Pyridine → N1-methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-((4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)carbamoyl)phenyl)isophthalamide

HRID 926848Notes

Reaction equation

HRID 926848 reaction equation
[NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:11]=1)=[O:5].N1C=CC=CC=1.[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])=[O:41]>ClCCl.C(OCC)(=O)C>[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40](=[O:41])[C:42]1[CH:50]=[CH:49][CH:48]=[C:44]([C:45]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:11]=2)=[O:46])[CH:43]=1

Participants

6

Reactant 3

HCID 1049PyridineHCID 867052033-(Methyl(2-morpholinoethyl)carbamoyl)benzoyl chlorideHCID 867052072-amino-5-(piperidin-1-yl)-N-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide

Product 1

HCID 56643723N1-methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-((4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)carbamoyl)phenyl)isophthalamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide (287 mg, 0.64 mmol, 1.00 equiv) in dichloromethane (3 mL), and pyridine (406 mg, 5.13 mmol, 8.00 equiv). This was followed by dropwise addition of a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride (300 mg, 0.97 mmol, 1.50 equiv) in dichloromethane (2 mL) with stirring. The resulting solution was stirred for 1 h at room temperature, then diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 1×20 mL of hydrogen chloride (1 N) and 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (300 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 120 mg (20%) of as a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 12.89(s, 1H), 10.93(s, 1H), 9.79(s, 1H), 8.26 (m, 2H), 8.00(m, 4H), 7.69(m, 4H), 7.53(s, 1H), 7.27(d, J=8.7 Hz, 1H), 4.01(s, 2H), 3.85(s, 2H), 3.63(s, 4H), 3.44(s, 2H), 3.17(m, 6H), 2.99(s, 3H), 1.70(m, 6H). MS (ES, m/z): 721 [M+H]+.

Workup

  1. customInto a 50-mL round bottom flask, was placed
  2. stirringThe resulting solution was stirred for 1 h at room temperature
  3. washThe resulting mixture was washed with 1×20 mL of hydrogen chloride (1 N) and 2×20 mL of brine
  4. dry with materialThe mixture was dried over anhydrous sodium sulfate
  5. concentrationconcentrated under vacuum
  6. customThe crude product (300 mg) was purified by reverse phase HPLC
  7. washeluting with a water/CH3CN gradient
  8. additioncontaining 0.05% TFA
  9. customThe product was obtained as 120 mg (20%) of as a yellow solid

Sources & evidence

ORD record
ord-164d4b63cf064fdc8432ec9d3bb314c9
Source dataset
uspto-grants-2016_03
Patent number
US09289430B2

Reaction notes

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