Diisopropylethylamine → (S)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 923851Notes

Reaction equation

HRID 923851 reaction equation
[Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 2733874(3S)-pyrrolidin-3-olHCID 867025955-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 86702636(S)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
140 °C

Procedure

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 2.37 g, 6.0 mmol) and (S)-pyrrolidin-3-ol (0.627 g, 7.2 mmol) were dissolved in iPrOH (6 mL). DIPEA (2.1 mL, 12 mmol) was added and the RM mixture was heated at 140° C. for 1 h in a MW vial. After cooling to RT, the RM was dissolved in EtOAc, and washed with 0.5 M HCl and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure until the crystallization began. The mixture was triturated with n-pentane, filtered and dried to afford the title compound as a beige crystalline solid. HPLC (Condition 4) tR=5.51 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=448.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74-2.03 (m, 2H) 3.55 (d, J=11.34 Hz, 1H) 3.64-3.74 (m, 1H) 3.78-3.89 (m, 2H) 4.33 (br. s, br. s, 1H) 4.97 (d, J=3.13 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.78-7.90 (m, 2H) 8.32 (d, J=1.56 Hz, 1H) 8.63-8.72 (m, 1H) 10.20 (s, 1H).

Workup

  1. temperatureAfter cooling to RT
  2. washwashed with 0.5 M HCl and brine
  3. dry with materialThe organic phase was dried over Na2SO4
  4. concentrationconcentrated under reduced pressure until the crystallization
  5. customThe mixture was triturated with n-pentane
  6. filtrationfiltered
  7. customdried

Sources & evidence

ORD record
ord-37760ab0acb8400686c2ebcdde5bd892
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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