Sodium Hydroxide → HCID 68650971, compound

HRID 646684Notes

Reaction equation

HRID 646684 reaction equation
[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19]C)=[O:18])=[N:6][C:7]=1[C:8]([NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:9].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([OH:19])=[O:18])=[N:6][C:7]=1[C:8]([NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:9]

Participants

4

Reactant 2

HCID 14798Sodium HydroxideHCID 68651269HCID 68651269, compound

Product 1

HCID 68650971HCID 68650971, compoundYield 15%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
92.5 °C

Procedure

Methyl 3-{5-amino-6-[(cyclopropylamino)carbonyl]pyrazin-2-yl}benzoate (480 mg, 1.5 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 the intermediate 3-{5-amino-6-[(cyclopropylamino)carbonyl]pyrazin-2-yl}benzoic acid. The acid (40 mg, 0.13 mmol) was dissolved in DMF (1 mL) and 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 1-[(3-dimethylamino)propyl]pyrazin-2-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-cyclopropyl-pyrazine-2-carboxamide (a tan color solid, 23 mg, 56% yield): 1H NMR (400 MHz, DMSO-d6): 8.87-8.86 (t, 1H), 8.85-8.83 (b, 1H), 8.65-8.64 (d, 1H), 8.45 (s, 1H), 7.83-7.81 (d, 1H), 7.53-7.51 (t, 1H), 7.41-7.39 (m, 2H), 7.26-7.21 (t, 1H), 4.63-4.61 (d, 2H), 2.85-2.81 (m, 1H), 0.73-0.64 (m, 4H); MS (EI) for C22H19ClFN5O2: 440 (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-ca63013d9da6446b9ab9e05b5bbd02b7
Source dataset
uspto-grants-2010_04
Patent number
US07704995B2

Reaction notes

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