Note: Descriptions are shown in the official language in which they were submitted.
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DESCRIPTION
SOLVENT-FREE CRYSTAL OF BENZIMIDAZOLE DERIVATIVE
AND ITS USE
This is a divisional application of Canadian
Patent Application No. 2,269,053 filed November 13, 1997.
The subject matter of this divisional application is
directed to a solvent-free and stable crystal of
2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-
yl]methylsulfinyl]benzimidazole. However, it should be
borne in mind that the expression "present invention"
encompasses the subject matter of both this divisional and
the parent applications.
Technical Field
The present invention provides crystals of
benzimidazole derivatives which are of value as a medicine
such as an anti-ulcer agent, and a method for producing the
crystals.
Background art
Benzimidazole derivatives, i.e. 2-(2-
pyridylmethylsulfinyl)benzimidazole derivatives which are of
value as a medicine such as anti-ulcer agent, have been known
in European Patent Application Publication No. 302720
(Japanese Patent Application Laid-open No. 1-131176),
European Patent Application Publication No. 5129 (Japanese
Patent Application Laid-open No. 58-192880), Japanese Patent
Application Laid-open No. 61-22079, Japanese Patent
Application Laid-open No. 64-6270, U.S. Patent No. 4,255,431,
European Patent Application Publication Nos. 45200, 74341,
80602, 174726, 175464, British Patent Application Publication
No. 2134523.
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European Application Publication No. 302720
(Japanese Patent Application Laid-open No. 1-131176)
describes in Example 1 that 2-[[3-methyl-4-(2,2,2-
trifluoroethoxy)pyridin-2-yl]methylsulfinyl]benzimidazole
was obtained as white crystals by subjecting a solution of
2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-
yl]methylthio]benzimidazole (monohydrate) in dichloromethane
to an oxidation reaction with hydrogen peroxide using
vanadium pentoxide as a catalyst, concentrating the reaction
mixture, adding ethanol-water (9:1) to the residue,
recovering the resulting crystals by filtration, rinsing
them, dissolving this crystal crop in ethanol-water (9:1) at
an elevated temperature (65-70°C), filtering the solution
when hot, cooling the filtrate with ice, recovering the
resulting crystals by filtration, rinsing them, and drying
them in vacuo.
Any compound in the 2-(2-pyridylmethylsulfinyl)-
benzimidazole derivatives tends to lose stability and
undergo decomposition when it contains traces of a solvent,
particularly water, in its crystal structure and, therefore,
this residual solvent in the crystal must be reduced to a
minimum.
However, when the production procedure for
2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-
yl]methylsulfinyl]benzimidazole as described in EP-302720 is
followed, water and ethanol can hardly be eliminated from
the product and the resulting crystals inevitably contain
fair amounts of water and ethanol. Thus, the benzimidazole
compound provided by the process described in the above
literature is a solvate containing one molecule each of
water and ethanol and it is very difficult to desolvate the
compound by vacuum drying without detracting from the
stability of the product.
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There is a serious problem with the above
benzimidazole compound in the form of a solvate,
particularly a hydrate, for being heat-labile, it is easily
decomposed in the vacuum drying step, particularly under
heating, thus depressing the purity of the product
benzimidazole compound. Therefore, there has been an
outstanding demand for a supply of solvent-free crystals of
the benzimidazole compound and development of a high-
production-scale, highly workable, and effective desolvation
technology for providing such crystals.
Disclosure of Invention
In view of the above state of the art, the
inventors of the present invention did an intensive
investigation directed to improvements in the above-mentioned
aspects for the purpose of providing substantially solvent-
free crystals of the benzimidazole compound which is of value
as a medicine, for example an anti-ulcer agent and so forth,
and a high-production-scale, highly workable, and effective
desolvation technology for providing such crystals. As a
consequence, they discovered to everybody's surprise that the
desired desolvation can be easily achieved by oxidizing the
2-(2-pyridylmethylthio)benzimidazole compound to the
corresponding 2-(2-pyridylmethylsulfinyl)benzimidazole
compound, recrystallizing the latter from aqueous alcohol to
give water- and alcohol-solvate crystals of the
2-(2-pyridylmethylsulfinyl)benzimidazole compound, and
suspending and stirring the crystals in warm water, which
procedure unexpectedly causes a transformation of the solvate
crystals into substantially solvent-free crystals, followed
by drying under reduced pressure. The inventors further
discovered to their own surprise that the substantially
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solvent-free crystals of the benzimidazole compound thus
obtained are remarkably stable as compared with the
conventional benzimidazole solvate, and completely free from
decomposition in the course of vacuum drying.
