DE3912263C2 - Process for the preparation of halogenated benzoic acid derivatives - Google Patents

Description

The present invention relates to a method for producing benzoin acid derivatives that are valuable intermediates for antibacterial synthesis highly effective quinolone carboxylic acids after the cycloaracylation process represent, for example, in the following patent applications be be written: DE 34 20 743 A1, EP 183 129 A1 and EP 184 035 A1.

The valuable intermediate 3-chloro-2,4-5-trifluorobenzoyl chloride can about a chlorination of 2,4,5-trifluorobenzoic acid can be produced. Disadvantageous in this process is that this is a mixture of nuclear chlorinated benzoin acids are formed, from which the 3-chloro-2,4,5-trifluoro after work-up benzoic acid must be isolated by repeated recrystallization. (DE 34 20 796 A1).

Another process describes the preparation of 3-chloro-2,4,5-trifluoro benzoyl chloride from 3-chloro-4-fluoro-aniline via an 11-step process. The disadvantage is the cumbersome way, in which a few steps moreover only with poor yield (European patent application 183 129). A an analogous process concerns the production of 3-bromo-2,4,5, trifluor benzoyl chloride (EP 183 129 A1). 2,3,4,5-tetrafluoro Benzoic acid is obtained from tetrachlorophthaloyl chloride (Zhurnal Obshchei Khimii 36, 139 [1966]), from tetrafluoroanthranilic acid (Bull. Chem. Soc. Jap. 45, 2909 [1972]) or from tetrafluorobenzene (Tetrahedron 23, 4719 [1967]); Z, Naturforsch, 31 B, 1667 [1976]) produced by sometimes complex steps.

A third process describes the preparation of 3-chloro-2,4,5-trifluorobenzoyl fluoride starting from 2,4-dichloro-5-fluorobenzoic acid (DE 36 31 906 A1, page 6, formulas lines 15-35) according to the following equation:

The acid chloride can be prepared from the acid fluoride with SiCl _{4 by known processes.}

It has now been found that starting from 2,4-dichloro-5-fluoro benzoic acid or even starting from 2,4-dichloro-5-fluorobenzoyl chloride under certain conditions the chlorine in 3-position also directly through the core can introduce chlorination with high selectivity.

The invention relates to a process for the preparation of 2,3,4-trichloro 5-fluorobenzoic acid or benzoyl chloride, which is characterized in that one 2,4-dichloro-5-fluorobenzoic acid or benzoyl chloride with the 1- to 20 times the molar amount of chlorine chlorinated, namely 2,4-dichloro-5-fluorine benzoic acid in the melt under pressure and / or in a solvent, in Presence of iodine and at 20 to 100 ° C and 2,4-dichloro-5-fluorobenzoyl chloride without solvents, in the presence of Friedel-Crafts catalysts and at 50 up to 150 ° C.

The starting compounds 2,4-dichloro-5-fluorobenzoic acid or benzoyl chloride are known from DE 36 31 906 A1 and DE 31 42 856 A1.

In the case of 2,4-dichloro-5-fluorobenzoic acid, the solvent z. B. chlorine sulfonic acid or oleum used and preferred at a temperature between 50 and 60 ° C are chlorinated.

In the case of the acid chloride, the Friedel-Crafts catalyst used is preferably Fe and / or FeCl ₃ . The temperature is preferably kept between 80 and 120 ° C. and particularly preferably between 95 and 105 ° C. during the chlorination. To accelerate the reaction, it is also possible to work under increased pressure.

The amounts of catalyst are adjusted as follows:

Fe 1 to 10% by weight FeCl ₃ 1 to 10% by weight Fe / FeCl ₃ 1 to 10% by weight (any ratio) iodine 1 to 10% by weight

Based on 1 mole of 2,4-dichloro-5-fluorobenzoic acid or benzoic acid chloride, 1 to 2 moles of Cl ₂ are preferably used for the chlorination.

