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

HRID 392954Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 392954
[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]

Komponenten

7

Edukt 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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 1140TolueneLösungsmittelHCID 31374DimethylacetamideLösungsmittel

Reaktionsbedingungen

Temperatur
105 °C

Versuchsvorschrift

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).

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-19f122d7136f4c22aeb42268e863abde
Quelldatensatz
uspto-grants-2004_10
Patentnummer
US06803388B2

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