JPH0312055B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a method for producing 3-aminopyrrolidine and its salts, which are useful as synthetic raw materials, and particularly suitable as constituents for producing physiologically active substances such as agricultural chemicals and medicines. [Prior Art] Until now, despite its simple structure, 3-aminopyrrolidine itself has only been used in the French Patent No. 2500833, and no synthesis method has been reported. It had never been separated, and its physical properties were completely unknown. Only a few methods for producing 3-aminopyrrolidine having a substituent at the 1- and/or 3-position nitrogen are known. For example, in 1967-1968 CD
Lunsford et al. described various 3
- Synthesized urea and indole derivatives of aminopyrrolidine [J.Med.Chem., 10 , 1015 (1967);
ibid., 11 , 1034 (1968)]. Recently, J. Matsumoto et al. have reported that 7-(3-amino-1
-pyrrolidinyl)-1-ethyl-6-fluoro-
reported that 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and its congeners showed the most effective antibacterial properties [J.
Med. CHem., 27 , 1543 (1984)]. As mentioned above, it has become clear that the 3-aminopyrrolidine skeleton exhibits excellent properties, but regarding the synthesis method of this 3-aminopyrrolidine moiety,
Little known. For example, the manufacturing method and physical properties of 3-acetylaminopyrrolidine, which is used as a raw material in the above-mentioned second example, have not been reported at all. This is Lunsford
1-benzyl- synthesized by a long route by et al.
It is thought that it can be obtained by acetylating 3-aminopyrrolidine (mentioned above) and then reducing it. [Problems to be Solved by the Invention] The main reasons why 3-aminopyrrolidine itself has not been synthesized in the past are as follows: 1. Long steps are required to arrive at the precursor for 3-aminopyrrolidine synthesis. 2. Because the nitrogen atom in the pyrrolidine ring has very strong nucleophilicity and basicity, it is impossible to introduce an amino group into the 3-position of the pyrrolidine ring unless this part is protected. 3 Hydrolysis is often used for deprotection in the final step of 3-aminopyrrolidine synthesis, but
3-Aminopyrrolidine is water-soluble and azeotropic with water, so it cannot be separated by distillation. This is thought to be due to the following. The object of the present invention is to provide useful bifunctional compounds, 3-
An object of the present invention is to provide a method for industrially conveniently producing aminopyrrolidine and its salts. [Means for Solving the Problems] The object compound of the present invention has the chemical formula: 3-aminopyrrolidine. It is expressed as , and has a normal pressure boiling point of 159 to 160 in its pure state.
℃, which is a colorless liquid at normal temperature and pressure.
It is a useful compound whose physical properties and manufacturing method have not been reported so far. According to the invention, such 3-aminopyrrolidine or general formula: (In the formula, HX represents a protic acid unrelated to the catalytic reduction reaction, and X represents an anionic residue that becomes a counter ion of the proton upon dissociation.)
-The protonate salt of aminopyrrolidine has the general formula: XCH ₂ CHYCH ₂ CH ₂ Z [wherein, represents an alkanesulfonyl group such as methanesulfonyl or an aromatic sulfonyl group such as toluenesulfonyl], the general formula: (In the formula, R ¹ is phenyl or substituted phenyl group,
In addition, ^R2 represents a hydrogen atom, an alkyl group, a phenyl group, or a substituted phenyl group) by reacting with an amino compound represented by the general formula: (wherein R ¹ and R ² are defined as above), the N,N'-disubstituted-3-aminopyrrolidine is prepared;
Aminopyrrolidine or general formula: (wherein R ¹ , R ² and HX are defined as above) in a suitable solvent and a suitable amount of a reduction catalyst. It can be obtained by reduction in the presence of hydrogen at appropriate hydrogen pressure and reaction temperature. HX here
specifically represents a protonic acid such as hydrochloric acid, hydrobromic acid, acetic acid, etc., which itself is unrelated to the catalytic hydrogen reduction reaction. Specifically, the 1,2,4-trisubstituted butanes used in this reaction include 1,2,4-trichlorobutane, 1,2,4-tribromobutane,
1,4-dibromobutane-2-methanesulfonate, 1,2-dibromo-4-chlorobutane, 1,
2,4-tris(methanesulfonoxy)butane,
Examples of raw materials include 1,2,4-tris(p-toluenesulfonoxy)butane, 3,4-dibromobutane-1-methanesulfonate, but are not limited to these. As each substituent, a combination of commonly used leaving groups, such as a halogen atom, an alkanesulfonyl group, and an aromatic sulfonyl group, in any order can be used. The production method, properties, reactions, etc. of these trifunctional butanes are largely unknown, and only 1,
2,4-tripromobutane is 1,2-dibromo-
By the reaction of 4-methoxybutane and hydrogen bromide,
