Pyridine → 3-(3,5-Dichloro-4-hydroxyphenyl)-N-(4-(4-fluoro-3-(trifluoromethyl)phenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide

HRID 222362Notes

Reaction equation

HRID 222362 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8]CC1C=CC(OC)=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46].N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][C:39]4[CH:40]=[CH:41][C:36]([F:35])=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:38]=4)=[CH:32][CH:33]=3)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[OH:8]

Participants

6

Reactant 3

HCID 1049PyridineHCID 177500514-Fluoro-3-(trifluoromethyl)benzeneboronic acidHCID 579196563-(3,5-Dichloro-4-(4-methoxybenzyloxy)phenyl)-N-(4-hydroxybenzyl)-1,2,4-oxadiazole-5-carboxamide2×

Product 1

HCID 1358704153-(3,5-Dichloro-4-hydroxyphenyl)-N-(4-(4-fluoro-3-(trifluoromethyl)phenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamideYield 71%

Reagents, catalysts & solvents 2

HCID 8895Cupric acetateCatalystHCID 6344DichloromethaneSolvent

Procedure

3-(3,5-Dichloro-4-(4-methoxybenzyloxy)phenyl)-N-(4-hydroxybenzyl)-1,2,4-oxadiazole-5-carboxamide (compound G, 60 mg, 0.12 mmol), 4-fluoro-3-(trifluoromethyl)phenylboronic acid (50 mg, 0.24 mmol), Cu(OAc)2 (44 mg, 0.24 mmol) and 3 Å powdered molecular sieves (70 mg) were stirred in an open tube in dichloromethane (3 mL). Pyridine (57 mg, 0.72 mmol) was added and the dark green suspension stirred vigorously at room temperature in an open tube for 1 d. The molecular sieves were filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (0.3 mL) was added. The dark solution was stirred at room temperature for 5 h, then methanol (1 mL) was added and the solution concentrated in vacuo. The residue was purified by preparative HPLC providing the title compound (46 mg, 0.085 mmol, 71%). 1H NMR δ (ppm) (DMSO-d6): 4.53 (2H, d, J=6.20 Hz), 7.06-7.13 (2H, m), 7.36-7.48 (4H, m), 7.53-7.60 (1H, m), 8.01 (2H, s), 10.03 (1H, t, J=6.20 Hz), 11.20 (1H, s). LCMS (10 cm_esci_Bicarb_MeCN) tR 3.48 min; m/z 540/542/544 [M−H]−.

Workup

  1. filtrationThe molecular sieves were filtered
  2. washwashed with dichloromethane
  3. concentrationthe filtrate concentrated in vacuo
  4. dissolutionThe residue was dissolved in dichloromethane (3 mL)
  5. additiontrifluoroacetic acid (0.3 mL) was added
  6. stirringThe dark solution was stirred at room temperature for 5 h
  7. additionmethanol (1 mL) was added
  8. concentrationthe solution concentrated in vacuo
  9. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-4f6bb63fda9b4d2aa4e4e207b8946f98
Source dataset
uspto-grants-2012_06
Patent number
US08207205B2

Reaction notes

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