1-Naphthoic acid → (2R)-3-[[3-(4-fluoro-3-methylphenoxy) phenyl][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

HRID 644963Notes

Reaction equation

HRID 644963 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:17]1[CH:18]=[C:19]([N:23]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=2)[CH2:24][C@@H:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:20]=[CH:21][CH:22]=1.C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>CN(C)C(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:21]2[CH:20]=[C:19]([N:23]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:40])([F:41])[F:42])[CH:33]=3)[CH2:24][C@@H:25]([OH:30])[C:26]([F:27])([F:28])[F:29])[CH:18]=[CH:17][CH:22]=2)=[CH:4][C:3]=1[CH3:9]

Participants

7

Reactant 4

HCID 68471-Naphthoic acidHCID 10796Cesium carbonate2×HCID 27373944-Fluoro-3-methylphenolHCID 86586491(2R)-3-[[(3-bromophenyl)] [[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

Product 1

HCID 57109777(2R)-3-[[3-(4-fluoro-3-methylphenoxy) phenyl][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolYield 23%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
105 °C

Procedure

A suspension of 4-fluoro-3-methylphenol (98.0 μL, 0.88 mmol) and cesium carbonate (319.5 mg, 0.98 mmol) in 1 mL of N,N-dimethylacetamide was preheated at 60° C. for 5 minutes. To this solution was added 4 mL of a stock solution containing (2R)-3-[[(3-bromophenyl)] [[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (200 mg, 0.437 mmol) from EX-33B, 1-naphthoic acid (164 mg, 0.95 mmol), copper(I) trifluoromethansulfonate benzene complex (21.8 mg, 0.0434 mmol), 4 Å sieves (105 mg), and 4 mL of toluene. The reaction mixture was stirred at 105° C. for 3 weeks and 2 days. During that time, additional cesium carbonate and catalyst were added (a spatula tip of each) to the reaction three different times. The reaction was cooled to room temperature, filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 35% to 90% acetonitrile in water to afford 50.5 mg (23%) of the desired (2R)-3-[[3-(4-fluoro-3-methylphenoxy)phenyl][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C24H20F7NO3: 504.1410 [M+H]+, found: 504.1389. 1H NMR (acetone-d6) δ 7.44 (t, 1H), 7.24 (d, 1H), 7.08-7.21 (m, 3H), 6.98 (t, 1H), 6.75-6.85 (m, 1H), 6.68-6.74 (m, 1H), 6.53 (d, 1H), 6.21-6.34 (m, 2H), 4.79 (t, 2H), 4.46-4.53 (m, 1H), 3.95 (dd, 1H), 2.61-2.72 (m, 1H), 2.20 (s, 3H).

Workup

  1. customto the reaction three different times
  2. temperatureThe reaction was cooled to room temperature
  3. filtrationfiltered through celite
  4. customthe solvent was evaporated
  5. customThe residue was purified by reverse phase HPLC
  6. washeluting with 35% to 90% acetonitrile in water

Sources & evidence

ORD record
ord-c47dcf6b5b5f421099cf38a14fd917dc
Source dataset
uspto-grants-2010_04
Patent number
US07700658B2

Reaction notes

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