JPH09255671A - Production of phenylpiperazine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To safely obtain a phenylpiperazine compound useful as an intermediate for various medicines in high yield and quality without releasing toxic substances produced during its production into the environment. SOLUTION: This phenylpiperazine compound of formula I (R is H, nitro, amino, cyano, a 1-6C alkyl, aryl, 1-6C alkoxy, aryloxy, halogeno, hydroxyl, etc.; (n) is 1-3) is obtained by reaction of an aniline compound of formula II with a bis(2-halogenoethyl)amine hydrohalogenide, without releasing the latter out of the reaction system, in a solvent (e.g. methanol) in the presence of a sodium or potassium (bi)carbonate, tertiary organic amine and nitrogen-contg. heterocyclic compound at a temperature close to the boiling point of the solvent. The bis(2-halogenoethyl)amine hydrohalogenide is prepared by halogenating diethanolamine.

Description

Detailed Description of the Invention

The present invention relates to a novel method for producing phenylpiperazines.

[0002]

BACKGROUND OF THE INVENTION Phenylpiperazines represented by the formula [I] are important compounds as intermediates for producing various pharmaceuticals.

[0003]

2. Description of the Related Art As a method for synthesizing phenylpiperazines, for example, a method of reacting an aniline derivative represented by the formula [I] with diethanolamine in the presence of hydrochloric acid (J. Am.
r.Chem.Soc.76,1853 (1954)), N- in the presence of phosphorus compounds.
A method of reacting a substituted dialkanolamine with ammonia is known. In the former method, since the reaction is carried out at a high temperature, various side reactions occur concurrently, especially the elimination of the substituted gas on the benzene ring occurs, and the yield In the latter case, the reactivity of N-substituted dialkanolamine and ammonia is poor and the special reaction equipment is required for the reaction under severe conditions of high temperature and high pressure (250 to 350 ° C, 34 to 270 atm). In addition to the above, the obtained compound is thermally decomposed, so that the substituted gas on the benzene ring is desorbed and the yield is lowered. In addition, the formula [I
I] represented by anilines and diethanolamine,
In the method of reacting at a high temperature of 140 to 250 ° C. in the presence of phosphoric acid or polyphosphoric acid (JP-A-57-42679), a large amount of sodium phosphate neutralized with phosphoric acid is duplicated in the post-treatment step and is industrially used. Absent. As an industrial method, a method of reacting an aniline represented by the formula [II] with bis (2-bromoethyl) amine hydrobromide in water in the presence of sodium hydroxide or potassium hydroxide (special However, since this method uses strongly basic sodium hydroxide or potassium hydroxide, hydrolysis of bis (2-bromoethyl) amine also occurs and the yield decreases. And by the side reaction of this hydrolyzate, the formula [III]

[0004]

Embedded image (In the formula, R is hydrogen, nitro group, amino group, cyano group, C1-C
6 alkyl group, substituted or unsubstituted aryl group, C1-C6 alkoxy group, substituted or unsubstituted aryloxy group, halogeno group, halogen-substituted C1-C6 alkyl group, mono- or di (C1-C6 alkyl or substituted or (Unsubstituted aryl) amino group, hydroxy group, (C1-C6 alkyl or,
(Substituted or unsubstituted aryl) amide group, (C1-C6 alkyl or substituted or unsubstituted aryl) carbamoyl group,
Mono- or di (C1-C6 alkyl or substituted or unsubstituted aryl) ureido group, (C1-C6 alkyl or substituted or unsubstituted aryl) carbonyl group, (C1-C6 alkyl or substituted or unsubstituted aryl) oxy Carbonyl group, thiol group, (C1-C6 alkyl or substituted or unsubstituted aryl) thio group, unsubstituted or N-substituted mono-
Or di- (C1-C6 alkyl or substituted or unsubstituted aryl) sulfamoyl group, unsubstituted or N-substituted C1-
C6 alkyl or unsubstituted or substituted (C1-C6 alkyl or substituted or unsubstituted aryl) sulfonamide group,
Unsubstituted or N-substituted C1-C6 alkyl, or unsubstituted or substituted (C1-C6 alkoxy or substituted or unsubstituted aryl) oxysulfonylamino group, represents a carboxyl group, n represents an integer of 1 to 3) A large amount of the compound represented is formed, which has a drawback that not only the yield but also the quality is deteriorated because it is difficult to separate the compound represented by the formula [I] from the phenylpiperazine. Further, bis (2-bromoalkyl) amine such as bis (2-bromoethyl) amine hydrobromide used in this method is corrosive,
Since it is a toxic substance and has a very high mutagenicity to biological tissues, it is extremely dangerous to take it out of the reaction system and handle it. Further, the crude bis (2-halogenoethyl) amine synthesized by the known method contains an excessive amount of hydrohalic acid, which inhibits the reaction with the anilines represented by the formula [II]. However, there is a problem that the reaction rate is lowered.

