An efficient procedure for the synthesis of Esomeprazole using a titanium complex with two chiral ligands

Article abstract of DOI:10.1134/s1070428008010168

A procedure has been proposed for the selective preparation of Esomeprazole via asymmetric oxidation of the corresponding prochiral sulfide in the presence of a catalytic complex derived from titanium(IV) isopropoxide and two different chiral ligands, diethyl d-tartrate and (R)-N,N-dimethyl-1-phenyl-ethanamine.

Full text of DOI:10.1134/s1070428008010168

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 1, pp. 124–127. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © T.M. Khomenko, K.P. Volcho, N.I. Komarova, N.F. Salakhutdinov, 2008, published in Zhurnal Organicheskoi Khimii, 2008,
Vol. 44, No. 1, pp. 126–129.
Dedicated to Full Member of the Russian Academy of Sciences
G.A. Tolstikov on his 75th anniversary
An Efficient Procedure for the Synthesis of Esomeprazole
Using a Titanium Complex with Two Chiral Ligands
T. M. Khomenko, K. P. Volcho, N. I. Komarova, and N. F. Salakhutdinov
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: volcho@nioch.nsc.ru
Received June 15, 2007
Abstract—A procedure has been proposed for the selective preparation of Esomeprazole via asymmetric
oxidation of the corresponding prochiral sulfide in the presence of a catalytic complex derived from tita-
nium(IV) isopropoxide and two different chiral ligands, diethyl D-tartrate and (R)-N,N-dimethyl-1-phenyl-
ethanamine.
DOI: 10.1134/S1070428008010168
chiometric amount of the expensive oxidant, and it
could not be regarded as efficient from the preparative
viewpoint.
Esomeprazole (I) is a modern highly effective anti-
ulcer drug; it is enantiomeric (S isomer) to Omepra-
zole, and it considerably exceeds the latter in clinical
effect [1]. The main procedure for the preparation of
Esomeprazole (I) has long been based on separation of
the corresponding racemic mixture [2–4], but most
part of the initial Omeprazole was not utilized, which
stimulated search for methods for asymmetric oxida-
tion of prochiral sulfide II. The oxidation of sulfide II
with Davis’ reagent [5], (3S,2R)-(−)-N-phenylsulfonyl-
(3,3-dichlorocamphoryl)oxaziridine, gave optically
active sulfoxide I with an optical purity of 40% [6]
(Scheme 1); however, this procedure required a stoi-
It seemed to be more promising to use modified
Sharpless procedures [7] for asymmetric oxidation, but
attempts to obtain Esomeprazole (I) according to these
procedures were unsuccessful. For example, the oxida-
tion of sulfide II following the procedure proposed in
[8] [oxidation with organic peroxides at –20 to –40°C
in the presence of a catalytic complex consisting of
titanium(IV) isopropoxide Ti(OPr-i)4, optically active
diethyl tartrate, and 1 equiv of water] resulted in the
isolation of racemic sulfoxide I [9]. Presumably, these
Scheme 1.
Me
OMe
Me
OMe
[O]
MeO
MeO
Me
Me
N
N
(S)
S
N
S
N
N
H
N
H
O
II
I
Me
OMe
MeO
Me
N
+
S
N
O
N
O
H
III
124

