JPH09278768A - Diphenylpiperazine derivative diastereomer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel diphenylpiperazine derivative diastereomer which is useful in determination of the optical purity of diphenylpiperazine derivatives being useful as a drug for circulatory diseases and a central nervous system drug and bearing asymmetric carbon. SOLUTION: This compound is represented by formula I [R1 and R2 are each H, a halogen; R3 and R4 are each a 6-12C (substituted) aromatic hydrocarbon group; R5 is a 1-4C alkyl; (m) and (n) are each 0-4], typically (R,R) 1-[4,4-bis (4-fluorophenyl)]-4- 2-hydroxy-3-[N-(naphtylmetylmethylaminocarbonyl)-N- phenylamino]} propylpiperazine. The compound of formula I is prepared by reaction of a compound of formula II with an optically active compound of formula III at a low temp. under stirring.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel diphenylpiperazine derivative diastereomer useful for determining the optical purity of a diphenylpiperazine derivative having an asymmetric carbon which is useful as a cardiovascular drug or as a central nervous system drug.

[0002]

The diphenylpiperazine derivative represented by the general formula (II) described below and physiologically acceptable salts thereof are very useful as a circulatory agent or a central nervous system agent. However, it is known that these compounds have an asymmetric carbon and that the potency of the pharmacological effect among stereoisomers is different. Therefore, in order to develop these compounds, it is necessary to control the stereoscopic structure. Under such circumstances, separation by a chiral column was found as a means for measuring the optical purity of the compound represented by the general formula (II). There was a problem that it was too low to chase.

On the other hand, the compound represented by the general formula (I) is a novel compound, and it has not been known that such diastereomers are easily separated from each other.

[0004]

The present invention has been made under such circumstances, and an object of the present invention is to provide a standard substance useful for measuring the optical purity of the compound represented by the general formula (II) described below.

[0005]

In view of such a situation,
The present inventors have made diligent efforts to find a method for separating optical isomers of the compound represented by the general formula (II), and as a result, the substance represented by the general formula (II) has
The inventors have found that it becomes possible to separate optical isomers by reacting the substance represented by I) with the diastereomer represented by the general formula (I), and completed the invention. Less than,
The present invention will be described in detail.

[0006]

[Chemical 6] Formula (I) (In the formula, R1 and R2 each independently represent a hydrogen atom or a halogen atom, and R3 and R4 are each independently an aromatic carbon atom which may have a substituent having 6 to 12 carbon atoms. Represents a hydrogen group, R5 represents an alkyl group having 1 to 4 carbon atoms,
m and n each independently represent an integer of 0 to 4 carbon atoms. )

[0007]

Embedded image General formula (II) (In the formula, R1, R2, R3, m, and n are the same as those in general formula (I).)

[0008]

Embedded image General formula (III) (provided that this is an optically active compound and R
4 and R5 are the same as those described in formula (I). )

