JPH0320391B2 - - Google Patents

Description

Detailed Description of the Invention [Industrial Application Field] This invention provides N, N', N'- The present invention relates to a method for producing substituted-3-aminopyrrolidine.

[Conventional technology]

Until now, there have been almost no reports on the physical properties, production methods, uses, etc. of N,N',N'-substituted-3-aminopyrrolidines, and only a few reports were reported in 1967-1968 by CDLunsford et al. There have only been reports of synthesis of 3-aminopyrrolidines having a substituent. They use 1-substituted-3-pyrrolidinol, treat it with thionyl chloride or tosyl chloride to give a 3-chloro or 3-tosyl compound, and react it with a primary amine to convert the 1- and 3-positions. 3-aminopyridine having a substituent on the nitrogen atom, or 3-chloro or 3-tosylpyrrolidine having a substituent at the 1-position, is reacted with phthalimido potash to form 3-(phthalimino)pyrrolidine, and then this A 1-substituted 3-aminopyrrolidine having no substituent at the 3-position was synthesized by decomposing it with hydrazine [J.Med, Chem., 10 , 1015
(1975); ibid., 11 1034 (1968)].

[Problem that the invention seeks to solve]

The conventional method for synthesizing N,N',N'-substituted-3-aminopyrrolidine using 1-substituted-3-pyrodinol as a raw material as described above requires a long process, and is not practical due to the time required, raw material cost, and labor cost. There are many problems from this point of view. An object of the present invention is to provide a new method for industrially convenient production of N,N',N'-substituted-3-aminopyrrolidines, including useful new compounds.

[Means for solving problems]

The target compound of the present invention is N,N',N'-substituted-
Chemical formula as 3-aminopyrrolidine: It is a compound represented by

According to the invention, such N,N',N'-substituted-3
-Aminopyrrolidine has the general formula: XCH ₂ CHYCH ₂ CH ₂ Z [wherein X, Y and Z are chlorine, bromine,
A trisubstituted compound represented by a halogen atom such as iodine, or an OR group (where R is an alkanesulfonyl group consisting of a C ₁ to _{C 4} lower alkyl group, or an aromatic sulfonyl group such as toluenesulfonyl) butane with the general formula: R ¹ NH ₂ (wherein R ¹ represents a C ₁ to _{C 20} alkyl group, an arylalkyl group such as benzyl, substituted benzyl, and phenethyl, and an aryl group such as phenyl and substituted phenyl). The expressed primary amine and ammonia or the general formula: R ² (R ³ )NH (wherein R ² and R ³ are each independently a hydrogen atom,
_C1 - _C20 alkyl group, benzyl, substituted benzyl,
Aryl alkyl groups such as phenethyl, phenyl,
It can be obtained by sequentially reacting a primary amine (representing an aryl group such as substituted phenyl) or a secondary amine.

Specifically, the 1,2,4-trisubstituted butanes used in this reaction include 1,2,4-trichlorobutane, 1,2,4-tribromobutane,
1,4-dibromo-2-methanesulfonoxybutane, 1,2-dibromo-4-chlorobutane, 1,
2,4-tris(methanesulfonoxy)butane,
Examples include 1,2,4-tris(p-toluenesulfonoxy)butane, 1,2-dibromo-4-methanesulfonoxybutane, etc., but raw materials are not limited to these, and butane skeleton As each of the above substituents, a combination of those commonly used as leaving groups, such as a halogen atom, an alkanesulfonyl group, and an aromatic sulfonyl group, in any order can be used.

As a result of research on the reaction of these 1,2,4-trisubstituted butanes with amines, the present inventors found that N,
We discovered a new, unprecedented reaction for synthesizing N',N'-substituted-3-aminopyrrolidine in one step, and completed the present production method by studying the reaction conditions in more detail.

Hereinafter, a specific method of the present invention will be explained in detail.

The conditions for this reaction vary depending on the reactivity of the 1,2,4-trisubstituted butane used and the reactivity of the amines used, but in general, R ¹ NH ₂ is first added to 1 equivalent of trisubstituted butane. One equivalent of the primary amine represented is reacted with two equivalents of base under mild conditions, and then ammonia or the amine represented by R ² (R ³ )NH is reacted with one equivalent of base.

