JP3107784B2 - Acid addition salts of optically active piperidine derivatives and their preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to (S) -4- [4-] which has excellent antihistamine activity and antiallergic activity.
[(4-Chlorophenyl) (2-pyridyl) methoxy]
Regarding the benzenesulfonate or benzoate of [piperidino] butanoic acid and a method for producing the same, the acid addition salt is a compound particularly suitable as a drug because it has low hygroscopicity and excellent physicochemical stability. The present invention also relates to a pharmaceutical composition comprising these as an active ingredient.

[0002]

2. Description of the Related Art The formula (II) described in JP-A-2-25465 is disclosed.

[0003]

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Wherein A represents a lower alkyl group, a hydroxyl group, a lower alkoxy group, an amino group, a lower alkylamino group, a phenyl group or a lower alkyl-substituted phenyl group, or a salt thereof. It has the characteristic that secondary effects such as stimulation or suppression on the central nervous system often seen in the case of conventional antihistamines are minimized, and allergic skin diseases such as urticaria, eczema and dermatitis, allergic It is expected as a medicine in the treatment and treatment of sneezing, nasal discharge, cough, and bronchial asthma caused by upper respiratory inflammation such as rhinitis and common cold. However, although this piperidine derivative has one asymmetric carbon, this method for isolating an optically active substance has not been known until now.

[0005]

It is generally known that optical isomers differ in pharmacological activity and safety, and also in metabolic rate and protein binding rate (Pharmacia, 25
(4), 311-336, 1989). Therefore, it is necessary to provide a pharmacologically preferable optical isomer with high optical purity in order to be a pharmaceutical. In addition, in order to ensure a high quality of the optical isomer as a pharmaceutical, it is desired that the optical isomer has properties excellent in physicochemical stability.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve this problem, and as a result, have found that the optically active (S) -4- [4-[(4 The inventors have found that benzenesulfonate and benzoate of -chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid have excellent stability which is preferable as a pharmaceutical, and have completed the present invention.

In the first aspect of the present invention, the formula (I)

[0008]

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The present invention relates to a benzenesulfonate and a benzoate of an optically active piperidine derivative having an absolute configuration represented by (S).

A second aspect of the present invention is the above-mentioned optically active piperidine derivative, which is obtained by subjecting an optically active piperidine derivative represented by the formula (I) whose absolute configuration is (S) to a salt-forming reaction with benzenesulfonic acid or benzoic acid. And a process for producing benzenesulfonate and benzoate.

A third aspect of the present invention is (S) -4- [4-
[(4-Chlorophenyl) (2-pyridyl) methoxy]
Piperidino] butanoic acid / benzenesulfonate or benzoic acid as an active ingredient.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION (S) -Piperidine derivative (I)
Is represented by the following reaction formula (1):

[0013]

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(Wherein HX represents benzenesulfonic acid or benzoic acid) (hereinafter referred to as a salt-forming reaction).

In the salt formation reaction, benzenesulfonic acid or benzoic acid is converted to the (S) -piperidine derivative (I)
0.8 to 2.5 times mol, preferably 0.9 to mol
It can be carried out using a 1.2-fold molar amount.

The solvent used in the salt-forming reaction is not particularly limited as long as it does not participate in the reaction. For example, nitriles such as acetonitrile and propionitrile, esters such as methyl acetate and ethyl acetate, methanol,
Examples include alcohols such as ethanol, 1-propanol and 2-propanol, acetone, dimethylformamide and the like, and preferred are ethanol, 2-propanol, acetonitrile and ethyl acetate. Further, as the solvent used in the present invention, the above-mentioned solvents may be used alone, or two or more arbitrary solvents may be mixed and used.

The amount of the solvent used in the salt forming reaction is
Usually, the amount is 0.5 to 30 L, preferably 0.8 to 20 L, more preferably 1 to 10 L, per 1 mol of the (S) -piperidine derivative (I).

The temperature of the salt forming reaction is, for example, 5 to 50 ° C.
The temperature is preferably 10 to 35 ° C, and the temperature at the time of salt precipitation is, for example, -30 ° C to 30 ° C, preferably -10 ° C to 15 ° C. The addition method is not particularly limited, and examples thereof include a method in which benzenesulfonic acid or benzoic acid is dissolved in a solvent and added to a mixture of the (S) -piperidine derivative and the solvent.

