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

HRID 2056017Notes

Reaction equation

HRID 2056017 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.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]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:34]=[CH:35][C:36]([CH2:39][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:37][CH:38]=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:27])([F:26])[F:28])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12

Participants

7

Reactant 4

HCID 8083Morpholine2×HCID 14798Sodium HydroxideHCID 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 9938989N1-(4-{4-amino-1-[4-(morpholinomethyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-fluoro-4-(trifluoromethyl)benzamideYield 7.9%

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), morpholine (0.024 mL, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.409 mmol) in dichloroethane (1.4 mL) was shaken at ambient temperature for 16 h. Additional portions of morpholine (0.012 mL, 0.14 mmol), sodium triacetoxyborohydride (0.043 g, 0.20 mmol), and acetic acid (0.016 mL) were added and the reaction mixture was stirred at ambient temperature for 24 h. 1 N NaOH (1 mL) was added and the reaction mixture was filtered to afford a gray solid which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 10-60% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 21-23 min was collected, concentrated, and lyopholized to afford N1-(4-{4-amino-1-[4-(morpholinomethyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.007 g, 0.011 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.93 (1H, s), 8.34-8.37 (2H, m), 8.14-8.18 (2H, m), 7.97-8.02 (1H, m), 7.87-7.91 (1H, m), 7.73-7.76 (1H, m), 7.45-7.51 (2H, m), 7.44 (1H, s), 7.38-7.43 (1H, m), 3.41-3.59 (8H, m), and 3.36 (2H, 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 11.72 min. MS: MH+ 622.2.

Workup

  1. stirringthe reaction mixture was stirred at ambient temperature for 24 h
  2. filtrationthe reaction mixture was filtered
  3. customto afford a gray solid which
  4. customwas purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm
  5. wait10-60% acetonitrile—0.05 M ammonium acetate over 25 min
  6. washthe fraction eluting from 21-23 min
  7. customwas collected
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-e3dc0d0e3d0b4559a4c96eb510a3bb8e
Source dataset
uspto-grants-2008_02
Patent number
US07332497B2

Reaction notes

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