JP2819800B2 - Method for producing optically active 1- (p-chlorophenyl) -1- (2-pyridyl) -3-dimethylaminopropane - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial application field> The present invention relates to dl-1- (p-chlorophenyl) -1-.
Optically active 1- (p-chlorophenyl) -1- (2) was obtained from (2-pyridyl) -3-dimethylaminopropane (hereinafter referred to as dl-chloropheniramine) by an optical resolution method.
-Pyridyl) -3-dimethylaminopropane (hereinafter referred to as chlorpheniramine).

d-Chlorpheniramine has an excellent antihistamine action and is currently used in large quantities as a pharmaceutical.

<Prior Art> As a conventionally known optical resolution method of dl-chlorpheniramine, dl-phenylsuccinic acid is optically resolved using an optically active natural base such as brucine or quinine, and the resulting d- A method for optically resolving dl-chloropheniramine using phenylsuccinic acid (U.S. Pat. No. 3,030,371) and dl-using N-tosyl-D-aspartic acid
-Method for performing optical resolution of chlorpheniramine
-36177).

<Problems to be Solved by the Invention> However, the former method known conventionally is not industrially advantageous in that the optical resolving agent itself has to be optically resolved. The latter method is 20
It is still impractical in that the salt must be left to crystallize at 3 ° C. for 3 days.

<Means for Solving the Problems> Accordingly, the present inventors have conducted intensive studies for the purpose of dividing dl-chlorpheniramine by a method that can be industrially used.

As a result, it was found that this object was achieved by optical resolution using a specific optically active carboxylic acid as a resolving agent.

That is, the present invention relates to dl-chlorpheniramine represented by the following formula (I) Optically active carboxylic acid represented by (hereinafter referred to as PTCP)
A method for producing optically active chlorpheniramine, comprising optically resolving the compound by using as a resolving agent.

 Hereinafter, the configuration of the present invention will be described in detail.

The optically active carboxylic acid used as a resolving agent in the present invention,
It is an optically active lactic acid derivative, and any of its D-form and L-form can be used.

Optically active lactate methyl ester used as a raw material when lactic acid is used as a derivative is currently widely used as a raw material for agricultural chemicals and is available at low cost. A derivative of lactic acid can be obtained in high yield by, for example, dissolving methyl lactate in a solvent, adding phenylisothiocyanate and performing a reaction at 60 ° C., and then adding water to hydrolyze the methyl ester. Of course, there is no problem even if manufactured by any other method. Further, this resolving agent is a very stable compound, and does not split or racemize at the time of split recovery. That is, the resolving agent used in the present invention is a compound which is industrially available at low cost.

In the present invention, dl-chlorpheniramine used as a raw material is not only a racemic mixture containing equal amounts of d-chloropheniramine and 1-chloropheniramine, but also any one of the optical isomers in an equivalent amount or more. And mixtures thereof.

Optical resolution of dl-chlorpheniramine is performed according to the following procedure and conditions.

First, 1.0 to dl-chlorpheniramine in a solvent.
~ 3.0 mol, preferably 1.5-2.5 mol, of optically active PTCP is contacted to form a diastereomer salt.

The solvent used here may be any solvent that dissolves dl-chlorpheniramine and PTCP, does not chemically alter these compounds in the solution, and precipitates diastereomeric salts. For example, alcohols such as ethanol and methanol, methyl acetate,
Esters such as ethyl acetate and ketones such as methyl ethyl ketone and acetone can be used. Further, these solvents can be used alone or as a mixed solvent. Further, these solvents can be used as a mixed solvent with water.

As a method of bringing PTCP into contact with dl-chlorpheniramine, dl-chlorpheniramine may be added to the solvent at once, or may be added sequentially. Dl
-After forming a salt formed from chlorpheniramine and a resolving agent, the salt may be dissolved in the solvent.

Next, the solution containing the diastereomer salt thus obtained is cooled and / or concentrated. Then, the sparingly soluble diastereomer salt crystallizes out of the solution.

The temperature at which the sparingly soluble diastereomer salt is precipitated from the solution may be in the range of from the freezing point to the boiling point of the solvent used, and is appropriately determined depending on the purpose.
A range of 100 ° C is sufficient.