[0005]

As described above, there are various problems to be solved in the synthesis of the phenylpiperazines represented by the formula [I] by the known method described above.
The present inventors suppress the elimination of the substituent on the benzene ring and the side reaction of the compound represented by the formula [III] without taking out bis (2-halogenoethyl) amine from the system, and thus the high yield is obtained. The present invention has been accomplished by finding a manufacturing method that is industrially advantageous in high rate and high purity.

[0006]

Means for Solving the Problem That is, the present inventors have found that anilines represented by the formula [II] and bis (2-chloroethyl) amine hydrochloride or bis (2-bromoethyl) amine hydrobromide. Of bis (2-halogenoethyl) amine hydrohalide in water, methanol, ethanol, isopropanol, n-
The desired compound of formula [I] is prepared by adding sodium carbonate or sodium bicarbonate, potassium carbonate or potassium bicarbonate, a tertiary organic amine, or a nitrogen-containing heterocyclic compound in a C1-C5 alcohol solvent such as butanol. It has been found that the phenylpiperazines represented by are synthesized in a very suitable yield and quality. The tertiary organic amine used in this reaction is preferably triethylamine, and the nitrogen-containing heterocyclic compound is preferably pyridine. Hereinafter, the present invention will be described in detail.

Condensation reaction step of anilines represented by the formula [II] and bis (2-halogenoethyl) amine hydrohalide. The base used in the present invention is sodium carbonate or sodium bicarbonate or potassium carbonate or potassium bicarbonate,
Alternatively, they are tertiary organic amines and nitrogen-containing heterocyclic compounds.
The amount of these weak bases used is 1.0 to 2.0 times mol, preferably 1.0 to 1.2 times mol, of the aniline represented by the formula [I], and added to the reaction system little by little. Or 10
% To 50%, preferably 30% as an aqueous solution. The reaction is carried out using bis (2-halogenoethyl) amine hydrohalide such as bis (2-chloroethyl) amine hydrochloride or bis (2-bromoethyl) amine hydrobromide in water or C1-C5 alcohols, preferably Dissolve in methanol, ethanol, isopropanol, butanol, add aniline represented by the formula [I], and add sodium carbonate or sodium bicarbonate or potassium carbonate or potassium bicarbonate little by little, or sodium carbonate or bicarbonate Add sodium or potassium carbonate or potassium bicarbonate aqueous solution dropwise, or
Add triethylamine and pyridine to react. The reaction temperature proceeds in the vicinity of the boiling point of the solvent used, and proceeds in about 2 to 30 hours. The reaction rate is 65 to 95%.

