JPH02138273A - Optically active piperazine derivative, its production and cerebral circulation improver containing the same - Google Patents

Abstract

NEW MATERIAL:(-)-1-(3,4-Dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl) ethanol of the formula (*represents an optically active carbon atom). USE:Cerebral circulation improver. It has excellent action to increase the blood flow rate in vertebrate animals, and is readily absorbed in the living bodies with reduced toxicity. PREPARATION:A mixture of optically active piperazine derivatives shown in the formula is allowed with an acidic optical resolution agent and the two kinds of diastereomers are resolved into the crystal and the solution utllizing their deference in solubility. Then, (-)-piperazine derivative or (+)-piperazine derivative is liberated from the separated diastereomer to collect an optically active piperazine derivative.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention is directed to the production of optically active piperazine derivatives from optically active (-)-piperazine derivatives and mixtures of optically active piperazine derivatives using diastereomer salts. Method,
The present invention also relates to a cerebral circulation improving agent containing an optically active (-)-piperazine derivative or a pharmacologically acceptable salt thereof as an active ingredient.

(Background of the Invention) A piperazine derivative represented by and this piperazine derivative have both the action of specifically dilating peripheral blood vessels, especially the vertebral artery and increasing blood flow, and the action of inhibiting platelet aggregation. It is publicly known that there is a
(See Publication No. 5).

The above piperazine derivative has two optical isomers (in the formula,
Among the optically active piperazine derivatives represented by (* indicates optical activity), (-) monolithic, (±) monolithic and (
+)- It was found that the peripheral vasodilator effect was greater than that of the body, and that it was highly safe. Therefore, in order to utilize optically active (-)-piperazine derivatives as medicines, it is necessary to efficiently separate them from a mixture of optical isomers.

[Object of the Invention] An object of the present invention is to provide the optically active (-)-piperazine derivative.

Another object of the present invention is to provide a method for efficiently producing an optically active piperazine derivative from a mixture of optical isomers of the piperazine derivative.

Another object of the present invention is to provide an excellent cerebral circulation improving agent containing the optically active (-)piperazine derivative.

[Structure of the Invention] The present invention resides in a (-)-optically active piperazine derivative represented by the following formula (I) (where * indicates optical activity).

A mixture of optically active piperazine derivatives represented by (in the formula, * indicates optical activity) is reacted with an acidic optical resolving agent, and the resulting two diastereomer salts are separated by a difference in solubility in the solvent. The present invention provides a method for producing an optically active piperazine derivative, which is characterized in that the (-)-piperazine derivative or (+)-piperazine derivative is liberated from the precipitated diastereomer salt.

The present invention also provides optical activity (
-)- A cerebral circulation improving agent characterized by containing a piperazine derivative or a pharmacologically acceptable salt thereof as an active ingredient.

[Detailed Description of the Invention] The mixture of optically active piperazine derivatives which is a raw material in the production method of the present invention is disclosed in JP-A-59-101475.
The racemic form of the piperazine derivative described in the above publication can be used, and this racemic form can be produced by the method described in the same publication. Furthermore, as the mixture of the above-mentioned piperazine derivatives, it is also possible to use a remaining isomer mixture in which a part of the optically active piperazine derivative is separated from the racemic form of the above-mentioned piperazine derivative by the production method of the present invention.

Examples of the acidic optical resolving agent in the production method of the present invention include tartaric acid, diacyltartaric acid, malic acid, camphor-10-sulfonic acid, mandelic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-8-sulfonic acid, and 8-bromocamphor-8-sulfonic acid.
Bromocamphor 10-sulfonic acid, cis-2-benzamidocyclohexanecarboxylic acid, O-benzoylmalic acid, glutamic acid, 0-methylmandelic acid, α-methoxy-α-trifluoromethylphenylacetic acid, and the like can be used. In addition, for example, as tartaric acid, both L-tartaric acid and D-tartaric acid can be used. In addition, examples of optically active diacyltartaric acid include dibenzoyltartaric acid, di-p-
Both (-) and (+) monomers such as toluoyl tartaric acid, diacetyl tartaric acid, and dibenzoyl tartaric acid can be used. For example, when (-)-dibenzoyltartaric acid is used as optically active diacyltartaric acid,
The optically active (+)-piperazine derivative precipitates from the solution as a poorly soluble diastereomeric salt, and the optically active (-
)-piperazine derivative remains in solution as a readily soluble diastereomeric salt. When (+)-dibenzoyltartaric acid is used, the optically active (-)-piperazine derivative precipitates from the solution as a poorly soluble diastereomer salt, and the optically active (+)-piperazine derivative forms a readily soluble diastereomer salt. Remains in solution as a salt.

