KR840002005B1 - Method for preparing piperazine derivatives - Google Patents

Abstract

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Description

[Name of invention]

Method for preparing piperazine derivatives

Detailed description of the invention

The present invention relates to a method for preparing a piperazine derivative.

In particular, the present invention relates to a piperazine derivative of the general formula (I) and a method for preparing a pharmaceutically acceptable acid addition salt thereof.

In formula (I), R is (C _1-7 ) alkyl, ring A is phenyl, (C _1-4 ) alkylphenyl or halogenophenyl, and n is an integer of 2-6.

Brain edema, a known complication of various brain diseases (eg, cerebral hemorrhage, cerebral hemorrhage, cerebral thrombosis, cerebral embolism, head injury, brain tumor, encephalomyelitis), causes an increase in intracranial pressure due to compression of adjacent brain tissue.

Moreover, such intracranial pressure increases are known to cause side effects in brain metabolism, disrupting brain circulation and further worsening brain edema.

Thus, intracranial pressure increase can be dangerous to the patient or sometimes fatal to the patient. As a result of various studies, it was found that the piperazine derivative (I) of the present invention resulted in a significant decrease in intracranial pressure. For example, test compound 1- [3- (4-acetamido-) was injected when the test compound solution in aqueous solution was injected at a rate of 0.2 ml / kg in 20 minutes through the femoral vein of a mouse. It was found that intracranial pressure decreased by about 27% after 40 minutes of administration of 2-methoxyphenoxy) -n-propyl] -4- (3-fluorophenyl) -piperazine (dosage 1 mg / kg).

In view of this effect of piperazine derivative (I) on intracranial pressure, the above-described compounds of the present invention can be used for brain impotence fractures, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, brain retinal hemorrhage, head injury, brain tumor, It is useful for treating the pain of increased intracranial pressure resulting from various brain diseases such as cerebral edema, encephalomyelitis and similar diseases. Moreover, since the piperazine derivative (I) of the present invention has a strong depressurizing effect in the central nervous system, this compound is also useful as a psychostable, analgesic and / or antiemetic agent.

Compound (I) of the present invention may be used for medicament as a free base or a pharmaceutically acceptable acid addition salt thereof. Examples of pharmaceutically acceptable acid addition salts of the compound (I) of the present invention include inorganic acid addition salts (eg, hydrochloride, bromate, sulfate, nitrate phosphate) and organic acid addition salts (eg, vinegar salt, lactate, hydroxide, citrate, tartarate, fumaric acid). Salts, maleates, methanesulfonates, benzoates). Compound (I) of the present invention may be administered orally or parenterally. The daily dosage of this compound (I) can be about 0.05 to 50 mg (freebase), in particular 0.1 to 10 mg (freebase) per kilogram of body weight.

In addition, the mixture (I) may be used in the form of a pharmaceutical containing the same compound in the present invention in combination or combined with a pharmaceutical excipient suitable for enteral or parenteral administration. Suitable excipients include, for example, gelatin, lactose, glucose, sodium chloride, starch, magnesium stearate, talcum, vegetable oils and other known excipients. The medicament may be in the form of a solid in powder, tablet or capshule; Or in liquid form, such as solution, suspension or emulsion. This mixture (I) may also be used in the form of injections for red wine injection.

Examples of piperazine derivatives of the invention include those in which R is (C _1-7 ) alkyl (eg methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl); Ring A is phenyl, (C _1-4 ) alkylphenyl (e.g. 2-methylphenyl, 3-methylphenyl, 4-methylphenyl) or halogenophenyl (e.g. 2-chlorophenyl, 3-chlorophene, 4-chlorophenal, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl); Moreover, the compound of general formula (I) whose n is an integer of 2-6 is mentioned.

Examples of preferred subspecies among the piperazine derivatives of the present invention are those in which R is (C _1-7 ) alkyl, ring A is phenyl, (C _1-4 ) alkylphenyl or halogenophenyl, and n is 2-4. The compound of general formula (I) is mentioned.

Examples of other preferred subgenus include compounds of formula (I) wherein R is (C _1-7 ) alkyl, ring A is phenyl, methylphenyl, chlorophenyl or fluorophenyl and n is 3 or 4. Examples of other preferred subgens include those in which R is methyl, isopropyl, t-butyl, ring A is phenyl, 3-methylphenyl, 2-fluorophenyl or 3-fluorophenyl, and n is 3 The compound of I).

According to the present invention, the compound (I) may be prepared by reacting a compound of formula (II) with a compound of formula (III).

In the above formulas (II) and (III), R, rings A and n are the same as defined above, W is hydrogen or a group of the formula-(CH ₂ ) _n -Y, _wherein Y is a reactive group or atom When W is of the formula-(CH ₂ ) _n -Z, W 'is hydrogen and W is hydrogen, W' is a group of the formula-(CH ₂ ) _n -Z, where Z is a reactive group or atom to be.

The above reaction is explained in more detail by the following technique.

Method (A): (W =-(CH ₂ ) _n -Y, W '= H)

(In the above scheme, R, Y, rings A and n are the same as defined above)

Method (B): (W = H, W '=-(CH ₂ ) _n -Z)

(In the above scheme, R, Z, rings A and n are the same as defined above)

Method (A)

Method (A) consists of the step of condensing compound (II-a) with compound (III-a) to produce compound (I). Examples of reactive groups or atoms (Y) in the starting compound (II-a) include alkylsulfonyloxy (e.g. methylsulfonyloxy), arylsulfonyloxy (e.g. p-toluenesulfonyloxy) and halogen atoms (e.g. , N-chlorine, bromine). The reaction can proceed in a solvent in the presence of an acid acceptor.

Alkanols (e.g. methanol, ethanol, isopropanol), dimethylformamide, dimethylsulfoxide and the like are suitable as solvents. Examples of acid acceptors include triethylamine, triethylenediamine or N-methylpiperidine. Organic base; And inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.

When compound (III-a) is excessively used in the reaction, the compound (III-a) acts as an acid acceptor, so it is not necessary to use the acid acceptor described above. It is preferable to perform reaction at the temperature of 20-100 degreeC.

Method (B)

Method (B) consists of condensing compound (II-b) with compound (III-b) to obtain compound (I). Examples of reactive groups or atoms (Z) in the compound (IIIb) include alkylsulfonyloxy (eg methylsulfonyloxy), arylsulfonyloxy (eg p-toluenesulfonyloxy) and halogen atoms (eg chlorine). Bromine). Alkanols (eg methanol, ethanol, isopropanol), dimethylformamide, dimethylsulfoxide and the like are suitable as solvents.

Examples of acid acceptors include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. It is preferable to advance reaction at 20 degreeC-100 degreeC temperature. The reaction is also preferably carried out in an inert gas (eg nitrogen gas) stream.

The starting compounds of the present invention, that is, compounds (II-b) and (III-b), can be prepared by the methods described in the following table.

(In the above scheme, R 'is (C _1-4 ) alkyl, X is halogen and R, Y and n are the same as defined above)

Synthesis of Compound (III-b)

(In the above scheme, R ', rings A, Z, X and n are the same as defined above)

[Experiment I]

Intravenous effect of test compound on intracranial pressure in rats

Male SD-rats (each group consisting of five rats) weighing 500-800 g were anesthetized with urethane. Only 5w / v% nee was injected through the femoral vein at a rate of 0.2 ml / kg / min for 20 min. (When this test compound was used in free base form, the above-mentioned solution was prepared by dissolving in 5 w / v% mannitol aqueous solution with the help of 0.5 N hydrochloric acid). Intracranial pressure (ie, cerebrospinal fluid pressure in the cerebellum) was continuously monitored through the tubing inserted into the cerebellum. The pipe was connected to the transmitter and the records were recorded on graph paper. The effect of the test compound on intracranial pressure was measured as the increase or decrease in intracranial pressure, which was calculated according to the following equation.

