Esomeprazole (Nexium®), the (S)-isomer of Omeprazole, is the first proton-pump inhibitor developed as a single isomer for the treatment of acid-related diseases. It is used for the treatment of peptic ulcers, gastroesophagal reflux disease, and erosive esophagitis. Herein, we report our synthetic study of esomeprazole sodium salt from the starting    2-mercapto-5-methoxybenzimidazole and 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride reagents. The Esomeprazole sodium salt was obtained from enantioselectivesulfoxidation reaction in moderate yield with high enantioselectivity

Giap, Tran Huu

Hue, Cao Thi

Minh Hang, Nguyen Thi

Minh, Chau Van

My Hue, Van Thi

Thanh, Le Nguyen

Tung, To Hai

English

Vietnam Academy of Science and Technology: Journals Online

 48 
VIETNAM JOURNAL OF CHEMISTRY         VOL. 53(2e) 48-51                                               APRIL 2015 
DOI: 10.15625/0866-7144.2015-2e-011 
  
 
 
SYNTHESIS OF ANTIULCER DRUG ESOMEPRAZOLE 
 
Tran Huu Giap
1
, To Hai Tung
1
, Van Thi My Hue
2
, Cao Thi Hue
1
, Nguyen Thi Minh Hang
1
,  
Chau Van Minh
1
, Le Nguyen Thanh
1*
 
1
Institute of Marine Biochemistry, Vietnam Academy of Science and Technology 
2
Hanoi University of Pharmacy 
Received 23 January 2015; Accepted for Publication 18 March 2015 
 
Abstract 
Esomeprazole (Nexium
®
), the (S)-isomer of Omeprazole, is the first proton-pump inhibitor developed as a single 
isomer for the treatment of acid-related diseases. It is used for the treatment of peptic ulcers, gastroesophagal reflux 
disease, and erosive esophagitis. Herein, we report our synthetic study of esomeprazole sodium salt from the starting    
2-mercapto-5-methoxybenzimidazole and 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride reagents. 
The Esomeprazole sodium salt was obtained from enantioselectivesulfoxidation reaction in moderate yield with high 
enantioselectivity. 
Keywords. Peptic Ulcer, Proton Pump Inhibitor, Omeprazole, Esomeprazole. 
 
 
1. INTRODUCTION 
 
Peptic ulcer is one of the most common diseases 
in modern society. For the treatment of  ulcer, proton 
pump inhibitors (PPIs) are the most important group 
of drugs because their activity is inhibiting the 
H
+
/K
+
-ATPase enzyme system of gastric parietal 
cells and decreasing the amount of acid produced in 
the stomach.Omeprazole, a racemic mixture, was the 
first PPI drug in 1987 and has been the best-selling 
drug on the market [1]. 
 
 
 
Esomeprazole, the (S)-enantiomer of 
Omeprazole, provides better acid control than 
current racemic PPIs and has a favorable 
pharmacokinetic profile relative to Omeprazole [2]. 
Esomeprazole became commercially available as the 
first single-optical-isomer PPI in 2001. Sales of 
Esomeprazole reached nearly 4 billion US dollars in 
2013, and it is one of the top 20 best-selling 
drugs.Thus, the preparation of esomeprazole has 
attracted much attention in both academia and 
industry. The synthesis of Esomeprazole was 
reported by several groups [3-9]. 
Herein, we report our preliminary synthetic 
study of Esomeprazole sodium salt from the starting 
2-mercapto-5-methoxybenzimidazole and 2-
(chloromethyl)-4-methoxy-3,5-dimethylpyridine 
hydrochloride reagents. The Esomeprazole sodium 
salt was obtained from enantioselectivesulfoxidation 
reactions in moderate yield with high 
enantioselectivity. 
 
2. MATERIALS AND METHODS 
 
      All chemicals were used as received from 
commercial sources without further purification. 
1
H 
and 
13
C NMR spectra were recorded on a 
BrukerAvance 500 (500 MHz, 
1
H; 125 MHz 
13
C) 
spectrometer. The chemical shifts (δ) are reported in 
parts per million (ppm) relative to tetramethylsilane 
(TMS) or the internal solvent signal of deuterated 
solvents (
13
C and 
1
H). Multiplicities are indicated by 
s (singlet), d (doublet), t (triplet), and m (multiplet). 
Coupling constants J are reported in Hertz. The mass 
spectra were recorded with aAgilent 1260LC/MS 
instrument. For thin layer chromatography, 
analytical TLC plates (70-230 mesh silica gel 
 49 
VJC, Vol. 53(2e), 2015                                                                                                   Le Nguyen Thanh, et al. 
(Merck) were used. Visualization was accomplished 
with UV (254nm). 
 