The reaction ratio between the piperazine derivative and the acidic optical resolving agent is not particularly limited, but the acidic optical resolving agent may be used in an amount of 1/4 to 1 mole per 1 mole of the piperazine derivative to be precipitated. preferable.

In the production method of the present invention, the piperazine derivative and the acidic optical resolution agent are reacted in a solvent in which the two diastereomeric salts produced exhibit a difference in solubility.

Such solvents include methanol, ethanol, 1
-propatool, 2-propatool, 1-butanol,
2-butanol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, butyl acetate, dioxane, T
HF or the like can be used alone, a mixture thereof, or a mixture of these solvents and water. It is particularly preferable to use methanol.

In the production method of the present invention, after reacting the above, the perazine derivative, and the above acidic optical resolution agent as described above, a solvent is added as needed, and the process is cooled until enough crystals are obtained. Maintain the specified temperature. At that time, stirring may be performed as necessary.

Also, in order to promote the precipitation of crystals, a small amount of crystals of the same salt as the diastereomeric salt to be precipitated may be added as seeds. The separation conditions, such as the type and composition of the solvent, solid content concentration, crystal precipitation temperature and time, are adjusted so that the purity of the desired optical isomer of the piperazine derivative in the precipitated diastereomeric salt is as high as possible. Select.

Those skilled in the art can easily select such conditions.

The diastereomeric salts precipitated as described above are collected by filtration, and then, if necessary, purified, for example, by partial dissolution or recrystallization in the same solvent used to produce the diastereomeric salts. A purified product of the mer salt can be obtained.

The obtained purified diastereomeric salt was treated with sodium carbonate,
The target optical isomer of the piperazine derivative can be obtained by treatment with a base such as sodium hydroxide, potassium carbonate, or potassium hydroxide for dissociation, followed by extraction, washing, drying, and other treatments.

If desired, the free form of the piperazine derivative of the above optical isomer can be prepared using an inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid) according to a conventional method.
Alternatively, it can be made into a pharmacologically acceptable salt such as an acid addition salt of an organic acid (eg, acetic acid, propionic acid, citric acid, tartaric acid, malic acid, oxalic acid, methanesulfonic acid).

As the mixture of optically active piperazine derivatives which is a raw material in the production method of the present invention, racemates of the piperazine derivatives may be used as described above, but for example, if the final objective optical isomer is (-)-piperazine derivative In this case, a part of the (+)-piperazine derivative is previously divided and removed from the racemic form of the piperazine derivative by the production method of the present invention, so that the content ratio of the (-)-piperazine derivative becomes relatively high ( When the production method of the present invention is carried out using a mixture of a -)-piperazine derivative and a (+)-piperazine derivative as a raw material, a (-)-piperazine derivative with high optical purity can be easily obtained.

In addition, the (-)-piperazine derivative of the present invention can be used as a stationary phase with acidic glycoprotein [e.g., α,-acidic glycoprotein coated silica gel column (4 mm 1.D,
) (Product name: LKB Enantio P
ac)] and a phosphate-containing mixed solvent [e.g., 8mM sodium phosphate buffer (p
H7,5)+0.1M NaCf1+0.5mMN,
N-dimethyloctylamine + 8% isopropanol]
It can also be obtained by optical resolution from a racemic compound or a mixture of (+)- and (-)-piperazine derivatives by high performance liquid chromatography using .

In addition, cellulose triester or tricarbamate derivatives are used as the stationary phase, and hexane-
Optical resolution can also be achieved by high performance liquid chromatography using a mixed solvent such as 2-propanol.

Next, (-)-1-(3
,4-dimethoxyphenyl) -2-(4-diphenylmethylpiperazinyl)ethanol dihydrochloride [(-)-
Compound A], (+)-1-(3,4-
dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanol dihydrochloride [(+)-Compound A
l, and (±)-1- used as a raw material in Example 1 below
(3,4-dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanol dihydrochloride [(±)
- The results of testing the peripheral vasodilatory effect (vertebral artery blood flow increasing effect) and acute toxicity of Compound A1 are shown.

