Sodium Hydroxide → N1-(4-{4-amino-1-[4-{([3-(1H-1-imidazolyl)propyl]amino}methyl)phenyl]-1H-pyrazolo [3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-fluoro-4-(trifluoromethyl)benzamide

HRID 897826Notes

Reaction equation

HRID 897826 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[NH2:41][CH2:42][CH2:43][CH2:44][N:45]1[CH:49]=[CH:48][N:47]=[CH:46]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][NH:41][CH2:42][CH2:43][CH2:44][N:45]4[CH:49]=[CH:48][N:47]=[CH:46]4)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12

Participants

7

Reactant 4

HCID 14798Sodium HydroxideHCID 787361H-Imidazole-1-propanamine2×HCID 5049666Sodium triacetoxyborohydride2×HCID 11444225N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide2×

Product 1

HCID 69204194N1-(4-{4-amino-1-[4-{([3-(1H-1-imidazolyl)propyl]amino}methyl)phenyl]-1H-pyrazolo [3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-fluoro-4-(trifluoromethyl)benzamideYield 43.6%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 63651,1-DichloroethaneSolvent

Procedure

A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 1-(3-aminopropyl)imidazole (0.034 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of 1-(3-aminopropyl)imidazole (0.1 mL) and sodium triacetoxyborohydride (0.086 g, 0.40 mmol) were added and the reaction mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 4 days. 1N NaOH (1 mL) was added and the reaction mixture was concentrated, dissolved in DMF (2 mL), filtered through a syringe-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile-0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 14.0-15.7 min was collected, concentrated, and lyopholyzed to afford N1-(4-{4-amino-1-[4-{([3-(1H-1-imidazolyl)propyl]amino}methyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.040 g, 0.061 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, s), 8.35-8.40 (2H, m), 8.16 (2H, d, J=7.6 Hz), 7.99 (1H, t, J=7.6 Hz), 7.89 (1H, d, J=10.0 Hz), 7.75 (1H, d, J=8.4 Hz), 7.59 (1H, s), 7.52 (2H, d, J=3.8 Hz), 6.45 (1H, s), 7.40 (1H, d, J=8.0 Hz), 7.16 (1H, s), 6.87 (1H, s), 4.04 (2H, t, J=7.0 Hz), 3.96 (3H, s), 3.77 (2H, s), 2.45-2.46 (2H, m), 1.91 (3H, s), and 1.86-1.90 (2H, m); 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 10.28 min. MS: MH+ 660.2.

Workup

  1. stirringthe reaction mixture was shaken for 3 days
  2. stirringthe reaction mixture was shaken for 4 days
  3. concentrationthe reaction mixture was concentrated
  4. dissolutiondissolved in DMF (2 mL)
  5. filtrationfiltered through a syringe-tip Acrodisc
  6. filtrationfilter
  7. custompurified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile-0.05 M ammonium acetate over 25 min, 21 mL/min)
  8. washthe fraction eluting from 14.0-15.7 min
  9. customwas collected
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-c036bf04e7c8461db95870c45364b4e5
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

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