The present invention provides:
(1) A solvent-free crystal of the compound
2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-
yl]methylsulfinyl]benzimidazole, which has a water content
of not higher than 500 ppm as measured by a Karl-Fisher
method and an ethanol content of not higher than 200 ppm as
measured by gas chromatography and which is a white needle
having a melting point of 177-178°C at which the crystal
decomposes.
(2) A medicine for use as an anti-ulcer agent,
which comprises: the solvent-free crystal as defined above,
and a pharmaceutically acceptable carrier or diluent.
(3) A method for preparing a freeze-dried product
for injection, which comprises: freeze-drying a sterilized
aqueous solution prepared from the solvent-free crystal as
defined above, sodium hydroxide, mannitol and meglumine.
(4) A use of the solvent-free crystal as defined
above for manufacturing a medicine for use as an anti-ulcer
agent.
(5) A use of the solvent-free crystal as defined
above for treating or preventing ulcer.
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The compound 2-[[3-methyl-4-(2,2,2-
trifluoroethoxy)pyridin-2-yl]methylsulfinyl]benzimidazole,
falls generally in the scope of benzimidazole derivatives of
the formula:
5 R3
/ Rz \ R4
N
~ I ~s-~HZ I , ( I )
R1 O N
wherein the ring A may optionally be substituted, R1
represents hydrogen or an N-protecting group, each of R2, R3
and R4 is (1) a hydrogen atom, (2) an alkyl group which may
optionally be substituted with halogen atoms) or (3) an
alkoxy group which may optionally be substituted with
halogen atoms) or alkoxy.
Best Mode for Carrvina out the Invention
The various definitions relevant to the above
chemical formula and the present invention in general and
preferred examples of species meeting the definitions are
now presented.
Referring to formula (I), the optional substituent
on ring A includes but is not limited to halogen, alkyl,
cyano, carboxy, alkoxycarbonyl, carboalkoxyalkyl, carbamoyl,
carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, halogenated
alkyl, halogenated alkoxy, acyl, carbamoyloxy, nitro,
acyloxy, aryl, aryloxy, alkylthio, and alkylsulfinyl.
The halogen mentioned above includes fluorine,
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chlorine, bromine, etc., with fluorine being
particularly preferred.
The alkyl mentioned above is preferably alkyl of 1
to 7 carbon atoms, such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, pentyl, hexyl, and heptyl.
The alkoxycarbonyl mentioned above is preferably
one containing 1 to 4 carbon atoms in the alkoxy
moiety, including methoxycarbonyl (CH300C-) and
ethoxycarbonyl (CZH500C-), among others.
The carboalkoxyalkyl mentioned above is preferably
one containing 1 to 4 carbon atoms in each of its
alkoxy and alkyl moieties, thus including
carbomethoxymethyl (CH300CCHz-), carbomethoxyethyl
( CH300CCZH4- ) , carboethoxymethyl ( CzH500CCHz- ) , _ and
c arboethoxyethyl ( CZH500CC2H4- ) , among others .
The carbamoylalkyl mentioned above is preferably
one containing 1 to 4 carbon atoms in its alkyl moiety,
including carbamoylmethyl (HZNCOCHZ-) and
carbamoylethyl (HZNCOCZH4-), among others.
The alkoxy mentioned above is preferably one
containing 1 to 5 carbon atoms, such as methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and
pentoxy.
The hydroxyalkyl mentioned above is preferably one
containing 1 to 7 carbon atoms in its alkyl moiety,
such as hydroxymethyl, 1-hydroxy-propyl-2, 1-hydroxy-
ethyl-2, and 1-hydroxy-2-methyl-propyl-2, among others.
The halogenated alkyl mentioned above is
preferably one containing 1 to 7 carbon atoms in its
alkyl moiety, including difluoromethyl and
trifluoromethyl, to name but a few preferred examples.
The halogenated alkoxy mentioned above is
preferably one containing 1 to 4 carbon atoms in its
alkoxy moiety, including difluoromethoxy as a typical
preferred example.
The acyl mentioned above is preferably one
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containing 1 to 4 carbon atoms, such as formyl, acetyl,
propionyl, butyryl, and isobutyryl.
The acyloxy mentioned above is preferably one
containing 1 to 4 carbon atoms in its acyl moiety,
including formyloxy, acetyloxy, propionyloxy,
butyryloxy, and isobutyryloxy.
The aryl mentioned above includes but is not
limited to phenyl, tolyl, and naphthyl.
The aryloxy mentioned above includes but is not
limited to phenyloxy, tolyloxy, and naphthyloxy.
The alkylthio mentioned above is preferably one
containing 1 to 6 carbon atoms in its alkyl moiety,
including but not limited to methylthio, ethylthio, and
propylthio.
The alkylsulfinyl mentioned above is preferably
one containing 1 to 6 carbon atoms, including but not
limited to methylsulfinyl, ethylsulfinyl, and
propylsulfinyl.
