JP2011195500A - Method for producing (s)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoic acid/benzenesulfonic acid salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing high-purity (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoic acid/benzenesulfonic acid salt represented by formula (1) at a high efficiency and high yield, with less residues of an organic solvent.SOLUTION: The method for producing (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoic acid/benzenesulfonic acid salt which is characterized by crystallizing the (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butanoic acid/benzenesulfonic acid salt in water is provided.

Description

  The present invention relates to a novel method for producing (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzene sulfonate, which is a pharmaceutical having an excellent antiallergic action. About.

  Following formula (1)

(S) -4- [4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzenesulfonate (hereinafter referred to as “bepotastine besylate”) ) Is used as an antihistamine. Bepotastine besylate has a feature that secondary effects such as stimulation or suppression of the central nervous system can be minimized, and it is a useful compound as a pharmaceutical (active drug substance) for allergic diseases. It is.

  A drug substance such as bepotastine besylate is an active ingredient of pharmaceuticals, and there is a risk of causing phytotoxicity or the like due to impurities contained therein, so that it is required to have a very high purity. From the industrial viewpoint, it is desired to develop a method capable of efficiently and safely synthesizing useful bepotastine besylate as described above on a larger scale.

  Conventionally, bepotastine besylate has the following formula (2):

(S) -4- [4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid (hereinafter sometimes referred to as “bepotastine-free”) represented by monobenzenesulfonic acid It is manufactured by performing crystallization after forming a salt.

  Specifically, bepotastine-free form and benzenesulfonic acid monohydrate were reacted in ethyl acetate, once dehydrated and concentrated, and then crystallized in ethyl acetate. There is known a method for producing bepotastine besylate by crystallizing it again in acetonitrile (see Patent Document 1). As another method, a method is known in which a salt of bepotastine-free form and benzenesulfonic acid monohydrate is formed in acetonitrile, and bepotastine besylate is crystallized in acetonitrile as it is. (See Patent Document 2).

Japanese Unexamined Patent Publication No. 2000-198784 International Publication No. 2008/153289 Pamphlet

  According to the methods of Patent Documents 1 and 2, bepotastine besylate can be produced with a relatively high purity.

  However, in the methods described in Patent Documents 1 and 2, the amount of solvent used for crystallization was 8 to 40 ml with respect to 1 g of bepotastine besylate, and the amount thereof was very large. Therefore, especially when producing a large amount of bepotastine besylate, it has been desired to develop a method that can further reduce the amount of solvent used.

  Further, in the method described in Patent Document 1, it is necessary to perform dehydration concentration once after adding benzenesulfonic acid monohydrate, and it takes time until crystals are precipitated in ethyl acetate, which is efficient. There was a problem that it was not.

  Furthermore, in the methods described in Patent Documents 1 and 2, since highly toxic acetonitrile is used as the final crystallization solvent, there is a concern that acetonitrile may remain in the bepotastine besylate as a residual solvent. Therefore, it has been desired to use a highly safe solvent as the crystallization solvent.

  Therefore, the object of the present invention is to use a safe crystallization solvent and to reduce the amount of use thereof, and to produce bepotastine besylate with higher purity and higher yield and higher productivity. It is to provide a method.

  The present inventors have intensively studied to solve the above problems. As a result, in the purification of bepotastine besylate, it was found that when water was used for crystallization, bepotastine besylate was obtained in a small amount of solvent and in a high yield and purity. The invention has been completed.

  That is, the present invention provides the following formula (1)

(S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzenesulfonate represented by the formula (S) -4 -[4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzenesulfonate.

  According to the present invention, bepotastine besylate can be obtained with high yield and high purity. Specifically, by using water as a crystallization solvent, bepotastine besylate having a yield of 70% or more and a purity of 99.80% or more can be produced. This purity is a value of area% when measured by high performance liquid chromatography (hereinafter referred to as HPLC).

  Moreover, if water crystallization is performed in the final step of the purification stage, an organic solvent-free bepotastine besylate can be produced, and safety can be improved.

