WO1992000280A1

WO1992000280A1 - Quinoline derivative and production thereof

Info

Publication number: WO1992000280A1
Application number: PCT/JP1991/000824
Authority: WO
Inventors: Masahiko Kitano; Ken-Ichi Nakamura; Tatsuhiko Kashima
Original assignee: Nippon Shinyaku Co., Ltd.
Priority date: 1990-06-22
Filing date: 1991-06-20
Publication date: 1992-01-09

Abstract

An intermediate of formula (I) for the synthesis of a compound of formula (III) which has an excellent antibacterial action; and a process for producing the intermediate of formula (I) by the ring closure of a compound of formula (II), wherein R1 represents hydrogen or lower alkyl, R2 represents a protective group of a nitrogen atom, and R3 represents a protective group of a sulfur atom.

Description

Rui Akira

Quinoline derivatives and manufacturing technology

The present invention relates to an important intermediate of a quinoline carboxylic acid derivative which has an antibacterial action and is useful as a therapeutic agent for various infectious diseases. The compound according to the present invention can be represented by the following general formula [I].

In the formula, R ¹ represents hydrogen or a low alkyl, R ³ represents a nitrogen atom protecting group, and R ³ represents a sulfur atom protecting group. The compound [II] and its derivative synthesized from the compound [I] according to the present invention as described below have excellent antibacterial activity, and can be used for infections caused by gram-negative bacteria, intractable chlorophyll infections, Useful for the treatment of Gram-positive bacterial infections.

CI) Dihalogenation

In the formula, R ¹ represents chromium or lower alkyl, R ² represents a protecting group for a nitrogen atom, R ³ represents a protecting group for a sulfur atom, and R represents hydrogen, alkyl, or fuunyl. Represent.

Background technology

The present inventors have found a quinoline carboxylic acid having an excellent antibacterial action, and have already filed patent applications (Japanese Patent Application Laid-Open Nos. 57-136588, 58-103393, 63-107990, and 63-107990). 3-12061).

In these patent applications, various methods for producing quinoline carboxylic acid conductors are described. According to these descriptions, it is considered that the compound and the production method according to the present invention will be shown depending on the combination of the substituents. However, none of these specifications disclose the compound [I] of the present invention having a fluorine at the 6-position and a biperazino group at the 7-position. Also, there is no specific disclosure of the production method of the present invention using the following compound [Π].

(The following page) (E)

In the formula, R ¹ , R ² and R ³ are the same as described above. Disclosure of the invention

In the production of compound (i) as an intermediate for the synthesis of compound (m), the following compound (IV) in which the biperazino group in compound (π) has been replaced by fluorine has been used as an intermediate so far. Have been.

However, in this method, the reverse

The derivative [VI] was generated in an amount of 5 to 20%, and the yield was poor. Furthermore, when [VI] is mixed into the reaction product, there is a technical problem that it is difficult to remove and purify the product.

(V) (VI) In the course of continuing research to overcome these points, the present inventors have found a manufacturing method that remarkably surpasses the above, and have completed the present invention.

Therefore, an object of the present invention was to develop a production method which is significantly superior to the existing production method.

The gist of the present invention lies in the chemical structure itself represented by the general formula [I].

The compound [I] of the present invention is a novel compound. The method of the present invention is a novel production method not described in the literature, and its feature lies in using the compound [π] as a raw material.

— In the general formula [I], the lower alkyl represented by R ′ is preferably a straight-chain or a lower alkyl having 1 to 4 carbon atoms, for example, methyl, ethyl, π-propyl, i Soprovir, η-butyl, isobutyl, sec-butyl, tert-butyl and the like can be mentioned.

—In the general formula [I], examples of the nitrogen-protecting group represented by R ² include alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, isobutyloxycarbonyl, etc.), and acyl (eg, , Holmil, acetyl, chloroethyl cetyl, benzoyl, P-anisyl, etc.), vinylidylylcarbonyl, penzyloxycarbonyl, ryjenyl (eg, allyl, etc.), rylarky (eg, Penzyl, diphenylmethyl), 2,4'-dinitrofuryl and the like can be used.