Referring, further, to formula (1), ring A is
preferably either unsubstituted or substituted by,
among the above-mentioned substituent groups, halogen,
alkyl, alkoxy, halogenoalkyl or halogenoalkoxy (more
preferably such species as methoxy, trifluoromethyl or
difluoromethoxy). Particularly preferred are cases in
which such a substituent is present in the 4- or 5-
position of the benzimidazole ring.
R1 in formula (1) represents hydrogen atom or an
N-protecting group.
The N-protecting group for R1 includes but is not
limited to alkyl, acyl, carboalkoxy, carbamoyl,
alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl,
alkoxycarbonylmethyl and alkylsulfonyl.
The alkyl mentioned just above is preferably one
containing 1 to 5 carbon atoms, including methyl,
ethyl, propyl, isopropyl, butyl, isobutyl and pentyl.
The acyl includes the same species as mentioned
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for the substituent on ring A.
The carboalkoxy includes the same species as
mentioned for the substituent on ring A.
The alkylcarbamoyl, which can be represented by
the formula: alkyl-NH-CO-, is preferably one containing
1 to 4 carbon atoms in its alkyl moiety, such as
methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,
isopropylcarbamoyl, etc.
The dialkylcarbamoyl, which can be represented by
the formula: (alkyl)ZN-CO-, is preferably one
containing 1 to 4 carbon atoms in each of its alkyl
moieties, including dimethylcarbamoyl,
diethylcarbamoyl, and N-methyl-N-ethylcarbamoyl, among
others.
The alkylcarbonylmethyl, which can be represented
by the formula: alkyl-CO-CHZ-, is preferably a group in
which said alkyl contains 1 to 4 carbon atoms, such as
acetylmethyl and propionylmethyl, among others.
The alkoxycarbonylmethyl, which can be represented
by the formula: alkyl-OCO-CHZ-, is preferably a group
in which said alkyl contains 1 to 4 carbon atoms, thus
including methoxycarbonylmethyl, ethoxycarbonylmethyl,
and propoxycarbonylmethyl, among others.
The alkylsulfonyl, which can be represented by the
formula: alkyl-SOZ-, is preferably one containing 1 to
4 carbon atoms in its alkyl moiety, including
methylsulfonyl, ethylsulfonyl, propylsulfonyl, and
isopropylsulfonyl, etc.
In formula (I), R1 preferably represents hydrogen.
In formula ( I ) , R2, R3, and R' are the same or
different and each represents hydrogen, alkyl
optionally substituted by halogen, or alkoxy optionally
substituted by halogen, or alkoxy.
The alkyl of said alkyl optionally substituted by
halogen as mentioned for RZ, R3, and R4 is preferably an
alkyl group of 1 to 4 carbon atoms, such as methyl,
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ethyl, propyl, isopropyl, butyl, and isobutyl. The
halogen of said alkyl optionally substituted by halogen
includes fluorine, chlorine, bromine, etc. and is
preferably fluorine.
The alkyl substituted by halogen is preferably
fluorine-substituted alkyl such as trifluoromethyl,
2,2,2-trifluoroethyl, 2,2,3,3-tetrafluoropropyl,
2,2,3,3,3-pentafluoropropyl, 1-(trifluoromethyl)-2,2,2-
trifluoroethyl, 2,2,3,3,4,4,4-heptafluorobutyl, etc.,
and as examples of chlorine- or bromine-substituted
alkyl, too, the species available upon replacement of
fluorine with chlorine or bromine in the species
mentioned above for fluorine-substituted alkyl can be
mentioned.
The alkyl optionally substituted by halogen as
mentioned for RZ, R3, and R4 is preferably an
unsubstituted alkyl group of 1 to 4 carbon atoms, with
methyl being particularly preferred.
The alkoxy of said alkoxy optionally substituted
by halogen or alkoxy as mentioned for RZ, R', and R' is
alkoxy containing 1 to 8 carbon atoms, preferably 1 to
4 carbon atoms, including methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, pentoxy, hexyloxy,
heptyloxy and octyloxy. The halogen of said alkoxy
optionally substituted by halogen includes fluorine,
chlorine, bromine, etc., with fluorine being
particularly preferred.
The alkoxy substituted by halogen is alkoxy of 1
to 8 carbon atoms, preferably 1 to 4 carbon atoms,
which are substituted by 1 to 8 (preferably 3 or 4)
fluorine atoms, such as 2,2,2-trifluoroethoxy,
2,2,3,3,3-pentafluoropropoxy, 1-(trifluoromethyl)-
2,2,2-trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy,
2,2,3,3,4,4,4-heptafluorobutoxy, 2,2,3,3,4,4,5,5-
octafluoropentoxy, etc. Particular preferred is 2,2,2-
trifluoroethoxy or 2,2,3,3-tetrafluoropropoxy. With
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regard to chlorine- or bromine-substituted alkoxy, too,
the species available upon replacement of fluorine with
chlorine or bromine in the species mentioned above for
fluorine-substituted alkoxy can be mentioned.
