Title of Invention

"A PROCESS FOR OPTICAL PURIFICATION OF OMEPRAZOLE"

Abstract A process for the optical purification of an enantiomerically enriched preparation of the omeprazole according to formula Ia characterized in that the process carried out at room temperature or below room temperature comprises the steps of treating an enantiomerically enriched preparation of the compound according to formula la, in favour of either its (+)- or (-)-enanatiomer with an organic solvent selected from acetone, 2-butanone, ethyl acetate, ethanol, acetonitril or toluene, or a mixture of water and the organic solvent from which the racemate of said compound is selectively precipitated, filtering off the precipitated racemate, and removal of the solvent to yield the single enantiomer with an enhanced optical purity.
Full Text The present invention relates to a process for optical purification of omeprazole. Prior art
There are a large number of patents and patent applications disclosing different substituted 2-(pyridinylmethylsulphmyl)-lH-benzimidazoles and structurally related sulphoxides. This class of compounds has properties making the compounds useful as inhibitors of gastric acid secretion. For example the coinpound(5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridmyl)-methyyl]sulphiny1]-1H-benzimidazole), having the generic name omeprazole, and therapeutically acceptable salts thereof are described in Ep 5129.Omeprazole and its alkaline salts are effective gastric acid secretion inhibitors,, and are useful as antiulcer agents. Other compounds also effective as gastric acid secretion inhibitors are the compounds 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]memyl]sulphinyl]-lH-benzimidazole having the generic name lansoprazole, described in EP-A1-174726; 2-([[4-(3-methoxypropoxy)-3-methyI-2-pyridmyl]methyl]sulphinyl]-l!i-benziniidazole having the generic name pariprazole, described in EP 268956; 2-[[2-(N-isobutyl-N-methylamino)benzyl]sulphinyl]-lH-benzknidazole having the generic name leminoprazole, described in GB 2163747 and 2-[(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)sulphinyl]-lH-benzimidazole which is described in EP 434999.