The results are listed in Table 1 below.

[Table 1]

[Experiment 2]

(Inhibitory Effects of Test Compounds on the Central Nervous System in Rats)

The inhibitory effect of the test compound on the central nervous system was measured by the following method.

(1) Inhibitory effect on spontaneous motor activity:

A test compound solution or suspension added in water or aqueous carboxymethylcellulose solution was administered intraperitoneally to males of 18 to 20 g (each group consisting of 5 mice) body weight. Test compounds were measured after 80 minutes of spontaneous motor activity by animex activity meter for 5 minutes. The 50% effective dose of the test compound (ED ₅₀ ) was calculated as the dose necessary to reduce the motor activity of the mice administered to 50% of the motor activity of the control (ie, non-dosed mice). The results are listed in Table 2.

(2) effect on hexobarbital sodium infusion anesthesia;

A test compound solution or suspension added in water or aqueous carboxymethylcellulose solution was administered intraperitoneally to males of 18 to 20 g body weight (each group consisting of 5 mice). Hemobarbital sodium (100 mg / kg) was administered intraperitoneally in rats 30 minutes after intraperitoneal administration of the test compound. And the sleep time between loss and recovery of cloves was measured. The sleep time of rats that received a 50% effective dose (ED ₅₀ ) of the test compound was calculated as the dose necessary to prolong the sleep time of the control group (ie, the non-dosed rats). The results are listed in Table 3.

(3) Anti apomorphine action:

A test compound solution or suspension added in an aqueous solution of water or carboxymethyl cellulose was administered intraperitoneally to 18 to 20 g males (each group consisting of 5 mice). Thirty minutes after administration of the test compound, apomorphine hydrochloride (2.5 mg / kg) was administered subcutaneously to the rats and the number of rats that could climb the rat cage was examined. The 50% effective dose of the test compound (ED ₅₀ ) was calculated as the dose required to reduce the number of rats that could climb the rat cage to 50% of the number of mice that could climb the rat cage. . The results are listed in Table 4.

[Table 2]

[Table 3]

[Table 4]

[Experiment 3]

18 to 22 g of test compound solution or suspension added in water or aqueous carboxymethylcellulose solution (each group consists of 5 rats) was administered intraperitoneally to males of body weight, and these mice were treated for 72 hours after administration of the test compound. Was observed. As a result, 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (3-fluorophenyl) -piperazine and 1- [3- (4-acet) The maximum permissible dose of amido-2-methoxyphenoxy) -n-propyl] -4- (2-fluorophenyl) -piperazine was at least 300 mg / kg.

Example 1

620 mg of 4- (4-methylphenyl0 piperazine and 355 mg of triethylamine in 1.3 ml of 1- (4-acetamido-2-methoxyphenoxy) -3- (p-toluenesulfonyloxy in 40 ml ethanol The mixture was added to the dissolved solution of) -n-propanol and the mixture was refluxed for 6 hours, after which the mixture was evaporated under reduced pressure to remove ethanol The residue was adjusted to pH 11 with saturated sodium hydride cold water solution. The extract was then washed with water and saturated aqueous sodium chloride solution, dried and then evaporated under reduced pressure. The residue was recrystallized from acetone to give 890 mg of 1- [3- (4-acetate). Amido-2-methoxy-phenoxy) -n-propyl] -4- (4-methylphenyl) -piperazine is obtained as a colorless leaflet.

The mother liquor was concentrated under reduced pressure and the residue was purified by silica gel chromatography (solvent; 3% methanol / chloroform). 270 mg of the same product as obtained above was prepared.

Overall yield: 85.5%

Melting Point 144-145 ℃

Scan: 3250, 1650, 1140, 1040

NMR (CDCl ₃ ) δ: 7.92 (wide s, -NH-), 7.32 (d, 1H, J = 1.5 Hz, aromatic), 7.3-6.8 (m, 2H, aromatic), 7.10 (d, 2H, J = 8.9 Hz, aromatic), 6.84 (d, 2H, J = 8.9 Hz, aromatic), 4.06 (t, 2H, J = 6.0 Hz, -COH ₂ CH _2- ), 3.80 (s, 3H, -OCH ₃ ), 3.16 (m, 4H), 2.58 (m, 6H), 2.26 (s, 3H, -ph-CH ₃ ), 2.11 (s, 3H, CH ₃ CONH-), 2.00 (m, 2H)

Mass m / e: 397 (m ⁺ ), 189 (reference peak)

Example 2

1.3 g 1- (4-acetamido-2-methoxyphenoxy) -3- (p-toluenesulfonyloxy) -n-propane, 690 mg 4- (4-chlorophenyl) piperazine, 335 mg Triethylamine and 40 ml of ethanol were treated in the same manner as described in Example 1. The crude product thus obtained was recrystallized in acetone to give 1.22 g of 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (4- (4-chlorophenyl ) -Piperazine was prepared as a colorless needle.

Yield: 85.5%

Melting Point 152-153 ℃

: 3320, 1650, 1055, 1045

: 3320, 1650, 1055, 1045

NMR (CDCl ₃ ) δ: 7.75 (wide s, -NH-), 7.30 (wide s, 1H, aromatic), 7.22 (d, 2H, J = 9 Hz, aromatic), 7.1-9.8 (m, 2H, aromatic) , 6.82 (d, 2H, J = 9 Hz, aromatic), 4.07 (t, 2H, J = 5.9 Hz, -COH ₂ CH _2- ), 3.82 (s, 3H, -OCH ₃ ), 3.4-3.0 (m , 4H), 2.8-2.4 (m, 6H), 2.3-1.8 (m, 2H), 2.12 (s, 3H, CH ₃ CONH-)

Mass m / e: 419, 417 (m ⁺ ), 211, 209 (reference peak)

Example 3

1.3 g 1- (4-acetamido-2-methoxyphenoxy) -3- (p-toluenesulfonyloxy) -n-propane, 630 mg 4- (4-fluorophenyl) piperazine, 355 mg Triethylamine and 40 ml of ethanol were treated in the same manner as in Example 1. The crude product thus obtained was recrystallized in acetone to give 1.18 g of 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (4- (4-fluoro Phenyl) -piperazine was prepared as a colorless prism.

Yield: 89%

Melting point 137-138 ℃

Scan: 3250-3070, 1650, 1135, 1040

NMR (CDCl ₃ ) δ: 7.92 (wide s, 1H, NH), 7.36 (d, 1H, J = 1.5 Hz, aromatic), 7.2-6.7 (m, 6H, aromatic), 4.09 (t, 2H, J = 6.6 Hz, -OCH ₂ CH _2- ), 3.84 (s, 3H, -OCH ₃ ), 3.4-2.9 (m, 4H), 2.9-2.4 (m, 6H), 2.13 (s, 3H, CH ₃ CONH- ), 2.1-1.8 (m, 2H)

Mass m / e: 401 (m ⁺ ), 193 (reference peak)

Example 4

1.3 g 1- (4-acetamido-2-methoxyphenoxy) -3- (p-toluenesulfonyloxy) -n-propane, 620 mg 4- (3-methylphenyl) piperazine, 355 mg tri Ethylamine and 40 ml of ethanol were treated in the same manner as in Example 1. The crude product thus obtained was recrystallized in acetone to give 1.21 g of 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (3-methylphenyl) -piperazine Was prepared as a colorless needle.