As the base, common alkalis such as sodium alcoholate, caustic soda, and potassium carbonate are used, but ammonia, primary amines, or secondary amines can be used instead. This reaction can be carried out in the presence or absence of a solvent. The reaction may be carried out in a homogeneous reaction system using ordinary solvents such as water, ethanol, isopropyl alcohol, benzene, toluene, etc., or it may be carried out in a two-phase system of a mixture of an organic solvent and an aqueous alkaline solution. good.

The initial reaction with the primary amine represented by R ¹ NH ₂ is usually carried out at a temperature of 40 to 120°C and is completed in 1 to 3 hours. The subsequent reaction with ammonia or an amine represented by R ² (R ³ )NH generally requires a higher temperature and longer reaction time than the first reaction, depending on the reactivity of the amine used.

In this latter half of the reaction, ammonia or R ²
It is desirable to use a larger amount of the amine represented by (R ³ )NH than the theoretical amount; for example, good results can be obtained by using 6 equivalents or more.

Generally, after the reaction of trisubstituted butane with the first amine, it is desirable to carry out the reaction with the second amine as quickly as possible, but depending on the type of trisubstituted butane and amine used, if necessary, It is also possible to carefully isolate the crude intermediate upon completion of the first half of the reaction and immediately use it for the next reaction.

As a special case, by the method of the invention 1-
It has the same substituent on the nitrogen atom at the position and the 3-position, and has the general formula: When producing N ^, N',-disubstituted-3-aminopyrrolidine represented by
= R ² , R ³ = H), in this case there is no need to add the primary amine sequentially, and the primary amine and trisubstituted butane are added in the presence or absence of a solvent in the presence or absence of a base. It is possible to react all at once in the presence of

〔Effect of the invention〕

According to the present invention, various raw materials that are easy to handle and are commercially available, such as 1,2,4-butanetriol, 4-
1,2,4-trisubstituted butanes, such as 1,2,4-trismethanesulfonoxybutane, 1,2, By reacting 4-tribromobutane with aminos, N,N',N'-substituted-3-aminopyrrolidines, which conventionally required long production steps, can be produced in a single step. You can get it at a high rate.

As expected from its structure, the N,N',N'-substituted-3-aminopyrrolidine obtained by the present invention can be used as a fiber treatment agent, a paper treatment agent, an agricultural chemical, a chelating agent, a coating agent, It can be used as a compound or derivative in adhesives and rubber chemicals, and as a synthetic raw material for pharmaceuticals and drug substances.

[Examples] Examples of the production method of the present invention will be shown below, but the method of the present invention is not limited to these Examples.

Example 1 (Synthesis of 1-benzyl-3-aminopyrrolidine) 26.7 g of caustic soda was dissolved in 100 ml of water, and 170 ml of toluene and 38 ml of benzylamine were added. While stirring, 113.3 g of 1,2,4-tris(methanesulfonoxy)butane (melting point 63.5-64.5°C) was added and heated to about 65°C. After reacting at the same temperature for 3 hours, it was cooled to around room temperature. The layers were separated, and the organic layer was washed with 100 ml of water and concentrated under reduced pressure to obtain crude 1-benzyl-3-methanesulfonoxypyrrolidine [NMR (CDCl ₃ ); δ=7.36 (s, 5H), 5.00 ~
5.37 (m, 1H), 3.67 (s, 2H), 2.97 (s, 3H),
1.73-3.13 (m, 6H). IR (neat); 1350, 1170,
950, 900cm ^-1 . ] Dissolve this in 170ml of isopropyl alcohol,
Transferred into an autoclave. liquid ammonia 400
ml at a temperature of 130℃ and an internal pressure of 76 to 80Kg/ ^cm2 .
Stirred for an hour. Concentrate the reaction solution and add 300% water to the residue.
Added ml. The separated oil layer was discarded, 66 g of caustic soda was dissolved in the aqueous layer, and the mixture was shaken twice with 150 ml of benzene. The benzene layers were combined, dried over magnesium sulfate, and concentrated to give the crude 1-benzyl-
38.1 g (65.5%) of 3-aminopyrrolidine was obtained as an oil. This is distilled under reduced pressure and has a boiling point of 107-108.
19.4 g (33.3%) of purified product with %/2 mmHg was obtained.

