JP2002338567A - Method for producing crystal - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing an optically active sulfoxide derivative in extremely high excess rate of an enantiomer, high yield and industrial large scale by an easy method. SOLUTION: This method for producing (S)-2-[[[3-methyl-4-(2,2,2,- trifluoroethoxy)-2-pyridyl]methyl]sulfonyl]benzimidazone.m'H2 O (m' is about 0 to about 0.1) or a salt thereof is characterized in that the (S)-2-[[[3- methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfonyl]benzimidazo le.m'H2 O or the salt thereof is crystallized from an organic solvent solution or suspension obtained by dissolving or suspending (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methyl]sulfonyl]benzimidazole.mH2 O (m is about 0.1 to about 1.0) or the salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active sulfoxide compound having an anti-ulcer action.

[0002]

2. Description of the Related Art (R) -2- having an anti-ulcer effect
[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole [hereinafter sometimes referred to as (R) -isomer] or (S)- 2-[[[[3-methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole [hereinafter (S)
-May be referred to as a body), for example, as described in JP-T-11-508590 (WO 97 /
No. 02261), a preparation enriched in either the (+)-enantiomer or the (-)-enantiomer, that is, one enantiomer-enriched preparation is added to a solvent, and the racemic compound is utilized by utilizing the crystallinity of the racemate. Is selectively precipitated from the solvent and the precipitated racemate is removed by filtration,
A method for optically purifying enantiomerically enriched preparations is described which subsequently removes the solvent to yield a single enantiomer of increased optical purity.

When the (R) -form or (S) -form is produced by asymmetric synthesis, 2-[[[3-methyl-4
-(2,2,2-trifluoroethoxy) -2-pyridyl] methyl] thio] benzimidazole (hereinafter sometimes referred to as a sulfide form) is subjected to asymmetric oxidation to obtain the desired (R)-or ( S)-Obtain the body. On this occasion,
The excess reactant, 2-[[[3-methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfonyl] benzimidazole (hereinafter sometimes referred to as a sulfone form) is produced. Therefore, in the (R) -form or (S) -form obtained by asymmetric synthesis, an unreacted sulfide form and an excess reactant sulfone form are usually present as related substances. Usually, it is difficult to remove the sulfone form present in sulfoxide having an anti-ulcer effect. For example, Japanese Patent Application Laid-Open No. 2000-16992 discloses that when sulfone is formed, the yield of the target sulfoxide decreases, and the physicochemical properties of the two are very similar, so that separation and purification are difficult. It is stated that there is. Similarly, in the case of the (R) -form or the (S) -form, column chromatography or the like was indispensable in order to remove the sulfone form present as an analog. For example, Japanese Patent Application Laid-Open No. 10-504290 (W
O 96/02535) In Example 21, (-)-2
-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] solution containing a large amount of benzimidazole (11% sulfide compound as a related substance, sulfone compound (7% is present) to obtain the desired product, followed by various operations to obtain 99.5% ee of the desired product in 29% yield. In addition, Example 2 of the publication
In (2), (+)-2-[[[3-methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole-rich solution (13% sulfide and 8% sulfone as analogs) to obtain the desired product Chromatography is performed, and after various operations,
The target compound of 99.6% ee was obtained in a yield of 14%. As described above, in the conventional method, an operation such as chromatography which is industrially disadvantageous is required to remove the sulfone form and the like, and the yield of the target product is also low.

[0004]

In the conventional production method, purification by column chromatography or the like is indispensable in order to remove a sulfone compound which is difficult to separate and purify.
There is a problem that the enantiomeric excess (optical purity) of the desired optically active sulfoxide is low and the yield is low. Therefore, a process for producing the (R) -isomer or (S) -isomer having an industrially advantageous anti-ulcer effect in the presence of analogous substances, enantiomeric excess, yield, productivity and economy is desired. It is rare.

[0005]

Means for Solving the Problems The present inventors have proposed (R)-
After various studies of the production method of the body and the (S) -body,
In the (R) -form and the (S) -form, there exists a crystal (including a solvate and a hydrate) having a specific crystal form different in physical properties from the sulfone form, and the specific crystal Surprisingly, when a crystal having a shape is crystallized,
For the first time, they found that the difficult-to-remove sulfone form can be easily removed, and that the desired product having an extremely high optical purity can be obtained, and that this method is a production method that can be sufficiently satisfied on an industrial scale. Based on the above, the present invention has been completed. That is, the present invention provides a method for selectively crystallizing (R) -form or a salt thereof from a solution containing [1] (R) -form or a salt thereof in a larger amount than (S) -form or a salt thereof. A method of producing crystals of the (R) -form or a salt thereof substantially free of the (S) -form or a salt thereof, wherein the crystallized crystals are collected; [2] (S The crystals of the (S) -form or its salt are selectively crystallized from a solution containing more than the (R) -form or its salt, and the crystallized crystals are collected. (3) a method for producing a crystal of the (S) -form or a salt thereof substantially free of the (R) -form or a salt thereof; [3] the (R) -form or a salt thereof in a solution or S)
The method of the above-mentioned [1] or [2], wherein the enantiomer excess of the isomer or a salt thereof is about 80% ee or more; [4] the crystallized crystal is obtained by (1) powder X-ray diffraction. Lattice spacing (d) is 5.88, 4.70, 4.35, 3.6
6, a crystal exhibiting a powder X-ray diffraction pattern in which characteristic peaks appear at 3.48 angstroms; (2) lattice spacing (d) of powder X-ray diffraction is 8.33, 6.63, 5.8
6. The crystal according to the above [1] or [2], which is a crystal showing a powder X-ray diffraction pattern showing a characteristic peak at 4.82 angstroms, or (3) a mixture of the crystals of the above (1) and (2). [5] The production method according to [1] or [2], wherein the crystallized crystals are collected and subjected to one or more recrystallizations; [6] (R) -2- [ [[3-methyl-4- (2,2,
2-trifluoroethoxy) -2-pyridyl] methyl]
Sulfinyl] benzimidazole · nH ₂ O (n is about
0.1 to about 1.0) or a salt thereof dissolved or suspended in an organic solvent solution or suspension, and (R) -2-[[[3-methyl-4- (2 , 2,
2-trifluoroethoxy) -2-pyridyl] methyl]
Sulfinyl] benzimidazole · n′H ₂ O (n ′
Represents about 0 to about 0.1) or a salt thereof; [7] (R) -2-[[[3-methyl-4- (2,2,
2-trifluoroethoxy) -2-pyridyl] methyl]
Sulfinyl] benzimidazole · nH ₂ O (n is about
0.1 to about 1.0) or a salt thereof is subjected to a dehydration step, and then is crystallized. [8] The organic solvent contains an acetic acid C _1-4 alkyl ester. The process according to [6] above,