Yield: 92.1%

Melting point 113-114 ℃

Scan: 3250, 1650, 1135, 1040

NMR (CDCl ₃ ) δ: 7.79 (broad s, 1H, -NH-), 7.6-6.5 (m, 7H, aromatic), 4.08 (t, 2H, J = 6.5 Hz, -COH ₂ CH _2- ), 3.83 (s, 3H, -OCH ₃ ), 3.4-3.30 (m, 4H), 2.8-2.3 (m, 6H), 2.32 (s, 3H, -ph-CH ₃ ), 2.3-1.8 (m, 2H), 2.12 (s, 3H, CH ₃ CONH-)

Mass m / e: 397 (m ⁺ ), 189 (reference peak)

Example 5

1.3 g 1- (4-acet amido-2-methoxyphenoxy) -3- (p-toluenesulfonyloxy) -n-propane, 630 mg 4- (3-fluorophenyl) piperazine, 355 mg Triethylamine and 40 ml of ethanol were treated in the same manner as in Example 1. The crude product thus obtained was recrystallized in isopropyl alcohol to give 1.14 g of 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (3-fluorophenyl )-Piperazine is prepared as a colorless acicular material.

Yield: 86%

Melting point 136-137 ℃

: 3275, 1660, 1135, 1035

: 3275, 1660, 1135, 1035

NMR (CDCl ₃ ) δ: 7.89 (wide s, 1H, -NH-), 7.5-6.2 (m, 7H, aromatic), 4.08 (t, 2H, J = 6.7 Hz, -COH ₂ CH _2- ), 3.84 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-2.3 (m, 6H), 2.3-1.8 (m, 2H), 2.13 (s, 3H, CH ₃ CONH-)

Mass m / e: 401 (m ⁺ ), 193 (reference peak)

Example 6

1.3 g 1- (4-acetamido-2-methoxyphenoxy) -3- (p-toluenesulfonyloxy) -n-propane, 690 mg 4- (2-chlorophenyl) piperazine, 355 mg Triethylamine and 40 ml of ethanol were treated in the same manner as in Example 1. The crude product thus obtained was recrystallized in isopropyl alcohol to give 1.26 g of 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (2-chlorophenyl) Piperazine was prepared as a colorless prism.

Yield: 91%

Melting point 115-116 ℃

: 3275, 1660, 1135, 1035

: 3275, 1660, 1135, 1035

NMR (CDCl ₃ ) δ: 7.84 (wide s, 1H, -NH-), 7.6-6.8 (m, 7H, aromatic), 4.11 (t, 2H, J = 6.7 Hz, -COH ₂ CH _2- ), 3.84 (s, 3H, -OCH ₃ ), 3.3-3.0 (m, 4H), 2.9-2.5 (m, 6H), 2.4-1.8 (m, 2H), 2.14 (s, 3H, CH ₃ CONH-)

Mass m / e: 419, 417 (m ⁺ ), 211, 209 (reference peak)

Example 7

1.3 g 1- (4-acetamido-2-methoxyphenoxy) -3- (p-toluenesulfonyloxy) -n-propane, 630 mg 4- (2-fluorophenyl) piperazine, 355 mg Triethylamine and 40 ml of ethanol were treated in the same manner as in Example 1.

The crude product thus obtained was recrystallized in isopropyl alcohol to yield 1.23 g of 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (2-fluorophenyl ) -Piperazine was prepared as a colorless needle.

Yield: 92.5%

Melting point 122.5-123.5 ℃

: 3270, 1655, 1140, 1040

: 3270, 1655, 1140, 1040

NMR (CDCl ₃ ) δ: 7.91 (wide s, 1H, -NH-), 7.37 (wide s, 1H, aromatic), 7.2-6.7 (m, 6H, aromatic), 4.11 (t, 2H, J = 6.6 Hz , -COH ₂ CH _2- ), 3.84 (s, 3H, -OCH ₃ ), 3.3-2.9 (m, 4H), 2.8-2.3 (m, 6H), 2.3-1.8 (m, 2H), 2.14 (s , 3H, CH ₃ CONH-)

Mass m / e: 401 (m ⁺ ), 193 (reference peak)

Hydrochloride:

Melting point 265-268 ° C (decomposition) (colorless, acicular, recrystallized in methanol)

: 3240-3100, 2600-2300, 1670, 1135, 1040

: 3240-3100, 2600-2300, 1670, 1135, 1040

Methanesulfonate:

Melting point 196-197 ° C (colorless needle, recrystallized in ethanol)

: 3250-3100, 2700-2400, 1670, 1170, 1030, 1040

: 3250-3100, 2700-2400, 1670, 1170, 1030, 1040

Example 8

2.0 g 1- (4-acetamido-2-methoxyphenoxy) -4- (p-toluenesulfonyloxy) -n-butane, 970 mg 4- (2-fluorophenyl) piperazine, 550 mg Triethylamine and 30 ml of ethanol were treated in the same manner as in Example 1. The crude product thus obtained was recrystallized in a mixture of isopropyl alcohol and isopropyl ether to obtain 1.3 g of 1- [4- (4-acetamido-2-methoxyphenoxy) -n-butyl] -4- (2-Fluorophenyl) -piperazine is prepared as a colorless needle.

Yield: 64.7%

Melting Point 115-116.5 ℃

: 3270, 3150, 1655, 1130, 1030

: 3270, 3150, 1655, 1130, 1030

NMR (CDCl ₃ ) δ: 7.89 (wide s, 1H, -NH-), 7.25-6.85 (m, 7H, aromatic), 3.98 (wide t, 2H, J = 5.5 Hz, -COH ₂ CH _2- ), 3.79 (s, 3H, -OCH ₃ ), 3.2-2.9 (m, 4H), 2.7-2.3 (m, 6H), 2.12 (s, 3H, CH ₃ CONH-), 2.1-1.7 (m, 2H),

Mass m / e: 415 (m ⁺ ), 235 (reference peak), 193

Methanesulfonate:

Melting point 169-170 ° C (colorless plate, recrystallized in isoproalcohol)

: 3250, 2700-2400, 1670, 1150, 1035

: 3250, 2700-2400, 1670, 1150, 1035

Example 9

A mixture of 5 g 1- (4-acetamido-2-methoxyphenoxy) -3- (p-toluenesulfonyloxy) -n-propane, 5.16 g 4-phenylpiperazine and 100 ml ethanol Time to reflux. After the reaction, the mixture is evaporated under reduced pressure to remove the solvent. Water is added to the residue, and this aqueous mixture is extracted with methylene chloride. The extract is washed with water, dried and evaporated to remove the solvent.

The residue is recrystallized in benzene to give 4.37 g of 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4-phenyl-4-piperazine as a colorless needle. .

Yield: 90%

Melting point 136-137 ℃

: 3240, 1650, 1130, 1040

: 3240, 1650, 1130, 1040

NMR (CDCl ₃ ) δ: 7.93 (wide s, 1H, -NH-), 7.6-6.7 (m, 8H, aromatic), 4.08 (t, 2H, J = 6.4 Hz, -COH ₂ CH _2- ), 3.82 (s, 3H, -OCH ₃ ), 3.5-3.1 (m, 4H), 2.8-2.4 (m, 6H), 2.35-1.8 (m, 2H), 2.12 (s, 3H, CH ₃ CONH-),

Mass m / e: 383 (m ⁺ ), 175 (peak)

Hydrochloride:

Melting point 281-283 ° C (decomposition) (colorless, acicular, recrystallized in methanol)

: 3230, 2450, 1655, 1600, 1130, 1035

: 3230, 2450, 1655, 1600, 1130, 1035

Methanesulfonate:

Melting point 197-199 ° C (colorless needle, recrystallized in ethanol)

: 3580, 3260, 1680, 1170, 1160, 1045

: 3580, 3260, 1680, 1170, 1160, 1045

Example 10

1.3 g 1- (4-acetamido-2-methoxyphenoxy) -3- (p-toluenesulfonyloxy) -n-propane, 690 mg 4- (3-chlorophenyl) piperazine, 355 mg Triethylamine and 40 ml of ethanol were treated in the same manner as in Example 1. The crude product thus obtained was recrystallized in isopropyl alcohol to give 1.27 g of 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (3-chlorophenyl) Piperazine was prepared as a colorless needle.