  Further, according to the present invention, the purity of bepotastine besylate can be increased with a much smaller amount of solvent compared to the case where ethyl acetate or acetonitrile is used as a crystallization solvent.

  The present invention crystallizes (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzenesulfonate (bepotastine besylate) in water. It is characterized by. Hereinafter, although explained in order, first, bepotastine besylate (hereinafter, sometimes referred to as crude bepotastine besylate) which is an object of crystallization will be explained.

(Crude bepotastine besylate)
In the present invention, bepotastine besylate (crude bepotastine besylate) to be crystallized can be produced by a known method. The crude bepotastine besylate can be prepared from a bepotastine-free product and benzenesulfonic acid monohydrate.

  The bepotastine-free body is not particularly limited and can be produced by a known method. For example, as described in Patent Document 1 above, ethyl (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoate is prepared in the presence of a base such as sodium hydroxide. It can be produced by hydrolysis at room temperature using a solvent such as ethanol.

  Moreover, as benzenesulfonic acid monohydrate, a commercially available product can be used as it is, or a purified product in some cases.

  Bepotastine besylate can be produced by contacting the bepotastine-free form with benzenesulfonic acid monohydrate to form a salt. What is necessary is just to use the usage-amount of a benzenesulfonic acid monohydrate in the range in which a salt is formed substantially 1: 1 with a bepotastine free body. Specifically, it is preferable to use 1 mol or more of benzenesulfonic acid monohydrate with respect to 1 mol of bepotastine-free form to be used. Benzenesulfonic acid monohydrate is a wet body, and it is difficult to accurately weigh, and considering the increase in the amount of water due to the addition of the hydrate, a slightly excessive amount may be used. Preferably, it is more preferably used in an amount of 1 to 5 mol, more preferably 1 to 2 mol, per mol of bepotastine-free body.

  In order to form a salt by bringing the bepotastine-free body and benzenesulfonic acid monohydrate into contact with each other, it is preferable to contact both in water or an organic solvent. Moreover, the mixed solvent of water and an organic solvent can also be used as needed.

  When water is used, bepotastine besylate may be crystallized as it is in the water, and crystallization can be carried out efficiently. In this case, bepotastine besylate obtained by bringing both into contact with water corresponds to the crude bepotastine besylate to be crystallized.

  Moreover, a bepotastine free body and benzenesulfonic acid monohydrate can also be made to contact in an organic solvent. Examples of usable organic solvents include halogenated hydrocarbons such as methylene chloride and chloroform, acetates such as methyl acetate and ethyl acetate, alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, Nitriles such as acetonitrile can be mentioned. Among these, when acetone or acetonitrile is used, it is easy to crystallize bepotastine besylate in these solvents, so that the operability can be improved, and furthermore, a high-purity product can be obtained. Can do. In particular, the purity can be increased by bringing both into contact in acetonitrile and crystallizing (crystallizing) the crude bepotastine besylate.

  In addition, when making both contact using water, when a yield, operativity, etc. are considered, it is preferable to use 3-5 ml of water with respect to 1 g of bepotastine free bodies. Moreover, when contacting both using the said organic solvent, what is necessary is just to determine suitably according to the solvent to be used, but when considering a yield and operativity, normally it is an organic solvent with respect to 1 g of bepotastine free bodies. It is preferable to use 3 to 15 ml.

  As a method of bringing the bepotastine-free form and benzenesulfonic acid monohydrate into contact, both may be mixed and brought into contact. Specifically, a bepotastine-free form is dispersed in water or an organic solvent, and benzenesulfonic acid monohydrate crystals (wet) are dispersed in the dispersion (which may be a solution in which the bepotastine-free form is dissolved). Body) may be added and mixed, or after the crystals (wet body) are charged into the reactor, the dispersion may be added to the reactor and mixed. Further, a solution in which benzenesulfonic acid monohydrate is dissolved in water or an organic solvent can be mixed with a dispersion in which a bepotastine-free product is dispersed in water or an organic solvent. In this case, the order in which both are added is not particularly limited, and the dispersion may be added to the solution, or the solution may be added to the dispersion. It is also possible to add both to the reactor simultaneously.

