Diisopropylethylamine → (R)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 923897Notes

Reaction equation

HRID 923897 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].C1CNC([CH2:28][OH:29])C1.Cl.CC[N:33]([CH:37]([CH3:39])C)[CH:34]([CH3:36])C>CC(O)C>[Br:1][C:2]1[C:3]([N:33]2[CH2:34][CH2:36][C@@H:39]([CH2:28][OH:29])[CH2:37]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

5

Reactant 3

HCID 81531Diisopropylethylamine2×HCID 17802800Pyrrolidin-2-ylmethanol hydrochloride2×HCID 867025955-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 89906134(R)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
140 °C

Procedure

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 500 mg, 1.264 mmol), (R)-beta-prolinol hydrochloride (191 mg, 1.39 mmol) and DIPEA (442 μL, 2.53 mmol) in iPrOH (1945 μL) were added to a MW vial and subjected to MW irradiation at 140° C. for 30 min. Additional (R)-beta-prolinol hydrochloride (34.8 mg, 0.253 mmol) and DIPEA (221 μL, 1.264 mmol) were added to the mixture which was heated at 140° C. for a further 30 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure treated with 0.5 M HCl (20 mL) and extracted with EtOAc. The combined extracts were washed with 0.5 M HCl (10 mL), water, dried over MgSO4 and evaporated to dryness under reduced pressure. Trituration in a cyclohexane/EtOAc mixture and filtration of the solid afforded the title compound as a white solid. UPLC-MS (condition 1) tR=2.76 min, m/z=460.0-462.0 [M+H]+, m/z=458.0-460.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.77 (m, 1H) 1.91-2.06 (m, 1H) 2.28-2.42 (m, 1H) 3.35-3.51 (m, 2H) 3.56 (dd, J=11.00, 7.34 Hz, 1H) 3.63-3.86 (m, 3H) 4.71 (br. s, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.34 (d, J=1.96 Hz, 1H) 8.68 (d, J=1.96 Hz, 1H) 10.22 (s, 1H).

Workup

  1. customsubjected to MW irradiation at 140° C. for 30 min
  2. temperatureThe vial was cooled to RT
  3. customthe RM was evaporated to dryness under reduced pressure
  4. additiontreated with 0.5 M HCl (20 mL)
  5. extractionextracted with EtOAc
  6. washThe combined extracts were washed with 0.5 M HCl (10 mL), water
  7. dry with materialdried over MgSO4
  8. customevaporated to dryness under reduced pressure
  9. filtrationTrituration in a cyclohexane/EtOAc mixture and filtration of the solid

Sources & evidence

ORD record
ord-6491bf546b1d43688b960682094f7800
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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