Also, 1,2,4-trichlorobutane is 1,2-
It is only synthesized by the reaction of dichloro-4-hydroxybutane and thionyl chloride. As a result of research into methods for synthesizing 1,2,4-trisubstituted butanes using various raw materials, the present inventors found that, for example, 1,2,4-butanetriol, 3-butene-1
It has become clear that trisubstituted butanes, including many of the novel ones mentioned above, can be obtained from trisubstituted butanes such as -ol, 4-chloro-1-butene, and 4-bromo-1-butene, and these can be combined with ammonia, primary amines, and protected By researching reactions with compounds with amino groups or various reagents that are expected to produce amine precursors, we have developed a completely new and unprecedented reaction that synthesizes a 3-aminopyrrolidine skeleton in one step. After discovering the following, we investigated the reaction conditions in more detail and completed this production method. As expected from its structure, 3-aminopyrrolidine and its salts obtained by the method of the present invention can be used in most of the applications where well-known ethylene amines are used, such as textile treatment agents, paper treatment agents, etc. Processing agents, pesticides, chelating agents, coating agents, adhesives,
It can be blended into rubber chemicals or used as a derivative. In particular, it can be used as a raw material for the synthesis of pharmaceuticals and drug substances with antibacterial effects. Hereinafter, specific reaction conditions of the method of the present invention will be explained in detail. First, regarding the reaction between a primary amine and trisubstituted butane, using benzylamine as the primary amine,
This will be explained in detail by taking as an example a case where 1,2,4-tribromobutane is used as the trisubstituted butane. This reaction is carried out in the presence or absence of a deoxidizing agent. As a deoxidizing agent, a common alkali such as caustic soda or potassium carbonate is used, but instead of this, a primary amine to be introduced, that is, benzylamine in this case, can be used. In any case, in order to improve the yield, it is desirable to add benzylamine in an amount several times the molar amount of the raw material in addition to the theoretical amount. This reaction may be carried out in a homogeneous reaction system using ordinary organic solvents such as isopropyl alcohol, dimethylformamide, benzene, or toluene, or it may be carried out in a two-phase system in which trisubstituted butane is added to a mixture of an aqueous alkaline solution and benzylamine. You can go there.
In this case, the reaction occurs in the organic phase, and the generated salt moves to the aqueous phase and comes into contact with an alkali to become a free amine and moves to the organic phase, so the reaction proceeds efficiently. Therefore, there is no need to use a phase transfer catalyst, and the target product can be obtained with higher purity if it is not used. This reaction is usually carried out at a temperature of 60 to 150°C for 30 to 20 minutes.
The reaction is completed in time. A crude product can be obtained by ordinary post-treatment operations, but it can be purified by acid-alkali purification, vacuum distillation, etc., if necessary. The N,N'-dibenzyl-33-aminopyrrolidine thus obtained can be fully used as an intermediate in the reduction reaction. Next, hydrogen reduction of N,N'-disubstituted-3-aminopyrrolidine and its salt will be explained. The deprotection reaction by hydrogen reduction is carried out in an autoclave using a single or mixed solvent such as water, methanol, isopropyl alcohol, tetrahydrofuran, acetic acid, etc., and a catalyst such as 5% Pd-
This is carried out using about 5 to 20 (W/W)% of C, 5% Pd-BaSO ₄ , PdO, PtO ₂ or the like to the target object. This reaction proceeds at a temperature of 20 to 150°C under pressure of about several kg to 30 kg/cm ² and is usually completed in 2 to 12 hours.
After the catalyst is filtered off, the solvent is distilled off, and the target product can be easily isolated. Next, the case of N,N'-dibenzyl-3-aminopyrrolidine will be explained as an example. Debenzylation by hydrogen reduction uses a solvent such as methanol or isopropyl alcohol, and a catalyst such as 5% Pd-C at a concentration of 5 to 20% of the target material.
(W/W)% is used. This reaction is 70-150
The process proceeds at a temperature of 10°C and under pressure of several kg to 30 kg/cm ² and is usually completed in 2 to 12 hours. After filtering off the catalyst, the solvent is distilled off under a nitrogen atmosphere, and 3-aminopyrrolidine can be easily isolated. This substance can be purified repeatedly as necessary,
A product of good purity can usually be obtained by distilling once or twice. Next, an example will be explained in which the hydrochloride of N,N'-dibenzyl-3-aminopyrrolidine is used. This reaction is carried out using, for example, 5% Pd-C as a catalyst in an amount of about 5 to 10 (W/W)% based on the target product.