  The temperature at which the bepotastine-free product and benzenesulfonic acid monohydrate are brought into contact with each other to form a salt is not particularly limited, but is preferably 1 to 40 ° C, particularly 5 to 25 ° C. Moreover, the time required to form the salt is usually 30 minutes to 3 hours.

  In this way, bepotastine besylate can be produced by contacting bepotastine-free form with benzenesulfonic acid monohydrate. When the obtained bepotastine besylate is produced using water, bepotastine besylate can be crystallized in water as it is. In addition, in the case of producing using an organic solvent, the concentrate obtained by distilling off the solvent can be converted into a crude bepotastine besylate salt, or obtained by crystallization in the organic solvent. The resulting crystals can also be crude bepotastine besylate. Crystallization in an organic solvent yields a crude bepotastine besylate of higher purity. In this case, it is preferable to use acetone or acetonitrile, particularly acetonitrile. Is preferred.

  In the present invention, the crude bepotastine besylate is not particularly limited, but usually has a purity of 99.0 to 99.8% except for water and organic solvents. It is preferable. In addition, the method of the present invention is effective when a crude bepotastine besylate salt containing an organic solvent is targeted.

  In the present invention, the crude bepotastine besylate obtained by the above method is crystallized in water. Next, the water, crystallization conditions, etc. will be described.

(Water, crystallization conditions)
In the present invention, when bepotastine-free and benzenesulfonic acid monohydrate are contacted in water, bepotastine besylate can be crystallized in water as it is. In this case, the crystallized bepotastine besylate can be fractionated as it is, or it can be dissolved again in the water and cooled to crystallize the bepotastine besylate in water. . Furthermore, in order to obtain bepotastine besylate of higher purity, the crystallized crystal is taken out, and the crystal is recrystallized with water as a crude bepotastine besylate (crystallization in water). You can also.

  On the other hand, when the bepotastine-free product and benzenesulfonic acid monohydrate were contacted in an organic solvent, the organic solvent was distilled off, and the resulting concentrate (crude bepotastine besylate) A high-purity product can be obtained by dissolving in water and crystallizing bepotastine besylate in the water. Alternatively, crystals of crude bepotastine besylate can be precipitated in an organic solvent, and the resulting crystals (crude bepotastine besylate) can be dissolved in water and crystallized in the water. In any case, the amount of organic solvent contained in the crude bepotastine besylate is preferably small, and usually about 0.1 to 25% by mass in the crude bepotastine besylate. If the amount of the organic solvent is within this range, the crystallization in water is not adversely affected, and the organic solvent residue in the bepotastine besylate fractionated after crystallization can be reduced.

  The present invention is characterized in that bepotastine besylate is crystallized in water. When another solvent, for example, an organic solvent exemplified when contacting bepotastine-free form with benzenesulfonic acid monohydrate is used as a crystallization solvent, bepotastine besylate hardly forms crystals. In addition, when acetone or acetonitrile is used as a crystallization solvent among organic solvents, bepotastine besylate can be crystallized. In this case, acetone or acetonitrile is highly purified from the obtained crystals. Needed to be removed. On the other hand, in the present invention, since water is used, it is advantageous in terms of safety, and bepotastine besylate is easily crystallized, and a high-purity product can be easily produced.

  As the water used in the present invention, purified water, ultrapure water, distilled water, ion exchange water, tap water and the like can be used without any limitation. The amount of water used should be 0.7 to 70 ml with respect to 1 g of bepotastine besylate contained in crude bepotastine besylate in terms of impurity removal efficiency and yield per batch. Is preferable, and more preferably 0.7 to 35 ml. Even when bepotastine-free and benzenesulfonic acid monohydrate are contacted in water, prepare the amount of water within the above range before crystallizing bepotastine besylate. Is preferred.