The salt of the (S) -piperidine derivative to be produced can be easily obtained by fractionating by filtration, centrifugation, etc., followed by washing and drying as appropriate according to a conventional method in this technical field. .

Generally, to obtain an optically active substance,
Methods such as asymmetric synthesis, fractional crystallization, optical resolution with an enzyme such as lipase, and fractionation with an optical resolution column are known. To produce the optically active (S) -piperidine derivative (I) in the present invention, the following reaction formula (2)

[0021]

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As shown in the above, the intermediate (±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine represented by the formula (III) is converted to a diastereomer salt, and this is converted to a diastereomer salt. Optically active (S) -4-[(4-chlorophenyl) obtained by optical resolution by the fractional crystallization method
(2-Pyridyl) methoxy] piperidine (IV) is used as an intermediate.

More specifically, the (S) -piperidine derivative (I) of the present invention is prepared by the following reaction formula (3)

[0024]

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(Wherein W is a group capable of leaving, for example, a halogen atom such as a chlorine atom, a bromine atom and an iodine atom, or a reactive ester group such as a methanesulfonyloxy group and a p-toluenesulfonyloxy group; Is a lower alkyl group such as methyl, ethyl and the like)).

In step A, the (S) -piperidine (IV)
-Alkylation reaction, 1 to 3 moles, preferably 1 to 1.5 moles of the ester (V) per mole of the piperidine (IV).
It can be carried out using a 1-fold molar amount. The above reaction is performed in an inert solvent. Suitable solvents include, for example, water;
Lower alcohols such as methanol, ethanol, propanol and butanol; nitriles such as acetonitrile and propionitrile; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane and tetrahydrofuran; Ketones such as ethyl methyl ketone and methyl isobutyl ketone; amides such as N, N-dimethylformamide; and preferred are water, acetonitrile, acetone and N, N-dimethylformamide. These may be used alone,
Any two or more solvents may be used as a mixture.

This reaction is preferably carried out in the presence of a base. Suitable bases include, for example, alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; potassium carbonate and the like. Alkaline earth metal carbonates such as calcium carbonate; alkali metal acid carbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride; alkaline earth metal hydrides such as calcium hydride; Alkali metal alkoxides such as sodium methoxide; trialkylamines such as triethylamine and pyridine compounds;
Preferably, it is sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate. These bases are 1
In the case of a valent base, it is used in an amount of 1 to 3 moles, preferably 1 to 1.5 moles, per 1 mole of (S) -piperidine (IV). If it is a divalent base, it is used in a molar amount of 0.5 to 1.5 times, preferably 0.6 to 1 time.

As a reaction accelerator, a small amount of metal iodide such as sodium iodide or potassium iodide may be added. The reaction can be performed at the reflux temperature of the reaction mixture, for example, 5 to 150 ° C, preferably 20 to 100 ° C.
° C. The reaction time is 2 to 24 hours.

Step B is a hydrolysis reaction of the (S) -ester (VI). In an aqueous alcohol such as aqueous methanol or aqueous ethanol, an inorganic base such as sodium hydroxide or potassium hydroxide is reacted with (S) ) -Ester (VI) can be carried out using 1 to 5 moles, preferably 1 to 3 moles, per 1 mole of the ester (VI). The reaction temperature is, for example, 5 to 90 ° C,
Preferably it is 15-70 degreeC. The reaction time is 1 to 10 hours. After completion of the reaction, the (S) -piperidine derivative (I) can be produced by neutralizing the reaction solution with a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid or oxalic acid.

[Pharmacological test] The difference in the pharmacological action of the optical isomers was tested using the following (S) -ester and (R) -ester of the optically active piperidine derivative ester. (S) -ester: (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid ethyl fumarate (prepared in Reference Example 3) (R) -ester: (R ) -4- [4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid ethyl fumarate (prepared in Reference Example 4)

Histamine Shock Death Inhibitory Effect Using a male Hartley guinea pig weighing 250 to 550 g, the method of Lands et al. (Lands, AM, Hoppe, JO, Si
egmund, OH and Luduena, FF, J. Pharmacol. Exp.
95, 45 (1949)). After the animals were fasted overnight (about 14 h), the test substance was orally administered at 5 ml / kg. Two hours after administration of the test substance, histamine hydrochloride was intravenously administered at 1.25 mg / kg to induce histamine shock. After the induction, the experimental animals were observed for symptoms and the time of onset of histamine shock was measured, and observation was made until respiratory arrest or recovery. Table 1 shows the test results.