Process for producing bis (2-halogenoethyl) amine hydrohalide The bis (2-halogenoethyl) amine hydrohalide used in the present invention is a reaction between diethanolamine and thionyl chloride or diethanolamine and hydrogen bromide. It can be obtained by a halogenation reaction of diethanolamine such as an acid reaction. Since these compounds are highly corrosive and toxic and have high mutagenicity, it is necessary to avoid taking them out of the reaction system for the purpose of purification and the like. In addition, the residual acid may reduce the reaction rate. In order to avoid these problems, we have overcome these problems by recovering the reaction solvent after the halogenation reaction is complete, adding water to the recovery residue to dissolve it, and recovering this water again to remove residual hydrohalic acid. However, without taking out the bis (2-halogenoethyl) amine hydrohalide from the reaction system, the condensation of the aniline represented by the formula [II] and the bis (2-halogenoethyl) amine hydrohalide is performed. The method of carrying out the reaction was established.

The halohydrogen salt of the phenylpiperazine represented by the formula [I] thus produced is taken out by a conventional isolation means, for example, neutralization with an alkali, and then distillation or recrystallization. Alternatively, a hydrohalide salt or the like can be easily isolated from the reaction mixture by cooling crystallization after the reaction.

[0010]

INDUSTRIAL APPLICABILITY According to the present invention, the target compound of formula [I] can be produced without leaking toxic substances produced during production to the environment.
In addition, it can be safely manufactured with high yield and high quality.

[0011]

EXAMPLES The present invention will be described in more detail with reference to specific compound examples of the phenylpiperazine represented by the formula [I] produced by the method of the present invention, but the present invention is not limited to these examples. Not a thing.

Example 1 55 g of thionyl chloride was added to 69 ml of acetonitrile, and 23.1 g of diethanolamine was added dropwise with stirring. After the dropping, the mixture was stirred overnight at room temperature and then refluxed for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, 25 ml of water was added to the residue to dissolve it, and water was recovered and dried. Water (60 ml) was added to the residue to dissolve it, and 4-aminophenol (21.8 g) was added and the mixture was heated to 100-110 ° C with stirring and stirred for 8 hours, and then 21.2 g of 30% sodium hydrogen carbonate aqueous solution was added dropwise over about 4 hours. did. After dropping, cool to room temperature and use 28% ammonia water 13.
4 g was added for crystallization, and this was collected by filtration to obtain crude N- (4-
28.3 g of hydroxyphenyl) piperazine was obtained (yield 80%). This crude product was suspended and purified in 42 ml of methanol to give 23.1 g of N- (4-hydroxyphenyl) piperazine.
Was obtained (yield 65%). Colorless scale-like crystals, melting point 218-220 ° C.

Examples 2 to 4 By the same procedure as in Example 1, using the appropriate starting materials, the following compounds were obtained. ○ N- (4-nitrophenyl) piperazine yellow crystals (recrystallization solvent; isopropyl alcohol). Yield 70% Melting point 133.5-134 ° C. N- (4-methylthiophenyl) piperazine White crystals (recrystallization solvent; n-hexane). Yield 75%. Melting point 60.5-61 ° C. N- (4-acetylphenyl) piperazine White crystals (recrystallization solvent; toluene). Yield 65%. Melting point 115-116 ° C

EXAMPLE 5 5.3 g of diethanolamine and 43.9% of 47% hydrobromic acid
g were mixed and boiled, reacted while concentrating excess hydrobromic acid, and concentrated. Water was added to the concentrate, and the concentrate was dissolved and collected again to dryness. This residue was dissolved in 50 ml of methanol, 5.4 g of 4-aminophenol was added, and the mixture was refluxed for 2 hours. Then, while maintaining this solution at 60 to 65 ° C, sodium carbonate 5.8
g was added little by little to the system every 2-3 hours. (Tota
(17 hours) After the reaction, the solvent was recovered under reduced pressure, and the residue was treated with 25 ml of water.
28% ammonia water is added under cooling to crystallize. The crystals were collected by filtration to obtain 7.6 g of crude N- (4-hydroxyphenyl) piperazine (yield 85%). The crude product was suspended and purified in 42 ml of methanol to obtain 6.3 g of N- (4-hydroxyphenyl) piperazine (yield 70
%). Colorless scale-like crystals, melting point 218-220 ° C.