Preparation of sulfide 3 (5-methoxy-2-[3,5-
dimethyl-4-methoxypyridinyl) methylthio]-1H-
benzimidazole) 
 
To a stirred solution of 2-mercapto-5-
methoxybenzimidazole (3.6 g, 20 mmol) and 
Na2CO3(4.62 g, 44 mmol) in EtOH (90 mL) was 
added 2-chloromethyl-3,5-dimethyl-4-methoxy 
pyridinehydrochloride (4.44g, 20 mmol) and the 
reaction mixture was refluxed for 4 hours. Reaction 
was cooled down and water was then added at room 
temperature, wherein the  of 5-methoxy-2-[3,5-
dimethyl-4-methoxypyridinyl)methylthio]-1H-
benzimidazole precipitated. The white product was 
separated, washed with water and dried in a vacuum. 
Product (6.12 g) was obtained with 93 % yield. Mp: 
48-51 
o
C.
1
H-NMR (500 MHz, DMSO-d6) δ(ppm): 
2.27 (s, 3H, CH3), 2.31 (s, 3H, CH3), 3.78 (s, 3H, 
OCH3), 3.84 (s, 3H, OCH3), 4.34 (s, 2H, CH2S),  
6.81 (dd, J = 2.5 Hz và J = 8.5 Hz, 1H, H-6), 7.03 
(brs, 1H, H-4), 7.40 (brs, 1H, H-7), 8.26 (s, 1H, H-
6’).13C-NMR (125 MHz, DMSO-d6) δ (ppm): 11.3 
(CH3), 13.4 (CH3), 35.0 (CH2S), 55.8 (OCH3), 60.0 
(OCH3), 97.2 (C-7), 111.0 (C-6), 115.3 (C-4), 125.4 
(C-5’), 126.3 (C-3’), 134.2 (C-8), 140.0 (C-9), 148.3 
(C-2), 149.4 (C-6’), 155.9 (C-2’), 156.0 (C-5), 165.1 
(C-4’). ESI-MS: m/z 330 [M+H]+. 
 
Synthesis of Esomeprazole 
 
To a stirred solution of sulfide 3 (1 g, 3 mmol) in 
toluene (6 mL) was added (S,S)-diethyl tartrate (371 
mg, 1.8mmol) and titanium tetraisopropoxide (0.27 
mL, 0.9mmol) and the mixture was stirred for 1 h at 
55°C. The reaction temperature was cooled to 30°C 
and subsequentlyN,N-diisopropylethylamine (0.14 
mL, 0.9mmol) and cumenehydroperoxide (80 % in 
cumene, 0.46 mL, 3mmol) were added. After 1 hour 
at 30°C the reaction mixture was extracted three 
times with aqueousammonium hydroxide (12.5% of 
NH3,3×6 mL). Then combined aqueous extracts 
were adjusted to pH =8 with aceticacid, extracted 
with methyl isobutyl ketone (2 x 3mL). A portion of 
organic extract was concentrated and purified by 
chromatography to give Esomeprazole as an oil. 
1
H-
NMR (500 MHz,DMSO-d6) δ(ppm): 2.16 (s, 3H, 
CH3); 2.19 (s, 3H, CH3); 3.67 (s, 3H, OCH3); 3.80 
(s, 3H, OCH3); 4.67 (d, J = 13.5 Hz, 1H, CH2S); 
4,75 (d, J = 13.5 Hz, 1H, CH2S); 6.92 (d, J = 9.0 Hz, 
1H, H-6); 7.09 (brs, 1H, H-4); 7.53 (d, J = 7.5 Hz, 
1H, H-7);  8.17 (s, 1H, H-6’).13C-NMR (125 MHz, 
DMSO-d6) δ (ppm): 11.1 (CH3), 12.9 (CH3), 55.5 
(OCH3), 59.8 (CH2S), 60.0 (OCH3), 100.4 (C-7), 
111.5 (C-6), 116.0 (C-4), 125.6 (C-5’), 126.5 (C-3’), 
131.0 (C-8), 139.8 (C-9), 149.1 (C-2), 149.6 (C-6’), 
157.5 (C-2’), 158.0 (C-5), 163.6 (C-4’). ESI-MS: 
m/z 346 [M+H]
+
. 
 
