JPH10182635A - Optically active piperidine derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a diasteremoer salt useful as an intermediate for syntheses of pharmaceuticals having antihistaminic and antiallergic activities by optically resolving a specific piperazine derivative by using L(+)-tartaric acid. SOLUTION: This diastereomer, which consists of (S)-(-)-4-[(4-chlorophenyl)(2- pyridyl)methoxyl]piperidine.L(+)-tartarate of formula I, is obtained by making a racemic modification of formula II react with L(+)-tartaric acid, and fractivonally crystallizing the formed salt. Furthermore, by treating this diastereomer slat with an alkali to decompose, (S)-(-)-4-[(4-chlorophenyl)(2- pyrizyl)methoxyl]piperidine can be obtained.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an optically active piperidine derivative which is a raw material for synthesizing a drug having, for example, antihistamine activity and antiallergic activity, and a method for producing the same.

[0002]

2. Description of the Related Art Formula (IV) derived from the optically active piperidine derivative of formula (II) of the present application, for example, described in JP-A-2-25465:

[0003]

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(Wherein A represents a lower alkyl group, a hydroxy group, a lower alkoxy group, a phenoxy group, an amino group, a lower alkylamino group, an alinino group, a phenyl group, and a phenyl group substituted with a lower alkyl group. Piperidine derivative or a salt thereof represented by the formula (1) represents a feature that secondary effects such as central nervous system irritation or suppression often seen in the case of conventional antihistamines are minimized. And urticaria,
Allergic skin diseases such as eczema and dermatitis, allergic rhinitis, sneezing due to upper respiratory tract inflammation, nasal discharge, cough,
It is useful as a pharmaceutical in the treatment and treatment of bronchial asthma.

[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. However, the piperidine derivative (I
The compound of the formula (II) of the present invention, which is a raw material for the synthesis of V), has one asymmetric carbon and can be obtained as a racemate. Therefore, it is desired that a racemate is optically resolved as a raw material of an optical isomer having a high pharmacological activity.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies for solving the problems, and as a result, reacted L (+)-tartaric acid with a racemic piperidine derivative represented by the following formula (I). The diastereomer salt produced was fractionally crystallized, and the salt was treated with an alkali and decomposed to obtain an optically active piperidine derivative (II). Thus, the present invention was completed.

A first aspect of the present invention is that of formula (II):

[0008]

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And an optically active piperidine derivative represented by the formula:
Formula (III) from (+)-tartaric acid:

[0010]

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The diastereomeric salt represented by the formula:

A second aspect of the present invention is a compound represented by the formula (I):

[0013]

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Wherein L (+)-tartaric acid is reacted with the racemic piperidine derivative represented by the formula (1), and the resulting diastereomer salt (III) is fractionated and crystallized. .

A third aspect of the present invention is that the diastereomer salt (III) of the optically active piperidine derivative of the formula (II) is separated and crystallized, and then treated with an alkali to decompose the optically active piperidine derivative. The present invention relates to the production method (II).

[0016]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In order to obtain an optically active substance, generally, methods such as asymmetric synthesis, optical resolution with an enzyme such as fractional crystallization or lipase, and fractionation with an optical resolution column are known. In the present invention, the optically active piperidine derivative (I
To produce I), for example, the following reaction scheme:

[0017]

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As shown in the formula (I), (±)
-4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidine is converted to a diastereomeric salt with L (+) tartaric acid, which is obtained by the method of fractional crystallization. And the salt decomposition thereof to obtain an optically active piperidine derivative (II).

In the above reaction formula, a salt formation reaction in which a piperidine derivative (racemate) and an optically active carboxylic acid (optical resolving agent) are reacted to form a diastereomer salt, and the subsequent reaction mixture is cooled, This means that a sparingly soluble diastereomer salt is crystallized and then isolated by salt decomposition.

The optical resolving agent of the present invention is L (+)-tartaric acid. The amount of the optical resolving agent used is, for example, 0.5 to 2 times, preferably 0.6 to 1.1 times the mol of the racemic form.

In order to carry out the process of the present invention, the (±) -piperidine derivative of the formula (I) is reacted with an optical resolving agent in a suitable solvent, and is dissolved by heating if necessary, and then cooled if necessary. To obtain diastereomeric salts that precipitate.