Solvent selection is important. Particularly good results are obtained when this reaction is carried out in a mixed solvent system such as water-methanol. This reaction is carried out at a temperature of 20 to 40°C with a mass of several kilograms or more.
Proceeds under pressure of hydrogen of ^about 10Kg/cm2, and usually 2~
Completed in 12 hours. After filtering off the catalyst, the solvent is distilled off to obtain 3-aminopyrrolidine hydrochloride.
Obtained with a yield of 91%. In this way, when N,N'-disubstituted-3-aminopyrrolidine undergoes hydrogen reduction in the form of a protonate salt,
This method is practically advantageous because it proceeds under mild conditions and the desired 3-aminopyrrolidine salt can be obtained with a simple isolation procedure, but it is also possible to neutralize 3-aminopyrrolidine with a protic acid. It can also be obtained by [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 Dissolve 36 g of caustic soda in 36 ml of water, add 192.9 g of benzylamine, and stir at room temperature.
1,2,4-tribromobutane 88.4g (boiling point 99.5
℃/5.5 mmHg) was added in about 5 minutes. It generates heat after addition.
It reached 105-110℃. After reacting at the same temperature for 2 hours, cool to around room temperature, add 100ml of water and 100ml of benzene.
ml was added to separate the layers, and the organic layer was washed with water and concentrated. Excess benzylamine was distilled off under reduced pressure to obtain 68.9 g (86.2%) of crude N,N'-dibenzyl-3-aminopyrrolidine as a red oil. This was distilled under reduced pressure to obtain 57.6 g (72.1%) of a purified product with a boiling point of 185-189°C/2 mmHg. Refractive index n ²⁰ _D 1.5691 Specific gravity SG ²⁰ ₂₀ 1.0454 NMR (CDCl ₃ ) δ=7.43 (s, 10H), 3.80
(s, 2H), 3.68 (s, 2H), 1.20~3.57 (m,
8H) IR (neat) 3300, 1140 cm ^-1 (-NH-) Elemental analysis (C ₁₈ H ₂₂ N ₂ ) Calculated value (%): C, 81.16; H, 8.32; N, 10.52 Actual value (%): C, 80.65; H, 8.48; N, 10.50 Derivative 1-benzyl-3-(N-acetyl-N-benzyl)aminopyrrolidine Boiling point 204-208℃/2mmHg NMR ( _CCl4 ) δ=1.3-3.0 (9H, m), 3.4
(s) ~ 3.5 (s) (total 2H), 4.6 (2H, s), 4.2 ~
5.2 (broad s, 1H), 7.1 (10H, s) IR (neat) 1645, 1420 cm ^-1 In an autoclave, N,N'-dibenzyl-
Dissolve 80 g of 3-aminopyrrolidine in 300 ml of methanol, add 4 g of 5% Pd-C catalyst, and heat to 115 ml.
The mixture was stirred for 12 hours at ℃ and hydrogen pressure of 20 kg/cm ² . After the reaction, the catalyst was filtered off, and the filtrate was concentrated under normal pressure. The concentrated liquid is further distilled at normal pressure under a nitrogen atmosphere, and the boiling point is 159-160.
16.0 g (61.9%) of 3-aminopyrrolidine was obtained. Refractive index n ²⁰ _D 1.4897 Specific gravity SG ²⁰ ₂₀ 0.9910 NMR (CDCl ₃ ) δ=3.30~3.70 (m, 1H),
2.43~3.23 (m, 4H), 1.13~2.26 (m, 2H),
1.50 (s, 3H) IR (neat) 3250, 1600, 870 cm ^-1 (-NH ₂ ) Derivative 3-aminopyrrolidine dihydrochloride NMR (DMSO-d ₆ ) δ=8.33-10.10 (s,
broad, 5H) 3.66~4.23 (m, 1H), 2.93~
3.66 (m, 4H), 1.93~2.50 (m, 2H) IR (KBr) 3200~2800, 1590~1550cm ^-1 (-
NH ⁺ ₃ ) Elemental analysis (C ₄ H ₁₂ N ₂ Cl ₂ ) Theoretical value (%): C, 30.21; H, 7.60; N, 17.61 Actual value (%): C, 29.93; H, 7.63; N, 17.45 Chlorine content Theoretical value (%): 44.58 Actual value (%): 43.74 Example 2 Dissolve 120 g of caustic soda in 240 ml of water, add 643 g of benzylamine, and while stirring, 1.
