1-Chloro-4-(trifluoromethyl)benzene → (+)-Fluoxetine

HRID 265426

Reaktionsgleichung

Reaktionsgleichung von HRID 265426
[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>CC(N(C)C)=O>[CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([O:6][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1

Komponenten

5

Edukt 3

HCID 73941-Chloro-4-(trifluoromethyl)benzeneHCID 24758Sodium hydrideHCID 7020931(1R)-3-(methylamino)-1-phenylpropan-1-ol

Produkt 1

HCID 1548970(+)-FluoxetineAusbeute 86 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 31374DimethylacetamideLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

To a solution of (R)-N-methyl-3-phenyl-3-hydroxy-propylamine (7) (1.23 g, 7.45 mmol) in dimethyl acetamide (7 mL) was added sodium hydride (215 mg, 8.95 mmol) with cooling. The mixture was heated at 90° C. for 1.5 h, and an orange solution resulted. To this solution was then added 4-chlorobenzotrifluoride (3.23 g, 2.40 mL, 17.9 mmol), and the mixture was heated at 100°-105° C. for 2.5 h. After cooling and dilution with toluene, the mixture was washed with water, and the aqueous layer was separated and extracted with toluene. The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate. Concentration provided (R)-fluoxetine as an orange oil (1.97 g, 86%). The oil was dissolved in ether and acidified with hydrogen chloride gas (pH=3-4) to give a acidic ethereal solution (no precipitate formed). The solution was concentrated at room temperature to give a yellow solid which was washed with ether to remove most of the orange color. The slightly yellow solid was then recrystallized from acetonitrile at -20° C. The solid was collected and washed with ether to provide (R)-fluoxetine hydrochloride (8) as a white powder (1.90 g, 75%): mp 140°-142° C. (lit.133b mp 140°-141.5° C.; [α]23D-2.16° (c 1.62, MeOH); (lit.133b [α]23D-1.97° [c 1.00, MeOH]); [α]23D +7.08° (c 1.30, H2O); (lit⟦alpha⟧sup.23 D +10.32° [c 1.00, H2O]); IR (KBr, CDCl3 2950, 2640, 2450, 1620, 1595, 1520, 1360, 1250, 1180, 1170, 1130, 1114, 1070, 840 cm-1; 1H NMR (CDCl3) δ9.72 (br, s, 2H), 7.40-7.43 (d, J=8.7 Hz, 2H), 7.25-7.33 (m, 5H), 6.88-6.92 (d, J=8.7 Hz, 2H), 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1H), 3.12 (br, s, 2H), 2.55-2.62 (br, s, 3H), 2.42-2.52 (m, 2H); Anal. Calcd. for C17H19ClF3NO: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 58.84; H, 5.55; N, 3.94; F, 16.28; Cl, 10.50.

Aufarbeitung

  1. temperaturewith cooling
  2. customan orange solution resulted
  3. temperatureAfter cooling
  4. washdilution with toluene, the mixture was washed with water
  5. customthe aqueous layer was separated
  6. extractionextracted with toluene
  7. washThe combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine
  8. dry with materialdried over magnesium sulfate
  9. concentrationConcentration

Quellen und Nachweise

ORD-Eintrag
ord-c9bd7d4d1baa48099e32505781358c03
Quelldatensatz
uspto-grants-1997_07
Patentnummer
US05648396

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