The document describes the synthesis of several drugs including ketoconazole, metronidazole, miconazole, celecoxib, metamizole sodium, terconazole, alprazolam, triamtrene, sulfamerazine, trimethoprim, hydroxychloroquine, quinine, chloroquine, quinacrine, amsacrine, prochlorperazine, promazine, chlorpromazine, and theophylline. The syntheses involve multiple reaction steps starting with various reagents and intermediates to ultimately form the target drug molecule through condensation, reduction, oxidation, hydrolysis, and other organic reactions.

1. Ajay Kumar, M. Pharm. (Pharmaceutical Chemistry),
NIET, Pharmacy Institute, Greater Noida, U. P., India.
Advanced Organic Chemistry - I
Unit – IV (B)

2. Ketoconazole Synthesis:-
Cl C CH2Br
Cl
O
2-Bromo-1-(2,4-dichloro-phenyl)-
ethanone
+
CH2OH
CH
CH2
OH
OH
Propane-1,2,3-triol
Cl C CH2Br
Cl
OO
CH2OH
[2-Bromomethyl-2-(2,4-dichloro-phenyl)-
[1,3]dioxolan-4-yl]-methanol
C Cl
O
N
N
H
Cl C
CH2
Cl
O
O
CH2COO
N
N
[2-(2,4-Dichloro-phenyl)-2-imidazol-1-ylmethyl-
[1,3]dioxolan-4-yl]-acetic acid phenyl ester
CH3SO3Cl
Cl C
CH2
Cl
O
O
H2C
N
N
O SO2CH3
Methanesulfonic acid 2-(2,4-dichloro-phenyl)-2-
imidazol-1-ylmethyl-[1,3]dioxolan-4-ylmethyl ester
N N C CH3OH
O
Cl
Cl
C C N
N
OO
CH2O NH N C CH3
O
KETOCONAZOLE

3. H2N
H2
C
H2
C NH2
Ethane-1,2-diamine
+ CH3CN
Acetonitrile
Zn
N
N
H
CH3
2-Methyl-1H-imidazole
P2O5, HNO3
N
N
H
CH3
O2N
2-Methyl-5-nitro-1H-
imidazole
ClCH2CH2OH
Reflux
N
N
CH3
O2N
CH2CH2OH
2-(2-Methyl-5-nitro-imidazol-1-yl)-ethanol /
METRONIDAZOLE
Metronidazole Synthesis:-

4. Miconazole Synthesis:-
Cl Cl
Br
O
+
2-Bromo-1-(2,4-dichloro-phenyl)-
ethanone
H
N
N
1H-Imidazole
Cl Cl
N
O
N
1-(2,4-Dichloro-phenyl)-2-imidazol-1-yl-ethanone
NaBH4
Cl Cl
N
OH
N
1-(2,4-Dichloro-phenyl)-2-imidazol-1-yl-ethanol
Cl
Br
Cl
Cl Cl
N
N
Cl
Cl
1-[2,4-Bis-(2,4-dichloro-phenyl)-butyl]-1H-
imidazole /
MICONAZOLE

5. N
N
O
F
F
F
2,2,2-Trifluoro-1-imidazol-
1-yl-ethanone
+
O
Acetophenone
NaN(TMS)2
O O
H
CF3
4,4,4-Trifluoro-3-hydroxy-1-p-tolyl-but-
2-en-1-one
S
NH2
O
O
H
N
NH2
EtOH
reflux
S
NH2
O
O
N
N
CF3
4-(5-p-Tolyl-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide /
CELECOXIB
Celecoxib Synthesis:-

6. PhNHNH2 +
EtO
O
Me
O
3-Oxo-butyric acid ethyl ester
N
N
Ph
O
Me
Met N
N
Ph
O
Me
Me
NaNO2/ H+
N
N
Ph
O
Me
Me
NO
[H] N
N
Ph
O
Me
Me
NH2
PhCHO N
N
Ph
O
Me
Me
N
Ph
5-Methyl-2-phenyl-2,4-dihydro-pyrazol-3-one
1,5-Dimethyl-4-nitroso-2-
phenyl-1,2-dihydro-
pyrazol-3-one
4-(Benzylidene-amino)-1,5-dimethyl-2-phenyl-
1,2-dihydro-pyrazol-3-one
N
N
Ph
O
Me
Me
N
Ph
Me2SO4
Me
H2O
Benzylidene-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazol-4-yl)-methyl-ammonium
N
N
Ph
O
Me
Me
NH
Me
1,5-Dimethyl-4-methylamino-2-phenyl-1,2-dihydro-
pyrazol-3-one
NaHSO3/ H2CO N
N
Ph
O
Me
Me
N
Me
SO3Na
METAMIZOLE SODIUM
MeOSO2
Metamizole Sodium Synthesis:-

