JPS6293272A - Piperazine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A piperazine derivative expressed by formula I (R<1> is halogen- substituted or unsubstituted phenyl; Alk is lower alkylene; R<2> and R<3> are H, lower alkyl or lower alkanoyl; Z is O or S; n is 1 or 2) or a salt thereof. EXAMPLE:(+ or -)-N-Methyl-2-[2-( 4-phenylpiperazin-1-yl )ethyloxy]phenyl] pyrrolidine-1-carboxamide. USE:A drug, having improved cardiotonic action, useful for treating and preventing congestive heart failure, e.g. edema, ascites, venous and right atrial hypertension, dyspnea, etc., and capable of selectively activating myocardium with slight side effect. PREPARATION:A compound expressed by formula II or a salt thereof is reacted with a compound expressed by formula III or IV (R<4> is H, lower alkyl, etc.; X<1> is reactive residue) to afford the aimed compound expressed by formula I.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to a novel piperazine derivative and a method for producing the same.

(Objective of the Invention) The object of the present invention is to provide a novel piperazine derivative having excellent cardiotonic action, a method for producing the piperazine derivative, and an intermediate for its synthesis.

(Structure and Effects of the Invention) The novel piperazine derivative of the present invention is represented by the following general formula.

(However, R1 is a halogen-substituted or unsubstituted phenyl group.

Alk is a lower alkylene group, t2z and R3 are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group, Z represents an oxygen atom or a sulfur atom, and n represents 1 or 2. ) The object compound (1) of the present invention and its salts exhibit an excellent cardiotonic effect with a long duration of action, and are useful for the treatment and prevention of congestive heart disease. Therefore, compound (1) can treat, prevent, and/or improve various symptoms of congestive heart disease, such as edema due to congestive heart failure, ascites, increased venous pressure and right shoulder pressure; dyspnea, cyanosis, and hypoxia. It can be used to For example, when a sample was intravenously administered to dogs to examine its inotropic effect, 1.
-(2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl]pyrrolidine-1-carbothioamide (oxalate) at a dosage of 0.
03Illr/kg can increase left ventricular contractility by 39%, and the effect lasts for about 40 minutes. In addition, the inotropic effect was investigated using the Langendorff method using isolated hearts of guinea pigs.
2-<2-(4-phenylpiperazin-1-yl)ethyloxy)phenyl]pyrrolidine-1-carbothioamide (oxalate) can increase myocardial contractility at a dose of 104. Further 9 target compounds of the present invention (1)
and its salts have the characteristics that they do not substantially exhibit adrenergic β-receptor stimulating effects, and therefore selectively activate the myocardium and have few side effects (for example, effects on heart rate).

Examples of the object compounds of the present invention include general formula (1) in which R1 is a phenyl group or a phenyl group substituted with a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom), and Alk is a lower alkylene group (e.g. , methylene group, ethylene group, trimethylene group, tetramethylene group)
and RZ and R3 are the same or different and are a hydrogen atom, a lower alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group), or a lower alkanoyl group (e.g., acetyl group, propionyl group, butyryl group) , -Z is an oxygen atom or a sulfur atom, and n is 1 or 2.

As a more preferable compound, in general formula (T), R
1 is a phenyl group or a fluorophenyl group, and 8lk
is an ethylene group or a trimethylene group, R2 and R3
are the same or different and are a hydrogen atom, a methyl group or an acetyl group, Z is an oxygen atom or a sulfur atom, and n is 1 or 2.

Since the object compound (1) of the present invention has an asymmetric carbon atom at the 2-position of the pyrrolidine ring or piperidine ring, two types of optical isomers may exist. It also includes.

According to the present invention, the target compound (1) is a piperazine compound or a salt thereof represented by the general formula (A) (where l?', Alk and n have the same meanings as above) and the general formula %formula%. ) (However, R4 is a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, XI represents a reactive residue, and pg, R3 and Z have the same meanings as above.) .