  In addition, at the time of crystallization, it is preferable to use only water in order to obtain a high-purity bepotastine besylate and simplify the post-treatment. However, an organic solvent may be contained within a range that does not adversely affect crystallization. For example, when the bepotastine-free product and benzenesulfonic acid monohydrate are contacted in an organic solvent, the obtained crude bepotastine besylate may contain an organic solvent. In the present invention, the organic solvent contained in the crude bepotastine besylate is not excluded. Therefore, in the water in which the crude bepotastine besylate is dissolved and crystallizes the bepotastine besylate, the organic solvent exemplified above is preferably 15 parts by mass or less with respect to 100 parts by mass of water, Preferably, it may be included in a range of 13 parts by mass or less.

  In the present invention, an aqueous solution in which crude bepotastine besylate is dissolved in water is prepared, and then a supersaturated state of bepotastine besylate is formed by distilling off water or cooling the aqueous solution. Crystallize in water. In order to ensure high purity and a high yield per batch, it is preferable to raise the temperature to 40 ° C. to 70 ° C. during the preparation of the aqueous solution, and to cool the aqueous solution after the aqueous solution becomes a homogeneous solution. . If the cooling rate is too fast, the purity is not improved, and even if it is too slow, it is not efficient. Therefore, cooling is preferably performed at 1 to 50 ° C./hr, more preferably 5 to 40 ° C./hr. At this time, if bepotastine besylate is difficult to crystallize, a seed crystal can be added.

  Further, the final reached temperature when the aqueous solution is cooled is preferably not less than the temperature at which the aqueous solution does not freeze and not more than 30 ° C., more preferably 0 to 30 ° C., from the viewpoints of purity and production efficiency. In particular, the temperature is preferably 1 to 15 ° C. By maintaining the final reached temperature for 1 to 2 hours, bepotastine besylate of high purity can be recovered in high yield.

  The crystals of bepotastine besylate crystallized in water as described above are subjected to a known method, specifically, solid-liquid separation by filtration, centrifugation, etc., followed by natural drying, air drying, vacuum drying It can isolate by performing dry processing, such as.

  According to the method of the present invention, since bepotastine besylate is crystallized in water, a highly safe product can be obtained. After the method of the present invention, bepotastine besylate can be purified by crystallization with other organic solvents or by column treatment, but the method of the present invention produces bepotastine besylate. In this case, it is preferable to apply it to the final purification step.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

  First, conditions for HPLC measurement of bepotastine-free body will be described.

(Measurement conditions for bepotastine-free HPLC)
Apparatus: 2695-2996-2489 manufactured by WATERS
Detector: UV absorptiometer (measurement wavelength: 225 nm)
Column: GL Science Co., Ltd. Product name Inertsil ODS-3, inner diameter 4.6 mm, length 15 cm (particle diameter 5 μm)
Column temperature: 40 ° C. Constant temperature Sample temperature: 25 ° C. Constant temperature mobile phase A: Dissolve 4.9 g of potassium dihydrogen phosphate in 1800 ml of water, add 20 ml of acetonitrile, add 10% phosphoric acid to adjust the pH to 3.8. .
Mobile phase B: 4.2 g of potassium dihydrogen phosphate is dissolved in 800 ml of water, 1200 ml of acetonitrile is added, and 10% phosphoric acid is added to adjust the pH to 3.8.
Transfer of mobile phase: The concentration ratio was controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1, and the sample was analyzed. The total flow rate of mobile phase A and mobile phase B was 1.2 ml / min.
Table 1 summarizes the solvent composition of the gradient.

(Results from the above HPLC analysis)
Benzenesulfonic acid: A peak is observed at about 2 minutes.
(S) -4- [4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid (bepotastine free form): A peak is observed at about 20 minutes.
(S) -4- [4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid ethyl: A peak is observed at about 42 minutes.