2,4-tris(methanesulfonoxy)butane
340g (melting point 63.5-64.5°C) was added. It gradually generated heat and the temperature rose to around 100℃. After reacting at the same temperature for 1.5 hours, it was cooled to around room temperature. 250ml water
and 500 ml of benzene were added to separate the layers, and the organic layer was washed with water and concentrated. Excess benzylamine was distilled off under reduced pressure to obtain 260 g (97.6%) of crude N,N'-dibenzyl-3-aminopyrrolidine as an oil. This was dissolved in 400 ml of benzene, cooled with water, and 300 ml of 20% hydrochloric acid water was added dropwise while stirring. The aqueous layer was separated, washed with 270 ml of benzene, and then 86 g of caustic soda was added and stirred under ice cooling. The layers were separated, the aqueous layer was extracted twice with 270 ml of benzene, and the organic layers were combined and washed with water. Benzene was distilled off and the residue was distilled under reduced pressure to produce 198g of purified product with a boiling point of 187-190℃/2mmHg.
(74.3%). NMR and IR in Example 1
It was consistent with N,N'-dibenzyl-3-aminopyrrolidine obtained in . In an autoclave, N,N'-dibenzyl-
Dissolve 198 g of 3-aminopyrrolidine in 200 ml of methanol, add 20 g of 5% Pd-C catalyst, and heat to 115 ml.
The mixture was stirred for 12 hours at a hydrogen pressure of 20 Kg/cm ² . After the reaction, the catalyst was filtered off, and the filtrate was concentrated under normal pressure. The concentrated liquid is further distilled at normal pressure under nitrogen atmosphere, and the boiling point is 159-160℃.
40g (62.5%) of 3-aminopyrrolidine was obtained.
NMR and IR of this product were 3 obtained in Example 1.
-Concordant with aminopyrrolidine. Example 3 Dissolve 28.8 g of caustic soda in 30 ml of water, add 154.3 g of benzylamine, and dissolve while stirring.
4-dibromobutane-1-methanesulfonate
74.3g (boiling point 137-139°C/1mmHg) was added.
It gradually generated heat and the temperature rose to around 100℃. Temperature 110~
After reacting at 115°C for 2.5 hours, it was cooled to around room temperature. 65 ml of water and 130 ml of benzene were added to separate the layers, and the organic layer was washed with water and concentrated. Excess benzylamine was distilled off under reduced pressure to obtain 56.4 g (88.1%) of crude N,N'-dibenzyl-3-aminopyrrolidine as an oil. This was dissolved in 100 ml of benzene, cooled with water, and 75 ml of 20% hydrochloric acid water was added dropwise while stirring. The aqueous layer was separated, washed with 70 ml of benzene, and then 22 g of caustic soda was added and stirred under ice cooling. The layers were separated, the aqueous layer was extracted twice with 70 ml of benzene, and the organic layers were combined and washed with water. Benzene is distilled off and the residue is distilled under reduced pressure to produce a purified product with a boiling point of 195-199℃/3mmHg.
40.7g (63.7%) was obtained. NMR and IR were consistent with N,N'-dibenzyl-3-aminopyrrolidine obtained in Example 1. N,N'-dibenzyl-3 in autoclave
-Dissolve 40g of aminopyrrolidine in 150ml of methanol, add 2g of 5% Pd-C catalyst, and
The mixture was stirred for 12 hours at ℃ and hydrogen pressure of 20 kg/cm ² . After the reaction, the catalyst was filtered off, and the filtrate was concentrated under normal pressure. The concentrated solution was further distilled under normal pressure under a nitrogen atmosphere to obtain 8.0 g (62%) of 3-aminopyrrolidine with a boiling point of 159 to 160°C. The NMR and IR of this product were the same as those obtained in Example 1.
It was consistent with aminopyrrolidine. Example 4 48.0 g of caustic soda was dissolved in 50 ml of water, 257.0 g of benzylamine was added, and while stirring, 1.
4-dibromobutane-2-methanesulfonate
124.0g was added. It gradually generated heat and the temperature rose to around 100℃. After reacting at a temperature of 105 to 110°C for 2.0 hours, it was cooled to around room temperature. 200ml water and benzene
200 ml was added to separate the layers, and the organic layer was washed with water and concentrated. Excess benzylamine was distilled off under reduced pressure.
95.0 g (89.0%) of crude N,N'-dibenzyl-3-aminopyrrolidine was obtained. Add this to benzene
Dissolve in 170ml of 20% hydrochloric acid water while stirring under water cooling.
