KR890001997B1 - Process for the preparation of halogenation benzoic acid derivatives - Google Patents

Abstract

2,4-Dihalo-5-fluorobenzoic acid derivatives of formula (I) [X=halogen atom; Y=hydroxy or C1-5 alkoxy , useful as intermediate in synthesizing various quinolone compounds were prepared with 2,4- dichloro-5-methylaniline as starting material.

Description

Process for preparing halogenated benzoic acid derivative

The present invention relates to a method for producing a halogenated benzoic acid derivative, and more particularly, to a method for preparing 2.4-dihalo-5-fluoro benzoic acid and derivatives thereof represented by the following structural formula (I).

In the above structural formula, X is a halogen group element, Y is a hydroxyl group or an alkoxy group having 1-5 carbon atoms.

The halogenated benzoic acid derivative of the above formula (I) is an intermediate compound which is useful for preparing various quinolone-based chemotherapeutic agents having excellent antimicrobial activity against gram-positive bacteria and gram-negative bacteria, and various preparation methods have been proposed in the past.

For example, in European Patent No. 0.078.362, halogenation of Structural Formula (I) is carried out using 2.4-dichloro-5-methylaniline as a starting material and undergoing four steps such as diazotization, fluorination, chlorination, and hydrolysis. A benzoic acid derivative is prepared.

However, this reaction process is not easy to prepare the starting material 2.4dichloro-5-methyl aniline, and furthermore, the process of chlorination photoreaction of the methyl group under ultraviolet light is not suitable for industrial purposes, there was a problem of lack of economic efficiency.

In addition, Zh. obshch. Khim 32,3131 (1962) describes a process for preparing 2.4-dihalo-5-fluoro acetophenone by condensing 2.4-dihalo fluorobenzene in the presence of anhydrous acetic acid and aluminum chloride to introduce an acetyl group at the 5-position. have.

Although this reaction process is relatively simple as a one-step process, it has been difficult to go through several fluorine introduction processes to obtain a reaction starting material.

Accordingly, an object of the present invention is to solve the above-mentioned problems of the prior art, and to provide a new method for preparing a high purity target compound in high yield.

Hereinafter, the present invention will be described in detail.

The present invention relates to a halogenated benzoic acid of the following structural formula (I) and a fluid thereof, wherein the compound of the following structural formula (II) is converted into a compound of the following structural formula (III) by diazotization and a fluorination agent, and then subjected to a high temperature decomposition reaction. It is a manufacturing method.

In the above structural formula, X is a halogen group element, Y is a hydroxy group or a lower alkoxy group having 1-5 carbon atoms, and Z represents BF ₄ .

In more detail, the present invention can be represented by the following reaction route.

X, Y, Z in the above scheme is as described above. The 2.4-dichloro-5-nitro benzoic acid ester compound used as a starting material in the present invention is Helv. CHem. In Acta 40. 1187 (1957), a method for producing the same is known. In summary, when an ester of 2.4-dichlorobenzoic acid, which is industrially mass-produced by halogenation of benzoic acid, is nitrated with a mixture of nitric acid and sulfuric acid under appropriate conditions, The starting materials of the invention can be readily obtained.

At this time, the substituent Y of the compound of formula (II) may be an organic acid salt forming group other than a hydroxy group and a lower alkoxy group, and may be a lower alkyl group having 1 to 5 carbon atoms, or a halogen group element such as chlorine or bromine.

In the reduction of 2.4-dihalo-5-nitro benzoic acid ester as a starting material of the present invention, there can be various reducing agents that can be generally thought of, but Fe + HC1, Sn + HC1 and the like show cheap and mild reaction conditions. Highest in yield.

The amine group formed by the reduction reaction is subjected to diazoation or other similar reactions such as triagen, and the like, which is a compound of the formula (III), which is a compound of the formula (III), respectively, which is represented by a fluorinating agent such as hydrofluoric acid, boric fluoride, fluorosilicate, or fluoric acid. It becomes a zonium salt.

At this time, in the compound of formula (III), Z may be PF ₆ group, SiF ₆ group, fluorine and other fluorinable atomic groups in addition to BF ₄ group, and these compounds may be very stable and liberated in a solid state, and may be appropriately inert. When heated in a solvent, in a solid state, or in a solution state, it decomposes to form a corresponding fluorine derivative while releasing nitrogen gas or the like.

The temperature of the pyrolysis reaction is suitably about 100 to 200 ° C.

