Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR PURIFYING 6-METHOXY OMEPRAZOLE
Background of the Invention
Until recently, omeprazole, the active ingredient in AstraZeneca's
proton pump inhibitor commercially sold in the United States under the brand
name PrilosecC~, was chemically believed to be 5-methoxy-2-[[(4-methoxy-
3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, in the solid
state,
represented by formula (1 b):
H
s N~2~~ N
//
H CO/ \4 N ~ CH3
3 3
H3C OCH3
1 b. 5-methoxy Omeprazole
However, Whittle, R.R., et al. disclosed in PCT patent application WO
01/14367 that omeprazole, as a free base or as a salt, hydrate, or
combination thereof, is actually two positional isomers co-crystallizing in a
single crystalline lattice: the above-referenced 5-methoxy omeprazole
represented by the formula (1 b), and its preferred 6-methoxy isomer: 6-
-1-
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methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-
benzimidazole, represented by formula (1 a):
H3C0 7 N O
1 \2-S~ N
~4 3 CH3
H3C OCHg
1 a. 6-methoxy Omeprazole
Whittle, et al. further disclosed that the stability of omeprazole is
affected by the ratio of 6-methoxy omeprazole to 5-methoxy omeprazole, with
omeprazole being more favorably stable as the percentage of 6-methoxy
omeprazole is increased. However, the processes presently available for
preparing a higher percentage of the more preferred isomer, 6-methoxy
omeprazole, and reduction in the 5-methoxy omeprazole percentage of the
less preferred require controlling the rate of recrystallization, the solvent
used,
and other environmental factors. An alternative to the expensive and time-
consuming method for increasing the percentage of 6-methoxy omeprazole in
the crystalline lattice from an amount of 5(6)-methoxy omeprazole, would be
technically and commercially beneficial.
Summary of Invention
Accordingly, the present invention provides methods for increasing the
solid state percentage of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
pyridinyl)methyl]sulfinyl]-1H-benzimidazole, or a pharmaceutically acceptable
salt, hydrate or combination thereof, from an amount of 5(6)-methoxy-2-[[(4-
methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazo1e, or a
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pharmaceutically acceptable salt, hydrate or combination thereof and, thus,
also decreasing the percentage of 5-methoxy omeprazole proportionately.
Detailed Description of the Preferred Embodiments
The present invention is described herein below in greater detail with
reference to its preferred embodiments. These embodiments, however, are
set forth to illustrate the invention and are not to be construed as a
limitation
thereof, the invention being defined by the claims.
It has been reported and further substantiated, that omeprazole API
having higher percentages of 6-methoxy omeprazole compound relative to the
respective 5(6)-methoxy omeprazole starting material typically provides
greater stability, resulting in better commercial viability. Improved
stability
may also provide an improved safety profile via the minimization of
degradants over time.
Accordingly, one aspect of the present invention provides processes
for increasing, in the solid state, the percentage of a compound of formula
(1a) compared to the percentage of such compound in co-crystallized (1a)
and (1b) starting material (also known as omeprazole active pharmaceutical
ingredient or "API"; and also referred to herein as 5(6)-methoxy-2-[[(4-
methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-benzimidazole, or 5(6)-
methoxy omeprazole or pharmaceutically acceptable salts, hydrates, or
combinations thereof). As used herein, the compound represented by formula
(1a) is also referred to as 6-methoxy omeprazole and the compound
represented by formula (1 b) is also referred to as 5-methoxy omeprazole.
As such, the starting material for the processes of the present invention
is 5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-
benzimidazole, or pharmaceutically acceptable salts, hydrates, or
combinations thereof. 5(6) methoxy omeprazole is prepared via various
known methods including, for example, the methods described in PCT
publication WO 01/14367 and U.S. Pat. No. 4,255,431.