In the general formula (I), examples of the sulfur-protecting group represented by R ³ include alkoxymethyl, substituted benzyl, and 2,4-dinitrophenyl. , Disulfide as a dimer of [Π], alkylthiomethyl, substituted carbamoyl, difluoromethyl, triphenylmethyl, picolyl, acetamidomethyl,, β, β-trifluoro- a-ylaminoethyl, β, β-diethoxykarponylethyl, acyl (eg, acetyl, penzyl), benzoylcarbonylcarbonyl, tetrahydrobiranyl, benzylthiomethyl, isobutoxymethyl, etc. Can be mentioned.

Representative examples of such protecting groups include, for example, methoxymethyl and methoxypentyl.

The compound [I] of the present invention has a protective group which is deprotected, if necessary, and has an excellent antibacterial effect by the methods described in, for example, JP-A-63-107990 and JP-A-11-29468Q. It can lead to a nor- nic carboxylic acid derivative.

The method of the present invention according to the method for producing the compound [I] of the present invention can be carried out as follows.

This ring closure reaction can be performed by a method known per se. For example, a method using heating, a method using an acidic substance, or the like can be used. For example, in the case of heating, the heating is carried out by heating to 100 to 300, preferably 110 to 150 "C in a solvent without or in a solvent. Examples of the solvent include diph Xnyl ether, liquid paraffin, diethylene glycol. When using a relatively low boiling point solvent such as dimethyl ether, tetralin, and dike pentene, when using an acidic substance, [〔] 1 mole to 1 mole per mole The reaction is usually carried out at 0 to 100 t, preferably at 0 to 60 t, using an excess, preferably 20 to 30 mol of acidic substance. As the acidic substance, oxylin chloride, pentachloride, lin trichloride, thioyukuride, fuming sulfuric acid, concentrated sulfuric acid, polyunic acid, polyphosphate ester, etc. should be used. Can be.

The starting compound [Π] will be described later as a reference example, and _β can be produced by a known method (eg, JP-A-57-136588).

The target compound [I] thus produced is isolated and purified by a method known per se, for example, concentration, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractionation, chromatography, etc. Can ο

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples according to the present invention.

Reference example 1

(1) Ν- (2-fluorophenyl) biradine

2-Fluoroaniline 11. lg, bis (2-bromoethyl) bromominobromate 34.3 g, and ice lloil solution are stirred at 80 t for 10 min. At the same temperature, an ice solution prepared by dissolving 13 g of peroxidative room in 50 ml of water is added dropwise over 1 hour. Stir for an additional 30 minutes. After cooling to room temperature, add water to dissolve, and add 10% sodium hydroxide to pH 10 under ice-ice cooling.齚 Extract with acid ethyl. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. This gave 18.0 g of the target compound as a light brown oily substance. (2) 1-ethoxycarbonyl-4- (2-fluorophenyl) piperazine

To a solution of 24.5 g of N- (2-fluorophenyl) biazine and 14.4 g of triethylamine dissolved in 123 rolls of chloroform was added, while cooling with ice and stirring, ethyl ester of chlorocarboxylic acid. 2 g is dripped in 20 minutes. The mixture is further stirred at the same temperature for 30 minutes and at room temperature for 2 hours. The reaction solution is poured into 120 ml of 0.5N hydrochloric acid, and extracted with chloroform. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. 31. Og of the target compound was obtained as a light brown oil.

(3) Ethoxycarponyl-4- (2-fluoro-5-nitrophenyl) biperazine

1-Ethoxycarbonyl-4- (2-fluorophenyl) biradine 30.1 g of a solution of 1 g of concentrated sulfuric acid dissolved in 120 ml of concentrated sulfuric acid was stirred under ice-cooling, and then stirred with 10 ml of concentrated sulfuric acid and 10.2 ml of 61% nitric acid. The mixture is added dropwise in 30 minutes. Stir at the same temperature for 4.5 hours. Pour the reaction mixture onto ice and extract with ethyl acetate. The extract is washed with 10% sodium hydrogen carbonate, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 32.9 g of the desired compound as pale brown crystals.

(4) 3- (4-ethoxycarbonyl) piperazinyl-4-fluorine

To a suspension of 1-ethoxycarbonyl-4- (2-fluoro-5-diphenyl) perazine 1.5 g, methanol 5FD 1 and 6 ml of 35% hydrochloric acid was added iron at room temperature under stirring. Flour 1. Add Og in 15 minutes. Stir at room temperature for another 2 hours. Pour the reaction mixture onto ice, adjust the pH to 7-8 with 10% sodium bicarbonate, and extract with ethyl acetate. 10% extract After washing with sodium bicarbonate, wash with water and dry with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.32 g of the target compound as pale brown crystals.