[9] The production method according to [8], wherein the C _1-4 alkyl acetate is ethyl acetate; [10] The production method according to [6], wherein n is about 0.2 to about 0.8; Is about 0.5; [12] (R) -2-[[[3-methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof can be prepared by converting (S) -2-[[[3-methyl-4- (2,2,2
-Trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a solution or suspension containing more than the salt thereof, to obtain (R) -2-[[[3-
Methyl-4- (2,2,2-trifluoroethoxy)-
2-pyridyl] methyl] sulfinyl] benzimidazole.nH ₂ O (n represents about 0.1 to about 1.0) or a salt thereof is selectively crystallized, and the obtained crystals are dissolved or suspended in an organic solvent. (S) -2-[[[[3-methyl-4-
(R) -2-[[[3-Methyl-4- (2,2,2) substantially free of (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof. , 2-trifluoroethoxy) -2-
Pyridyl] methyl] sulfinyl] benzimidazole · n′H ₂ O (n ′ represents about 0 to about 0.1) or a salt thereof; [13] selective crystallization in an organic solvent containing water [14] The method according to [12], wherein the organic solvent is selected from esters, ketones, ethers, hydrocarbons, and aromatic hydrocarbons.
[15] (R) -2-[[[3-methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole · n′H ₂ O
(N ′ represents about 0 to about 0.1), and the crystal plane spacing (d) of powder X-ray diffraction is 11.68, 6.77, 5.84,
5.73, 4.43, 4.09, 3.94, 3.89,
[16] (R) -2-[[[3-methyl-], which is a crystal showing a characteristic peak at 3.69, 3.41 and 3.11 angstroms; 4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof can be prepared by converting (S) -2-[[[3-methyl-4- (2,2,2
-Trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a solution containing more than the salt thereof, from a solution containing (R) -2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof is selectively crystallized, and the obtained crystal is further subjected to a dehydration step to crystallize. Characterized by the fact that
(R)-which is substantially free from (S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof. 2-[[[3-methyl-4- (2,2,
2-trifluoroethoxy) -2-pyridyl] methyl]
A method for producing crystals of sulfinyl] benzimidazole or a salt thereof; [17] (S) -2-[[[3-methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole.mH ₂ O (m
Represents about 0.1 to about 1.0) or a salt thereof dissolved or suspended in an organic solvent solution or suspension. (S) -2-[[[3-Methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole · m′H ₂ O
(M ′ represents about 0 to about 0.1) or a method for producing crystals of a salt thereof; [18] (S) -2-[[[3-methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole.mH ₂ O (m
Represents about 0.1 to about 1.0) or a salt thereof, which is subjected to a dehydration step and then crystallized; [19] the organic solvent is a C _1-4 alkyl ester of acetic acid; [20] The method according to [19], wherein the acetic acid C _1-4 alkyl ester is ethyl acetate; [21] m is about 0.2 to about 0.8. [22] The production method according to [17], wherein m is about 0.5; [23] (S) -2-[[[3-methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof can be prepared by treating (R) -2-[[[3-methyl-4- (2,2,2
-Trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a solution or suspension thereof containing more than the salt thereof, to obtain (S) -2-[[[3-
Methyl-4- (2,2,2-trifluoroethoxy)-
2-pyridyl] methyl] sulfinyl] benzimidazole · mH ₂ O (m represents from about 0.1 to about 1.0) or selectively crystallized crystals salt thereof, is dissolved or suspended and the resulting crystals organic (R) -2-[[[[3-methyl-4-
(S) -2-[[[3-Methyl-4- (2,2) substantially free of (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof. , 2-trifluoroethoxy) -2-
Pyridyl] methyl] sulfinyl] benzimidazole · m′H ₂ O (m ′ is about 0 to about 0.1) or a salt thereof; [24] selective crystallization in an organic solvent containing water [25] The method according to [23], wherein the organic solvent is selected from esters, ketones, ethers, hydrocarbons, and aromatic hydrocarbons.
[26] (S) -2-[[[3-Methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole · m′H ₂ O
(M ′ represents about 0 to about 0.1), and the crystal lattice spacing (d) of powder X-ray diffraction is 11.68, 6.77, 5.84,
5.73, 4.43, 4.09, 3.94, 3.89,
The above-mentioned [17] or [23] which is a crystal showing a characteristic peak at 3.69, 3.41 and 3.11 Å.
[27] (S) -2-[[[3-methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof can be prepared by treating (R) -2-[[[3-methyl-4- (2,2,2
-Trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a solution containing more than the salt thereof, from a solution containing (S) -2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof is selectively crystallized, and the obtained crystal is further subjected to a dehydration step to crystallize. Characterized by the fact that
(S)-which is substantially free from (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof. 2-[[[3-methyl-4- (2,2,
2-trifluoroethoxy) -2-pyridyl] methyl]
[28] A method for producing crystals of sulfinyl] benzimidazole or a salt thereof; [28] (R) -2-[[[3-
Methyl-4- (2,2,2-trifluoroethoxy)-
2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof or (S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-]
[12], [16], [23] or [27], wherein the enantiomeric excess of pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof is about 80% ee or more.
[29] The selectively crystallized crystal has (1) an X-ray powder diffraction lattice spacing (d) of 5.88, 4.70, 4.3.
Crystals exhibiting characteristic peaks at 5, 3.66 and 3.48 angstroms; (2) lattice spacing (d) of powder X-ray diffraction is 8.33, 6.63, 5.86, 4.82 angstroms Or (3) the production method according to [12], [16], [23] or [27], which is a mixture of the crystals of (1) and (2); The above [12], [1], wherein the crystal obtained by selective crystallization is further subjected to one or more crystallization steps.
6], the production method according to [23] or [27]; [31] (R) -2-[[[3-methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole.nH ₂ O (n
Represents about 0.1 to about 1.0) or a salt thereof; [32] (S) -2-[[[3-methyl-4- (2,
2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole.mH ₂ O (m
Represents about 0.1 to about 1.0) or a salt thereof; [33] a lattice spacing (d) of powder X-ray diffraction of 5.88;
The crystal according to the above [31] or [32], which is a crystal showing a characteristic peak at 4.70, 4.35, 3.66, 3.48 angstroms; [34] lattice spacing of powder X-ray diffraction ( d) is 8.33,
[31] or [3], which is a crystal showing a characteristic peak at 6.63, 5.86, or 4.82 angstroms.
2] The crystal as described above.

As the “salt” of the (R) -form and the “salt” of the (S) -form, pharmaceutically acceptable salts are preferable, for example, salts with inorganic bases, salts with organic bases, and basic salts. And salts with amino acids. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt and the like. Suitable examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine and the like. Of these, alkali metal salts or alkaline earth metal salts are preferred. Particularly, a sodium salt is preferable.

(R) -form nH ₂ O (n is about 0.1 to about 1.0)
Or a salt thereof may be obtained from “a solution or suspension containing the (R) -form or a salt thereof in a larger amount than the (S) -form or a salt thereof” from the (R) -form · nH ₂ O (n Is about 0.1 to about 1.
0) or a salt thereof is selectively crystallized. In addition, (S) -form · mH ₂ O (m
Represents about 0.1 to about 1.0) or a salt thereof, from a “solution or suspension containing the (S) -form or a salt thereof more than the (R) -form or a salt thereof”, from the (S) -form・ MH ₂ O (m
Represents about 0.1 to about 1.0) or a salt thereof, which is selectively crystallized. Here, “· nH
₂ O "or" · mH ₂ O "refers to n or m-hydrate, respectively.

[0008] "Solution or suspension containing the (R) -form or its salt more than the (S) -form or its salt" and "The (S) -form or its salt, "Solution or suspension containing more than its salt" can be prepared by a method known per se, for example, Japanese Patent Application Laid-Open No. 10-504290 (WO
96/02535) or a method analogous thereto, or the following method. 2-
[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] thio] -1H-benzimidazole and excess (about 1.5 to 10 molar equivalents)
Oxidizing agents (eg, peroxides such as hydrogen peroxide, tert-butyl hydroperoxide, cumene hydroperoxide, etc.)
And an asymmetric induction catalyst (eg, an optically active diol, a titanium (IV) alkoxide and a complex of water), an organic solvent [eg, alcohols such as methanol, ethanol, propanol, and isopropanol; benzene, toluene, xylene, etc. Aromatic hydrocarbons; diethyl ether, diisopropyl ether, butyl methyl ether,
Ethers such as dioxane and tetrahydrofuran; esters such as ethyl acetate and methyl acetate; ketones such as acetone and methyl isobutyl ketone; chloroform;
Halogenated hydrocarbons such as dichloromethane, ethylene dichloride and carbon tetrachloride; amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; acetic acid and the like] and bases (eg, alkalis such as potassium carbonate and sodium carbonate) Inorganic bases such as alkali metal hydroxides such as metal carbonates, sodium hydroxide and potassium hydroxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide and sodium ethoxide , Alkali metal carboxylate salts such as sodium acetate, piperidine, piperazine, pyrrolidine, morpholine, triethylamine, tripropylamine, tributylamine, trioctylamine, diisopropylethylamine, dimethylphenate Organic bases such as amines such as luminamine, pyridines such as pyridine and dimethylaminopyridine, and basic amino acids such as arginine, lysine, and ornithine] at about -20 to 20 ° C. and about 0.1 to 50 ° C. The reaction is allowed to proceed for a period of time, and the "solution or suspension containing the (R) -form or a salt thereof more than the (S) -form or a salt thereof" or the "solution or suspension containing the (S) -form or a salt thereof with the (R)-
A solution or suspension "that contains more than the body or its salts. The “(R) -form or its salt” and “(S) -form or its salt” in the above solution or suspension may be any of a solid (crystal, amorphous) and an oily substance, and may be isolated and purified. It does not have to be. Examples of the solvent for preparing the “solution or suspension” include water, esters, ketones, phenols, alcohols, ethers, aromatic hydrocarbons, amides, sulfoxides, and hydrocarbons. , Nitriles, halogenated hydrocarbons, pyridines or a mixture of two or more of these. The enantiomer excess of the (R) -form or salt thereof or the (S) -form or salt thereof in the solution or suspension is, for example, about 80% ee or more, preferably about 90% ee.
e or more.