Yield: 92%

Melting point 138-139 ℃

: 3280, 1655, 1140, 1040

: 3280, 1655, 1140, 1040

NMR (CDCl ₃ ) δ: 7.79 (wide s, 1H, -NH-), 7.5-6.6 (m, 7H, aromatic), 4.10 (t, 2H, J = 6.1 Hz, -COH ₂ CH _2- ), 3.85 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-2.3 (m, 6H), 2.3-1.8 (m, 2H), 2.14 (s, 3H, CH ₃ CONH-),

Mass m / e: 419, 417 (m ⁺ ), 211, 209 (reference peak)

Example 11

1.3 g 1- (4-acetamido-2-methoxyphenoxy) -3- (p-toluenesulfonyloxy) -n-propane, 620 mg 4- (2-methylphenyl) piperazine, 355 mg tri Ethylamine and 40 ml of ethanol were treated in the same manner as in Example 1. The crude product thus obtained was recrystallized in acetone to give 1.31 g of 1- [3- (4-acetamino-2-methoxyphenoxy) -n-propyl] -4- (2-methylphenyl) -piperazine Was prepared as a colorless prism.

Yield: 92%

Melting point 109-110 ℃

: 3275, 1655, 1135, 1040

: 3275, 1655, 1135, 1040

NMR (CDCl ₃ ) δ: 7.82 (wide s, 1H, -NH-), 7.5-6.7 (m, 7H, aromatic), 4.08 (t, 2H, J = 6.4 Hz, -COH ₂ CH _2- ), 3.82 (s, 3H, -OCH ₃ ), 3.15-2.8 (m, 4H), 2.8-2.4 (m, 6H), 2.30 (s, 3H, -ph-CH ₃ ), 2.3-1.8 (m, 2H), 2.12 (s, 3H, CH ₃ CONH-),

Mass m / e: 397 (m ⁺ ), 189 (reference peak)

Example 12

3 g of 1- (4-acetamido-2-methoxyphenoxy) -4- (p-toluenesulfonyloxy) -n-butane, 1.78 g 4-phenylpiperazine, 1.1 g triethylamine 50 ml of ethanol were treated in the same manner as in Example 1. The crude product thus obtained was recrystallized in benzene to give 2.71 g of 1- [4- (4-acetamido-2-methoxyphenoxy) -n-butyl] -4-phenyl-piperazine as a colorless needle. Was prepared.

Yield: 92.5%

Melting point 128-129 ℃

: 3250, 1650, 1135, 1040

: 3250, 1650, 1135, 1040

NMR (CDCl ₃ ) δ: 7.45 (wide s, 1H, -NH-), 7.1-6.3 (m, 3H, aromatic), 3.78 (t, 2H, J = 5.2 Hz, -COH ₂ CH _2- ), 3.59 (s, 3H, -OCH ₃ ), 3.2-2.8 (m, 4H), 2.65-2.1 (m, 6H), 1.97 (s, 3H, CH ₃ CONH-), 1.9-1.3 (m, 4H)

Mass m / e: 397 (m ⁺ ), 217 (peak), 175

Methanesulfonate:

Melting point 1840185 ° C (colorless plate, recrystallized in ethanol)

: 3400, 3280, 2800-2300, 1670, 1165, 1145, 1045

: 3400, 3280, 2800-2300, 1670, 1165, 1145, 1045

Example 13

1.07 g of 4- (2-fluorophenyl) piperazine and 1.5 ml of triethylamine are added to 1.5 g of 2- (4-acetamido-2-methoxyphenoxy) -1 in 10 ml of anhydrous dimethylformamide. -(p-toluenesulfonyloxy) is added to the dissolved solution, and the mixture is stirred at 100 ° C for 6 hours. After the reaction, the mixture is poured into ice water and the aqueous mixture is extracted with chloroform. The extract is washed successively with water and saturated aqueous sodium chloride solution, and the extract is dried and then evaporated to remove the solvent under reduced pressure. The residue was purified by silica gel chromatography (solvent: 2% methanol / chloroform) and then recrystallized in a mixture of ethyl acetate and n-hexane to give 1.3 g of 1- [2- (4-acetamido-2-methoxy Phenoxy) ethyl] -4- (2-fluorophenyl) -piperazine was prepared on a colorless scale.

Yield: 85%

Melting point 118-119 ℃

: 3250, 3200, 1655, 1140

: 3250, 3200, 1655, 1140

NMR (CDCl ₃ ) δ: 8.00 (wide s, 1H, -NH-), 7.4-6.45 (m, 7H, aromatic), 4.11 (t, 2H, J = 6.0 Hz, -COH ₂ CH _2- ), 3.75 (s, 3H, -OCH ₃ ), 3.45-2.45 (m, 10H), 2.10 (s, 3H, CH ₃ CONH-)

Mass m / e: 387 (m ⁺ ), 207, 193 (reference peak)

Hydrochloride:

Melting point 178.5-179.5 ° C (colorless needle, recrystallized in a mixture of isopropyl alcohol and isopropyl ether)

Scan: 3250, 2700-2300, 1670, 1140, 1030, 1010

Example 14

1.5 g 6- (4-acetamido) -2-methoxyphenoxy) -1- (p-toluenesulfonyl oxy) -n-hexane, 670 mg 4-phenylpiperazine, 520 mg triethylamine 20 ml of anhydrous dimethylform amide are treated in the same manner as in Example 13. The crude product thus obtained was recrystallized in ethyl acetate to give 1.07 g of 1- [6- (4-acetamido-2-methoxyphenoxy-n-hexyl) -4phenyl-piperazine as a colorless scale substance. Was prepared.

Yield: 73%

Melting point 103-104 ℃

: 3250, 3200, 1600, 1140, 1030

: 3250, 3200, 1600, 1140, 1030

NMR (CDCl ₃ ) δ: 7.7 (wide s, 1H, -NH-), 7.45-6.5 (m, 8H, aromatic), 3.97 (t, 2H, J = 6 Hz, -COH ₂ CH _2- ), 3.78 ( s, 3H, -OCH ₃ ), 3.5-2.95 (m, 4H), 2.8-1.0 (m, 14H), 2.10 (s, 3H, CH ₃ CONH-)

Mass m / e: 425 (m ⁺ ), 175 (peak)

Hydrochloride:

Melting point 183-185 ° C. (decomposition) (colorless needles, recrystallized from a mixture of methanol and isopropyl alcohol)

: 3250, 2700-2400, 1680, 1130, 1030

: 3250, 2700-2400, 1680, 1130, 1030

Example 15

1.13 g of powdered sodium hydroxide is added to a solution in which 5.08 g of 4-acetamido-2-methoxyphenol is dissolved in 70 ml of anhydrous dimethyl sulfoxide under a stream of nitrogen. The mixture is stirred at 50 ° C. for 2 hours. A solution of 6 g of 1- (3-chloro-n-)-4- (2-propylfluorophenyl) -piperazine in 20 ml of anhydrous dimethylsulfoxide was added dropwise to the above mixture at 20 ° C.