Preparation of Esomeprazole sodium salt 
 
To the combined methyl iso-butyl ketone 
extracts were added an aqueous solution of sodium 
hydroxide 50% (168 mg, 2.1mol) and acetonitrile 
(12mL). The solution was concentrated during 
which the product gradually precipitated. 
Esomeprazole sodium (528 mg, 48% in overall 
yield) was obtained  as a white solid. [α]D
20
 = +30 (c 
1.0, H2O); ee > 99% (measured by HPLC on AD-H 
column, hexane-iso-propanol-acetic acid (50: 50: 
0.1) as the eluent, flow rate: 0.6 mL/min, 
wavelength 300 nm). 
1
H-NMR (500 MHz,DMSO-
d6) δ(ppm): 2.16 (s, 3H, CH3); 2.21 (s, 3H, CH3); 
3.70 (s, 3H, OCH3); 3.75 (s, 3H, OCH3); 4.46 (d, J = 
13.0 Hz, 1H, CH2S); 4.72 (d, J = 13.0 Hz, 1H, 
CH2S); 6.60 (d, J = 8.5 Hz,2.5 Hz, 1H, H-6); 7.02 
(d, J = 2.5 Hz, 1H, H-4); 7.37 (d, J = 8.5 Hz, 1H, H-
7);  8.25 (s, 1H, H-6’).13C-NMR (125 MHz, DMSO-
d6) δ (ppm): 11.3 (CH3), 12.9 (CH3), 55.2 (OCH3), 
58.6 (CH2S),59.7 (OCH3), 99.4 (C-7), 109.0 (C-6), 
117.5 (C-4), 124.9 (C-5’), 126.5 (C-3’), 141.6 (C-8), 
147.0 (C-9), 149.1 (C-2), 151.9 (C-6’), 153.7 (C-2’), 
161.8 (C-5), 163.4 (C-4’).ESI-MS: m/z 344 [M-Na]- 
 
 
 
 50 
VJC, Vol. 53(2e), 2015                                                                                           Synthesis of antiulcer drug… 
3. RESULTS AND DISCUSSION 
 
Esomeprazole was prepared from starting 2-
mercapto-5-methoxybenzimidazole and 2-
(chloromethyl)-4-methoxy-3,5-dimethylpyridine 
hydrochloride reagents. Firstly, the reaction of two 
above compounds was heated in the presence of 
sodium carbonate (2.2 eq) in EtOH to give the 
sulfide product in excellent yield, up to 90-95 % 
[10]. The structure of sulfide 3 was confirmed by 
NMR and MS spectroscopic data. The 
1
H-NMR 
shows the signals of protons of benzimidazole ring 
at δH 6.81 (dd, J = 2.5 Hz and J = 8.5 Hz, 1H, H-6); 
7.03 (brs, 1H, H-4); 7.40 (brs, 1H, H-7). A signal of 
H-6 of pyridine unit appears at δH 8.26 ppm. Methyl 
group and methoxy group signals are found at δH 
2.27, 2.31 and 3.78, 3.81 ppm, respectively. And a 
methylen group signal (CH2S) appears at 4.34 ppm. 
The molecular ion peak [M+H]
+
 was found at 330 in 
the ESI-MS spectrum. These spectroscopic data was 
identical with previously reported studies [10]. 
Next, the oxidation reaction of sulfide to 
Esomeprazole was studied. Among numerous 
catalysts for enantioselective oxidation of sulfide, 
those applied in the preparation of esomeprazole 
include titanium/diethyltartrate [3], titanium/chiral 
diol [4], titanium/tartramide [5, 6], the condition of 
titanium/diethyltartrate is the most important one for 
application.Thus, the reaction condition was chosen 
as followed: sulfide 3 3 mmol, titanium 
tetraisopropoxide 0.9mmol, (S,S)-diethyl tartrate 
1.8mmol, N,N-diisopropylethylamine 0.9 mmol and 
cumenehydroperoxide 3 mmol. A small amount of 
product Esomeprazole was purified to confirm the 
chemical structure. 
 