The method of “selectively crystallizing” includes, for example, a method of stirring the solution or suspension, a method of seeding the solution or suspension, and a method of adjusting the temperature of the solution or suspension. Examples thereof include a method of changing the solvent composition, a method of changing the solvent composition of the solution or suspension, a method of reducing the volume of the solution or suspension, and a method of combining two or more of these methods. As the “method of stirring the solution or suspension”, for example, a solution or suspension containing a large amount of either the (R) -form or a salt thereof or the (S) -form or a salt thereof may be prepared by mixing the solution or suspension with about -80 to 120 ° C., preferably about −20 to 60 ° C., for about 0.01 to 100 hours, preferably about 0.1 to 10 hours. The “method of adding seed crystals to a solution or suspension” includes, for example, a solution or suspension containing a large amount of either the (R) -form or a salt thereof or the (S) -form or a salt thereof,
(1) The lattice spacing (d) of powder X-ray diffraction is 5.88;
Crystals exhibiting characteristic peaks at 4.70, 4.35, 3.66, 3.48 angstroms; (2) lattice spacing (d) in powder X-ray diffraction is 8.33, 6.63, 5. 86,
Crystals exhibiting a characteristic peak at 4.82 angstroms, (3) transferring to the above (1) to (3) in a mixture of the crystals of the above (1) and (2) or in a solution or suspension (4). Solid (e.g., lattice spacing (d) in powder X-ray diffraction is 1
1.68, 6.77, 5.84, 5.73, 4.43,
4.09, 3.94, 3.89, 3.69, 3.41;
A crystal showing a characteristic peak at 3.11 Å,
The lattice spacing (d) of powder X-ray diffraction is 8.86, 8.0
1, 6.58, 5.91, 5.63, 5.02, 4.4
Crystals showing a characteristic peak at 8 Å, powder X
The lattice spacing (d) of the line diffraction is 8.37, 4.07, 5.
65, 5.59, 5.21, 4.81, 4.21 angstrom, etc.) as a seed crystal. The “method of changing the temperature of the solution or suspension” includes, for example, changing the temperature of a solution or suspension containing a large amount of either the (R) -form or its salt or the (S) -form or its salt. Let
Preferably, a method of cooling (eg, lowering the liquid temperature by 5 to 100 ° C.) is used. As the "method of changing the solvent composition of the solution or suspension", for example, a solution or suspension containing a large amount of either the (R) -form or a salt thereof or the (S) -form or a salt thereof is added to water , Organic solvents (eg, esters, ketones, phenols, alcohols, ethers, aromatic hydrocarbons, amides, sulfoxides, hydrocarbons, nitriles, halogenated hydrocarbons,
Pyridines or a mixture of two or more thereof; preferably, a low-polarity organic solvent (eg, esters, ethers,
Aromatic hydrocarbons, hydrocarbons, halogenated hydrocarbons or a mixture of two or more thereof), ketones or a mixture of two or more thereof. Preferably, in the presence of water, esters, ketones,
A method in which one or more organic solvents selected from ethers and hydrocarbons are added. As an addition method, water, an organic solvent or a mixture thereof is added dropwise to a solution or a suspension containing a large amount of either the (R) -form or its salt or the (S) -form or its salt under stirring. Alternatively, a method of dropping a solution or suspension containing a large amount of either the (R) -form or its salt or the (S) -form or its salt in water, an organic solvent, or a mixed solution thereof with stirring may be used. . The “method of reducing the solution volume of a solution or a suspension” includes, for example, removing a solvent from a solution or a suspension containing a large amount of either the (R) -form or a salt thereof or the (S) -form or a salt thereof. , Distillation and evaporation.

[0010] Of these, preferably, (i) a method of stirring the solution or suspension, (ii) a method of changing the solvent composition of the solution or suspension, (iii) a method of stirring the solution or suspension, and (Iv) a method of stirring the solution or suspension and a method of changing the temperature of the solution or suspension, and (v) a method of adding seeds to the solution or suspension. A method of stirring the suspension and a method of changing the solvent composition of the solution or suspension; (vi) a method of stirring the solution or suspension and a method of reducing the volume of the solution or suspension (Vii) a method of stirring the solution or suspension, a method of changing the temperature of the solution or suspension, and a method of performing seeding on the solution or suspension,
(Viii) a method of stirring the solution or suspension, a method of changing the solvent composition of the solution or suspension, and a method of adding seed crystals to the solution or suspension, and (ix) a solution or suspension. Stirring the solution, reducing the volume of the solution or suspension, and seeding the solution or suspension together, (x) stirring the solution or suspension, A method of changing both the temperature of the suspension and the method of changing the solvent composition of the solution or suspension, (xi) a method of stirring the solution or suspension, and a method of changing the temperature of the solution or suspension. The method of changing the solvent composition of the solution or suspension and the method of seeding the solution or suspension, (xi
i) a method of stirring the solution or suspension, a method of changing the temperature of the solution or suspension and a method of reducing the volume of the solution or suspension, and (xiii) A method of stirring, a method of changing the temperature of the solution or suspension, a method of reducing the volume of the solution or suspension, and a method of seeding the solution or suspension are both performed. Among the above, the methods (ii), (v) and (x) are preferred, and the method (x) is more preferred.
A more preferred embodiment as a method for “selectively crystallizing” is described below. (R) -form or salt thereof or (S)-
In a solution or a suspension containing a large amount of either the body or a salt thereof, the organic solvent contained in the solution or the suspension includes, in particular, esters, ketones, ethers,
One selected from hydrocarbons and aromatic hydrocarbons,
Alternatively, a mixture of two or three kinds is preferable, and C _6-10 alkanes (eg, hexane, heptane, octane, etc.), t-butyl methyl ether, diethyl ether, diisopropyl ether, acetone, toluene, xylene or a mixture thereof are more preferable. preferable. Organic solvents added in the presence of water include hydrocarbons (eg, C _6-10 alkanes such as hexane, heptane, octane, etc.) and ethers (eg, t-butyl methyl ether, diethyl ether, diisopropyl ether, etc.) And ketones (eg, acetone, etc.) are particularly preferred. As an addition method, under stirring,
A mixture of water and an organic solvent is added dropwise to a solution or suspension containing a large amount of either the (R) -form or its salt or the (S) -form or its salt, or the mixture of water and the organic solvent is stirred. A method of dropping a solution or suspension containing a large amount of either the (R) -form or a salt thereof, or the (S) -form or a salt thereof, into the mixed solution may, for example, be mentioned. If desired, more water may be added dropwise. That is, the selective crystallization is preferably performed in an organic solvent containing water. When the (R) -form or its salt or (S) -form or its salt obtained by asymmetric synthesis is used by the method for selectively crystallizing, for example, analogous substances in the precipitated crystals (eg, , 2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy) -2-pyridyl] methyl] thio] benzimidazole and / or 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2] -Pyridyl] methyl] sulfonyl] benzimidazole).

The crystallized crystals can be collected by a method such as filtration or centrifugation. Crystals selectively crystallized by the above method include (R) -form.nH ₂ O
(N is approximately shows a 0.1 to about 1.0) or a salt thereof or (S) - Body · mH ₂ O (m represents from about 0.1 to about 1.0) or the like salt thereof. n or m is preferably about 0.2 to about 0.8, particularly preferably about 0.5.
The crystal thus obtained [eg, the above-mentioned (R) -form. NH ₂ O
(N represents from about 0.1 to about 1.0) or a salt thereof or (S) - Body · mH ₂ O (m represents from about 0.1 to about 1.0) or organic solvent is dissolved or suspended crystal] of a salt thereof By crystallization from a solution or suspension, the (R) -form
n'H ₂ O (n 'represents about 0 to about 0.1) or a salt thereof or (S) - Body · m'H ₂ O (m' a represents about 0 to about 0.1) or a crystal of a salt thereof Can be manufactured. Here, the relationship between n and n ′ and m and m ′ in the above process
Are n> n ′ and m> m ′. Thus, for example, when n or m is 0.1, the corresponding n 'and m' are each less than 0.1. Organic solvents used for dissolution or suspension include esters, ketones,
Phenols, alcohols, ethers, aromatic hydrocarbons, amides, sulfoxides, hydrocarbons, nitriles, halogenated hydrocarbons, pyridines or a mixture of two or more of these, preferably esters , Hydrocarbons or mixtures thereof, among which organic solvents containing esters such as C _1-4 alkyl acetate (eg, ethyl acetate, propyl acetate, butyl acetate, etc.) are preferred. More preferably, C _1-4 alkyl acetates (eg, ethyl acetate, propyl acetate, butyl acetate, etc.), C _6-8 hydrocarbons (eg, C _6-8 alkanes such as hexane, heptane, octane, etc.) or these And the like. The crystallization is carried out, for example, by the above (R) -form · n
H (where n represents about 0.1 to about 1.0) ₂ O or a salt thereof, or (S) - Body · mH ₂ O (m represents from about 0.1 to about 1.0) or dissolved or suspended crystals of the salt in an organic solvent Cloudy,
Then, it is preferable to crystallize after the dehydration step.
That is, the step of “crystallizing from the organic solvent solution or suspension” in the production method of the present invention may include a “dehydration step” and a “crystallization step”. As the dehydration step,
Any ordinary dehydration method may be used, for example, esters, ketones, phenols, alcohols, ethers, aromatic hydrocarbons, amides, sulfoxides, hydrocarbons, nitriles, halogenated hydrocarbons. Organic solvents such as, pyridines or a mixture of two or more thereof, preferably esters such as C _1-4 alkyl acetate (eg, ethyl acetate, propyl acetate, butyl acetate, etc.) with the above (R)
- Body · nH ₂ O (n denotes from about 0.1 to about 1.0) or a salt thereof or (S) - Body · mH ₂ O (m represents from about 0.1 to about 1.0) or or dissolve the crystals of the salt suspension It is carried out by a method of turbidity and liquid separation, a method of concentration, a method using a dehydrating agent [eg, anhydrous magnesium sulfate, anhydrous sodium sulfate, molecular sieve (trade name)], or a method combining these. The above concentration method is preferably performed under reduced pressure. Further, after the dehydration step, the obtained organic solvent of the crystals [eg, esters, ketones, phenols, alcohols, ethers, aromatic hydrocarbons,
Amides, sulfoxides, hydrocarbons, nitriles,
Halogenated hydrocarbons, pyridines or a mixture of two or more thereof, preferably C _6-8 hydrocarbons (eg, C _6-8 alkanes such as hexane, heptane and octane)
Hydrocarbons etc.] Crystallize from solution or suspension (recrystallization)
By doing so, the desired crystal can be obtained.