125 ml was added dropwise. The aqueous layer was separated, washed with 120 ml of benzene, and then 37 g of caustic soda was added and stirred under ice cooling. The layers were separated, the aqueous layer was extracted twice with 120 ml of benzene, and the organic layers were combined and washed with water. Benzene is distilled off, and the residue is distilled under reduced pressure to obtain a boiling point of 195-199.
68.3g (64.0%) of purified product was obtained with a temperature of ℃/mmHg.
NMR and IR are N,N′- obtained in Example 1.
It was consistent with dibenzyl-3-aminopyrrolidine. In an autoclave, N,N'-dibenzyl-
60.0g of 3-aminopyrrolidine and 250ml of methanol
3 g of 5% Pd-C catalyst was added, and the temperature
The mixture was stirred for 12 hours at 115° C. and under a hydrogen pressure of 20 kg/cm ² . After the reaction, the catalyst was filtered off, and the filtrate was concentrated under normal pressure. The concentrated liquid is further distilled at normal pressure under a nitrogen atmosphere to a boiling point of 159-160℃.
12.0 g (62%) of 3-aminopyrrolidine was obtained.
NMR and IR of this product were 3 obtained in Example 1.
-Concordant with aminopyrrolidine. Example 5 Dissolve 60 g of caustic soda in 100 ml of water, add 320 g of benzylamine, and while stirring, 1.
250 g of 2,4-tris(p-toluenesulfonoxy)butane (melting point 91.0-91.7°C) was added. It gradually generated heat and the temperature rose to around 100℃. Temperature 100~
After reacting at 105°C for 3.0 hours, it was cooled to around room temperature. One part of water and one part of benzene were added to separate the layers, and the organic layer was washed with water and then concentrated. Excess benzylamine was distilled off under reduced pressure to obtain 50 g (42.7%) of crude N,N'-dibenzyl-3-aminopyrrolidine. This was dissolved in 500 ml of benzene, cooled with water, and 100 ml of 20% hydrochloric acid water was added dropwise while stirring. The aqueous layer was separated, washed with 500 ml of benzene, and then 40 g of caustic soda was added and stirred under ice cooling. The layers were separated, the aqueous layer was extracted twice with 300 ml of benzene, and the organic layers were combined and washed with water. Benzene was distilled off and the residue was distilled under reduced pressure to produce 36g of purified product with a boiling point of 195-199℃/3mmHg.
(30.7%). In an autoclave, N,N'-dibenzyl-
Dissolve 36 g of 3-aminopyrrolidine in 250 ml of methanol, add 4 g of 5% PD-C catalyst, and heat to 115 ml.
The mixture was stirred for 12 hours at ℃ and hydrogen pressure of 20 kg/cm ² . After the reaction, the catalyst was filtered off, and the filtrate was concentrated under normal pressure. The concentrated liquid is further distilled at normal pressure under a nitrogen atmosphere, and the boiling point is 159-160.
7.2 g (62.5%) of 3-aminopyrrolidine was obtained. NMR and IR of this product were consistent with 3-aminopyrrolidine obtained in Example 1. Example 6 180 g of caustic soda was dissolved in 200 ml of water, 964 g of benzylamine was added, and 376 g of 1,2-dibromo-4-chlorobutane (boiling point 87.5-88.5°C/8 mmHg) was added at room temperature while stirring. After the addition, the mixture was gradually heated and reacted at 100 to 105°C for 19 hours. The mixture was cooled to around room temperature, 500 ml of water and 500 ml of benzene were added to separate the layers, and the organic layer was washed with water and concentrated. Excess benzylamine was distilled off under reduced pressure to obtain crude N,
N'-dibenzyl-3-aminopyrrolidine 183g
(45.8%) was obtained as a tan oil. This is distilled under reduced pressure to produce a crude product with a boiling point of 186-187℃/2mmHg.
107g (26.8%) was obtained. In an autoclave, N,N'-dibenzyl-
Dissolve 107 g of 3-aminopyrrolidine in 200 ml of methanol, add 10 g of 5% Pd-C catalyst, and heat to 115 ml.
The mixture was stirred for 12 hours at ℃ and hydrogen pressure of 20 kg/cm ² . After the reaction, the catalyst was filtered off, and the filtrate was distilled under nitrogen atmosphere under normal pressure to obtain 3-aminopyrrolidine 21.4% with a boiling point of 159-160°C.
g (62%) was obtained. NMR and IR of this product were consistent with 3-aminopyrrolidine obtained in Example 1. Example 7 161 g of 1,2,4-trichlorobutane (boiling point
61.5-62.0℃/4mmHg) to 1072g of benzylamine
Add it inside and gradually heat it while stirring until it reaches 140~
The reaction was carried out at 150°C for 19 hours. Ice-cold benzene 500ml
The precipitated crystals were filtered off, the filtrate was concentrated, and the excess benzylamine was distilled off under reduced pressure.