And this mixture is stirred at 100 degreeC for 1.5 hours. After cooling, the reaction mixture is poured into ice water. Filtration collects crystalline precipitate to give crude product. The mother liquor obtained after the crude product has been separated is extracted with chloroform. The extract is washed with water, dried and evaporated under reduced pressure to remove the solvent to yield another crude product. The two crude products obtained as described above are dissolved in warm isopropyl alcohol and then treated with activated carbon. This produces 6.95 g of 1- [3- (4-acet amido-2-methoxyphenoxy-n-propyl) -4- (2-fluorophenyl) -piperazine as a colorless needle.

Yield: 74%

The physicochemical properties of this product are the same as those of the sample obtained in Example 7.

Example 16

10.13 g of 4-acet amido-2-methoxyphenol, 2.24 g of sodium hydroxide, 12.14 g of 1- (3-chloro-n-propyl-4-phenyl-piperazine and 300 ml of anhydrous dimethylsulfoxide The crude product thus obtained was recrystallized in a mixture of benzene and ethyl acetate to give 17.2 g of 1- [3- (4-acetamido-2-methoxyphenoxy)-. n-propyl] -4-phenyl-piperazine is obtained.

Yield: 88%

The physicochemical properties of this product are the same as the samples obtained in Example 9.

Example 17

2.54 g 4-acet amido-2-methoxyphenol, 585 g sodium hydroxide, 2.62 g 1- (2-chloroethyl) -4-phenyl-piperazine and 60 ml anhydrous dimethylsulfoxide Treat it in the same way. The crude product thus obtained was recrystallized in benzene to give 3.48 g of 1- [2- (4-acetamido-2-methoxyphenoxy) ethyl] -4-phenyl-piperazine as a colorless prismatic material. .

Yield: 67.6%

Melting point 134-135 ℃

: 3200, 1645, 1600, 1150, 1140, 1030

: 3200, 1645, 1600, 1150, 1140, 1030

NMR (CDCl ₃ ) δ: 7.96 (wide, 1H, -NH-, D ₂ O. .disappear), 7.5-6.5 (m, 8H, aromatic), 4.14 (t, 2H, J = 5.9 Hz, -COH ₂ CH _2- ), 3.78 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 3.0-2.4 (m, 6H), 2.10 (s, 3H, CH ₃ CONH-)

Mass m / e: 369 (m ⁺ ), 189, 175 (reference peak)

Methanesulfonate:

Melting point 147-148 ° C. (colorless prism phase, recrystallized in isopropyl alcohol)

: 3300-3000, 2800-2400, 1665, 1600, 1165, 1130, 1040

: 3300-3000, 2800-2400, 1665, 1600, 1165, 1130, 1040

[Examples 18 to 21]

The following compounds were prepared in the same manner as described in Example 15.

18: 1- [3- (4-isobutylamino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine, colorless acicular substance point 171 to 172 ° C (recrystallized in ethyl acetate)

: 3270, 1650, 1135, 1040

: 3270, 1650, 1135, 1040

NMR (CDCl ₃ ) δ: 7.6-6.7 (m, 9H, aromatic and -CO-NH-), 4.07 (t, 2H, J = 6.5 Hz,-(-O-CH ₂ CH _2- ), 3.85 (s , 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-2.3 (m, 7H), 2.3-1.8 (m, 2H), 1.23 (d, 6H, J = 6.9Hz, -CH (CH ₃ ) ₂

Mass m / e: 411 (m ⁺ ), 203, 175 (reference peak)

19: 1- [3- (4-t-butylcarbonylamino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine, colorless acicular material,

Melting point 140-142 ° C (recrystallized from isopropyl alcohol)

: 3370, 1645, 1140, 1040

: 3370, 1645, 1140, 1040

NMR (CDCl ₃ ) δ: 8.40 (wide s, 1H, -NH-), 7.5-7.6 (m, 8H, aromatic), 4.05 (t, 2H, J = 6.5 Hz, -COH ₂ CH _2- ), 3.82 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-2.3 (m, 6H), 2.0 (m, 2H), 1.29 (s, 9H, -C (CH ₃ ) ₃

Mass m / e: 425 (m ⁺ ), 203, 175

20: 1- [3- (4-pentaneamino-2-methoxyphenoxy) -n-propyl] -4-phenylpiperazine: colorless acicular material

Melting point 117-118 ° C. (recrystallized from isopropyl alcohol)

: 3300, 1650, 1140, 1040, 1020

: 3300, 1650, 1140, 1040, 1020

NMR (CDCl ₃ ) δ: 7.65 (wide s, 1H, -NH-), 7.5-6.7 (m, 8H, aromatic), 4.03 (t, 2H, J = 6.5 Hz, -COH ₂ CH _2- ), 3.79 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-1.0 (m, 14H), 0.91 (wide t, 3H, J = 6.5 Hz, CH ₃ CH _2- )

Mass m / e: 425 (m ⁺ ), 203, 175

21: 1- [3- (4-n-octanamino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine, colorless acicular material

Melting point 124-126 ° C. (recrystallized from ethyl acetate)

: 3280, 1650, 1135, 1040, 1020

: 3280, 1650, 1135, 1040, 1020

NMR (CDCl ₃ ) δ: 7.7-6.7 (m, 9H, aromatic and -NH-), 4.07 (t, 2H, J = 6.3 Hz, -COH ₂ CH _2- ), 3.83 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, (4H), 2.8-1.0 (m, 20H), 0.88 (wide t, 3H, -CH ₂ CH ₃ )

Mass m / e: 467 (m ⁺ ), 203, 175

Preparation Example 1

(1) It is dissolved in 80 ml of dimethyl sulfoxide under 13.4 g of 4-acetamido-2-methoxyphenoxyol nitrogen stream, and 2.96 g of powdered sodium hydroxide is added. The mixture is stirred at 50 ° C. to 55 ° C. for 3 hours. A solution of 10 g of 2-chloro-1- (tetrahydropyran-2-yl-oxy) ethanol dissolved in 20 ml of dimethyl sulfoxide is added dropwise to this mixture, and the mixture is stirred at 100 ° C for 1 hour. After the reaction, the mixture is poured into ice water, and the aqueous mixture is extracted with ethyl acetate. The extract is washed successively with water and saturated aqueous sodium chloride solution. The extract is dried and evaporated to remove the solvent under reduced pressure. The residue was recrystallized in a mixture of ethyl acetate and n-hexane to give 15.5 g of 1- (4-acetamido-2-methoxyphenoxy) -2- (tetrahydropyran-2-yl-oxy)- Prepared with ethanol colorless needles.

Yield: 82.5%

Melting point 88-90 ℃

(2) The 15.5 g product obtained in (1) above is dissolved in 140 ml of water and 70 ml of ethanol mixture, and 0.1 ml of concentrated hydrochloric acid is added thereto. The mixture is stirred at room temperature for 2 days. After the reaction, the mixture is evaporated under reduced pressure to remove ethanol.

The residue is cooled and the crystal precipitates collected and recrystallized in ethanol. This was made of 9.43 g of 1- (4-acet amido-2-methoxyphenoxy) -2-hydroxy-ethanol colorless prismatic material.

Yield: 84%

Melting point 157-159 ℃

(3) 55 g of the product obtained in (2) above was dissolved in 120 ml of pyridine and a solution of 5 g of n-toluenesulfonyl chloride dissolved in 30 ml of pyridine was added dropwise at 0 ° C to 5 ° C. .

The mixture is left under ice cooling for 5 days. This mixture is then poured into ice water and the aqueous mixture is extracted with ethyl acetate. The extract is washed successively with 10% hydrochloric acid and water, and the extract is evaporated under reduced pressure to remove the solvent.