Hereinafter, the (R) -form nH ₂ O (n
Represents about 0.1 to about 1.0) or a salt thereof or (S)-
The step of crystallizing from a solution or suspension of an organic solvent in which crystals of mH ₂ O (m represents about 0.1 to about 1.0) or a salt thereof are dissolved or suspended will be described in detail. First, the (R) -form nH ₂ O (n is about 0.1 to
Or about 1.0) or its salt or (S) -form mH ₂
O (m represents about 0.1 to about 1.0) or a crystal of the salt thereof as it is or, if necessary, drying, and then, if necessary, once or twice or more (preferably twice or more)
(3 times) crystallization step (this crystallization step may include a step of dissolving or suspending in a solvent, a recrystallization step, a dehydration step, etc.). In one or more crystallization steps, a dehydration step is preferably included immediately before the last crystallization (recrystallization) step. The "dry"
Examples thereof include drying under reduced pressure, through-flow drying, heating drying, and natural drying. Specifically, the obtained crystals or the dried crystals thereof are mixed with a solvent (eg, water, esters, ketones, phenols, alcohols, ethers, aromatic hydrocarbons, amides, sulfoxides, hydrocarbons). , Nitriles, halogenated hydrocarbons, pyridines or a mixture of two or more of these, preferably water and hydrocarbons [eg, C _6-8 hydrocarbons (eg, hexane, heptane, octane, etc.) C _6-8 alkanes, etc.), aromatic hydrocarbons (eg, toluene, xylene, etc.), ketones (eg, acetone, etc.) and ethers (eg, t-butyl methyl ether, diethyl ether, diisopropyl ether) ) Or two or more (preferably 2
~ 3) dissolved or suspended in a mixture with an organic solvent,
Crystals are crystallized after a dehydration step if necessary. Preferably, the obtained crystal or its dried crystal is subjected to one or more (preferably two to three) crystallization steps described above, and immediately before the final crystallization step (recrystallization), The crystals are subjected to a dehydration step, and then the desired crystals are crystallized. The "dehydration"
Examples of the method include a method similar to the dehydration method described above.
One or more times as described above (preferably two to three times)
Examples of the “crystallization” method in the crystallization step include the method described in the above “selective crystallization method”. After subjecting to the dehydration step, as a method of crystallizing the target crystals, the organic solvent of the crystals obtained in the dehydration step [eg, esters, ketones, phenols, alcohols, ethers, aromatic hydrocarbons] , Amides, sulfoxides, hydrocarbons, nitriles, halogenated hydrocarbons,
Pyridines or a mixture of two or more thereof, preferably hydrocarbons of C _6-8 hydrocarbons (eg, C _6-8 alkanes such as hexane, heptane, octane, etc.)] solutions or suspensions Recrystallization is preferred.

The crystals obtained after the above-mentioned crystallization step (recrystallization) are as follows: (1) The lattice spacing (d) of powdery X-ray diffraction of the undried crystals is 5.88, 4.70, 4.35. , 3.66,
A crystal exhibiting a characteristic peak at 3.48 angstroms, and (2) a lattice spacing (d) of powdery X-ray diffraction of the undried crystal is 8.33, 6.63, 5.86, and 4.82 angstroms. (3) a mixture of the crystals of (1) and (2), or (4) a lattice spacing (d) of powder X-ray diffraction of 11.68, 6.77,
5.84, 5.73, 4.43, 4.09, 3.94,
Crystals exhibiting characteristic peaks at 3.89, 3.69, 3.41 and 3.11 angstroms are exemplified. Also,
The amount of analogs in the crystals is less than 1% by weight, preferably less than 0.4% by weight.

The crystals crystallized in the above-mentioned crystallization step (eg, recrystallization) can be separated by, for example, a method such as filtration or centrifugation. As the crystal (target crystal) obtained in the final crystallization step, for example, the lattice spacing (d) of powder X-ray diffraction is 11.68, 6.77, 5.8.
4, 5.73, 4.43, 4.09, 3.94, 3.8
(R)-or (S) -form crystals exhibiting characteristic peaks at 9, 3.69, 3.41 and 3.11 angstroms. The fractionated crystals can be dried, for example, by a method such as drying under reduced pressure, aeration drying, heating drying, and natural drying.

[0015] The present invention in order finally crystallized "(R) - Body · n'H ₂ O (n 'is about 0 to show about 0.1) or a salt crystals" or "(S) - form or "Crystals of the (R) -form or its salt substantially free of its salt" refer to the (R) -form or its salt containing 0 to 3%, preferably 0 to 1% of the (S) -form or its salt. Means a crystal. The “(S) -form · m′H ₂ O (m ′ is about 0 to about 0.1
Or a crystal of a salt thereof) or “(S) -form or a crystal of a salt thereof substantially free of the (R) -form or a salt thereof” refers to a (R) -form or a salt thereof of 0 to 1 % Of (S) -form or a salt thereof. Here, the "· n'H ₂ O" or "· m'H ₂ O", respectively n '
Or m 'hydrate. In the production method of the present invention, for example, once or twice or more (preferably twice or more)
Crystallization process three times), followed by performing the dehydration step and the final crystallization step (R) - Body · n'H ₂ O (n 'represents about 0 to about 0.1) or a salt thereof, or ( S)-body
m'H ₂ O (m 'is about 0 to show about 0.1) can be obtained or crystal or anhydrous crystal has little water of hydration, such as a salt thereof, as such crystals, a powder X-ray The lattice spacing (d) for diffraction is 11.68, 6.77, 5.
84, 5.73, 4.43, 4.09, 3.94, 3.
89, 3.69, 3.41 and 3.11 angstroms. n 'or m' is preferably from about 0 to about 0.1, and more preferably n is 0 or m is 0, that is, anhydrous crystal.

Examples of the "esters" include C _1-4 alkyl acetates such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate, and ethyl formate. Examples of the “ketones” include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone, and the like. Examples of the "phenols" include anisole. As the "alcohols", for example,
Methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, pentanol, 3-methyl-1
Lower alcohols such as -butanol; lower alcohols substituted with C _1-3 alkoxy such as 2-methoxyethanol and 2-ethoxyethanol: ethylene glycol and the like. Examples of the “ethers” include t-butyl methyl ether, diethyl ether,
Examples thereof include 1,1-diethoxypropane, 1,1-dimethoxypropane, 2,2-dimethoxypropane, isopropyl ether, tetrahydrofuran, and methyltetrahydrofuran. Examples of the “aromatic hydrocarbons” include chlorobenzene, toluene, xylene, cumene and the like. Examples of the “amides” include formamide, N, N, -dimethylacetamide, N, N-dimethylformamide, N-methylpyrrolidone, and the like. Examples of the “sulfoxides” include dimethyl sulfoxide.
As the aforementioned "hydrocarbons", for example, propane, butane, pentane, hexane, heptane, octane, C _3-10 alkane such as iso-octane, and the like, preferably a C _{6- 10} alkanes. Examples of the “nitrile” include acetonitrile and the like. The “halogenated hydrocarbons” include, for example, halogens (eg, fluorine, chlorine, bromine, iodine) such as chloroform, dichloromethane, dichloroethene, and trichloroethene, from 1 to 5;
An optionally substituted C _1-6 alkane is exemplified.
Examples of the “pyridines” include pyridine and the like.