The alkoxy-substituted alkoxy includes C1_4 alkoxy-
C1_e alkoxy (particularly C1_4 alkoxy-C1_4 alkoxy) such as
3-methoxypropoxy, 2-methoxyethoxy, 3-ethoxypropoxy, 2-
ethoxyethoxy, etc., with 3-methoxypropoxy being
particularly preferred.
In formula (I), preferably Rz and R4 are the same
or different and each represents hydrogen, methyl, or
methoxy and R3 represents alkoxy containing 1 to 5
carbon atoms, preferably 2 to 4 carbon atoms, which has
been substituted by 3 to 4 halogen atoms, or,methoxy.
Referring, further, to the compound of formula
(I), the preferred specific compounds are such that
ring A is unsubstituted or the 4- or 5-position of the
benzimidazole ring is substituted by methoxy,
difluoromethoxy, or trifluoromethyl, R1 is hydrogen, RZ
is methyl or methoxy, R3 is CZ_4 alkoxy substituted by 3
or 4 fluorine atoms, methoxy, or 3-methoxypropoxy, and
R4 is hydrogen or methyl.
The salt of the compound of formula (I) is
preferably a pharmaceutically acceptable salt, which
includes salts with inorganic bases, salts with organic
bases, and salts with basic amino acids. Preferred
salts with inorganic bases are salts with alkali metals
such as sodium and potassium, salts with alkaline earth
metals such as calcium and magnesium, and ammonium
salts. Preferred salts with organic bases are salts
with trimethylamine, triethylamine, pyridine, picoline,
ethanolamine, diethanolamine, triethanolamine,
dicyclohexylamine, and N,N'-dibenzylethylenediamine.
Preferred salts with basic amino acids are salts with
arginine, lysine, ornithine, etc. The preferred salt
of the compound of formula (I) according to the present
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invention includes salts with alkali metal salts and
alkaline earth metal salts. The sodium salt is
particularly preferred.
Specifically, the compound of formula (I) includes
but is not limited to .
2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-
yl]methylsulfinyl]benzimidazole,
2-[[3,5-dimethyl-4-methoxypyridin-2-yl]methylsulfinyl]-
5-methoxybenzimidazole,
2-[[4-(3-methoxypropoxy)-3-methylpyridin-2-
yl]methylsulfinyl]benzimidazole sodium salt, and
5-difluoromethoxy-2-[(3,4-dimethoxypyridin-2-
yl)methylsulfinyl]benzimidazole.
Particularly preferred is
2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-
yl]methylsulfinyl]benzimidazole.
The benzimidazole compound of the formula (I) can
be produced by manners described in the above-mentioned
literatures, i.e. European Patent Application
Publication No. 302720 (Japanese Patent Application
Laid-open No. 1-131176), European Patent Application
Publication No. 5129 (Japanese Patent Application Laid-
open No. 58-192880), Japanese Patent Application Laid-
open No. 61-22079, Japanese Patent Application Laid-
open No. 64-6270, U.S. Patent No. 4,255,431, European
Patent Application Publication Nos. 45200, 74341,
80602, 174726, 175464, British Patent Application
Publication No. 2134523, or analogous methods thereto.
The benzimidazole compound has an asynmmetric
center at the sulfur atom. Namely it can be present as
0 O
two types of isomers, ,
-g- or -s-
The above benzimidazole compound can be obtained
as crystals of its water- and alcohol-solvate by
recrystallization from the corresponding aqueous
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alcohol in accordance with, for example, the
purification procedure disclosed in European Patent
Application Publication No. 302720 (Japanese Patent
Application Laid-open No. 1-131176) or any procedure
analogous thereto. The alcohol mentioned above
includes C1_6 alcohols (e. g. methanol, ethanol,
isopropyl alcohol, etc.), ethanol being particularly
preferred. The. aqueous alcohol may for example be one
containing about 2 to about 30 parts by volume of an
alcohol (especially ethanol), preferably about 5 to
about 15 parts by volume of an alcohol (especially
ethanol) for each part by volume of water. To be
specific, a mixture consisting of an alcohol
(especially ethanol) and water in a ratio of about 9:1,
v/v can be used.
The crystals of such a solvate of the compound of
formula (I) or its salt can be easily confirmed by the
known analytical techniques such as powder X-ray
diffraction analysis.