The residue was recrystallized in a mixture of ethyl acetate and n-hexane to yield 5.9 g of 1- (4-acetamido-2-methoxyphenoxy) -2- (p-phenoxy) -2-(-toluenesulphate Obtained as ponyloxy) ethanol colorless needles.

Yield: 70%

Melting point 106-107.5 ℃

Production Example 2

(1) (1-a) 33 g of ethyl acrylate is added with 6 g of 4-acetamido-2-methoxyphenol) and 0,5 ml of 40% benzyltri methylammonium hydroxide / methanol is added thereto. The mixture is stirred at 100 ° C. for 6 days. After the reaction, the mixture is concentrated under fitting to remove excess ethyl acrylate. To this residue is added chloroform and the chloroform solution is washed with 2% hydrochloric acid, water and saturated aqueous sodium chloride solution. The chloroform solution is dried and then evaporated under reduced pressure to remove the solvent.

The residue is purified by silica gel chromatography (solvent: 2% methanol / chloroform). Thus, 1.47 g of 1- (4-acet amido-2-methoxyphenoxy) -2- (ethoxycarbonyl) ethane is obtained.

Melting point: 103-104 ° C (colorless needle, recrystallized in benzene)

(1-b) 138 g of ethyl arlylate is added to 25 g of 4-acet amido-2-methoxyphenol and 250 ml of powdered sodium hydroxide is added thereto. The mixture is refluxed for 6 days and then concentrated under reduced pressure to remove excess ethyl acrylate.

Chloroform is added to the residue and the chloroform solution is washed with saturated aqueous sodium chloride solution, dried and then evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography (solvent: 2% methanol / chloroform).

Thus, 8.55 g of 1- (4-acet amido-2-methoxyphenoxy) -2- (ethoxycarbonyl) ethane is obtained.

Yield: 22%

The physicochemical properties of this product are the same as the samples obtained in (1-a).

(2) In 500 ml of tetrahydrofuran, a solution of 21 g of 1- (4-acetamido-2-methoxyphenoxy) -2- (ethoxycarbonyl) ethane dissolved in 300 ml of anhydrous tetrahydrofuran was dissolved. 5.55 g of lithium aluminum hydride is stirred and added dropwise at a temperature of 0 deg. C or lower, and the mixture is stirred at the same temperature for 3 hours. Excess lithium aluminum hydride is decomposed and the insoluble material is filtered off. The filtrate is concentrated under reduced pressure to remove the solvent. The residue is recrystallized in a mixture of acetone and ethyl acetone to yield 14.47 g of 1- (4-acetamido-2-methoxyphenoxy) -3-hydroxy-n-propane as a colorless needle.

Yield: 81%

Melting point 121-122 ℃

(3) Preparation of 14.47 g of 1- (4-acetamido-2-methoxyphenoxy) -3-hydroxy-n-propane, 175 g of p-toluenesulfonyl chloride and 130 ml of pyridine Process in the same manner as (3). The crude product thus obtained was recrystallized in benzene to give 21.67 g of 1- (4-acetamido-2-methoxyphenoxy) -3- (p-toluenesulfonyloxy) -n-propane colorless prism. To obtain.

Yield: 91%

Melting point 90-91 ℃

Preparation Example 3

A solution of 5.6 g of methylsulfonyl chloride dissolved in 10 ml pyridine was dissolved in 9.5 g of 1- (4-acetamido-2-methoxyphenoxy) -3-hydroxy-n-propane in 90 ml pyridine under ice cooling. It is added to the solution. The mixture is stirred at a temperature of 10 ° C. or less for 2 hours. The reaction mixture is poured into ice water, and the aqueous mixture is extracted with ethyl acetate. The extract is washed successively with 1% hydrochloric acid and water. The extract is dried and then evaporated under reduced pressure to remove the solvent. The residue was recrystallized in a mixture of ethyl acetate and isopropyl ether to give 10.54 g of 1- (4-acetamido-2-methoxyphenoxy) -3- (methylsulfonyloxy) -n-propane as a colorless needle. Obtained as

Yield: 81.3%

Melting point 90-91 ℃

Production Example 4

(1) 10 g 4-acet amido-2-methoxyphenol, 3.5 g 96% powdered potassium hydroxide, 10.9 g 3-chloro-1- (tetrahydrofuran-2-yl-oxy) -n-propane And 100 ml of dimethyl sulfoxide are treated in the same manner as in Production Example 1- (1). The crude product thus obtained was recrystallized in a mixture of benzene and isopropyl ether to give 15.55 g of 1- (4-acetamido-2-methoxyphenoxy) -3- (tetrahydrofuran-2-yl-oxy ) -n-propane is obtained as a colorless needle.

Yield: 87%

Melting point 86-87 ℃

(2) 13.25 g of 1- (4-acet amido-2-methoxy phenoxy) -3- (tetrahydrofuran-2-yl-oxy) -n-propane was dissolved in a mixture of 60 ml ethanol and 120 ml water In addition, 0.1 ml of concentrated hydrochloric acid is added thereto. The mixture is stirred at room temperature for 3 hours. The reaction mixture is stirred again at 50 ° C. for 2 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residue was recrystallized in acetone to convert 9.67 g of 1- (4-acetamido-2-methoxyphenoxy) -3-hydroxy-n-propane into a colorless needle. To obtain.

Yield: 93.6%

The physicochemical properties of this product were the same as the samples obtained in Preparation Example 2- (2).

(3) The product obtained in (2) above was treated in the same manner as described in Production Example 1- (3) to give 1- (4-acetamido-2-methoxyphenoxy) -3- ( p-toluenesulfonyloxy) -n-propane is obtained.

Production Example 5

(1) 5 g of 4-acet amide-2-methoxyphenol are dissolved in 30 ml of dimethyl sulfoxide under a stream of nitrogen and 1.75 g of 96% powdered potassium hydroxide are added thereto. The mixture is stirred at 55 ° C. for 2 hours. 2.83 g of 3-chloropropanol is then added to the mixture at 30 ° C and the mixture is stirred at 55 ° C for 2 hours. The reaction mixture is poured into ice water and the aqueous mixture is extracted with chloroform. The extract is washed with water, dried and then evaporated to remove the solvent. The wells are recrystallized in acetone to yield 1.85 g of 1- (4-acetamido-2-methoxyphenoxy) -3-hydroxy-n-propane as a colorless needle. The physicochemical properties of this product were the same as the samples obtained in Preparation Example 2- (2) described above.

(2) The product obtained in (1) above was treated in the same manner as described in Production Example 1- (3) above to obtain 1- (4-acetamido-2-methoxyphenoxy) -3 -(p-toluenesulfonyloxy) -n-propane is obtained.

Preparation Example 6

(1) 12.7 g 4-acet amido-2-methoxyphenol, 2.95 g powdered sodium hydroxide, 11.7 g 4-chloro-1- (tetrahydropyran-2-yl-oxy) -n-butane 180 ml of dimethyl sulfoxide are treated by the same method described in Preparation Example 1- (1). The crude product thus obtained was recrystallized in a mixture of benzene and isopropyl ether to yield 18.08 g of 1- (4-acetamido-2-methoxy) -4- (phenoxytetrahydropyran-2-yl-oxy ) -n-butane is obtained as a colorless blade material.

Yield: 76.5%

Melting point 85-86 ℃

(2) 18 g of 1- (4-acet amido-2-methoxyphenoxy) -4- (tetra hydropyran-2-yl-oxy) -n-butane, 60 ml ethanol, 120 ml water and 0.1 ml Concentrated hydrochloric acid is treated in the same manner as described in Production Example 1- (2). The crude product thus obtained is recrystallized in ethyl acetate to give 13.3 g of 1- (4-acetamido-2-methoxyphenoxy) -4-hydroxy-n-butane as a colorless needle.