The crystals crystallized by the method of the present invention or the dried crystals thereof are substantially free of enantiomers and have excellent anti-ulcer action, gastric acid secretion inhibitory action, mucosal protective action, anti-Helicobacter pylori action and the like. It is useful as a pharmaceutical because of its low toxicity. The dried crystals of the (R) -form or the (S) -form or a salt thereof are more stable than the crystallized crystals of the (R) -form or the (S) -form or a salt thereof (undried crystals). When it is used, a crystal of the (R) -form or (S) -form or a salt thereof as a dried product is preferably used. For example, crystals or dried crystals crystallized by the method of the present invention can be used in mammals (eg, humans, monkeys, sheep, cows, horses, dogs, cats, rabbits, rats, mice, etc.) to treat peptic ulcers (eg, Gastric ulcer, duodenal ulcer, anastomotic ulcer, Zollinger Ellison (Zollinge
r-Ellison) syndrome, gastritis, reflux esophagitis, NUD
(Non Ulcer Dyspepsia), gastric cancer (interleukin-
(Including gastric cancer associated with promotion of interleukin-1β production by the gene polymorphism 1), treatment and prevention of gastric MALT lymphoma, eradication of Helicobacter pylori, peptic ulcer,
Inhibition of upper gastrointestinal bleeding due to acute stress ulcer and hemorrhagic gastritis, invasive stress (for cerebrovascular disorders requiring intensive care and intensive care after surgery, head trauma, multiple organ failure, extensive burns) It is useful for the suppression of upper gastrointestinal bleeding due to stress that occurs, the treatment and prevention of ulcers caused by nonsteroidal anti-inflammatory drugs; the treatment and prevention of hyperacidity and ulcers due to post-operative stress, and the administration before anesthesia. For eradication of Helicobacter pylori, crystals or dried crystals crystallized by the method of the present invention are combined with a penicillin antibiotic (eg, amoxicillin) and an erythromycin antibiotic (eg, clarithromycin). It is preferably used.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. X-ray powder diffraction is an X-ray
Diffractometer RINT Ultim
It measured using a + (Rigaku). The enantiomeric excess (% ee) was measured by high performance liquid chromatography using an optically active column under the following condition (A). The abundances of the sulfide form and the sulfone form were measured by high performance liquid chromatography using an optically active column under the following condition (A) or high performance liquid chromatography under the condition (B). Column: CHIRALCEL OD (manufactured by Daicel Industries, Ltd.) Moving layer: hexane / ethanol = 90/10 Flow rate: 1.0 ml / min Detection: UV285 nm High-performance liquid chromatography conditions (B); Column: Capcell Pak (manufactured by Shiseido Co., Ltd.) Moving layer: A mixture adjusted to pH 7.0 by adding phosphoric acid to a mixture of acetonitrile: water: triethylamine (50: 50: 1). Flow rate: 1.0 ml / min Detection: UV 285 nm

[0019]

EXAMPLES Reference Example 1 Production of Solution Containing (R) -Form and (S) -Form by Asymmetric Oxidation Under a nitrogen atmosphere, 2-[[[3-methyl-4- (2,2,2)
2-trifluoroethoxy) -2-pyridyl] methyl]
Thio] benzimidazole (50.0 g, 0.14 mo
1, containing 16.7 mg of water), toluene (250 m
l), water (283 mg, 0.016 mol, total water content 0.017 mol), (+)-diethyl tartrate (1
0.6 ml, 0.062 mol).
Stirred at C for 30 minutes. Under a nitrogen atmosphere, titanium (I
V) Isopropoxide (8.29 ml, 0.028 mol
l) was added and stirred at 50-55 ° C for 1 hour. Under a nitrogen atmosphere and under cooling, diisopropylethylamine (8.13 ml, 0.047 mol) was added to the obtained mixed solution, and then cumene hydroperoxide (7
6.50 ml, content 82%, 0.43 mol)
The reaction was carried out by stirring at −10 to 10 ° C. for 4.5 hours. The reaction solution was analyzed by high performance liquid chromatography (condition (A)). As a result, 0.74% of a sulfide compound and 1.46% of a sulfone compound were present as analogs in the reaction solution. Did not exist. The enantiomeric excess of the (R) -isomer in the reaction solution was 96.5% ee.

Example 1 Method for producing (R) -isomer [Reaction solution (R) -isomer and (S) obtained according to Reference Example 1]
-Containing 14.63 g of a mixture of isomers, enantiomeric excess of 97.0
% Ee] at 0 to 10 ° C, heptane (200 ml) was added dropwise at 2 ° C, and the mixture was stirred at the same temperature for 2 hours. ) -Isomer (yield after drying: 12.96 g, yield after drying: 88.6%). The results of analyzing the wet crystals by powder X-ray diffraction are shown below. The wet crystal had a lattice spacing (d) of 5.88, 4.70, 4.3 in powder X-ray diffraction.
The powder X-ray diffraction pattern showed characteristic peaks at 5, 3.66 and 3.48 angstroms. The crystals were analyzed by high performance liquid chromatography (condition (A)). As a result, the enantiomer excess of the crystals was 100% ee.

Example 2 Method for producing (R) -isomer The reaction solution prepared according to Reference Example 1 was used and (R) -2-[[[[3-methyl-4] obtained according to Example 1. −
(2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole (1
3.0 g, enantiomeric excess 100% ee, sulfone 1.
5%) was dissolved in acetone (100 ml). Water (360 ml) was added dropwise to the obtained solution, and the mixture was stirred under ice cooling for 1 hour. The precipitated crystals are separated and wet crystals of the (R) -form having the following lattice spacing (d) of powder X-ray diffraction (yield after drying: 12.5 g, yield after drying: 96.2%)
I got The results of analyzing the wet crystals by powder X-ray diffraction are shown below. The wet crystal showed a powder X-ray diffraction pattern in which characteristic peaks appeared at lattice spacings (d) of 8.33, 6.63, 5.86, and 4.82 angstroms in powder X-ray diffraction. The crystals were analyzed by high performance liquid chromatography (condition (B)), and as a result, the abundance of the sulfone form in the crystals was 0%, and no other related substances were present.

Example 3 Method for producing (R) -isomer (1) 2-[[[3-methyl-4- (2,2)
2,2-trifluoroethoxy) -2-pyridyl] methyl] thio] benzimidazole (4.5 kg, 12.7
mol, containing 1.89 g of water), toluene (22
L), water (25 g, 1.39 mol, total water content 1.49 mol) and diethyl (+)-tartrate (0.4 g).
958 L, 5.60 mol). Under a nitrogen stream,
At 50-60 ° C., titanium (IV) isopropoxide (0.747 L, 2.53 mol) was added to the mixture, and the mixture was stirred at the same temperature for 30 minutes. At room temperature under a nitrogen stream, diisopropylethylamine (0.733 L,
After addition of 4.44 mol), cumene hydroperoxide (6.88 L, content 82%, 37.5 m) at -5 to 5 ° C.
ol) and stirred at -5 to 5 ° C for 1.5 hours to obtain a reaction solution. The reaction solution was analyzed by high performance liquid chromatography (condition (B)). As a result, 1.87% of a sulfide compound and 1.59% of a sulfone compound were present as related substances in the reaction solution, and the other related substances were Did not exist.

(2) A 30% aqueous solution of sodium thiosulfate (17 L) was added to the reaction solution obtained in the above (1) under a nitrogen stream.
Was added to decompose the remaining cumene hydroperoxide. The layers were separated and the resulting organic layer was added to water (4.5 L), heptane (13.5 L), t-butyl methyl ether (18
L) and heptane (27 L) were sequentially added, and crystallized at about 10 ° C. with stirring. The crystals were separated, washed with t-butyl methyl ether-toluene (t-butyl methyl ether: toluene = 4: 1) (4 L), and had the following lattice spacing (d) of powder X-ray diffraction (R). -The body was obtained as wet crystals. The results of analyzing the wet crystals by powder X-ray diffraction are shown below. The wet crystal had a lattice spacing (d) of 5.88, 4.70, 4.35, 3.66 in powder X-ray diffraction,
The powder X-ray diffraction pattern showed a characteristic peak at 3.48 angstroms. An X-ray powder diffraction chart is shown in FIG. The crystals were analyzed by high performance liquid chromatography (condition (A)). As a result, 0.90% of a sulfone form was present as a related substance in the crystal, and no sulfide form and other related substances were present. The enantiomeric excess of the (R) -form of the crystal was 100% ee.

(3) Under stirring, a suspension of the wet crystals obtained in the above (2) in acetone (20 L) was added dropwise to a mixture of acetone (7 L) and water (34 L).
L) and stirred at about 10 ° C. Separating the precipitated crystals,
After washing with acetone-water (acetone: water = 1: 3) (4 L) and water (12 L), an (R) -form having the following lattice spacing (d) of powder X-ray diffraction was obtained as wet crystals. . The results of analyzing the wet crystals by powder X-ray diffraction are shown below.
The wet crystal has a lattice spacing (d) of 8.3 in powder X-ray diffraction.
The powder X-ray diffraction pattern showed characteristic peaks at 3, 6.63, 5.86, and 4.82 angstroms. The X-ray powder diffraction chart is shown in FIG. The crystals were analyzed by high performance liquid chromatography (condition (A)). As a result, there were no sulfones, sulfides and other related substances as related substances in the crystals. The enantiomeric excess of the (R) -form in the crystal was 100% ee.

