JP2002105056A - Method for purifying 2-chloro-4-(1-piperidinylmethyl) pyridine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for purifying 2-chloro-4-(1-pyperidinylmethyl) pyridine which is useful as a raw material for a medicine, an agrochemical or the like, easily effectively on an industrial scale. SOLUTION: 2-Chloro-4-(1-pyperidinylmethyl)pyridine is converted to a salt with an organic or inorganic acid, and crystallized out. Subsequently, the salt is neutralized inversely with a basic aqueous solution to purify it to a highly pure product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for purifying 2-chloro-4- (1-piperidinylmethyl) pyridine, a compound useful as a raw material for medicines, agricultural chemicals and the like.

[0002]

2. Description of the Related Art As a method for producing 2-chloro-4- (1-piperidinylmethyl) pyridine, a compound obtained by chlorinating 2-chloro-4-methylpyridine is treated with hydrogen and piperidinyl in the presence of a hydrogenation catalyst. (Japanese Unexamined Patent Application Publication No.
231288), a method of piperidinating 2-chloro-4-chloromethylpyridine and the like are known.

[0003]

In order to remove a few percent of by-produced impurities, purification by distillation is possible, but the boiling point of 2-chloro-4- (1-piperidinylmethyl) pyridine is 119 to 120. Because of high temperature of 1 ° C / mmHg and poor purification efficiency, it is difficult to mass produce high purity products industrially. Therefore, a simple purification method has been required for industrially producing 2-chloro-4- (1-piperidinylmethyl) pyridine.

[0004]

Means for Solving the Problems The inventors of the present invention have intensively studied a method for purifying and removing impurities, and have found that crude 2-chloro-4- (1-piperidinylmethyl) pyridine can be converted into an organic acid or an inorganic acid in a solvent. After neutralization with an acid and crystallization of the formed salt, reverse neutralization with a basic aqueous solution gives purified 2-chloro-4-.
The inventors have found that (1-piperidinylmethyl) pyridine can be obtained, and have reached the present invention.

[Detailed Description of the Invention] That is, according to the present invention, a salt formed by neutralizing crude 2-chloro-4- (1-piperidinylmethyl) pyridine with an organic acid or an inorganic acid is crystallized, 2-chloro-4- (1-
Piperidinylmethyl) pyridine.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, 2-chloro-4- of the present invention is described.
The method for purifying (1-piperidinylmethyl) pyridine will be described in detail.

[0007] The 2-chloro- represented by the formula [1] of the present invention.
4- (1-Piperidinylmethyl) pyridine may be produced by any method, for example, 2-chloro-
It is obtained by piperidinylation of 4-chloromethylpyridine.

The organic acids used in the present invention include oxalic acid, fumaric acid, maleic acid, trifluoroacetic acid, p-
Examples thereof include toluenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid. Among them, oxalic acid, fumaric acid, and maleic acid, which easily form salt crystals, are more preferable.

The inorganic acids used in the present invention include hydrochloric acid, sulfuric acid, nitric acid and the like. Among them,
Hydrochloric acid and sulfuric acid, which easily form salt crystals, are more preferred.

The amount of the organic acid or inorganic acid used is 2-chloro-4- (1-piperidinylmethyl).
What is necessary is just to use 0.5 molar equivalent or more with respect to pyridine,
Preferably 0.5 to 5 molar equivalents, more preferably 0.5 to 2 molar equivalents.

The method for preparing the salt of the present invention comprises 2-chloro-4
What is necessary is just to determine suitably according to the combination of-(1-piperidinylmethyl) pyridine and an acid.
It can be prepared by directly adding and mixing chloro-4- (1-piperidinylmethyl) pyridine and an acid, or by preparing respective solutions in advance and mixing the solutions.

The solvent used for salt formation is crude 2-chloro-4
There is no particular limitation as long as it does not react with-(1-piperidinylmethyl) pyridine, an acid or a salt thereof, and it may be appropriately determined according to the solubility upon heating and the recovery of crystals precipitated upon cooling. Examples of such a solvent include alcohols such as methanol, ethanol, isopropanol and 1-propanol, and water. Among them, methanol, ethanol and isopropanol are more preferable. These solvents can be used alone or as a mixture.