Yield: 98.6%

Melting point 107-108 ℃

(3) 12.4 g of 1- (4-acetamido-2-methoxyphenoxy) -4-hydroxy-n-butane, 14.1 g of p-toluene sulfonyl chloride and 150 ml of pyridine were prepared in Example 1 Treatment is carried out in the same manner as described in-(3). The crude product thus obtained was recrystallized in benzene to give 11.37 g of 1- (4-acetamido-2-methoxyphenoxy) -4- (p-toluenesulfonyloxy) -n-butane as a colorless needle. Obtained as

Yield: 57%

Melting point 117-118 ℃

Analysis of C ₂₀ H ₂₅ NO ₆ .1 / 2C6H6

Calculation C, 59.98; H, 6. 23: N, 3. 34; S, 7.62

Actual C, 59.71; H, 6. 30; N, 3.44; S, 7.41

Production Example 7

(1) 40 ml of 3.05 g of 4-acetamido-2-methoxyphenoxy, 670 mg of sodium hydroxide, 3.1 g of 6-chloro-1- (tetrahydropyran-2-yl-oxy) -n-hexane Dimethyl sulfoxide was treated in the same manner as described in Production Example 1- (1). The crude product thus obtained was recrystallized in a mixture of ethyl acetate and n-hexane to give 4.85 g 1- (4-acetamido-2-methoxyphenoxy) -6- (tetrahydropyran-2-yl-oxy ) -n-hexane is obtained as a colorless needle.

Yield: 95%

Melting point 74-75.5 ℃

(2) 4.88 g 1- (4-acet amido-2-methoxyphenoxy) -6- (tetrahydropyran-2-yl-oxy) -n-hexane, 40 ml ethanol, 80 ml water and 0.1 ml of concentrated hydrochloric acid is treated in the same manner as described in Production Example 1- (2). The crude product thus obtained is recrystallized in ethanol to give 2.91 g of 1- (4-acetamido-2-methoxyphenoxy) -6-hydroxy-n-hexane as a colorless needle.

Yield: 77.4%

: 3270, 3150, 1660, 1140, 1030

: 3270, 3150, 1660, 1140, 1030

NMR (CDCl ₃ ) δ: 9.47 (wide s, 1H, -NH-), 7.2-6.5 (m, 3H, aromatic), 4.5-3.0 (m, 5), 3.65 (s, 3H, -OCH ₃ ), 1.95 (s, 3H, CH ₃ CONH-), 2.2-1.0 (m, 8H)

Mass m / e: 281 (m ⁺ ), 181 (reference peak), 139

(3) 2.5 g of 1- (4-acetamido-2-methoxyphenoxy) -6-hydroxy-n-hexane, 2.03 g of p-toluenesulfonyl chloride and 50 ml of pyridine were prepared in Example 1 Treatment is performed in the same manner as described in-(3). The crude product thus obtained was recrystallized in ethyl acetate to give 2.46 g of 1- (4-acetamido-2-methoxyphenoxy) -6- (p-toluenesulfonyl oxy) -n-hexane as a colorless needle. Obtained as material.

Yield: 64%

Melting Point 92-93 ℃

Preparation Example 8

(1) 0.5 ml of acetic acid is added to a mixture of 20 g of 4-phenyl piperizine and 70 g of ethyl acrylate under cooling, and the mixture is stirred at room temperature for 1.5 hours. Benzene is added to the reaction mixture and the mixture is extracted with 10% hydrochloric acid.

The extract is brought to pH 11 with 10% sodium hydroxide and sodium carbonate, and extracted with benzene. The benzene extract is washed with saturated aqueous sodium chloride solution, dried and then evaporated to remove the solvent under reduced pressure.

The residue is distilled off under reduced pressure to afford 31.7 g of 1- (2-ethoxy carbonylethyl) -4-phenyl-piperazine as a colorless oily substance.

Yield: 98%

Boiling point 154-155 ° C (2 mmHg)

(2) 6.75 g of 1- (2-ethoxycarbonylethyl) -4-phenyl-piperazine was dissolved in 100 ml of anhydrous tetrahydrofuran and this solution was dissolved in 1.96 g of lithium hydride in 200 ml of anhydrous tetrahydrofuran. To the suspension to which aluminum is added is added dropwise at a temperature below 5 ° C.

The mixture is stirred at the same temperature for 2 hours. After dissolving excess lithium aluminum hydride, the insoluble matter is filtered off. The filtrate is concentrated under reduced pressure and dried, and the residue is recrystallized in isopropyl ether. 5.34 g of 1- (3-hydroxy-n-propyl) -4-phenyl-piperazine are obtained as a colorless granular material.

Yield: 94%

Melting Point 72-73 ℃

(3) 10 g of 1- (3-hydroxy-n-propyl) -4-phenyl-piperazine and 5.6 g of triethylamine are dissolved in 125 ml of methylene chloride and 6.95 g of chloride in 75 ml of methylene chloride A solution of p-toluesulfonyl dissolved is added dropwise. This mixture is refluxed for 10 hours. After cooling, the reaction mixture is washed with water, dried and then evaporated to remove the solvent. The residue is distilled under reduced pressure to yield 7.68 g of 1- (3-chloro-n-propyl) -4-phenyl-piperazine as an oily substance.

Yield: 71%

Boiling Point 155-158 ° C (0.5mmHg)

Preparation Example 9

(1) 5 g of 4- (2-fluorophenyl) piperazine, 13.9 g of ethyl acrylate and 0.2 ml of acetic acid were treated in the same manner as described in Production Example 8- (1) to give 6.0 g of 1 -(2-Ethoxycarbonyl-ethyl) -4- (2-fluorophenyl) -piperazine is obtained as a colorless oily material.

Yield: 77.2%

Boiling Point 188-190 ℃

(2) 6.0 g of 1- (2-ethoxycarbonyl-ethyl) -4- (2-fluorophenyl) -piperazine, 1.22 g of lithium aluminum hydride and 250 ml of anhydrous ether were prepared. Process in the same manner as described in 2).

The crude product thus obtained is recrystallized in isopropyl ether to give 4.65 g 1- (3-hydroxy-n-propyl) -4- (2-fluorophenyl) -piperazine as a colorless platelet.

Yield: 91.2%

Melting point 77-79 ℃

(3) 10.74 g 1- (3-hydroxy-n-propyl) -4- (2-fluorophenyl) -piperazine, 5.92 g triethylamine, 11.2 g p-toluenesulfonyl chloride and 180 ml Methylene chloride was treated in the same manner as described in Preparation Example 8- (3). The crude product thus obtained was purified by silica gel chromatography (solvent: 2% methanol / chloroform) to give 11.37 g of 1- (3-hydroxy-n-propyl) -4- (2-fluorophenyl) -piperazine. Is obtained as a pale yellow oily substance.

Yield: 98%

: 1600, 1240

: 1600, 1240

NMR (CDCl ₃ ) δ: 7.5-6.6 (m, 4H, aromatic), 3.63 (t, 2H, J = 6.7 Hz, -CH ₂ CH ₂ Cl), 3.35-2.87 (m, 4H), 2.85-2.32 ( m, 6H), 2.3-1.65 (m, 2H)

Mass m / e: 258, 256 (m ⁺ ), 193 (reference peak)

Preparation Example 10

(1) 8.44 g of 4- (3-methylphenyl) piperazine, 24 g of ethyl acrylate and 0.2 ml of acetic acid were treated in the same manner as described in Preparation Example 8- (1), to obtain 11.33 g of 1- (2 -Ethoxycarbonylethyl) -4- (3-methylphenyl) -piperazine is obtained as a colorless oily material.