NMR (CDCl ₃ ); δ=7.34 (s, 5H), 3.63 (s,
2H), 3.02-3.77 (m, 1H), 1.01-2.97 (m,
6H), 1.37 (s, 2H) IR (neat); 3350, 3250, 1600, 880 cm ^-1 Example 2 (Synthesis of 1-benzyl-3-methylaminopyrrolidine) Dissolve 81.8 ml of benzylamine in 175 ml of isopropyl alcohol. , while stirring 1, 2, 4
-Tris(methanesulfonoxy)butane 85.2g
(melting point 63.5-64.5°C) was added and heated to 82°C.
After reacting at the same temperature under reflux for 2 hours, the mixture was cooled to around room temperature. Put the reaction solution in an autoclave, add 300ml of 40% aqueous solution of methylamine, and incubate at 90℃ for 2 hours.
Stirred for an hour. Next, concentrate the reaction solution and use the residue as
It was added to 500ml of 5N caustic soda aqueous solution. To this aqueous solution, 200 ml of toluene was added and shaken, and the toluene layer was separated, washed with water, and then concentrated. The residue was distilled under reduced pressure to remove excess benzylamine and by-produced N,N'-
Dibenzyl-3-aminopyrrolidine was removed and crude 1-benzyl-3-methylaminopyrrolidine
Obtained 17.6 g (36.9%) as an oil. This is distilled under reduced pressure to produce a crude product with a boiling point of 102-103℃/1mmHg.
12.9g (27.1%) was obtained.

Example 3 (Synthesis of 1-benzyl-3-ethylaminopyrrolidine) a 26.7 g of caustic soda was dissolved in 100 ml of water, and 170 ml of toluene and 38 ml of benzylamine were added.
While stirring, add 113.3 g of 1,2,4-tris(methanesulfonoxy)butane (melting point 63.5-64.5).
) and heated to approximately 65°C. 3 at the same temperature
After reacting for a time, the mixture was cooled to around room temperature and separated. Place the organic layer in an autoclave, add 400ml of ethylamine, and heat at 150℃ and internal pressure at 25Kg/cm2 ^.
and stirred for 2 hours. After the reaction, cool and add the reaction solution to 600 ml of water, 330 ml of 1N caustic soda solution, and 600 ml of water.
ml of crude 1-benzyl-3-ethylaminopyrrolidine.
%) was obtained as an oil. This was distilled under reduced pressure and 16.4g of purified product with a boiling point of 106-107℃/1mmHg
(24.3%).

NMR (CDCl ₃ ); δ=7.30 (s, 5H), 3.60 (s,
2H), 3.07-3.47 (m, 1H), 1.27-2.90 (m,
8H), 1.07 (t, J = 6Hz, 3H) IR (neat); 3250cm ^-1 b 26.7g of caustic soda was dissolved in 100ml of water and 170ml of toluene and 38ml of benzylamino were added. 1,2,4-tribromobutane while stirring.
Add 97.3g (boiling point 99.5℃/5.5mmHg), about 65
Heated to ℃. After reacting at the same temperature for 3 hours, the mixture was cooled to around room temperature and separated. The organic layer was taken, washed with water, dehydrated over sodium sulfate, and placed in an autoclave. Ethylamine 400ml
was added and stirred for 2 hours at a temperature of 150°C and an internal pressure of 25 kg/cm ² . After cooling, the reaction solution was washed successively with 600 ml of water, 330 ml of a 1N caustic soda solution, and 600 ml of water, and then concentrated to obtain 31.7 g (47.1%) of crude 1-benzyl-3-ethylaminopyrrolidine. This was distilled under reduced pressure to obtain 16.4 g (24.3%) of a purified product with a boiling point of 106-107°C/1 mmHg.