In accordance with the process of the invention,
the solvate crystals mentioned above are suspended left
standing or stirred in water. As the result of this
procedure, the solvate crystals are desolvated due to a
morphological transformation. While the conditions of
this leaving standing or suspending procedure, such as
the quantity and temperature of water used and
agitation time, can be selected judiciously, the
following conditions may be typically mentioned. As to
the quantity of water, water can be used in a
proportion of about 2 to about 20 parts by volume,
preferably about 5 to about 10 parts by volume,
relative to the solvate crystals. The water
temperature may range from room temperature (ca 15 to
ca 30°C) to about 90°C, preferably from about 30° to
about 50°C. The agitation time may range from about
0.5 tv about S hours, preferably from about 1 to about
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2 hours.
The solvent-free crystals available upon said
morphological transformation of solvate crystals are
then collected by a per se known procedure, such as
filtration, and dried, if necessary, by a ger se known
procedure, whereby the objective substantially solvent-
free crystals of the particular benzimidazole compound
are obtained. The drying procedure referred to above
is preferably drying under reduced pressure or in
vacuo, where the drying temperature may for example be
about 20° to about 60°C, preferably about 30° to about
50°C, and the drying time may be about 5 to about 48
hours, preferably about 10 to about 20 hours.
It is understood that the water content of the
substantially solvent-free crystals according to the
present invention is not higher than about 500 ppm,
preferably not higher than about 300 ppm, and, for
still better results, not higher than about 200 ppm,
and the alcohol (e. g. ethanol) content is not higher
than about 200 ppm, preferably not higher about 100
ppm, and, for still better results, not higher about 80
ppm. The water content and alcohol content of the
crystals depend on the conditions used in said
suspending procedure and drying procedure (particularly
the treating times) and, therefore, if the degree of
desolvation is found to be insufficient, the duration
of said suspending procedure and/or of said drying
procedure can be extended so as to achieve more
thorough desolvation.
The substantially solvent-free crystals of the
compound of formula (1) or its salt as produced in the
above manner can be easily verified by a known
technique such as powder X-ray diffraction analysis and
the water content and alcohol (ethanol) content thereof
can be determined by per se known analytical
procedures. Specifically, Karl-Fischer (KF) method may
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be mentioned for water content, and gas chromatography for
alcohol content.
The. substantially solvent-free crystals obtained
above can be processed together with pharmaceutically
acceptable carriers or diluents as well as optional other
known additives into the desired dosage forms by the routine
pharmaceutical procedures and be put to use as medicines,
for example, anti-ulcer agents which are used for treating
or preventing ulcer. For pharmaceutical manufacture, the
procedures described in the Reference Examples, for instance,
can be employed.
The present invention is explained in detail in
the following working examples, but is not limited to that
illustrated in the Examples: In the following, water
content was measured by the Karl-Fisher method, and -alcohol
content was measured by gas chromatography.
Reference Example 1.
Production of 2,3-dimethylpyridine N-oxide:
One hundred g. of 2,3-lutidine was dissolved into
200 ml. of glacial acetic acid, followed by dropwise
addition of 120 g. of 35o aqueous hydrogen peroxide solution
at about 40°C. The mixture was allowed to react at 105°C
for about 2 hours. After completion of the reaction, the
mixture was cooled down to about 50°C, followed by addition
of 5.0 g. of p-formaldehyde. The resultant mixture was
heated to 105°C to cause the reaction to take place for
about 10 minutes. The resultant mixture was cooled down to
about 40°C, followed by addition of 150 g. of 98% sulfuric
acid. The resultant mixture was subjected to distillation
under reduced pressure to evaporate the glacial acetic acid
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14a
off to give 2,3-dimethylpyridine N-oxide as a sulfuric acid
solution.
Reference Example 2.
Production of 2,3-dimethyl-4-nitropyridine N-oxide:
To the whole sulfuric acid solution of 2,3-
dimethylpyridine N-oxide as obtained in Reference
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Example 1, were dropwisely added 130 g. of 98~ sulfuric
acid and 130 g. of 98~ nitric acid at about 80°C for 4
hours. The resultant mixture was allowed to react at
the same temperature for 5 hours. The resultant
5 mixture was cooled down to about 40°C and poured into 1
L of cold water at below 5°C, followed by dropwise
addition of 0.6 L of 30o sodium hydroxide solution at
below 30°C. The resultant mixture was extracted three
times, each with 1 L. methylenechloride. The obtained
10 methylenechloride layers were pooled and concentrated
under reduced pressure to give 2,3-dimethyl-4-
nitropyridine N-oxide as a pale yellow crystalline
residue. Yield:I41 g. (90o based on 2,3-lutidine)