Next, a method for quantifying benzenesulfonic acid will be described.
(HPLC conditions (quantification of benzenesulfonic acid))
Apparatus: 2695-2996-2489 manufactured by WATERS
Detector: UV absorptiometer (measurement wavelength: 254 nm)
Column: GL Science Co., Ltd. Product name Inertsil ODS-3, inner diameter 4.6 mm, length 15 cm (particle diameter 5 μm)
Column temperature: 40 ° C Constant temperature Sample temperature: 25 ° C Constant temperature Mobile phase: Dissolve 7.7 g of ammonium acetate in 1000 ml of water, add 500 ml of acetonitrile, and add 20 ml of acetic acid.
Flow rate: 1.0 ml / min Benzenesulfonic acid: A peak is observed at about 2 minutes.

(Quantitative (measurement method))
First, a solution of benzenesulfonic acid 0.01 mol / l to 0.1 mol / l was prepared, and a calibration curve was prepared by the HPLC analysis. The above HPLC analysis was performed by dissolving 20 mg of bepotastine besylate obtained in Examples and Comparative Examples in 3 ml of mobile phase. The ratio of benzenesulfonic acid and bepotastine-free body was determined from a calibration curve.

  In the following Examples and Comparative Examples, the HPLC purity of bepotastine besylate was confirmed by confirming that benzenesulfonic acid and bepotastine-free form were present at a ratio of 1: 1. This is a value obtained by converting the purity of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid in consideration of the amount.

Production Example 1
Synthesis of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid ethyl (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy 2.45 g (8.09 mmol) of piperidine is dissolved in 19.6 ml of acetone, and 1.89 g (9.71 mmol) of ethyl 4-bromobutanoate and 1.34 g (9.71 mmol) of potassium carbonate are added to the solution under nitrogen atmosphere. The mixture was stirred with heating under reflux for an hour. After confirming the disappearance of the raw materials, the reaction solution was cooled to room temperature, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure to give (S) -4- [4-[(4-chlorophenyl) (2 There was obtained 3.67 g (yield 99.3%) of ethyl -pyridyl) methoxy] piperidino] butanoate.

Production Example 2 (Production of bepotastine-free body)
Synthesis of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid (bepotastine free form) (S) -4- [4 obtained in Production Example 1 -3.67 g of ethyl [[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoate was dissolved in 22.0 ml of ethanol, 1.6 ml of 5N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. After confirming disappearance of the raw materials, the mixture was neutralized by adding 16.2 ml of 1N hydrochloric acid under ice cooling. The reaction mixture was concentrated under reduced pressure and the residue was extracted twice with chloroform. All the chloroforms used for extraction were combined, washed with water, and concentrated under reduced pressure to give (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid ( 2.78 g (bepotastine free form) (HPLC purity 99.339%, yield 88.4%) was obtained.

Example 1
Distilling 0.87 g (2.24 mmol) of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid (bepotastine free form) obtained in Production Example 2 When dissolved in 2.61 ml of water, 0.43 g (2.46 mmol) of benzenesulfonic acid monohydrate was added and stirred at room temperature for 30 minutes to precipitate crystals. The reaction solution (aqueous solution) was heated to 60 ° C. to dissolve the crystals, and then the system (aqueous solution) was cooled to 5 ° C. at 10 ° C./hr, and further stirred at 5 ° C. for 1 hour to precipitate crystals. It was. The resulting crystals were filtered, dried in vacuo for 12 hours, (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzenesulfonate (bepotastine) 0.87 g (yield 71.0%) of white crystals of besylate) was obtained. When the purity was confirmed by HPLC, it was 99.879%.

Example 2
The same operation as in Example 1 was performed except that the distilled water in Example 1 was replaced with tap water. As a result, 0.88 g of white crystals of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzenesulfonate (bepotastine besylate) were obtained. 71.5%). When the purity was confirmed by HPLC, it was 99.877%.

