JP5360605B2 - Acid addition salt of optically active piperidine derivative and process for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound having an excellent stability suitable as a medicine by forming a salt of a specific derivative with benzene sulfonic acid, etc. SOLUTION: This acid adduct salt of an optically active piperidine derivative is an objective salt expressed by the formula and having an absoluyte configuration of (S) compound, preferably (S)-4- 4-[(4-chlorophenyl)(2-pyridyl) methoxy]piperidino}butanoic acid.benzene sulfonic acid salt. Further, in order to obtain the above salt, it is preferable to form the salt by using 0.8-2.5 fold mol of benzene sulfonic acid or benzoic acid based on 1mol of (S)-piperidine derivative expressed by the formula in a solvent such as ethanol a 5-50 deg.C reaction temperature.

Description

  The present invention relates to a benzenesulfonate salt of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid having excellent antihistaminic activity and antiallergic activity, and a process for producing the same On the other hand, the acid addition salt is a particularly suitable compound as a pharmaceutical because it has low hygroscopicity and excellent physicochemical stability. Moreover, this invention relates to the pharmaceutical composition which uses these as an active ingredient.

  Formula (II) described in JP-A-2-25465

(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 piperidine derivative represented by the above or a salt thereof is a conventional antihistamine Secondary effects such as irritation or suppression of the central nervous system often seen in the case of allergic diseases, allergic skin diseases such as urticaria, eczema, dermatitis, allergic rhinitis, cold It is expected as a medicine for the treatment and treatment of sneezing due to upper respiratory tract inflammation, nasal discharge, cough, and bronchial asthma. However, although this piperidine derivative has one asymmetric carbon, this method for isolating an optically active substance has not been known so far.

  In general, it is known that pharmacological activity and safety are different between optical isomers, and that metabolic rate and protein binding rate are also different (Pharmacia, 25 (4), 311-336, 1989). Therefore, it is necessary to provide a pharmacologically preferable optical isomer with high optical purity to obtain a pharmaceutical product. Moreover, in order to ensure the high quality as a pharmaceutical of this optical isomer, it is desired to have a property excellent in physicochemical stability.

  As a result of intensive studies to solve this problem, the present inventors have obtained an optically active (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy group represented by the above formula (I). It has been found that benzenesulfonate and benzoate of piperidino] butanoic acid have excellent stability preferable as a pharmaceutical product, and the present invention has been completed.

  The first of the present invention is the formula (I)

It is related with the benzenesulfonate and benzoate of the optically active piperidine derivative whose absolute configuration represented by (S) is.

  According to a second aspect of the present invention, the optically active piperidine derivative, benzenesulfone, which undergoes a salt-forming reaction between the optically active piperidine derivative represented by the formula (I) whose absolute configuration is (S) and benzenesulfonic acid or benzoic acid. The present invention relates to a method for producing acid salts and benzoates.

  The third aspect of the present invention relates to a pharmaceutical composition comprising (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid / benzenesulfonate or benzoic acid as an active ingredient. .

  The benzenesulfonate or benzoate of (S) -piperidine derivative (I) is represented by the following reaction formula (1):

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

  In the salt formation reaction, benzenesulfonic acid or benzoic acid is used in an amount of 0.8 to 2.5 times mol, preferably 0.9 to 1.2 times mol for 1 mol of (S) -piperidine derivative (I). Can be used.

  The solvent used in the salt formation 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, ethanol , Alcohols such as 1-propanol and 2-propanol, acetone, dimethylformamide and the like, and ethanol, 2-propanol, acetonitrile and ethyl acetate are preferable. Further, as the solvent used in the present invention, the above-mentioned solvents may be used alone, or any two or more kinds of solvents may be mixed and used.

  The amount of the solvent used for the salt formation reaction is usually 0.5 to 30 L, preferably 0.8 to 20 L, more preferably, with respect to 1 mol of (S) -piperidine derivative (I). 1 to 10 L.

  The temperature of the salt formation reaction is, for example, 5 to 50 ° C., 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. Moreover, there is no restriction | limiting in particular in the addition method, For example, the method of dissolving benzenesulfonic acid or benzoic acid in a solvent to the liquid mixture of a (S) -piperidine derivative and a solvent can be mentioned.

