4-Morpholineacetic acid → 2-(2-(3-((N-methyl-2-morpholinoacetamido)methyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide

HRID 625348Notes

Reaction equation

HRID 625348 reaction equation
[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[F:23][C:24]([F:66])([F:65])[C:25]1[CH:26]=[C:27]([CH:62]=[CH:63][CH:64]=1)[CH2:28][NH:29][C:30](=[O:61])[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]2[CH:42]=[C:41]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:40]=[CH:39][C:38]=2[NH:49][C:50](=[O:60])[C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][NH:58][CH3:59])[CH:52]=2)[CH:32]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:59][N:58]([CH2:57][C:53]1[CH:52]=[C:51]([CH:56]=[CH:55][CH:54]=1)[C:50]([NH:49][C:38]1[CH:39]=[CH:40][C:41]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:42][C:37]=1[C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][N:34]=1)[C:30]([NH:29][CH2:28][C:27]1[CH:62]=[CH:63][CH:64]=[C:25]([C:24]([F:65])([F:23])[F:66])[CH:26]=1)=[O:61])=[O:60])[C:8](=[O:10])[CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1

Participants

6

Reactant 3

HCID 4389684-Morpholineacetic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 66586835N-(3-(trifluoromethyl)benzyl)-2-(2-(3-((methylamino)methyl)-benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide

Product 1

HCID 696311712-(2-(3-((N-methyl-2-morpholinoacetamido)methyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamideYield 38.3%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

Into a 50-mL round-bottom flask, was placed a solution of 2-morpholinoacetic acid (25.0 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (10 mL), EDC.HCl (50.0 mg, 0.26 mmol, 1.50 equiv), 4-dimethylaminopyridine (32.0 mg, 0.26 mmol, 1.50 equiv), and N-(3-(trifluoromethyl)benzyl)-2-(2-(3-((methylamino)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (1000 mg, 1.66 mmol, 1.00 equiv). The resulting solution was stirred for 6 h at 25° C. in an oil bath. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 2×30 mL of aqueous NH4Cl. The resulting mixture was washed with brine. The mixture was dried over 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 47.4 mg (26%) of a pale-yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.90-8.98 (m, 1H), 8.57-8.64 (m, 1H), 8.40 (s, 1H), 7.84-8.00 (m, 4H), 7.54-7.72 (m, 7H), 4.72-4.76 (m, 4H), 4.36-4.38 (m, 2H), 3.96 (m, 4H), 3.58-3.61 (m, 4H), 3.01 (s, 3H), 1.99-2.00 (m, 4H), 1.75 (m, 2H). MS (ES, m/z) 729 [M+H]+.

Workup

  1. customInto a 50-mL round-bottom flask, was placed
  2. washThe resulting mixture was washed with 2×30 mL of aqueous NH4Cl
  3. washThe resulting mixture was washed with brine
  4. dry with materialThe mixture was dried over sodium sulfate
  5. concentrationconcentrated under vacuum
  6. customThe crude product (120 mg) was purified by reverse phase HPLC
  7. washeluting with a water/CH3CN gradient
  8. additioncontaining 0.05% TFA

Sources & evidence

ORD record
ord-1d336cc56e394543a6adecccbaec0985
Source dataset
uspto-grants-2016_04
Patent number
US09301951B2

Reaction notes

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