These compounds omeprazole, lansoprazole, pariprazole and leminoprazole all
have a stereogenic centre at the sulphur atom and thus exist as two stereoisomers
(enantiomers). The compound 2-[(4-methoxy-6/7A9-tetrahydro-5Hcyclohepta[
b]pyridin-9-yl)sulphinyl]-lH-benzimidazole has two stereogenic
centers, one centre at the methine carbon atom adjacent to the sulphur atom and
one at the sulphur atom. Thus, this compound exists as four stereoisomers (two
pair of enantiomers). Even though the 2-(pyridinylmethylsulphinyl)-lHbenzimidazole
class of chiral sulphoxides, including omeprazole, have been
described in the scientific literature since the late seventies, there is not yet any
efficient asymmetric process reported for the synthesis of the single enantiomers
thereof. The single enantiomers of pharmacologically active compounds have met
an increased interest in the last years because of improved pharmacokinetic and
biological properties. Therefore, there is a need for a process that can be used in
large scale for the preparation of the single enantiomers of omeprazole and of
other optical pure omeprazole analogues. Generally, asymmetric processes for
obtaining chiral sulphoxides afford optically active sulphoxides in
enantiomerically enriched forms rather than in pure single enantiomeric forms
unless the processes are enzymatic transformations or resolution methods.
Therefore, there is also a need for a method that can be used in large scale for the
enhancement of optical purity for enantiomerically enriched preparations of
optically active omeprazole and other optically active omeprazole analogues.
Prior art discloses processes for resolution of different substituted 2-(2-
pyridinylmethylsulphinyl)-lH-benzimidazoles. For example in DE 4035455 and
WO 94/27988 such resolution processes are described. These processes involve
reaction steps wherein a diastereomeric mixture is synthesised from the racemate
of the corresponding substituted 2-(2-pyridinylmethylsulphinyl)-lHbenzimidazoles.
The diastereomers are then separated and finally the separated
diastereomer is converted to the optically pure sulphoxide in a hydrolytic step.
These resolution methods involving diastereomeric intermediates, suffer from at
least three fundamental disadvantages namely:
1) The substituted 2-(2-pyridinylmethylsulphinyl)-lH-benzimidazole/ as a
racemic intermediate, has to be further processed in a couple of reaction steps
before the single enantiomers can be obtained.
2) The resolution processes involve complicated separation steps.
3) There is a large waste of highly refined material when the unwanted
stereoisomer, in the form of the opposite diastereomer, is discarded.
Further, prior art discloses for instance enantioselective synthesis of a 2-(2-
pyridinylmethylsulphinylMH-benzimidazole derivative, namely the single
enantiomers of the sulphoxide agent (5,7-dihydro-2-[[(4-methoxy-3-methyl -2-
pyridinyOmethyll-sulphinyll-S^^^-tetramethylindeno-tS^-dJ-imidazol-S-ClH)-
one) see Euro. T. Biochem. 166 (1987) 453-459. This process is based on an
enantioselective oxidation of the corresponding prochiral sulphide to said
sulphoxide. The authors state that the crude product of the sulphoxide, showing
an enantiomeric excess (e.e.) of about 30%, can be purified to optical pure
sulphoxide [(e.e.) > 95%] by several steps of crystallisation. However, the yields
and the number of crystallisation steps are not reported.
This proposed crystallization method is not suitable for the kind of substances
according to the compounds of formula la- le in the present application.
Summary of the invention.
The object of the present invention is to provide a novel process for the
enhancement of the optical purity (enantiomeric excess, e.e.) for enantiomerically
enriched preparations of omeprazole, lansoprazole, pariprazole, leminoprazole
and2-[(4-methoxy-6/7/8,9-tetrahydro-5H-cyclohepta[b]pyriclin-9-yl)sulphinyl]-
IH-benzimidazole. Surprisingly, the racemates of these compounds are very
selectively precipitated from a solvent yielding the single enantiomers with an
enhanced optical purity.
The process of the invention is defined in claim 1 and further preferred
embodiments of the invention are disclosed in claims 2-9. Preferred compounds
prepared by the new process are defined in claims 10-19.
Detailed description of the invention.
The process of the present invention is characterised by the steps of treating an
enantiomerically enriched preparation of optically active omeprazole of the
formula la
(Figure Removed)
or of optically active lansoprazole of the formula Ib
(Figure Removed)

or of optically active pariprazole of the formula Ic
(Figure Removed)

or of optically active leminoprazole of the formula Id
or of optically active 2-[(4-methoxy-6/7/8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-
yl)sulphinyl]-lH-benzimidazole of the formula le
le
with a solvent from which the racemate is selectively precipitated. The
precipitated benzimidazole derivative as a racemate, or as a racemate together
with a small amount of the desired enantiomer is filtered off and the single
enantiomer of the benzimidazole derivative, either as its (-)-enantiomer or as its
(+)-enantiomer, with a dramatically enhanced optical purity is obtained by
removing the solvent of the filtrate. The solvent is preferably removed by
evaporation. The substituted 2-(2-pyridinylmethylsulphinyl)-lH-benzimidazole/
to be treated in the process, is preferably omeprazole.
The precipitation is carried out in a protic or a non-protic solvent. The solvent
facilitate the crystallisation and is necessary for the separation. The choice of
solvent from which the racemate is precipitated is not essential for the process.
Preferably the solvent is an organic solvent. A suitable organic solvent can be a
ketone such as acetone or 2-butanone, or an ester such as ethyl acetate, or an
alcohol such as ethanol, or a nitrile such as acetonitrile, or a hydrocarbon such as
toluene. The solvent may also be an ether, an amide or any other organic solvent
from which the racemate of the compounds according to formula la-Ie can be
selectively precipitated. The solvent may also be a mixture of different organic
solvents or a mixture of water and organic solvents. Preferably the solvent is one
selected among acetone, toluen or acetonitril.
The temperature is not important for the process of the invention. However, if the
temperature is too high the solubility increases, the selectivity decreases and the
compound decomposes. Therefore, room temperature is preferred, but also
temperatures below room temperature are suitable.
Thus, a preferred feature of the process of the invention is that the racemates of
the compounds according to formula la-Ie surprisingly are very selectively
crystallised from an organic solvent. A dramatically enhancement of the
enantiomeric excess of the (-)-enantiomer or the (+)-enantiomer of the present
compounds is obtained in the mother liquor (filtrate), even after only one racemate crystallisation. Therefore, the process becomes highly effective. Consequently, the single enantiomers can be obtained with a very high enantiomeric excess even from optically impure preparations. This means that a high enantioselectivity is not essential for the asymmetric synthesis of the said optical active compounds, e.g. the asymmetric oxidation of corresponding prochiral sulphide. Thus, a broader scope of synthetic methods can be considered when choosing the most appropriate asymmetric synthesis processes for obtaining the compounds according to formula Ia-Ie. For example chemical yield, cost of reagents reaction time and-grade of dangerousness of-handling reagents may..thus be as important factors as enantioselectivety when making the choice of synthetic method.
The invention is illustrated more in detail by the following examples 1-16. The invention is illustrated together with an asymmetric synthesis in examples 7-9 .
A process for the optical purification of an enantiomerically enriched preparation
of the omeprazole according to formula la

