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

HRID 726090Notes

Reaction equation

HRID 726090 reaction equation
[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

Participants

5

Reactant 3

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

Product 1

HCID 1548970(+)-FluoxetineYield 86%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
90 °C

Procedure

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 be 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. [α]23D +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, 2 H), 7.40-7.43 (d, J=8.7 Hz, 2 H), 7.25-7.33 (m, 5 H), 6.88-6.92 (d, J=8.7 Hz, 2 H), 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1 H), 3.12 (br, s, 2 H), 2.55-2.62 (br, s, 3 H), 2.42-2.52 (m, 2 H); Anal. Calcd. for C17 H19ClF3NO: 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.

Workup

  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. customdried
  9. concentrationConcentration

Sources & evidence

ORD record
ord-c6f35eea01ab42118fbc5de559f68519
Source dataset
uspto-grants-1998_01
Patent number
US05708035

Reaction notes

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