Example 3
(Production of crude bepotastine besylate in acetonitrile)
0.87 g (2.24 mmol) of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid (bepotastine free form) obtained in Production Example 2 was added to acetonitrile. When dissolved in 7.83 ml, 0.43 g (2.46 mmol) of benzenesulfonic acid monohydrate was added and stirred for 30 minutes at room temperature to precipitate crystals. The crystals were filtered off and acetonitrile was distilled off. The obtained crude bepotastine besylate had an HPLC purity of 99.772% and acetonitrile contained 18.7% by mass.

(Crystallization in water)
3.48 ml of distilled water was added to 1.5 g of the crude bepotastine besylate, and the resulting aqueous solution was heated to 60 ° C. to completely dissolve the crude bepotastine besylate. The mixture was cooled to 5 ° C at a rate of ° C / hr and further stirred at 5 ° C for 1 hour to precipitate crystals. The resulting crystals were filtered and dried in vacuo for 12 hours, and (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzenesulfonate (bepotastine) 0.86 g (yield 70.2%) of white crystals of besylate) was obtained. When the purity was confirmed by HPLC, it was 99.921%. The results are shown in Table 2.

Example 4
(Production of crude bepotastine besylate in acetone)
0.87 g (2.24 mmol) of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid (bepotastine free form) obtained in Production Example 2 was added to acetone. When dissolved in 7.83 ml, 0.43 g (2.46 mmol) of benzenesulfonic acid monohydrate was added and stirred for 30 minutes at room temperature to precipitate crystals. The crystals were filtered off and acetone was distilled off. The obtained crude bepotastine besylate had an HPLC purity of 99.329% and acetone containing 18.3% by mass.

(Crystallization in water)
3.48 ml of distilled water was added to 1.5 g of the crude bepotastine besylate, and the resulting aqueous solution was heated to 60 ° C. to completely dissolve the crude bepotastine besylate. The mixture was cooled to 5 ° C at a rate of ° C / hr and further stirred at 5 ° C for 1 hour to precipitate crystals. The resulting crystals were filtered and dried in vacuo for 12 hours, and (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzenesulfonate (bepotastine) 0.87 g (yield 71.0%) of white crystals of besylate) was obtained. When the purity was confirmed by HPLC, it was 99.812%. The results are shown in Table 2.

Comparative Examples 1-8
Crude bepotastine besylate produced in acetonitrile produced in Example 3 was used for crystallization. Table 2 shows the type of organic solvent, the amount used, and the crude bepotastine besylate at the temperature at which the crude bepotastine besylate was dissolved (the temperature after raising the temperature, and the heating temperature in Table 2). Attempted crystallization. The amount of the solvent used is described as the minimum amount that forms a homogeneous solution when the crude bepotastine besylate and the organic solvent are mixed and heated to the heating temperature. Further, in Table 2, a circle in the crystal precipitation column indicates that the crystal was obtained, and a cross indicates that the crystal was not obtained and became an oily product.

  The other conditions, the solution cooling rate, the reached temperature, the holding time at that temperature, the stirring conditions, the filtration, and the drying conditions were the same as in Example 3.

Comparative Examples 9-16
Crude bepotastine besylate produced in acetone produced in Example 4 was used for crystallization. Table 3 shows the types of organic solvents, the amounts used, and the crude bepotastine besylate at the temperature at which the crude bepotastine besylate was dissolved (the temperature after raising the temperature, and the heating temperature in Table 3). Attempted crystallization. The amount of the solvent used is described as the minimum amount that forms a homogeneous solution when the crude bepotastine besylate and the organic solvent are mixed and heated to the heating temperature. Further, in Table 3, “◯” in the crystal precipitation column indicates that the crystal was obtained, and “x” indicates that the crystal was not obtained and became an oily product.

  The other conditions, the cooling rate of the solution, the reached temperature, the holding time at that temperature, the stirring conditions, the filtration, and the drying conditions were the same as in Example 4.

Claims (1)

Following formula (1)

(S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzenesulfonate represented by the formula (S) -4 -[4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzenesulfonate manufacturing method.