The amount of the recrystallization solvent to be used is not particularly limited as long as the salt before purification completely or partially dissolves when heated, and is appropriately determined according to the recovery rate of the crystals precipitated upon cooling. Good. Usually, it is sufficient to use 1 volume or more with respect to the crude 2-chloro-4- (1-piperidinylmethyl) pyridine acid salt, preferably 1 to 100 volumes, particularly 1 volume.
~ 50 volumes are preferred.

In the present invention, by adding a seed crystal, crystals can be deposited smoothly and efficiently. The amount of the seed crystal used is preferably 1/10 to 1/10000 weight, more preferably 1/20 to 1/1000 weight, based on the salt before purification.

The temperature conditions for the recrystallization operation can be appropriately determined depending on the boiling point and the freezing point of the solvent used.
The salt before purification can be dissolved at room temperature (25 ° C.) to a temperature near the boiling point of the recrystallization solvent, and crystals can be precipitated at −40 to 80 ° C.

[0016] Since the purity of the crystals crystallized by recrystallization is improved, the precipitated crystals are recovered by filtration or the like.
High purity 2-chloro-4- (1-piperidinylmethyl)
A pyridine acid salt can be obtained. In addition, 2 after filtration
-Chloro-4- (1-piperidinylmethyl) pyridine
By repeating the recrystallization operation in accordance with the desired purity of the acid salt, higher purity crystals can be obtained.

The organic solvent used for reverse neutralization extraction of the obtained 2-chloro-4- (1-piperidinylmethyl) pyridine acid salt with an aqueous base solution is 2-chloro-4-neutralized.
(1-piperidinylmethyl) An inert solvent that dissolves pyridine and is immiscible with the aqueous base solution, such as halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, and esters such as ethyl acetate. Can be suitably used.

Examples of the base used to neutralize the salt include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. And alkali metal bicarbonates.

Further, if necessary, 2-chloro-4- (1
The organic solvent from which (piperidinylmethyl) pyridine has been extracted can be distilled off to recover high-purity 2-chloro-4- (1-piperidinylmethyl) pyridine.

[0020]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. Example 1 30 g of crude 2-chloro-4- (1-piperidinylmethyl) pyridine (97.3% purity), 18.2 g of maleic acid, and ethanol in a 300 mL glass flask equipped with a stirrer and a reflux condenser After adding 120 mL and heating with stirring, the internal temperature becomes the reflux temperature, and after uniform dissolution,
The mixture was gradually cooled, and when the internal temperature reached 5 ° C., stirring was further performed for 2 hours. The crystallized and precipitated 2-chloro-4- (1-piperidinylmethyl) pyridine maleate is filtered and dried, and 2-chloro-4- (1-piperidinylmethyl) pyridine maleate 41 is dried. 0.0 g (purity 99.2%, yield 88.3%) was obtained.

Again, 300 mL equipped with a stirrer and a reflux unit
The obtained 2-chloro-4- (1-
Piperidinylmethyl) pyridine maleate 41.0
g and 123 mL of ethanol were added, and crystallization was performed in the same manner. The precipitated 2-chloro-4- (1-piperidinylmethyl) pyridine maleate was filtered and dried, and purified 2-chloro-4- (1-piperidinylmethyl) pyridine maleate 39.0 g. (Purity: 99.4%, yield: 84.0%).

The obtained purified 2-chloro-4- (1-piperidinylmethyl) pyridine maleate (39.0 g) was obtained.
Then, 117 mL of toluene was charged into a 500 mL glass flask, and 25% aqueous potassium carbonate solution 1 was stirred while stirring.
47.3 g was gradually added dropwise, and after neutralization, the content was transferred to a separating funnel, and the toluene layer was recovered. The water layer is 500m again
The mixture is charged into an L glass flask, 78 mL of toluene is added, and the mixture is stirred for 30 minutes. The recovered toluene layer, the re-extracted toluene layer, and 75 g of water were charged into a separating funnel and washed, and the toluene layer was recovered.