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

  In general, for obtaining an optically active substance, methods such as asymmetric synthesis, optical resolution with an enzyme such as fractional crystal or lipase, and fractionation with an optical resolution column are known. In order to produce the optically active (S) -piperidine derivative (I) in the present invention, the following reaction formula (2)

(±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine represented by the formula (III), which is an intermediate, is derived into a diastereomeric salt, which is separated into fractional crystals. In the method, optically active (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine (IV) obtained by optical resolution is used as an intermediate.

  More specifically, the (S) -piperidine derivative (I) of the present invention has the following reaction formula (3):

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

  Step A is an N-alkylation reaction of (S) -piperidine (IV). The ester (V) is 1 to 3 moles, preferably 1 to 1.5 moles per mole of piperidine (IV). Can be used. 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; 1,4-dioxane And ethers such as tetrahydrofuran; ketones such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; and amides such as N, N-dimethylformamide, preferably water, acetonitrile, acetone, N, N-dimethyl. Formamide. These may be used alone or in combination with any two or more kinds of solvents.

  This reaction is preferably performed in the presence of a base. Examples of suitable bases include alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metals such as potassium carbonate. Carbonates; alkaline earth metal carbonates such as calcium carbonate; alkali metal acid carbonates such as sodium hydrogen carbonate; alkali metal hydrides such as sodium hydride; alkaline earth metal hydrides such as calcium hydride; sodium methoxide Alkali metal alkoxides such as trialkylamines such as triethylamine and pyridine compounds are preferable, and sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate is preferred. If these bases are monovalent bases, they are used in an amount of 1 to 3 moles, preferably 1 to 1.5 moles per mole of (S) -piperidine (IV). In the case of a divalent base, 0.5 to 1.5 times mol, preferably 0.6 to 1 times mol is used.

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

  Step B is a hydrolysis reaction of (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 converted to (S) -ester. (VI) The reaction can be carried out using 1 to 5 times mol, preferably 1 to 3 times mol per mol. The reaction temperature is, for example, 5 to 90 ° C, preferably 15 to 70 ° C. 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 following optically active piperidine derivative esters (S) -esters and (R) -esters were used to test differences in pharmacological action due to optical isomers.
(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 Hartley male guinea pig weighing 250 to 550 g, the method of Lands et al. (Lands, AM, Hoppe, JO, Siegmund, OH and Luduena, FF, J. Pharmacol. Exp. Ther. 95, 45 (1949)) was tested for histamine shock death inhibitory action. The experimental animals were fasted overnight (about 14 h), and then 5 ml / kg of the test substance was orally administered. Two hours after administration of the test substance, histamine hydrochloride 1.25 mg / kg was intravenously administered to induce histamine shock. After induction, experimental animals were observed for symptoms and the onset time of histamine shock was measured and observed until respiratory arrest or recovery. The test results are shown in Table 1.

7 days homologous PCA reaction inhibitory action Using a Hartley male guinea pig weighing 250 to 550 g, Levine et al. (Levine, BB, Chang, Jr. H., and Vaz, NM, J. Immunol. 106, 29 (1971) ) And PCA reaction inhibitory action was tested. 0.05 ml of guinea pig anti-BPO / BGG-IgE serum diluted 32 times with physiological saline was intradermally administered to two points on the left and right sides of the midline of the back of the guinea pigs shaved the day before.
Seven days later, 1 ml of 1% Evans Blue physiological saline containing 500 μg of benzylpenicilloyl bovine serum albumin (BPO / BSA) as an antigen was intravenously administered to induce a PCA reaction. After 30 minutes, the blood was exhaled, and the amount of pigment leaked after peeling the skin was determined according to the method of Katayama et al. (Katayama, S., Shinoya, H. and Ohtake, S., Microbiol. Immunol. 22, 89 (1978)). Measured. The experimental animals were fasted overnight (about 16 h), and the test substances were orally administered 2 hours before antigen administration. The test results are shown in Table 2.

From the test results of Table 1, both (S) -ester and (R) -ester showed a dose-dependent inhibitory action, and the ED ₅₀ values of (S) -ester and (R) -ester determined from a dose-response curve. Were 0.023 mg / kg and 1.0 mg / kg, respectively, and the (S) -ester showed about 43 times stronger activity than the (R) -ester. 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 a dose that suppresses 50% (ie, 35%), (S) -ester is about 100 times stronger than (R) -ester. showed that. From these, a clear difference in pharmacological action was recognized between the optical isomers, and it was confirmed that (S) -ester was superior to (R) -ester.

