Sodium Carbonate → N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide

HRID 2056014Notes

Reaction equation

HRID 2056014 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[NH:37][C:38](=[O:50])[C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:40]=1[F:49].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].COC1C=C(B2OC(C)(C)C(C)(C)O2)C=CC=1NC(=O)C1C=CC(C(F)(F)F)=CC=1F>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:26]3[CH:25]=[CH:24][C:23]([NH:37][C:38](=[O:50])[C:39]4[CH:44]=[CH:43][C:42]([C:45]([F:47])([F:48])[F:46])=[CH:41][C:40]=4[F:49])=[C:22]([O:21][CH3:20])[CH:27]=3)[C:3]=12

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 223468554-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzaldehydeHCID 22347319N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-fluoro-4-(trifluoromethyl)benzamide

Product 1

HCID 11444225N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamideYield 67%

Reagents, catalysts & solvents 4

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 22347319N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-fluoro-4-(trifluoromethyl)benzamideCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzaldehyde (0.400 g, 1.09 mmol), N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-fluoro-4-(trifluoromethyl)benzamide (0.735 g, 1.20 mmol), palladium tetrakis(triphenylphosphine) (0.127 g, 0.110 mmol), and sodium carbonate (0.279 g, 2.63 mmol) in DME (10 mL) and water (10 mL) was heated at 85° C. for 1 h. Additional N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-fluoro-4-(trifluoromethyl)benzamide (0.026 g, 0.059 mmol) was added and the reaction mixture was heated at 85° C. for 4 h. The reaction mixture was cooled to ambient temperature and filtered. The residual solid was washed with methanol (50 mL) and DMF (50 mL), and the combined filtrates were concentrated to afford N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a beige solid (0.402 g, 0.730 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 10.05 (1H, s), 9.96 (1H, d, J=4.0 Hz), 8.62 (1H, d, J=8.4 Hz), 8.46 (1H, s), 8.39 (1H, d, J=6.8 Hz), 8.12 (2H, d, J=8.8 Hz), 8.02-8.03 (1H, m), 7.84-8.00 (1H, m), 7.75-7.77 (1H, m), 7.51 (1H, s), 7.43 (1H, d, J=8.0 Hz), 3.97 (3H, s); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 12.46 min. MS: MH+551.2.

Workup

  1. temperaturethe reaction mixture was heated at 85° C. for 4 h
  2. temperatureThe reaction mixture was cooled to ambient temperature
  3. filtrationfiltered
  4. washThe residual solid was washed with methanol (50 mL) and DMF (50 mL)
  5. concentrationthe combined filtrates were concentrated

Sources & evidence

ORD record
ord-e2bae3c853e7490bac2b0d204c7d32d4
Source dataset
uspto-grants-2008_02
Patent number
US07332497B2

Reaction notes

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