(B) A phenol compound or a salt thereof represented by the general formula (I?", R', Z and n have the same meanings as above) and the general formula (5.X2 represents a reactive residue) (R1 and Alk have the same meanings as above.) or (C) with the general formula (where y and 3 represent reactive residues, R", R" ,
Alk, Z and n have the same meanings as above. ) It can be produced by reacting an alkylphenyl ether compound or a salt thereof with a piperazine compound or a salt thereof represented by the general formula (wherein R1 has the same meaning as above).

Raw material compound ([1), (1-a), (IV),
(V).

(Vl) and (■) can be used as ti-separated or as their salts. For example, compound (■)
As the salts of compounds (rV) and (■), ordinary acid addition salts such as hydrochloride, hydrobromide, sulfate, and nitrate can be suitably used. Salts include alkali metal salts such as sodium salts and potassium salts,
Organic amine salts and the like can be suitably used. Also,
As the salt of compound (ITI-a) (R'=If), an alkali metal salt such as sodium salt or potassium salt can be used. Furthermore, starting compound (III-b)
, (V) and (Vl) (7) Reactive residue W (X'
y, Z and 13'> are 3, for example, a halogen atom such as a chlorine atom or a bromine atom, a substituted or unsubstituted phenylsulfonyloxy group such as a toluenesulfonyloxy group,
Examples include lower alkylsulfonyloxy groups such as methanesulfonyloxy groups.

Piperazine compound (If) or its salt and compound (■-a
) or a salt thereof can be carried out in a suitable solvent. As the solvent, for example, methanol, ethanol, tetrahydrofuran, dioxane, acetonitrile, etc. are preferably used. This reaction is about 25-100℃
It is particularly preferred to carry out the reaction at a temperature of about 60 to 80°C. When R4 is a hydrogen atom in the compound (Iff-a), the reaction between the salt of the compound and the piperazine compound (■) or its salt can also be carried out in an appropriate solvent in the presence of an acid. As the acid, for example, acetic acid, hydrochloric acid, sulfuric acid, etc. can be suitably used, and as the solvent, for example, water, tetrahydrofuran, dioxane, methanol, ethanol, etc. can be used.

It is preferable to use propatool or a mixed solvent thereof. This reaction is preferably carried out at a temperature of about 0 to 60°C, especially 10 to 25°C.

On the other hand, piperazine compound (II) or its salt and compound (
The reaction with m-b) can be carried out in a suitable solvent in the presence or absence of a deoxidizing agent. Examples of deoxidizers include alkali metal hydroxides (eg.

Inorganic bases such as sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate), alkali metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate), triethylamine, N-
Any organic base such as methylmorpholine, pyridine, diisopropylethylamine, etc. can be suitably used. As a solvent.

For example, tetrahydrofuran, dioxane, pyridine,
Dimethylformamide and the like can be used, and the reaction is preferably carried out at a temperature of about 0-80°C, particularly about 25-60°C.

In addition, the reaction between the phenol compound (rV) or its salt and the piperazine compound (V) or its salt and the reaction between the alkylphenyl ether compound (Vl) or its salt and the piperazine compound (■) or its salt are carried out in an appropriate solvent. It can be carried out in the presence or absence of a deoxidizing agent. As the deoxidizing agent, any deoxidizing agent used in the reaction between compound (n) and compound (III-b) can be used, and as the solvent, dimethylformamide can be used.

dimethyl sulfoxide, acetonitrile, dioxane,
Tetrahydrofuran, acetone, methanol.

Ethanol and the like are preferred. Preferably, the reaction is carried out at about 60-80°C.

Since all of the above reactions proceed without racemization, if an optically active form is used as the starting compound (If), (IV) or (VI), the target compound (1) can be obtained as an optically active form.

