KR890004198B1 - Process for preparing 3-pyridine propanoic acid derivatives - Google Patents

Abstract

A process for prepg. 3-pyridine propionic acid derivs. of formula (I) comprises (a) reacting 2,6-dichloro-5-fluoronicotinate nitrile with piperazin derivs., (b) addn.-reacting with bromoacetate ester in the presence of dipositive metal i.e. Mg, Zn, Cu, and (c) hydrolyzing. In (I), R1=H or C1-6 lower alkyl; R2=H or C1-4 lower alkyl or acetyl. (I) are useful for the prepn. of 1,8-naphthylridine which has an antibacterial activity.

Description

Method for preparing 3-pyridine propionic acid derivative

The present invention relates to a method for producing a 3-pyridine propanoic acid derivative represented by the following structural formula (I).

In the above formula, R ₁ represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R ₂ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms or an acetyl group.

Compounds represented by the above formula (I) are known to be useful for preparing 1,8-naphthyridine derivatives that exhibit excellent antimicrobial activity.

German Patent Publication No. 3,514,076 proposes a method for preparing a 3-pyridine propionic acid derivative represented by the above general formula (I), which is firstly a 2,6-dichloro-5-fluoro nicotinyl chloride. To condensation reaction with ethyl malonate in the presence of magnesium, followed by hydrolysis to decarbonation, followed by reaction with an amine to prepare the compound of formula (I). However, this method has a disadvantage in that the reaction step is long in preparing 2,6-dichloro-5-fluoro nicotinyl chloride used as a starting material, and the manufacturing process is complicated and thus it is uneconomical.

That is, 2,6-dichloro-5-fluoro nicotinyl chloride used as a starting material in the German Patent Publication is prepared by chlorination of 2,6-dichloro-5-fluoro nicotinic acid. In general, however, in preparing a pyridine compound in which a carboxylic acid group is substituted, such as 2,6-dichloro-5-fluoronicotinic acid, in the case of synthesizing a pyridine ring directly from the compound, Since the carboxylic acid group may be decomposed, the carboxylic acid group had to be introduced through a complicated process such as synthesizing a cyclic compound substituted with ester, amide or methyl, and then hydrolyzing or chlorinating the compound. . Therefore, since the 2,6-dichloro-5-fluoro nicotinyl chloride can be obtained by chlorination of the substituted nicotinic acid compound prepared through the complicated process as described above, of course, the entire reaction step is lengthened and prepared. There was a problem that the process is also complicated.

Accordingly, the present inventors have diligently studied to solve the above conventional problems, and as a result, 2,6-dichloro is substituted for the 2,6-dichloro-5-fluoro-nicotinyl chloride used as a starting material in the conventional method. The use of -5-fluoro-nicotinic acid nitrile has led to the present invention by finding a method for preparing the 3-pyridine propionic acid derivative of formula (I) in a simpler and more economical way.

That is, an object of the present invention is to provide a method for producing a derivative of 3-pyridine propionic acid represented by the above formula (I) in a more economical and simple process.

Hereinafter, the present invention will be described in detail.

The present invention reacts 2,6-dichloro-5-fluoronicotinic acid nitrile represented by the following structural formula (II) with a piperazine derivative to prepare a compound represented by the following structural formula (III), and then adds bromoacetic acid to this compound. It is characterized in that the ester is added to react with +2 in the presence of a metal, and hydrolyzed to prepare 3-pyridine propionic acid derivative represented by the following structural formula (I).

In the above formulas, R ₁ and R ₂ are as described above.

Referring to the present invention in more detail as follows.

In the method for preparing a compound represented by the general formula (III) from the compound represented by the above formula (II), such a reaction is carried out by the nicotinic acid natril compound represented by the above formula (II) ethanol, acetonitrile, dioxane, Reacted by mixing with a suitable piperazine derivative in an inert solvent such as dimethylformamide, dichloromethane, detrahydrofuran, benzene, toluene, xylene or ether, at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. At a temperature of < RTI ID = 0.0 > ° C., ≪ / RTI >

The nicotinic acid nitrile compound represented by Structural Formula (II) used as a starting material in the present invention can be prepared and used, for example, by the method proposed in Japanese Patent Application Laid-Open No. 57-72981, which is represented by the following scheme. .