N'-dibenzyl-3-aminopyrrolidine 254g
(95.6%) was obtained as a yellow oil. This is distilled under reduced pressure and the purified product 152 has a boiling point of 180-182℃/3mmHg.
g (57.2%). In an autoclave, N,N'-dibenzyl-
Dissolve 152 g of 3-aminopyrrolidine in 200 ml of methanol, add 15 g of 5% Pd-C catalyst, and heat to 115 ml.
The mixture was stirred for 12 hours at a hydrogen pressure of 20 Kg/cm ² . After the reaction, the catalyst was filtered off, and the filtrate was distilled at normal pressure under a nitrogen atmosphere to obtain 3-aminopyrrolidine with a boiling point of 159 to 160°C.
g (62.5%). NMR and IR of this product were consistent with 3-aminopyrrolidine obtained in Example 1. Example 8 Dissolve 60 g of caustic soda and 120 ml of water,
363.5 g of phenylethylamine was added, and 170.2 g of 1,2,4-tris(methanesulfonoxy)butane (melting point 63.5-64.5°C) was added while stirring. The mixture was gradually heated to 110°C, reacted at the same temperature for 3 hours, and then cooled to room temperature. 50 ml of water and 400 ml of benzene were added to separate the layers, and the organic layer was washed with water and concentrated. Excess 1-phenylethylamine was distilled off under reduced pressure to obtain 133.5 g of crude N,N'-bis(1-phenylethyl)-3-aminopyrrolidine as an oil. Dissolve this in 200ml of benzene,
137 ml of 20% hydrochloric acid water was added dropwise under ice cooling. Separate the water layer,
After washing with 100 ml of benzene, 43.5 g of caustic soda was added and stirred while cooling on ice. Water layer benzene 200
ml twice, and the organic layers were combined and washed with water.
Benzene was distilled off, the residue was distilled under reduced pressure, and the boiling point
87.4 g (59.3%) of purified product was obtained at 175-177°C/2 mmHg. Refractive index n ²⁰ _D 1.5552 Specific gravity SG ²⁰ ₂₀ 1.0201 NMR (CDCl ₃ ) δ=7.30 (s, 10H), 3.53~
3.93 (m, 1H), 2.87~3.40 (m, 2H), 1.47~
2.83 (m, 7H), 1.40 (d, 3H), 1.28 (d,
3H). IR (neat) 1150cm ^-1 . Elemental analysis (C ₂₀ H ₂₆ N ₂ ) Calculated value (%): C, 81.59; H, 8.90; N, 9.51 Actual value (%): C, 81.62; H, 8.48; N,9.52 Dissolve 73.6 g of N,N'-bis(1-phenylethyl)-3-aminopyrrolidine in 200 ml of methanol in an autoclave, and add 15 g of 5% Pd-C catalyst.
was added and stirred for 20 hours at a temperature of 120°C and a hydrogen pressure of 18 kg/cm ² . After the reaction, the catalyst was filtered off, and the filtrate was distilled under normal pressure under a nitrogen atmosphere to collect 16.0 g of a fraction with a boiling point of 142 to 160°C. This was rectified at normal pressure under a nitrogen atmosphere to separate the by-product ethylbenzene (boiling point 136°C) and 8.8g of 3-aminopyrrolidine with a boiling point of 159-160°C.
(yield 36.8%). Example 9 48 g of caustic soda was dissolved in 100 ml of water, 439.8 g of benzhydrylamine was added, and while stirring, 136.1 g of 1,2,4-tris(methanesulfonoxy)butane (melting point 63.5-64.5°C) was added. The mixture was gradually heated to 110°C, reacted at the same temperature for 5 hours, and then cooled to around room temperature. 50ml water and benzene
400 ml was added to separate the layers, and the organic layer was washed with water and concentrated. Excess benzhydrylamine was distilled off under reduced pressure to obtain crude N,N'-bis(diphenylmethyl).
146.4 g (87.4%) of -3-aminopyrrolidine was obtained as an oil. Dissolve this in 500ml of benzene,
While stirring under ice-cooling, 210 ml of 10% hydrochloric acid water was added dropwise.
Separate the benzene layer and add caustic soda to the aqueous layer under ice cooling.
33.6g was added and stirred. 400 ml of benzene was added to separate the layers, and the aqueous layer was further extracted with 300 ml of benzene.