Raw material compounds (n), (rV) and (Vl) of the present invention
9 For example, the piperazine compound (ff) has the general formula (wherein R1 and Alk have the same meanings as above).
A compound represented by or a salt thereof (e.g., hydrochloride, nitrate, sulfate) is subjected to a reductive ring-closing reaction in an appropriate solvent (e.g., methanol, ethanol, dioxane) in the presence of a catalyst (e.g., Raney nickel, palladium-carbon). (However, R1 and Alk have the same meanings as above.)
The compound is dissolved in an appropriate solvent (e.g., tetrahydrofuran, ether, dioxane) in the presence of a reducing agent (e.g., lithium aluminum hydride, sodium borohydride) or in an appropriate solvent (e.g., methanol, ethanol) in the presence of a catalyst (e.g., platinum), or with a compound represented by 2 or a salt thereof (e.g., hydrobromide) and the general formula % () (where R5 is a protecting group). C represents a reactive residue) in a suitable solvent (e.g., ethyl acetate, chloroform) and a base (e.g., an inorganic base such as potassium hydroxide, potassium carbonate, sodium hydrogen carbonate, triethylamine, A compound represented by the general formula (wherein R5 has the same meaning as above) is prepared by reacting it in the presence of an organic base such as pyridine, and the compound or a salt thereof is reacted with the compound (V) or a salt thereof. The compound (IV) was reacted under the same conditions as the reaction of the compound (■) to form the general formula (where R', Al
k and R5 have the same meanings as above. ) and treating the compound with hydrogen bromide-acetic acid or in a suitable solvent (e.g. lower alkanol, tetrahydrofuran, dioxane).

It can be produced by removing the protecting group (R') by catalytic reduction with palladium-carbon.

In addition, the phenol compound (rV) is a compound represented by the general formula (where n has the same meaning as above) or a salt thereof (e.g., hydrochloride, hydrobromide, sulfate, nitrate)
and compound (III-a) or compound (III-b); and compound (II) and compound (Ill-a) or compound (Ill-a).
The alkylphenyl ether compound (Vl) can be produced by reacting with the compound (TV) or a salt thereof (e.g., sodium salt, potassium salt, organic amine salt) and the general formula % formula % () (where x4 represents a reactive residue, Alk and X″L
@L@ has the above meaning. ) can be produced by reacting the compound (IV) with the compound (V) under the same conditions as the reaction between compound (IV) and compound (V).

The object compound (1) of the present invention can be used as a medicine either in free form or in the form of a salt.

Examples of pharmaceutically acceptable salts of compound (I) include inorganic acid addition salts such as hydrochloride, sulfate, nitrate, phosphate, and hydrobromide, acetate, and oxalate.

fumarate, citrate, succinate, maleate,
Lactate, glucuronate, sulfamate.

Pyruvate, tartrate, benzenesulfonate.

Examples include organic acid addition salts such as methanesulfonate salts, and alkali metal salts such as sodium salts and potassium salts. These salts can be easily obtained by treating free Compound (I) with an acid or alkaline reagent in a conventional manner.

The object compound (1) of the present invention or a salt thereof can be administered orally or parenterally. However, since compound (1) or a salt thereof exhibits an excellent cardiotonic effect even when administered orally, it is particularly preferable to use it orally. The object compound N) of the present invention or a salt thereof can be used in the form of a conventional preparation 1, for example, a solid preparation such as a single tablet, powder, capsule, or granule, or a liquid preparation. As excipients, calcium carbonate, calcium phosphate, corn starch, potato starch, cornstarch, lactose, talc, magnesium stearate, etc. can be used as appropriate. Also, if it is a liquid,
For example, it can be used in the form of an aqueous or oily suspension, a solution, an elixir, and the like.

In addition, in the case of parenteral administration, the object compound (I) of the present invention
or a salt thereof can be used, for example, as an injection or a suppository. Injectables can be used in the form of solutions or suspensions1.For their formulation, distilled water, essential oils (e.g., peanut oil, corn oil), hydrophobic solvents (e.g., polyethylene glycol, polypropylene glycol, lanolin, coconut oil) are used. ) etc. can be used as appropriate. Furthermore, the formulation may be sterilized and may contain other additives such as preservatives, stabilizers, etc.

The dosage of the object compound (I) of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, the age and weight of the patient, the condition and the type of disease, but is usually 2.