(Formula Removed)

characterized in that the process carried out at room temperature or below room temperature comprises the steps of
treating an enantiomerically enriched preparation of the compound according to formula la, in favour of either its (+)- or (-)-enanatiomer with an organic solvent selected from acetone, 2-butanone, ethyl acetate, ethanol, acetonitril or toluene, or a mixture of water and the organic solvent from which the racemate of said compound is selectively precipitated,

- filtering off the precipitated racemate, and
- ' removal of the solvent to yield the single enantiomer with an enhanced optical purity.
EXAMPLES
The enantiomeric excess value in each example given below gives an indication of the relative amount of each enantiomer. The value is defined as the difference between the relative percentages for the two enantiomers. Thus, for example, when the percentage of the (-)-enantiomer of the sulphoxide is 97.5% and the percentage for the (+)-enantiomer is 2.5%, the enantiomeric excess for the (-)-enantiomer is 95%.
The enantiomeric composition of each sulphoxide was determined by chiral HPLC on either a Chiralpak AD Column or a Chiral AGP Column under the following conditions:
Compound of formula la.
Column Chiralpak AD 50x4.6 mm
Eluent iso-Hexane (100 ml), ethanol (100 ml) and acetic acid (lOul)
Flow 0.5 ml/min
Inj.vol. 50 ul
Wavelength 302 nm
Retention time for the (-)-enantiomer 4.0 min
Retention time for the (+)-enantiomer 5.8 min
Compound of formula Ib,
Column Chiral AGP 100x4.0 mm
Eluent Sodium phosfate buffer solution (pH 7.0), 1=0.025 (500 ml) and
acetonitrile (70 ml)
Flow 0.5 ml/min
Inj.vol. 20 ul
Wavelength 210 nm
Retention time for the (+)-enantiomer 6.2 min
Retention time for the (-)-enantiomer 7.2 min
Compound of formula Ic.
Column Chiral AGP 100x4.0 mm
Eluent Sodium phosfate buffer solution (pH 7.0), 1=0.025 (430 ml) and
acetonitrile (70 ml)
Flow 0.5 ml/min
Inj.vol. 20 ul
Wavelength 210 nm
Retention time for the (+)-enantiomer 4.1 min
Retention time for the (-)-enantiomer 6.8 min
Compound of formula Id.
Column Chiralpak AD 50x4.6 mm
Eluent iso-Hexane (200 ml) and ethanol (10 ml)
Flow 0.5 ml/min
Inj.vol. 50 |il
Wavelength 285 nm
Retention time for the (-)-enantiomer 9.0 min
Retention time for the (+)-enantiomer 9.8 min
Compound of formula le.
Column Chiralpak AD 50x4.6 mm
Eluent iso-Hexane (150 ml) and 2-propanol (50 ml)
Flow 0.4 ml/min
Inj.vol. 50 (ol
Wavelength 285 nm
Retention time for the (-)-enantiomer of diasteremor A 6.9 min
Retention time for the (+)-enantiomer of diasteremor A 8.1 min
Retention time for the (+)-enantiomer of diasteremor B 8.8 min
Retention time for the (-)-enantiomer of diasteremor B 11.0 min
The first diastereomer of compound (le) eluted on straight phase (achiral silica
gel, see below) is named diastereomer A and second as diastereomer B.
Example 1. Enhancement of optical purity from 60% e.e. to 98.4% e.e. for
(-)-5-methoxy-2-[[(4-methoxy-3.5-dimethyl-2-pyridinyl)-methynsulphinyn-
IH-benzimidazole, (-)-(Ia)
2.35 g of a mixture of the enantiomers of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-
2-pyridinyl)methyl]sulphinyl]-lH-benzimidazole (60% e.e.. in favour of the (-)-
enantiomer) as a yellow syrup was dissolved in 20 ml of acetonitrile. Almost
immediately the racemate as a solid appeared and after 30 minutes in a
refrigerator this white solid was filtered off. The solvent of the filtrate was
evaporated to yield 1.2 g of the (-)-enantiomer of omeprazole as a yellow syrup
with an optical purity of 98.4% e^e.
Example 2. Enhancement of optical purity from 20% e.e to 91.4% e.e for
(-)-5-methoxy-2-rf(4-methoxy-35-dimethvl-2-pyridinvD-methynsulphinyl1-
IH-benzimidazole. (-)-(Ia)
2.35 g of a mixture of the enantiomers of 5-methoxy-2-[[(4-methoxy-3/5-dimethyl-
2-pyridinyl)methyl]sulphinyl]-lH-benzimidazole (20% e-e., in favour of the (-)-
enantiomer) as a yellow syrup was dissolved in 20 ml of 2-butanone. Almost
immediately the racemate as a solid appeared and after one hour in a refrigerator
this white solid was filtered off. The solvent of the filtrate was evaporated to yield
0.48 g of the (-)-enantiomer of omeprazole as a yellow syrup with an optical
purity of 91.4% e.e.
Example 3. Enhancement of optical purity from 50% e.e. to 97.3% e.e. for
(-)-5-methoxy-2-f[(4-methoxy-3.5-dimethyl-2-pyridinyl)-methynsulphinyl1-
IH-benzimidazole. (-)-(Ia)