[0032]

[Table 1]

Inhibition of homologous PCA reaction for 7 days Using male Hartley guinea pigs weighing 250-550 g, the method of Levine et al. (Levine, BB, Chang, Jr. H.,
and Vaz, NM, J. Immunol. 106, 29 (1971)). A guinea pig anti-BPO / BGG-IgE diluted 32 times with saline was placed at two points on the left and right sides of the back of the guinea pig shaved the day before.
Serum was administered 0.05 ml intradermally. 7 days later be
nzylpenicilloyl bovine serum albumin (BPO / BS
A) A PCA reaction was induced by intravenously administering 1 ml of 1% Evans Blue physiological saline containing 500 μg. Thirty minutes later, blood was released, the skin was peeled off, and the amount of the leaked pigment was determined by the method of Katayama et al. (Katayama, S., Shinoya, H. and Ohtake, S.,
Microbiol. Immunol. 22, 89 (1978)). Experimental animals were fasted overnight (about 16 h) and test substances were administered orally 2 hours before challenge. Table 2 shows the test results.

[0034]

[Table 2]

From the test results shown in Table 1, both (S) -ester and (R) -ester exhibited a dose-dependent inhibitory effect, and the (S) -ester and (R) -ester were determined from dose-response curves. ED ₅₀ values are each 0.023 mg / kg
, 1.0 mg / kg, and (S) -ester was (R)-
It showed about 43 times stronger activity than the ester. In addition, in the PCA reaction inhibition test shown in Table 2, both (S) -ester and (R) -ester inhibited the reaction in a dose-dependent manner.
The maximum inhibition rate in this test is estimated to be about 70%, and when compared with the 50% (ie, 35%) inhibitory dose, the (S) -ester has about 100 times stronger action than the (R) -ester. showed that. from these things,
There is a clear difference in pharmacological action between the optical isomers,
It was confirmed that (S) -ester was superior to (R) -ester.

However, the above (S) -ester is hygroscopic as shown in the stability test results (Table 4) described below.
Also, (S) of formula (I) which is a metabolite of (S) -S
-Piperidine derivatives exhibit the same pharmacological action as (S) -esters, but themselves are compounds with extremely poor crystallinity, and are usually obtained as candy-like substances, ensuring and maintaining high quality as pharmaceuticals. Was difficult. Therefore, crystallization of various acid addition salts of the (S) -piperidine derivative of the formula (I) was examined by the following method.

Experimental Example 1 The (S) -piperidine derivative of the formula (I) was dissolved in an organic solvent, acidified as shown in Table 3 was added, and the mixture was allowed to stand. When no precipitate was obtained, the solvent was distilled off, a poorly soluble solvent was added, and the mixture was allowed to stand again. Except when the acid addition salt was oily or candy-like, the obtained solid was collected by filtration and dried under reduced pressure. As shown in Table 3, many of the obtained acid addition salts were oily substances or hygroscopic crystals.

[0038]

[Table 3]

However, the benzenesulfonate and benzoate of the (S) -piperidine derivative of the formula (I) were obtained as non-hygroscopic crystals.

[Stability test] Benzenesulfonic acid salt: (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzenesulfonic acid salt (prepared in Example 1) ) Benzoate: (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzoate (prepared in Example 2)

Each of the above compounds was pulverized and passed through a 500 μm sieve to obtain a test sample. Each sample was divided into glass dishes and stored at 40 ° C and 75% humidity.
After being taken out after a month, the content of related substances and (R) -isomer content by racemization were measured and compared with the content at the start of the test.

(A) Change in the content of related substances A sample was dissolved in a mobile phase, and about 1 ml of the sample was dissolved in 1 ml of this solution.
%. With respect to 25 μl of the sample solution, each peak area percentage was measured by an automatic integration method by liquid chromatography. Operating conditions Detector: UV absorption spectrophotometer (225 nm) Column: Cosmosil 5 ph 4.6 mm x 150 mm (trade name,
Column temperature: room temperature Mobile phase: (S) -ester: 0.01 M potassium dihydrogen phosphate buffer solution (adjusted to pH 5.8 with 0.1 N sodium hydroxide solution) and a mixture of acetonitrile (65: 35) Benzenesulfonate, benzoate: a mixture of acetonitrile (72: 2) and 0.01 M potassium dihydrogen phosphate buffer (adjusted to pH 5.8 with 0.1 N sodium hydroxide solution)
8) Flow rate: 0.9ml / min Area measurement range: 50 minutes after sample injection

(B) (R) Body Weight About 5 mg of a sample was dissolved in the mobile phase to prepare 1 ml of this solution so that about 0.1% of the sample was contained. Sample solution 1.5μ
For each l, the percentage of each peak area was measured by an automatic integration method by liquid chromatography, and the (R) body weight (%) was calculated by the following equation.