However, the (S) -ester is hygroscopic as shown in the stability test results (Table 4), and the (S) -piperidine derivative of the formula (I), which is a metabolite of (S) -SL, is , Which shows a pharmacological action equivalent to that of (S) -ester, but is itself a compound with extremely poor crystallinity, usually obtained as a rod-like substance, and it is difficult to secure and maintain a high quality as a pharmaceutical product. It was.
Therefore, crystallization of various acid addition salts of the (S) -piperidine derivative of the formula (I) was examined by the following method.

[Experiment 1]
The (S) -piperidine derivative of the formula (I) was dissolved in an organic solvent, and the acid shown in Table 3 was added to make it uniform, and then allowed to stand. When no precipitate was obtained, the solvent was distilled off, and a hardly soluble solvent was added and left again. Except for the case where the acid addition salt was oily or candy-like, the resulting solid was collected by filtration and dried under reduced pressure. As shown in Table 3, the properties of the various acid addition salts obtained were mostly oily or hygroscopic crystals.

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

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

  After pulverizing each of the above compounds, a test sample was passed through a 500 μm sieve. Divide each sample into a glass petri dish, store it at 40 ° C. and 75% humidity, remove it after one month, measure the content of related substances and the content of (R) -form by racemization, and start the test Compared with the content of time.

(A) Change in content of related substances A sample was dissolved in a mobile phase and prepared so that about 1% of the sample was contained in 1 ml of this liquid. With respect to 25 μl of the sample solution, each peak area percentage was measured by an automatic integration method by a liquid chromatography method.
Operating conditions Detector: UV absorption photometer (225nm)
Column: Cosmosil 5 ph 4.6 mm x 150 mm (trade name, manufactured by Nacalai Tesque)
Column temperature: Room temperature Mobile phase:
(S) -ester: mixed solution of 0.01M potassium dihydrogen phosphate buffer (adjusted to pH 5.8 with 0.1N sodium hydroxide solution) and acetonitrile (65:35)
Benzenesulfonate, benzoate: 0.01M potassium dihydrogen phosphate buffer (adjusted to pH 5.8 with 0.1N sodium hydroxide solution) and acetonitrile (72:28)
Flow rate: 0.9ml / min
Area measurement range: 50 minutes after sample injection

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

Operating conditions Detector: UV absorption photometer (220nm)
Column: ULTRON ES-OVM 4.6mm x 150mm (trade name, manufactured by Shinwa Kako)
Column temperature: Room temperature Mobile phase:
(S) -ester: 0.02M potassium dihydrogen phosphate buffer (adjusted to pH 4.6 with 0.1N sodium hydroxide solution) and ethanol (100: 13)
Benzenesulfonate, benzoate: 0.02M potassium dihydrogen phosphate buffer (adjusted to pH 5.5 with 0.1N sodium hydroxide solution) and acetonitrile (100: 16)
Flow rate: 0.9ml / min
Area measurement range: (S) range about twice the retention time of body Retention time: (R) body about 7-10 min
(S) Body about 13-15min

  From the test results of Table 4, it was found that (S) -esters showed a significant increase in related substances due to decomposition, and the optical purity decreased with an increase in (R) body weight. Therefore, it is a physicochemically unstable compound, and it cannot be said that high quality can be secured for a long time as a pharmaceutical product. On the other hand, it was confirmed that benzenesulfonate and benzoate showed no significant increase in the related substances and (R) body weight, and the hygroscopicity was low. Therefore, these are compounds having physicochemical stability as optically active substances.

  As described above, the benzenesulfonate and benzoate of (S) -piperidine derivative (I) are superior optically active substances having antihistamine activity and antiallergic activity, and act as active bodies in vivo. In addition, since it exhibits excellent physicochemical stability, it has suitable properties as a pharmaceutical product.

  The present invention will be described in more detail with reference to the following reference examples and examples, but the scope of the present invention is not limited thereto.