Table 1:
1
H, 
13
C- NMR data of Esomeprazole, Esomeprazole sodium salt. 
 
 
1
H-NMR (δ) ppm 
 
13
C-NMR (δ) ppm 
Esomeprazole 
Esomeprazole 
sodium 
Esomeprazole 
sodium 
a,
[3, 7] 
Esomeprazole 
Esomeprazo
le sodium 
Esomeprazol
e sodium
 a
[7] 
H-6
’
 8.17 (s) 8.25 (s) 8.24 (s) C-4
’
 163.6 163.4 163.3 
H-7 7.54 (brs) 7.37 (d) 7.35 (d) C-5 158.0 161.8 161.1 
H-4 7.09 (brs) 7.02 (d) 7.00 (d) C-2
’
 157.5 153.7 153.5 
H-6 6.81(dd) 6.60 (dd) 6.57 (dd) C-6
’
 149.6 151.9 151.6 
CH2S 
4.67(d) 
and 4.75(d) 
4.46 (d) 
and 4.72 (d) 
4.41 (d) 
and 4.60 (d) 
C-2 149.1 149.1 148.9 
OCH3 3.80 (s) 3.75 (s) 3.72 (s) C-9 139.8 147.0 146.7 
OCH3 3.67(s) 3.70 (s) 3.68 (s) C-8 131.0 141.6 141.3 
CH3 2.19 (s) 2.21 (s) 2.21 (s) C-3
’
 126.5 126.5 126.3 
CH3 2.16 (s) 2.16 (s) 2.16 (s) C-5
’
 125.6 124.9 124.9 
    C-4 116.0 117.5 117.3 
    C-6 111.5 109.0 108.9 
    C-7 100.4 99.4 99.3 
    OCH3 60.0 59.7 60.4 
    OCH3 55.5 55.2 55.1 
    CH2S 59.8 58.6 59.6 
    CH3 12.9 12.9 12.8 
    CH3 11.1 11.3 11.2 
a1
H,
13
C spectra were recorded in DMSO-d6, 400 MHz. 
 
The NMR spectra show similar signals to that of 
sulfide compound, except the signals of methylene 
group attached to S=O. Two proton signals of 
methylene group, that appeared as the singlet at 4.34 
ppm, was found at 4.67 and 4.75 ppm as 2 doublets. 
In the 
13
C-NMR, the signal of CH2S=O moved to 
59.8 ppm from 35.0 ppm in  the spectrum of sulfide 
3. The molecular ion peak [M+H]
+
 was found at 346 
in the ESI-MS, hence the chemical formula is 
C17H19N3O3S. 
Esomeprazole was converted to its more stable 
salt using reaction with sodium hydroxide in 
acetonitrile. The sodium salt was crystallized and 
 51 
VJC, Vol. 53(2e), 2015                                                                                                   Le Nguyen Thanh, et al. 
obtained with high enantioselectivity (ee > 99 %) in 
moderate overall yield (48 %). 
 
4. CONCLUSION 
 
In summary, a proton pump inhibitor, 
esomeprazolesodium,was obtained from 2-
mercapto-5-methoxybenzimidazole and 2-
chloromethyl-3,5-dimethyl-4-methoxypyridine 
hydrochloride in 3 steps with 44 % overall yield. 
Further works on optimization of reaction condition 
and amplification of synthetic scale are under 
investigation and will be reported in due course.  
 
Acknowledgement. The research is financially 
supported by Vietnam Academy of Scienceand 
Technology under project number VAST-04.09/14-
15. 
 
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Corresponding author: Le Nguyen Thanh 
Institute of Marine Biochemistry, Vietnam Academy of Science and Technology 
      18 Hoang Quoc Viet, CauGiay, Hanoi Vietnam 
      E-mail: lethanh@imbc.vast.vn 
      Tel: 0983882573. 


Synthesis of antiulcer drug esomeprazole.

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Synthesis of antiulcer drug esomeprazole.

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