AN EFFICIENT PROCEDURE FOR THE SYNTHESIS OF ESOMEPRAZOLE
125
catalytic systems are unsuitable for asymmetric oxida-
tion of sulfides having bulky substituents with compa-
rable sizes.
ester (V). Compound V was added in a large excess
with respect to both Ti(OPr-i)4 (740 mol %) and sul-
fide II (250 mol %). The yield of Esomeprazole (I)
was lower (40%) than in [10], but the concentration of
sulfone III in the product was less than 1%.
Oxidation of sulfide II could give rise to a number
of by-products such as sulfone III resulting from pro-
found oxidation of the sulfur atom and decomposition
products; these side processes considerably affect the
yield of the target product, thus strongly restricting
the choice of reagents and oxidation conditions.
The above data show that no perfect procedure has
been developed so far for the synthesis of Esomepra-
zole (I) with a high yield and low (<1%) concentration
of sulfone III.
In 1996, Larsson et al. [10] proposed a modified
procedure for the stereoselective oxidation of sulfide II
to Esomeprazole (I) on the basis of the method de-
scribed in [8]. The following modifications were made
[10]: (1) the catalytic complex was prepared from
titanium(IV) isopropoxide, diethyl D-tartrate (IV), and
water in the presence of sulfide II; (2) the complex
was preliminary held (before addition of the oxidant)
at elevated temperature; (3) the reaction was carried
out in the presence of a base, preferably N,N-diiso-
propylethanamine. Each modification resulted in in-
creased enantioselectivity, but the best results were
obtained when all three modifications were applied
simultaneously. 1-Methyl-1-phenylethyl hydroperox-
ide was used as oxidant, and toluene, as solvent; the
amounts of Ti(OPr-i)4 and diethyl D-tartrate (IV) were
30 and 60 mol %, respectively. After appropriate treat-
ment of the reaction mixture, the crude product with
an optical purity of up to 94% was converted into the
corresponding sodium salt, and the optical purity of
sulfoxide I increased to almost 100% (yield 55%).
As we already noted, an important factor affecting
the optical purity of Esomeprazole (I) obtained accord-
ing to the procedure proposed in [10] is the presence
of a base (N,N-diisopropylethanamine). The role of
N,N-diisopropylethanamine remains so far unclear, but
the use of other amines, such as triethylamine, 4-meth-
ylmorpholine, 1,1,3,3-tetramethylguanidine (VI), or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, VII) re-
sulted in sharp decrease of the optical purity of the
product [10]. We found that aromatic N,N-diethyl-
aniline (VIII) as a base gives rise to a complex mixture
of products. Thus the amine structure strongly affects
both reaction direction and product purity. Presumably,
N,N-diisopropylethanamine directly participates in the
formation of chiral catalytic complex. Therefore, we
expected that proper choice of an optically active
amine as ligand for complex formation with Ti(OPr-i)4
and diethyl tartrate could enhance the enantioselec-
tivity of the oxidation and process and/or the chemical
purity of Esomeprazole (I).
N
NEt2
NH
O
OMe
O
OH
N
Me2N
NMe2
OEt
EtO
OH
VI
VII
VIII
OH
IV
O
NMe2
Me
NMe2
Me
V
An essential disadvantage of the above procedure is
formation of an appreciable amount (about 4%) of
sulfone III which is fairly difficult to separate [11]. If
the concentration of III exceeds 1%, preparation of
pharmaceutically pure compound I is strongly com-
plicated [11]. Further studies in this field were focused
mainly on variation of procedures for the treatment of
the reaction mixture with a view to increase purity of
the target product, while the stage of enantioselective
oxidation fell out of the scope of these studies [12, 13].
IX
X
In fact, the oxidation of sulfide II with 1-methyl-1-
phenylethyl hydroperoxide in the presence of a cata-
lytic complex derived from titanium(IV) isopropoxide
(46 mol %), diethyl D-tartrate (IV, 70 mol %), and
(S)-N,N-dimethyl-1-phenylethanamine (IX, 49 mol %)
gave 57% of Esomeprazole sodium salt with an optical
purity of no less than 99.5%, and the impurity of
sulfone III did not exceed 0.3%. Replacement of
compound IX by its enantiomer, (R)-N,N-dimethyl-1-
phenylethanamine (X) allowed us to raise the yield of
In 2003, Thennati et al. [11] modified the procedure
proposed in [10] via replacement of diethyl D-tartrate
by a unidentate ligand, (S)-(+)-mandelic acid methyl
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 1 2008

