JPS62201864A - 3-aminopyrrolidine and its preparation - Google Patents

Abstract

NEW MATERIAL:3-Aminopyrrolidine that is represented by formula I, boils at 159-160 deg.C under normal pressure in its pure state and is liquid at room temperature under normal pressure. USE:A synthetic intermediate of physiologically active substance such as agrochemicals or medicines. PREPARATION:Ammonia is allowed to react with a trisubstituted butane of formula II [X, Y, Z are halogen, OR (R is alkanesulfonyl, aromatic sulfonyl)] to give the compound of formula I.

Description

[Detailed Description of the Invention] [Industrial Field of Application] This invention provides useful synthetic JJX products, especially physiologically active v! This invention relates to 5-aminopyrrolidine that is suitable for use as a JAL rope, and a method for producing the same.

[Conventional technology]

Until now, despite its simple structure, 5-aminopyrrolidine itself has never been synthesized or isolated from natural products, and its physical properties are completely unknown. Only a few 5-aminopyrrolidines are known which have substitutions at the 1-position and/or the 5-position nitrogen system. Therefore, have any potentially useful substances been synthesized directly from 5-aminopyrrolidine itself? 1 jri
Although not reported, it is known that there are useful compounds that exhibit physiological activity with a 3-aminopyrrolidine skeleton in their molecules. For example, in 1967-1968 O, D, L
un5ford etc. have a substituent at the 1-position.
We synthesized aminopyrrolidine on urea and indole derivatives, investigated its pharmacological effects on the central nervous system, and found that it suppressed sedative effects (J, Mad.

Chem, 10.1015 (1967): 1 bid.
, 11°1054 (196B)).

Makoto, J., and MatSullOtO et al. have constructed a complete set of compounds in which cyclic amines are introduced at fixed positions in pyrido/based compounds exhibiting antibacterial properties, and their in vitro development.

and antibacterial screening with Invisa.

As a result, a compound, 7
-(3-amino-1-pyrrolidinyl)-1-ethyl-6
-Fluoro-1゜4-dihydro-4-oxo-1,8-
Naphthyridine-5-carvone #R and its homologues are
It has been reported that it has the most effective antibacterial properties and has an effective therapeutic effect against Staphylococcus and Gutuidomonas infections (CJ, Mad, Cham, 27).

1543 (1984)].

The above-mentioned 5-aminopyrrolidine skeleton has excellent properties fX
However, little is known about the method for synthesizing this 3-aminopyrrolidine moiety.

For example, the 5 used as raw material in the second example above
- Regarding acetylaminopyrrolidine, its manufacturing method and physical properties have not been reported at all. This is Lunafor
1-benzyl-5- synthesized by a long route by
After acetylation of aminopyrrolidine (cited above),
It is thought that it can be obtained through reduction.

[Problem that the invention seeks to solve]

The present inventors have focused on the core 3-aminopyrrolidine as the most basic and stable 5-aminopyrrolidine compound that can be used for the above-mentioned general purposes, and have studied all methods for its synthesis.

Conventionally, 5-aminopyrrolidine itself has not been synthesized, and the nine main reasons are: 1) Long steps are required to arrive at the precursor for 5-aminopyrrolidine synthesis.

2) Since the nitrogen atom in the pyrrolidine ring is extremely nucleophilic and basic, it is impossible to introduce an amino group into the 5-position of the pyrrolidine ring unless this part is protected.

5) In the final deprotection step of 3-aminopyrrolidine synthesis, hydrolysis is often used, but 5-aminopyrrolidine is aqueous and can be separated by distillation, which is azeotropic with water. @Nothing.

This is thought to be due to the following.

It is an object of the present invention to provide a useful new difunctional compound, 5-aminopyrrolidine, and to provide a complete process for the production of this new compound in an industrially convenient manner.