In the present invention, when the compound of formula (I) is a fluorinated benzoic acid ester, it can be easily converted to 2.4-dihalo-5-fluorobenzoic acid by alkali hydrolysis of the compound and then making the pH acidic.

Hereinafter, the present invention will be described in detail by way of examples. However, the present invention is not limited only to these examples.

Example 1

2.4-dichloro-5-nitrobenzoic acid methyl ester (25.0 g) was dissolved in methyl alcohol (100 ml), distilled water (10 ml), hydrochloric acid (1.0 ml) and iron (50 g) were added thereto, and the mixture was stirred under reflux for 5 hours. And excess iron was filtered off and the solution was evaporated to dryness and then recrystallized from alcohol to give 2.4-dichloro-5-amino benzoic acid methyl ester (20.4 g). (Yield 92.7%) Melting Point: 103-104 degrees Celsius.

NMR (CDCL ₃ δ); 3.9 (S, 3H, -CH ₃ ), 4.2 (S, 2H, -NH ₂ ), 7.2 (S, 1H, aromatic-H), 7.3 (S, 1H, aromatic-H) 1R (KBr, Cm-1 ); 3440,3350,2850,1700.

Example 2

2.4-dichloro-5-amino benzoic acid methyl ester (20.0 g) was added to a mixture of water (100 ml) and concentrated hydrochloric acid (25 ml), followed by dropwise addition of a solution of nitrous acid (6.4 g) in a small amount of water dropwise. Keep below 5 ° C. After stirring at the same temperature for 30 minutes, a solution of boric acid (5.8 g) dissolved in 50% hydrofluoric acid (17.3 g) is added at 10 ° C or below, and then stirred at a temperature for 1 hour.

The resulting crystals were filtered, washed with water, methyl alcohol, ether, and then dried under reduced pressure for 10 hours to obtain 2.4-dichloro-5-methoxy carbonyl benzene diazoniumtetrafluoroboric acid (27.2 g). (Yield 93.8%) Melting Point: 165 占 폚 (Decomposition).

NMR (DMSO d ₆ , δ); 3.8 (S, 3H, -CH ₃ ), 6.95 (S, 1H, C ₃ -H), 8.8 (S, 1H, C ₆ -H) 1R (KBr, Cm ^-1 ); 3450,3100,2250,1730.

Example 3

When 2.4-dichloro-5-methoxycarbonyl benzene diazonium tetrafluoroboric acid (21.4 g) is transferred to a suitable decomposition vessel and heated to 160 ° C., the compound slowly decomposes, generating nitrogen and BF ₃ gas.

When the internal temperature is slowly raised to about 180 ° C., the decomposition reaction is completed, and the contents are vacuum distilled to obtain pure 2.4-dichloro-5-fluorobenzoic acid methyl ester (13.9 g). (Yield 92.8%) Boiling Point: 140-146 ° C (10mmHg)

NMR (CDCL _3, δ); 3.9 (S, 3H, -CH ₃ ), 7.5-7.8 (t, 2H, aromatic-H).

Example 4

2.4-dichloro-5-fluoro benzoic acid methyl ester (13.3 g), water (50 ml) and caustic soda (7.2 g) were allowed to undergo a Hallyu reaction for 4 hours, then cooled to room temperature and acidified with dilute hydrochloric acid to form crystals.

The mixture is filtered, washed thoroughly with water and dried in vacuo to yield 2.4-dichloro-5-fluoro benzoic acid (12.0 g). (Yield 95.7%) Melting Point: 141-143 占 폚.

NMR (DMSO d ₆ , S); 7.8 (d, 1H, C ₆ -H), 7.9 (S, 1H, C _3-H ),

1R (KBr, Cm ⁻¹ ); 3000,1700.

Claims (3)

A process for preparing a halogenated benzoic acid or a derivative thereof of the following formula (I), wherein the compound of the following formula (II) is subjected to a diazotization and a fluorinating agent to change the compound of the following formula (III) and then subjected to high temperature decomposition.

In the above structural formula, X is a halogen group element, Y is a hydroxyl group or an alcohol group having 1-5 carbon atoms, and Z is a BF ₄ group. The method of claim 1, wherein the thermal decomposition reaction of the compound of formula III is carried out at 100 ° -200 ° C. The method of claim 1, wherein the compound of formula (II), which is a starting material, uses an ester compound wherein Y is an alkoxy group having 1-5 carbon atoms.