In addition, since nitrile is generally stable unlike carboxylic acid or acid chloride, the nicotinic acid nitrile compound represented by Structural Formula (II) may be prepared directly from a reactant having a nitrile group when synthesizing a pyridine ring as shown in the following scheme. This method is the technique described in Applicant's patent 26838.

Here, the mixing method of the raw material compounds may be any method, but in particular, it is preferable to add the compound of the structural formula (II) dropwise to the piperazine derivative solution, wherein the amount of the piperazine derivative is used as the raw material of the structural formula (II). Although one equivalent is sufficient for one equivalent of the compound, in order to neutralize the hydrogen chloride generated during the present reaction, it is generally preferable to use two equivalents or more, and in some cases, tertiary amines such as triethyl amine and pyridine, potassium carbonate, Inorganic salts such as sodium carbonate, potassium hydroxide and sodium hydroxide may also be used.

In addition, the piperazine derivative used in the reaction preferably has one nitrogen atom having a suitable protecting group, which protecting group can be removed without breaking the structure of the compound formed by the reaction of the present invention. Examples thereof include formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, benzyloxy carbonyl, p-methoxy benzyloxycarbonyl, tert-butoxycarbonyl, vinyloxycarbonyl, β substituted carbonyl groups such as-(p-toluene sulfonyl) ethoxycarbonyl, triphenylmethyl (ie trityl), trimethylsilyl, trilower alkyl silyl groups such as tert-butyldimethylsilyl, p-toluene sulfonyl group , o-nitrophenylsulphenyl group, or diphenyl phosphinyl group. Among the preferred protecting groups are groups that can be readily hydrolyzed, such as acetyl, trifluoro acetyl and ethoxycarbonyl groups.

Further, in preparing the compound of formula (I), which is the target compound of the present invention, from the compound of formula (III), the reaction solvent is an aromatic hydrocarbon such as benzene, toluene, xylene, dioxane, tetrahydrofuran, diethylene It is preferable to use ethers such as glycol and 1,2-methoxyethane, and the reaction temperature at this time is not particularly limited, but a temperature of 20 ° C to 180 ° C is particularly preferable. In the present invention, the compound of formula (III) is reacted in the solvent with +2 in the presence of a metal to prepare the compound of formula (1), wherein +2 is selected from zinc, magnesium or copper as the metal. Good to do.

Yield in the reaction is somewhat changed according to the mixing method of the raw material, as soon as the bromoacetic acid ester is slowly added dropwise to the solvent being heated to the above temperature to produce a metal alkylate of the formula (III) Most preferred is reacting with the compound.

As such, the bromoacetic acid esters used in the present invention preferably use lower alcohols having 1 to 6 carbon atoms, in particular methyl, ethyl, isopropyl or tert-butyl alcohol, in which the alcohol moiety of the ester is generally 1 to 6 carbon atoms.

Then, when the compound prepared by the above method is diluted with inorganic acid such as hydrochloric acid, acetic acid or sulfuric acid, and then added to the reaction solution, hydrolysis occurs and ammonia is generated. In this case, the target compound of Structural Formula (I) The compound can be extracted from the reaction solution in a conventional manner using a suitable solvent or precipitated in water to obtain a solid phase.

Hereinafter, the present invention will be described in detail with reference to Examples.