(5) 3- (4-ethoxycarbonylbiperazinyl) -4-fluorophenylisothiocinate

3- (4-Ethoxycarbonyl) biperazinyl-4-fluoralineline In a solution of 2.68 g in 13 ml of toluene, stir at room temperature, 0.84 g of carbon disulfide and 1. lg of triethylamine in order. In addition, stir at room temperature for 12:00. The reaction mixture is cooled with ice water, and while stirring, 1.lg of triethylamine and 1.2 g of chlorocarboxylic acid ethyl ester are added to the mixture, and the mixture is stirred on an ice-ice bath for 3 hours. Dilute the reaction solution with water and extract with π-form. The extract is washed with 2% hydrochloric acid, washed forever, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a light brown residue. Purification by silica gel column chromatography gave 2.64 g of the target compound as colorless crystals.

(6) [3- (4-ethoxycarbonylperazinyl) -4-fluoro mouth phenyl] methyl methoxymethylthiomethylenemalonic acid

1 Powder hydroxide force Li © beam 0. 83 g, 4-Jiokisan 39m liquid suspended in l, at room temperature攢拌, was added dropwise Ma ¹ P phosphate Jefferies chill ester 2. Og, 1 hour攙拌I do. Then, add 1.94 g of 3- (ethoxycarbonylpiperazinyl) -4-fluorene fluorinated sothiocinate and stir at room temperature for 1 hour. The reaction mixture is cooled with ice and ice, and 0.72 g of chloromethyl methyl ether is added dropwise with stirring. Stir for 15 minutes at the same temperature and for 2 hours at room temperature. Water And extract with ether. Wash the extract with 1% hydrochloric acid, then wash with 10% sodium bicarbonate, wash forever, and dry with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.93 g of the desired compound as pale yellow crystals.

Melting point 104.0-; 105.0 to

Similarly, using dimethyl malonate in place of dimethyl malonate, [3- (4-ethoxycarbonylbiradizinyl) -4-fluorofluorophenyl] aminomethoxy having a melting point of 122 123 t was used. Methyl thiomethylene malonic acid dimethyl ester

1½ 0

Example 1

2-Methoxymethylthio-1-4-hydroxy 6-Fluoro D-7- (4-ethoxycarbonylbiperazinyl) -3-quinolinecarboxylic acid

[3- (4-ethoxycarbonylbiradinyl) -4-fluorophenyl] dimethylaminomethylthiomethylenemalonic acid dimethyl ester 2.50 g and diphenyl ether 7.5 rol mixture at 170: 1 Stir for hours. The reaction solution is cooled to room temperature, 10 ml of n-hexane is added, and the mixture is cooled with ice water for 1 hour. The precipitated crystals were collected, washed with n-hexane, and dried under reduced pressure to obtain 1.99 g of the desired compound as pale yellow crystals.

Mp 156.0 at 157.5.

The following compound was obtained in the same manner.

Example 2

2-methoxymethylthio-1-hydroxy-6-fluoro 7-(· 4 2-ethoxycarbonyldibiperazinyl) _3-quinolinecarboxylic acid methyl ester

Melting point 161 ~: at 162.5

Elemental analysis planted (C ₃₀ H: as PN _{3 (3} ₆ S)

Theory «C: 52.97 H: 5.33 N: 9.27

Actual measurement (50 C: 53.04 H: 5.56 N: 9.31

The invention's effect

In the present invention, by using [II] as a raw material, by-products are not generated, the reaction proceeds almost quantitatively, and the target compound can be obtained in an extremely high yield and purity. In addition, the raw material for obtaining [I] can be produced at very low cost and at low cost compared to the conventional method. Therefore, the present invention provides an industrially advantageous medium body and is a very useful production method.

Claims

The scope of the claims

The following general formula (I)

R

A quinoline carboxylic acid derivative represented by the formula:

Here, in the formula, R ¹ represents an aryl or low-alkyl, R ² represents a protecting group for a nitrogen atom, and R ³ represents a protecting group for a sulfur atom.

2. The following general formula [Π]

[E]

Subjecting the dialkyl malonate represented by the formula to the closed it reaction:

R ² —

A method for producing a quinoline carboxylic acid derivative represented by the formula:

In the formula, represents hydrogen or lower alkyl, R ² represents a protecting group for a nitrogen atom, and R ³ represents a protecting group for a sulfur atom.