Trifluoroacetic acid → 4-(2-Hydroxyethoxy)-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

HRID 629073Notes

Reaction equation

HRID 629073 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[OH:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].C([O:26][CH2:27][CH2:28]Br)(=O)C.C([O-])([O-])=O.[K+].[K+].[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1.[OH-].[Na+].C(O)(C(F)(F)F)=O>CC(C)=O.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.CO.COCCOC.CCO>[OH:26][CH2:27][CH2:28][O:22][C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:40]1[CH:41]=[N:36][CH:37]=[N:38][CH:39]=1

Participants

12

Reactant 6

HCID 6422Trifluoroacetic acidHCID 11430Potassium CarbonateHCID 135641-Acetoxy-2-bromoethaneHCID 14798Sodium HydroxideHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 89906927HCID 89906927, compound

Product 1

HCID 722018734-(2-Hydroxyethoxy)-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

Reagents, catalysts & solvents 5

HCID 178418476HCID 178418476, compoundCatalystHCID 180AcetoneSolventHCID 702EthanolSolventHCID 887MethanolSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
75 °C

Procedure

A suspension of 3-bromo-4-hydroxy-N-(4-(trifluoromethoxy)phenyl)benzamide (50 mg, 0.133 mmol), 2-bromoethyl acetate (21.94 μL, 0.199 mmol) and powdered K2CO3 (92 mg, 0.665 mmol) in acetone (500 μL) was stirred at 75° C. for 16 h and the solvent was evaporated off under reduced pressure. The residue, together with pyrimidin-5-ylboronic acid (57.61 mg, 0.465 mmol), Pd(PPh3)2Cl2 (18.66 mg, 0.026 mmol) water (125 μL), EtOH (62 μL) and DME (550 μL) were added to a vial, which was sealed, evacuated/purged with argon and the RM stirred at 80° C. for 20 h. The RM was diluted with THF (3 mL) then stirred with Si-Thiol (Silicycle, 105 mg, 0.133 mmol) for 2 h, filtered and the filtrate was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 12 g, cyclohexane/EtOAc from 30% to 95% EtOAc) to afford the acylated product, which was treated with aq. 4 M NaOH (138 μL, 0.552 mmol) and MeOH (250 μL) at and stirred at RT for 4 h. The RM was acidified with TFA and purified by preparative HPLC (Condition 8, 50% for 0.2 min then 50% to 80% in 14 min) to afford the title compound as a beige solid. UPLC-MS (Condition 1) tR=2.24 min, m/z=420.0 [M+H]+, m/z=418 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.64-3.82 (m, 2H) 4.21 (t, J=4.6 Hz, 2H) 4.91 (t, J=5.4 Hz, 1H) 7.32-7.41 (m, 3H) 7.88 (d, J=9.0 Hz, 2H) 8.07 (dd, J=8.8, 2.2 Hz, 1H) 8.12 (d, J=2.2 Hz, 1H) 9.13 (s, 2H) 9.18 (s, 1H) 10.32 (s, 1H).

Workup

  1. customthe solvent was evaporated off under reduced pressure
  2. customwas sealed
  3. customevacuated/purged with argon
  4. stirringthe RM stirred at 80° C. for 20 h
  5. additionThe RM was diluted with THF (3 mL)
  6. filtrationfiltered
  7. customthe filtrate was evaporated off under reduced pressure
  8. customto give the crude product which
  9. customwas purified by flash chromatography (Silica gel column, 12 g, cyclohexane/EtOAc from 30% to 95% EtOAc)
  10. customto afford the acylated product, which
  11. stirringstirred at RT for 4 h
  12. custompurified by preparative HPLC (Condition 8, 50% for 0.2 min

Sources & evidence

ORD record
ord-98eb6623127841128289459c820b2b49
Source dataset
uspto-grants-2016_04
Patent number
US09315489B2

Reaction notes

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