Yield: 85.5%

Boiling point 160-162 ℃ (0.65mmHg)

(2) 11.3 g of 1- (2-ethoxycarbonyl-ethyl) -4- (2-methylphenyl) -piperazine, 3.12 g of lithium aluminum hydride and 300 ml of anhydrous tetrahydrofuran were prepared. Process in the same manner as described in 2). The crude product thus obtained is recrystallized in isopropyl ether to give 8.61 g of 1- (3-hydroxy-n-propyl) methylphenyl) -piperazine as a colorless braid.

Yield: 90%

Melting Point: 78-79 ℃

(3) 5 g of 1- (3-hydroxy-n-propyl) -4- (3-methylphenyl) -piperazine, 2.83 g of triethylamine, 5.35 g of p-toluenesulfonyl chloride and 90 ml of methylene chloride Is treated in the same manner as described in Preparation Example 8- (3). The crude product thus obtained was purified by silica gel chromatography (solvent: 2% methanol / chloroform) to give 4.2 g of 1- (3-chloro-n-propyl) -4- (3-methylphenyl) -piperazine in pale yellow color. Obtained as a routine substance.

Yield: 85%

: 1605, 1250

: 1605, 1250

NMR (CDCl ₃ ) δ: 7.3-6.5 (m, 4H, aromatic), 3.61 (t, 2H, J = 6.2 Hz, -COH ₂ CH ₂ Cl), 3.4-3.0 (m, 4H), 2.8-2.3 ( m, 6H), 2.30 (s, 3H, -CH ₃ ), 2.2-1.6 (m, 2H)

Mass m / e: 254, 252 (M ⁺ ), 189 (reference peak)

Production Example 11

(1) 11.55 g of 4- (3-chlorophenyl) piperazine, 29.5 g of ethyl acrylate and 0.3 ml of acetic acid were treated in the same manner as described in Preparation Example 8- (2), and 16.12 g of 1- (2-Ethoxycarbonylethyl) -4- (3-chlorophenyl) -piperazine is obtained as a colorless oily material.

Yield: 92.5%

Boiling point 160-162 ° C (0.15mmHg)

(2) 16 g of 1- (2-ethoxycarbonyl-ethyl) 4- (3-chlorophenyl) -piperazine, 4.1 g of lithium aluminum hydride and 400 ml of anhydrous tetrahydrofuran were prepared. Process in the same manner as described in section. The crude product thus obtained is recrystallized in isopropyl ether to give 12.4 g of 1- (3-hydroxy-n-propyl) -4- (3-chlorophenyl) -piperazine as a colorless needle.

Yield: 91%

Melting point 86-87 ℃

(3) 5 g of 1- (3-hydroxy-n-propyl) -4- (3-chlorophenyl) -piperazine, 2.58 g of triethylamine, 4.86 g of p-toluenesulfonyl chloride and 90 ml of chloride Methylene is treated in the same manner as described in Preparation Example 8- (3). The crude product thus obtained was purified by silica gel chromatography (solvent: 2% ethanol / chloroform) to give 3.73 g of 1- (3-chloro-n-propyl) -4- (3-chlorophenyl) -piperazine pale yellow. Obtained as an oily substance.

Yield: 87%

: 1595, 1245

: 1595, 1245

NMR (CDCl ₃ ) δ: 7.4-6.6 (m, 4H, aromatic), 3.62 (t, 2H, J = 6.3 Hz, -COH ₂ CH ₂ Cl), 3.4-3.0 (m, 4H), 2.8-2.3 ( m, 6H), 2.2-1.6 (m, 2H)

Mass m / e: 276, 274, 272 (M ⁺ ), 211, 209 (reference peak)

Preparation Example 12

(1) 10 g of 4- (3-fluorophenyl) piperazine, 28 g of ethyl acrylate, and 0.2 g of acetic acid were treated in the same manner as described in Preparation Example 8- (1), to obtain 14.27 g of 1- ( 2-Ethoxycarbonylethyl) -4- (3-fluorophenyl) -piperazine is obtained as a colorless oily material.

Yield: 91.6%

Boiling Point 148-150 ° C (0.25mmHg)

(2) 14.2 g of 1- (2-ethoxycarbonylethyl) -4- (3-fluorophenyl) -piperazine, 3.79 g of Lithium hydride aluminum and 400 ml of anhydrous tetrahydrofuran -Process in the same way as described in (2). The crude product thus obtained is recrystallized in isopropyl ether to give 10.84 g of 1- (3-hydroxy-n-propane) -4- (3-fluorophenyl) -phenylpiperazine as a colorless needle. .

Yield: 90%

Melting point 74-75 ℃

(3) 90 ml with 5 g of 1- (3-hydroxy-n-propyl) -4- (3-fluorophenyl) -piperazine, 2.79 g of triethylamine, 5.37 g of p-toluenesulfonyl chloride Methylene chloride was treated in the same manner as described in Preparation Example 8- (3). The crude product thus obtained was purified by silica gel chromatography (solvent: 2% methanol / chloroform) to give 4.3 g of 1- (3-chloro-n-propyl) -4- (3-fluorophenyl) -piperazine. Is obtained as a pale yellow oily substance.

Yield: 87%

: 1615

: 1615

NMR (CDCl ₃ ) δ: 7.45-6.3 (m, 4H, aromatic), 3.61 (t, 2H, J = 6.4 Hz, -COH ₂ CH ₂ Cl), 3.4-3.0 (m, 4H), 2.8-2.3 ( m, 6H), 2.2-1.6 (m, 2H)

Mass m / e: 285, 256 (M ⁺ ), 193 (reference peak)

Preparation Example 13

(1) 5.0 g of 4-phenylpiperazine is dissolved in 50 ml of ethanol, and 3.92 g of ethylene chlorohydrin and 6.4 g of potassium carbonate are added thereto. This mixture is refluxed for 10 hours. The mixture is then evaporated under reduced pressure to remove ethanol.

Water is added to the residue and the aqueous mixture is extracted with methylene chloride. The extract is washed with water, dried and then evaporated under reduced pressure. The residue is recrystallized in isopropyl ether to give 5.55 g of 1- (2-hydroxyphenyl0-4-phenyl-piperazine as a colorless needle.

Yield: 87.5%

Melting Point 81-82.5 ℃

(2) 5 g of 1- (2-hydroxyethyl) -4-phenyl-piperazine 3.64 g of triethylamine, 6.95 g of p-toluenesulfonyl chloride and 80 ml of methylene chloride were prepared in Example 8- (3 Treatment is carried out in the same manner as described in the above section. The crude product thus obtained is purified by silica gel chromatography (solvent: 2% methanol / chloroform) to yield 2.8 g of 1- (2-chloro-ethyl) -4-phenyl-piperazine.

Yield: 51.7%

Melting point 59-60 ° C. (colorless needle, recrystallized in n-hexane)

Claims (1)

A method for preparing a piperazine derivative of the following general formula (I) and a pharmaceutically acceptable acid addition salt thereof by reacting a compound of the following general formula (II) with a compound of the following general formula (III).

In the general formulas (I), (II) and (III), R is (C _1-7 ) alkyl, Ring A is phenyl, (C _1-4 ) alkylphenyl or halogenophenyl, n is 2 to 6 Wherein W is hydrogen or a group of the formula-(CH ₂ ) _n -Y, _wherein Y is a reactor or a reaction atom, and W is a group of the formula-(CH ₂ ) _n -Y Is hydrogen, and when W is hydrogen, W 'is a group of the formula-(CH ₂ ) _n -Z where Z is a reactor or a reactive atom.