Reference example 1
(S)-(−)-4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidine (a) (±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine 18.58 g (61.36 mmol) was dissolved by heating in 1,000 ml of methyl acetate, and 6.93 g (18.42 mmol) of (−)-dibenzoyl-L-tartaric acid monohydrate was added and stirred. White precipitated crystals (Crystal 1) were filtered off, and the filtrate was concentrated under reduced pressure. The filtrate was concentrated to 100 ml, and the precipitated white crystals (crystal 2) were filtered off, and the filtrate was again concentrated under reduced pressure. About the obtained crystal | crystallization and filtrate concentrate, the composition ratio ((S) body: (R) body)) of each optical isomer was measured by the high performance liquid chromatograph method using an optical resolution column.
Crystal 1: 18.37 g ((S) isomer: (R) isomer = 29.51: 70.49)
Crystal 2: 0.57 g ((S) isomer: (R) isomer = 33.42: 66.58)
Filtrate concentrate: 7.70 g ((S) isomer: (R) isomer = 79.94: 20.06)

  (B) 7.70 g (25.43 mmol) of the filtrate concentrate obtained in (a) above was dissolved by heating in 280 ml of ethanol, and 3.82 g (25.45 mmol) of L-(+)-tartaric acid was added again. Heated to a homogeneous solution. After slow cooling, a small amount of seed crystals was added and allowed to stand. The precipitated crystals were collected by filtration and dried under reduced pressure at 40 ° C. Yield 8.68 g ((S) form: (R) form = 87.44: 12.56)

(C) About 8.68 g of the white crystals obtained in the above (b), ethanol recrystallization was repeated until the purity of the (S) isomer exceeded 99.5% (optical purity: 99.0% de).
Yield 3.87 g ((S) isomer: (R) isomer = 99.72: 0.28).

(D) To 2.13 g (4.70 mmol) of the white crystals obtained in the above (c), 15 ml of 1N aqueous sodium hydroxide solution was added and extracted with about 50 ml of chloroform. The extract is washed with water, dried over anhydrous sodium sulfate and concentrated to give the desired (S)-(−)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine as a pale yellow oil. Got as. 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) To crystal 1 obtained in Reference Example 1 (a), 200 ml of 0.5N aqueous sodium hydroxide solution was added. And extracted twice with about 100 ml of toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give 10.29 g of a pale yellow oil.

(B) 10.29 g of the pale yellow oil obtained in (a) above was dissolved by heating in 500 ml of methyl acetate, and 1.96 g (5.21 mmol) of (+)-dibenzoyl-D-tartaric acid monohydrate was added. Added and stirred. White precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure. About the obtained crystal | crystallization and filtrate concentrate, the composition ratio ((S) body: (R) body) of each optical isomer was measured by the high performance liquid chromatograph method using an optical resolution column.
White crystal: 4.31 g ((S) isomer: (R) isomer = 65.52: 34.48)
Filtrate concentrate: 7.93 g ((S) isomer: (R) isomer = 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 in 400 ml of ethanol by heating and overnight at room temperature. I left it alone. The precipitated crystals were collected by filtration and dried under reduced pressure at 40 ° C. Yield 8.56 g ((S) isomer: (R) isomer = 9.05: 90.95)

  (D) About 8.55 g of the white crystals obtained in the above (c), ethanol recrystallization was repeated until the purity of the (R) isomer exceeded 99.5% (optical purity: 99.0% de). Yield 4.15 g ((S) isomer: (R) isomer = 0.24: 99.76).

(E) To 4.00 g (8.83 mmol) of the white crystals obtained in the above (d), 15 ml of 1N aqueous sodium hydroxide solution was added and extracted with about 50 ml of chloroform. The extract is washed with water, dried over anhydrous sodium sulfate and concentrated to give the desired (R)-(+)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine as a pale yellow oil. Got as. Yield 2.66 g (Yield: 99.6%). [Α] _D ^23.5 + 12.2 ° (c = 2, MeOH)

Reference example 3
Synthesis of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid ethyl fumarate (a) (S)-(−) − obtained according to Reference Example 1 4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidine 1.33 g (4.39 mmol, optical purity: 99.4% ee) was dissolved in 15 ml of acetone to obtain 1.03 g of ethyl 4-bromobutanoate (5 .28 mmol) and 0.73 g (5.28 mmol) of potassium carbonate were added, and the mixture was heated to reflux with stirring for 7 hours. Insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the resulting pale yellow oil was separated by silica gel column chromatography using a mixed solvent of chloroform and methanol (solubility ratio 30: 1) as a developing solvent. . The isolated fraction of the target compound was concentrated under reduced pressure, and 1.71 g (yield) of oily (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoate was obtained. Ratio: 93.4%, optical purity: 99.4% ee). [Α] _D ²⁵ −6.6 ° (c = 1, MeOH)