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The compounds of the present invention have the general formula (I)
Is represented by The compound represented by the general formula (I) is obtained by mixing the compound represented by the general formula (II) with the compound represented by the general formula (III) in a solution state at a low temperature such as under ice cooling for several hours to several days. Can be easily and quantitatively obtained. At this time, the mixing ratio of the compound represented by the general formula (III) is preferably slightly higher than that of the compound represented by the general formula (II). As the solvent, an organic solvent is preferable, and any organic solvent that does not react with the compound represented by the general formula (III) can be used without particular limitation, and examples thereof include acetonitrile, acetone, and tetrahydrofuran. Preferred examples include benzene, chloroform, diethyl ether and the like. Since this substance has two asymmetric centers, diastereomers that are not mirror images of each other are produced, and this substance has a larger difference in physical properties than those that are mirror images of each other, and therefore is more separated than those of mirror images. Easier to do. Further, since it has a chromophore of N- (C = O) -N, it is convenient because it can be detected with high sensitivity in performing absorbance analysis or fluorescence intensity analysis. Therefore, the optical purity of the compound represented by the general formula (II) can be easily and highly sensitively measured by introducing the substance having such a form.
To exemplify the compound of the present invention, R, R 1- (4
4-bis (4-fluorophenyl) butyl) -4- (2
-Hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 1), S, R 1- (4,4-bis (4
-Fluorophenyl) butyl) -4- (2-hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 2), S, R 1-bis (4-fluoro) Phenyl)
Methyl-4- (2-hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 3), R, R 1-
Bis (4-fluorophenyl) methyl-4- (2-hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 4), S, R 1- (2- Acetoxy-3-
(N- (naphthylmethylmethylaminocarbonyl) -N
-Phenylamino))-4- (4,4-bis (4-fluorophenyl) butyl) propylpiperazine (Compound 5), R, R 1- (2-acetoxy-3- (N- (naphthylmethylmethylaminocarbonyl) ) -N-Phenylamino))-4- (4,4-bis (4-fluorophenyl) butyl) propylpiperazine (Compound 6), S, R
1- (4,4-bis (4-fluorophenyl) butyl) -4- (2-methoxyoxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 7), R, R 1-
(4,4-bis (4-fluorophenyl) butyl) -4
-(2-Methoxyoxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 8), S, R 1- (4,4-
Bis (4-fluorophenyl) butyl) -4- (2-hydroxy-3- (N- (4-chlorophenyl) -N-
(Naphthylmethylmethylaminocarbonyl) amino))
Propylpiperazine (Compound 9), R, R 1- (4,
4-bis (4-fluorophenyl) butyl) -4- (2
-Hydroxy-3- (N- (4-chlorophenyl) -N
-(Naphthylmethylmethylaminocarbonyl) amino)) propylpiperazine (Compound 10), S, R 1
-(4,4-bis (4-fluorophenyl) butyl)-
4- (2-hydroxy-3- (N- (4-methoxyphenyl) -N- (naphthylmethylmethylaminocarbonyl) amino)) propylpiperazine (Compound 11),
R, R 1- (4,4-bis (4-fluorophenyl)
Butyl) -4- (2-hydroxy-3- (N- (4-methoxyphenyl) -N- (naphthylmethylmethylaminocarbonyl) amino)) propylpiperazine (Compound 1
2), S, R 1- (4,4-bis (4-fluorophenyl) propyl) -4- (2-hydroxy-3- (N-
(Naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 13),
R, R 1- (4,4-bis (4-fluorophenyl)
Propyl) -4- (2-hydroxy-3- (N- (naphthylmethylmethylaminoaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 14), S, R
1- (4,4-bis (4-fluorophenyl) pentyl) -4- (2-hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 15), R, R 1
-(4,4-bis (4-fluorophenyl) pentyl)
-4- (2-Hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 16), S, S 1- (4
4-bis (4-fluorophenyl) butyl) -4- (2
-Hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 17), R, S 1- (4,4-bis (4-fluorophenyl) butyl) -4 -(2-Hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 18), S, S1-bis (4-fluorophenyl) methyl-4- (2 -Hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 19), R, S
1-bis (4-fluorophenyl) methyl-4- (2
-Hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 20), S, S 1- (2-acetoxy-3- (N- (naphthylmethylmethylaminocarbonyl) ) -N-Phenylamino))-4- (4,4-bis (4-fluorophenyl) butyl) propylpiperazine (Compound 21), R, S 1- (2-acetoxy-3-).
(N- (naphthylmethylmethylaminocarbonyl) -N
-Phenylamino))-4- (4,4-bis (4-fluorophenyl) butyl) propylpiperazine (Compound 2
2), S, S1- (4,4-bis (4-fluorophenyl) butyl) -4- (2-methoxyoxy-3- (N-
(Naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 23),
R, S 1- (4,4-bis (4-fluorophenyl)
Butyl) -4- (2-methoxyoxy-3- (N- (naphthylmethylmethylaminoaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 24), S, S
1- (4,4-bis (4-fluorophenyl) butyl)
-4- (2-hydroxy-3- (N- (4-chlorophenyl) -N- (naphthylmethylmethylaminocarbonyl) amino)) propylpiperazine (Compound 25),
R, S 1- (4,4-bis (4-fluorophenyl)
Butyl) -4- (2-hydroxy-3- (N- (4-chlorophenyl) -N- (naphthylmethylmethylaminocarbonyl) amino)) propylpiperazine (Compound 2
6), S, S1- (4,4-bis (4-fluorophenyl) butyl) -4- (2-hydroxy-3- (N- (4
-Methoxyphenyl) -N- (naphthylmethylmethylaminocarbonyl) amino)) propylpiperazine (Compound 27), R, S 1- (4,4-bis (4-fluorophenyl) butyl) -4- (2-hydroxy) -3- (N
-(4-Methoxyphenyl) -N- (naphthylmethylmethylaminocarbonyl) amino)) propylpiperazine (Compound 28), S, S 1- (4,4-bis (4-fluorophenyl) propyl) -4- ( 2-hydroxy-
3- (N- (naphthylmethylmethylaminocarbonyl)
-N-phenylamino)) propylpiperazine (Compound 29), R, S 1- (4,4-bis (4-fluorophenyl) propyl) -4- (2-hydroxy-3- (N
-(Naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 30),
S, S 1- (4,4-bis (4-fluorophenyl)
Pentyl) -4- (2-hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 31), R, S
1- (4,4-bis (4-fluorophenyl) pentyl) -4- (2-hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 32), S, R 1
-(4,4-bis (4-fluorophenyl) butyl)-
4- (2-Hydroxy-3- (N-phenyl-N- (phenylmethylmethylaminocarbonyl) amino)) propylpiperazine (Compound 33), R, R1- (4,4-
Bis (4-fluorophenyl) butyl) -4- (2-hydroxy-3- (N-phenyl-N- (phenylmethylmethylaminocarbonyl) amino)) propylpiperazine (Compound 34), S, S 1- (4 , 4-bis (4-
Fluorophenyl) butyl) -4- (2-hydroxy-
3- (N-phenyl-N- (phenylmethylmethylaminocarbonyl) amino)) propylpiperazine (Compound 35), R, S 1- (4,4-bis (4-fluorophenyl) butyl) -4- (2 -Hydroxy-3- (N-
Examples include phenyl-N- (phenylmethylmethylaminocarbonyl) amino)) propylpiperazine (Compound 36). These compounds are 1- (4,4-bis (4
-Fluorophenyl) butyl) -4- (2-hydroxy-3-phenylaminopropyl) piperazine, 1-bis (4-fluorophenyl) methyl-4- (2-hydroxy-3-phenylaminopropyl) piperazine, 1-
(4,4-bis (4-fluorophenyl) butyl) -4
-(2-acetoxy-3-phenylaminopropyl) piperazine, 1- (4,4-bis (4-fluorophenyl) butyl) -4- (2-methoxy-3-phenylaminopropyl) piperazine, 1- ( 4,4-bis (4
-Fluorophenyl) butyl) -4- (3- (4-chlorophenyl) amino-2-hydroxypropyl) piperazine, 1- (4,4-bis (4-fluorophenyl) butyl) -4- (2-hydroxy- 3- (4-methoxyphenyl) aminopropyl) piperazine, 1- (4,4-
Bis (4-fluorophenyl) propyl) -4- (2-
Hydroxy-3-phenylaminopropyl) piperazine, 1- (4,4-bis (4-fluorophenyl) pentyl) -4- (2-hydroxy-3-phenylaminopropyl) piperazine, etc. are shown in the general formula (II). Compound or a physiologically acceptable salt thereof and R (−) 1-
(1-naphthyl) ethyl isocyanate, S (+)
1- (1-naphthyl) ethyl isocyanate, R
(+) 1-phenylethyl isocyanate, S
It can be obtained by reacting (-) 1-phenylethylisocyanate with a compound represented by the general formula (III). Among these, the most useful one in industry is 1- (4,4-bis (4-fluorophenyl) butyl) -4- (2-hydroxy-3-phenylaminopropyl) piperazine, which is currently under development for new drugs. And / or compounds 1 and 2 derived from physiologically acceptable salts thereof.