Approximately 0.003-30■/kg per day, especially 0.01
It is preferable to set it to about 20 trw/kg.

9 In this specification, "lower alkyl group", "lower alkylene group" and "lower alkanoyl group" refer to an alkyl group having 1 to 4 carbon atoms, an alkylene group having 1 to 4 carbon atoms, and an alkylene group having 2 to 4 carbon atoms, respectively. Represents an alkanoyl group.

Experimental Example 1 (Method) A male mongrel dog (body weight: 10-20+r) was anesthetized with bendoparbital sodium (30 mg/kg, intravenous administration), and an incision was made at the fourth left intercostal space under one artificial respiration. The left heart pressure was measured using a pressure transducer, and the maximum rate of change in left heart pressure was determined. The sample is 0.03mg per 1kg of body weight.
was dissolved in a 5% glucose solution and administered intravenously. The inotropic effect of the specimen was determined as the rate of increase in the maximum rate of change in left heart intracardial pressure.

(result) The results are shown in Table 1 below.

Table 1 Note: All of the above compounds are racemic and administered as the oxalate salt.

Experimental Example 2 (Method) The isolated heart of a male guinea pig (body weight: approximately 28M) was perfused by the Langendorff method using Lockringer's solution (30°C) containing 2% rabbit defibrinated blood as the perfusate. Cardiac contractility was measured using a transducer. The specimen was dissolved in physiological saline and administered into the aortic cannula. The inotropic effect of the sample was determined as the minimum dose required to increase cardiac contraction in isolated guinea pig hearts.

(result) The results are shown in Table 2 below.

Table 2 Example l (Sat)-2-(2-+2-(4-phenylpiperazine-
1-yl)ethyloxy)phenylpiperazine 1.53
20J of tetrahydrofuran? 0.2 methyl isocyanate in the liquid! Add 1 of tetrahydrofuran srr & solution and stir at room temperature for 2 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residual aroma was recrystallized from a mixture of ethyl acetate and hexane to give (±)-N-methyl-2-(2-(
2-(4-phenylpiperazin-1-yl)ethyloxy)phenyl)pyrrolidine-1-carboxamide 1,I
Get IF. Yield: 65.4%, p, 151.5-154°C Oxalate M, 9.165-168°C (decomposition) (recrystallized from methanol-acetone-ether) Examples 2-5 Corresponding raw material compounds The following compound is obtained by treating in the same manner as in Example 1 according to method (A) above.

Example 6 (±)=2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxy)phenyl]pyrrolidine 1.
53i A mixture of 0.37.9 mm of methyl isothiocyanate and 30 mm of ethanol is refluxed for 1.5 hours. The solvent was distilled off from the reaction solution under reduced pressure.

The residual aroma was purified by silica gel chromatography [solvent: chloroform-methanol (9:1)].

