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

HRID 2406109Notes

Reaction equation

HRID 2406109 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[N:63]=[CH: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[CH:60]=[N:59][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:63][CH:62]=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 665869432-amino-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-5-(piperidin-1-yl)benzamide

Product 1

HCID 56599398N1-(2-((5-(3,4-dimethylphenyl)pyrimidin-2-yl)carbamoyl)-4-(piperidin-1-yl)phenyl)-N3-(2-(2-hydroxyethoxy)ethyl)isophthalamideYield 9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Into a 10-mL round bottom flask, was placed a solution of 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoic acid (227.1 mg, 0.90 mmol, 3.00 equiv) in N,N-dimethylformamide (6 mL), HATU (397.5 mg, 1.05 mmol, 3.50 equiv), N,N-diisopropylethylamine (192.8 mg, 1.49 mmol, 5.00 equiv), and 2-amino-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-5-(piperidin-1-yl)benzamide (120 mg, 0.30 mmol, 1.00 equiv) and the resulting solution was stirred overnight at 25° C. in an oil bath. The reaction was then quenched with 100 mL of water and the resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined, washed with 2×50 mL of brine and then dried over sodium sulfate. The solids were filtered out and the resulting mixture was concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA to afford 16.8 mg (9%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.34 (s, 1H), 11.24 (s, 1H), 8.71˜8.68 (m, 3H), 8.38 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 8.04˜7.99 (m, 2H), 7.66˜7.58 (m, 1H), 7.47˜7.38 (m, 1H), 7.28˜7.19 (m, 2H), 7.15 (d, J=6.3 Hz, 1H), 4.42 (s, 1H), 3.56˜3.44 (m, 9H), 3.31 (m, 4H), 2.32 (s, 3H), 2.16 (s, 3H), 1.71˜1.58 (m, 6H). MS (ES, m/z): 637 [M+H]+.

Workup

  1. customInto a 10-mL round bottom flask, was placed
  2. customThe reaction was then quenched with 100 mL of water
  3. extractionthe resulting solution was extracted with 3×50 mL of ethyl acetate
  4. washwashed with 2×50 mL of brine
  5. dry with materialdried over sodium sulfate
  6. filtrationThe solids were filtered out
  7. concentrationthe resulting mixture was concentrated under vacuum
  8. customThe crude product (120 mg) was purified by reverse phase HPLC
  9. washeluting with a water/CH3CN gradient
  10. additioncontaining 0.05% TFA

Sources & evidence

ORD record
ord-bf3748e075e74befb9c41ef14cd40e27
Source dataset
uspto-grants-2014_08
Patent number
US08809339B2

Reaction notes

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