8.58 (d, J=3.01 Hz, 1H), 8.66 (d, J=3.01 Hz, 1H); ESIMS found for C7H4BrN3O2 m/z 242.1 (M+H).
92%
at 0 - 90℃; for 3 h;
A suspension of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XV) (70 mg, 0.27 mmol) in aqueous IN NaOH solution (20 mL) was heated at 90°C for 3 h until the solution became clear. The solution was then cooled to 0°C and acidified with a 10percent HC1 solution. The solids formed were filtered, washed with cold water and dried at room temperature under vacuum to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVI) as a white solid (60 mg, 0.25 mmol, 92percent yield). 1H NMR (CDCl3) δ ppm 8.58 (d, J=3.01Hz, 1H), 8.66 (d, J=3.01Hz, 1H); ESIMS found for C7H4BrN3O2 m/z 242.1 (M+H).
Compound Ib (3.4 g, 13.2 mmol) in MeOH (50 mL) was refluxed with 2MNaOH (10 mL) for 4 hrs. The mixture was cooled to room temperature and acidified with hydrochloric acid to give Compound Ic (3.22 g, 100%). 1H NMR (300 MHz,CD3OD) delta 8.62 (s, IH), 8.58 (s, IH);' MS (ESI) m/z: 359 (M+H+).
92%
Step 7[00181] A suspension of methyl 5-bromo-lH-pyrazolo[3,4-£]pyridine-3- carboxylate (VII) (70 mg, 0.27 mmol) in aqueous IN NaOH solution (20 mL) was heated at 90C for 3 h until the solution became clear. The solution was then cooled to 0C and acidified with a 10%> HC1 solution. The solids formed were filtered, washed with cold water and dried at room temperature under vacuum to give 5-bromo-lH-pyrazolo[3,4- £]pyridine-3-carboxylic acid (VIII) as a white solid (60 mg, 0.25 mmol, 92% yield). 1H NMR (CDCls) delta ppm 8.58 (d, J=3.01 Hz, 1 H), 8.66 (d, J=3.01 Hz, 1 H); ESIMS found for C7H4BrN302 mlz 242.1 (M+H).
92%
spension of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) (70 mg, 0.27 mmol) in aqueous 1N NaOH solution (20 mL) was heated at 90 C. for 3 h until the solution became clear. The solution was then cooled to 0 C. and acidified with a 10% HCl solution. The solids formed were filtered, washed with cold water and dried at room temperature under vacuum to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVIII) as a white solid (60 mg, 0.25 mmol, 92% yield). 1H NMR (CDCl3) delta ppm 8.58 (d, J=3.01 Hz, 1H), 8.66 (d, J=3.01 Hz, 1H); ESIMS found for C7H4BrN3O2 m/z 242.1 (M+H).
92%
With water; sodium hydroxide; at 90℃; for 3h;
Step 7 A suspension of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XV) (70 mg, 0.27 mmol) in aqueous 1N NaOH solution (20 mL) was heated at 90 C. for 3 h until the solution became clear. The solution was then cooled to 0 C. and acidified with a 10% HCl solution. The solids formed were filtered, washed with cold water and dried at room temperature under vacuum to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVI) as a white solid (60 mg, 0.25 mmol, 92% yield). 1H NMR (CDCl3) delta ppm 8.58 (d, J=3.01 Hz, 1H), 8.66 (d, J=3.01 Hz, 1H); ESIMS found for C7H4BrN3O2 m/z 242.1 (M+H).
92%
With water; sodium hydroxide; at 0 - 90℃; for 3h;
A suspension of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XV) (70 mg, 0.27 mmol) in aqueous IN NaOH solution (20 mL) was heated at 90C for 3 h until the solution became clear. The solution was then cooled to 0C and acidified with a 10% HC1 solution. The solids formed were filtered, washed with cold water and dried at room temperature under vacuum to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVI) as a white solid (60 mg, 0.25 mmol, 92% yield). 1H NMR (CDCl3) delta ppm 8.58 (d, J=3.01Hz, 1H), 8.66 (d, J=3.01Hz, 1H); ESIMS found for C7H4BrN3O2 m/z 242.1 (M+H).