[Means to solve all problems]

The object compound of the present invention *rC15-aminopyrrolidine is represented by the chemical formula: Kuramoto, and has a normal pressure boiling point of 159 to 160 in a pure state.
It is a new, completely unknown compound that is a colorless liquid at room temperature and pressure. Other physical properties of this compound are shown in the examples below.

5-Aminopyrrolidine of the present invention can be produced, for example, by the method below.

That is, the method for producing 3-aminopyrrolidine of the present invention is carried out using the general formula: I
Aromatic
A trisubstituted butane represented by a sulfonyl group) is reacted with ammonia.

1,2.4-3It! used in this reaction! l! Specific examples of 1-butanes include 1,2.4-) IJ dichlorobutane, 1,2.4-tribromobutane, 1.4-
-dibromobutane-2-methanesulfonate, 1,2-
dibromo-4-chlorobutane, 1,2.4-)lis(
Examples include methanesulfonoxy)butane, 1,2,4-tris(p-toluenesulfonoxy)butane, 5゜4-dibromobutane-1-methanesulfonate, but the raw materials are limited to these. Instead, each substituent on the butane skeleton can be a combination of groups commonly used as leaving groups, such as a halogen atom, an alkylsulfonyl group, an arylsulfonyl group, in any order.

The manufacturing method, properties, reactions, etc. of these trifunctional butanes are as follows.
Although little known, 1゜2.4-tribromobutane can be converted into 1゜2.4-tribromobutane by the reaction of 1,2-dibromo-4-methoxybutane with hydrogen bromide. - Trichlorobutane is only synthesized by the reaction of 1,2-dichloro-4-hydroxybutane and thionyl chloride.

Non-inventors, etc., use each building material to 1,2.4-3! As a result of further refinement of the synthesis method for substituted butanes, for example, 1,2.4-
Butanetriol, 5-buten-1-ol, 4-chloro-1-butene, 4-bromo-1-butene, etc. Many of the above compounds are common? It has become clear that trisubstituted butanes containing nine are obtained, and these and ammonia: primary amines, protected amines, ? The reaction with various reagents that are expected to produce a 5-aminopyrrolidine skeleton prior to amines or compounds that can be synthesized in one step has not been completed in the past. See all the new reaction headings,
Furthermore, the reaction conditions were investigated in detail, and the present production method was completely completed.

Hereinafter, the specific reaction process and separation and purification method of the method of the present invention will be clearly explained.

The reaction between trisubstituted butane and ammonia is usually carried out using liquid ammonia in an autoclave under pressure and heating conditions. The reaction temperature and reaction time vary depending on the type of ester used, but for example, when 1,2,4-)ribromobutane gold is used, the reaction is photoconcentrated in 20 hours at a temperature of 45 to 50°C. In this reaction, the side reaction in which t3-aminopyrrolidine, once generated, reacts sequentially with the raw material trisubstituted butane cannot be ignored, so it is necessary to have liquid ammonia 3-aminopyrrolidine present in the system in a sufficient amount relative to the butane. is desirable. For example, when 1,2,4-tribromobutane is used, 5-aminopyrrolidine can be obtained in a yield of 22 to 55% when the total molar ratio of ammonia to the raw material is 56S72 times.

The method for separating and purifying the target product after the completion of the reaction varies depending on the raw materials used, but it can be carried out, for example, as follows. After distilling off the over-temperature ammonia, a residue consisting of a mixture of 6-aminopyrrolidine salt and ammonium salt is obtained, which is acidified in aqueous alkaline water and the ammonia water is separated by distillation. 5-aminopyrrolidine azeotropes with water and then distills out, so it cannot be separated from water by distillation, but it is neutralized by adding, for example, hydrochloric acid water, and once it is isolated in the form of 6-aminopyrrolidine hydrochloride. Let go. Next, add m to this hydrochloric acid and methanol, add sodium methoxide, and add 3 m
- The aminopyrrolidine is brought into free form and separated by distillation. 5-aminopyrrolidine does not azeotrope with methanol and can be separated. This product may be further purified by distillation if necessary.