2.35 g of a mixture of the enantiomers of 5-methoxy-2-[[(4-methoxy-3/5-dimethyl-
2-pyridinyl)methyl]sulphinyl]-lH-benzimidazole (50% e.e., in favour of the (-)-
enantiomer) as a yellow syrup was dissolved in 20 ml of acetone. Almost
immediately the racemate as a solid appeared and after one hour in a refrigerator
this white solid was filtered off. The solvent of the filtrate was evaporated to yield
1.0 g of the (-)-enantiomer of omeprazole as a yellow syrup with an optical purity
of 97.3%
Example 4. Enhancement of optical purity from 80% e.e. to 95.4% e.e. for
(+V5-methoxy-2-fr(4-methoxy-3.5-dimethyl-2-pvridinyn-methvnsulphinvl1-
IH-benzimidazole. (+V(Ia)
2.35 g of a mixture of the enantiomers of 5-methoxy-2-[[(4-methoxy-3^-dimethyl-
2-pyridinyl)methyl]sulphinyl]-lH-benzimidazole (80% e.6., in favour of the (+)-
enantiomer) as a yellow syrup was dissolved in 20 ml of ethyl acetate. Almost
immediately the racemate as a solid appeared and after one hour in a refrigerator
this white solid was filtered off. The solvent of the filtrate was evaporated to yield
1.7 g of the (+)-enantiomer of omeprazole as a yellow syrup with an optical purity
of 95.4% e.e.
Example 5. Enhancement of optical purity from 40% e.e. to 88.7% e.e. for
(+)-5-methoxy-2-[f(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyn-
IH-benzimidazole. (+)-(Ia)
2.35 g of a mixture of the enantiomers of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-
2-pyridinyl)methyl]sulphinyl]-lH-benzimidazole (40% e.e.. in favour of the (+)-
enantiomer) as a yellow syrup was dissolved in 20 ml of ethanol. Almost
immediately the racemate as a solid appeared and after one hour in a refrigerator
this white solid was filtered off. The solvent of the filtrate was evaporated to yield
1.0 g of the (+)-enantiomer of omeprazole as a yellow syrup with an optical purity
of 88.7%
Example 6. Enhancement of optical purity from 30% e.e. to 97.0% e.e. for
(+)-5-methoxy-2-[r(4-methoxy-3.5-dimethyl-2-pyridinyl)-methyl1sulphinyl1-
IH-benzimidazole. (+)-(Ia)
2.35 g of a mixture of the enantiomers of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-
2-pyridinyl)methyl]sulphinyl]-lH-benzimidazole (30% e.e.. in favour of the (+)-
enantiomer) as a yellow syrup was dissolved in 20 ml of toluene. Almost
immediately the racemate as a solid appeared and after one hour in a refrigerator
this white solid was filtered off. The solvent of the filtrate was evaporated to yield
0.62 g of the (+)-enantiomer of omeprazole as a yellow syrup with an optical
purity of 97.0% e£.
Example 7. Asymmetric synthesis followed by optical purification of
(+)-5-methoxy-2-fr(4-methoxv-3.5-dimethyl-2-pyridinyl)methynsulphinvl1-lHbenzimidazole.
(+)-(Ia)
A mixture of 5-methoxy-2-[[(4-methoxy-3/5-dimethyl-2-pyridinyl)-methyl]thio]-
IH-benzimidazole (0.47 g, 1.46 mmol), (3'S,2RM-)-N-(phenylsulphonyl)-(3,3-
dichlorocamphoryDoxaziridine (0.55 g, 1.46 mmol), triethylamine (0.07 ml, 0.5
mmol) and carbon tetrachloride 20 ml was stirred for 96 hours at ambient
temperature. After removal of the solvent the residue was dissolved in methylene
chloride (25 ml). The mixture was extracted with two portions of aqueous
solutions of sodium hydroxide (0.1 M, 15 ml). The combined aqueous solutions
were neutralised with an aqueous solution of ammonium chloride in the presence
of methylene chloride. The phases were separated and the aqueous solution was
extracted with two portions of methylene chloride. The combined organic
solutions were dried over sodium sulphate and then the solvent was removed.
The residue (200 mg, 40% e.e.) was dissolved in 2-butanone (3 ml) and the formed
solid was filtered off. The solvent of the filtrate was evaporated to yield 0.11 g
(22%) of the title compound with an optical purity of 94% e.e.
Example 8. Asymmetric synthesis followed by optical purification of
(-)-5-methoxy-2-rr(4-methoxy-3.5-dimethyl-2-pyridinyl)methynsulphinyn-lHbenzimidazole.
(-)-(Ia)
1.6 kg (5.0 mol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-
methyl]thio]-lH-benzimidazole was dissolved in 5.01 of ethyl acetate. To the
solution was added 31 ml (1.7 mol) of water. To the mixture was added 856 ml
(5.0 mol) of (-)-diethyl D-tartrate, 744 ml (2.5 mol) of titanium(IV) isopropoxide
and 435 ml (2.5 mol) of diisopropylethylamine at room temperature. The addition
of 830 ml (4.5 mol) cumene hydroperoxide was then performed at 30°C After
