Cesium carbonate → (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol

HRID 2086449Notes

Reaction equation

HRID 2086449 reaction equation
[F:1][C:2]([F:29])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:22][C@@H:23]([OH:28])[C:24]([F:27])([F:26])[F:25])[C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[F:1][C:2]([F:29])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([C:31]([F:30])([F:40])[F:41])[CH:33]=3)[CH:16]=2)[CH2:22][C@@H:23]([OH:28])[C:24]([F:26])([F:27])[F:25])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 1230611-(Bromomethyl)-3-(trifluoromethyl)benzeneHCID 86586490(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy]phenyl]methyl][3,3,3-trifluoro-2-hydroxypropyl) amino]phenol

Product 1

HCID 10167240(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanolYield 47%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy]phenyl]methyl][3,3,3-trifluoro-2-hydroxypropyl)amino]phenol (100 mg, 0.23 mmol) from EX-20B and 3-trifluoromethylbenzyl bromide (70.0 mg, 0.27 mmol) in 2.5 mL of acetone was added cesium carbonate (100 mg, 0.31 mmol). The reaction mixture was heated at 60° C. for 18 h then cooled to room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 63.3 mg (45%) of the desired (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C26H21F10NO3: 586.1440 [M+H]+, found: 586.1419. 1H NMR (acetone-d6) δ 7.61-7.82 (m, 4H), 7.41 (t, 1H), 7.25 (d, 1H), 7.10-7.21 (m, 3H), 6.34-6.67 (m, 4H), 5.73 (d, 1H), 5.19 (s, 2H), 4.82 (s, 2H), 4.34-4.48 (m, 1H), 3.99 (dd, 1H), 3.68 (dd, 1H).

Workup

  1. temperaturethen cooled to room temperature
  2. filtrationThe reaction mixture was filtered through celite
  3. concentrationthe filtrate was concentrated
  4. customThe residue was purified by reverse phase HPLC
  5. washeluting with 50% to 90% acetonitrile in water

Sources & evidence

ORD record
ord-3669a4918eb3404f830c0cad4e991761
Source dataset
uspto-grants-2004_04
Patent number
US06723752B2

Reaction notes

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