The organic layers were combined, washed with water, and then benzene was distilled off. The residue was heated and dissolved in 400 ml of isopropyl alcohol, and crystallized while slowly cooling. The precipitated crystals were collected by filtration, washed with 200 ml of isopropyl alcohol, and dried under vacuum to obtain N,N'-bis(diphenylmethyl)-3-. 73.6g of crude crystals of aminopyrrolidine
(43.9%). This was recrystallized from 200ml of isopropyl alcohol, yielding 57.9g (34.5%) of the crude product.
I got it. Melting point 106~107℃ NMR ( _CDCl3 ) δ=6.87~7.60 (m, 20H),
4.80 (s, 1H), 4.17 (s, 1H), 3.00~3.43
(m, 1H), 1.30-2.83 (m, 7H). IR (KBr) 3350cm ^-1 . Elemental analysis (C ₃₀ H ₃₀ N ₂ ) Calculated value (%): C, 86.06; H, 7.22; N, 6.69 Actual value (%): C, 86.33; H, 7.34; N,6.82 50.0 g of N,N'-bis(diphenylmethyl)-3-aminopyrrolidine was added in an autoclave.
The mixture was dissolved in 200 ml of THF, 10 g of 5% Pd-C catalyst was added, and the mixture was stirred for 3 hours at a temperature of 105° C. and a hydrogen pressure of 16 kg/cm ² . After the reaction, the catalyst was filtered off, and the filtrate was concentrated under normal pressure. The concentrated solution was further distilled under reduced pressure under a nitrogen atmosphere.
Boiling point 40-60℃/11mmHg, including some by-product diphenylmethane (boiling point 264.5℃/760mmHg) 3
-Aminopyrrolidine was collected and further distilled under nitrogen atmosphere at normal pressure to obtain 6.0g (58.4%) of 3-aminopyrrolidine with a boiling point of 159-160°C. Example 10 150 g of N,N'-dibenzyl-3-aminopyrrolidine synthesized by the method of Example 1 (boiling point 185-189
℃/2 mmHg) was added dropwise to a solution of 600 ml of ethanol containing 42 g of hydrogen chloride gas while stirring under ice-cooling. During this time, heat was generated and the temperature rose to 40°C. After dropping, stir under ice cooling for 2 hours, collect the precipitated crystals by filtration, add 100 ml of ethanol, then 200 ml of isopropyl ether.
Wash with ml of N,N'-dibenzyl-
Crude crystals of 3-aminopyrrolidine dihydrochloride were obtained. This was dissolved in 880 ml of ethanol while hot, treated with 8.8 g of activated carbon, cooled, the precipitated crystals were collected by filtration, dried, and N,N'-dibenzyl-
White crystals of 3-aminopyrrolidine dihydrochloride
184.8g (yield 96.8%) was obtained. Melting point 235.2-236.8℃ (decomposed), chlorine content (C ₁₈ H ₂₄ N ₂ Cl ₂ ); actual value 20.86%, theoretical value 20.90% N,N'-dibenzyl-3 in autoclave
-85g of aminopyrrolidine dihydrochloride in methanol
Dissolve 5% Pd-C in a mixture of 160 ml and 40 ml of water.
8.5 g of catalyst was added and stirred for 5 hours at a temperature of 35° C. and a hydrogen pressure of 10 Kg/cm ² . After the reaction, most of the solvent is distilled off under reduced pressure, and ethanol is added to the residue containing a small amount of water.
Add 100ml and distill off the water together with ethanol.
Crude crystals of 3-aminopyrrolidine dihydrochloride were obtained. After adding 100 ml of ethanol and stirring, the mixture was filtered under suction to obtain 35.4 g (88.9%) of white crystals of 3-aminopyrrolidine dihydrochloride. NMR (DMSO- _d6 ) δ=8.33~10.10(s,
broad, 5H), 3.66~4.23 (m, 1H), 2.93~
3.66 (m, 4H), 1.93-2.50 (m, 2H). IR (KBr) 3200~2800, 1590~1550cm ^-1 (−
NH ⁺ ₃ ). Elemental analysis (C ₄ H ₁₂ N ₂ Cl ₂ ) Theoretical value (%): C, 30.21; H, 7.60; H, 17.61 Actual value (%): C, 29.93; H, 7.63; N, 17.45 Chlorine content Theory Value (%): 44.58 Actual value (%): 43.74 In this reaction, N,N'-dibenzyl-3-
5% Pd for 85g of aminopyrrolidine dihydrochloride
- Using 4.3g of catalyst, 160ml of methanol and 40ml of water
Reduction was carried out in a mixed solvent of 11 Kg/cm ² at a hydrogen pressure of 11 kg/cm 2 and a temperature of 40°C for 10 hours, followed by post-treatment in the same manner as above.