stirring for one hour at 30°C the reaction was complete. Crural and achiral
chromatographic analyses showed that the mixture consited of 71.4% sulphoxide
with an enantiomeric excess (e.e.) of 72.9%. The mixture was cooled to 10°C and
after addition of 1.71 of isooctane, the product was extracted three times with an
aqueous ammonia (12%) solution with a total volume of 101. The combined
aqueous phases were neutralised by addition of 1.51 of concentrated acetic acid in
the presence of ethyl acetate (31). The phases were separated and the aqueous
phase was extracted with ethyl acetate (31). The solvent of the combined organic
solutions was removed and at the end of the evaporation acetonitrile (1.51) was
added to facilitate the removal of solvent. Acetone (2.51) was added to precipitate
the racemate of omeprazole which was filtered off (254 g). HPLC-analyses (achiral
and chiral columns) of the filtrate showed that this solution consited of 88%
sulphoxide with an optical purity of 96.3% e.e. and thus the optical purity has
been improved from 72.9% e.e. to 96.3% e.e. simply by one precipitation of
racemic omeprazole. Further, a content analysis (HPLC) of the filtrate showed that
the yield was 0.8 kg (46%). The (-)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-
dimethyl-2-pyridinyl)methyl]sulphinyl]-lH-benzimidazole was not isolated in its
neutral form but further processed to corresponding sodium salt.
Example 9. Asymmetric synthesis followed by optical purification of
(+)-5-methoxy-2-[r(4-methoxy-33-dimethyl-2-pyridinyl)methyl1sulphinyl1-lHbenzimidazole.
(+)-(Ia)
1.6 kg (5.0 mol) of 5-methoxy-2-[[(4-methoxy-3^-dimethyl-2-pyridinyl)-
methyl]thio]-lH-benzimidazole was dissolved in 7.51 of ethyl acetate. To the
solution was added 31 ml (1.7 mol) water. To the mixture was added 856 ml (5.0
mol) of (+)-diethyl L-tartrate, 744 ml (2.5 mol) of titanium(IV) isopropoxide and
436 ml (2.5 mol) diisopropylethylamine at room temperature. The addition of 830
ml (4.5 mol) cumene hydroperoxide was then performed at 30°C After stirring for
one hour at 30°C the reaction was complete. Chiral and achiral chromatographic
analyses showed that the mixture consited of 75% sulphoxide with an
enantiomeric excess (ejL) of 80%. The mixture was cooled to 10°C and after
addition of 1.51 of isooctane and ethyl acetate (0.51), the product was extracted
three times with an aqueous ammonia (12%) solution with a total volume of 141.
The combined aqueous phases were neutralised by addition of 1.51 of
concentrated acetic acid in the presence of ethyl acetate (41). The phases were
separated and the aqueous phase was extracted with ethyl acetate (41). The
solvent of the combined organic solutions was removed. Acetone (3.01) was
added to precipitate the racemate of omeprazole which was filtered off. HPLCanalyses
(achiral and chiral columns) of the filtrate showed that this solution
consited of 90% sulphoxide with an optical purity of 95% e.e. and thus the optical
purity has been improved from 80% e.e. to 95% e.e. simply by one precipitation of
racemic omeprazole. Further, a content analysis (HPLC) of the filtrate showed that
the yield was 1.0 kg (58%). The (+)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-
dimethyl-2-pyridinyl)methyl]sulphinyl]-lH-benzimidazole was not isolated in its
neutral form but further processed to corresponding sodium salt.
The starting material in form of enantiomerically enriched preparations for the
>
optical purification of one of the compounds according to formulas Ib, Ic, Id or le
is prepared as described in examples 8 and 9.
Example 10. Enhancement of the optical purity of two of the stereoisomers of 2-
[(4-methoxy-6.7.8.9-tetrahydro-5H-cycloheptarb1pyridin-9-yl)sulphinyl1-lHbenzimidazole,
(le).
In the following example, the first diastereomer of the title compound eluted on
straight phase (silica gel) is named diastereomer A and second as diastereomer B.
The stereoisomeric composition of the title compound in a crude mixture as a
syrup (0.25 g) was as follows; The ratio of diastereomers was 4:3 in favour of
diastereomer A. The optical purity of the (-)-enantiomer of diastereomer A was
76% ejL and the optical purity of the (+)-enantiomer of diastereomer B was 68%
Separation of foe diastereomers. A chromatographic preparation (methanolmethylene
chloride 0 to 5%) afforded a separation of the two diastereomers. Thus,