In the present invention, as a pretreatment for forming a diastereomer salt of a racemate and an optically active tartaric acid, the composition ratio of the optical isomer in the crystal and the mother liquor is changed by using another optically active tartaric acid. Later, the optically active tartaric acid of the present invention can act. Such another optically active tartaric acid can be, for example, (-)-dibenzoyl-L-tartaric acid or (+)-dibenzoyl-D-tartaric acid. In this pretreatment, for example, a piperidine derivative (racemic) is used in a weight ratio of 30 to 200 times, preferably 50 to 100 times.
It is dissolved in the same amount of a solvent to be described later, and for example, (-)-dibenzoyl-L-tartaric acid monohydrate is used in an amount of, for example, 0.2 to 0.5 mol per mol of the piperidine derivative (racemic form).
Preferably, the reaction can be performed by adding 0.25 to 0.3 times mol.

For example, the diastereomer salt obtained by the above pretreatment contains a large amount of the (R) form, and the mother liquor contains a large amount of the (S) form. For example, when (+)-dibenzoyl-D-tartaric acid monohydrate is used, a composition having a composition ratio opposite to the above can be obtained. Salt decomposition from these diastereomeric salts can be conveniently carried out in the same manner as described below.

Accordingly, in the present invention, the L (+)-tartaric acid of the present invention is allowed to act on a mother liquor or a diastereomer salt containing a large amount of the desired (S) form by the above pretreatment. Can be obtained more efficiently.

The solvent used in the salt formation reaction of the present invention is
There is no particular limitation as long as the solvent does not participate in the reaction. Examples thereof include acetonitrile, nitriles such as propionitrile, methyl acetate, esters such as ethyl acetate, methanol, ethanol, 1-propanol, and 2-propanol. Alcohols, acetone, dimethylformamide and the like can be mentioned, and preferred are ethanol, 1-propanol and ethyl acetate. Further, the solvent used in the present invention may be used alone the above solvent,
Any two or more solvents may be used as a mixture.

The solvent used in the salt formation reaction in the pretreatment of the present invention is not particularly limited as long as it does not participate in the reaction. For example, nitriles such as acetonitrile and propionitrile, methyl acetate, acetic acid Esters such as ethyl and ketones such as acetone and methyl ethyl ketone can be mentioned.

The amount of the solvent used in the salt formation reaction is
Usually, the amount is, for example, 3 to 50 times (weight), preferably 5 to 40 times (weight) the piperidine derivative (racemate).

The temperature of the salt formation reaction of the present invention is, for example, 10
To 150 ° C, preferably 20 to 100 ° C, and the temperature at the time of salt precipitation is -30 to 80 ° C, preferably -5 to 70 ° C. The pre-treatment salt formation reaction and salt precipitation can be carried out at the same temperature as described above.

In the salt-forming reaction of the present invention, the order of addition of the starting materials is not particularly limited, and examples thereof include a method of adding a piperidine derivative to a solution in which an optical resolving agent is dissolved. The same can be performed in the salt formation reaction of the pretreatment.

In the present invention, the diastereomer salt can be fractionated by recrystallizing the salt from a suitable solvent. In this case, the solvent used in the above-mentioned salt forming reaction can be used in the same manner, and it may be used alone or as a mixture of two or more solvents. The amount of the solvent used in the fractional crystallization is, for example, 3 to 100 times (by weight), preferably 5 to 50 times (by weight) the diastereomer salt. The salt dissolution temperature is, for example, 10 to 15
The temperature is 0 ° C, preferably 20 to 100 ° C, and the temperature at the time of precipitation is -30 to 80 ° C, preferably -5 to 70 ° C. This fractional crystallization can be repeated until a certain optical purity is reached.

The diastereomer salt (poorly soluble salt) obtained as described above can be separated into an optically active piperidine derivative and an optical resolving agent by treating with an aqueous alkali solution. The aqueous alkali solution used here is, for example, an aqueous alkali metal hydroxide solution such as sodium hydroxide or potassium hydroxide, and contains at least an equimolar amount of the alkali metal hydroxide with respect to the diastereomer salt. The optically active piperidine derivative can be isolated from the aqueous alkali solution by extracting it with an extraction solvent such as ethyl acetate, ether, toluene, chloroform or methylene chloride, and concentrating the extracted solution under reduced pressure. The aqueous alkali solution after the extraction is, for example, acidified with hydrochloric acid, sulfuric acid or the like, and then extracted using an extraction solvent such as ethyl acetate,
The optical resolving agent can be recovered by concentrating the extraction solution under reduced pressure, and the recovered optical resolving agent can be used repeatedly if it is purified, for example, by recrystallization.