7. Cl Cl
C NH
OO
CH2OMs
N
N
Methanesulfonic acid 2-(2,4-dichloro-
phenyl)-2-[1,2,4]triazol-1-ylmethyl-
[1,3]dioxolan-4-ylmethyl ester
+ NN
CH3
CH3
OH
4-(4-Isopropyl-piperazin-1-yl)-phenol
Cl Cl
N
N
N
O
O
O
N
N CH3
CH3
1-{4-[2-(2,4-Dichloro-phenyl)-2-[1,2,4]triazol-1-ylmethyl-[1,3]dioxolan-4-ylmethoxy]-phenyl}-4-isopropyl-
piperazine / TERCONAZOLE
Terconazole Synthesis:-

8. N
Cl
Cl
2,6-Dichloro-4-phenyl-quinoline
NH2NH2
N
Cl
NH
NH2
(6-Chloro-4-phenyl-quinolin-2-yl)-hydrazine
CH3C(OC2H5)3
N
Cl
N
N
H3C
7-Chloro-1-methyl-5-phenyl-[1,2,4]triazolo[4,3-
a]quinoline
NaIO4/ RuO2
O
N
Cl
N
N
H3C
[5-Chloro-2-(3-methyl-[1,2,4]triazol-4-yl)-
phenyl]-phenyl-methanone
HCHO/
PBr3
O
N
Cl
N
N
H3C
CH2Br
[2-(3-Bromomethyl-5-methyl-[1,2,4]triazol-
4-yl)-5-chloro-phenyl]-phenyl-methanone
NH3
N
Cl N
N
NH3C
8-Chloro-1-methyl-6-phenyl-4H-2,3,5,10b-
tetraaza-benzo[e]azulene / ALPRAZOLAM
Alprazolam Synthesis:-

9. NH
NH2N
H2N
NH2
NH
1,2-Dihydro-pyrimidine-
2,4,5,6-tetraamine
N
H
NH2N
H2N
NH2
NH2
1,2-Dihydro-pyrimidine-
2,4,5,6-tetraamine
+ Benzaldehyde
C-5 Condensation
CH N
N
NH2N NH2
HCN
C
H
N
H
N
NH2N NH2
CN
NH2
alpha amino nitrile derivative
OH
Cyclisation
N
N
N
NH2N
H NH2
NH2
H
Dihydropyrazine derivative
Spontaneous
air-oxidation
N
N
N
NNH2 NH2
NH2
TRIAMTRENE
Triamtrene Synthesis:-

10. Me
O
OEt
O
+
H2N NH2
NH HN
N
O
H2N Me
3-Oxo-butyric acid ethyl
ester
Guanidine 2-Amino-6-methyl-3H-pyrimidin-4-one
POCl3
HN
N
Cl
H2N Me
6-Chloro-4-methyl-1,6-
dihydro-pyrimidin-2-
ylamine
H2/ Pd-C
N
NH2N Me
4-Methyl-pyrimidin-2-ylamine
NHAc SO2Cl
OH
H2N
S
N
H
N
N
Me
O
O
4-Amino-N-(4-methyl-pyrimidin-2-yl)-benzenesulfonamide /
SULFAMERAZINE
Sulfamerazine Synthesis:-

11. H3CO
H3CO
H3CO
H2
C
H2
C COOC2H5
3-(3,4,5-Trimethoxy-phenyl)-propionic acid ethyl
ester
+ HCOOC2H5
Na
H3CO
H3CO
H3CO
CH2
Formic acid ethyl ester
COOC2H5
CH OH
NH
H2N NH2
H3CO
H3CO
H3CO
CH2
N
N
H2N
OH
3-Hydroxy-2-(3,4,5-trimethoxy-benzyl)-acrylic
acid ethyl ester
4-Amino-5-(3,4,5-trimethoxy-benzyl)-pyrimidin-2-ol
POCl3
NH3
H3CO
H3CO
H3CO
CH2
N
N
H2N
NH2
5-(3,4,5-Trimethoxy-benzyl)-pyrimidine-2,4-diamine /
TRIMETHOPRIM
Trimethoprim Synthesis:-

12. H3C C
H2
C
H2
C
H2
C Cl
O
6-Chloro-hexan-2-one
+ H N
C2H5
H2C
H2
C OH
2-Ethylamino-ethanol
CH3 C
H2
C
H2
C CH2
O
N
C2H5
H2C
H2
C OH
5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentan-2-one
H2, NH3 /
[Raney-Ni]
NH2 C
H2
C
H2
C CH2
O
N
C2H5
H2C
H2
C OH
4-[Ethyl-(2-hydroxy-ethyl)-amino]-butyramide
N
Cl
Cl
N
HN
Cl
C
H2
C
H2
C CH2
O
N
C2H5
H2C
H2
C OH
N-(7-Chloro-quinolin-4-yl)-4-[ethyl-(2-hydroxy-ethyl)-amino]-butyramide /
HYDROXYCHLOROQUINE
Hydroxychloroquine Synthesis:-

13. OH
O H
3-Hydroxy-benzaldehyde
OEtOEt
NH2
OH
N
OEt
OEt
N
OH
Isoquinolin-7-ol
N
OH
N
8-Piperidin-1-ylmethyl-isoquinolin-7-ol
N
OH
CH3
N
H
OH
CH3
8-Methyl-1,2,3,4-tetrahydro-
isoquinolin-7-ol8-Methyl-isoquinolin-7-ol
Quinine Synthesis:-