KHOMENKO et al.
126
Esomeprazole sodium salt to 64%, the optical purity
and the concentration of sulfone III remaining almost
the same.
and diethyl (–)-D-tartrate (Alfa Aesar, ee > 99%) were
used. Toluene was preliminarily dehydrated by azeo-
tropic distillation. 5-Methoxy-2-[(4-methoxy-3,5-di-
methylpyridin-2-yl)methylsulfanyl]-1H-benzimidazole
(II) was synthesized according to the procedure
described in [14] from 5-methoxy-1H-benzimidazole-
2-thiol (Alfa Aesar) and 2-chloromethyl-3,5-dimethyl-
4-methoxypyridine hydrochloride (Alfa Aesar).
Appreciable differences in the optical purities of the
crude products (84% using compound X against 79%
using amine IX) and in the yields of Esomeprazole
sodium salt suggest considerable effect of the absolute
configuration of N,N-dimethyl-1-phenylethanamine on
the reaction stereoselectivity. Amine IX or X is likely
to act as the second chiral ligand. We have found no
published data on the use of metal complexes with
two different chiral ligands in asymmetric oxidation
of sulfides.
(S)-N,N-Dimethyl-1-phenylethaneamine (IX), [α]D26
=
–62.7° (c = 2.4, CHCl3), and (R)-N,N-dimethyl-1-
phenylethanamine (X), [α]D27 = +61.9° (c = 2.1,
CHCl3), were prepared by methylation of the corre-
sponding amines with formaldehyde in aqueous formic
acid according to the procedure reported in [15].
The oxidation of sulfide II in the presence of the
complex derived from ligands IV and X occurs at
a much lower rate (reaction time 4.5 h) than the reac-
tions performed according to the procedures described
in [10, 11] (1.5 and 2 h, respectively). Presumably, the
high yield of Esomeprazole (I) according to our proce-
dure is largely determined by high chemoselectivity of
the process; this is confirmed, e.g., by the low concen-
tration of sulfone III.
Asymmetric synthesis of (S)-5-methoxy-2-[(4-
methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-
1H-benzimidazole (I, Esomeprazole) and its sodium
salt. a. A suspension of 0.545 g (1.66 mmol) of com-
pound II in 2.5 ml of toluene was heated to 55°C, 9 μl
(0.50 mmol) of water, 0.240 g (1.16 mmol) of diethyl
D-tartrate (IV), and 0.220 g (0.77 mmol) of titani-
um(IV) isopropoxide were added, and the mixture was
stirred for 1 h at 55°C. The mixture was then cooled to
30°C, 0.120 g (0.81 mmol) of amine IX was added, the
mixture was stirred for 15 min, 0.270 μl (1.58 mmol)
of 1-methyl-1-phenylethyl hydroperoxide (a 86.5% so-
lution in isopropylbenzene) was added, and the mix-
ture was stirred for 4.5 h at 30°C and extracted with
12.5% aqueous ammonia (3×3 ml). The aqueous ex-
tracts were combined, 3 ml of methylene chloride was
added, the mixture was neutralized with acetic acid,
the organic phase was separated, and the aqueous
phase was extracted with methylene chloride (2×
5 ml). The extracts were combined and evaporated to
obtain 0.514 g of a mixture containing (according to
the HPLC data) 82.4% of sulfoxide I, 9.0% of initial
sulfide II, and ≤0.3% of sulfone III; the optical purity
of sulfoxide I was 79%.
To conclude, we have developed a procedure for
highly selective synthesis of Esomeprazole (I) via
asymmetric oxidation of prochiral sulfide II in the
presence of a catalytic complex derived from titani-
um(IV) isopropoxide and two different chiral ligands,
diethyl D-tartrate (IV) and (R)-N,N-dimethyl-1-phenyl-
ethanamine (X).
EXPERIMENTAL
1
The H NMR spectrum was recorded on a Bruker
AV-300 spectrometer. The optical rotations were meas-
ured on an Optical Activity Polar 3005 polarimeter.
The ratios of compounds I–III were determined by
HPLC using a Millikhrom A-02 liquid chromatograph
equipped with a 75×2-mm ProntoSIL-120-5-C18 AQ
column (grain size 5.0 μm; eluent 0.1% of trifluoro-
acetic acid in methanol, flow rate 150 μl/min; UV
detector, λ 210 nm; temperature 35°C); retention
times: 6.9 (II), 6.5 (I), 6.3 min (III). The optical purity
of compound I was determined by chiral HPLC using
a Millikhrom 1 instrument (64×2-mm Kromasil CHI-
DMB column, grain size 10 μm; eluent 10% of iso-
propyl alcohol in hexane, flow rate 100 μl/min; UV
detector, λ 210 nm; temperature 35°C); retention times
6.1 and 7.5 min for the (S)- and (R)-enantiomers of I,
respectively.
The product mixture, 0.498 g, was dissolved in
4 ml of acetonitrile, a solution of 0.070 g of sodium
hydroxide in 0.075 ml of water was added, and the
mixture was stirred for 1 h at room temperature. The
precipitate was filtered off, washed with acetone, and
dried on a filter. We isolated 0.335 g of (S)-5-methoxy-
2-[(4-methoxy-3,5-dimethylpyridin-2-yl)-methylsul-
finyl]-1H-benzimidazole sodium salt. Overall yield
57% (with account taken of the fraction of the crude
product converted into sodium salt), optical purity
>99.5%, [α]D24 = +36.0° (c = 0.3, H2O). The H NMR
1
Commercial (S)-1-phenylethanamine (Acros, ee >
99%), (R)-1-phenylethanamine (Alfa Aesar, ee > 99%),
spectrum of (S)-5-methoxy-2-[(4-methoxy-3,5-dimeth-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 1 2008