By recrystallizing from a mixture of ethyl acetate and hexane, (±)-N-methyl-2-C2-[2-(4-phenylpiperazin-1-yl)ethyloxy)phenyl]pyrrolidine-1-carbothioamide 1.1 ．． ! Get i+. Yield: 59.5% M, p, 100-103
°C Oxalate: M, p, 163-168 °C (decomposition) (recrystallized from methanol) Example 7 (±)-2-(2-+3- (4-phenylpiperazin-1-yl)propyloxy)phenyl ] By treating pyrrolidine in the same manner as in Example 6, (±)-N-
Methyl-2-(2-(3-(4-phenylpiperazine-
1-yl)propyloxy)phenyl]pyrrolidine-1
-obtain the carbothioamide. Yield near 7.8% h, p, i3t~133°C (recrystallized from ethyl acetate-hexane) oxalate; gate, p, 117~121°C (recrystallized from methanol-ether) Example 8 (±) -2-(2-(2-(4-phenylpiperazine-
1-yl)ethyloxy)phenyl]pyrrolidine23.
Add 0.82 g of sodium cyanate to a mixture of 20-1 ethanol, 1-1 water, and 2-acetic acid, and stir at room temperature for 2.5 hours. The reaction solution was poured into an aqueous potassium carbonate solution and extracted with chloroform. After washing the extract with water and drying, the solvent was distilled off and the residual aroma was recrystallized from a mixture of ethyl acetate and hexane to obtain (±)-'2- (2-(2-(-4
-Phenylpiperazin-1-yl)ethyloxy)phenyl]pyrrolidine-1-rupoxamide 1°693 is obtained. Yield near 5.3%, p, 122-124°C Oxalate 1/3 hydrate; M, 9.136-138°C (decomposition) (recrystallized from acetone) Example 9 (±)- N-methyl-2-(2-hydroxyphenyl)
Pyrrolidine-1-carbothioamide 0°645.1-(
2-chloroethyl) -4-(3-fluorophenyl)
Piperazine hydrochloride 0.76J, potassium carbonate 0.37
L A mixture of 0.4.05 g of sodium iodide and 10-dimethylformamide is heated at 90° C. for 10 hours. Furthermore, 0.38 g of 1-(2-chloroethyl)-4-(3-fluorophenyl)piperazine hydrochloride was added and heated to 90°C for 8 hours. The solvent is distilled off from the reaction solution under reduced pressure, and the residual aroma is dissolved in ethyl acetate. After washing with water and drying, the solvent is distilled off. The residual fragrance was removed by silica gel chromatography.
After purification with chloroform acetone (5:1)], by recrystallizing from a mixture of ethyl acetate and hexane,
(±)-N-Methyl-2-[2-C2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl]pyrrolidine-1-carbothioamide is obtained.

M, p, 94-99"C oxalate; gate, p, 149-152°C (decomposed) (recrystallized from acetone) Example 10 (±) -2-C2-+2- (4-phenylpiperazine-1 -yl)ethyloxy)phenyl]pyrrolidine 2
3. Potassium carbonate 1.18.9. Dimethylformamide 30- and dimethylcarbamoyl chloride 0.92
Stir the mixture of g at 50° C. for 5 hours. Add water to the reaction solution and extract with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off, and the residual aroma was purified by silica gel column chromatography [solvent: chloroform-methanol (9:1)].
(±)-N,N-dimethyl-
2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxy)phenyl)pyrrolidine-I-rupoxamide 2.06y is obtained as an oil.

Yield: 85.6% oxalate; salt, p, 156-158°C (decomposition) (recrystallized from acetone) ) phenyl)piperidine-1-rupoxamide 1.
26L 1-phenylpiperazine 0.76i) ethylamine 0.475. Sodium iodide 0.6
A mixture of 4.9 and dimethyl sulfoxide 15TI& is heated to 90° C. for 20 hours.

Add water to the reaction solution and extract with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off, the residual aroma was purified by silica gel column chromatography (solvent: ethyl acetate), and recrystallized from a mixture of ethyl acetate and ether.
0.62 J of (±)-N-methyl-2-C2-(2-(4-phenylpiperazin-1-yl)ethyloxy)phenylcopiperidine-1-carboxamide is obtained.

The physical properties of the main island matched those of the target object in Example 5.

[Synthesis of raw material compounds]

Production Example 1 (1) 2-C2-(4-phenylpiperazin-1-yl)ethyloxy]benzaldehyde 15J2 Morpholine 120&, p-)luenesulfonic acid (hydrate) 10.
1. A mixture of 50°F and tetrahydrofuran was heated at 80°
Heat to C for 1.5 hours.

A solution of 4.73 potassium cyanide (50 nf) in water is then added and heated to 100° C. for 1.5 hours. After cooling, the reaction solution was extracted with ethyl acetate, the extract was washed with water, the solvent was distilled off after drying, and the residual aroma was recrystallized from a mixture of ethyl acetate and hexane to obtain (±)-2-(2-(2 -(4-phenylpiperazin-1-yl)ethyloxy[phenyl]
-2-morpholinoacetonitrile 18.3! get i.