[0044]

(Equation 1)

Operating conditions Detector: UV absorption spectrophotometer (220 nm) Column: ULTRON ES-OVM 4.6 mm × 150 mm (trade name,
Column temperature: room temperature Mobile phase: (S) -ester: 0.02 M potassium dihydrogen phosphate buffer (adjusted to pH 4.6 with 0.1 N sodium hydroxide solution) and ethanol (100: 13) Benzene sulfonate, benzoate: a mixture of 0.02 M potassium dihydrogen phosphate buffer (adjusted to pH 5.5 with 0.1 N sodium hydroxide solution) and acetonitrile (100:
16) Flow rate: 0.9 ml / min Area measurement range: (S) Range about twice as long as the body retention time

[0046]

[Table 4]

From the test results shown in Table 4, it was clarified that analogous substances of (S) -ester were remarkably increased by decomposition, and that the optical purity was decreased with an increase in the amount of (R) -isomer. Therefore, it is a physicochemically unstable compound, and it cannot be said that a high quality as a pharmaceutical can be ensured for a long period of time. On the other hand, it was confirmed that benzenesulfonate and benzoate did not show a remarkable increase in the amount of analogous substances and (R) isomers, and had low hygroscopicity. Therefore, these are compounds having physicochemical stability as optically active substances.

As described above, the benzenesulfonate and benzoate of the (S) -piperidine derivative (I) are more excellent optically active substances having antihistamine activity and antiallergic activity, and are active in vivo. Since it acts as a main body and exhibits excellent physicochemical stability, it has properties suitable as pharmaceuticals.

[0049]

The present invention will be described in more detail with reference to the following Reference Examples and Examples, which should not be construed as limiting the scope of the present invention.

Reference Example 1 (S)-(-)-4-[(4-chlorophenyl) (2-
(Pyridyl) methoxy] piperidine (a) 18.58 g of (±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine (61.3)
6 mmol) in 1,000 ml of methyl acetate under heating.
6.93 g of (-)-dibenzoyl-L-tartaric acid monohydrate
(18.42 mmol) was added and stirred. White precipitated crystals (crystal 1) were separated by filtration, and the filtrate was concentrated under reduced pressure. 100 filtrates
The filtrate was concentrated under reduced pressure again after filtering off the precipitated white crystal (crystal 2) by filtration. The composition ratio of the optical isomer ((S) form:
(R) form)) was measured by high performance liquid chromatography using an optical resolution column. Crystal 1: 18.37 g ((S) form: (R) form = 2)
9.51: 70.49) Crystal 2: 0.57 g ((S) form: (R) form = 3)
3.42: 66.58) Filtrate concentrate: 7.70 g ((S) form: (R) form = 7)
9.94: 20.06)

(B) 7.70 g (25.43 mmol) of the filtrate concentrate obtained in the above (a) was dissolved by heating in 280 ml of ethanol, and 3.82 g (25.4 g) of L-(+)-tartaric acid was dissolved.
(5 mmol) and heated again to obtain a homogeneous solution. After slow cooling, a small amount of a seed crystal was added and allowed to stand. The precipitated crystals are collected by filtration,
It dried under reduced pressure at 40 degreeC. Yield 8.68 g ((S) form:
(R) -form = 87.44: 12.56)

(C) Ethanol recrystallization of 8.68 g of the white crystals obtained in (b) above until the purity of the (S) form exceeds 99.5% (optical purity: 99.0% de). Repeated. Yield 3.87 g ((S) form: (R) form =
99.72: 0.28).

