KR100196462B1 - Novel pyrrolidine derivatives and process for the preparations thereof - Google Patents

Abstract

The present invention relates to a novel pyrrolidine derivative represented by the following general formula (I) and a method for producing the same.

Wherein M is halogen, -OR ₁ or -SR ₂ (wherein R ₁ , R ₂ are the same as or different from each other, each represent a hydrogen atom or a lower alkyl group of 1 to 3 carbon atoms), and n is 1 or 2 Is an integer.

Compounds represented by formula (I) include optical isomers due to the asymmetric carbon at position 3. The present invention also provides a method for preparing the general formula (I) compound.

Description

New pyrrolidine derivatives and preparation methods thereof

The present invention relates to a novel pyrrolidine derivative represented by the following general formula (I) and a preparation method thereof.

Wherein M is a halogen atom, -OR ₁ or -SR ₂ (wherein R ₁ , R ₂ are the same as or different from each other, each represent a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms), and n is 1 or 2 Is an integer.

Compounds represented by formula (I) include optical isomers due to the asymmetric carbon at position 3. Therefore, all optical isomers and mixtures thereof are conveniently expressed as single structural formula. Thus, the scope of the invention is not limited to either optical isomers or mixtures thereof.

In general, the quinolone carboxylic acid antimicrobial agent is already widely used as an excellent antimicrobial activity and a wide range of antimicrobial active compounds, and representative examples thereof are nofloxacin, enoxacin, ciprofloxacin, and oploxacin.

However, these antimicrobial agents show excellent antimicrobial activity against gram-negative bacteria, but the antimicrobial activity of Gram-positive bacteria is significantly lowered and development of new antimicrobial agents has been required due to the expression of resistant bacteria.

Accordingly, the present inventors have completed the present invention as a result of finding a new introducer at the C-7 position of the existing quinolone mother nucleus in order to compensate for the disadvantage of the quinolone antibacterial agent as described above.

It is therefore an object of the present invention to provide very useful intermediates to be incorporated into quinolone antibacterial compounds.

Looking at the novel method for preparing a compound of the general formula (I) of the present invention as a starting material is a compound represented by the following general formula (II) known compounds as shown in the following scheme.

The compound represented by formula (II) was subjected to a cyclization reaction with ethyl 2,3-dibromopropionate in the presence of a base such as triethylamine to form aziridine ring of formula (III), followed by lithium aluminum The hydride was used to prepare an alcohol compound represented by the following general formula (IV), and then benzyl group was removed by hydrogen reaction using 10% palladium as a catalyst to synthesize the target compound of the general formula (I), wherein M is a hydroxy group. do.

The synthetic route is shown in the following process chart.

In the formula, M and n are as defined above.

The introduction of various functional groups in the general formula (I) synthesizes the general formula (IV) as a starting material.

In the general formula (IV), thionyl chloride is used to introduce a chlorine group of the general formula (V), and is converted to a methanesulfonyl derivative of the general formula (VI), and then a fluorine group is introduced through a substitution reaction using tetraammonium fluoride. To produce a general formula (Ⅶ).

Hydrogen reactions of formulas (V) and (iii) yield the desired compounds in which M is chlorine and fluorine, respectively.

As such, the novel pyrrolidine derivatives of the general formula (I) prepared according to the present invention are very useful as intermediates, which are raw materials used as introduction materials in the preparation of various quinolone derivative compounds having antimicrobial activity, and the novel compounds of the present invention Quinolone antimicrobial agent introduced into the mother nucleus shows excellent antimicrobial activity.

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited by the following examples.

Example 1

Preparation of 1-benzyl-3- (2-ethoxycarbonyl) aziridino pyrrolidine (III)

10.5 g (59.7 mmol) of 1-benzyl-3-amino pyrrolidine was added to 200 ml of acetonitrile and 16.64 g (119.4 mmol) of triethylamine and 8.67 ml (59.7 mmol) of ethyl 2,3-dibromopropionate It was added sequentially and stirred for 3 hours at room temperature.