The NMR and IR spectra of this product were consistent with those of 1-benzyl-3-ethylaminopyrrolidine obtained in Example 3a.

c. 26.7 g of caustic soda was dissolved in 100 ml of water, and 170 ml of toluene and 38 ml of benzylamine were added.
While stirring, add 91.7 g of 1,2-dibromo-4-methanesulfonoxybutane (boiling point 137-139℃/
1 mmHg) and heated to approximately 65°C. After reacting at the same temperature for 3 hours, it was cooled to around room temperature.
The liquid was separated. Place the organic layer in an autoclave;
Add 400ml of ethylamine, temperature 150℃, internal pressure 25
Kg/cm ² and stirred for 2 hours. After the reaction was cooled, the reaction solution was mixed with 600 ml of water, 330 ml of 1N caustic soda aqueous solution,
After sequentially washing with 600 ml of water and concentrating, the crude 1-
Benzyl-3-ethylaminopyrrolidine 31.7g
(47.1%) was obtained as an oil. This is distilled under reduced pressure to produce a purified product with a boiling point of 106-107℃/1mmHg.
16.4g (24.3%) was obtained.

The NMR and IR spectra of this product were consistent with those of 1-benzyl-3-ethylaminopyrrolidine obtained in Example 3a.

Example 4 (1-benzyl-3-(N,N-dimethyl)
Synthesis of aminopyrrolidine) Dissolve 81.8ml of benzylamine in 175ml of isopropyl alcohol and add 1,2,4-
85.2 g of tris(methanesulfonoxy)butane (melting point 63.5-64.5°C) was added. The mixture was heated to 82° C., reacted at the same temperature under reflux for 2 hours, and then cooled to around room temperature.

The reaction solution was transferred to an autoclave, 300 ml of a 50% dimethylamine aqueous solution was added, and the mixture was stirred at 90°C for 2 hours. Then, the reaction solution was concentrated, and the residue was diluted with 5N
500 ml of caustic soda aqueous solution and 200 ml of toluene were added and separated. The organic layer was washed with water and then concentrated. The residue was distilled under hydraulic pressure to remove excess benzylamine and by-produced N,N'-dibenzyl-3-aminopyrrolidine, resulting in crude 1-benzyl-3-(N,N-
24.1 g (47.1%) of dimethyl)aminopyrrolidine were obtained as an oil. This was further distilled under reduced pressure through a 20cm Vigrieu tube, and the boiling point was 103-104℃/1mm.
17.1 g (33.5%) of purified Hg was obtained.

n ² _D ⁰ 1.5185 NMR (CDCl ₃ ); δ=7.33 (s, 5H), 3.60 (s,
2H), 2.20 (s, 6H), 1.37-3.03 (m, 7H) Example 5 (Synthesis of N,N'-dimethyl-3-aminopyrrolidine) 1, 2,
4-Tris(methanesulfonoxy)butane 170.2
g (melting point 63.5-64.5°C) was added thereto, and the mixture was gradually heated while stirring and reacted at 84-94°C for 2.5 hours.
Next, concentrate the reaction solution and add 200g of caustic soda to the residue.
A solution of was dissolved in 400 ml of water was added. This was shaken twice with 300 ml of benzene, the benzene layers were combined and dried over magnesium sulfate, and the benzene was distilled off at normal pressure to yield 50.7 g (88.8%) of crude N,N'-dimethyl-3-aminopyrrolidine. was obtained as an oil. This is distilled through a 20cm Vigreux tube under nitrogen atmosphere at normal pressure, resulting in a purified product with a boiling point of 148-149℃.
26.8g (46.9%) was obtained.

n ²⁰ _D 1.4562 SG ²⁰ ₂₀ 0.8824 NMR (CDCl ₃ ); δ = 3.07 to 3.40 (m, 1H), 2.40
(s, 3H), 2.37 (s, 3H), 1.33~2.83 (m,
7H) IR (neat); 3250cm ^-1 Example 6 (Synthesis of N,N'-diethyl-3-aminopyrrolidine) 1,2,
4-tribromobutane 294.9g (boiling point 99.5℃/5.5
mmHg) and gradually heat while stirring.
The reaction was carried out at 83-85°C for 1.5 hours. The reaction solution was then concentrated, and a solution of 400 g of caustic soda dissolved in 800 ml of water was added to the residue. Add this to 300ml of benzene and 2
The benzene layers were combined and dried over magnesium sulfate, and then the benzene was distilled off at normal pressure to obtain crude N,N'-diethyl-3-aminopyrrolidine.
114.1g (80.2%) was obtained. This was distilled at normal pressure under a nitrogen atmosphere, resulting in 77.5g of distillate with a boiling point of 178-182℃.
(54.5%).

