Sytheses & metabolism of selected weak and strong
analgesics
© Oldřich Farsa 2019
Synthesis of paracetamol
OH
OH
NO2
OH
NO2
OH
NH2
CH3
CH3
O
O
O
OH
NH
CH3
O
OH
NO2
OH
NH
CH3
O
HNO3 Fe, HCl
phenol
2-nitrophenol
4-nitrophenol 4-aminophenol 4-(acetylamino)phenol
Sn
CH3COOH
Morse, Chem. Ber. 11, 232 (1878)
Metabolism of paracetamol
O
N
CH3
O
OH
N
CH3
O
H
OH
N
CH3
O
NH2
O
S
OH
N
CH3
O
O
S
O
O
O
H
O
O
OHOH
OH
OH
O
N
O
CH3
H
OH
NH
CH3
O
N
O
O
N
O
S H
N
O
OH
H
H
H
OH
OH
NH
CH3
O
NH2
O
S
N
O
OH
H
OH
N
CH3
O
NH
O
S
OH
CH3
O
N-acetyl-p-benzoquinoneimine
N-(4-oxocyclohexa-2,5-diene-1-yli
dene)acetamide
NAPQI
GSH
(glutathione)
conjugationconjugation
4 %
42 % 52 %
2% urine
paracetamol glucuronide paracetamol sulfate
urine
urine
urine
cytochrome
P-450

subst. mercapturic acid
GSH transferase
peptidase
peptidase
N-acetyltransferase
Thiols detoxicating N-acetyl-p-benzoquinoneimine
N
OSH
OH
CH3
O
H
N
O O
N
O
SH
H N
O
OHHH H
OH
N-acetyl-L-cysteine
glutathione
Glu-Cys-Gly
syn. mercapturic acid
mucolytic
ACC®, Mucobene®
Syntheses of acetylsalicylic acid (ASA)
OHO
OH CH3 Cl
O OHO
O
CH3
O
OHO
OH
OHO
O
CH3
O
CH3
CH3
O
O
O
Gerhardt, Justus Liebigs Ann. Chem. 87, 164 (1853)
Gilm, Justus Liebigs Ann. Chem. 112, 181 (1859)
Kraut, Justus Liebigs Ann. Chem. 150, 10 (1869)
Felix Hoffmann 1897; since 1899 Aspirin ®
Bayer
Metabolism of ASA
• runs in liver
•all metabolits are
excreted by urine
OHO
O CH3
O
OHO
OH
O
OH
OH
O
OH
O
OH
O OH
O
O
OHOH
OH
OH
O OH
O
O
OH
NH
OH
O
OHO
OH
OH
ASA
salicylic acid.
10 %
+ CH3COOH
O1-salicyoylglucuronic acid
5 %
O1-(2-carboxyphenyl)glucuronic acid
10 %
glucuronation
salicyluric acid
(N-salicyoylglycine)
75 %
conjugation with Gly
gentisic acid
< 1 %
hydroxylation
t1/2= 15
min.
Synthesis of aminophenazone and metamizole
NH
NH2
O
O
O
NH
N
O N
N
O
N
N
O
NO
N
N
O
NH
H
N
N
O
N
N
N
O
N
S
O
O
O
Na
+
+
"technical pyrazolone"
(CH3)2SO4
phenazone
NO2
-, H+
red.
NaHSO3
aminophenazone
HCOH
HCOOH
HCOH
NaHSO3
metamizole sodium salt
syn. dipyrone [USAN]
Aminophenazone cancerogenity
N
N
O
N
N
N
O
N
H
N
N
O
N
N O
NO3
-
methyltransferase
(nitrite reductase
Campylobacter jejuni)
aminophenazone
1,5-dimethyl-4-methylamino-2-phenyl
-1,2-dihydropyrazole-3-one
(desmethylaminophenazone)
1,5-dimethyl-4-methyl(nitroso)amino
-2-phenyl-1,2-dihydropyrazole-3-one
NO2
-, H+
nitrate reductase
CANCEROGENIC
Main metabolic routes of aminophenazone and metamizole
A large scale synthesis of nimesulide
Main metabolites of nimesulide
Main circulating metabolite
O
O
OHO
OH
OH
OHH
H
SO
O
NH
N
+
O
O
-
O
Excreted by urine
Morphine metabolism: glucuronidation
UGT - UDP-glucuronosyltransferases
no analgesic activity;
morphine antagonist
crosses BBB; much more
analgesic than morphine
Synthesis of fentanyl
N
O
C6H5NH2
C6H5SO3H, tolene
N
N
LiAlH4
diethyether
N
NH
(CH3CH2CO)2O
N
N
CH3
O
1. H2; Pd/C
2. C6H5CH2CH2Br; Na2CO3
N
N
CH3
O
fentanyl
The major route of fentanyl metabolism is via oxidative Ndealkylation
to the inactive desphenethyl metabolite
norfentanyl (2). Another known (but minor) human metabolite
is despropionyl fentanyl (4), which is also known as 4-ANPP.
This amide hydrolysis metabolite can coincidentally be formed
as a metabolic product of several different fentanyl analogs,
so its presence isn’t particularly diagnostic. It is also a
precursor contaminant found in seized illicit fentanyl and
fentanyl analog powders, further adding to the complexity of
identifying it in urine analysis. There are numerous
hydroxylated compounds that are typically less abundant (3,
5, 7, 8, 9, and 10). It has been reported, for example, that
hydroxylation can occur on the ethyl linker of the phenethyl
moiety (either at the α or β position), at the 2 or 3 position on
the piperidine ring, along the amide alkyl chain, or on the
phenyl ring of the phenethyl moiety. Some of these
hydroxylated metabolites, such as 4’-hydroxy fentanyl (5), are
potentially bioactive, but most are believed to be inactive.
Hydroxy fentanyls like 5 can be further biotransformed via a
second hydroxylation to afford a catechol that is then Omonomethylated
to yield metabolite 6. This methylation
conjugation reaction is presumably catalyzed by the enzyme
catechol-O-methyltransferase and is believed to occur at the
3’ position. This is technically a phase II metabolic product,
but it is detected in both hydrolyzed and non-hydrolyzed urine
specimens due to its stability. Norfentanyl (2) is also further
oxidized (Figure 1). Keep in mind that most of the metabolites
depicted in Figure 1 can potentially undergo further
transformations to yield additional metabolites and often the
exact positioning of the hydroxyl group is unknown.
Synthesis of pethidine
DE 679 281 IG Farben 1937
Partial synthesis of piritramide
A synthesis of tramadol
Mannich condensation
Metabolism of tramadol
active metabolite mainly responsible for the activity