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 2056018ノート

反応式

HRID 2056018 の反応式
[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

参加物

6

反応物 4

HCID 76771-(2-Hydroxyethyl)piperazine2 回HCID 14798Sodium HydroxideHCID 5049666Sodium triacetoxyborohydride2 回HCID 11444225N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide2 回

生成物 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)benzamide収率 36.4%

試薬・触媒・溶媒 1

HCID 63651,1-Dichloroethane溶媒

実験手順

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 A, 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.

後処理

  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 A, 25 cm
  4. wait10-60% acetonitrile—0.05 M ammonium acetate over 25 min
  5. washthe fraction eluting from 21.9-22.9 min
  6. customwas collected
  7. concentrationconcentrated

出典と根拠

ORDレコード
ord-3a87aec0cfdc4e92a704b8a02c9e9461
出典データセット
uspto-grants-2008_02
特許番号
US07332497B2

反応ノート

読み込み中…