1-Fluoronaphthalene → Duloxetine

HRID 41610

Reaction equation

HRID 41610 reaction equation
[CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].F[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[K+]>CS(C)=O>[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:6][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:22]=12)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1

Participants

5

Reactant 3

HCID 94501-FluoronaphthaleneHCID 100950473-(N-Methylamino)-1-(2-thienyl)-1-propanol, (-)-HCID 23665647Potassium tert-butoxide

Product 1

HCID 60835Duloxetine

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
60 °C

Procedure

(S)-(−)-3-methylamino-1-(2-thienyl)-propan-1-ol (20.0 g) and 1-fluoronaphthalene (68.3 g) were charged into a 4-neck round bottomed flask. Potassium tert-butoxide (13.1 g) and DMSO (36.0 g) were then added, and the resulting mixture was heated to 60° C. for 8 hours. After completion of the reaction, the reaction mixture was cooled down and washed with water. Layers were separated, and the organic layer was further extracted with 32% HCl(aq) (14.7 g) to separate Duloxetine® from 1-floronaphthalene. The acidic aqueous layer was adjusted to pH 12-13 with 45% NaOH(aq) (17.6 g) to obtain Duloxetine® in a free base form as an oily liquid (31.3 g, 90%). Optical purity of the resulting Duloxetine® measured by chiral HPLC was 95% e.e.

Workup

  1. customAfter completion of the reaction
  2. temperaturethe reaction mixture was cooled down
  3. washwashed with water
  4. customLayers were separated
  5. extractionthe organic layer was further extracted with 32% HCl(aq) (14.7 g)
  6. customto separate Duloxetine® from 1-floronaphthalene

Sources & evidence

ORD record
ord-c03510cd2eef4182a781137295957622
Source dataset
uspto-grants-2013_09
Patent number
US08530674B2

Linked notes

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