In one embodiment, an amount of 5(6)-methoxy omeprazole is placed
in a suitable container or, preferably, a Buchner funnel, to which is added an
aliquot of short carbon chain (C~- C4) alcohol solvent including, for example,
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methanol, ethanol, and isopropyl alcohol, or a furan-based solvent such as,
for example tetrahydrofuran ("THF"). THF has solvent properties similar to
such short carbon chain alcohol solvents. Sufficient solvent is added to
substantially cover and wet the starting material with gentle and thorough
stirring. The solvent is then removed via methods known in the art, preferably
under vacuum. As used herein, this process is referred to as "rinsing" the
5(6)-methoxy omeprazole API.
The amount of time required for such rinsing will typically be
proportionate to the size of the starting material sample. In addition, the
length of time the wetted material is stirred, as well as the percentage of 5-
methoxy omeprazole in the starting material, can affect the final yield with
longer wetting/stirring times providing potentially lower yields. As such, it
may
be better to minimize such wetting/stirring time, vacuum off the solvent, then
re-rinse the starting material one or more times using the same procedure
until the desired ratio of 6-methoxy omeprazole to 5-methoxy omeprazole is
obtained.
Typically, this rinsing process is carried out at ambient temperature.
Unexpectedly, it was discovered that of the organic solvents examined,
only THF and the short carbon chain alcohol solvents used in the processes
of the present invention were capable of substantially selectively
solubilizing
the 5-methoxy omeprazole in the starting material, leaving a higher
percentage of 6-methoxy omeprazole in the resulting product. Other solvents
tested included, for example, ethyl acetate, isopropyl ether, acetone,
acetonitrile, and water. Furthermore, it was discovered that the effectiveness
of the rinsing process was directly related to the length of the carbon chain
of
such solvent, with the shorter chain alcohol solvents being preferred and
methanol being especially preferred.
Accordingly, the rinsing portion of the instant process can last from
about 5 seconds to about 30 seconds and more typically from about 10
seconds to about 20 seconds for small, test batches, and considerably longer
as batch size increases.
The second step of the present process is drying the product from the
rinse step. Generally, drying can be accomplished by a multitude of methods
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known to the ordinarily skilled artisan provided, if heat is used, the amount
of
heat used is insufficient to degrade or modify the product from the first
step.
Typically, the product is placed in an appropriate, inert vessel, which is
placed in a vacuum oven. Preferably, the oven is set at about Omm Hg and
ambient temperature (about 25°C) until the produpt is dry, although
other
conditions may possibly be employed. For small test samples, product is
dried for about 24 hours, with drying time being increased for larger amounts
of such product.
Preferably, the processes of the present invention provide 5(6)-
methoxy omeprazole (or 6-methoxy omeprazole essentially devoid of 5-
methoxy omeprazole) having a 5-methoxy percentage not greater than about
ten percent of the sum of the total percentage of 5-methoxy omeprazole and
6-methoxy omeprazole. However, incremental reduction in the amount of 5-
methoxy omeprazole compared to the respective starting material typically
can provide improved stability attributes. As such, relative stability of the
final
product of the present processes increases as the percent of 5-methoxy
omeprazole decreases, for example, from about 30% to about 25% to about
20% to about 15% to about 10% to about 5% to about 0%. Typically, the
processes of the present invention are most effective at reducing the 5-
methoxy omeprazole percentage to a range from about 6% to about 9%.
Thus, processes of the present invention are most effective for reducing the
level of 5-methoxy omeprazole in an amount of 5(6)-methoxy omeprazole
when the percentage of such 5-methoxy omeprazole in the starting material is
greater than about nine percent.
The measurement of the ratio of 5-methoxy omeprazole to 6-methoxy
omeprazole in a given sample is best accomplished using Fourier Transform
(FT) Raman Spectroscopy with methods as described in PCT publications
WO 01/13919 and WO 01/14367. Such FT Raman methods can be
abbreviated for in-process testing by reducing the number of replicates and
scans per sample, recognizing that the optimal resolution set forth in the
preferred embodiments of such PCT publications will not be obtained. Thus,
abbreviated methods should only be used as estimates during process
development or for in-process testing when optimal resolution is not required.
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Another aspect of the present invention provides for 5(6)-methoxy
omeprazole, or pharmaceutically acceptable salts, hydrates, or combinations
thereof, when prepared by the process of the present invention. Preferably,
such compounds comprise not more than about 9% of 5-methoxy
omeprazole.