5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (2-amino-4-trifluoromethoxy-phenyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
A mixture of S-bromo-lH-pyrazoloP^-bjpyridine-S-carboxyric acid Compound Ic (0.68 g, 1.93 mmol), Compound 16b (0.373 g, 1.93 mmol), HATU (0.73 g, 1.9 mmol) and DIPEA (1 mL, 5.8 mmol) in DMF (30 mL) was stirred at room temperature overnight. The solvent was removed under vacuum and the resulting yellow residue was mixed with AcOEt, sequentially washed with saturated aqueous NH4Cl, IM HCl, water and saturated aqueous NaHCO3, then dried over Na2SO4. The solvent was evaporated to dryness to provide 5-bromo-lH-pyrazolo[3,4-b]pyridine-3- carboxylic acid (2-amino-4-trifluoromethoxy-phenyl)-amide Compound 16c (0.67 g, 83% yield) as a yellow solid. LC-MS major peak 3.03 min, MS (ESI) m/z 416.0 (M+)/417.0 (M+H+).
5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (2-amino-5-methoxy-phenyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 45℃;
A mixture of S-bromo-lEta-pyrazoloCS^-bjpyridine-S-carboxylic acidCompound Ic (200 mg, 0.826 mmol), 4-methoxy-benzehe-l,2-diamine Compound 19a (114 mg, 0.826 mmol), EtaATU (314 mg, 0.826 mmol) and DIPEA (213 mg, 1.652 mmol) in DMF (10 mL) was stirred and heated to 45 C overnight. The mixture was diluted with AeOEt (60 mL) and washed with water. The organic layer was separated, dried and evaporated to give a brown solid residue. The residue was recrystallized with AcOEt/hexane mixture to give 5-bromo-lEta-pyrazolo[3,4-b]pyridine-3-carboxylic acid (2-amin-5-methoxy-phenyl)-amide Compound 19b (221 mg, 74% yield) as a light brown powder. MS m/z 362 (M+).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
A mixture of 5-bromo-lH-pyrazolo[3,4-b]pyridine-3-carboxylic acidCompound Ic (0.72 g, 2.05 mmol), Compound 18c (0.58 g, 2.05 mmol), HATU (0.78 g, 2.05 mmol) and DIPEA (1.1 mL, 6.15 mmol) in DMF (30 mL) was stirred at room temperature overnight. The solvent was removed in vacuo and the resulting yellow residue was mixed with AcOEt, sequentially washed with saturated aqueous NH4Cl, 0 IM HCl, H2O and saturated aqueous NaHCO3 and dried over Na2SO4. The solvent was , ' " evaporated to dryness to provide 5-bromo-lH-pyrazolo[3,4-b]pyridine-3-carboxylic acid { 2-amino-4-[2-(tert-butyl-dimethyl-silanyl)-ethoxy] -phenyl } -amide Compound 18d (1.02 g, 98% yield) as a reddish solid. LCMS major peak, 3.523 min, MS (ESI) , m/z 506.1 (M+)/507.1 (M+H+).
5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine[ No CAS ]
[ 916325-85-4 ]
Yield
Reaction Conditions
Operation in experiment
To a solution of NaOH (27 Kg, 675 mol) in water (617 L) was added 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (XXI) (9.8 Kg, 46.2 mol). The solution was heated at 90 C. for 3 hours under nitrogen before adding a solution of KMnO4 (53.6 Kg, 339 mol) in water (870 L) slowly over 2 hours. The reaction was heated at 95 C. for 5 hours under nitrogen. The solution was cooled to 75 C. and filtered through diatomaceous earth (11 Kg) followed by washing the diatomaceous earth with water (150 L) heated at 75 C. The solution was cooled to 0 C. under nitrogen before the pH was adjusted to 1 with aqueous 35% HCl (75 L). The solution was warmed to room temperature before adding n-BuOH (473 L) which was stirred for 25 min and then the organic layer was separated. n-BuOH (473 L) was again added to the aqueous layer, stirred for 25 min and separated. The combined organic phases were concentrated under vacuum to a volume of 54 L. The n-BuOH was removed by adding to the solution 9×n-heptane (78 L) dropwise over 1 hour and then concentrating the volume to 54 L after each addition of n-heptane. The solid was filtered and washed 3×n-heptane (17 L). The solid was dried under vacuum at 45 C. to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVIII) (3.2 Kg, 13.2 mol, 64.4% purity, 29.0% assay yield). 1H NMR (DMSO-d6, 400 MHz) delta ppm 8.57 (d, J=2.4 Hz, 1H), 8.71 (d, J=2 Hz, 1H), 13.45 (brs, 1H), 14.65 (s, 1H); ESIMS found C7H4BrN3O2 m/z 243.8 (M+H).
