JPS6157579A - Preparation of 3-aminopyrrolidine or its salt - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for producing an antibacterial agent by a simple operation, by reacting a 1-alkoxycarbonyl-3- phthalimidopyrrolidine with a mineral acid. CONSTITUTION:A compound shown by the formula I (R<1> is lower alkyl) is reacted with a mineral acid such as conc. hydrochloric acid, conc. sulfuric acid, diluted sulfuric acid, etc. at 100-150 deg.C for 5-20hr to give 3-aminopyrrolidine. The compound shown by the formula I is proudced from a compound (e.g., 1-ethoxycarbonyl-3-pyridone) shown by the formula II by a method following the equation. Prepared 3-aminopyrrolidine is extremely useful as an intermediate for producing a quinolinecarboxylic acid and naphthyridinecarboxylic acid compound shown by the formula III (R<2> is lower alkyl, lower alkenyl, or phenyl; X is C, or N) suitable as an antibacterial agent.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing 3-aminopyrrolidine or a salt thereof. More specifically, the present invention provides - [wherein ⇠l represents a lower alkyl group. The present invention relates to a method for producing 3-aminopyrrolidine or a salt thereof, which comprises reacting a compound represented by the following with a mineral acid.

3-Aminopyrrolidine or its salt obtained by the method of the present invention has the general formula (I[]NH) useful as a synthetic antibacterial agent.

It is an extremely useful compound as an intermediate in the production of quinoli/carboxylic acid and naphthyridine carboxylic acid compounds represented by

[Prior art]

Conventionally, 3-aminopyrrolidine or its salt has been produced according to the following route (Journal of
Medicinal Chemistry, Volume 11, No. 1034~
Page 1037 (1968) itaha! ! ! f Kaisho 53-2
Publication No. 8161).

[Problem that the invention seeks to solve]

However, according to the conventional method described above, since the 1-position of pyrrolidine is protected with a benzyl group, it is necessary to eliminate it by catalytic reduction in the final step, so this method cannot be implemented industrially. It was extremely difficult to do so.

[Means to solve the problem]

Under such circumstances, the present inventors have developed the industrially advantageous 3-
As a result of intensive research to develop a method for producing aminopyrrolidine or its salt, the present invention was completed.

According to the method of the present invention, RI Q
By using a compound of the general formula CI) into which a C-group (R1 has the same meaning as above) as a raw material and reacting it with a mineral acid to simultaneously remove the protecting groups at the 1st and 3rd positions. 3-Aminopyrrolidine or its salt can be easily obtained. Therefore, the method of the present invention is not only easy to operate, but also economically superior and industrially advantageous.

The method of the present invention will be explained in detail below.

In addition, in this specification, "lower alkyl group" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl, tart
-01-4 alkyl group such as butyl, and "lower alkenyl group" refers to C
8-4 alkenyl group shall be meant.

The mineral acids used in the method of the present invention include, for example, hydrochloric acid,
Concentrated sulfuric acid, diluted sulfuric acid, etc. are mentioned, and these have the general formula CII
It is used in an amount of about 10 to 50 times the molar amount of the compound. The method of the present invention is also carried out by reacting at 100-150° C. for 5-20 hours, followed by conventional desalting or salt-forming reactions, if desired.

Salts of 3-aminopyrrolidine include salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid or sulfuric acid.

Further, the compound of general formula CI), which is a raw material for the method of the present invention, can be produced, for example, by the method described in US Pat. No. 3,365,450, according to the following production route.

[■]

Next, the present invention will be explained with reference to Examples, but the present invention is not limited thereto.

Example (1) 1-ethoxycarbonyl-3-pyrrolidone 100
? was dissolved in 300 ml of methanol, and 6.02 f of sodium borohydride was dissolved in 401 nt of water.
Add dropwise at 0°C over 30 minutes. After further reacting at the same temperature for 15 minutes, 5214.3 d of salt and 250 d of saturated loam water were added.
PILt and 300 d of methylene chloride are added sequentially. Next, the organic layer was separated and washed with 100 liters of saturated saline solution.
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain oily 1-ethoxycarbonyl-3-hydroxypyrrolidine. (yield 98.7%).

IR (knee) cm-” i νc=o 167
ONMR (CDCIs) δ value; 1.30 (3H, t, J=7Hz, CH, CH,
−).

4.15 (2H, q, J=7Hz, CH3C
H2-).

(2+ 100 t of 1-ethoxycarbonyl-3-human 0-roxyvirolidine is dissolved in 500 d of methylene chloride, 63.5 t of triethylamine is added, and then 72 liters of mesyl chloride is added dropwise at 0°C over 1 hour. After stirring at the same temperature for 20 minutes, add 500 d of water.

Then, the organic layer was separated, washed with 200111t of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain oily 1-ethoxycarbonyl-
128t of 3-mesyloxypyrrolidine (yield 85.9%)
).

to IR) ctn-1i =0168ONM
R (CDCI, ) δ value; 1.28 (3H, L, J=7Hz, CHIC
H, -).

3.08 (3u, a, -oso2cm).

4.16 (2H,q, J=7Hz, CH3C
H2-).

(3) 100 t f of 1-ethoxycarbonyl-3-mesyloxypyrrolidine dissolved in 750 d of N,N-dimethylformamide, and 78 t of N-potassium phthalimide.
Add f and react at 100°C for 2 hours.

After cooling to room temperature, 500 ml of methylene chloride and 2250 ml of water were added, and the pH was adjusted to 11.5 with 20 ml of aqueous sodium hydroxide solution. The organic layer was separated and 0.
After sequentially washing with 500 Int of IN-hydrochloric acid, 500 Int of water and 250 Int of saturated brine, and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Diisopropyl ether 200#Eg was added to the obtained residue, and the precipitated crystalline substance was collected by F. 1-ethoxycarbonyl-3-phthalimidopyrrolidine having a melting point of 81 to 82°C was obtained at 52.0°C. (yield: 42.8%).

IR(KBr) ctn(;νc=o 170ON
MR (cnc13) δ value; 1.28 (3H, t, J=7Hz, CH, CH2-).

-〇4.10 (2H, q, J=7Hz, CH2CH
2-).

(4) l-ethoxycarbonyl-3-7thalimidopyrrolidine 50. Add salt #500 to OF and heat to reflux for 1 hour. Then, after cooling the reaction solution to room temperature,
Remove insoluble matter. If the F solution is distilled off under reduced pressure and the obtained crystalline substance is washed with ethanol 25-, the hygroscopic 3
-Aminopyrrolidine dihydrochloride 24.2fC yield 87.
7%).

IR (Nujol) cIn-” i νNH2”*
HH,” 5000~20'0ONMB(D*O)
a value; (5) 3-aminopyrrolidine dihydrochloric acid! Add 50-methanol to 15.9P, and then add 10.8F of sodium methylate. After stirring at room temperature for 1 hour, the insoluble matter was removed and the resulting F solution was distilled to have a boiling point of 156°C.
3-aminopyrrolidine is obtained.

rg (knee) cm-1: Nu, NH, 33
50-315ONMR (CDCh) δ value;

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents a lower alkyl group. A method for producing 3-aminopyrrolidine or a salt thereof, which comprises reacting a compound represented by the following with a mineral acid.