EXAMPLE

Example 1: Preparation of 6- (4-acetyl-1-piperazinyl) -2-chloro-5-fluoro-β-oxo-3-pyridine propionic acid ethyl ester

17.2 g (0.2 mole) of piperazine was suspended in 50 ml of dichloromethane and the solution was cooled to a temperature of 10 ° C. using a water bath, and then 19.1 g of 2,6-dichloro-5-fluoronicotinic acid nitrile was added thereto. The solution dissolved in 50 ml was slowly added dropwise and stirred for about 2 hours, followed by the addition of 20 g (0.2 mole) of acetic anhydride and 30 g of potassium carbonate. Then, the solution was stirred for 1 hour, and then 200 g of ice water was added thereto to separate the organic layer, and the aqueous layer was extracted twice with dichloromethane and then mixed with the separated organic layer and washed with water. Then, dried over anhydrous forget-me-not, filtered and distilled under reduced pressure, and then recrystallized from ethanol to give 25.4 g of 6- (4-acetyl-1-piperazinyl) -2-chloro-5-fluoronicotinic acid nitrile (yield) ; 90%).

117 g (1.8 mole) of a compound obtained in the above manner and zinc metal were added to 400 ml of benzene, and heated to reflux. Then, 40 g (0.27 mole) of bromoethyl acetate was slowly added dropwise thereto, followed by heating to reflux for 10 hours. Acetic acid was added to hydrolyze. The solution was then filtered to remove unreacted zinc and the filtrate was washed with water and ethyl acetate, extracted three times with ethyl and then again with water and dried over anhydrous forget-me-not.

This was filtered and distilled under reduced pressure to obtain 27 g of the target compound in the solid phase (yield: 81%).

Example 2

Preparation of 2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) -β-oxo-3-pyridine propionic acid ethyl ester

17.2 g (0.2 mole) of piperazine was suspended in 50 ml of dichloromethane, and the solution was cooled to a temperature of 10 ° C. using a water bath, and then 19.1 g of 2,6-dichloro-5-fluoronicotinic acid nitrile was added thereto. The solution dissolved in 50 ml of methane was slowly added dropwise and stirred for about 2 hours, followed by addition of 37.8 g (0.3 mole) of dimethyl sulfate and 30 g of potassium carbonate. Then, the solution was stirred for 1 hour, 200 g of ice water was added thereto to separate the organic layer, and the aqueous layer was extracted twice with dichloromethane and mixed with the separated organic layer. It was washed with water, dried over anhydrous forget-me-not, filtered and distilled under reduced pressure, and then recrystallized from ethanol to give 23.0 g of 2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinic acid nitrile ( Yield: 90%).

117 g (1.8 mole) of a compound obtained in the above manner and zinc metal were added to 400 ml of benzene, heated to reflux, and then heated to reflux for 40 hours with 40 g (0.27 mole) of ethyl bromoacetate slowly added thereto. Hydrolysis was performed by adding 10% acetic acid. The solution was then filtered to remove zinc that remained without reaction.

After washing with water and ethyl acetate, the filtrate was extracted three times with ethyl acetate, washed again with water and dried over anhydrous forget-me-not.

The resulting solution was filtered and distilled under reduced pressure to give 23.7 g of the target compound as a solid (yield: 76.6%).

Claims (4)

In preparing a 3-pyridine propionic acid derivative, a compound represented by the following structural formula (II) is prepared by reacting 2,6-dichloro-5-fluoro nicotinic acid nitrile represented by the following structural formula (II) with a piperazine derivative. A bromoacetic acid ester is added to the compound in the presence of a +2 metal to react with the compound and hydrolyzed to produce the 3-pyridine propionic acid derivative represented by the following structural formula (I).

In the above formula, R ₁ represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R ₂ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms or an acetyl group. The method of claim 1 wherein the +2 metal is selected from zinc, magnesium and copper. The piperazine derivative formyl or acetyl, trifluoro acetyl, ethoxycarbonyl, benzyloxy carbonyl, p-methoxybenzyloxy carbonyl, tert-butoxy carbonyl, vinyloxy carbonyl having a protecting group β- (p-toluenesulfonyl) ethoxy carbonyl, triphenylmethyl, trimethylsilyl, tert-butyldimethylsilyl, p-toluene sulfonyl, o-nitrophenylsulphenyl or diphenyl phosphinyl Characterized in that the method. The method of claim 1 wherein the bromoacetic acid ester is characterized in that the alcoholic portion of the ester is methyl, ethyl, isopropyl or tert-butyl alcohol.