Sodium hydride → 3-(3-bromo-5-methylpyridin-2-ylamino)-5-chloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one

HRID 2060907Notes

Reaction equation

HRID 2060907 reaction equation
[H-].[Na+].[NH2:3][C:4]1[C:9]([Br:10])=[CH:8][C:7]([CH3:11])=[CH:6][N:5]=1.Cl[C:13]1[C:14](=[O:29])[N:15]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:16]=[C:17]([Cl:19])[N:18]=1>O1CCCC1>[Br:10][C:9]1[C:4]([NH:3][C:13]2[C:14](=[O:29])[N:15]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH:16]=[C:17]([Cl:19])[N:18]=2)=[N:5][CH:6]=[C:7]([CH3:11])[CH:8]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 5193802-Amino-3-bromo-5-methylpyridineHCID 154984631-(4-methoxybenzyl)-3,5-dichloropyrazine-2(1H)-one

Product 1

HCID 588801533-(3-bromo-5-methylpyridin-2-ylamino)-5-chloro-1-(4-methoxybenzyl)pyrazin-2(1H)-oneYield 56%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

An oven dried, 2 L, three necked round bottom flask was charged with NaH (60% dispersion in oil, 11.9 g, 298.11 mmol), suspended in anhydrous tetrahydrofuran (500 mL) and cooled in an ice bath. To the cooled mixture, was added the solution of 2-amino-3-bromo-5-methylpyridine (39.4 g, 210.433 mmol, 150 mL of anhydrous THF). The ice bath was removed and the reaction was allowed to warm to room temperature over a 1 h period. Via addition funnel, the solution of 3,5-dichloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one (50.0 g, 175.36 mmol, 150 mL anhydrous tetrahydrofuran) was added in a rapid, drop-wise fashion, attached a reflux condenser and stirred in an oil bath heated at 72° C. (exothermic reaction occurred upon heating). After 3 h, the flask was removed from the oil bath, cooled to room temperature, quenched with isopropanol (15 mL) and BHT (0.075 g), and concentrated in vacuo to a dark crude. Chromatography on silica gel plug with ethyl acetate/DCM (3/97) afforded the desired product as a light tan solid. The mix fractions were combined, concentrated and the desired product was purified by recrystallization in ethyl acetate/diethyl ether and isolated by vacuum filtration. The two solid pools were combined (43 g, 56% yield) and verified by 1H-NMR and analytical LCMS. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3H) 3.74 (s, 3H) 5.00 (s, 2H) 6.93 (d, J=8.84 Hz, 2H) 7.39 (s, 2H) 7.42 (s, 1H) 8.01 (s, 1H) 8.28 (s, 1H) 9.50 (s, 1H). ESI-MS: m/z 437.2 (M+H)+.

Workup

  1. customAn oven dried
  2. temperaturecooled in an ice bath
  3. customThe ice bath was removed
  4. additionVia addition funnel
  5. temperatureheated at 72° C.
  6. custom(exothermic reaction occurred upon heating)
  7. customthe flask was removed from the oil bath
  8. temperaturecooled to room temperature
  9. customquenched with isopropanol (15 mL) and BHT (0.075 g)
  10. concentrationconcentrated in vacuo to a dark crude

Sources & evidence

ORD record
ord-20790848c980488c827da0cd42af11b2
Source dataset
uspto-grants-2012_10
Patent number
US08278450B2

Reaction notes

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