Examples 6 to 8 By the same procedure as in Example 5, using the appropriate starting materials, the following compounds were obtained. ○ N- (4-nitrophenyl) piperazine Yellow crystals (recrystallization solvent; isopropyl alcohol). Yield 82% Melting point 133.5 to 134 ° C. 4- (1-Piperidinyl) benzamide White crystal (recrystallization solvent; water-ethanol). Yield 50
%. Melting point 240-243 ° C. N- (4-ethoxycarbonylphenyl) piperazine White scale crystals (recrystallization solvent; n-hexane-toluene). Yield 62%. Melting point 104-104.5 ° C

Example 9 55 g of thionyl chloride was added to 69 ml of acetonitrile, and 23.1 g of diethanolamine was added dropwise with stirring. After the dropping, the mixture was stirred overnight at room temperature and then refluxed for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, 25 ml of water was added to the residue to dissolve it, and water was recovered and dried. This residue is ethanol 50
Dissolve in 3 ml and add 23.6 g of 4-aminobenzonitrile and add 2
After refluxing for an hour, 12.3 g of sodium carbonate was added little by little to the system every 2-3 hours while maintaining the solution at 78-80 ° C. (Total 20 hours) Next, the reaction solution is cooled with ice and the precipitated crystals are collected by filtration. The crystals were washed with a mixed solution of water-ethanol to obtain 31.3 g of 4- (1-piperazinyl) benzonitrile monohydrochloride (yield 70%).

Example 10 5.3 g diethanolamine and 43.9% hydrobromic acid 47%
g were mixed and boiled, reacted while concentrating excess hydrobromic acid, and concentrated. Water was added to the concentrate, and the concentrate was dissolved and collected again to dryness. To this residue, 210 ml of water was added and dissolved, 4.0 g of aniline was added, and the mixture was heated to 100 to 110 ° C. with stirring and 5.4 g of a 30% sodium hydrogen carbonate aqueous solution was added dropwise over about 4 hours. After the dropping, the mixture was cooled to room temperature, sodium hydroxide was added for neutralization, and the mixture was extracted with methyl isobutyl ketone.
The extract was concentrated to give a crude product. The crude product was distilled under reduced pressure to obtain 5.8 g (yield: 83%) of N-phenylpiperazine as a colorless oil. Boiling point 121-122 ℃ / 4mmHg

Examples 11 to 12 By the same procedure as in Example 10, using the appropriate starting materials, the following compounds were obtained. ○ N- (4-fluorophenyl) piperazine colorless oil, yield 70%, boiling point 120-130 ° C / 2mmHg ○ N- (3-methoxyphenyl) piperazine colorless oil, yield 85% boiling point 140 ° C / 2mmHg

Example 13 To 69 ml of acetonitrile was added 55 g of thionyl chloride, and 23.1 g of diethanolamine was added dropwise with stirring. After the dropping, the mixture was stirred overnight at room temperature and then refluxed for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, 25 ml of water was added to the residue to dissolve it, and water was recovered and dried. To the residue, 60 ml of methanol was added to dissolve the residue, and 21.8 g of 4-aminophenol was added and the mixture was heated with stirring at 64-65 ° C for 7 hours. Then 22.2
Triethylamine (g) was added in portions every 2 hours. After the addition, the mixture was heated at 64-65 ° C for 7 hours, cooled with ice and the precipitated crystals were collected by filtration to give crude N- (4-hydroxyphenyl).
42.9 g of piperazine was obtained. This crude is then mixed with 60 ml of water
13.4 g of 28% aqueous ammonia was added for crystallization, and this was filtered to obtain 25.7 g of N- (4-hydroxyphenyl) piperazine (yield 60%). Colorless scale-like crystals, melting point 218-220 ° C.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location C07D 295/12 C07D 295/12 A 295/14 295/14 A