15 Reference Example 3.
Production of 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)-
pyridine N-oxide
To all the amount of 2,3-dimethyl-4-nitropyridine
N-oxide which was obtained in Reference Example 2 was
added 0.4 L. of 70~ aqueous acetonitril solution to
make a solution, followed by the addition of 280 g. of
trifluoroethanol, 9 g. of a 50~ aqueous
benzyltributylammonium chloride solution and 225 g, of
potassium carbonate. The mixture was allowed to react
at a refluxing temperature for about 25 hours. The
resultant mixture was cooled down to about 60°C,
followed by addition of 0.2 L. of water. The resultant
mixture was stirred and left standing. The resultant
organic layer was taken by decantation and concentrated
under reduced pressure. 0.5 L. of water was added to
the concentrate to make it into a solution, followed by
three extractions with 0.5 L. methylenechloride. The
methylenechloride layer was pooled and concentrated to
give 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)pyridine N-
oxide as pale yellow crystalline residue. Yield:144
g.(70~ based on 2,3-lutidine).
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Reference Example 4.
Production of 2-hydroxymethyl-3-methyl-4-(2,2,2-
trifluoroethoxy)pyridine(HYD)
Into 0.3 L. of glacial acetic acid was dissolved
all the amount of 2,3-dimethyl-4-(2,2,2-
trifluoroethoxy)pyridine N-oxide which was obtained in
Reference Example 3, followed by addition of 0.3 L. of
acetic anhydride. The resultant mixture was allowed to
react at about 115°C for about 6 hours. After
completion of the reaction, the resultant mixture was
cooled down to about 60°C, followed by addition of 0.3
L. of water. The resultant mixture was concentrated
under reduced pressure, followed by addition of 25 ml.
of methanol and 0.2 L. of water. To the resultant
mixture was added dropwise 0.2 L. of 30~ aqueous sodium
hydroxide solution at about 30°C to adjust its pH at
13, followed by stirring at about 35°C for 12 hours.
The resultant mixture was left standing, and the
supernatant was taken off. To the resultant residue
was added 100 ml. of methanol, followed by stirring at
about 45°C for about 30 minutes to solubilize the
precipitated crystals. While the resultant solution
was kept at about 20°C, 0.5 L. of water was added in
order to precipitate crystals. The resultant mixture
was cooled down to about 5°C and kept standing. The
precipitated crystals were collected by filtration,
washed with water and dissolved into a mixed solution
of 75 ml. of 35~ hydrochloric acid, 0.4 L. of water and
2.5 g. of diatomaceous earth. The resultant solution
was adjusted to a pH of about 3 with a 30~ aqueous
sodium hydroxide solution, and the insolubles were
filtered off. The filtrate was washed three times,
each with 200 ml. of methylenechloride. After addition
of 5.0 g. of activated charcoal, the mixture was
stirred at about 40°C for about 12 hours. The
activated charcoal was filtered off, and 80 ml. of
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ethanol was added to the filtrate. The resultant
mixture was neutralized to pH 7 with 30~ aqueous sodium
hydroxide solution to precipitate crystals. The
mixture was cooled down to below 5°C, and the
precipitated crystals were collected by filtration and
washed with water. The obtained crystals were dried at
about 37°C under reduced pressure for about 24 hours to
give 2-hydroxymethyl-3-methyl-4-(2,2,2-
trifluoroethoxy)pyridine as white crystals. Yield:95
g.(46~ based on 2,3-lutidine).
Reference Example 5.
Production of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-
2-pyridyl]-methyl]thio]benzimidazole monohydrate
49.9 g. of 2-hydroxymethyl-3-methyl-4-(2,2,2-
trifluoroethoxy)pyridine was dissolved into 0.4 L. of
methylene-chloride, followed by dropwise addition of 24
ml. of thionylchloride for about 30 minutes. The
mixture was allowed to react at more than about 30°C
for about 1 hour. After completion of the reaction,
0.1 L. of water was added, and the methylenechloride
was evaporated off under reduced pressure. The residue
was dissolved into 0.4 L, of methanol, followed by
addition of 34.2 g, of 2-benzimidazolethiol. To the
mixture was added dropwise 60 ml. of a 30~ aqueous
sodium hydroxide solution at about 25°C for about 1
hour. The mixture was allowed to react at room
temperature for about 0.5 hour. To the resultant
mixture was added 0.3 L. of water, followed by stirring
at below 10°C for about 30 minutes. The resultant
mixture was adjusted to a pH of about 9 with 35~
hydrochloric acid in order to precipitate crystals.
The resultant crystals were collected by filtration and
washed with, in turn, 0.1 L. of 50~ methanol and 0.2 L.
of water. The obtained crystals were dried with hot
air at below 50°C to give 2-[[[3-methyl-4-(2,2,2-
CA 02539815 1997-11-13
18
trifluoroethoxy)-2-pyridyl]-methyl]thio]benzimidazole
as white crystals.Yie1d:81.0 g.(96.7~ based on HYD).
