JP3252741B2 - Racemization method for optically active piperidine compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for racemizing an optically active piperidine compound. The above-mentioned optically active piperidine compound has a general formula (II) useful as, for example, a drug, especially an anti-allergic drug.

[0002]

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Is useful as an intermediate when synthesizing an optically active piperidine derivative represented by the following formula (Japanese Patent Application No. 8-347).
No. 895).

[0004]

2. Description of the Related Art As described in Japanese Patent Application No. 8-347895, a conventional optically active piperidine derivative is prepared by optically resolving a racemic piperidine compound by a fractional crystallization method. After obtaining a piperidine compound, the compound represented by the general formula (III)

[0005]

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Wherein W is a group which can be eliminated, 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 and ethyl) to obtain an ester form. From the obtained ester form,
For example, an optically active piperidine derivative can be obtained by performing a hydrolysis reaction using an inorganic base. However, since the uncorresponding piperidine compound obtained during the optical resolution is not used, the yield of the optically active piperidine derivative in terms of the racemic piperidine compound is extremely low, so that it is not a method industrially satisfactory.

[0007]

DISCLOSURE OF THE INVENTION The present invention relates to an optically active piperidine compound which is obtained in good yield by optically resolving a racemic piperidine compound and then racemizing and recycling the other unnecessary optically active piperidine compound. It is an object to obtain a derivative.

[0008]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in order to improve the above-mentioned problems in the known production method, and as a result, have found that, after optically resolving a racemic piperidine compound, another unnecessary optical activity is obtained. By heating a piperidine compound in an alcohol in the presence of a base, it has been found that the optically active piperidine compound can be efficiently turned into a racemic piperidine compound, and the present invention has been completed.

The present invention relates to a compound of the formula (I)

[0010]

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An optically active piperidine compound represented by the formula:
The present invention relates to a method for racemizing an optically active piperidine compound, which is heated in an alcohol in the presence of a base.

In the present invention, preferred embodiments are as follows. 1) The above-mentioned racemization method, wherein the base is sodium hydroxide, potassium hydroxide or sodium methoxide. 2) The racemization method as described above, wherein the alcohol is n-butanol. 3) The above-mentioned racemization method wherein the reaction temperature is 90 to 110 ° C. 4) The above-mentioned racemization method, wherein the base is sodium hydroxide, potassium hydroxide or sodium methoxide, the alcohol is n-butanol, and the reaction temperature is 90 to 110 ° C.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION

The production method of the present invention employs, for example, the following reaction formula (1):

[0015]

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Can be represented by

The optically active piperidine compound represented by the formula (I) used in the production method of the present invention [hereinafter referred to as compound (I)
Is also referred to as (S) -4-[(4-chlorophenyl)
(2-pyridyl) methoxy] piperidine or (R) -4
Represents-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine. Compound (I) can be obtained by optically resolving the corresponding racemic 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine.
When used in the production method of the present invention, there is no particular limitation on the optical purity of compound (I).

The alcohol used in the process of the present invention
Examples of methanol include methanol, ethanol, n-propanol, iso-propanol, n-butanol, and t.
Aliphatic alcohols having 1 to 6 carbon atoms such as -butanol, n-amyl alcohol, iso-amyl alcohol, t-amyl alcohol, and n-hexanol, and preferably n -Butanol.

The alcohol used in the process of the present invention
The amount of the compound to be used is generally 0.5 to 10 based on compound (I).
The capacity is 0 times, preferably 1 to 50 times. The alcohol used in the production method of the present invention can be used alone or as a mixture.

The base used in the production method of the present invention includes, for example, hydroxides such as sodium hydroxide and potassium hydroxide, sodium methoxide, potassium methoxide, and the like.
Sodium ethoxide, potassium ethoxide, sodium n-propoxide, potassium n-propoxide, sodium iso-propoxide, potassium iso-propoxide, sodium n-propoxide, potassium n-propoxide, sodium n-butoxide, potassium Examples thereof include alkali metal alkoxides such as n-butoxide, sodium t-butoxide, and potassium t-butoxide, and preferred are sodium hydroxide, potassium hydroxide, and sodium methoxide.

The amount of the base used in the production method of the present invention is usually at least 0.1 mole, preferably 0.1 to 2 moles, per 1 mole of compound (I). When the base used in the production method of the present invention is an alkali metal alkoxide, the alkyl portion of the alkoxide of the alkali metal alkoxide and the alkyl portion of the alcohol may or may not match. .

