1-(2-Hydroxyethyl)piperazine → N1-{4-[4-amino-1-(4-{[4-(2-hydroxyethyl)piperazino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide

HRID 897821Notes

Reaction equation

HRID 897821 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.[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)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:47]4[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][OH:41])[CH2:45][CH2:46]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:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12

Participants

6

Reactant 4

HCID 76771-(2-Hydroxyethyl)piperazine2×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 69203433N1-{4-[4-amino-1-(4-{[4-(2-hydroxyethyl)piperazino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamideYield 36.4%

Reagents, catalysts & solvents 1

HCID 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), N-(2-hydroxyethyl)piperazine (0.035 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 14 h. Additional portions of N-(2-hydroxyethyl)piperazine (0.010 g, 0.077 mmol) and sodium triacetoxyborohydride (0.020 g, 0.094 mmol) were added and the reaction mixture was shaken for 16 h. 1N NaOH (1.5 mL) was added and the precipitate was collected by filtration and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10-60% acetonitrile-0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 21.9-22.9 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[4-(2-hydroxyethyl)piperazino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.034 g, 0.051 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, s), 8.35-8.37 (2H, m), 8.15 (2H, d, J=8.8 Hz), 8.00 (1H, t, J=8.0 Hz), 7.90 (1H, d, J=10.4 Hz), 7.75 (1H, d, J=8.0 Hz), 7.49 (1H, s), 7.46 (2H, d, J=7.2 Hz), 7.40 (1H, d, J=8.4 Hz), 3.96 (3H, s), 3.51 (2H, s), 3.46-3.49 (4H, m), and 2.35-2.44 (8H, 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 10.92 min. MS: MH+ 664.7.

Workup

  1. stirringthe reaction mixture was shaken for 16 h
  2. filtrationthe precipitate was collected by filtration
  3. custompurified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10-60% acetonitrile-0.05 M ammonium acetate over 25 min, 21 mL/min)
  4. washthe fraction eluting from 21.9-22.9 min
  5. customwas collected
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-6079b6acdfc344a19402d87a0222d057
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

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