Pa, p, 108-110°C (2) To a solution of 35 g of the product from (1) above in 200 J of tetrahydrofuran, add a 30% methanol solution of potassium hydroxide l-. Furthermore, a solution of 6.85y of acrylonitrile in 50% of tetrahydrofuran was added dropwise over a period of 2 hours, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residual aroma was dissolved by adding ethyl acetate, washed with water, dried, and then the solvent was distilled off.

100% acetic acid for residual fragrance. , Ill, Tetrahydrofuran 20
Add 0- and 50- of water and leave at room temperature for 5 days. The solvent is distilled off under reduced pressure, the residual aroma is made alkaline with a 10% aqueous potassium carbonate solution, and then extracted with ethyl acetate. Wash the extract with water,
After drying, the solvent was distilled off, and the residual aroma was purified by silica gel column chromatography (solvent: benzene-ethyl acetate (1:1).
) and recrystallized from a mixture of ethyl acetate and hexane to give 4-(2-(2-(4-phenylpiperazin-1-yl)ethyloxy)phenylcou 4
- Obtain 22.6 & oxobutanenitrile.

Lp, 98-100°C (3) Product 10S of (2) above, ethanol 40〇-
A mixture of Raney nickel and Raney nickel 40- is subjected to catalytic reduction treatment at room temperature and pressure. After filtering off the catalyst from the reaction solution, the solvent is distilled off from the filtrate. The residue was dissolved in 100% of tetrahydrofuran and added dropwise to a suspension of 23% of lithium aluminum hydride in 20% of tetrahydrofuran. After the mixture was refluxed for 1.5 hours, it was cooled with water and decomposed by adding aqueous ether, and the inorganic substances were filtered off. After drying, the solvent was distilled off and the residue was purified by silica gel column chromatography [vehicle: chloroform-methanol-triethylamine (23:1:1)] to give (±)-2-(2-+2-( 7.93# of 4-phenylpiperazin-1-yl)ethyloxy)phenylpiperazine is obtained as an oil.

IRν"(am-'): 33oo, 1590Mass
(m/e): 351 (M') Production Examples 2 and 3 The following compounds are obtained by treating the corresponding starting compounds in the same manner as in Production Example 1.

■ Table 4 Note: Both of the above compounds are racemic.

Production Example 4 3.8M of 2-(2-hydroxyphenyl)piperidine hydrobromide was added to 40% of a 5% aqueous sodium hydroxide solution, and further 3.87M of benzyloxycarbonyl chloride was added.
g was added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Warm the reaction solution to room temperature.

Add 20% of IJum aqueous solution (10% hydroxide) and stir for an additional hour. After washing the reaction solution with ether.

The aqueous layer was neutralized with 10% hydrochloric acid and extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off to remove the remaining 3
．． Get 96#. The remaining amount is 1-(2-chloroethyl)-
4-phenylpiperazine hydrochloride 3.30.9. Add 3.5 g of potassium carbonate, 0.5 g of sodium iodide and 60% of dimethylformamide, and heat under argon atmosphere.
．． Heat at 0°C for 10 hours. 1.53 of 1-(2-chloroethyl)-4-phenylpiperazine hydrochloride was added to the reaction solution.
and heat at 90°C for an additional 5 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in ethyl acetate.

The solution is washed with an aqueous sodium hydroxide solution and water, and after drying, the solvent is distilled off to obtain an oily substance 1.713.

Add 10 mL of methylene chloride to the nuclear oil to dissolve it, add 25% hydrogen bromide-acetic acid 2- to the solution, and stir at room temperature for 1 hour. The solvent is distilled off from the reaction solution under reduced pressure, and the residue is washed with ether, made alkaline with a 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography (CR medium: chloroform-ethanol (10:1)) to obtain 2-(2-(2-(4-phenylpiperazine). -1-yl)ethyloxy)phenylpiperazine 0.63.9 is obtained as an oil.