Reference Example 6.
Production of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-
pyridin-2-yl]methylsulfinyl]benzimidazole monohydrate,
monoethanol solvate.
Forty mg. of acetylacetone vanadium(IV) was
dissolved in 150 ml. of ethanol, followed by addition
of 20.0 g. of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-
pyridin-2-yl]methylthio]benzimidazole monohydride and
further dropwise addition of 6.14 g. of 35~ aqueous
hydrogen peroxide solution at 20 to 25°C. The mixture
was allowed to react at the same tempertaure for about
5 hours. After completion of the reaction, aqueous
solution of sodium thiosulfate(2.7 g./16 ml.) was
added, followed by vigorous stirring for about 10
minutes. The precipitated crystals were collected by
filtration and washed with ice-cooled ethanol-water
mixture (8:2). To the resultant crystals was added 90
ml. of ethanol-water mixture(9:1), and the mixture was
heated to 60 to 70°C under stirring to dissolve the
crystals. The insolubles were filtered off while the
mixture was hot. The filtrate was ice-cooled to
precipitate crystals. The precipitated crystals were
collected by filtration, washed with ice-cooled
ethanol-water(8:2) and dried under reduced pressure at
room temperature to give 2-[[3-methyl-4-(2,2,2-
trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-
benzimidazole monohydrate, monoethanolate solvate as
white needles. Yield:21.2 g.(91.0~).
Example 1
Production of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-
. pyridin-2-yl]methylsulfinyl]benzimidazole substantially
free from solvent(hereinafter sometimes abbreviated to
CA 02539815 1997-11-13
19
as Compound A).
To 75 ml. of ethanol-water mixture(9:1) was added
701. of 25~ aqueous ammonia solution. While the
solution was heated to about 60°C, 13.0 g. of 2-[[3-
methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-
yl)methylsulfinyl)benzimidazole monohydrate,
monoethanolate solvate which was obtained in Reference
Example 6, was added to the solution to be dissolved.
The insolubles were removed by filtration off while the
solution was hot. The filtrate was cooled with ice to
precipitate.crystals. The precipited crystals were
collected by filtration to give wet crystals of 2-[[3-
methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-
yl)methylsulfinyl] benzimidazole monohydrate,
monoethanolate solvate. Thus obtained wet crystals
were suspended in 53 ml of water and the suspension was
stirred for 1 hour while keeping the temperature at
30°C. The emerged crystals were recovered by
filtration, washed with 10 ml of water, and then were
dried at 40°C in vacuum for 10 hours to give 2-[[3-
methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-
methylsulfinyl)benzimidazole as white needles.
Yield:9.72 g.(87.7~). m. p. 177-178(decomp.). Water
content:0.01~. Ethanol content:63 ppm.
Comparative Example 1.
Production of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-
pyridin-2-yl)methylsulfiny1] benzimidazole by a known
method.
To 58 ml. of ethanol-water mixture(9:1) was added
541, of 25~ aqueous ammonia solution. The mixture was
heated to about 60°C, followed by addition of 10.0 g.
of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-
yl]methylsulfinyl]benzimidazole monohydrate,
monoethanolate solvate, which was dissolved.
Insolubles were removed off by filtration while the
CA 02539815 1997-11-13
mixture was hot. The filtrate was cooled with ice to
precipitate crystals. The precipitated crystals were
collected by filtration to give 2-([3-methyl-4-(2,2,2-
trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-
5 benzimidazole monohydrate, monoethanolate solvate as
wet crystals. The crystals were dried at 40°C for 20
hours in vacuum to give 2-[(3-methyl-4-(2,2,2-
trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-
benzimidazole as white needles. Yield:7.58 g.(89.0 ~)
10 m. p. 177-178°C(decomp.)
Water content:0.12
Ethanol content:360ppm
Reference Example 7.
15 Preparation (1) of an injection containing Compound A
An aqueous solution of sodium hydroxide was added
to 15g, of Compound A, and the mixture was prepared
into a solution. To the solution were added 30g. of
mannitol and 5 g. of meglumine, and the mixture was
20 prepared into a solution of 1000m1. having pH 11.2.
The solution was sterilized by filtration by a
conventional method. The resultant solution was sealed
into ampuls each in an amount of 1 ml. and freeze-dried
by a conventional method to prepare freeze-dried
product containing Compound A.
In the meantime, 750 g. of macrogol 400 is diluted
with water for injection, followed by addition of
hydrochloric acid to prepare 2500 ml. of an aqueous
solution with pH 4.5. The resultant solution was
sterilized by filtration by a conventional method and
filled into ampuls in an each amount of 2.5 ml. The
ampuls were sealed and sterilized with high pressure
steam. For administration, an injection is prepared by
adding 2.5 ml. of the macrogol solution to the freeze-
dried product containing Compound A and dissolving it.