the (-)-enantiomer of diastereomer Awas obtained as a syrup (0.145 g) with an
optical purity of 77% e.e. The (+)-enantiomer of diastereomer B was also obtained
as a syrup (0.085 g) with an optical purity of 68%_e.e. , however, diastereomer B
was contaminated with ca. 10% of diastereomer A.
Optical purification: The optical purity of the (-)-enantiomer of diastereomer A
was enhanced by the addition of ca. 2 ml of acetonitrile to the enantiomerically
enriched preparation of diastereomer AJ0.145 g). After stirring over night, the
formed precipitate (almost racemic diastereomer A) was filtered off and the
solvent of the filtrate was removed by film evaporation. Thus, there was obtained
85 mg of the (-)-enantiomer of diastereomer A as a syrup with an optical purity of
88% e.e. The optical purity of the (+)-enantiomer of the diastereomer B was
enhanced in a similar way. Thus, by addition of acetonitrile (2 ml) to the
enantiomerically enriched preparation of diastereomer B (0.085 g) followed by
stirring over night resulted in a precipitate which was filtered off. From the
filtrate there was obtained 0.050 g of the (+)-enantiomer of diastereomer B with an
optical purity of 95% e.e.
Example 11. Enhancement of the optical purity of (-)-2-f[f3-methyl-4-(2.2.2-
trifluoroethoxy)-2-pyridinyl1methyl1sulphinyl1-lH-benzimidazole. (-)-(Ib).
1.2 g of a crude mixture of the tide compound with an enantiomeric excess (e.e.) of
55% was treated with acetonitrile (a few ml) and there was obtained a precipitate
that was removed by filtration. Evaporation of the filtrate afforded an oil with
enhanced optical purity. Repeating this procedure a couple of times afforded 0.63
g of the desired compound as an oil with an optical purity of 99.5% e.e.
Example 12. Enhancement of the optical purity of (+)-2-rrr3-methyl-4-(2.2.2-
trifluoroethoxy)-2-pyridinyl1methyllsulphinyl1-lH-benzimidazole.
0.85 g of a crude mixture of the title compound with an enantiomeric excess (e.e.)
of 46% was treated with acetonitrile (a few ml) and there was obtained a
precipitate that was removed by filtration. Evaporation of the filtrate afforded an
oil with enhanced optical purity. Repeating this procedure a couple of times
afforded 0.31 g of the desired compound as an oil with an optical purity of 99.6%
e.e.
Example 13. Enhancement of the optical purity of (-)-2-riT4-(3-methoxypropoxy)-3-
methyl-2-pyridinyllmethyllsulpMnyll-lH-benzimidazole. (-)-(Ic).
1.62 g of a crude mixture of the title compound with an enantiomeric excess (e.e.)
of 90% was treated with acetonitrile (a few ml) and there was obtained a
precipitate that could be removed by filtration. Concentrating the filtrate afforded
1.36 g of the title compound as an oil with an optical purity of 91.5% e.e.
Example 14. Enhancement of the optical purity of (+)-2-fff4-(3-methoxypropoxy)-
3-methyl-2-pyridinyllmethyllsulphinyll-lH-benzimidazole. (+)-(Ic).
1.63 of a crude mixture of the title compound with an enantiomeric excess (e.e.) of
91% was treated with acetonitrile (a few ml) and there was obtained a precipitate
that could be removed by filtration. Concentrating the filtrate afforded 1.1 g of the
title compound as an oil with an optical purity of 96.0% e.e.
Example 15. Enhancement of the optical purity of (-)-2-[2-(N-isobutyl-Nmethylamino)
benzylsulphinyl1benzimidazole. (-)-(Id).
1.6 g of a crude mixture of the title compound with an enantiomeric excess (e.e.) of
92% was treated with a small amount of acetonitrile in order to enhance the
optical purity. A formed precipitate was removed by filtration. The solvent of the
filtrate was removed by film evaporation and there was obtained 1.2 g of the
desired compound as an oil. The optical purity of the material was 96% e.e.
according to chiral HPLC.
Example 16. Enhancement of the optical purity of (+)-2-f2-(N-isobutyl-Nmethylamino)
benzylsulphinynbenzimidazole.
3.0 g of a crude mixture of the title compound (91% e.e.), contaminated with (-)-
diethyl D-tartrate, was dissolved in 40 ml of a mixture of ethyl acetate and hexane
(10% EtOAc). A formed precipitate (140 mg) was removed by filtration. The
solvent of the filtrate was removed by film evaporation and the residue was
purified by column chromatography (silica gel, EtOAc/Hexane 15:85). There was
obtained 0.95 g of the title compound showing an optical purity of 96% e.e.
according to chiral HPLC.