[Peripheral vasodilatory effect] Test method Male and female dogs weighing approximately 10 kg were used. Bendoparbital sodium (35 mg/kg, i.

v, ) to the postanesthesia value, and under artificial respiration, (+1
11 Measurement of pressure and heart rate) Vertebrae, femoral and common carotid arteries Ik
The flow rate was measured by an electromagnetic flowmeter (11 Kikoden, MF-27 and MFV-1100) via an internal probe.

The drug was dissolved in distilled water and administered through a polyethylene cannula inserted into the lateral cutaneous vein.

Table 1 shows the doses and test results.

Table 1 [Acute Toxicity] Female SD rats (body weight 120-200 g) - Group 10
Each substance was dissolved in distilled water, sterilized by filtration, and administered to the tail vein of a mouse, followed by observation for two weeks, and the LD5° value was calculated using the 1' rob i method.

As a result, as is clear from the above test results, optical activity (-)-
Piperazine derivatives have a stronger effect of increasing vertebral artery blood flow than optically active (+)-piperazine derivatives and (±)-piperazine derivatives.

In addition, after one administration to pegle dogs, (-)-Compound A showed an immediate concentration (area of the blood concentration curve) nearly twice that of (+)-Compound A.

Normally, the stronger the action of an optically active substance, the stronger the toxicity, but as is clear from the above results, the (-)-piperazine derivative of the present invention has a stronger action, contrary to the normal one. Despite this, the toxicity has been removed.

Therefore, the optically active (-)-piperazine derivative of the present invention has a stronger effect than (+) monolithic and (±) monolithic derivatives,
It is highly absorbable and has no toxicity, making it an excellent medicine.

The optically active (-)-piperazine derivatives of the present invention can be used - numerically orally or parenterally, such as by injection or by blanching.

Examples of dosage forms for oral administration include tablets, capsules,
Examples include powders, granules, syrups, etc., and dosage forms for parenteral administration include injections, tablets, etc. For their preparation, conventional excipients, disintegrants, binders, lubricants, dyes, diluents, etc. are used. Excipients include glucose, lactose, etc. Disintegrants include starch, carboxymethylcellulose calcium, etc. Lubricants include magnesium stearate, talc, etc. Binders include hydroxypropyl cellulose, gelatin, Polyvinylpyrrolidone and the like are used.

The dosage for adults is usually about 10 doses of the active ingredient per day.
The dose ranges from mg to 400 mg, but it can be increased or decreased depending on age, symptoms, etc.

Next, the present invention will be explained in more detail with reference to Examples.

[Example 1] (a) 1-(3,4-dimethoxyphenyl)-2-(
(±)-racemic form of 4-diphenylmethylpiperazinyl) ethanol E, hereinafter referred to as "compound A"] 25.95
g (60 mmol) was added to 100,100 O of methanol and dissolved by heating, and then 16.93 g of (-)-dibenzoyltartaric acid -hydrate was added to this at the methanol reflux temperature.
(45.0 mmol) in 200 mfi of methanol was added dropwise to the mixture, heated under reflux for a while, and left at room temperature for two nights. The precipitated crystals were filtered, and (+)-Compound A and (-)-
Assembly of diastereomeric salts with dibenzoyltartaric acid 18
．． 21 g was obtained.

(b) (+)-Compound A・(-) obtained in (a) above
18.11 g of the -dibenzoyl tartrate complex was recrystallized twice from methanol to obtain 6.96 g of the purified product.

[α]. 23-22.9° (cO,105,MeO
H) (C) (+)-Compound A・( obtained in (b) above)
-)-dibenzoyl tartrate purified product 5.62 g (5,
0 mmol) was added with saturated sodium carbonate water, extracted with dichloromethane, washed with saturated brine, and dried over potassium carbonate. The solvent was distilled off to give (10)-Crystals of Compound A 4.0
Obtained 0g.

[α],” +35.0° (c 1.57.CHC
l5) (d) 3.83 g (8.9 mmol) of the crystals of compound A obtained in step c) above were added to 1.53 g of acetic acid.
m1 and water 0.38mj! In addition to which mixed solvent, add 2 ml of isopropyl alcohol and 1.63 mJ2 of concentrated hydrochloric acid.
was added to completely dissolve the crystals. To this, 30 ml of isopropyl alcohol was added and stirred overnight. The precipitated crystals were collected by filtration, hexane was added to the mother liquor, and the precipitated crystals were collected by filtration.

