Diisopropylethylamine → 1-{4-[(Benzyl-methyl-amino)-methyl]-2-methoxy-phenyl}-3-(5-methyl-pyrazin-2-yl)-urea

HRID 1821800Notes

Reaction equation

HRID 1821800 reaction equation
C[C:2]1[N:3]=[CH:4][C:5]([C:8](O)=O)=[N:6][CH:7]=1.C([N:14]([CH:17](C)C)CC)(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:27])C=CC=CC=1.[CH2:37]([N:44]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([NH2:53])=[C:49]([O:54][CH3:55])[CH:48]=1)[CH3:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:37]([N:44]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:17]([NH:14][C:2]2[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=2)=[O:27])=[C:49]([O:54][CH3:55])[CH:48]=1)[CH3:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 1228315-Methyl-2-pyrazinecarboxylic acidHCID 199401P,P-Diphenylphosphinic azideHCID 220463124-[(Benzyl-methyl-amino)-methyl]-2-methoxy-phenylamine

Product 1

HCID 220465131-{4-[(Benzyl-methyl-amino)-methyl]-2-methoxy-phenyl}-3-(5-methyl-pyrazin-2-yl)-ureaYield 40.4%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

In a 50 mL round bottom flask, 5-methylpyrazine-2-carboxylic acid (250 mg, 1.8 mmol) and diisopropylethylamine (330 μL, 1.9 mmol) in 20 mL toluene, was stirred under a nitrogen atmosphere until the acid dissolved. Diphenylphosphoryl azide (523 mg, 1.9 mmol) was added and the solution was heated to 90° C. After 20 minutes, nitrogen evolution had subsided, and the solution had darkened to a caramel color. The reaction was cooled to 65° C., and 4-[(benzyl-methyl-amino)-methyl]-2-methoxy-phenylamine (486 mg, 1.9 mmol) was added as a solution in 5 mL toluene. The reaction was allowed to stir at 65° C. for 6 h, and was then cooled to room temperature, diluted with 30 mL EtOAc, and washed with 15 mL 5% NH4OH. The aqueous phase was extracted with EtOAc (2×20 mL) and the combined organics were washed with 30 mL brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography to give 285 mg (40%) of the desired product, which was further purified by trituration with diethyl ether. Mp=142-143° C. 1H NMR (400 MHz, CDCl3): δ 11.33 (s, 1H), 9.51 (s, 1H), 8.41 (s, 1H), 8.27 (d, J=8.61 Hz, 1H), 8.08 (s, 1H), 7.2-7.4 (m, 5H), 6.96 (d, J=7.83 Hz, 1H) 3.97 (s, 3H), 3.53 (s, 4H), 2.53 (s, 3H), 2.22 (s, 3H). 13C. NMR (400 MHz, CDCl3): δ 153.70, 149.03, 147.48, 147.4, 145.99, 138.73, 137.38, 134.81, 129.19, 128.42, 127.16, 121.89, 119.81, 111.05, 104.49, 94.98, 87.22, 61.81, 56.37, 42.5. MS (APCI-pos)M+1=392.0.

Workup

  1. dissolutiondissolved
  2. temperatureThe reaction was cooled to 65° C.
  3. temperaturewas then cooled to room temperature
  4. washwashed with 15 mL 5% NH4OH
  5. extractionThe aqueous phase was extracted with EtOAc (2×20 mL)
  6. washthe combined organics were washed with 30 mL brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe resulting residue was purified by flash chromatography

Sources & evidence

ORD record
ord-f4f32f7afff648ad8d6c26ac6c1607db
Source dataset
uspto-grants-2009_10
Patent number
US07608618B2

Reaction notes

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