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

HRID 625363Notes

Reaction equation

HRID 625363 reaction equation
[F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:38])[C:29]2([CH2:35][NH:36][CH3:37])[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]([OH:54])=O)[CH2:47][CH2:46]1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[F:43][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:38])[C:29]2([CH2:35][N:36]([CH3:37])[C:52](=[O:54])[CH2:51][N:48]3[CH2:47][CH2:46][O:45][CH2:50][CH2:49]3)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1

Participants

6

Reactant 3

HCID 4389684-Morpholineacetic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 86705956N-(3-(trifluoromethyl)benzyl)-2-(2-(2-((methylamino)methyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide

Product 1

HCID 86705955N-(3-(trifluoromethyl)benzyl)-2-(2-(2-((N-methyl-2-morpholinoacetamido)-methyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamideYield 93.2%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

Into a 50-mL vial, was placed N-(3-(trifluoromethyl)benzyl)-2-(2-(2-((methylamino)methyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (10 mL), 2-morpholinoacetic acid (28.9 mg, 0.20 mmol, 1.20 equiv), EDC HCl (47.4 mg, 0.25 mmol, 1.50 equiv), and 4-dimethylaminopyridine (30.4 mg, 0.25 mmol, 1.50 equiv). The resulting solution was stirred for 4 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 3×50 mL of aqueous NH4Cl, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 116 mg (59%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 9.12 (m, 1H), 8.86 (d, J=9.2 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.17 (m, 1H), 8.12 (m, 1H), 8.01 (m, 1H), 7.95 (m, 1H), 7.80 (m, 3H), 7.60 (m, 3H), 4.96 (m, 2H), 4.72 (s, 2H), 4.50 (m, 2H), 3.98 (m, 4H), 3.70 (m, 4H), 3.1 (s, 3H), 2.10 (m, 4H), 1.98 (s, 2H). MS (ES, m/z): 730 [M+H]+.

Workup

  1. washThe resulting mixture was washed with 3×50 mL of aqueous NH4Cl
  2. dry with materialdried over anhydrous sodium sulfate
  3. concentrationconcentrated under vacuum
  4. customThe crude product (200 mg) was purified by reverse phase HPLC
  5. washeluting with a water/CH3CN gradient
  6. additioncontaining 0.05% TFA

Sources & evidence

ORD record
ord-dec4cd0cc7bd489796f4443a06f23954
Source dataset
uspto-grants-2016_04
Patent number
US09301951B2

Reaction notes

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