(D) To 2.13 g (4.70 mmol) of the white crystals obtained in (c) above, 15 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with about 50 ml of chloroform.
The extract was washed with water, dried over anhydrous sodium sulfate and concentrated, and the desired (S)-(-)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine was obtained as a pale yellow oil. As obtained. Yield 1.40 g (Yield: 98.
6%). [Α] _D ²⁴ -10.0 ° (c = 1, MeOH)

Reference Example 2 (R)-(-)-4-[(4-chlorophenyl) (2-
Pyridyl) methoxy] piperidine (a) 200 ml of a 0.5N aqueous sodium hydroxide solution was added to the crystal 1 obtained in Reference Example 1 (a), and toluene
Extracted twice with ml. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated to give a pale yellow oil.
29 g were obtained.

(B) 10.29 g of the pale yellow oil obtained in the above (a) was dissolved by heating in 500 ml of methyl acetate.
1.96 g of (+)-dibenzoyl-D-tartaric acid monohydrate
(5.21 mmol) was added and stirred. The white precipitated crystals were separated by filtration, and the filtrate was concentrated under reduced pressure. The composition ratio of the optical isomer ((S) form:
(R) form) was measured by high performance liquid chromatography using an optical resolution column. White crystals: 4.31 g ((S) form: (R) form = 65.
52: 34.48) Filtrate concentrate: 7.93 g ((S) form: (R) form = 16.
61: 83.39)

(C) 7.90 g (26.09 mmol) of the filtrate concentrate obtained in the above (b) and 3.90 g (25.98 mmol) of D-(-)-tartaric acid were dissolved by heating in 400 ml of ethanol. Left at room temperature overnight. The precipitated crystals are collected by filtration, and 4
It dried under reduced pressure at 0 degreeC. Yield 8.56 g ((S) form:
(R) -form = 9.05: 90.95)

(D) With respect to 8.55 g of the white crystals obtained in the above (c), ethanol recrystallization was performed until the purity of the (R) form exceeded 99.5% (optical purity: 99.0% de). Repeated. Yield 4.15 g ((S) form: (R) form =
0.24: 99.76).

(E) To 4.00 g (8.83 mmol) of the white crystals obtained in the above (d), 15 ml of a 1N aqueous sodium hydroxide solution was added, and extracted with about 50 ml of chloroform.
The extract was washed with water, dried over anhydrous sodium sulfate and concentrated, and the desired (R)-(+)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine was added to a pale yellow oil. As obtained. Yield 2.66 g (Yield: 99.
6%). [Α] _D ^23.5 + 12.2 ° (c = 2, MeO
H)

Reference Example 3 Synthesis of ethyl fumarate of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoate (a) Obtained according to Reference Example 1 )-(-)-
1.33 g (4.39 mmol, optical purity: 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine
99.4% ee) was dissolved in 15 ml of acetone, 1.03 g (5.28 mmol) of ethyl 4-bromobutanoate and 0.73 g (5.28 mmol) of potassium carbonate were added, and the mixture was stirred under reflux for 7 hours. The insoluble material was separated by filtration, the filtrate was concentrated under reduced pressure, and the obtained pale yellow oil was separated by silica gel column chromatography using a mixed solvent of chloroform and methanol (solution ratio: 30: 1) as a developing solvent. . The isolated fraction of the target compound was concentrated under reduced pressure to obtain oily (S) -4.
1.71 g of ethyl-[4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoate (yield: 93.4%, optical purity: 99.4% ee) were obtained.
[Α] _D ²⁵ -6.6 ° (c = 1, MeOH)

(B) 1.70 g (4.08 mmol) of the ethyl ester obtained in the above (a) and 0.48 g of fumaric acid
(4.14 mmol) was dissolved in 40 ml of ethanol to form a homogeneous solution, and the mixed solution was concentrated under reduced pressure. Ethyl acetate (18 ml) was added to the residue to make a homogeneous solution again, a small amount of seed crystals were added, and the mixture was allowed to stand overnight. The precipitated crystals were collected by filtration, and 1.97 g of the desired ethyl (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoate was obtained (yield: 90.1). %, Optical purity: 99.
0% ee). 123-124 ° C

Elemental analysis value (%): C ₂₂ H ₂₉ ClN ₂ O ₃
· C ₄ H ₄ O ₄ Calculated: C60.84 H6.24 N5.26 Found: C60.73 H6.32 N5.21

Reference Example 4 Synthesis of ethyl fumarate of (R) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid (a) Obtained according to Reference Example 2 )-(+)-
Using 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine (optical purity: 99.5% ee),
In the same manner as in (a) of Reference Example 3, (R) -4- [4-
[(4-Chlorophenyl) (2-pyridyl) methoxy]
Piperidino] ethyl butanoate (optical purity: 99.5% e
e) obtained. [Α] _D ²⁵ + 6.6 ° (c = 1, MeO
H)

