KR950008528B1 - A process for the preparation of halogenated quinolone carboxylic acids - Google Patents

Abstract

The halogenated quinolinecarboxylic acid of formula(I) is used as an intermediate of antibiotic drugs. In the formula, R1 is C1-C4 alkyl, cyclopropyl, phenyl, 2-fluoroethyl, 4-fluorophenyl or 2,4-difluorophenyl; X1 halogen, specially Cl or F; and X2 hydrogen or halogen, specially F. The manufacturing method comprises :1) transforming aniline to formanilide through alkylation and formylation; 2) reacting the product with malonyl chloride or acetyl chloride deriv. at 80-100 degree C; and 3) cyclocondensing the product with sodium or potassium hydroxide solution to hydrolyse. This reaction condition is mild and total production yield is very high.

Description

Method for preparing halogenated quinoline carboxylic acid

The present invention relates to a process for the preparation of halogenated quinolinecarboxylic acids of the general formula (I), which are effective intermediates in the synthesis of medicaments with antimicrobial activity, and to novel intermediates useful in the preparation process.

Wherein R ₁ is alkyl having _1-4 carbon atoms, cyclopropyl, phenyl, 2-fluoroethyl, 4-fluorophenyl or 2,4-difluorophenyl, X ₁ is a halogen element, preferably chlorine or Fluorine, X ₂ is hydrogen or a halogen element, preferably fluorine

As a conventional technique for preparing the halogenated quinoline carboxylic acid, for example, the manufacturing process of British Patent No. 2057440 is shown as follows.

Wherein R ₁ is alkyl having 1-4 carbon atoms, cyclopropyl, phenyl, 2-fluoroethyl, 4-fluorophenyl or 2,4-difluorophenyl, X ₁ is a halogen element, X ₂ is hydrogen Or a halogen element.

However, the process is complicated by a four step reaction, yields 44%, very low compared to the method provided by the present invention, and involves vigorous reaction conditions during the cyclization reaction in step B (250-260). ℃). In addition, the overall reaction time (A stage: 2 hours, B stage: 1-2 hours, C stage: 10-15 hours, D stage: 2-3 hours) has a long disadvantage.

In contrast, the present invention prepares the target compound (I) in a substantially two step process. This is shown as follows.

Wherein R ₁ , X ₁ and X ₂ are the same as above, and X represents —COOCH ₃ or —CN.

The present invention also provides the desired compound (I) in high yield (70-85%: see Examples) even under mild reaction conditions.

That is, the present invention is completely different from the previous production method, and provides a method of producing the target compound in a short and easy yield and high yield under very mild conditions.

The configuration of the present invention in detail as follows. That is, the aniline derivative of the following general formula (II) is converted to the formanilide derivative of the following general formula (III), and then reacted with a malonyl chloride derivative or an acetyl chloride derivative of the following general formula (IV) to obtain a new intermediate. The compound of the following general formula (V) is obtained and subjected to a ring condensation reaction and a hydrolysis reaction to obtain a compound of the following general formula (I) as a target substance.

This is shown as follows.

Wherein X, X ₁ , X ₂ and R ₁ are as defined above.

The formanilide derivatives of the general formula (Ш) can be prepared from aniline derivatives of the general formula (II) by conventional methods such as alkylation and formylation. That is, the compound of general formula (II) can be prepared by treating with a suitable alkylating agent, followed by addition of excess formic acid (; formic acid) to formylate. In particular, when R ₁ is lower alkyl having ₁ to 4 carbon atoms, trialkyl ortho formate (where alkyl represents methyl, ethyl, propyl or butyl) and sulfuric acid are easily used in high yield in one process. It is possible to prepare a compound of formula (III).

Thus obtained compound of general formula (Ш) is 80-100 in the presence of phosphoryl chloride of general formula (IV), such as methyl malonyl chloride (X = COOCH ₃ ) or cyanoacetyl chloride (X = CN) Reaction at ℃ gives quantitatively new intermediates of the general formula (V), and the new intermediate compounds of the general formula (V) are treated with sodium hydroxide solution or potassium hydroxide solution without separate separation and purification process. By condensation reaction and hydrolysis reaction, halogenated quinoline carboxylic acid derivative (I) is obtained in high yield.