The fish salted during the reaction was filtered, and the filtrate was collected, concentrated, diluted with 200 ml of dichloromethane, washed with saturated sodium hydrogen carbonate solution (100 ml × 2), and dried to obtain 13.95 g of the target compound. (86% yield)

Example 2

Preparation of 1-benzel-3- (2-hydroxymethyl) aziridino pyrrolidine (IV)

13.95 g (51.1 mmol) of 1-benzyl-3 (2-ethoxycarbonyl) aziridinopyrrolidine diluted in 200 ml of anhydrous tetrahydrofuran solvent is maintained in nitrogen atmosphere and 1.94 g of lithium aluminum hydride (51.1) at -10 ° C. mmol) was added and stirred at room temperature for 5 hours.

2 ml of distilled water and 2 ml of 15% sodium hydroxide solution were added sequentially, and then the filtrate was concentrated by filtration, diluted with 200 ml of ethyl acetate, washed with water, dried and concentrated to obtain 8.1 g of the target compound (yield 67.5%).

Example 3

Preparation of 3- (2-hydroxymethyl) aziridino pyrrolidine (I)

Dilute 1.2 g (5.7 mmol) of 1-benzyl-3- (2-hydroxymethyl) aziridino pyrrolidine in 150 ml of ethanol, add 0.6 g of 10% palladium, and hydrogen pressure of 4-5 bar at 60 ° C. Stirred for 5 hours.

The reaction was filtered and concentrated under reduced pressure to give 620 mg. (85% yield)

Example 4

Preparation of 1-benzyl-3- (2-methanesulfonylhydroxymethyl) aziridino pyrrolidine (IV)

2.4 g (10 mmol) of 1-benzyl-3- (2-hydroxymethyl) aziridino pyrrolidine was diluted in 50 ml of dichloromethane, 2.78 ml (20 mmol) of triethylamine was added, and 1.21 ml of methanesulfonyl chloride at 0 ° C. (15 mmol) is slowly added dropwise.

After stirring for 3 hours at room temperature, 10 ml of ice water was added to the reaction vessel, extracted with dichloromethane and saturated sodium hydrogen carbonate solution, dried and concentrated to obtain 3.2 g of the target compound. (92% yield)

Example 5

Preparation of 1-benzyl-2- (2-fluoromethyl) aziridino pyrrolidine

1.11 g (3.6 mmol) of 1-benzyl-3- (2-methanesulfonylhydroxymethyl) aziridino pyrrolidine was diluted with 30 ml of anhydrous tetrahydrofuran and 10.6 ml (10.8 mmol) of tetrabutyl ammonium fluoride were added to give 1 Reflux for time.

The solvent was concentrated, diluted with 50 ml of ethyl acetate, washed with saturated sodium hydrogen carbonate, dried, concentrated and separated and purified by silica gel column chromatography to obtain 0.53 g of the target compound. (Yield 64%)

Example 6

Preparation of 3- (2-fluoromethyl) aziridino pyrrolidine (I)

0.51 g (2.3 mmol) of 1-benzyl-3- (2-fluoromethyl) aziridino pyrrolidine was reacted as a starting material under the same conditions as in Example 2 to obtain 0.21 g of the target compound. (Yield 72% )

Claims (2)

A new pyrrolidine derivative represented by the following general formula (I) and comprising an optical isomer produced by asymmetric carbon at position 3. Wherein M is halogen, -OR ₁ or -SR ₂ (wherein R ₁ , R ₂ are the same as or different from each other, each represent a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms), and n is 1 or 2 Is an integer. The compound represented by formula (II) was subjected to cyclization reaction with ethyl 2,3-dihalopropionate to form a compound of formula (III), followed by the following formula (IV) using lithium aluminum hydride. Method of preparing the target compound (I) by removing the benzyl group through the hydrogen reaction after preparing the alcohol compound represented by. Wherein M is halogen, -OR ₁ or -SR ₂ (wherein R ₁ , R ₂ are the same as or different from each other, each represent a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms), and n is 1 or 2 Is an integer.