(B) Using the ethyl ester obtained in (a) above, (R) was prepared in the same manner as in (b) of Reference Example 3.
-4- [4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid ethyl fumarate (optical purity: 99.3% ee) was obtained. Melting point: 117-1
19 ° C

Elemental analysis value (%): C ₂₂ H ₂₉ ClN ₂ O ₃
· C ₄ H ₄ O ₄ Calculated: C60.84 H6.24 N5.26 Found: C60.65 H6.11 N5.06

Reference Example 5 Synthesis of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid (S) -4 obtained according to Reference Example 3 (a). − [4
-Ethyl [-((4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoate 126.0 g (0.3
02mol) was dissolved in 760 ml of ethanol, 120.8 ml of a 5N aqueous sodium hydroxide solution was added, and the mixture was allowed to stand at room temperature overnight. After confirming the disappearance of the raw materials, the mixture was neutralized by adding 121.1 ml of 5N hydrochloric acid. After the precipitated salt was separated by filtration, the reaction mixture was concentrated under reduced pressure, 600 ml of methyl acetate was added, and the mixture was concentrated again under reduced pressure. The residue was dissolved in 600 ml of dichloromethane and dried sufficiently with anhydrous magnesium sulfate. After filtering off the insolubles, the filtrate was concentrated to give the desired product as an orange candy (125.3 g). This candy was further dried under reduced pressure to give a foam (120.2 g). [Α] _D ²⁵ + 3.4 ° (c
= 5, MeOH)

Example 1 Synthesis of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzenesulfonate (S) obtained according to Reference Example 5. -4- [4-
[(4-Chlorophenyl) (2-pyridyl) methoxy]
Piperidino] butanoic acid (0.5 g, 1.29 mmol) was dissolved in ethyl acetate (25 ml), benzenesulfonic acid monohydrate (0.20 g, 1.14 mmol) was added, and the mixture was concentrated under reduced pressure.
When 25 ml of ethyl acetate was added again to the residue and left for about one week, a part of the candy crystallized. After stirring with a spatula and leaving it to stand, the whole crystallized. The crystals were recrystallized from 5 ml of acetonitrile to obtain 0.42 g of the desired product (yield: 67.3%, optical purity: 99.2% ee) as pale gray prism crystals. [Α] _D ²⁰ + 6.0 ° (c = 5,
MeOH). Melting point: 161-163 ° C

Elemental analysis value (%): C ₂₁ H ₂₆ ClN ₂ O ₃
· C ₆ H ₇ O ₃ S Calculated: C59.28 H5.71 N5.12 Found: C59.27 H5.74 N5.10

Example 2 Synthesis of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid monobenzoate (S)-obtained according to Reference Example 5 4- [4-
[(4-Chlorophenyl) (2-pyridyl) methoxy]
0.91 g (2.34 mmol) of piperidino] butanoic acid was dissolved in 30 ml of acetone, and 0.29 g (2.37 g) of benzoic acid was dissolved.
mmol), and concentrated under reduced pressure. When 50 ml of isopropyl ether was added to the residue and left for 2 days, a part of the candy crystallized. Stirring with a spatula, and further leaving the whole crystallized. The crystals were recrystallized from 36 ml of ethyl acetate to give 0.87 g of the desired product (yield:
72.8%, optical purity: 99.4% ee) were obtained as white powder crystals. [Α] _D ²³ -4.6 ° (c = 1, EtO
H). Melting point: 136-140 ° C

Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61P 43/00 113 A61P 43/00 113 // C07M 7:00 (72) Inventor Shinji Takamura 5 Ube, 1978 Kogushi, Oji, Ube City, Yamaguchi Prefecture (56) References JP-A-2-25465 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 401/12 A61K 31/445 A61P 11/00 A61P 17/00 A61P 37/08 A61P 43/00 113 C07M 7:00 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A compound of the formula (I) A benzoate of an optically active piperidine derivative having an absolute configuration represented by (S) -form. 2. The optically active piperidine according to claim 1, wherein the optically active piperidine derivative having the absolute configuration represented by the formula (I) and having the (S) configuration is reacted with benzoic acid. A method for producing an acid addition salt of a derivative. 3. A pharmaceutical composition comprising (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid / benzoate as an active ingredient.