This product was further purified in the form of hydrochloride as follows. That is, ethanol containing 41.7 g of hydrogen chloride.
This fraction was added dropwise into 180 ml, and the amount of precipitate was collected by filtration.
This was recrystallized again from 150 ml of ethanol,
88.0 g (77.1%) of N'-diethyl-3-aminopyrrolidine dihydrochloride was obtained as white crystals [mp 170-172°C, chlorine content: calculated value (%) 32.96,
Actual value (%) 32.88].

This was gradually added to 200 ml of methanol containing 44.1 g of sodium methoxide, heated under reflux for 30 minutes, cooled, and the precipitated sodium chloride was filtered off. The filtrate was concentrated at normal pressure, and the residue was distilled at normal pressure under nitrogen atmosphere to obtain 41.8 g (71.8%) of N,N'-diethyl-3-aminopyrrolidine with a boiling point of 180-182°C.

n ² _D ⁰ 1.4553 NMR (CDCl ₃ ); δ = 3.10 to 3.46 (m, 1H), 1.30
~2.90 (m, 11H), 1.10 (t, J = 6Hz, 6H) IR (neat); 3200cm ^-1 Example 7 (Synthesis of N,N'-diphenyl-3-aminopyrrolidine) Add 6g of caustic soda to 15ml of water. Dissolve and add 27.3 ml of aniline. 1,2,4- while stirring
Tribromobutane 14.7g (boiling point 99.5℃/5.5mmHg)
was added and gradually heated, and the mixture was reacted at 100°C for 3 hours.
Next, cool to around room temperature and add 30 ml of benzene and 10 ml of water.
ml was added, shaken, and separated. The benzene layer was washed with 30 ml of water, dried over sodium sulfate and concentrated. Excess aniline from the residue was distilled off under reduced pressure (36
~37°C/4 mmHg), 10.3 g (86.4%) of crude N,N'-diphenyl-3-aminopyrrolidine was obtained as an amorphous material. This was distilled under reduced pressure under a nitrogen atmosphere,
Solid with boiling point 193-194℃/1mmHg, melting point 68-70℃
8.4g (70.7%) was obtained. Add this to 17ml of ethanol
Recrystallization was performed to obtain 7.7 g (65.0%) of white crystals of N,N'-diphenyl-3-aminopyrrolidine.

Melting point 68-70℃ NMR (CDCl ₃ ); δ = 6.43-7.47 (m, 10H), 4.00
~4.37 (m, 1H), 3.03~3.80 (m, 5H), 1.67~
2.57 (m, 2H) IR (neat); 3350, 1595cm ^-1

Claims (1)

[Claims] 1 General formula: XCH ₂ CHYCH ₂ CH ₂ Z [wherein, ], a primary amine represented by the general formula: R ¹ NH ₂ (wherein R ¹ represents an alkyl group, an aryl group, or an arylalkyl group), and ammonia or a trisubstituted butane represented by the general formula : R ² (R ³ )NH (wherein, R ² and R ³ are each independently a hydrogen atom,
A general formula characterized by sequentially reacting primary or secondary amines represented by an alkyl group, an aryl group, or an arylalkyl group: A method for producing N,N',N'-substituted-3-aminopyrrolidine represented by 2. The production method according to claim 1, wherein the amine represented by the general formula R ² (R ³ )NH is the same as the amine represented by the general formula R ¹ NH ₂ . 3. The manufacturing method according to claim 1 or 2, wherein the halogen atom is a chlorine, bromine, or iodine atom.