A concise and highly efficient synthesis of praziquantel as an anthelmintic drug

Article abstract of DOI:10.3987/COM-16-13538

A concise and practical synthesis of praziquantel as anthelmintic drug is described. The key steps include a monoalkylation of ethanolamine for the preparation of 2-(2-hydroxyethylamino)-N-phenethylacetamide and a mild oxidation protocol with SO₃-Py/DMSO as oxidant to transform alcohol into the corresponding aza-acetal. The telescoped synthesis is composed of five steps without purification of the intermediates, providing an overall yield of 80% with 99.8% purity after crystallization.

Full text of DOI:10.3987/COM-16-13538

Supporting Information
A CONCISE AND HIGHLY EFFICIENT SYNTHESIS OF
PRAZIQUANTEL AS AN ANTHELMINTIC DRUG
Zhezhou Yang, Lin Zhang, Huirong Jiao, Rusheng Bao, Weiwei Xu, and Fuli Zhang*
*Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry,
285 Gebaini Road, Shanghai 201203, China; zhangfuli1@sinopharm.com

HN
Cl
O
3
1H NMR spectrum of 2-chloro-N-phenethylacetamide (3) (400 MHz, CDCl3)
HN
Cl
O
3
13C NMR spectrum of 2-chloro-N-phenethylacetamide (3) (100 MHz, CDCl3)

HN
Cl
O
3
FT-IR spectrum of 2-chloro-N-phenethylacetamide (3)
HN
Cl
O
3
HRMS spectrum of 2-chloro-N-phenethylacetamide (3)

HN
O
HO
N
H
9
1H NMR spectrum of 2-(2-hydroxyethylamino)-N-phenethylacetamide (9) (400 MHz, CDCl3)
HN
O
HO
N
H
9
1H NMR spectrum of 2-(2-hydroxyethylamino)-N-phenethylacetamide (9) (400 MHz,
DMSO-d6)

HN
O
HO
N
H
9
13C NMR spectrum of 2-(2-hydroxyethylamino)-N-phenethylacetamide (9) (100 MHz,
CDCl3)
HN
O
HO
N
H
9
FT-IR spectrum of 2-(2-hydroxyethylamino)-N-phenethylacetamide (9)

HN
O
HO
N
H
9
HRMS spectrum of 2-(2-hydroxyethylamino)-N-phenethylacetamide (9)
HN
N
O
HO
O
11
1H NMR spectrum of N-(2-hydroxyethyl)-N-(2-oxo-2-(phenethylamino)ethyl)cyclohexaneca-
rboxamide (11) (400 MHz, CDCl3)

HN
N
O
HO
O
11
13C NMR spectrum of N-(2-hydroxyethyl)-N-(2-oxo-2-(phenethylamino)ethyl)cyclohexaneca-
rboxamide (11) (100 MHz, CDCl3)
HN
N
O
HO
O
11
FT-IR spectrum of N-(2-hydroxyethyl)-N-(2-oxo-2-(phenethylamino)ethyl)cyclohexanecarb-
oxamide (11)

HN
N
O
HO
O
11
HRMS spectrum of N-(2-hydroxyethyl)-N-(2-oxo-2-(phenethylamino)ethyl)cyclohexanecarb-
oxamide (11)
N
N
O
HO
O
13
1H NMR spectrum of 4-(cyclohexanecarbonyl)-6-hydroxy-1-phenethylpiperazin-2-one (13)
(400 MHz, CDCl3)

N
N
O
HO
O
13
13C NMR spectrum of 4-(cyclohexanecarbonyl)-6-hydroxy-1-phenethylpiperazin-2-one (13)
(100 MHz, CDCl3)
N
N
O
HO
O
13
DEPT spectrum of 4-(cyclohexanecarbonyl)-6-hydroxy-1-phenethylpiperazin-2-one (13) (100
MHz, CDCl3)

