JP2853929B2 - Method for producing 2-chloro-4,5-difluoro-3-methoxybenzoic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 2-chloro-4,5-difluoro-3-methoxybenzoic acid which is a valuable intermediate for producing a novel quinolonecarboxylic acid having a methoxy group at the 8-position useful as a pharmaceutical. The present invention relates to a method for producing an acid.

[0002]

2. Description of the Related Art A quinolone carboxylic acid-based antibacterial agent having a methoxy group attached to the quinoline skeleton of a new quinolone-based synthetic antibacterial agent and having various antibacterial properties has been actively developed. (For example, Japanese Patent Application Laid-Open No. 62-252772).

A process for producing a valuable intermediate for producing these 8-methoxyquinolone carboxylic acids is disclosed in JP-A-64-46746, which discloses 4,5-difluoro-2-halogeno-3-methoxybenzoic acid. Is proposed. This is represented by the chemical formula, (Z and X each represent the same or different halogen atoms).

This method requires three steps in the process of converting a halogen atom represented by Z into a carboxylic acid, requires a large amount of treatment of a cyan waste liquid, and has a low total yield. Was not always satisfactory.

[0005]

Under such circumstances, the present inventors have studied to improve the above-mentioned invention, and as a result, have completed the present invention.

The present invention relates to a method for producing 2-chloro-4,5-difluoro-3-methoxybenzoic acid comprising the following steps. 1) 3-Bromo-2-chloro-5,6-difluoroanisole is reacted with magnesium to give a Grignard compound. 2) The obtained Grignard compound is reacted with carbon dioxide.

[0007]

According to the present invention, 2-chloro-chloroform is obtained at a much higher yield than the method described in JP-A-64-16746.
4,5-difluoro-3-methoxybenzoic acid can be produced.

In the first step, 3-bromo-2-chloro-5,
The reaction between 6-difluoroanisole and magnesium is
For example, it is preferable to carry out the reaction in a solvent such as tetrahydrofuran or ether at room temperature to 40 ° C. It is also preferable to add iodine or methyl iodide to promote the reaction. The obtained Grignard compound can be used in the next step without isolation and purification.

The reaction of the Grignard compound with carbon dioxide in the second step is preferably carried out by reacting the Grignard compound with carbon dioxide gas or dry ice in a solvent such as tetrahydrofuran or ether under cooling.
Since it is an exothermic reaction, it is particularly preferable to use dry ice. A method of adding the reaction solution after the first step to dry ice can also be used.

[0010]

EXAMPLES The present invention will be described in further detail below with reference to working examples according to the present invention as examples.

Example 1 2-chloro-4,5-difluoro-3-methoxybenzoic acid

To 10.20 g of magnesium was added 212 ml of tetrahydrofuran. 3-Bromo-2-chloro-5,6-difluoroanisole 10 with vigorous stirring
A small amount of a solution of 5.9 g of 106 ml of tetrahydrofuran was added dropwise, and the reaction solution was heated to 30 ° C. When the reaction started, the remaining solution was added dropwise at 30 to 35 ° C., stirred at the same temperature for 1 hour, and cooled with ice. 1 kg of dry ice is added to the reaction solution, and the mixture is further stirred. When dry ice disappeared, the reaction solution was poured into 1500 ml of water, 85 ml of 6N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain 89.37 g of the desired product.

122-127 ° C. NMR (δ in CDCl ₃ ): 4.03 (3H,
d, J = 1.6 Hz), 7.56 (1H, dd, J =
8.0, 10.1 Hz), 11.46 (1H, s)

The starting material, 3-bromo-2-chloro-
5,6-Difluoroanisole can be synthesized from 2,3,4-trifluoroaniline, which is widely used as a raw material for quinolone carboxylic acid, through three steps.

Reference Example 1 6-bromo-2,3,4-trifluoroaniline

2,3,4-trifluoroaniline 147
g was dissolved in 700 ml of glacial acetic acid.
g of acetic acid in 160 ml was added dropwise at 40 ° C. for 1 hour. After the reaction solution was stirred at room temperature for 1 hour, it was poured into 2 L of ice water, and the precipitated crystals were collected by filtration.
The extract was washed successively with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate and concentrated to give the target compound 21 as pale brown crystals.
8.1 g were obtained.

Melting point 58-59 ° C. NMR (δ in CDCl ₃ ): 7.10 (ddd,
J = 2.6, 7.4, 9.2 Hz)

Elemental analysis value (%): C ₆ H ₃ BrF ₃ N Calculated value: C; 31.98, H; 1.34, N;
20 found: C; 31.85, H; 1.38, N;
33

Reference Example 2 1-bromo-2-chloro-3,4,5-trifluorobenzene

213 g of 6-bromo-2,3,4-trifluoroaniline and 152 g of anhydrous cupric chloride are added to 800 ml of anhydrous acetonitrile, and while stirring, 116 g of t-butyl nitrite is added thereto at 45-47 ° C. and 30 ° C. Dropped in minutes. After stirring in a greenhouse for 30 minutes, the reaction solution was poured into a dilute aqueous hydrochloric acid solution, and the precipitated oil was extracted with petroleum ether. The organic layer was washed successively with dilute hydrochloric acid, water and an aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate and concentrated. The residue was purified by distillation to obtain 150.9 g of the desired product.

Melting point 82-83 ° C./30 mmHg NMR (δ in CDCl ₃ ): 7.34 (ddd,
J = 2.2, 7.0, 9.2 Hz)

Reference Example 3 3-Bromo-2-chloro-5,6-difluoroanisole

170.1 g of 1-bromo-2-chloro-3,4,5-trifluorobenzene was added to 1 L of anhydrous methanol solution of sodium methoxide, and the precipitated oil was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated, and the residue was purified by distillation to obtain 142.2 g of the desired product.

Boiling point 95-108 ° C./13 mmHg NMR (δ in CDCl ₃ ): 4.02 (3H,
d, J = 1.8 Hz), 7.24 (1H, dd, J =
7.4, 9.2 Hz)

The 2-chloro-produced according to the invention
4,5-Difluoro-3-methoxybenzoic acid can be converted to industrially useful 8-methoxyquinolone carboxylic acid according to the following steps.

[0026]

────────────────────────────────────────────────── (5) References JP-A-64-16746 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07C 65/21 C07C 51/15 CAOLD (STN ) CAPLUS (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. 2-chloro-4,5 comprising the following steps:
A method for producing difluoro-3-methoxybenzoic acid. 1) 3-Bromo-2-chloro-5,6-difluoroanisole is reacted with magnesium to give a Grignard compound. 2) The obtained Grignard compound is reacted with carbon dioxide.