-Aminopyrrolidine dihydrochloride 36.1g (90.6%)
I got it. In addition, when 85 g of N,N'-dibenzyl-3-aminopyrrolidine dihydrochloride and 8.5 g of 5% Pd-C catalyst were reacted in 200 ml of water at a hydrogen pressure of 10 Kg/cm ² and a temperature of 60°C, after 7.5 hours hydrogen Absorption ceased and after treatment in the same manner as above, a mixture consisting of 32.4 g (81.5%) of 3-aminopyrrolidine dihydrochloride and 5.1 g (8.7%) of monobenzyl-3-aminopyrrolidine dihydrochloride was obtained. Also, the same reaction was performed with methanol 200
ml at a hydrogen pressure of 11 Kg/cm ² and a temperature of 60°C, hydrogen absorption stopped after 16 hours and 28.6 g (72.0%) of 3-aminopyrrolidine dihydrochloride and 15.8 g of monobenzyl-3-aminopyrrolidine dihydrochloride were added. A mixture consisting of g (26.8%) was obtained. Example 11 66.6 g of N,N'-dibenzyl-3-aminopyrrolidine synthesized by the method of Example 1 (boiling point 185-189
℃/2mmHg) was dissolved in 200ml of acetic acid in an autoclave, 8g of 5% Pd-C catalyst was added, and the temperature was 40°C.
The mixture was stirred for 20 hours at a hydrogen pressure of 10 kg/cm ² . After the reaction,
Most of the acetic acid was distilled off under reduced pressure, toluene was added to the residue containing a small amount of acetic acid, and the acetic acid was distilled off together with the toluene to obtain crude 3-aminopyrrolidine diacetate.
44.4g (86.1%) was obtained. Add this to 90ml of ethanol
After heating to dissolve and treating with activated carbon, most of the ethanol was distilled off under reduced pressure, and 90 ml of benzene was added to the residue and stirred. The precipitated crystals were filtered with suction to obtain 33.4 g (64.8 g) of white crystals of 3-aminopyrrolidine diacetate.
%) was obtained. Melting point 89.0~93.0℃ NMR (DMSO- _d6 ) δ=8.20~8.33 (s,
broad, 5H), 3.50~3.93 (m, 1H), 2.73~
3.50 (m, 4H), 1.57-2.43 (m, 2H), 1.83
(s, 6H). IR (KBr) 3650-3100, 1550, 1400 cm ^-1 elemental analysis (C ₈ H ₁₈ N ₂ O ₄ ) Theoretical value (%): C, 46.59; H, 8.80; N, 13.59 Actual value (%): C , 45.66; H, 8.62; N, 13.32

[Claims]

1. When producing an N-substituted maleimide by dehydrating a dicarboxylic acid monoamide obtained from maleic anhydride and a primary amine in the presence of an acid catalyst in a nonpolar solvent, an onium compound represented by the following general formula is added. 1. A method for producing an N-substituted maleimide, which comprises reacting as follows. [R ¹ R ² R ³ MR ⁴ ] ⁺ Y ^- () R ¹ R ² R ³ M ⁺ CH ₂ COO ^- () (In the general formula, R ¹ , R ² , R ³ and R ⁴ are the number of carbon atoms In the general formula, R ¹ , R ² and R ³ are hydrocarbon groups having a total of 10 to 80 carbon atoms, M ⁺ is N ⁺ , P ⁺ ,
AS ⁺ or Sb ⁺ , Y ^- is Cl ^- , Br ^- , I ^- , HSO ₄ ^- ,
ClO ₄ ^- , CN ^- , H ₂ PO ₄ ^- , CH ₃ SO ₃ ^- ,

[Formula] or OH ^- )

Claims (1)

manufacturing method. 2. The production method according to claim 1, wherein the halogen atom is a chlorine, bromine, or iodine atom. 3 The alkyl group of the alkanesulfonyl group is C ₁ ~
Claim 1 which is a C ₄ lower alkyl group
Manufacturing method described in section. 4. The manufacturing method according to claim 1, wherein the substituent of the substituted phenyl group is selected from the group consisting of a halogen atom, an alkoxy group, and a lower alkyl group. 5. The manufacturing method according to claim 1, wherein the alkyl group is a _C1 to _C4 lower alkyl group. 6. The production method according to claim 1, wherein the protonic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, and acetic acid.