To a solution of NaOH (27 Kg, 675 mol) in water (617 L) was added 5-bromo- 3-methyl-1H-pyrazolo[3,4-b]pyridine (XXXIII) (9.8 Kg, 46.2 mol). The solution was heated at 90oC for 3 hours under nitrogen before adding a solution of KMnO4 (53.6 Kg, 339 mol) in water (870 L) slowly over 2 hours. The reaction was heated at 95oC for 5 hours under nitrogen. The solution was cooled to 75oC and filtered through diatomaceous earth (11 Kg) followed by washing the diatomaceous earth with water (150 L) heated at 75oC. The solution was cooled to 0oC under nitrogen before the pH was adjusted to 1 with aqueous 35% HCl (~75 L). The solution was warmed to room temperature before adding n-BuOH (473 L) which was stirred for 25 min and then the organic layer was separated. n-BuOH (473 L) was again added to the aqueous layer, stirred for 25 min and separated. The combined organic phases were concentrated under vacuum to a volume of ~54 L. The n-BuOH was removed by adding to the solution 9 x n-heptane (78 L) dropwise over 1 hour and then concentrating the volume to ~54 L after each addition of n-heptane. The solid was filtered and washed 3 x n-heptane (17 L). The solid was dried under vacuum at 45oC to give 5- bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XXXIV) (3.2 Kg, 13.2 mol, 64.4% purity, 29.0% assay yield).1H NMR (DMSO-d6, 400 MHz) d ppm 8.57 (d, J=2.4Hz, 1H), 8.71 (d, J=2Hz, 1H), 13.45 (brs, 1H), 14.65 (s, 1H); ESIMS found C7H4BrN3O2 m/z 243.8 (M+H).
Step 8[00182] To a solution of 5-bromo-lH-pyrazole[3,4-£]pyridine-3-carboxylic acid (VIII) (0.242 g, 1 mmol) in dry DMF (5 mL) was added CDI (0.178 g, 1.1 mmol) and heated for 3 h at 65C under nitrogen. The solution was cooled to room temperature and Nu,Omicron-dimethyl hydroxylamine hydrochloride (0.107 g, 1.1 mmol) was added to the solution. The solution was again heated for 3 h at 65C under nitrogen. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM, washed successively with a 10% HC1 solution, a saturated NaHC03 solution and brine. The organic phase was dried over MgS04, filtered and concentrated under reduced pressure to produce 5-bromo-N-methoxy-N-methyl-lH-pyrazolo[3,4- £]pyridine-3-carboxamide (IX) as a white solid (260 mg, 0.91 mmol, 92%> yield). 1H NMR (CDC13) delta ppm 3.55 (s, 3H), 3.78 (s, 3H), 8.59 (d, J=3.01 Hz, 1 H), 8.67 (d, J=3.01 Hz, 1 H); ESIMS found for C9H9BrN402 mlz 285.4 (M+H).
92%
To a solution of 5-bromo-1H-pyrazole[3,4-b]pyridine-3-carboxylic acid (XVIII) (0.242 g, 1 mmol) in dry DMF (5 mL) was added CDI (0.178 g, 1.1 mmol) and heated for 3 h at 65 C. under nitrogen. The solution was cooled to room temperature and N,O-dimethyl hydroxylamine hydrochloride (0.107 g, 1.1 mmol) was added to the solution. The solution was again heated for 3 h at 65 C. under nitrogen. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM, washed successively with a 10% HCl solution, a saturated aqueous NaHCO3 solution and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (XIX) as a white solid (260 mg, 0.91 mmol, 92% yield). 1H NMR (CDCl3) delta ppm 3.55 (s, 3H), 3.78 (s, 3H), 8.59 (d, J=3.01 Hz, 1H), 8.67 (d, J=3.01 Hz, 1H); ESIMS found for C9H9BrN4O2 m/z 285.4 (M+H).