Claims (2)

[Claims] 1. A phenylpiperazine compound represented by the formula [I] which is an intermediate of various pharmaceuticals. (In the formula, R is hydrogen, nitro group, amino group, cyano group, C1-C
6 alkyl group, substituted or unsubstituted aryl group, C1-C6 alkoxy group, substituted or unsubstituted aryloxy group, halogeno group, halogen-substituted C1-C6 alkyl group, mono- or di (C1-C6 alkyl or substituted or (Unsubstituted aryl) amino group, hydroxy group, (C1-C6 alkyl or,
(Substituted or unsubstituted aryl) amide group, (C1-C6 alkyl or substituted or unsubstituted aryl) carbamoyl group,
Mono- or di (C1-C6 alkyl or substituted or unsubstituted aryl) ureido group, (C1-C6 alkyl or substituted or unsubstituted aryl) carbonyl group, (C1-C6 alkyl or substituted or unsubstituted aryl) oxy Carbonyl group, thiol group, (C1-C6 alkyl or substituted or unsubstituted aryl) thio group, unsubstituted or N-substituted mono-
Or di- (C1-C6 alkyl or substituted or unsubstituted aryl) sulfamoyl group, unsubstituted or N-substituted C1-
C6 alkyl or unsubstituted or substituted (C1-C6 alkyl or substituted or unsubstituted aryl) sulfonamide group,
Unsubstituted or N-substituted C1-C6 alkyl, or unsubstituted or substituted (C1-C6 alkoxy or substituted or unsubstituted aryl) oxysulfonylamino group, represents a carboxyl group, n represents an integer of 1 to 3) The phenylpiperazines represented are represented by the formula [II] (In the formula, R is hydrogen, nitro group, amino group, cyano group, C1-C
6 alkyl group, substituted or unsubstituted aryl group, C1-C6 alkoxy group, substituted or unsubstituted aryloxy group, halogeno group, halogen-substituted C1-C6 alkyl group, mono- or di (C1-C6 alkyl or substituted or (Unsubstituted aryl) amino group, hydroxy group, (C1-C6 alkyl or,
(Substituted or unsubstituted aryl) amide group, (C1-C6 alkyl or substituted or unsubstituted aryl) carbamoyl group,
Mono- or di (C1-C6 alkyl or substituted or unsubstituted aryl) ureido group, (C1-C6 alkyl or substituted or unsubstituted aryl) carbonyl group, (C1-C6 alkyl or substituted or unsubstituted aryl) oxy Carbonyl group, thiol group, (C1-C6 alkyl or substituted or unsubstituted aryl) thio group, unsubstituted or N-substituted mono-
Or di- (C1-C6 alkyl or substituted or unsubstituted aryl) sulfamoyl group, unsubstituted or N-substituted C1-
C6 alkyl or unsubstituted or substituted (C1-C6 alkyl or substituted or unsubstituted aryl) sulfonamide group,
Unsubstituted or N-substituted C1-C6 alkyl, or unsubstituted or substituted (C1-C6 alkoxy or substituted or unsubstituted aryl) oxysulfonylamino group, represents a carboxyl group, n represents an integer of 1 to 3) When reacting the represented anilines with a bis (2-halogenoethyl) amine hydrogen halide salt obtained by halogenating diethanolamine, the bis (2-halogenoethyl) amine hydrogen halide salt is removed from the reaction system. Without taking out into the formula [II]
Characterized by reacting with an aniline represented by
A method for producing a phenylpiperazine represented by the formula [I]. 2. In the production of phenylpiperazine represented by the formula [I], water or C1-C5 alcohol is used as a solvent, and sodium or potassium carbonate or bicarbonate, or a tertiary organic amine is used. Alternatively, the method according to claim 1, wherein a nitrogen-containing heterocyclic compound is used.