Ethanol → 6-(3-Hydroxy-3-methylazetidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 923960Notes

Reaction equation

HRID 923960 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]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].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[OH:27][C:24]1([CH3:26])[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1

Participants

8

Reactant 4

HCID 702EthanolHCID 10340Sodium CarbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 899064985-Bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 899081486-(3-Hydroxy-3-methylazetidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

5-Bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1, 89 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (50 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M Na2CO3 (0.300 mL, 0.6 mmol) and EtOH (120 μL) were added, the mixture was flushed with argon, Pd(PPh3)2Cl2 (17 mg, 0.02 mmol) was added and the RM was heated at 95° C. for 3 h in a pressure safe vial. After cooling at RT, the RM was treated with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, first EtOAc/MeOH from 0 to 10% MeOH; then second flash DCM/MeOH, from 2% to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a white crystalline solid. HPLC (Condition 4) tR=4.74 min, UPLC-MS (Condition 7) m/z=446.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.29 (s, 4H) 3.50-3.64 (m, 3H) 5.49 (s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.83 (d, J=8.99 Hz, 2H) 8.09 (d, J=1.56 Hz, 1H) 8.78 (d, J=1.95 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.20 (s, 1H).

Workup

  1. additionwas added
  2. temperatureAfter cooling at RT
  3. washwashed with brine
  4. dry with materialThe organic phase was dried over Na2SO4
  5. customevaporated to dryness under reduced pressure
  6. customThe crude product was purified by flash chromatography (RediSep® Silica gel column, first EtOAc/MeOH from 0 to 10% MeOH
  7. additionthen second flash DCM/MeOH, from 2% to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH

Sources & evidence

ORD record
ord-4989b817ea984483b6fade8877d3240a
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

Loading…