These crystals were combined, washed with isopropyl alcohol, and then dried under reduced pressure to obtain 3.97 g of white crystals of (+)-Compound A dihydrochloride.

[αlo” +23.2° (c 1.01. Meo
ll) [Example 2] (a) In Example 1(a), (+)-Compound A(-)
- The mother liquor from which the dibenzoyl tartrate complex was filtered off was concentrated, saturated sodium carbonate water was added to the residue, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over potassium carbonate. Then, the solvent was distilled off to obtain 12.90 g of a mixture crystal of (-)-Compound A and (+)-Compound A containing an excess of (-)-Compound A. This mixture crystal 12゜8
9 g (29.8 mmol) was added to 500 ml of methanol, and after heating and dissolving, 7.04 g of (+)-dibenzoyltartaric acid hydrate was added to this at the reflux temperature of methanol.
A 100 mfi methanol solution of (18.7 mmol) was added dropwise to the mixture, heated under reflux for a while, and left overnight at room temperature. The precipitated crystals were filtered, and (-)-Compound A and (+)-
Diastereomeric salt assembly 12 with dibenzoyltartaric acid
98 g was obtained.

(b) (-)-Compound A・(+) obtained in (a) above
12.88 g of the -dibenzoyl tartrate complex was recrystallized once from methanol to obtain 8.62 g of the purified product.

[α1o23 + 1 g, 6° (c O,
102, MeOH) (C) (-) obtained in (b) above
-Purified product of compound A/(+)-dibenzoyl tartrate 5
, 62 g (5.0 mmol) was added with saturated sodium carbonate water, extracted with dichloromethane, washed with saturated brine,
Dry with potassium carbonate. The solvent was distilled off to obtain 3.99 g of crystals of (=)-Compound A.

[α]. ”-34,2° (c 1.56.C) lc1
3) (d) 3.83 g (8.9 mmol) of crystals of the (-)-compound obtained in (C) above were added to 1.53 m of acetic acid.
In addition to the mixed solvent of ff1 and water 0.38 mJ2,
Isopropyl alcohol 2mf and salt making vi 1.63mf
f1 was added to completely dissolve the crystals. To this, 30 mj2 of isopropyl alcohol was added and stirred overnight.

The precipitated crystals were reduced, hexane was added to the mother liquor, and the precipitated crystals were collected by filtration.

These crystals were combined, washed with isopropyl alcohol, and then dried under reduced pressure to obtain 4.29 g of white crystals of (-)-Compound A dihydrochloride.

[α1,23 −23.1°(c 1.01 , Me
Example 3 (a) 2595 mg (±)-racemate of compound A (6,
0 mmol) was added to 80 ml of methanol and dissolved by heating, and then a solution of 565 mg (1.5 mmol) of (-)-dibenzoyltartaric acid-hydrate in 10 ml of methanol was added dropwise to the methanol at reflux temperature, and the mixture was heated for a while. It was refluxed and left at room temperature overnight. The precipitated crystals were filtered to obtain 1435 mg of a diastereomeric salt combination of +)-Compound A and (-)-dibenzoyltartaric acid.

(b) (+)-Compound A・(-) obtained in (a) above
1328 mg of the -dibenzoyl tartrate complex was recrystallized once from methanol to obtain 867 mg of the purified product.

[α1,14 −18.4° (c O,10:l,
IAeoll) (C) Purified product 763 of (+)-Compound A (-)-dibenzoyl tartrate obtained in (b) above
mg (0.62 mmol) was added with saturated sodium carbonate water, extracted with dichloromethane, washed with saturated brine, and dried over potassium carbonate. The solvent was distilled off to obtain 537 mg of crystals of (+)-Compound A.

[α]f, Is +32. Oo(c 1.43.
Cl1C13) (d> 460 mg (1.1 mmol) of the crystals of (+)-Compound A obtained in <c> above were dissolved in 5 ml of acetone, and a solution of 0.18 mf of concentrated hydrochloric acid in 3.4 ml of acetone was added. Stirred overnight at room temperature. The precipitated crystals were collected by filtration, washed with acetone, and dried under reduced pressure to obtain 407 mg of white crystals of (+)-Compound A dihydrochloride.
I got it.