The reaction temperature used in the process of the present invention is usually 30 to 150 ° C., preferably 50 to 150 ° C.
To 110 ° C, more preferably 90 to 110 ° C.

The reaction time used in the process of the present invention varies depending on the concentration of compound (I) used, the reaction temperature, the amount of base used, etc., but the reaction is usually completed in 0.5 to 10 hours.

In the production method of the present invention, the method of obtaining the target compound from the reaction mixture containing the produced racemic piperidine compound may be performed by a combination of ordinary washing operations and separation operations.

[0025]

According to the present invention, the optically active piperidine compound is optically resolved, and then the other unnecessary optically active piperidine compound is racemized and reused. Obtainable.

[0026]

EXAMPLES 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. The analysis conditions for liquid chromatography in the examples and comparative examples are as follows.

Analysis conditions for liquid chromatography (in the case of using an optical resolution column) Column: ULTRON ES-OVM 4.6 mmφX
150 mm (manufactured by Shinwa Kako Co., Ltd.) Temperature; 30 ° C. Eluent: Eluent obtained by mixing potassium dihydrogen phosphate buffer solution and acetonitrile at a ratio of 100: 10 (volume ratio). Preparation of potassium dihydrogen phosphate buffer solution: One liter of distilled water is added to 2.72 g of potassium dihydrogen phosphate and dissolved to prepare an aqueous potassium dihydrogen phosphate solution. A 0.1N aqueous sodium hydroxide solution is added to the obtained aqueous potassium dihydrogen phosphate solution to adjust the pH to 5.5. Flow rate: 0.7 ml / min Detection wavelength: 220 nm

[0028] Liquid Chromatography - (for internal standard method) analysis conditions _{Column; TSK-gel ODS-80T M} 4.6m
mφX250 mm (manufactured by Toso Corporation) Temperature: 40 ° C. Eluent: Eluent obtained by mixing potassium dihydrogen phosphate buffer solution and acetonitrile at a ratio of 40:60 (volume ratio). Preparation of potassium dihydrogen phosphate buffer solution: 400 ml of distilled water is added to 1.08 g of potassium dihydrogen phosphate and dissolved to prepare an aqueous solution of potassium dihydrogen phosphate. Flow rate: 1 ml / min Detection wavelength: 254 nm Internal standard substance: methyl p-nitrobenzoate

Example 1: Racemization of [(R) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine] (R) -4-[(4-chlorophenyl) (2-pyridyl) methoxy 42.6 g of piperidine (0.14 mol,
81.7% ee) was dissolved in 47 ml of n-butanol to obtain an alcohol solution. After adding 2.8 g (0.07 mol) of sodium hydroxide to the obtained alcohol solution, the mixture was reacted under heating and refluxing for 2.5 hours. After the reaction solution obtained after completion of the reaction was cooled to room temperature, 141 ml of toluene was added. After washing twice with 47 ml of water, the obtained organic layer was concentrated under reduced pressure to obtain a concentrated solution. When the optical purity of the obtained concentrate was measured by liquid chromatography, the optical purity was 1.3%.
ee. When the obtained concentrate was measured by an internal standard method using liquid chromatography, 4-
[(4-chlorophenyl) (2-pyridyl) methoxy]
It was found that 42.5 g of piperidine was produced.

Example 2: Racemization of [(S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine] (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy 6.0 g (0.02 mol, optical purity 94.5% ee) of piperidine was dissolved in 24 ml of n-butanol to obtain an alcohol solution. 1.2 g of 28% sodium ethoxide was added to the obtained alcohol solution.
006 mol), and the mixture was reacted by heating under reflux for 7 hours. After the reaction solution obtained after the completion of the reaction was cooled to room temperature, 48 ml of toluene was added. Water 12
After washing twice with milliliter, the obtained organic layer was concentrated under reduced pressure to obtain a concentrated liquid. When the optical purity of the obtained concentrate was measured by liquid chromatography, the optical purity was 1.2.
% Ee. When the obtained concentrate was measured by an internal standard method using liquid chromatography, 4-
[(4-chlorophenyl) (2-pyridyl) methoxy]
It was found that 6.0 g of piperidine was produced.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-6-336480 (JP, A) JP-A-4-234342 (JP, A) JP-A-50-50317 (JP, A) WO 96/23759 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 401/12 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula (I) In the presence of a base, an optically active piperazine compound represented by
A method for racemizing an optically active piperidine compound by heating in alcohol.