JP3522945B2 - Method for producing optically active diphenylpiperazine derivative - Google Patents

Description

Description: TECHNICAL FIELD [0001] The present invention relates to an optically active diphenylpiperazine derivative and / or an optically active agent useful as a cardiovascular drug, an anti-dementia drug, an antidepressant drug and an anti-Parkinson drug. It relates to a method for producing these physiologically acceptable salts. [0002] The following general formula (3): [Wherein R ¹ and R ² each independently represent a phenyl group which may have a substituent, Ar represents an aromatic group which may have a substituent, and X represents A sulfur atom or a —N (R ³ ) — group (where R ³ represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group); m represents an integer of 0 to 4; And * indicates the position of an asymmetric carbon.] The diphenylpiperazine derivative represented by the formula (1) and / or a physiologically acceptable salt thereof is
Excels in calcium antagonism, antioxidant action, dopamine reuptake inhibitory action, serotonin reuptake inhibitory action, and is known to be a useful compound as a cardiovascular drug, an antiparkinsonian drug, an anti-dementia drug and an antidepressant drug. I have. Further, it is already known that these compounds have significantly different medicinal effects depending on the stereostructure and optical purity of the asymmetric carbon in the 2-propanol structure. The optically active compound (3) is prepared by binding a piperazine derivative having a diphenylalkyl group bonded to one of nitrogen to an optically active epichlorohydrin and then condensing it with an amino group of an arylamine. Had been manufactured. However, as described above, the compound (3) and / or a physiologically acceptable salt thereof has a significant difference in efficacy due to the steric structure and optical purity.
Further, a method for producing the compound (3) having high optical purity and / or a physiologically acceptable salt thereof has been desired. Accordingly, an object of the present invention is to provide a method for obtaining a compound (3) having a higher optical purity. [0008] In view of such circumstances, the present inventors have conducted intensive studies to obtain compound (3) having higher optical purity and / or a physiologically acceptable salt thereof. As a result, the compound represented by the general formula (1) obtained by reacting the compounds represented by the following general formulas (4) and (5) and the compound represented by the general formula (2) are condensed, whereby The inventors have found that compound (3) having optical purity and / or a physiologically acceptable salt thereof can be obtained, and have completed the present invention. The method of the present invention can be represented by the following reaction formula. [0010] Wherein Y represents a leaving group, and R ¹ and R ² A
r, m, n, X and * are the same as described above. That is, the present invention relates to a phenylamine compound represented by the general formula (4) and an optically active leaving group represented by the general formula (5). Represented by the general formula (3), characterized by condensing an optically active propanol derivative represented by the general formula (1) obtained by reacting with an epoxy compound having the same with a piperazine derivative represented by the general formula (2). It is intended to provide an optically active diphenylpiperazine derivative and / or a physiologically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION The optically active propanol derivative (1), which is one of the raw materials for the method of the present invention, has the general formula (1)
Wherein the phenyl group represented by Ar in the formula is an alkyl group having 1 to 4 carbon atoms, a halogenoalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxyl group, and a nitro group. , An amino group, a cyano group, an alkanoyl group having 2 to 5 carbon atoms or a halogen atom. Here, as the alkyl group having 1 to 4 carbon atoms, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-
Butyl group, i-butyl group, t-butyl group and the like. Further, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Carbon number 1
Examples of the halogenoalkyl group 4 include a chloromethyl group, a trifluoromethyl group and a chloroethyl group.
Examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, and an n-butoxy group. Examples of the alkanoyl group having 2 to 5 carbon atoms include an acetyl group, a propionyl group,
Butyryl group, valeryl group and the like. Among the groups represented by R ³ , the alkyl group is a methyl group, an ethyl group, an n-propyl group, an i-
Propyl group, n-butyl group, i-butyl group, t-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and the like.Examples of the aryl group include phenyl group, naphthyl group, and anthracenyl group. Examples of the aralkyl group include a benzyl group and a phenylethyl group. The leaving group represented by Y is not particularly limited as long as the leaving group is eliminated together with the hydrogen atom bonded to the nitrogen atom of piperazine of the compound (2) and undergoes a condensation reaction. As such a leaving group, for example, a methanesulfonyloxy group, an alkanesulfonyloxy group having 1 to 10 carbon atoms such as a paratoluenesulfonyloxy group or an arylsulfonyloxy group, chlorine, bromine, iodine, etc. And a halogen atom. The optically active propanol derivative represented by the general formula (1) comprises a phenylamine compound (4) and an epoxy compound (5) having an optically active leaving group without a catalyst. To obtain. The reaction time may be several days at room temperature and several hours at a temperature near the boiling point. The solvent used in this reaction is not particularly limited as long as it is an organic solvent, and examples thereof include alcohols such as methanol and ethanol, esters such as ethyl acetate and methyl formate, nitriles such as acetonitrile, diethyl ether and tetrahydrofuran. Ethers, halogenated hydrocarbons such as chloroform and methylene chloride, and ketones such as acetone and methyl ethyl ketone. Of these, alcohols are preferable. The reaction product can be purified by a usual method such as column chromatography or recrystallization. The compound represented by the general formula (2) is widely known. In the formula, substituents of the phenyl group which may have a substituent represented by R ¹ and R ² include an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms,
Halogen atoms may be mentioned, of which halogen atoms are preferred, and fluorine atoms and chlorine atoms are particularly preferred. The condensation reaction between compound (1) and compound (2) is carried out, for example, using an alkali as a catalyst and an appropriate solvent.
What is necessary is just to stir these compounds. The alkali used here is not particularly limited as long as it is miscible with the solvent, and examples thereof include organic amines such as triethylamine and carbonates such as potassium carbonate. Solvents used in this reaction include, for example, alcohols such as methanol and ethanol, esters such as ethyl acetate and methyl formate, nitriles such as acetonitrile, ethers such as diethyl ether and tetrahydrofuran, and halogenated compounds such as chloroform and methylene chloride. Examples thereof include hydrocarbons, ketones such as acetone and methyl ethyl ketone, and among them, alcohols are preferable. The reaction time may be several days at room temperature and several hours at a temperature near the boiling point. In the present method, a conventional method, for example, reacting optically active epichlorohydrin or glycidyl tosylate with 1- (4,4-bis (fluorophenyl)) piperazine, and then reacting with aniline Unlike the reaction method, purification by column chromatography can be omitted. Moreover, according to this method, the optical purity can be further improved. The resulting compound (3) may be converted into a salt by a conventional method, for example, by reacting with an acid in a polar or non-polar solvent. Examples of physiologically acceptable salts include mineral acid salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and the like, and organic acid salts with maleic acid, tartaric acid, citric acid, fumaric acid, and the like. EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. Reference Example 1 Synthesis of (S)-(-)-N- (3-chloro-2-hydroxypropyl) aniline 3.87 g (0.0415 mol) of aniline was dissolved in 21 ml of ethanol, and (S)- 1.92 g (0.0208 mmol) of (+)-epichlorohydrin was added, and the mixture was heated and refluxed for 4 hours under a nitrogen atmosphere. Thereafter, ethanol was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform), and the chloroform effluent was collected.
After concentration, 3.17 g (82.3% yield) of the desired product was obtained.
