IE852380L - 2,4, - dichloro-5- fluoro- benzoic acid. - Google Patents

Abstract

1. Pocess for the preparation of 2,4-dichloro-5-fluoro-benzoic acid of the formula (I) see diagramm : EP0176026,P5,F1 characterized in that 2,4-dichlorofluorobenzene is reacted with acetyl chloride, in the presence of acylation catalysts an optionally in the presence of diluents, at temperatures between 108C an 1508C and the reaction product, 2,4-dichloro-5-fluoro-acetophenone of the formule (II) see diagramm : EP0176026,P5,F2 formed in this way is, if appropriate after isolation, reacted with a sodium hypochlorite solution (in the form of the so-called chlorinated soda solution) at a temperature between 08C and 1408C and the compound of the formula (I) is isolated by conventional methods. [EP0176026A1]

Description

72493 *3} The present invention relates to a new process for the preparation of 2,4-di ch loro~5~f luoro-bensoi c acid, which is an intermediate product tor the preparation of en bacterial agents.

It is already known that trihalogenobenzoic acids can be prepared by saponification of a trihalogeno-tri-halogenoraethyl-benzene. Thus, 2,4-dichloro-5-fluoro-benzoi c acid is formed in the saponi fi cation of 2^4-di-eh loro-5-f luoro-t ri eh lorossethy Ibensene (EP-OS (European Published Specification) 78,362).

It is also known that acylation with aliphatic carboxy lie acid ha Ii des is very difficult in the esse of dihalogenobenzenes, and it is said that it does not proceed in the ease of trihalogenobenzenes Cconpared Methoden der organischen Cheaie CMethods of organic chemistry! {Houben-Weyl-Huller> Volume 7(2a, 43 (1973), Thieae-Verlag Stuttgart).

In addition,? it is known that 2,4-di chloro-5-fluoro-acetophenone is obtained in poor yield from 2,4-di ch lorof luorobenzene in the acylation with carboxyli c acid anhydr i des, such as, for exatnp le, acetic anhydride,? in the presence of aluminium trichloride (cotapa re CA 58, 11243 g)» Surprisingly, it has now been found that 2^4-di chloro-5-fluoro-benzoic acid of the for*uI* CI) is obtained in very goad yield and high purity, when 2,4-dichlorofluorobenzene is reacted with acetyl ch lori de, in the presence of an acylation catalyst and optionally in the presence of a diluent, at temperatures between "20°c and 150°C and the react i on product, 2,4-di chloro-5-fluoro- 1 AQ% "1 & hj acetophenone of the f orsau La (IX) 21) formed in this way is, optionally after isolation, reacted with a sodium hypochlorite solution (in the form of the 5 so-called chlorinated soda solution) at a temperature between 0°C and 140°c..

Surprisingly, it is possible by means of the process according to the invention to effect an acylation of 2^4-dichLorofLuorobenssne with a carborcylic acid chloride, 10 in high yield and with a high selectivity, in the Beta-position relative to the more electronegative halogen* This is the more surprising since, according to the stats of the art, acylation in the ortho-position or para-position relative to the aore electronegative halogen was 15 to be expected in the acylation of halogenobenzenes (Methoden der organi schen Chemi e CMethods of organi c chemistry3 (Houben-Weyl~Muller> volume 7/2a 43 C1973), Th i ewe-Ve rIag, Stuttgart).

The abovementioned known processes have a number 20 of disadvantages. Thus, in the preparation of 2,4-di" chloro-5-fluoro-trichloronethylbenzene, a triazene, which is very difficult to handle because of its unfavourable physiological properties, is prepared as an intermedi ate product 25 Moreover, this process for the preparation of 2,4-dichloro~5-f luoro-benzoic acid requires several stages.

