Diisopropylethylamine → N1-(2-((5-(3,4-dimethylphenyl)pyrazin-2-yl)carbamoyl)-4-(piperidin-1-yl)-phenyl)-N3-(2-(2-hydroxyethoxy)ethyl)isophthalamide

HRID 926771Notes

Reaction equation

HRID 926771 reaction equation
[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:52][C:53]1[CH:75]=[CH:74][C:73]([N:76]2[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]2)=[CH:72][C:54]=1[C:55]([NH:57][C:58]1[CH:63]=[N:62][C:61]([C:64]2[CH:69]=[CH:68][C:67]([CH3:70])=[C:66]([CH3:71])[CH:65]=2)=[CH:60][N:59]=1)=[O:56]>CN(C)C=O>[CH3:71][C:66]1[CH:65]=[C:64]([C:61]2[N:62]=[CH:63][C:58]([NH:57][C:55]([C:54]3[CH:72]=[C:73]([N:76]4[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]4)[CH:74]=[CH:75][C:53]=3[NH:52][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])=[O:9])[CH:11]=3)=[O:56])=[N:59][CH:60]=2)[CH:69]=[CH:68][C:67]=1[CH3:70]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 665867923-((2-(2-Hydroxyethoxy)ethyl)carbamoyl)benzoic acidHCID 665869342-amino-N-(5-(3,4-dimethylphenyl)pyrazin-2-yl)-5-(piperidin-1-yl)benzamide

Product 1

HCID 56601992N1-(2-((5-(3,4-dimethylphenyl)pyrazin-2-yl)carbamoyl)-4-(piperidin-1-yl)-phenyl)-N3-(2-(2-hydroxyethoxy)ethyl)isophthalamideYield 28.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

Into a 50-mL round bottom flask, was placed a solution of 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoic acid (189.3 mg, 0.75 mmol, 3.00 equiv) in N,N-dimethylformamide (5 mL), HATU (331.2 mg, 0.87 mmol, 3.50 equiv), N,N-diisopropylethylamine (160.6 mg, 1.24 mmol, 5.00 equiv), and 2-amino-N-(5-(3,4-dimethylphenyl)pyrazin-2-yl)-5-(piperidin-1-yl)benzamide (100 mg, 0.25 mmol, 1.00 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction was then quenched with 50 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 44.8 mg (28%) of a light yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.36 (s, 1H), 11.06 (s, 1H), 9.38 (d, J=1.5 Hz, 1H), 9.03 (d, J=1.5 Hz, 1H), 8.74˜8.66 (m, 1H), 8.39 (s, 1H), 8.10˜8.01 (m, 3H), 7.92 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.66˜7.51 (m, 2H), 7.37 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 3.56˜3.34 (m, 13H), 2.32˜2.28 (m, 6H), 1.72˜1.61 (m, 6H). MS (ES, m/z): 637 [M+H]+.

Workup

  1. customInto a 50-mL round bottom flask, was placed
  2. customThe reaction was then quenched with 50 mL of water
  3. extractionThe resulting solution was extracted with 3×30 mL of ethyl acetate
  4. washThe resulting mixture was washed with 2×50 mL of brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated under vacuum
  7. customThe crude product (120 mg) was purified by reverse phase HPLC
  8. washeluting with a water/CH3CN gradient
  9. additioncontaining 0.05% TFA

Sources & evidence

ORD record
ord-fba7a01c17b64bfe926e2bdad75274f9
Source dataset
uspto-grants-2016_03
Patent number
US09289429B2

Reaction notes

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