14. NCl
Cl
4,7-Dichloro quinoline
+ HNH
H
C (CH2)3N(C2H5)2
CH3
4-Amino-1-diethylamino pentane
Condensed
NCl
HN CH (CH2)3N(C2H5)2
CH3
CHLOROQUINE
Chloroquine Synthesis:-

15. Cl Cl
CO2H
2,4-Dichloro-benzoic acid
+
NH2
OMe
4-Methoxy-phenylamine
Cu/ K2CO3
CO2H
H
NCl
OMe
4-Chloro-2-(4-methoxy-phenylamino)-benzoic
acid
POCl3
NCl
Cl
OMe
6,9-Dichloro-2-methoxy-acridine
H2N (CH2)3
Me
N
Et
Et
NCl
HN
OMe
(CH2)3 NEt2
QUINACRINE
Quinacrine Synthesis:-

16. NO2
OMe
NH2
3-Methoxy-4-nitro-
phenylamine
MeSO2Cl
NO2
OMe
N
H
S
CH3
O
O
N-(3-Methoxy-4-nitro-phenyl)-methanesulfonamide
Fe/ HCl
H2N
OMe
N
H
SO2Me
N-(4-Amino-3-methoxy-phenyl)-
methanesulfonamide
N
Cl
N
HN
MeO
H
N
SO2Me
AMSACRINE
Amsacrine Synthesis:-

17. N
H
S
Cl
2-Chloro-10H-phenothiazine
+
Cl N
N
Me
1-(3-Chloro-propyl)-4-methyl-piperazine
NaNH2
N
S
Cl
N
N
Me
2-Chloro-10-[3-(4-methyl-piperazin-1-yl)-propyl]-10H-phenothiazine /
PROCHLORPERAZINE
Prochlorperazine Synthesis:-

18. N
H
S
10H-Phenothiazine
+ Cl N
(3-Chloro-propyl)-dimethyl-amine
NaNH2
N
S
N
Dimethyl-(3-phenothiazin-10-yl-propyl)-
amine /
PROMAZINE
Promazine Synthesis:-

19. S
N
H
Cl
2-Chloro-10H-phenothiazine
+ Cl
H2
C
H2
C
H2
C N
CH3
CH3
(3-Chloro-propyl)-dimethyl-amine
Reflux in presence of
toluene and sodamide
S
N Cl
H2C
H2
C
H2
C N
CH3
CH3
[3-(2-Chloro-phenothiazin-10-yl)-propyl]-dimethyl-amine /
CHLORPROMAZINE
Chlorpromazine Synthesis:-

20. NHMe NHMe
O
1,3-Diimino-propan-
2-one
+
EtO
CN
O
Cyano-acetic acid ethyl ester
Ac2O MeN
CN
O
NHMeO
1-(2-Cyano-acetyl)-1,3-dimethyl-urea
NaOH
N
N
O
NH2O
6-Amino-1,3-dimethyl-
1H-pyrimidine-2,4-dione
HNO2
N
N
O
NH2O
NO
6-Amino-1,3-dimethyl-5-
nitroso-1H-pyrimidine-2,4-dione
[H] N
N
O
NH2O
NH2
5,6-Diamino-1,3-dimethyl-
1H-pyrimidine-2,4-dione
HCONH2
N
N
O
O
N
H
N
1,3-Dimethyl-3,7-dihydro-purine-2,6-dione
/ THEOPHYLLINE
Theophylline Synthesis:-

21. NH2 C NH2
O
Urea
+ OC2H5
O
C2H5O
O
Malonic acid diethyl ester
N
N
O
O O
H
H
Pyrimidine-2,4,6-trione
HNO2
N
N
O
O O
H
H
NO
5-Nitroso-pyrimidine-
2,4,6-trione
Sn/ HCl
N
N
O
O O
H
H
NH2
5-Amino-pyrimidine-
2,4,6-trione
H-N=C=O
N
N
O
O O
H
H
H
N C NH2
O
(2,4,6-Trioxo-hexahydro-pyrimidin-5-yl)-
urea
N
N
O
O
H
H
N
N
H
H
O
Tetrahydro-purine-2,6,8-trione
PCl5
N
N
Cl
Cl
N
N
H
Cl
2,6,8-Trichloro-9H-purine
NaOH
N
N
OH
Cl
N
N
H
Cl
2,8-Dichloro-9H-purin-6-ol
HI
N
N
OH
N
N
H
9H-Purin-6-ol
P2S5
N
N
SH
N
N
H
9H-Purine-6-thiol /
MERCAPTOPURINE
Mercaptopurine Synthesis:-

22. N
N
N
N
Cl
Cl
OH
NH3
N
N
N
N
Cl
H2N
OH
HI
N
N
N
N
H2N
OH
P2S5
N
N
N
N
H2N
SH
THIOGUANINE
Thioguanine Synthesis:-