CA 02539815 1997-11-13
21
Reference Example 8.
Preparation(2) of an injection containing Compound A.
Three hundred grams of Compound A, 600 g. of .
mannitol, 100 g. of meglumine and an aqueous solution
of sodium hydroxide were mixed by homomixer and
solubilized to prepare 20 L. of a solution containing
Compound A having pH 11.2. The resultant solution was
sterilized by filtration by a conventional method,
filled into vials each in an amount of 2 ml. and
freeze-dried in a conventional method to prepare
freeze-dried product containing Compound A.
In the meantime, 15 kg. of macrogol 400 was
diluted with water for injection, followed by addition
of hydrochloric acid to prepare 50 L, of an aqueous
I5 solution of pH 4.5. The resultant solution was
sterilized by filtration in a conventional manner and
filled into ampuls each in an amount of 5 ml. The
ampuls were sealed and sterilized with high pressure
steam. Upon use, 5 ml. of the latter solution is added
to the freeze-dried product containing Compound A, and
the resultant mixture is prepared into a solution and
used.
Reference Example 9.
Production(3) of an injection containing Compound A.
150 g. of Compound A was mixed with 300 g. of
mannitol, followed by addition of an aqueous solution
of sodium hydroxide and dissolved it. To the resultant
solution was added 50 g. of meglumine, which was
dissolved to prepare 10 L. of a solution of pH 11.3
containing Compound A. The resultant solution was
sterilized by filtration by a conventional method,
filled into vials in an each amount of 4 ml. and
freeze-dried by a conventional method to prepare
freeze-dried product containing Compound A.
In the meantime, 7.5 kg. of macrogol 400 was
CA 02539815 1997-11-13
24205-1189
22
diluted with water for injection, followed by addition
of hydrochloric acid to prepare 25 L. of an aqueous
solution of pH 4.5. The resultant solution was
sterilized by filtration by a conventional method,
filled into ampuls each in an amount of 10 ml., sealed
and sterilized with high pressure steam. Upon
administration, injection is prepared by adding 10 ml.
of the macrogol solution to the freeze-dried product
and dissolving it.
Reference Example 10.
Preparation of capsules containing-Compound A.
Capsules of the formula as indicated in the Table
3 were prepared by the following method with the feed
amount (1) or (2) as shown in the Table 1 or Table 2,
respectively.
(1) Compound~A and ingredients from the item (3)
to (6) were well mixed to prepare powders.
(2) Nonpareils Were put into a centrifugally fluidized
coating granulator(made by Freunt Industry Co. Ltd.,
CF-1000 in the case of the feed from the Table 2 and
CF-1300 in the case of the feed from the Table 3) and
coated with the above prepared dusting powder under
spraying with an aqueous solution~(7) of
hydroxypropylcellulose dissolved in purified water.
The resultant spherical granules were dried in
vacuum at 40°C for 16 to 18 hours and sieved (500 ~m
and 1190 Vim) to give granules of an active ingredient.
Two batches of the granules were put into a
Flowcoater*(made by Powrex Corp.) and coated with a
suspension of (8)methacrylic acid copolymer LD-
(12)polysorbate BO in purified water. To the coated
granules was added (13)talc, and the mixture was
sieved(600 ~m and 1420 Vim) and dried in vacuum at 42°C
for 16 to 18 hours to give enteric granules.
(14)Talc and (15)light anydride silicic acid were
*Trade-mark
CA 02539815 1997-11-13
23
added to 1 batch of the enteric granules(in the
processed amount in the Table 2, mixing is possible up
to 5 batches, and in the processed amount in Table 3,
mixing is possible up to 3 batches). The mixture was
prepared into mixed granules by a tumbler mixer(made by
Showa Chemical Machinery Co.).
The mixed granules were filled by a capsule
filling machine(MG2 Co. or Zanasi Co.) into (16)
gelatin capsules No. 1 in an each amount of 30 mg. and
into (17)gelatin capsules No. 3 each in an amount of 15
mg.
CA 02539815 1997-11-13
24205-1189
24
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CA 02539815 1997-11-13
Industrial Applicability
The present invention provides a method for
producing crystals of the benzimidazole compounds
substantially solvent-free and of uniform purity, which
5 are of value for medicines such as, for example, anti-
ulcer agents, and which is an industrially advantageous
method for a large scale production.
The substantially solvent-free crystals which can
be produced by the present method are more stable than
IO those hitherto known crystals of solvate, and the
degree of decomposition of the compound is extremely
low in the course of production step and storage.