The present invention further provides pharmaceutical formulations,
preferably in unit dosage form, comprising at least one compound prepared
by the processes of the present invention, and at least one pharmaceutically
acceptable carrier, diluent, excipient or combination thereof. Preferably,
such
at least one compound is pressed into tablets or encapsulated for oral
administration. It is especially preferred to enterically coat such oral
dosage
forms. Methods for the preparation of oral dosage forms and preferred
dosage strengths are as set forth, for example, in PCT publication WO
01 /14367.
In addition, compounds of the present invention, preferably formulated
into the above-referenced oral dosage forms, are effective for inhibiting
gastric
acid secretion in mammals and, thus are, beneficial for treating, preventing,
or
inhibiting disease states related to the secretion of gastric acids.
Accordingly,
the present invention provides a method of inhibiting gastric acid secretion
in
mammals, preferably humans, comprising administering to a mammal in need
of treatment a therapeutically effective amount of a pharmaceutical
formulation of the present invention.
The following examples are intended to illustrate the present invention
and are not to be construed as limiting the scope of the present invention. As
used herein, the phrase "5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2
pyridinyl)methyl]sulfinyl]-1H-benzimidazole,or its pharmaceutically acceptable
salts, hydrates, or combinations thereof' refers to co-crystallized 5-methoxy-
2-
[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-benzimidazole,or
its
pharmaceutically acceptable salts, hydrates, or combinations thereof, and 6-
methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-
benzimidazole, and its pharmaceutically acceptable salts, hydrates, or
combinations thereof, respectively.
-6-
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Example 1
Preparation of 5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
pyridinyl)methyl]sulfinyl]-1H-benzimidazole having an increased amount
of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-
1 H-benzimidazole
To a 50mL ceramic Buchner funnel was added a sample of about 1.8g
of 5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-
benzimidazole having about 33% 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
pyridinyl)methyl]sulfinyl]-1 H-benzimidazole. To the sample was added 20mL
of methanol, and the sample was stirred until the sample was substantially
covered and wetted. The mixture was allowed to sit for about 15 seconds,
and the solvent was removed under vacuum at ambient temperature. To the
resulting product was added an additional aliquot of 10mL of methanol, and
the sample was again stirred for about 15 seconds until the sample was again
substantially covered and wetted. The additional solvent was again removed
under vacuum at ambient temperature. The resulting product was completely
dispensed into a 25mL beaker that was placed in a vacuum oven set at Omm
Hg and about 25°C. The product was dried for 24 hours. Yield of
the title
product was 49%, and the percentage of 6-methoxy-2-[[(4-methoxy-3,5-
dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole was increased from
about 67% to about 91 %.
Example 2
Preparation of 5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
pyridinyl)methyl]sulfinyl]-1H-benzimidazole having an increased amount
of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-
1 H-benzimidazole
The process in Example 1 was used except ethanol was used in lieu of
methanol and the second aliquot of solvent added was 20mL of ethanol.
Yield of the title product was 65%, and the percentage of 6-methoxy-2-[[(4-
_7_
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methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-benzimidazole was
increased from about 67% to about 76%.
Example 3
Preparation of 5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
pyridinyl)methyl]sulfinyl]-1H-benzimidazole having an increased amount
of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-
1 H-benzimidazole
The process in Example 1 was used except isopropyl alcohol was used
in lieu of methanol, the second aliquot of solvent added was 20mL of
isopropyl alcohol, and 2.0g of starting material was used. Yield of the title
product was 85% and the percentage of 6-methoxy-2-[[(4-methoxy-3,5-
dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole was increased from
about 67% to about 69%.
Example 4
Preparation of 5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
pyridinyl)methyl]sulfinyl]-1H-benzimidazole having an increased amount
of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-
1 H-benzimidazole
The process in Example 1 was used except tetrahydrofuran was used in lieu
of methanol and the second aliquot of solvent added was 20mL of
tetrahydrofuran. Yield of the title product was 53% and the percentage of 6-
methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-
benzimidazole was increased from about 67% to about 73%.
_g_