[0010]

Embedded image Compound 1

[0011]

Embedded image Compound 2

The compound of the present invention can be used as a standard sample in the analysis of the optical purity of the compound represented by the general formula (II). That is, the compound of the general formula (I) obtained by reacting the compound of the general formula (II) and the compound of the general formula (III) which have been previously formed into optically active compounds are used as a standard sample, The optical properties of an unknown compound of the general formula (II) can be determined by comparing the reaction of the compound of the general formula (II) with the compound of the general formula (III) having a high purity by analysis such as high performance liquid chromatography. Purity can be obtained. This is because the reaction between the compound of general formula (II) and the compound of general formula (III) proceeds with little influence of steric effects. Here, the compound represented by the general formula (II) is currently being developed as a cerebral circulation improving drug and an anti-Parkinson's disease drug,
The synthetic method is already known. In addition, the general formula (II
The compound represented by I) is commercially available as a reagent and is easily available. The compound represented by the general formula (I) thus produced can be purified by ordinary silica gel column chromatography and the like.

[0013]

The present invention will be described in detail below with reference to examples, but it goes without saying that the present invention is not limited to these examples.

Example 1 240 mg of S (-) 1- (4,4-bis (4-fluorophenyl) butyl) -4- (2-hydroxy-3-phenylaminopropyl) piperazine and R (-) 1-
(1-naphthyl) ethyl isocyanate (hereinafter referred to as -NE
IC) 210 mg of dehydrated acetonitrile 5
It was dissolved in ml, mixed under an ice-cold nitrogen atmosphere, reacted for 40 minutes, then returned to room temperature and further reacted for 19 hours. The reaction solution is concentrated and subjected to silica gel column chromatography (elution solvent; hexane: chloroform: chloroform: methanol = 50: 50: 0: 0 → 0: 0: 100: 0) →
0: 0: 100: 2) purified and 250 mg of R, R 1-
(4,4-bis (4-fluorophenyl) butyl) -4
-(2-Hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 1) was obtained. [Α] 23 / D is-
51.27, and the infrared absorption is 2937.5, 164
3.8, 1648.1, 1653.9, 1596.1,
1508.2, 1221.7, 1157.5, 778.
It was 8 Kaiser. Proton NMR (solvent; DMSO
-D6, delta ppM) is 1.36 (br, 2H), 1.
44 (d, 3H), 1.93 to 2.03 (m, 2H),
2.10 to 2.30 (m, 7H), 3.33 (s, 3
H), 3.50 to 3.54 (m, 1H), 3.55
3.81 (m, 1H), 3.95 (t, 1H), 4.9
5 (d, 1H), 5.61 (t, 1H), 7.05
7.63 (m, 17H), 7.80 (d, 1H), 7.
The values were 90 (d, 1H) and 8.14 (d, 1H). Furthermore, 675 (M-1) was observed by mass spectrometry (FAB). This is HPLC (column: 5 μm ODS)
4.6 × 250 mm, mobile phase: 55% acetonitrile-
10 mM phosphate buffer (pH 4.0), flow rate: 1.5 ml
/ Min, detection: UV 254 nm, column temperature: 40
A single peak was observed at. This chromatogram is shown in FIGS.