The assay of the optical purity of the obtained optically active piperidine derivative can be performed by high performance liquid chromatography using an optical resolution column.

HPLC area ratio method: A sample is dissolved in acetonitrile to prepare a sample solution. The peak area percentages of the S-form and the R-form of the sample solution are measured by an automatic integration method, and the optical purity (ee or de) is calculated from the following equation.

[0034]

(Equation 1)

Operating conditions Detector: UV absorption spectrophotometer (220 nm) Column: ULTRON ES-OVM 4.6 mm × 150 mm (trade name:
Column temperature: constant temperature around 30 ° C. Mobile phase: potassium dihydrogen phosphate buffer and acetonitrile are mixed at a ratio of 100: 10 (volume ratio). Preparation of potassium dihydrogen phosphate buffer: One liter of water was added to 2.72 g of potassium dihydrogen phosphate and dissolved.
Adjust to pH 5.5 with N sodium hydroxide solution. Flow rate: 0.7ml / min S-body retention time 15-18mi
Adjust to n. Area measurement range: (S) about twice as long as the retention time of the body. Retention time: (R) about 10 to 13 min. (S) about 15 to 18 min.

[0036]

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

Optical Resolution of (S)-(-)-4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidine Example 1 (a) (±) -4-[(4-chlorophenyl) (2 -Pyridyl) methoxy] piperidine 18.58 g (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 = 29.
51: 70.49) Crystal 2: 0.57 g ((S) form: (R) form = 33.
42: 66.58) Filtrate concentrate: 7.70 g ((S) form: (R) form = 79.
94: 20.06)

(B) 7.70 g (25.43 mmol) of the filtrate concentrate obtained in the above (a) was dissolved in 280 ml of ethanol while heating, 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 (optical purity: 7
4.9% de)

(C) With respect to 8.68 g of the white crystal obtained in the above (b), the optical purity of the (S) form is 99.0%.
The ethanol recrystallization was repeated until it exceeded de. The yield was 3.87 g (optical purity: 99.4% de). (Α) _D
²⁵ 11.4 ° (c = 1, MeOH). Melting point: 181-
183 ° C Elemental analysis value (%): C ₁₇ H ₁₉ ClN ₂ O · C ₄ H ₆ O ₆
Calculated value: C55.69 H5.56 N6.19 Actual value: C55.59 H5.56 N6.06

(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 (98.6)
%). [Α] _D ²⁴ -10.0 ° (c = 1, MeOH)

Example 2 0.50 g (3.33 mmol) of L-(+)-tartaric acid was dissolved by heating in 20 ml of ethanol, and (±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine 1 was added. 0.000 g (3.30 mmol) was added and stirred. Further, 10 ml of ethyl acetate was added, and the mixture was stirred for 3 hours. The precipitated white crystals were collected by filtration and dried at 40 ° C. under reduced pressure. The composition ratio of the optical isomer ((S) -form: (R) -form) of the obtained crystal was measured by a high-performance liquid chromatography method using an optical resolution column. Yield 0.82 g (optical purity: 34.5% de)

Reference Example 1 (a) 200 ml of 0.5N aqueous sodium hydroxide solution was added to the crystal 1 obtained in Example 1 (a), and about 100 parts of toluene were added.
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)

[0044]

As described above, the racemic form (S)
The method of the present invention for obtaining-(-)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine is a simple and efficient method. Further, the obtained optically active compound is useful as a raw material for synthesizing a drug having antihistamine activity and antiallergic activity.

Claims (3)

[Claims] (1) Formula (II): Formula (III) from an optically active piperidine derivative represented by the following formula and L (+)-tartaric acid: A diastereomer salt represented by the formula: 2. Formula (I): Wherein L (+)-tartaric acid is reacted with a racemic piperidine derivative represented by the formula (1), and the resulting diastereomeric salt is fractionated and crystallized (III)
Manufacturing method. 3. The optically active piperidine derivative (II), characterized in that the diastereomer salt (III) of the optically active piperidine derivative obtained by the method according to claim 2 is fractionated and crystallized and then treated with an alkali to decompose it. ) Manufacturing method.