Syntheses & metabolism of selected antidepressants
© Oldřich Farsa 2019
Synthesis of imipramine
Metabolism of imipramine
Synthesis of amitriptyline
O
+
Mg N
Cl
CH3
CH3
OMg
Br
N
CH3
CH3
OH
N
CH3
CH3
N
CH3
CH3
HCl
-H2O
Et2O H2O
HCl
- MgBrOH
Metabolism of amitriptyline
stronger inhibitor of NA than 5HT reuptake
Syntheses of fluoxetine
Syntheses of fluoxetine (continued)
Metabolism of fluoxetine
O
F F
F
NH CH3
H
O
F F
F
NH2
H
P 450 2D6, 3A4, 2C9, 3A5, 2C19
norfluoxetine glucuronide
oxidative deamination
O
F F
F
OH
H
"norfluoxetine alcohol"
O
F F
F
OH
H
O
"norfluoxetine
acid"
2C19, 3A4
OH
F F
F
4-(trifluoromethyl)phenol
O NH
OH
O
2C19, 3A4
hippuric acid
CH3
N
O
F
F
F
O
OH
OHOH
OH O
H
fluoxetine glucuronide
glucuronosyltranserase
NH
O
F F
F
H
OH
OH
O
OH
OH
OH
glucuronosyltransferase
norfluoxetine - active
Synthesis of paroxetine
Metabolism of paroxetine
Excretion: 62% in urine as metabolites,
2% in urine as parent drug, 36% in feces
via bile (<1% as parent drug)
Metabolism of atomoxetine
Synthesis of sertraline
Metabolism of sertraline