Example 2 240 mg of R (+) 1- (4,4-bis (4-fluorophenyl) butyl) -4- (2-hydroxy-3-phenylaminopropyl) piperazine and R (-) 1-
(1-naphthyl) ethyl isocyanate (hereinafter referred to as -NE
210 mg of each IC) was dissolved in 5 ml of dehydrated THF, mixed under an ice-cold nitrogen atmosphere, reacted for 40 minutes, then returned to room temperature and further reacted for 19 hours. The reaction solution is concentrated and subjected to silica gel column chromatography (elution solvent;
Hexane: chloroform: chloroform: methanol =
50: 50: 0: 0 → 0: 0: 100: 0 → 0: 0: 1
00: 2) purified and 250 mg of S, R 1- (4,4-
Bis (4-fluorophenyl) butyl) -4- (2-hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 2) was obtained. Infrared absorption is 2876.2, 2
774.6, 1643.8, 1653.7, 1596.
2, 1505.8, 1450.3, 1221.4, 11
It was 57.5, 1026.0, 1013.8, and 778.9 Kaiser. Proton NMR (solvent; DMSO-d
6, δppM) is 1.27 (br, 2H), 1.57
(D, 3H), 1.91 to 1.99 (m, 2H), 2.
00-2.40 (m, 12H), 3.35 (s, 1
H), 3.43 to 3.52 (m, 1H), 3.68 to
3.82 (m, 2H), 3.95 (t, 1H), 5.0
0 (d, 1H), 5.65 (m, 1H), 6.50
(D, 1H), 7.05 to 7.63 (m, 17H),
7.80 (d, 1H), 7.93 (d, 1H), 8.1
It was 4 (d, 1H). Furthermore, 675 (M-1) was observed by mass spectrometry (FAB). This is HPLC
(Column: 5 μm ODS 4.6 × 250 mm, mobile phase: 55% acetonitrile-10 mM phosphate buffer (pH
4.0), flow rate: 1.5 ml / min, detection: ultraviolet 2
A single peak was observed at 54 nm, column temperature: 40 ° C. This chromatogram is shown in FIGS.

Example 3 1- (4,4-bis (4-fluorophenyl) butyl)
Example of 0.01M anhydrous tetrahydrofuran solution of 4- (2-hydroxy-3-phenylaminopropyl) piperazine (racemic form) and 0.01M anhydrous tetrahydrofuran solution of -NEIC stirred at 5 ° C for 48 hours The same HPLC analysis as in 1 was performed. As a result, the racemate itself was observed as one peak. The main peaks of the reaction solution were two peaks having almost the same area, which were different from the racemate and -NEIC, and one of them was in agreement with the retention time of Example 1. From this, it is understood that the compound of the present invention is a useful standard substance for measuring the optical purity of the compound represented by the general formula (II). This chromatogram is shown in FIGS.

Example 4 1- (4,4-bis (4-fluorophenyl) butyl)
-4- (2-methoxy-3-phenylaminopropyl)
The piperazine (racemic compound) was subjected to HPLC treatment in the same manner as in Example 2 to obtain two peaks different from the raw material. From this, it is understood that the compound of the present invention is a useful standard substance for measuring the optical purity of the compound represented by the general formula (II).
This chromatogram is shown in FIGS.

Example 5 1- (4,4-bis (4-fluorophenyl) butyl)
-4- (3- (4-Chlorophenyl) amino-2-hydroxypropyl) piperazine (racemic form) was subjected to HPLC treatment in the same manner as in Example 2 to obtain two peaks different from the starting material. From this, it is understood that the compound of the present invention is a useful standard substance for measuring the optical purity of the compound represented by the general formula (II). The chromatograms are shown in FIGS.

Example 6 1- (4,4-bis (4-fluorophenyl) butyl)
-4- (2-Hydroxy-3- (4-methoxyphenyl) aminopropyl) piperazine (racemic form) was subjected to HPLC treatment in the same manner as in Example 2 to obtain two peaks different from the starting material. From this, the compound of the present invention is
It can be seen that it is a useful standard substance for measuring the optical purity of the compound represented by I). This chromatogram is shown in Figs.
I will name it 2.

Example 7 1- (4,4-bis (4-fluorophenyl) propyl) -4- (2-hydroxy-3-phenylaminopropyl) piperazine (racemic form) was added to HP in the same manner as in Example 2.
LC treatment gave two peaks different from the raw material. From this, it is understood that the compound of the present invention is a useful standard substance for measuring the optical purity of the compound represented by the general formula (II). This chromatogram is shown in FIGS.

Example 8 1- (4,4-bis (4-fluorophenyl) pentyl) -4- (2-hydroxy-3-phenylaminopropyl) piperazine (racemic form) was added to HP in the same manner as in Example 2.
LC treatment gave two peaks different from the raw material. From this, it is understood that the compound of the present invention is a useful standard substance for measuring the optical purity of the compound represented by the general formula (II). This chromatogram is shown in FIGS.