At this time, in the case of methylmalonyl chloride having X = COOCH ₃ in the general formula (IV), after stirring overnight at room temperature in the presence of sodium hydroxide solution or caloric hydroxide solution, the compound of general formula (I) is obtained in high yield. In the case of cyanoacetyl chloride having X = CN, an amide is formed at the 3-position of the compound of general formula (I) when reacted with sodium hydroxide or potassium hydroxide solution and hydrolyzed under acidic conditions to give the target compound (I). Can get

This is represented by the reaction mechanism as follows.

One). Reaction to produce general formula (I) in general formula (Ш).

i). If X = COOCH ₃

Wherein X, X ₁ , X ₂ and R ₁ are as defined above.

A characteristic feature of the present invention is that, in the preparation of the quinoline carboxylic acid of the general formula (I) from the aniline derivative of the general formula (II), the production process is very short in 2-3 steps, and the yield is high. Second, the reaction conditions are very mild in the whole manufacturing process, it is easy to separate and enter the target compound.

The invention is embodied in the following examples.

Example 1

One). A catalytic amount of concentrated sulfuric acid was added to a mixture of 5.0 g of 2,3,4-trifluoroaniline and 10.1 g of triethyl ortho formate and reacted at a temperature of 160 ° C. for about 5 hours. Ethanol produced during the reaction was distilled off. The reaction was cooled down and made basic with sodium hydroxide and then extracted with methylene chloride. The extract was washed with water, dried, filtered, concentrated under reduced pressure and purified by column chromatography as needed to obtain 5.8 g of N-ethyl-N- (2,3,4-trifluoro) formanile in 84% yield.

NMR (CD ₂ C _{1 2} ): 1.0-1.3 (t, 3H, -CH ₃ ), 3.5-3.8 (q, 2H, -CH ₂ ), 6.9-7.2 (m, 2H, aromatic), 8.1-8.3 (s , lH, aldehyde H)

2). 2.0 g of methyl malonyl chloride was added to a mixture of 5.6 g of N-ethyl-N- (2,3,4-trifluoro) formanilide and 13.4 g of phosphoryl chloride obtained in 1) above. The reaction was carried out at a temperature for about 1.5 hours. After the reaction was cooled and placed in an ice bath, about 100 ml of distilled water was added thereto, 10 ml of sodium hydroxide solution was added thereto to make basic, followed by stirring at room temperature overnight. The reaction product was filtered, the suspended solids were filtered and the filtrate was acidified with concentrated hydrochloric acid (catalyst amount; 0.1 ml). -Trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid was obtained (yield: 83%, mp; 262-266 ° C).

NMR (TFA-d): 1.5-1.9 (t, 3H, -CH ₃ ), 4.8-5.2 (q, 2H, -N-CH _2- ), 8.0-8.4 (m, 1H, aromatic), 9.3 (s , 1H, C ₂ -H)

Example 2

0.64 g of cyanoacetyl chloride was added to a mixture of 2.5 g of N-ethyl-N- (2,3,4-trifluoro) formanilide synthesized by the method of Example 1) and 5.7 g of phosphoryl chloride, It was made to react at 85 degreeC for about 1.5 hours. The reaction mixture was cooled, placed in an ice bath, about 50 ml of distilled water was added, 10 ml of sodium hydroxide solution was added thereto, and then stirred at room temperature overnight. After acidification by adding concentrated hydrochloric acid (catalyst amount; 0.1 ml) and stirring under reflux for 3-5 hours, the resulting solid was filtered, washed with distilled water and dried to give 2.4 g of 1-ethyl-6,7,8-tree. Fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid was obtained.

Yield: 72%

Claims (3)

A formanilide derivative of the following general formula (III) is prepared from an aniline derivative of the following general formula (II), and reacted with a compound of the following general formula (IV) to prepare an intermediate of the following general formula (V), followed by separation To prepare a halogenated quinoline carboxylic acid of the following general formula (I) through a condensation reaction and a hydrolysis reaction without purification. Wherein R ₁ is alkyl having 1-4 carbons, X ₁ is a halogen element, X ₂ is hydrogen or a halogen element, and X is —COOCH ₃ or —CN. The compound of formula (III) according to claim 1, wherein when R ₁ is alkyl having ₁ to 4 carbon atoms, aniline derivative of formula (II) is reacted with trialkyl orthoformate under sulfuric acid catalyst. A process for producing a halogenated quinoline carboxylic acid of formula (I), characterized in that the preparation. The process for producing a halogenated quinoline carboxylic acid of formula (I) according to claim 2, wherein the trialkyl ortho formate is triethyl ortho formate.