(4) The wet crystals obtained in the above (3) were dissolved in ethyl acetate (45 L) and water (3 L) and then separated. The trace amount of insolubles in the organic layer was removed by filtration, then, triethylamine (0.2 L) was added, and the mixture was concentrated under reduced pressure until the liquid amount became about 7 L. Methanol (2.3 L) in the concentrate,
About 12.5% ammonia water (23L) at about 50 ° C, about 5
T-Butyl methyl ether (22 L) at 0 ° C was added, and the mixture was separated. About 12.5% aqueous ammonia (11 L) for organic layer
Was added, and the mixture was separated (this operation was repeated once). The aqueous layers were combined, ethyl acetate (22 L) was added, and under cooling,
Acetic acid was added dropwise to adjust the pH to about 8. The layers were separated, and the aqueous layer was extracted with ethyl acetate (11 L). The organic layers were combined and washed with about 20% saline (11 L). After adding triethylamine (0.2 L), the organic layer was concentrated under reduced pressure. Acetone (5 L) was added to the concentrate, which was concentrated under reduced pressure. The concentrate is dissolved in acetone (9 L), and the solution is dissolved in acetone (4.5 L).
And water (22.5 L), and then water (18 L) was added dropwise to the resulting mixture and stirred at about 10 ° C. The precipitated crystals were separated, and cold acetone-water (1: 3) (3
L) and water (12 L) were sequentially washed to obtain (R) -form having the following lattice spacing (d) of powder X-ray diffraction as wet crystals. The results of analyzing the wet crystals by powder X-ray diffraction are shown below. The wet crystal has a lattice spacing (d) of powder X-ray diffraction.
Showed a powder X-ray diffraction pattern in which characteristic peaks appeared at 8.33, 6.63, 5.86, and 4.82 angstroms. An X-ray powder diffraction chart is shown in FIG. The crystals were analyzed by high performance liquid chromatography (condition (A)), and as a result, sulfones,
Sulfides and other related substances were not present. The enantiomeric excess of the (R) -form in the crystal is 100%
ee.

(5) The wet crystals obtained in the above (4) were dissolved in ethyl acetate (32 L). The separated aqueous layer was separated by a liquid separation operation, and the obtained organic layer was concentrated under reduced pressure until the liquid amount became about 14 L. Ethyl acetate (36 L) and activated carbon (270 g) were added to the residual liquid, and after stirring, the activated carbon was removed by filtration. The filtrate was concentrated under reduced pressure until the liquid volume was about 14 L. At about 40 ° C., heptane (90 L) was added dropwise to the remaining liquid. After stirring at the same temperature for about 30 minutes, the crystals were separated, and ethyl acetate-heptane (1: 8,6
L). Drying afforded 3.4 kg of the title compound. The results of analyzing the crystals by powder X-ray diffraction are shown below. The crystal has a lattice spacing (d) of 1 in powder X-ray diffraction.
1.68, 6.77, 5.84, 5.73, 4.43,
4.09, 3.94, 3.89, 3.69, 3.41;
The powder X-ray diffraction pattern showed a characteristic peak at 3.11 Å. The X-ray powder diffraction chart is shown in FIG. The crystals were analyzed by high performance liquid chromatography (condition (A)). As a result, there were no sulfones, sulfides and other related substances as related substances in the crystals. The enantiomeric excess of the (R) -form in the crystal was 100% ee.

Example 4 (S) -Production Method (1) 2-[[[3-Methyl-4-
(2,2,2-trifluoroethoxy) -2-pyridyl] methyl] thio] benzimidazole (50.0 g,
0.14 mol, containing 20 mg of water), toluene (2
50 ml), water (130 mg, 0.0072 mol, 0.0083 mol as a total water content) and diethyl (-)-tartrate (5.31 ml, 0.031 mol) were mixed. Under a nitrogen atmosphere, the mixture was mixed with titanium (I
V) Isopropoxide (4.14 ml, 0.014 mo
l) was added and stirred at 50-55 ° C for 1 hour. Under a nitrogen atmosphere and under cooling, diisopropylethylamine (8.13 ml, 0.047 mol) was added to the obtained mixed solution, and then cumene hydroperoxide (7
6.50 ml, content 82%, 0.42 mol)
The mixture was stirred at −5 to 5 ° C. for 3.5 hours to obtain a reaction solution. The reaction mixture was analyzed by high performance liquid chromatography (condition (A)). As a result, the enantiomer excess of the (S) -isomer in the reaction mixture was 9
It was 6.5% ee. The reaction solution was analyzed by high performance liquid chromatography (condition (B)). As a result, 1.90% of a sulfone compound and 1.50% of a sulfide compound were present as analogs in the reaction solution, and the other analogs were Did not exist.

(2) The reaction solution obtained in the above (1) was added to a 30% aqueous solution of sodium thiosulfate (180 m
l) was added to decompose the remaining cumene hydroperoxide. Liquid separation was performed, and water (50 ml), heptane (150 ml), t-butyl methyl ether (2
00 ml) and heptane (300 ml) were added sequentially.
Crystallized. The crystals were separated and t-butyl methyl ether-toluene (t-butyl methyl ether: toluene =
4: 1) (45 ml) to obtain an (S) -form having the following lattice spacing (d) of powder X-ray diffraction as wet crystals. The results of analyzing the wet crystals by powder X-ray diffraction are shown below. The wet crystal has a lattice spacing (d) of powder X-ray diffraction.
5.88, 4.70, 4.35, 3.66, 3.48
A powder X-ray diffraction pattern showing a characteristic peak in Angstrom was shown. The powder X-ray diffraction chart is shown in FIG.
Shown in The crystals were analyzed by high performance liquid chromatography (condition (A)). As a result, the enantiomer excess of the crystals was 1
It was 00% ee. The crystals were analyzed by high performance liquid chromatography (condition (B)). As a result, 0.72% of a sulfone form was present as analogous substances in the crystals, and no sulfide form and other analogous substances were present.

(3) A suspension of the wet crystals obtained in the above (2) in acetone (220 ml) was added dropwise to a mixture of acetone (75 ml) and water (370 ml).
20 ml) was added. The precipitated crystals were separated, and acetone-water (acetone: water = 1: 3) (44 ml) and water (13
0 ml) to obtain (S) -form having the following lattice spacing (d) of powder X-ray diffraction as wet crystals. As a result of analyzing the wet crystals by powder X-ray diffraction, the lattice spacing (d) of the powder X-ray diffraction was 8.33, 6.63, 5.86,
The powder X-ray diffraction pattern showed a characteristic peak at 4.82 Å. The X-ray powder diffraction chart is shown in FIG. The crystals were analyzed by high performance liquid chromatography (condition (A)). As a result, the enantiomer excess of the crystals was 100% ee. The crystals were analyzed by high-performance liquid chromatography (condition (B)). As a result, there were no sulfones, sulfides or other related substances as related substances in the crystals.

Example 5 Method for producing (S) -isomer Wet crystals obtained according to Example 4 (title compound 35.3)
7 g contained, analogous substance abundance: 0%, enantiomeric excess: 10
0% ee, powder X-ray diffraction chart: see FIG. 7) was dissolved in ethyl acetate (340 ml). The separated aqueous layer was separated by a liquid separation operation, and the obtained organic layer was separated to a liquid volume of about 10%.
It concentrated under reduced pressure until it became 0 ml. Ethyl acetate (400 ml) and activated carbon (3 g) were added to the remaining liquid, and after stirring, the activated carbon was removed by filtration. When the filtrate is about 1 volume
It concentrated under reduced pressure until it became 00 ml. At about 40 ° C., heptane (1000 ml) was added dropwise to the remaining liquid. About 3 at the same temperature
After stirring for 0 minutes, the crystals were separated and ethyl acetate at about 40 ° C.
Washed with heptane (1: 8, 63 ml). After drying, 35.08 g (yield: 99.2%) of the title compound was obtained. The results of analyzing the crystals by powder X-ray diffraction are shown below.
The crystal had a lattice spacing (d) of 11.6 in powder X-ray diffraction.
8, 6.77, 5.84, 5.73, 4.43, 4.0
9, 3.94, 3.89, 3.69, 3.41, 3.1
The powder X-ray diffraction pattern showed a characteristic peak at 1 angstrom. The powder X-ray diffraction chart is shown in FIG. The crystals were analyzed by high performance liquid chromatography (condition (A)). As a result, there were no sulfones, sulfides and other related substances as related substances in the crystals. The enantiomeric excess of the (R) -form in the crystal was 100% ee.

Reference Example 2 (R) -2-[[[3-Methyl-4-
Production of a solution containing (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)-] 2-pyridyl] methyl] thio] benzimidazole (30.0 g, 0.085 mol, water 31
mg), toluene (150 mL), water (59 m
g, 0.0033 mol, 0.0050 as total water content
mol) and (+)-diethyl tartrate (3.19 m
L, 0.019 mol) and heated to 50-55 ° C. Titanium (IV) isopropoxide (2.49 mL, 0.0085 mol) was added to the mixture under a nitrogen atmosphere, and the mixture was stirred at 50 to 55 ° C for 30 minutes. Under a nitrogen atmosphere and under cooling, diisopropylethylamine (4.88 mL, 0.028 mol) was added to the resulting mixture, and then cumene hydroperoxide (46.0) at -5 to 5 ° C.
mL, 0.26 mol), and reacted by stirring at −5 to 5 ° C. for 5.5 hours. As a result of analyzing the reaction solution by high performance liquid chromatography (condition (B)),
Related substances in the reaction solution include a sulfide 2.3.
%, 2.0% of a sulfone derivative, and no other related substances.