Example 9 1-Bis (4-fluorophenyl) methyl-4- (2-
Hydroxy-3-phenylaminopropyl) piperazine (racemic form) was subjected to HPLC treatment in the same manner as in Example 2 to obtain two peaks different from the starting material. From this, it is understood that the compound of the present invention is a useful standard substance for measuring the optical purity of the compound represented by the general formula (II). This chromatogram is shown in FIGS.

Example 10 1- (2-acetoxy-3-phenylaminopropyl)
-4- (4,4-bis (4-fluorophenyl) butyl) piperazine (racemic form) was treated with HPL in the same manner as in Example 2.
C treatment was performed to obtain two peaks different from the raw material. From this, it is understood that the compound of the present invention is a useful standard substance for measuring the optical purity of the compound represented by the general formula (II). This chromatogram is shown in FIGS.

[0024]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a standard substance useful for measuring the optical purity of the compound represented by the general formula (II), which is useful as a cardiovascular drug or a central drug.

[Brief description of drawings]

1 is a chromatograph of a raw material of Example 1. FIG.

2 is a chromatograph of the product of Example 1. FIG.

3 is a chromatograph of the raw material of Example 2. FIG.

FIG. 4 is a chromatograph of the product of Example 2.

5 is a chromatograph of the raw material of Example 3. FIG.

FIG. 6 is a chromatograph of the product of Example 3.

7 is a chromatograph of the raw material of Example 4. FIG.

FIG. 8 is a chromatograph of the product of Example 4.

9 is a chromatograph of the raw material of Example 5. FIG.

FIG. 10 is a chromatograph of the product of Example 5.

11 is a chromatograph of the raw material of Example 6. FIG.

FIG. 12 is a chromatograph of the product of Example 6.

FIG. 13 is a chromatograph of the raw material of Example 7.

FIG. 14 is a chromatograph of the product of Example 7.

15 is a chromatograph of the raw material of Example 8. FIG.

16 is a chromatograph of the product of Example 8. FIG.

FIG. 17 is a chromatograph of the raw material of Example 9.

FIG. 18 is a chromatograph of the product of Example 9.

19 is a chromatograph of the raw material of Example 10. FIG.

20 is a chromatograph of the product of Example 10. FIG.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Norihiro Nakamichi 560 Kashio-cho, Totsuka-ku, Yokohama, Kanagawa Pola Tokasei Kogyo Co., Ltd. (72) Makoto Kimura 560, Kashio-cho, Totsuka-ku, Yokohama, Kanagawa Industrial Co., Ltd.Totsuka Research Institute (72) Inventor Noriyuki Kawakatsu 560 Kashio-cho, Totsuka-ku, Yokohama, Kanagawa Pola Kasei Co., Ltd. (72) Inventor Motohiko Takahashi 560 Kashio-cho, Totsuka-ku, Yokohama, Kanagawa Pola Kasei Kogyo Co., Ltd. Company Totsuka Institute

Claims (4)

[Claims] 1. A diphenylpiperazine derivative diastereomer represented by the general formula (I). Embedded image Formula (I) (In the formula, R1 and R2 each independently represent a hydrogen atom or a halogen atom, and R3 and R4 are each independently an aromatic carbon atom which may have a substituent having 6 to 12 carbon atoms. Represents a hydrogen group, R5 represents an alkyl group having 1 to 4 carbon atoms,
m and n each independently represent an integer of 0 to 4 carbon atoms. ) 2. The compound represented by the general formula (I) is R,
R 1- (4,4-bis (4-fluorophenyl))-
4- (2-hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 1) or S, R 1- (4,4
-Bis (4-fluorophenyl))-4- (2-hydroxy-3- (N- (naphthylmethylmethylaminocarbonyl) -N-phenylamino)) propylpiperazine (Compound 2). Embedded image Compound 1 Compound 2 3. A compound of general formula (II)
A compound obtained by mixing and reacting the compound of I) at a low temperature. Embedded image General formula (II) (wherein R1, R2, R3, m, and n are the same as those in general formula (I)) General formula (III) (provided that this is an optically active compound and R
4 and R5 are the same as those described in formula (I). ) 4. Use of the compound according to any one of claims 1 to 3 as a standard sample for measuring the optical purity of the compound represented by the general formula (II).