〔Effect of the invention〕

As expected from its structure, the novel compound 5-aminopyrrolidine of the present invention can be used in most of the applications where well-known ethylene amines are used, namely textile treatment agents, paper treatment agents, agricultural chemicals, and chelating agents. , adhesives, rubber chemicals, etc., or used as a derivative. In particular, it can be used as a raw material for pharmaceuticals and drug substances with antibacterial effects.

〔Example〕

Below is the invention! I! ! An example of the manufacturing method will be shown, but the method of the present invention is not limited to this example.

Example 1 In an autoclave, 88 g of 1,2,4-tribromobutane (boiling point: 99.5°C, 15.5% Hg) was
01! of liquid ammonia at 45-50℃ and 70℃.
The mixture was stirred for 20 hours under a pressure of kg/cm2.

After the reaction, remove excess ammonia and use the remaining tap water as 50 C1
1jiC@dissolve, add 72g of caustic soda to the blade, 5
- Distill aminopyrrolidine with water at normal pressure. Bath temperature 1
Fraction 215I with a boiling point of 101-114°C at 50-170°C
T-dye, add 55ml of hydrochloric acid and evaporate to dryness,
Crude 5-aminopyrrolidine dihydrochloride 18.9 #
(Yield 59.8%). This product was added to Mfi of methanol 801 containing 15.2 J 1 & of sodium methoxide under a nitrogen atmosphere and heated under reflux for 30 minutes. After cooling, the precipitated sodium chloride was filtered off and distilled under nitrogen atmosphere to obtain 8.1 N of 5-aminopyrrolidine (yield: 51.7%) with a boiling point of 159-160°C.

"1413? 7 Refractive index nl) Specific gravity 5G2oO,? 9 1 ONMR (
CDOj, ) δ = 5.50-5.70 (m, IH)
, 2.45-3.25 (m, 4H), 1.15-
2.26 CDI, 2H), 1.50 (s, AH).

rR(n6at) 5250,1600.87017
1 (-NH2).

Comprehension: Extremely soluble in water, ethanol, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, chloroform, tetrachloride, and Hensen; slightly soluble in hexane.

Derivative 5-aminopyrrolidine dihydrochloride NMR (DMSO-c16) δ = 8.55% IO
, I Q (s, broad, 51().

ξ66~4.25 (m, IH), 2.95S5.6
6 (m, 4H).

1.95 to 2.50 (m, 2H).

IR(KBr) 5200-2800, 15905
1550 capital-1 (-NHi).

Chlorine content (C4H,2N2C/2) Theoretical value (%): 44,58 Actual value (%): 45.55 N,Nl-diacetyl-5-aminopyrrolidine NMR (
CDOj, ) δ = 7.00 ~ 7.40 (s, bro
ad, IH).

4.17-4.73 (m, IH), 5.15 S5
．． 90 (m, 4h).

1.77-2.47 (m, 8H).

IR(neat)3400-3250.1670-1
620゜1550/W"' N Nl-di-t-butoxycarbonyl-3-aminopyrrolidine NMR (cpcz3>δ=4.90S5.17 (d
, broad, IH).

5.93~4.50 (11, IH), 2.90~5
．． 87 (m, 4H).

1.05A-2,55 (m, 2H), 1.47 (s
, [H).

I R (neat) 3500.1670.1520m
.

Claims (1)

[Claims] 1. Chemical formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Represented by the following, and has a boiling point at normal pressure of 159 to 160 in a pure state.
3-Aminopyrrolidine is a colorless liquid at room temperature and pressure. 2. General formula: XCH_2CHYCH_2CH_2Z [wherein, X, Y and Z are each a halogen atom or O
1. A method for producing 3-aminopyrrolidine, which comprises reacting trisubstituted butane represented by the R group (R represents an alkanesulfonyl group or an aromatic sulfonyl group) with ammonia. 3. The manufacturing method according to claim 2, wherein the halogen atom is a chlorine atom, a bromine atom, or an iodine atom.