AN EFFICIENT PROCEDURE FOR THE SYNTHESIS OF ESOMEPRAZOLE
127
4. Deng, J., Chi, Y., Fu, F., Cui, X., Yu, K., Zhu, J., and
Jiang, Y., Tetrahedron: Asymmetry, 2000, vol. 11,
p. 1729.
ylpyridin-2-yl)methylsulfinyl]-1H-benzimidazole
sodium salt coincided with that reported in [9].
b. Following an analogous procedure, from 0.545 g
(1.66 mmol) of compound II, 9 μl (0.50 mmol) of
water, 0.240 g (1.16 mmol) of diethyl D-tartrate (IV),
0.220 g (0.77 mmol) of Ti(OPr-i)4, and 0.120 g
(0.81 mmol) of amine X we obtained 0.537 g of a mix-
ture containing (according to the HPLC data) 82.3%
of sulfoxide I, 8.8% of initial sulfide II, and ≤0.3%
of sulfone III; the optical purity of crude sulfoxide I
was 84%.
5. Davis, F.A. and Sheppard, A.C., Tetrahedron, 1989,
vol. 45, p. 5703.
6. Von Unge, S., WO Patent no. 9702261, 1997; Chem.
Abstr., 1997, vol. 126, no. 186087.
7. Volcho, K.P., Salakhutdinov, N.F., and Tolstikov, A.G.,
Russ. J. Org. Chem., 2003, vol. 39, p. 1537.
8. Pitchen, P., Dunach, T., Desmukh, N.N., and Ka-
gan, H.B., J. Am. Chem. Soc., 1984, vol. 106, p. 8188.
9. Cotton, H., Elebring, T., Larsson, M., Li, L., Soren-
sen, H., and von Unge, S., Tetrahedron: Asymmetry,
2000, vol. 11, p. 3819.
10. Larsson, E.M., Stenhede, U.J., Sorensen, H., von
Unge, P.O.S., and Cotton, H.K., WO Patent
no. 9602535, 1996; Chem. Abstr., 1996, vol. 125,
no. 58516.
11. Thennati, R., Rehani, R.B., Soni, R.R., Chhabada, V.C.,
and Patel, V.M., WO Patent Publ. no. 2003089408,
2003; Chem. Abstr., 2003, vol. 139, p. 350735.
12. Hashimoto, H. and Maruyama, H., WO Patent Publ.
no. 2001087874, 2001; Chem. Abstr., 2001, vol. 136,
no. 5990.
A 0.440-g portion of the isolated mixture was dis-
solved in 3.5 ml of acetonitrile, a solution of 0.070 g of
sodium hydroxide in 0.075 ml of water was added, and
the mixture was stirred for 1 h at room temperature.
The precipitate was filtered off, washed with acetone,
and dried on a filter. We thus isolated 0.320 g of
(S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-
yl)methylsulfinyl]-1H-benzimidazole sodium salt.
Overall yield 64% (with account taken of the fraction
of the crude product converted into sodium salt), op-
tical purity >99.5%.
13. Hashimoto, H. and Urai, T., WO Patent Publ.
no. 2001083473; Chem. Abstr., 2001, vol. 135,
no. 357923.
REFERENCES
1. Andersson, T., Rohss, K., Hassan-Alin, M., and Bred-
berg, E., Gastroenterology, 2000, vol. 118, p. A1210.
2. Erlandsson, P., Isaksson, R., Lorentzon, P., and Lind-
14. Carlsson, E.I., Junggren, U.K., Larsson, H.S., and von
Wittken Sundell, G.W., EP Patent no. 074341, 1983;
Chem. Abstr., 1983, vol. 99, no. 194956.
berg, P., J. Chromatogr., 1990, vol. 532, p. 305.
3. Kohl, B. and Senn-Bilfinger, J., DE Patent no. 4035455,
15. Angres, I. and Zieger, H.E., J. Org. Chem., 1975,
1990; Chem. Abstr., 1992, vol. 117, no. 90285.
vol. 40, p. 1457.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 1 2008