Isoquinolin-3-Amine → Morpholine-4-carboxylic acid (4-{[2-(isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide

HRID 2100416

Reaction equation

HRID 2100416 reaction equation
[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:24]=1.C[Al](C)C>ClCCCl.C(=O)([O-])O.[Na+]>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:1][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])[CH:24]=2)=[O:13])[N:3]=1

Participants

6

Reactant 3

HCID 311869Isoquinolin-3-AmineHCID 16682925TrimethylaluminumHCID 57798919HCID 57798919, compound

Product 1

HCID 11612737Morpholine-4-carboxylic acid (4-{[2-(isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amideYield 32%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
120 °C

Procedure

To a stirred solution of 3-aminoisoquinoline (75 mg, 0.52 mmol) and 2-({2-[(morpholine-4-carbonyl)-amino]-pyridin-4-ylmethyl}-amino)-benzoic acid methyl ester (149 mg, 0.40 mmol) in DCE (6 mL) at 0° C., under argon, was added trimethylaluminium (2M in toluene, 0.4 mL, 0.8 mmol). The reaction was heated at 120° C. (bath temperature) for 3 hours. On cooling the reaction was diluted with aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phase was washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on Isolute® flash NH2 (Separtis) (Eluant: EtOAc) to give morpholine-4-carboxylic acid (4-{[2-(isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (60 mg, 32%) as a resin; 1H-NMR (300 MHz, d6-DMSO) 10.69 (1H, s), 9.21 (1H, s), 9.18 (1H, s), 8.60 (1H, s), 8.16-8.20 (2H, m), 8.10 (1H, d), 7.96 (1H, d), 7.90 (1H, d), 7.82 (1H, d), 7.75 (1H, t), 7.57 (1H, t), 7.28 (1H, t), 6.98 (1H, d), 6.63 (1H, t), 6.58 (1H, d), 4.48 (2H, d), 3.55-3.59 (4H, m), 3.41-3.45 (4H, m); m/z (ES+) 483 [M+H]+, 242.

Workup

  1. temperatureOn cooling the reaction
  2. extractionextracted with dichloromethane
  3. washThe organic phase was washed with water
  4. customdried
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by chromatography on Isolute® flash NH2 (Separtis) (Eluant: EtOAc)

Sources & evidence

ORD record
ord-2d081de20bb34e8f876f4280e5410b34
Source dataset
uspto-grants-2009_08
Patent number
US07572794B2

Linked notes

Loading…