92%
Step 8 To a solution of 5-bromo-1H-pyrazole[3,4-b]pyridine-3-carboxylic acid (XVI) (0.242 g, 1 mmol) in dry DMF (5 mL) was added CDI (0.178 g, 1.1 mmol) and heated for 3 h at 65 C. under nitrogen. The solution was cooled to room temperature and N,O-dimethyl hydroxylamine hydrochloride (0.107 g, 1.1 mmol) was added to the solution. The solution was again heated for 3 h at 65 C. under nitrogen. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM, washed successively with a 10% HCl solution, a saturated aqueous NaHCO3 solution and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (XVII) as a white solid (260 mg, 0.91 mmol, 92% yield). 1H NMR (CDCl3) delta ppm 3.55 (s, 3H), 3.78 (s, 3H), 8.59 (d, J=3.01 Hz, 1H), 8.67 (d, J=3.01 Hz, 1H); ESIMS found for C9H9BrN4O2 m/z 285.4 (M+H).
92%
To a solution of 5-bromo-1H-pyrazole[3,4-b]pyridine-3-carboxylic acid (XVI) (0.242 g, 1 mmol) in dry DMF (5 mL) was added CDI (0.178 g, 1.1 mmol) and heated for 3 h at 65C under nitrogen. The solution was cooled to room temperature and Nu,Omicron-dimethyl hydroxylamine hydrochloride (0.107 g, 1.1 mmol) was added to the solution. The solution was again heated for 3 h at 65C under nitrogen. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM, washed successively with a 10%) HCl solution, a saturated aqueous NaHCO3 solution and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-6]pyridine-3-carboxamide (XVII) as a white solid (260 mg, 0.91 mmol, 92% yield). 1H NMR (CDCl3) delta ppm 3.55 (s, 3H), 3.78 (s, 3H), 8.59 (d, J=3.01Hz, 1H), 8.67 (d, J=3.01Hz, 1H); ESIMS found for C9H9BrN4O2 m/z 285.4 (M+H).
7.94 g
<strong>[916325-85-4]5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid</strong> ((III), 7.91 g, 32.7 mmol) and 1,1?- carbonyldiimidazole (5.83 g, 35.9 mmol) were stirred in 200 mL of DMF at 60C for 45 minutes. To the resulting suspension was added N,O-dimethylhydroxylamine hydrochloride (3.51 g, 35.9 mmol) and the mixture was stirred for 4 h at 65 C. Most of the solvent was removed under vacuum and to the residue half sat. NaHCO3-solution was added. The solids were collected by suction filtration, washed with water and dried at 110 C. Yield: 7.94 g, HPLC purity: 96 %, 1H NMR (200 MHz, DMSO) delta 14.46 (s, 1H), 8.62 (d, J = 20.4 Hz, 2H), 3.76 (s, 3H), 3.44 (s, 3H), [M-H]- = 283.0 / 285.0.
To a solution of <strong>[916325-85-4]5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid</strong> (XVIII) (1.6 Kg, 6.6 mol) in anhydrous MeOH (32 L) was added H2SO4 (160 mL). The reaction was slowly heated to 70 C. and stirred for 20 hours. The solution was concentrated under vacuum to a volume of 1.6 L. The residue was partitioned between DCM (120 L) and aqueous 10% NaHCO3 (32 L). The organic phase was separated and washed with aqueous 25% NaCl (32 L), dried over Na2SO4 and concentrated to a volume of 4.8 L. The product was crystallized by charging the solution with 3×n-heptane (8 L) while concentrating the volume to 4.8 L after each addition of n-heptane. The solid was filtered and dried under vacuum at 50 C. to produce methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) (1.53 Kg, 6.0 mol, 80.6% purity, 90.4% assay yield). 1H NMR (DMSO-d6, 400 MHz) delta ppm 3.95 (s, 3H), 8.62 (d, J=2 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H), 14.78 (brs, 1H); ESIMS found C8H6BrN3O2 m/z 256.0 (M+H).
With sulfuric acid; at 70℃; for 2h;Large scale;
To a solution of <strong>[916325-85-4]5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid</strong> (XXXIV) (1.6 Kg, 6.6 mol) in anhydrous MeOH (32 L) was added H2SO4 (160 mL). The reaction was slowly heated to 70oC and stirred for 20 hours. The solution was concentrated under vacuum to a volume of 1.6 L. The residue was partitioned between DCM (120 L) and aqueous 10% NaHCO3 (32 L). The organic phase was separated and washed with aqueous 25% NaCl (32 L), dried over Na2SO4 and concentrated to a volume of 4.8 L. The product was crystallized by charging the solution with 3 x n-heptane (8 L) while concentrating the volume to 4.8 L after each addition of n- heptane. The solid was filtered and dried under vacuum at 50oC to produce methyl 5-bromo-1H- pyrazolo[3,4-b]pyridine-3-carboxylate (XXXV) (1.53 Kg, 6.0 mol, 80.6% purity, 90.4% assay yield).1H NMR (DMSO-d6, 400 MHz) d ppm 3.95 (s, 3H), 8.62 (d, J=2Hz, 1H), 8.73 (d, J=2.4Hz, 1H), 14.78 (brs, 1H); ESIMS found C8H6BrN3O2 m/z 256.0 (M+H).