  (B) 1.70 g (4.08 mmol) of the ethyl ester obtained in (a) above and 0.48 g (4.14 mmol) of fumaric acid were dissolved in 40 ml of ethanol to obtain a homogeneous solution, and then the mixed solution was reduced in pressure. Concentrated under. 18 ml of ethyl acetate was added to the residue to make a homogeneous solution again, and a small amount of seed crystals was added and left overnight. The precipitated crystals were collected by filtration and 1.97 g (yield: 90.1) of the desired (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid ethyl fumarate. %, Optical purity: 99.0% ee). Melting point: 123-124 ° C

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

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

  (B) (R) -4- [4-[(4-chlorophenyl) (2-pyridyl)] in the same manner as in (b) of Reference Example 3 using the ethyl ester obtained in (a) above. Methoxy] piperidino] butanoic acid ethyl fumarate (optical purity: 99.3% ee) was obtained. Melting point: 117-119 ° C

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

Reference Example 5
Synthesis of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid (S) -4- [4-[( 126.0 g (0.302 mol) of ethyl 4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoate was dissolved in 760 ml of ethanol, and 120.8 ml of 5N aqueous sodium hydroxide solution was added and left overnight at room temperature. After confirming disappearance of the raw materials, 121.1 ml of 5N hydrochloric acid was added to neutralize. After the precipitated salt was filtered off, the reaction mixture was concentrated under reduced pressure, added with 600 ml of methyl acetate and concentrated again under reduced pressure. The residue was dissolved in 600 ml of dichloromethane and sufficiently dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated to give the object product as an orange bowl (125.3 g). When this cocoon was further dried under reduced pressure, it became 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) -4- [4- obtained according to Reference Example 5 [(4-Chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid 0.5 g (1.29 mmol) is dissolved in 25 ml of ethyl acetate, and 0.20 g (1.14 mmol) of benzenesulfonic acid monohydrate is added. And concentrated under reduced pressure. When 25 ml of ethyl acetate was added again to the residue and allowed to stand for about 1 week, a part of the rod-like material crystallized. When mixed with a spatula and allowed to stand further, the whole crystallized. The crystals were recrystallized from 5 ml of acetonitrile to obtain 0.42 g (yield: 67.3%, optical purity: 99.2% ee) of the target product as light gray prism crystals. [Α] _D ²⁰ + 6.0 ° (c = 5, MeOH). Melting point: 161-163 ° C

Elemental analysis value (%): as C ₂₁ H ₂₆ ClN ₂ O ₃ .C ₆ H ₇ O ₃ S
Calculated value: 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) -4- [4- [obtained according to Reference Example 5 0.91 g (2.34 mmol) of (4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid is dissolved in 30 ml of acetone, and 0.29 g (2.37 mmol) of benzoic acid is added and homogenized. The bottom was concentrated. When 50 ml of isopropyl ether was added to the residue and allowed to stand for 2 days, a part of the rod-like substance crystallized. The whole was crystallized by stirring with a spatula and further standing. The crystals were recrystallized from 36 ml of ethyl acetate to obtain 0.87 g of the desired product (yield: 72.8%, optical purity: 99.4% ee) as white powder crystals. [Α] _D ²³ −4.6 ° (c = 1, EtOH). Melting point: 136-140 ° C

Claims (2)

Formula (IV)

A process for producing (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine represented by the formula:
Formula (III)

After adding (−)-dibenzoyl-L-tartaric acid monohydrate to a solution containing (±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine represented by Then, L-(+)-tartaric acid is added to the solution containing the filtrate to induce a diastereomeric salt with (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine, and the crystals are precipitated. The method including the process to make . Formula (I)

A method for producing a benzenesulfonate salt of an optically active piperidine derivative having an absolute configuration represented by (S),
(1) The method according to claim 1, wherein the formula (IV)

And (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine represented by formula;
(2) The (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine represented by the above formula (IV) obtained in the step (1) is converted into the following reaction formula (3).

(Wherein W is a detachable group and R is a lower alkyl group), and is converted into an optically active piperidine derivative having an absolute configuration represented by the above formula (I) of (S). ;
  And further comprising the step of converting it to benzene sulfonate.