Reference Example 3 Method for Purifying (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole Reference Example 2 above 25% to the reaction solution obtained in
An aqueous solution of sodium thiosulfate (81 g) was added to decompose the remaining cumene hydroperoxide. About 150 liquid
It concentrated under reduced pressure until it became mL. While maintaining 0 to 10 ° C., heptane-t-butyl methyl ether (heptane:
(t-butyl methyl ether = 1: 1) (120 mL) was added dropwise, followed by heptane (420 mL). The precipitated crystals were separated, and cold heptane-t-butyl methyl ether (heptane: t-butyl methyl ether = 1: 1) (6)
0 mL) to obtain 67.2 g of the wet crystals. The crystals were analyzed by high performance liquid chromatography (condition (A)), and as a result, (R) -2-[[[[3-methyl-
The enantiomeric excess of 4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole was 98.2% ee. The crystals were analyzed by high performance liquid chromatography (condition (B)). As a result, the analogs in the crystals were 0.8
5% and 1.7% of a sulfone compound were present, and no other related substances were present.

Example 6 3.00 g of the wet crystals obtained in Reference Example 3 were mixed with acetone 1
The suspension was suspended in 0 mL, and water (40 mL) was added dropwise. After stirring for 6 hours, the precipitated crystals were separated. As a result of analyzing the wet crystal by powder X-ray diffraction, the wet crystal had a lattice spacing (d) of 8.33, 6.63, 5.86, and 4. for powder X-ray diffraction.
Powder X with characteristic peak at 82 Å
The line pattern is shown. X-ray powder diffraction chart [Fig. 9]
Shown in The wet crystals were analyzed by high performance liquid chromatography under (condition (B)). As a result, 0.61% of a sulfide compound and 0.56% of a sulfone compound were present as related substances in the crystals. Did not exist.

Example 7 The wet crystals obtained in Example 6 were dried. As a result of analyzing the crystals by powder X-ray diffraction, the crystals were found to have a lattice spacing (d) of 8.33, 6.63, 5.8 in powder X-ray diffraction.
The powder X-ray pattern showed a characteristic peak at 6,4.82 angstroms. The X-ray powder diffraction chart is shown in FIG. The crystals were analyzed by high performance liquid chromatography under (condition (A)). As a result, (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)] in the crystals was analyzed. The enantiomeric excess of -2-pyridyl] methyl] sulfinyl] benzimidazole is 99.8.
% Ee.

Example 8 3.00 g of the wet crystal obtained in Reference Example 3 was suspended in 10 mL of tetrahydrofuran, and water (80 mL) was added dropwise. After stirring for 5 hours, the precipitated crystals were separated. As a result of analyzing the wet crystals by powder X-ray diffraction, the wet crystals were found to have a lattice spacing (d) of 8.33, 6.63,
The powder X-ray pattern showed characteristic peaks at 5.86 and 4.82 angstroms. The powder X-ray diffraction chart is shown in FIG. The wet crystals were analyzed by high performance liquid chromatography under (condition (B)). As a result, 0.63% of a sulfide compound and 0.50% of a sulfone compound were present as related substances in the crystals. Did not exist.

Example 9 The wet crystals obtained in Example 8 were dried. As a result of analyzing the crystals by powder X-ray diffraction, the crystals were found to have a lattice spacing (d) of 8.33, 6.63, 5.8 in powder X-ray diffraction.
The powder X-ray pattern showed a characteristic peak at 6,4.82 angstroms. The powder X-ray diffraction chart is shown in FIG. The crystals were analyzed by high performance liquid chromatography under (condition (A)). As a result, (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)] in the crystals was analyzed. The enantiomeric excess of -2-pyridyl] methyl] sulfinyl] benzimidazole is 99.8.
% Ee.

Example 10 3.00 g of the wet crystal obtained in Reference Example 3 was suspended in 10 mL of isopropanol, and water (40 mL) was added dropwise.
After stirring for 5 hours, the precipitated crystals were separated. As a result of analyzing the wet crystals by powder X-ray diffraction, the wet crystals were found to have a lattice spacing (d) of 8.33, 6.63, 5.8 in powder X-ray diffraction.
The powder X-ray pattern showed a characteristic peak at 6,4.82 angstroms. The X-ray powder diffraction chart is shown in FIG. The wet crystals were analyzed by high-performance liquid chromatography under (condition (B)). As a result, 0.68% of a sulfide compound and 0.2% of a sulfone compound were found as analogous substances in the crystals.
64% were present and no other analogs were present.

Example 11 The wet crystals obtained in Example 10 were dried. As a result of analyzing the crystals by powder X-ray diffraction, the crystals were found to have a lattice spacing (d) of 8.33, 6.63, 5.8 in powder X-ray diffraction.
The powder X-ray pattern showed a characteristic peak at 6,4.82 angstroms. The powder X-ray diffraction chart is shown in FIG. The crystals were analyzed by high performance liquid chromatography under (condition (A)). As a result, (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)] in the crystals was analyzed. -2-pyridyl] methyl] sulfinyl] benzimidazole has an enantiomeric excess of 99.7.
% Ee.

Example 12 3.00 g of the wet crystals obtained in Reference Example 3 above were suspended in 10 mL of N, N-dimethylformamide, and water (40 mL) was added.
Was added dropwise. After stirring for 5 hours, the precipitated crystals were separated.
As a result of analyzing the wet crystal by powder X-ray diffraction, the wet crystal had a lattice spacing (d) of 8.33 and 6.
The powder X-ray pattern showed characteristic peaks at 63, 5.86, and 4.82 angstroms. An X-ray powder diffraction chart is shown in FIG. The wet crystals were analyzed by high performance liquid chromatography under (condition (B)).
As analogs in the crystals, there were 0.70% of sulfides and 0.41% of sulfones, and no other analogs.

Example 13 The wet crystals obtained in Example 12 were dried. As a result of analyzing the crystals by powder X-ray diffraction, the crystals were found to have a lattice spacing (d) of 8.33, 6.63, 5.8 in powder X-ray diffraction.
The powder X-ray pattern showed a characteristic peak at 6,4.82 angstroms. The X-ray powder diffraction chart is shown in FIG. The crystals were analyzed by high performance liquid chromatography under (condition (A)). As a result, (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)] in the crystals was analyzed. -2-pyridyl] methyl] sulfinyl] benzimidazole has an enantiomeric excess of 99.7.
% Ee.

Example 14 3.00 g of the wet crystal obtained in Reference Example 3 was suspended in 10 mL of methanol, and water (40 mL) was added dropwise. After stirring for 6 hours, the precipitated crystals were separated. As a result of analyzing the wet crystals by powder X-ray diffraction, the wet crystals were found to have a lattice spacing (d) of 8.33, 6.63, 5.86, and powder X-ray diffraction.
The powder X-ray pattern showed a characteristic peak at 4.82 angstroms. The X-ray powder diffraction chart is shown in FIG. The wet crystals were analyzed by high performance liquid chromatography under (condition (A)), and as a result, (R) in the crystals was analyzed.
The enantiomeric excess of 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole is 99.5% e
e. The wet crystals were analyzed by high performance liquid chromatography under (condition (B)). As a result, 0.72% of a sulfide compound and 0.60% of a sulfone compound were found as analogous substances in the crystals.
Was present and no other related substances were present.

Example 15 The wet crystals obtained in Example 14 were dried. As a result of analyzing the crystals by powder X-ray diffraction, the crystals were found to have a lattice spacing (d) of 8.33, 6.63, 5.8 in powder X-ray diffraction.
The powder X-ray pattern showed a characteristic peak at 6,4.82 angstroms. The powder X-ray diffraction chart is shown in FIG.

Example 16 3.00 g of the wet crystals obtained in Reference Example 3 were suspended in 10 mL of ethanol, and water (40 mL) was added dropwise. After stirring for 6 hours, the precipitated crystals were separated. As a result of analyzing the wet crystals by powder X-ray diffraction, the wet crystals were found to have a lattice spacing (d) of 8.33, 6.63, 5.86, and powder X-ray diffraction.
The powder X-ray pattern showed a characteristic peak at 4.82 angstroms. The powder X-ray diffraction chart is shown in FIG. The wet crystals were analyzed by high performance liquid chromatography under (condition (A)), and as a result, (R) in the crystals was analyzed.
The enantiomeric excess of -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole is 100% ee
Met. The wet crystals were analyzed by high performance liquid chromatography under (condition (B)). As a result, the sulfide form was 0.68% and the sulfone form was 0.63% as analogous substances in the crystals.
Was present and no other related substances were present.

Example 17 The wet crystals obtained in Example 16 were dried. As a result of analyzing the crystals by powder X-ray diffraction, the crystals were found to have a lattice spacing (d) of 8.33, 6.63, 5.8 in powder X-ray diffraction.
The powder X-ray pattern showed a characteristic peak at 6,4.82 angstroms. The X-ray powder diffraction chart is shown in FIG.

Example 18 3.00 g of the wet crystal obtained in Reference Example 3 was suspended in 10 mL of acetonitrile, and water (40 mL) was added dropwise. 6
After stirring for hours, the precipitated crystals were separated. As a result of analyzing the wet crystals by powder X-ray diffraction, the wet crystals were found to have a lattice spacing (d) of 8.33, 6.63, 5.8 in powder X-ray diffraction.
The powder X-ray pattern showed a characteristic peak at 6,4.82 angstroms. The powder X-ray diffraction chart is shown in FIG. The wet crystals were analyzed by high performance liquid chromatography under (condition (A)). As a result, (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) in the crystals was analyzed. ) -2-Pyridyl] methyl] sulfinyl] benzimidazole has an enantiomeric excess of 100%
ee. The wet crystals were analyzed by high performance liquid chromatography under (condition (B)). As a result, as analogs in the crystals, sulfide form 0.80%, sulfone form 0.33
% And no other related substances were present.

