Sodium Hydroxide → HCID 68650663, compound

HRID 646682Notes

Reaction equation

HRID 646682 reaction equation
[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18]C)=[O:17])=[N:6][C:7]=1[C:8]([NH:10][CH2:11][CH3:12])=[O:9].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([OH:18])=[O:17])=[N:6][C:7]=1[C:8]([NH:10][CH2:11][CH3:12])=[O:9]

Participants

4

Reactant 2

HCID 14798Sodium HydroxideHCID 68650403HCID 68650403, compound

Product 1

HCID 68650663HCID 68650663, compoundYield 97.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
92.5 °C

Procedure

Methyl 3-{5-amino-6-[(ethylamino)carbonyl]pyrazin-2-yl}benzoate (480 mg, 1.6 mmol) was suspended in a 20 mL of 1:1 MeOH-5% aqueous sodium hydroxide and heated at 90-95° C. for 4 hours. The homogeneous reaction mixture was cooled to room temperature, concentrated to half the initial volume, cooled in an ice-bath, and acidified to pH 4 with concentrated HCl. A white solid precipitated and was collected by filtration, washed with water and dried in vacuo to give 3-{5-amino-6-[(ethylamino)carbonyl]pyrazin-2-yl}benzoic acid (445 mg, 97% yield). The acid (40 mg, 0.14 mol) was dissolved in DMF (1 mL) and 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (30 mg, 0.16 mmol), and 4-methylmorpholine (30 mg, 0.28 mol) were added sequentially. After one hour, 2-chloro-6-fluorobenzylamine (30 mg, 0.19 mmol) was added to the reaction mixture and stirring was continued at room temperature for 18 hours. It was then diluted with ethyl acetate (10 mL), washed with water, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate, filtered, and concentrated. The oily residue was purified by flash chromatography (silica gel, eluted with ethyl acetate-hexanes gradient from 15% to 80% yield) to give 3-amino-6-[3-({[(2-chloro-6-fluorophenyl)methyl]amino}carbonyl)phenyl]-N-ethylpyrazine-2-carboxamide (a tan color solid, 31 mg, 51% yield): 1H NMR (400 MHz, DMSO-d6): 8.86 (s, 1H), 8.85-8.83 (b, 1H), 8.45 (s, 1H), 8.33-8.31 (d, 1H), 7.83-7.81 (d, 1H), 7.53-7.51 (t, 1H), 7.39-7.34 (m, 2H), 7.26-7.21 (t, 1H), 4.63-4.61 (d, 2H), 3.38-3.29 (m, 2H), 1.15-1.11 (t, 3H); MS (EI) for C21H19ClFN5O2: 428 (MH+).

Workup

  1. temperatureThe homogeneous reaction mixture was cooled to room temperature
  2. concentrationconcentrated to half the initial volume
  3. temperaturecooled in an ice-bath
  4. customA white solid precipitated
  5. filtrationwas collected by filtration
  6. washwashed with water
  7. customdried in vacuo

Sources & evidence

ORD record
ord-07fc1c1d3d5542edb5d4a375e899223e
Source dataset
uspto-grants-2010_04
Patent number
US07704995B2

Reaction notes

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