5-bromo-N,N-dimethyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 55℃;
General procedure: To a stirred mixture of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)acetic acid (2.0 g, 7.14 mmol) and 5-(1- (trifluoromethyl)cyclopropyl)isoxazol-3-amine (2.74 g, 14.3 mmol) in anhydrous DMF (50 mL) were added O-(7-azabenzotriazol- 1 -yl)-N, N, N?, N?-tetramethyluronium hexafluorophosphate (3.54 g, 9.3 mmol) and DIEA (3.72 mL, 21.4 mmol). The resulting mixture was stirred at rt forh, heated at 55 C for lh, and then stirred at rt overnight. The mixture was partitioned between EtOAc (100 mL) and water (100 mL), and the aqueous layer was separated and extracted with EtOAc (1 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc in hexanes to give 2-(2-fluoro-4-(4,4,5,5- tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenyl)-N-(5 -(1 -(trifluoromethyl)cyclopropyl)isoxazol-3 - yl)acetamide (1.2 g, 37%) as a white solid. LC-MS (ESI) m/z 455 (M+H). Further elution with 20-40% EtOAc in hexanes afforded unreacted 5 -(1 -(trifluoromethyl)cyclopropyl)isoxazol-3 - amine (2.0 g).[000231] Step 1: 5 -Bromo-N,N-dimethyl- 1 H-pyrazolo [3 ,4-b]pyridine-3 -carboxamide (300 mg, 90%) was obtained using a procedure analogous to that described in Step 2 of Example 4, substituting 5 -bromo- 1 H-pyrazolo [3 ,4-b]pyridine-3 -carboxylic acid for the 2-(2-fluoro-4- (4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenyl)acetic acid used in Example 4 and dimethylamine hydrochloride for the 5 -(1 -(trifluoromethyl)cyclopropyl)isoxazol-3 -amine used in Example 4. LC-MS (ESI) m/z 269, 271 (M+H).
N-(5-(3-(7-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pentanamide[ No CAS ]
N-(5-(3-(7-(3-(2-(dimethylamino)ethylamino)-5-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pentanamide[ No CAS ]
3-(4-(5-methylthiophen-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine[ No CAS ]
3-(4-(5-methylthiophen-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine[ No CAS ]
With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In methanol; N,N-dimethyl-formamide; at 60℃; for 8h;Inert atmosphere;
5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine ((II), 10.44 g, 32.2 mmol) was combined with DMF, MeOH and triethylamine (75 mL each). The vessel was evacuated and flushed with argon (4x). XantPhos (1.12 g, 1.93 mmol) and Pd(OAc)2 (217 mg, 0.97 mmol) were added and carbon monoxide (generated from formic acid and sulfuric acid) was bubbled through the solution while heating to 60 C. The mixture was stirred under an atmosphere of carbon monoxide (balloon) for 8 h. Every 1.5 h carbon monoxide was bubbled through the solution for 5 minutes. The mixture was concentrated under reduced pressure and the residue was triturated with 2N HCl. The solids were heated at 95 C in about 100 mL 1N NaOH overnight. After cooling to RT, the mixture was acidified with conc. HCl and the precipitate collected by suction filtration and washed with water. The solids were dried in an oven at 110 C to constant mass. The solids were sonicated in 100 mL of toluene for 5 minutes and stirred for 30 minutes. The product was filtered, washed with an additional 20 mL of toluene and dried at 110 C. Yield: 7.92 g HPLC purity: > 99 %, 1H NMR (200 MHz, DMSO) delta 8.64 (d, J = 7.9 Hz, 2H), 5.69 (bs, 1H); 13C NMR (50 MHz, DMSO) delta 163.27, 150.97, 149.67, 136.69, 132.65, 115.73, 113.6; [M-H]- = 239.9 / 241.9.
N-[2,4-difluoro-3-[1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[3,4-b]pyridine-3-carbonyl]phenyl]propane-1-sulfonamide[ No CAS ]
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