Mass (m/e): 365 (M”) Manufacturing example
5 2-(2-methoxyphenyl)pyrrolidine hydrochloride 1.
A mixture of 53.9 and 47% hydrobromic acid 10-120
Heat at ℃ for 4 hours. The solvent is distilled off from the reaction mixture under reduced pressure, the residual aroma is made alkaline by adding an aqueous solution of sodium hydrogen carbonate, and the mixture is extracted with ethyl acetate. After drying the extract, the solvent is distilled off, and the remaining aroma is dissolved in 25% of ethanol. 0.7 g of methyl isothiocyanate is added and refluxed for 2 hours. The solvent was distilled off from the reaction solution, and the residual aroma was chromatographed on silica gel [solvent: chloroform-ethanol (40:1)]
) and recrystallized from a mixture of methanol and ether to give N-methyl-2-(2-hydroxyphenyl)pyrrolidine-l-carbothioamide 0.69
Get 11.

Gate, p, 2oo~202℃ Production example 6 (1) 2-(2-hydroxyphenyl)piperidine・
Hydrobromide 3.30g,) ethylamine 2.0g,
A mixture of 0.88 g of methyl isocyanate and 35 ml of tetrahydrofuran is stirred at room temperature for 18 hours. Add water to the reaction solution and extract with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off, and the residual aroma was removed by silica gel flash column chromatography [solvent: ethyl acetate:hexane (1
:1)] and recrystallized from a mixture of ethyl acetate and hexane to obtain N-methyl-2-(2-hydroxyphenyl)piperidine-1-carboxamide 1.8
Obtain 2g.

(2) 1.74 g of N-methyl-2-(2-hydroxyphenyl)piperidine-1-carboxamide + 1.92 g of 1-toluenesulfonyloxy-2-chloroethane
, potassium carbonate 1.23g and dimethylformamide 5
The mixture of 01 is stirred at room temperature for 3 days. Ethyl acetate is added to the reaction solution, washed with water, dried, and then the solvent is distilled off. The residual aroma is purified by silica gel column chromatography [solvent: ethyl acetate-hexane (3:2)] and recrystallized from a mixture of ethyl acetate and hexane. By this, N-methyl-2-
(2-(2-chloroethyloxy)phenyl) 1.31 g of piperidine-1-carboxamide are obtained. Yield: 5
9.7% Lp, 1 38-140℃

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is a halogen-substituted or unsubstituted phenyl group,
Alk is a lower alkylene group, R^2 and R^3 are the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkanoyl group, Z represents an oxygen atom or a sulfur atom, and n represents 1 or 2. ) A piperazine derivative or a salt thereof. 2. (A) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is a halogen-substituted or unsubstituted phenyl group,
Alk represents a lower alkylene group, and n represents 1 or 2. ) or its salt and the general formula Z=C=N-R^4 or ▲mathematical formula, chemical formula, table, etc.▼ (However, R^2 and R^3 are the same or different and are hydrogen atoms, lower alkyl group or lower alkanoyl group, R^4 is a hydrogen atom, lower alkyl group or lower alkanoyl group, Z is an oxygen atom or sulfur atom, X^1 is a reactive residue) or a salt thereof. (B) A compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^2, R^3, Z and n have the same meanings as above.) or a salt thereof. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, X^2 represents a reactive residue, R^1 and Alk
has the same meaning as above. ), or (C) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, X^3 represents a reactive residue, R^2, R^3 ,
Alk, Z and n have the same meanings as above. ) React the compound or its salt represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^1 has the same meaning as above), and (D) If necessary, there is a general formula ▲ mathematical formula, chemical formula, table, etc. that is characterized by the product being its salt ▼ (However, R^1, R^2, R^3, Alk, Z and n are the same as above ) has the same meaning as ). 3. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is a halogen-substituted or unsubstituted phenyl group,
Alk represents a lower alkylene group, and n represents 1 or 2. ) or a salt thereof. 4. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^2 and R^3 are the same or different and are a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, Z is an oxygen atom or a sulfur atom, and n is 1 or 2) or a salt thereof. 5. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, Alk is a lower alkylene group, R^2 and R^3
are the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkanoyl group, Z represents an oxygen atom or a sulfur atom, n represents 1 or 2, and X^3 represents a reactive residue. ) or a salt thereof.