It can be seen from the optical rotation that this is an optically active substance. Yield; 82.3% mp .; 35-36.5 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.24 (1 H, dd, J = 7.8 Hz, J = 14.6 Hz), 3.3
9 (1H, dd, J = 7.8Hz, J = 14.0Hz), 3.6-3.7 (2H, m), 4.0-4.1 (1
H, m), 6.64 (2H, d, J = 7.8Hz), 6.73 (1H, t, J = 7.8Hz), 7.16
(2H, t, J = 7.8Hz) IR (KBr tablet); 3264, 1606, 1464, 1303, 1242, 748 (cm
^-1 ) EI-MS m / z; 185 (M ⁺ ) [α] _D ²⁵ ; -11.04 ° (c = 1.0, CHCl ₃ ) For this compound, consider the absolute configuration determination by the Mosher method. As a result, it was confirmed that the arrangement was (S). Reference Example 2 Synthesis of (R)-(+)-N- (3-chloro-2-hydroxypropyl) aniline Reference Example 1 using (R)-(-)-epichlorohydrin
The desired product was obtained in the same manner as in the above. It can be seen from the optical rotation that this is an optically active substance. Yield; 87.2% mp .; 35-36.5 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.24 (1H, dd, J = 7.8 Hz, J = 14.6 Hz), 3.3
9 (1H, dd, J = 7.8Hz, J = 14.0Hz), 3.6-3.7 (2H, m), 4.0-4.1 (1
H, m), 6.64 (2H, d, J = 7.8Hz), 6.73 (1H, t, J = 7.8Hz), 7.16
(2H, t, J = 7.8Hz) IR (KBr tablet); 3265, 1606, 1465, 1303, 1243, 749 (cm
^-1 ) EI-MS m / z; 185 (M ⁺ ) [α] _D ²⁵ ; + 10.10 ° (c = 1.0, CHCl ₃ ) Example 1 (S)-(+)-1- [4 Production Example of 1,4-bis (4-fluorophenyl) butyl] -4- (2-hydroxy-3-phenylaminopropyl) piperazine (Compound 1) 1- [4,4-bis (4-fluoro Phenyl) butyl] piperazine 160.7 g
(0.486 mol), 100.36 g of (S)-(-)-N- (3-chloro-2-hydroxypropyl) aniline
(0.540 mol) and 82.16 g of potassium carbonate
(0.594 mol) and 572 ml of ethanol
And heated to reflux while stirring for 7 hours under a nitrogen atmosphere. After completion of the reaction, the reaction solution was subjected to suction filtration while hot, and the filtrate was allowed to stand at room temperature for 2 days. The precipitated crystals were subjected to suction filtration, and the collected crystals were air-dried for 24 hours. Then, 152.50 g of compound 1 was obtained as crystals (yield: 64.7%).
2.50 g (0.318 mol) was added to 763 ml of ethanol, and the mixture was refluxed under a nitrogen atmosphere (completely dissolved at an internal temperature of about 60 ° C.). After refluxing for about 10 minutes, the solution was suction filtered while hot and the filtrate was left overnight at room temperature. The precipitated crystals were filtered by suction, and the collected crystals were air-dried for 2 days to obtain 140.3 g of Compound 1 as crystals. (Yield 92.1
%) 140.43 g (0.293 mol) of these crystals
In addition to 2 ml of ethanol, the mixture was refluxed under a nitrogen atmosphere (completely dissolved at an internal temperature of about 60 ° C.). After refluxing for about 10 minutes, the solution was suction filtered while hot and the filtrate was left overnight at room temperature. The precipitated crystals were filtered by suction, and the collected crystals were air-dried for 2 days to obtain 128.12 g of Compound 1 as crystals. (Yield 91.2%) ¹ H-NMR (CDCl ₃ ) δ; 1.5-1.6 (m, 2H), 2.0-
2.1 (m, 2H), 2.3-2.6 (m, 10H), 2.6-2.7 (m, 2H), 3.06 (dd, J =
5.9Hz, J = 12.9Hz, 1H), 3.25 (dd, J = 4.1Hz.12.4Hz, 1H), 3.8
6 (t, J = 7.8Hz, 1H), 3.9-4.0 (m, 1H), 6.63 (d, J = 7.6Hz, 2H),