We claim;
1. A process for the optical purification of an enantiomerically enriched preparation of the omeprazole according to formula Ia

(Formula Removed)
characterized in that the process carried out at room temperature or below room temperature comprises the steps of
treating an enantiomerically enriched preparation of the compound according to formula la, in favour of either its (+)- or (-)-enanatiomer with an organic solvent selected from acetone, 2-butanone, ethyl acetate, ethanol, acetonitril or toluene, or a mixture of water and the organic solvent from which the racemate of said compound is selectively precipitated, - filtering off the precipitated racemate, and
removal of the solvent to yield the single enantiomer with an enhanced optical purity.
2. A process as claimed in claim 1 wherein optical purity of the (-)-enantiomer of the compound according to formula la is enhanced.
3. A process as claimed in claim 1 wherein optical purity of the (+)- enantiomer of the compound according to formula la is enhanced.
4. A process as claimed in claim 1 wherein the solvent is removed by evaporation.

5. A' process as claimed in claim 1 wherein the enantiomerically enriched preparation is treated with a mixture of organic solvents.
6. A process as claimed in claim 1 wherein the enantiomerically enriched preparation is treated with a mixture of water and one or more organic solvents.
7. A process as claimed in claim 6 wherein the mixture of water and one or more
organic solvents contains 8. A process as claimed in claim 5 wherein the organic solvent is acetone,
acetonitrile or toluene.
9. A process for the optical purification of enantiomerically enriched preparations
of one of the compound according to formula la substantially as herein described
with reference to the foregoing examples.

