Syntheses and metabolism of selected general &
local anesthetics
General anesthetics
Syntheses of some inhalation general anesthetics
Preparation of nitrous oxide: heating of ammonium nitrate to 180 – 250°C:
NH4
NO3
 N2
O + H2
O
Synthesis of diethyl ether
●
known since 10th
-11th
century: Abu al-Khasim al-Zahravi Ibn Zuhr, an Arab alchemist
Cl
Cl
Cl
H
S b C l3 / H F
F
F
F Cl
H
B r 2
F
F
F Cl
Br
Synthesis of halothan
CH3 OH
H 2 S O 4
CH3 O CH3
2
Metabolism of sevoflurane
Synthesis of midazolam
N-desmethylquazepam
trimethyl orthoacetate
R. I. Fryer, A. Walser, DE 2540522; US 4280957 (1976, 1981 both to Hoffmann-La Roche); A. Walser et al., J. Org.
Chem. 43, 936 (1978).
Metabolism of benzodiazepins, especially midazolam
A detail of midazolam oxidative metabolism
Synthesis of propofol
OH
+ CH2 CH3
A l2 O 3
4 0 0 ° C2
OH
CH3
CH3
CH3
CH3
Metabolism of propofol
Local anesthetics
Classical sythesis of lidocaine
CH 3
C H 3
N H C O C H 2 N
C 2
H 5
C 2
H 5
CH 3
C H 3
N H 2
C l C O C H 2 C l
C H 2
C O O N a
CH 3
C H 3
N H C O C H 2
C l
( C 2 H 5 ) 2 N H
( 1 ) ( 2 )
( 3 )
An alternative: a one-pot synthesis of lidocaine: Ugi condensation
CH3
CH3
N
+ C
–
+
O
H H
+ NH
CH3
CH3
CH3
CH3
NH
O
N
CH3
CH3
Main methabolic pathways of lidocaine
Proposed further metabolism of 2,6-xylidine
Stereoselectivity of metabolism in prilocaine
Local anaesthetics of anilide series: prilocaine
●
anaesthetic activity of R and S enantiomers does not
markedly differ
NH
CH3
NH
CH3
O
CH3
S - ( + )
NH2
CH3
NH
CH3
O
CH3
OH
(2R)-2-(propylamino)propanoic acid
R - ( - )
h y d r o la s e
a r o m a t ic r in g
h y d r o x y la t io n
NH2
CH3OH
NH2
CH3
OH
+
+
H2O
●
toxic metabolites
●
methemoglobinemia
●
administration of the pure S-(-)
enantiomer can eliminate the toxicity