N
N
O
HO
O
13
13C NMR spectrum of 4-(cyclohexanecarbonyl)-6-hydroxy-1-phenethylpiperazin-2-one (13)
(100 MHz, DMSO-d6)
N
N
O
HO
O
13
FT-IR spectrum of 4-(cyclohexanecarbonyl)-6-hydroxy-1-phenethylpiperazin-2-one (13)

N
N
O
HO
O
13
HRMS spectrum of 4-(cyclohexanecarbonyl)-6-hydroxy-1-phenethylpiperazin-2-one (13)
N
N
O
O
1
1H NMR spectrum of 2-(cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]iso-
quinolin-4-one (1) (400 MHz, CDCl3)

N
N
O
O
1
13C NMR spectrum of 2-(cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]is-
oquinolin-4-one (1) (100 MHz, CDCl3)
N
N
O
O
1
FT-IR spectrum of 2-(cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoq-
uinolin-4-one (1)

N
N
O
O
1
HRMS spectrum of 2-(cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoq-
uinolin-4-one (1)
1H NMR spectrum of 2-(N-(2-oxo-2-(phenethylamino)ethyl)cyclohexanecarboxamido)acetic
acid (14) (400 MHz, CDCl3)

13C NMR spectrum of 2-(N-(2-oxo-2-(phenethylamino)ethyl)cyclohexanecarboxamido)acetic
acid (14) (100 MHz, CDCl3)
DEPT spectrum of 2-(N-(2-oxo-2-(phenethylamino)ethyl)cyclohexanecarboxamido)acetic
acid (14) (100 MHz, CDCl3)

FT-IR spectrum of 2-(N-(2-oxo-2-(phenethylamino)ethyl)cyclohexanecarboxamido)acetic
acid (14)
HRMS spectrum of 2-(N-(2-oxo-2-(phenethylamino)ethyl)cyclohexanecarboxamido)acetic
acid (14)

HN
N
O
O
HO
NH
10
1H NMR spectrum of 2,2'-(2-hydroxyethylazanediyl)bis(N-phenethylacetamide) (10) (400
MHz, CDCl3)
HN
N
O
O
HO
NH
10
13C NMR spectrum of 2,2'-(2-hydroxyethylazanediyl)bis(N-phenethylacetamide) (10) (100
MHz, CDCl3)

HN
N
O
O
HO
NH
10
FT-IR spectrum of 2,2'-(2-hydroxyethylazanediyl)bis(N-phenethylacetamide) (10)
HN
N
O
O
HO
NH
10
HRMS spectrum of 2,2'-(2-hydroxyethylazanediyl)bis(N-phenethylacetamide) (10)

O
O
N
N
O
15
1H NMR spectrum of 4-(cyclohexanecarbonyl)-1-phenethylpiperazine-2,6-dione (15) (400
MHz, CDCl3)
O
N
N
O
O
15
13C NMR spectrum of 4-(cyclohexanecarbonyl)-1-phenethylpiperazine-2,6-dione (15) (100
MHz, CDCl3)

O
O
N
N
O
15
FT-IR spectrum of 4-(cyclohexanecarbonyl)-1-phenethylpiperazine-2,6-dione (15)
O
N
N
O
O
15
HRMS spectrum of 4-(cyclohexanecarbonyl)-1-phenethylpiperazine-2,6-dione (15)

N
N
O
O
16
1H NMR spectrum of 4-(cyclohexanecarbonyl)-1-phenethyl-3,4-dihydropyrazin-2-one (16)
(400 MHz, CDCl3)
N
N
O
O
16
13C NMR spectrum of 4-(cyclohexanecarbonyl)-1-phenethyl-3,4-dihydropyrazin-2-one (16)
(100 MHz, CDCl3)

N
N
O
O
16
FT-IR spectrum of 4-(cyclohexanecarbonyl)-1-phenethyl-3,4-dihydropyrazin-2-one (16)
N
N
O
O
16
HRMS spectrum of 4-(cyclohexanecarbonyl)-1-phenethyl-3,4-dihydropyrazin-2-one (16)