[Q] o"+20.5'" (cl, 02,
MeOH) [Example 4] (a) In Example 3(a), (+)-Compound A(-)
- The J8 solution obtained by filtering the dibenzoyl tartrate assembly and the recrystallization mother liquor in Example 3(b) were concentrated together, saturated sodium carbonate water was added to the residue, extracted with dichloromethane, and the extract was saturated. Washed with brine and dried with potassium carbonate. Then, the solvent was distilled off to obtain 1905 mg of a mixture crystal of (=)-Compound A and (+)-Compound A containing an excess of (-)-Compound A. This mixture crystal 1900
mg (4.4 mmol) was added to 60 mj2 of methanol, and after heating and dissolving, 531 mg of (+)-dibenzoyltartaric acid-hydrate was added to this at the reflux temperature of methanol.
(1.4 mmol) in 10 ml of methanol was added dropwise, heated under reflux for a while, and left overnight at room temperature. The precipitated crystals were filtered and a combination of diastereomeric salts of (-)-Compound A and (+)-dibenzoyltartaric acid 1527m was obtained.
I got g.

(b) (-)-Compound A・(+) obtained in (a) above
1418 mg of the -dibenzoyl tartrate complex was recrystallized once from methanol to obtain 1009 mg of the purified product.

[al,” +21.6°(c O,+02.Me
oll) (C) (-)-Compound A obtained in (b) above
・(+)-Dibenzoyl tartrate purified product 902mg
(0.74 mmol) was added with saturated sodium carbonate, extracted with dichloromethane, washed with saturated brine, and dried over potassium carbonate. The solvent was distilled off to obtain 632 mg of crystals of (-)-Compound A.

[α], "-32,1° (c 1.41.
ClCl, ) (d) 579 mg (1.3 mmol) of the crystals of (-)-Compound A obtained in (C) above were dissolved in 5 ml of acetone, and 0.22 ml of concentrated hydrochloric acid and 4.2 soj! of acetone were dissolved. The solution was added and stirred overnight at room temperature. The precipitated crystals were collected by filtration, washed with acetone, and dried under reduced pressure to obtain 537 mg of white crystals of (-)-Compound A dihydrochloride.
I got it.

ICEID” -20,7°(c 1.01.Me
oll) [Example 5] As a high-performance liquid chromatography mm column, a column of the following formula: (wherein R is a group represented by the following formula: The (±)-racemate of Compound A used in Example 1 was resolved using RA1.CELODJ). Compound A was supplied by dissolving 20 mg of Compound A in absolute ethanol to make 10 ml of the solution.

Mobile phase (eluent): ethanol/hexane/diethylamine (80/2010.1), flow rate: 1 mff1/min column temperature: room temperature detection: ultraviolet detector (278 nm, range: 0
．． 08) Injection amount = 10 μU The obtained chromatogram is shown in FIG.

Solvent retention time = 3.09 minutes, (+) combined retention time =
7.62 minutes, (-) integral retention time = 26.85 minutes.

The preparative column should be used under these eluent conditions +) and (
−) and the whole were separated.

[Example 6] Formulation example (tablet) One tablet (220mg) contains the following ingredients.

Active ingredient 50mg lactose
100mg starch
50 mg magnesium stearate
5mg Hydroxypropyl cellulose 15mg [Example 7] Formulation example (capsule) One hard gelatin capsule contains the following ingredients.

Active ingredient 40mg lactose
200mg starch
70mg polyvinylpyrrolidone 5
mg crystalline cellulose 35 mg [Example 8] Formulation example (!I'1 grain) 1 g of granules contains the following ingredients.

Active ingredient 200mg lactose
450mg corn starch
300mg hydroxypropylcellulose 50mg

[Brief explanation of the drawing]

FIG. 1 is a chromatogram obtained by high performance liquid chromatography obtained in Example 5. Patent applicant Nippon Chemifa Co., Ltd. Representative Patent attorney Hatao Yanagawa

Claims (1)

[Claims] 1. A (−)-optically active piperazine derivative represented by the following formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, * indicates optical activity). 2. A mixture of optically active piperazine derivatives represented by the following formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, * indicates optical activity)
By reacting an acidic optical resolving agent, two types of diastereomer salts are separated by utilizing the difference in solubility in the solvent.
A method for producing an optically active piperazine derivative, which comprises then releasing a (-)-piperazine derivative or a (+)-piperazine derivative from the precipitated diastereomeric salt. 3. Optically active (-)-piperazine derivative or its pharmacologically acceptable formula (I) below: ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, * indicates optical activity) A cerebral circulation improving agent characterized by containing a salt that can be used as an active ingredient.