ꢀꢀꢀꢁ
2ꢀ
ꢀG. Zhou and Y. Guan: R-enantiomer impurity of esomeprazole
O
O
HCl
H
N
H
N
H
N
Cl
O
S
O
N
Oxaziridinium 4
S
S
N
N
Na2CO3, MeOH, ∆
N
N
H
CH2Cl2, -70°C to rt
O
O
O
N
2
1
3
(R)
C8H17
Oxaziridinium:
TBDPSO
N
F4B
O
4
Scheme 1ꢀAsymmetric synthesis of the R-enantiomer of esomeprazole.
(500 mL) and compound 2 (8.22 g, 25 mmol). With stirring, the solu-
tion was cooled to -70°C under argon and treated with a solution of
salt 4 (16.43 g, 25 mmol) in dichloromethane. The temperature of
the mixture was allowed to reach slowly room temperature (about
3 h) before work up. The progress of the reaction was monitored by
TLC. Afer the reaction has completed, the mixture was concentrated
under reduced pressure and the residue was purified by silica gel
chromatography to furnish white crystals of the sulfoxide 3; yield
7.42 g (86%); enantiomeric excess 98%; purity 99.5% (HPLC); mp
Experimental
Melting points (mp) were determined on a Buchi 535 capillary
melting apparatus and are not corrected. The H NMR (400 MHz)
1
and 13C NMR (100 MHz) spectra were recorded in CDCl3 on a Mercury
Plus Varian 400 spectrometer. The low-resolution ESI mass spec-
trum was acquired on a Thermo Scientific LCQ spectrometer and the
high-resolution mass spectrum was obtained using a Thermo Fisher
Scientific LTQ FT Ultra spectrometer. IR spectra were determined on
a Nicolet NEXUS-470 FT-IR spectrometer in KBr pellets.
Analytical TLC was performed on a Merck precoated TLC (silica
gel 60 F254) plate.
1
154.0–156.0°C; [α]20 +155 (c ꢁ=ꢁ 0.5, CHCl3); H NMR: δ 2.18 (m, 6H),
3.66 (s, 3H), 3.81 (s,D3H), 4.80 (m, 2H), 6.90 (m, 2H), 7.60 (s, 1H), 8.17
(s, 1H); 13C NMR: δ 164.4, 157.7, 151.2, 149.6, 148.8, 138.2, 135.4, 126.9,
126.4, 120.7, 113.6, 94.6, 60.7, 59.9, 55.7, 13.3, 11.5; HRMS: m/z 346.1225
+
[M + H] ; IR: v 2937, 1624, 1589, 1566, 1471, 1431, 1396, 1305, 1269, 1205,
1151, 1076, 1026, 810, 621 cm-1.
5-Methoxy-2-[3,5-dimethyl-4-methoxy-2-pyridyl]
methylsulfanyl-1H-benzimidazole (2)
Acknowledgments: This work was supported by Science
and Technology Project of Taizhou (No. 131KY07), Sci-
entific Research Fund of Zhejiang Provincial Education
Department (No. Y201329469), the Research Foundation
for Post-doctoral Scientists of Taizhou (No. 2013BSH01)
and the Program for Changjiang Scholars and Innovative
Research Team in Chinese University (No. IRT 1231).
A 500 mL three-necked round bottom flask equipped with an
efficient mechanical stirrer was charged with methanol (400 mL),
2-chloromethyl-3,5-dimethyl-4-methoxypyridineꢀhydrochloride
(48.6 g, 0.22 mol), 5-methoxybenzimidazol-1H-2-thione (1, 36.0 g,
0.2 mol) and sodium carbonate (46.6 g, 0.44 mol). The mixture was
heated under reflux for 1.5 h while the progress of the reaction was
monitored by TLC. Afer completion of the reaction, the mixture was
filtered and the filtrate was concentrated under reduced pressure.
The residue was dissolved in toluene and the solution was washed
with aqueous solution of sodium carbonate and concentrated. The
residue was crystallized from toluene to furnish 62.25 g (95%) of 2;
References
[1] Venkata Subbaiah, B.; Sree Ganesh, K. K.; Prakash, L.;
Subramanyam Reddy, K. Preparative isolation and UPLC-TOF
MS identification of eight degradants from stressed tablets
of esomeprazole. J. Liq. Chromatogr. Relat. Technol. 2013, 36,
1243–1250.
[2] Federsel, H. J.; Larsson, M. In Asymmetric Catalysis on Industrial
Scale. , H.-U., Schmidt, E., Eds. Wiley-VCH, Weinheim, 2004,
p 413.
1
purity 99% (HPLC); mp 120.0–121.8°C; H NMR: δ 2.26 (s, 3H), 2.30
(s, 3H), 3.76 (s, 3H), 3.82 (s, 3H), 4.38 (s, 3H), 6.79 (m, 1H), 7.03 (d, 1H,
J ꢁ=ꢁ 2.5), 7.39 (d, 1H, J ꢁ=ꢁ 8.5), 8.24 (s, 1H); 13C NMR: δ 165.0, 155.9, 150.8,
148.5, 126.3, 125.5, 114.8, 110.9, 97.5, 60.1, 55.8, 35.2, 13.6, 11.3; MS: m/z
+
330.2 [M + H] ; IR: v 2958, 1635, 1593, 1456, 1436, 1404, 1344, 1263, 1190,
1155, 1080, 1029, 837, 806, 657cm-1.
[3] Cotton, H.; Elebring, T.; Larsson, M.; Li, L.; Soensen, H.; Unge, S. V.
Asymmetric synthesis of esomeprazole. Tetrahedron: Asymmetry
2000, 11, 3819–3825.
(R)-5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-
pyridinylmethyl)sulfinyl]-1H-benzimidazole (3)
[4] Federsel, H. J. Asymmetry on large scale. The roadmap to the
stereoselective processes. Nat. Rev. Drug Discovery 2005, 4,
685–697.
A 1000 mL three-necked round bottom flask equipped with an
efficient mechanical stirrer, was charged with dichloromethane
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