The method of DE 34 20 796 A1 is in DE 36 31 906 A1 because of the unsatisfactory, selective chlorination rated as disadvantageous been. However, the process route disclosed here has another one great advantage (over the route described in DE 34 20 796 A1), the not yet clearly recognized at the time of application of DE 36 31 906 A1 was and therefore has not been named. Ultimately for the production of the valuable intermediate 3-chloro-2,4,5-trifluorobenzoyl mentioned above chloride necessary introduction of fluorine in the 2- and 4-position Chlorine / fluorine exchange with potassium fluoride can be achieved with 2,3,4-trichlorobenzoyl chloride much more easily and with better selectivity.

example 1

700 g (3.076 mol) 2,4-dichloro-5-fluorobenzoyl chloride (1) and 40 g Fe chips are presented and the mixture at approx. 20 ° C saturated with chlorine within approx. 10 min. The bath is heated with further introduction of chlorine within a further 10 minutes to approx. 80-95 ° C. the The reaction mixture is heated together with the heat tint kept at about 100 °. After total 300 g (4.2 mol) of chlorine were added within 5 hours will be in the cool-down phase, beginning at approx. 90 ° C, the unreacted chlorine due to Aus bubbles mostly removed with nitrogen. You get 780 g of a crude product which still contains approx. 41.5% starting material contains and approx. 48% of the desired 2,3,4-trichloro-5- fluoro-benzoyl chloride. That corresponds to a selectivi 82% with a turnover of 58.5%.

Of the undesired isomer 2,4,6-trichloro-5-fluoro Benzoyl chloride is only 0.7%. Since the 6 position in the In contrast to the 3-position due to the acid chloride group is activated, it will be found in the next level following fluorination in the case of the undesired iso A Cl / F exchange takes place in all positions, while with the 2,3,4-trichloro-5-fluoro-benzoyl chloride, as desired, the chlorine is obtained in the 3-position remain. With that the two connections are no more isomeric and can be separated by distillation. That at the Chlorination to approx. 2% resulting perchlorination pro duct 2,3,4,6-tetrachloro-5-fluorobenzoyl chloride can be Separate by distillation even before the fluorination. the other small amounts of by-products halobenzenes formed by decarbonylation which just like the starting material 2,4-dichloro-5-fluorobenzoyl let the chloride separate easily.

Example 2

52.5 g (0.25 mol) of 2,4-trichloro-5-fluorobenzoic acid and 52 ml of chlorosulfonic acid are heated to 50 ° -60 ° C., 1 g of iodine is added and then 17.75 g at 50 ° -60 ° C. (0.25 mol) Cl ₂ introduced. The duration of the experiment is 40 minutes.

Working up: For cooling, the mixture is poured onto approx. 200 g of ice, filtered off with suction, _{washed 3 × with H 2} O and dried at 60 ° in a high vacuum.

The yield is 55 g. (Mp. 122 ° -123 °)
60% educt (2,4-dichloro-5-fluorobenzoic acid)
40% product (2,3,4-trichloro-5-fluorobenzoic acid)

After conversion into the acid chlorides, Destil lation can easily be separated.

Half the batch size with the same amount of chlorine (100% excess) is obtained
27 g (m.p .: 130 ° C-140 ° C)
33% educt (2,4-dichloro-5-fluorobenzoic acid)
65% product (2,3,4-trichloro-5-fluorobenzoic acid)
2% dichlorinated product (2,3,4,6-tetrachloro-5-fluorobenzoic acid).

Example 3 (comparison)

25 g (0.133 mol) 2,4,5-trifluorobenzoyl chloride and 0.8 g FeCl ₃ subl. _{are presented, saturated with Cl 2 for} 10 min. at RT and chlorinated at 100 ° C.-110 ° C. within 6 hours.
Yield: 27 g.

Composition:
30% educt (2,4,5-trifluorobenzoyl chloride)
20% monochlorination product (2,4,5-trifluoro-3-chlorobenzoyl chloride
0.5% dichlorinated product (2,4,5-trifluoro-3,6-dichlorobenzoyl chloride) and other by-products.

The selectivity based on monochlorination is <29%.

To optimize the process according to the invention, the following reaction variants of Example 1 were carried out (50 g of starting material):

Claims (3)

1. A process for the preparation of 2,3,4-trichloro-5-fluorobenzoic acid or benzoyl chloride, characterized in that 2,4-dichloro-5-fluorobenzoic acid or benzoyl chloride is chlorinated with 1 to 29 times the molar amount of chlorine, namely 2,4-dichloro-5-fluorobenzoic acid in the melt under pressure and / or in a solvent, in the presence of iodine and at 20 to 100 ° C and 2,4-dichloro-5-fluorobenzoyl chloride without a solvent, in the presence of Friedel-Crafts catalysts and at 50 to 150 ° C. 2. The method according to claim 1, characterized in that the solvent Chlorosulfonic acid used. 3. The method according to claim 1, characterized in that there is used as Friedel-Crafts catalyst Fe, FeCl ₃ or a mixture of both.