Crystals of the sparingly soluble diastereomer salt can be easily separated by ordinary solid-liquid separation methods such as filtration and centrifugation.

On the other hand, the remaining mother liquor from which the sparingly soluble diastereomer salt has been separated may be cooled and / or concentrated to precipitate the readily soluble diastereomer salt, and then separated.

By decomposing each diastereomer salt thus obtained by an appropriate method, d-chlorpheniramine or 1-chlorpheniramine and a resolving agent can be separated and collected.

The method of resolving the diastereomer salt is arbitrary, and for example, a method of treating with an acid or alkali in an aqueous solvent can be applied. For example, when a diastereomer salt is dissolved or decomposed in water and a mineral acid such as sulfuric acid or hydrochloric acid is added, an optically active carboxylic acid hardly soluble in water precipitates out, and d-chlorpheniramine or l-chloropheniramine is dissolved. The mineral salt dissolves in the water.

After solid-liquid separation of the resolving agent by ordinary means, the mother liquor is concentrated and crystallized to obtain d-chlorpheniramine or l-chloropheniramine mineral acid salt. Furthermore, after adding the obtained mineral salt to an aqueous alkali solution such as sodium hydroxide and extracting with an organic solvent such as toluene and chloroform,
Concentration and distillation yield d-chloropheniramine or 1-chlorpheniramine.

PTCP used as a resolving agent in the present invention is hardly soluble and can be recovered in high yield from a diastereomer salt solution, and does not decompose or racemize during the recovery process.

That is, since this resolving agent retains its optical activity, it can be reused for optical resolution.

<Example> Hereinafter, the present invention will be specifically described with reference to examples.

In the examples, the optical purity of chlorpheniramine (% e
e) High-performance liquid chromatography (HPL) under the following conditions:
The analysis was performed according to C).

Column: CHIRALPAK AD (Daicel) Moving bed: n-hexane / isopropanol / diethylamine mixture (97.5: 2.5: 0.025) Flow rate: 1.0 ml / min Detector: UV254 nm Retention time: d-form 11.3 min l-form 13.4 min Example 1 27.4 g (0.1 mol) of dl-chlorpheniramine D-PTCP45
g (0.2 mol) and 300 ml of methanol were charged into a flask, and dissolved by heating at about 50 ° C. for 30 minutes. This was cooled to room temperature, d-chloropheniramine and several pieces of diastereomeric salt crystals of D-PTCP were added, and the mixture was stirred at room temperature for 30 minutes, and the precipitated crystals were separated by filtration to obtain d-chlorophenylamine. To obtain 11.3 g of white crystals of D-PTCP salt.

These crystals were suspended in 100 ml of a 1N aqueous sodium hydroxide solution, and d-chloropheniramine was extracted with 200 ml of toluene. This toluene solution is washed with water, concentrated and distilled,
4.2 g of d-chloropheniramine was obtained as a pale yellow oil. The yield was 30.7% based on the amount of d-chlorpheniramine used, HP
As a result of analysis by LC, the optical purity was 94% ee.

On the other hand, concentrated sulfuric acid was added to the extracted mother liquor, the mixture was made strongly acidic, and the mixture was stirred for about 1 hour. The crystals were washed with water and dried to obtain 6.7 g of D-PTCP. (Recovery rate: 96%) <Effect of the Invention> (1) Since the resolving agent used in the present invention can be obtained in high yield from inexpensive raw materials, it is a compound that can be supplied industrially.

(2) Since the resolving agent used in the present invention is chemically very stable, it can be recovered from the diastereomer salt solution in a very high yield without racemization, so that the resolving agent can be reused. It is.

(3) The method of the present invention is superior in yield and optical purity to that of the conventional method without any grandchild.

(4) Therefore, according to the present invention, it is possible to provide a method for producing optically active chlorpheniramine that can be industrially practically used.

──────────────────────────────────────────────────続 き Continued on front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 213/38 C07B 57/00

Claims (1)

(57) [Claims] (1) dl-1- (p-chlorophenyl) -1-
(2-Pyridyl) -3-dimethylaminopropane is represented by the following formula (I) A method for producing optically active 1- (p-chlorophenyl) -1- (2-pyridyl) -3-dimethylaminopropane, comprising optically resolving using an optically active carboxylic acid represented by the formula (1) as a resolving agent.