Documents:

1344-DEL-1996-Abstract-(16-10-2008).pdf

1344-DEL-1996-Abstract-(29-05-2008).pdf

1344-del-1996-abstract.pdf

1344-DEL-1996-Claims-(16-10-2008).pdf

1344-DEL-1996-Claims-(29-05-2008).pdf

1344-del-1996-claims.pdf

1344-del-1996-complete specification (granted).pdf

1344-DEL-1996-Correspondence-Others-(29-05-2008).pdf

1344-del-1996-correspondence-others.pdf

1344-del-1996-description (complete).pdf

1344-del-1996-description (complete)16-10-2008.pdf

1344-del-1996-description (complete)29-05-2008.pdf

1344-DEL-1996-Form-1-(16-10-2008).pdf

1344-DEL-1996-Form-1-(29-05-2008).pdf

1344-del-1996-form-1.pdf

1344-del-1996-form-13.pdf

1344-del-1996-form-18.pdf

1344-DEL-1996-Form-2-(16-10-2008).pdf

1344-del-1996-form-2.pdf

1344-DEL-1996-Form-3-(29-05-2008).pdf

1344-del-1996-form-3.pdf

1344-del-1996-form-4.pdf

1344-del-1996-form-6.pdf

1344-DEL-1996-GPA-(16-10-2008).pdf

1344-DEL-1996-GPA-(29-05-2008).pdf

1344-del-1996-gpa.pdf

1344-DEL-1996-Petition-137-(29-05-2008).pdf

1344-DEL-1996-Petition-138-(29-05-2008).pdf


Patent Number 225920
Indian Patent Application Number 1344/DEL/1996
PG Journal Number 01/2009
Publication Date 02-Jan-2009
Grant Date 03-Dec-2008
Date of Filing 19-Jun-1996
Name of Patentee ASTRAZENECA AB
Applicant Address S-151 85 SODERTALJE, SWEDEN.
Inventors:
# Inventor's Name Inventor's Address
1 SVERKER VON UNGE ALVäGEN 4, S-430 33 FJäRåS, SWEDEN.
PCT International Classification Number C07D 401/12
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 PCT/SE95/00817 1995-07-03 PCT