7.01 (t, J = 7.6 Hz, 1H), 6.9-7.0 (m, 4H), 7.2-7.3 (m, 6H) mp .; 98.5-99.5 ° C IR; 3328, 2817, 1603, 1506, 1220, 828, 751 (cm ^-1 ) Specific rotation; + 12.2 ° (c = 1.0, CHCl ₃ ) EI-MS m / z; 480 (M + H) Example 2 (R) − (−) ) -1- (4,4-Bis (4-fluorophenyl) butyl] -4- (2-hydroxy-3-phenylaminopropyl) piperazine (Compound 2) Production Example (R)-(+)-N- Compound 2 was obtained in the same manner as in Example 1 except that (3-chloro-2-hydroxypropyl) aniline was used. ¹ H-NMR (CDCl ₃ ) δ; 1.5-1.6 (m, 2H), 2.0-
2.1 (m, 2H), 2.3-2.6 (m, 10H), 2.6-2.7 (m, 2H), 3.06 (dd, J
= 5.9Hz, J = 12.9Hz, 1H), 3.25 (dd, J = 4.1Hz, J = 12.4Hz, 1H),
3.86 (t, J = 7.8Hz, 1H), 3.9-4.0 (m, 1H), 6.63 (d, J = 7.6Hz, 2
H), 7.01 (t, J = 7.6Hz, 1H), 6.9-7.0 (m, 4H), 7.2-7.3 (m, 6
H) mp .; 98.5-99.5 ° C IR; 3328, 2817, 1603, 1506, 1220, 828, 751 (cm ^-1 ) Specific rotation; -12.5 ° (c = 1.0, CHCl ₃ ) EI-MS m / z 480 (M + H) Example 3 (S)-(-)-1- [4,4-bis (4-fluorophenyl) butyl] -4- (2-hydroxy-3-phenylaminopropyl ) Preparation Example of Piperazine Trihydrochloride (Compound 3) To 128.12 g (0.267 mol) of Compound 1 was added 640 ml of ethanol, and the mixture was stirred under a nitrogen atmosphere and slowly heated to reflux (completely dissolved at an internal temperature of about 60 ° C). did).
After refluxing for about 10 minutes, the internal temperature is 6 while stirring slowly.
It was allowed to cool to 0 ° C. 6. When the internal temperature reaches 60 ° C.
126 ml (3.8 eq) of 0N hydrochloric acid / ethanol solution
Was added all at once (the internal temperature rose to 72 ° C.). When the reaction liquid became cloudy, the stirring was stopped and the mixture was left overnight. The precipitated crystals were filtered by suction, and the collected crystals were air-dried for 3 days. Then, 152.34 g of Compound 3 was obtained as crystals (yield: 96.
8%) ¹ H-NMR (d ₆ -DMSO) δ; 1.5-1.6 (m, 2H), 2.0-
2.1 (m, 2H), 3.1-3.3 (m, 2H), 2.2-2.9 (m, 10H), 4.02 (t, J =
7.8Hz, 1H), 4.2-4.3 (m, 1H), 6.83 (1H, t, J = 7.3Hz), 6.92 (2
. H, d, J = 7.8Hz ), 7.1-7.3 (6H, m), 7.4-7.7 (m, 4H) mp; 230.5-232 ℃ IR; 3152, 2373, 1602, 1493, 1221, 827 (cm - ¹ ) Specific rotation; -7.62 ° (c = 0.5, CH ₃ OH) Elemental analysis Calculated: C, 59.14%; H, 6.50%; N, 7.13%; Cl, 18.06% Measured: C, 59.24%; H, 6.50%; N, 7.13%, Cl, 17.83% Example 4 (R)-(+)-1- [4,4-bis (4-fluorophenyl) butyl] -4- (2- Preparation Example of (Hydroxy-3-phenylaminopropyl) piperazine Trihydrochloride (Compound 4) Compound 4 was obtained in the same manner as in Example 3 except that Compound 2 was used. Yield; 96.6% ¹ H-NMR (d ₆ -DMSO) δ; 1.5-1.6 (m, 2H), 2.0-2.1 (m, 2H),
3.1-3.3 (m, 2H), 2.2-2.9 (m, 10H), 4.02 (t, J = 7.8Hz, 1H),
4.2-4.3 (m, 1H), 6.83 (1H, t, J = 7.3Hz), 6.92 (2H, d, J = 7.8H
z), 7.1-7.3 (6H, m), 7.4-7.7 (m, 4H) mp .; 230-233 ° C IR; 3152, 2373, 1602, 1493, 1221,827 (cm ^-1 ) Specific rotation; 8.10 ° (c = 0.5, CH ₃ OH) Elemental analysis Calculated: C, 59.14%; H, 6.50%; N, 7.13%; Cl, 18.06% Measured: C, 59.17%; H, 6.53%; N, 7.24%; Cl, 18.21% Test Example 1 Measurement of Chemical Purity and Optical Purity Chemical purity and optical purity were measured under the following conditions. Table 1 shows the results. From this table, it is understood that the compound of the general formula (3) having high optical purity and / or a physiologically acceptable salt thereof can be obtained by the production method of the present invention. 1. Column for measuring chemical purity: TSKgel ODS-80TM (4.6