Example 19 The wet crystals obtained in Example 18 were dried. As a result of analyzing the crystals by powder X-ray diffraction, the crystals were found to have a lattice spacing (d) of 8.33, 6.63, 5.8 in powder X-ray diffraction.
The powder X-ray pattern showed a characteristic peak at 6,4.82 angstroms. The powder X-ray diffraction chart is shown in FIG.

Example 20 3.00 g of the wet crystals obtained in Reference Example 3 were suspended in 10 mL of dimethyl sulfoxide, and water (40 mL) was added dropwise. After stirring for 7 hours, the precipitated crystals were separated. As a result of analyzing the wet crystals by powder X-ray diffraction, the wet crystals were found to have a lattice spacing (d) of 8.33, 6.63,
The powder X-ray pattern showed characteristic peaks at 5.86 and 4.82 angstroms. The powder X-ray diffraction chart is shown in FIG. The wet crystals were analyzed by high performance liquid chromatography under (condition (A)). As a result, (R) -2-[[[3-methyl-4- (2,2,2)
-Trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole has an enantiomeric excess of 9
It was 9.6% ee. The wet crystals were analyzed by high performance liquid chromatography under (condition (B)). As a result, 0.79% of a sulfide form and 0.37% of a sulfone form were present as related substances in the crystals, and the other related substances were as follows. Did not exist.

Example 21 The wet crystals obtained in Example 20 were dried. As a result of analyzing the crystals by powder X-ray diffraction, the crystals were found to have a lattice spacing (d) of 8.33, 6.63, 5.8 in powder X-ray diffraction.
The powder X-ray pattern showed a characteristic peak at 6,4.82 angstroms. The powder X-ray diffraction chart is shown in FIG.

[0049]

According to the production method of the present invention, the difficult-to-remove sulfone form contained in the (R) -form or its salt or the (S) -form or its salt can be easily removed, and an extremely high mirror image can be obtained. Crystals of the (R) -form or a salt thereof or the (S) -form or a salt thereof having a body excess can be efficiently produced on a large-scale industrial scale with a high yield and a simple method.

[0050]

[Brief description of the drawings]

FIG. 1 is a powder X-ray diffraction chart showing wet crystals of Example 3 (2).

FIG. 2 is a powder X-ray diffraction chart showing wet crystals of Example 3 (3).

FIG. 3 is an X-ray powder diffraction chart showing wet crystals of Example 3 (4).

FIG. 4 is an X-ray powder diffraction chart showing the crystals of Example 3 (5).

FIG. 5 is a powder X-ray diffraction chart showing wet crystals of Example 4 (2).

FIG. 6 is an X-ray powder diffraction chart showing wet crystals of Example 4 (3).

FIG. 7 is a powder X-ray diffraction chart showing a wet crystal (raw material) of Example 5.

FIG. 8 is an X-ray powder diffraction chart showing the crystal (object) of Example 5.

FIG. 9 is a powder X-ray diffraction chart showing the wet crystals of Example 6.

FIG. 10 is a powder X-ray diffraction chart showing the crystal of Example 7.

FIG. 11 is a powder X-ray diffraction chart showing wet crystals of Example 8.

FIG. 12 is a powder X-ray diffraction chart showing the crystal of Example 9.

FIG. 13 is a powder X-ray diffraction chart showing the wet crystals of Example 10.

FIG. 14 is a powder X-ray diffraction chart showing the crystal of Example 11.

FIG. 15 is a powder X-ray diffraction chart showing the wet crystals of Example 12.

16 is a powder X-ray diffraction chart showing the crystal of Example 13. FIG.

FIG. 17 is a powder X-ray diffraction chart showing the wet crystals of Example 14.

FIG. 18 is a powder X-ray diffraction chart showing the crystal of Example 15.

FIG. 19 is a powder X-ray diffraction chart showing the wet crystals of Example 16.

20 is a powder X-ray diffraction chart showing the crystal of Example 17. FIG.

21 is a powder X-ray diffraction chart showing the wet crystals of Example 18. FIG.

FIG. 22 is a powder X-ray diffraction chart showing the crystal of Example 19.

FIG. 23 is a powder X-ray diffraction chart showing the wet crystals of Example 20.

FIG. 24 is a powder X-ray diffraction chart showing the crystal of Example 21.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61P 1/04 A61P 1/04 35/00 35/00 C07M 7:00 C07M 7:00 F term (reference) 4C063 AA01 BB08 CC26 DD12 EE01 4C086 AA02 AA04 BC39 GA08 GA15 GA16 MA04 ZA68 ZB26

Claims (17)

[Claims] (1) (S) -2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy) -2-pyridi
[Methyl] sulfinyl] benzimidazole / mH
_TwoO (m represents about 0.1 to about 1.0) or its salt
From an organic solvent solution or suspension
(S) -2-[[[3-methyl-4
-(2,2,2-trifluoroethoxy) -2-pyridi
[Methyl] sulfinyl] benzimidazole m '
H_TwoO (m 'represents about 0 to about 0.1) or a salt thereof
Manufacturing method. (2) (S) -2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy) -2-pyridi
[Methyl] sulfinyl] benzimidazole / mH
_TwoO (m shows about 0.1 to about 1.0) or its salt
2. The crystallization after the sintering.
The manufacturing method described. 3. The method according to claim 1, wherein the organic solvent is a solvent containing an acetic acid C _1-4 alkyl ester. 4. The method according to claim 3, wherein the acetic acid C _1-4 alkyl ester is ethyl acetate. 5. The method of claim 1, wherein m is from about 0.2 to about 0.8. 6. The method of claim 1 wherein m is about 0.5. (7) (S) -2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof is converted to (R) -2-[[[3-methyl-4- (2,
From a solution or suspension containing more than 2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof, (S) -2-
[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole · mH ₂ O (m represents about 0.1 to about 1.0)
Or selectively crystallizing crystals of a salt thereof, and crystallizing the resulting crystals from an organic solvent solution or suspension in which the crystals are dissolved or suspended, wherein (R) -2-[[[3 -Methyl-4- (2,2,2-trifluoroethoxy) -2
(S) -2- which is substantially free from -pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof.
(Indicating the m 'is about 0 to about 0.1) [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole · m'H ₂ O or A method for producing crystals of the salt. 8. The method according to claim 7, wherein the selective crystallization is carried out in an organic solvent containing water. 9. The method according to claim 8, wherein the organic solvent is one or more selected from esters, ketones, ethers, hydrocarbons and aromatic hydrocarbons. (10) (S) -2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole.m '
H ₂ O (m 'is about 0 to about 0.1 are shown) crystal lattice spacing of the powder X-ray diffraction (d) is 11.68,6.77,5.8
4, 5.73, 4.43, 4.09, 3.94, 3.8
8. A crystal showing a characteristic peak at 9, 3.69, 3.41 and 3.11 angstroms.
The manufacturing method described. (11) (S) -2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof is converted to (R) -2-[[[3-methyl-4- (2,
From a solution containing more than 2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof, (S) -2-[[[3-methyl-4- (2,2,2 -Trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof is selectively crystallized, and the obtained crystal is further subjected to a dehydration step to crystallize.
(S)-which is substantially free from (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or a salt thereof. 2-[[[3-methyl-4- (2,2,
2-trifluoroethoxy) -2-pyridyl] methyl]
Sulfinyl] benzimidazole or a salt thereof. 12. (R) -2- in a solution or a suspension.
[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or its salt or (S) -2-
The enantiomeric excess of [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole or its salt is about 8
The method according to claim 7 or 11, wherein the content is 0% ee or more. 13. The crystal selectively crystallized, wherein (1) the lattice spacing (d) of powder X-ray diffraction is 5.88, 4.70;
Crystals exhibiting characteristic peaks at 4.35, 3.66, 3.48 angstroms; (2) lattice spacing (d) of powder X-ray diffraction is 8.33, 6.63, 5.86, 4. 12. The production method according to claim 7, wherein the crystal is a crystal showing a characteristic peak at 82 angstroms, or (3) a mixture of the crystals of (1) and (2). 14. The method according to claim 7, wherein the crystal obtained by selectively crystallizing is further subjected to one or more crystallization steps. (15) (S) -2-[[[3-methyl-4-
(2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole.mH
₂ O (m represents about 0.1 to about 1.0) or a salt thereof. 16. The lattice spacing (d) of powder X-ray diffraction is 5.
A crystal showing a characteristic peak at 88, 4.70, 4.35, 3.66, 3.48 angstroms.
5. The crystal according to 5. 17. The lattice spacing (d) of powder X-ray diffraction is 8.
The crystal according to claim 15, which is a crystal showing a characteristic peak at 33, 6.63, 5.86, or 4.82 angstroms.