The obtained toluene layer is concentrated under reduced pressure, and 27.6 g of purified 2-chloro-4- (1-piperidinylmethyl) pyridine (purity: 86%, toluene 14%, 2-chloro-4- ( 1-piperidinylmethyl) pyridine purity: 9
9.4%, purity conversion yield: 79.8% / crude 2-chloro-
4- (1-Piperidinylmethyl) pyridine) was obtained. Example 2 30 g of crude 2-chloro-4- (1-piperidinylmethyl) pyridine (96.8% purity) and oxalic acid 1 in a 300 mL glass flask equipped with a stirrer and a reflux condenser
4.2 g, 255 mL of ethanol and 45 mL of water were added,
The mixture was heated with stirring, the internal temperature became the reflux temperature, and the mixture was uniformly dissolved. Then, the mixture was gradually cooled.
Stirring was performed for hours. Crystallized and precipitated 2-chloro-4-
The (1-piperidinylmethyl) pyridine oxalate was filtered and dried, and 32.0 g of 2-chloro-4- (1-piperidinylmethyl) pyridine oxalate (purity 98.3) was used.
%, Yield 85.5%).

Again, 300 mL equipped with a stirrer and a reflux unit
The obtained 2-chloro-4- (1-
Piperidinylmethyl) pyridine oxalate 32.0
g, 163 mL of ethanol and 29 mL of water were added, and crystallization was performed in the same manner. The precipitated 2-chloro-4- (1-piperidinylmethyl) pyridine oxalate was filtered and dried, and purified 2-chloro-4- (1-piperidinylmethyl) pyridine oxalate 28.0 g. (Purity 98.8%, yield 87.
4%).

The purified 2-chloro-4- (1-piperidinylmethyl) pyridine oxalate (28.0 g) and toluene (90 mL) were charged into a 500 mL glass flask, and stirred with a 25% aqueous potassium carbonate solution. 113
g was gradually added dropwise, and after neutralization, the content was transferred to a separating funnel, and a toluene layer was recovered. The aqueous layer was again charged into a 500 mL glass flask, added with 60 mL of toluene, stirred for 30 minutes, transferred to a separating funnel, and extracted again into the toluene layer.
The recovered toluene layer, the re-extracted toluene layer, and 60 g of water were charged into a separating funnel and washed, and the toluene layer was recovered.

The obtained toluene layer is concentrated under reduced pressure, and 22.5 g of purified 2-chloro-4- (1-piperidinylmethyl) pyridine (purity: 83%, toluene 17%, 2-chloro-4- ( 1-piperidinylmethyl) pyridine purity: 9
8.8%, purity conversion yield: 63.5% / crude 2-chloro-
4- (1-Piperidinylmethyl) pyridine) was obtained.

[0027]

Industrial Applicability 2-Chloro-4- (1-piperidinylmethyl) pyridine, a compound useful as a raw material for medicines, agricultural chemicals, etc., can be purified industrially simply and efficiently.

 ────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Akihiro Fukui 2805 Imafukunakadai, Kawagoe-shi, Saitama F-term in Chemical Research Laboratory, Central Glass Co., Ltd. 4C055 AA01 BA02 BA39 CA01 DA27 DB10 FA41 GA01

Claims (3)

[Claims] [Claim 1] Formula [1] Wherein the salt formed by neutralizing crude 2-chloro-4- (1-piperidinylmethyl) pyridine represented by the formula (1) with an organic acid or an inorganic acid is crystallized, and then reverse neutralized with an aqueous base solution. A method for purifying 2-chloro-4- (1-piperidinylmethyl) pyridine. 2. The organic acid according to claim 1, wherein the organic acid is selected from the group consisting of oxalic acid, fumaric acid, maleic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid. Purification method. 3. The method according to claim 1, wherein the inorganic acid is hydrochloric acid or sulfuric acid.
Purification method described in 1.