X250mm) Mobile phase: CH ₃ CN-10mL phosphate buffer (pH
4.0) Mixed system flow rate: 1.0 mL / min. Column temperature: 40 ° C. Detection: 245 nm Injection volume: 10 μl Optical purity measurement conditions Column: Chiral cell OD-R (4.6 × 250 mm) Mobile phase: 0.5 M NaClO ₄ (HClO ₄ , pH 2.0): CH ₃ CN = 70: 30 Flow rate: 0.8 mL / min. Column temperature: 40 ° C. Detection: 245 nm Injection volume: 20 μl Test Example 2 As a comparative example of comparison with the conventional method, Compound 1 was condensed with the conventional method (1- [4,4-bis (4-fluorophenyl) butyl] piperazine and optically active epichlorohydrin, and then mixed with aniline. ) And Compound 1 synthesized by the production method of the present invention were compared in optical purity (specific optical rotation) and yield. Table 2 shows the results. From this, it can be seen that according to the method of the present invention, a compound represented by the general formula (3) and / or a physiologically acceptable salt thereof can be obtained with high yield and high optical purity. [Table 2] According to the present invention, a diphenylpiperazine derivative having high optical purity and / or a physiologically acceptable salt thereof can be provided in a high yield.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 25/16 A61P 25/16 25/24 25/24 25/28 25/28 43/00 111 43/00 111 C07M 7:00 C07M 7:00 (72) Inventor Miho Minda 560 Paula-cho, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside the Totsuka Research Laboratories Co., Ltd. Inside Totsuka Laboratory Co., Ltd. (72) Inventor Rie Maejima 560, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside Totsuka Laboratory Co., Ltd. (56) References JP-A-4-226986 (JP, A) −279887 (JP, A) WO 92/005165 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 295/08 C07D 295/12 C07B 53/00 CA (STN) REGISTRY (STN )

Claims (1)

(57) [Claims] [Claim 1] The following general formula (4): Ar— (CH ₂ ) _m —XH (4) wherein Ar is an alkyl group having 1 to 4 carbon atoms, 1 to
4 halogenoalkyl group, alkoxy group having 1 to 4 carbon atoms, hydroxyl group, nitro group, amino group, cyano group, 2 carbon atoms
And X represents an N (R ³ ) group (where R ³ represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group). And m represents an integer of 0 to 4] and a phenylamine compound represented by the following general formula (5): [Wherein, Y represents a leaving group, and * represents the position of the asymmetric carbon]
An optically active epoxy compound represented by the following formula is reacted without a catalyst to give the following general formula (1): [Wherein, Ar, X, Y, m, and * represent the same as described above].
Next, this is added to the general formula (2). [Wherein, R ¹ and R ² each independently represent an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a phenyl group which may have a substituent selected from the group consisting of halogen atoms. And n represents an integer of 0 to 4], wherein the piperazine derivative represented by the following general formula (3) is condensed in the presence of an alkali catalyst. [Wherein R ¹ , R ² , X, Ar, m, n and * represent the same as described above] and a method for producing an optically active diphenylpiperazine derivative and / or a physiologically acceptable salt thereof. .