In the acylation, described in the literature, of 2,4-dichloro-5-f luorobenzene in the presence of acetic 30 anhydride, the yield of reaction product is very Lou. 2,4' •dichlorofluorobenzene and acetyl chloride as starting mat eri a Is, aluminium chloride as the cat aly s* and chlorinated soda solution are used, the reaction sequence can be reproduced by the following sat of equations: rci CI A CH3-CO-CI ^ICJ 3 > CI- CO-CH Ci 3 F F Chlorinated soda solution 1 CDOH * — 2^4-oichlorof luorobenzene is a known compound of organic chemi st ry.

The reaction temperature can be varied within a fairly wide range™ Thus, temperatures between 10°C ©nd 150°C, preferably between 20°C and 1I30°C#, in particular between 80°C and 130°c, are generally used in the acy~ lat i on. Th® subsequent oxi dat i on with the so-called chlorinated soda solution is in general carried out at tempera tures between 0°C and 140°C, preferably between 20°C and 120°C. In general,, the reaction is carried out under norma I pressure.

The process according to the indention is preferably carried out without a diluent,., Catalysts which can be used for the process according to the invent i on are a cy lat i on catalysts^ such as, for exaaple, ironCIU) chloride^ zinc chloride or aluminium chloride^ preferably aluminium chloride, sodium hypochlorite solution in water, can be used as the oxidising agent for the process according to the invention. i nvent i on, 11 to 3 mo I of acetyl chloride and 1 to 3 no I of aluminium chloride are in general emp loyed per II mo I of 2,4-dich lorofluorobenzene. After the reaction has ended, the reaction mi xtu r e is poured onto ice and taken So-called chlorinated soda solution, which is a When carrying out the process according to the up in a diluent which is insni scible with water,, such as# for exanp le, methylene chloride or chloroform., However, the reaction product can also be separated off without the use of diluents. If appropriate after reoovaI of the extraction agent, the residue is oxidised in the presence of 2 to 4 1, preferably H.1 to 3-3 1, of chlorinated soda solution (150 g of active chlorine/1) per no I of starting snaterial. Subsequent ly , the 2,4-di eh loro-5-f luoro-bensene acid is precipitated with a tai nera I acid, such as, for example, hydrochloric acid, and then filtered off with suction. readily accessible by the process according to the invention, can be used, for exaapIe, for the synthesis of anti-bacterial agents., Thus, substituted oxoquinoline-carboxy-lic acids, which are compounds of high bactericidal potency, can be prepared fro® this acid, for e xaap le in accordance with the following equations £ conpa re, for e xaaple, EP-OS (European Published Specification) 78,362): 2^4-Dichloro-5-fluoro-bansoic acid, which is 8 oc2H5 HC(0C?HO_3 > C1 // \YCO„(!_COOC2H5 Ci .CI CH -^3yC0-?-C00C2H5 fv^vA^C00C2H5 > JLC'f I CI COOH / "\ RN SMH v f OOH RM N A R H„ a Iky I Preparation Exsaplc 10 15 /T$ CI CIV \ V-COOH F- 4D 23, ,3 i In this way, 35.5 g (80% of theory) of 2,4-di-chloro-5-fluoro-benzoic ©cid are obtained as a colourless powder of aeIting point 139°C. 8

Claims (1)

Claims

1. - A process for the preparation of 2,.4-di ch loro-5* fluoro-benzoic acid of the fonula CI J;r* ii _^VCQ0H jt) —/ r which comprises reacting 2,4-dichlorofluorobenzene with acetyl chloride, in the presence of an acylation catalyst, at a temperature between 10°C and 150°C and reacting 2,4-dichloro-5-fluoro-acetophenone of the formula (II) 01 (II) 10 thereby obtained, optionally after isolation, with a sodium hypochlorite solution (in the form of the so-called chlorinated soda solution) at a temperature between 0°C and 140°C and isolating the compound of the formula (I) thereby obtained in conventional manner. 15 2„ A process according to Claim 1, wherein the acylation step is carried out in the presence of a diluent. 3. A process according to C lai a 1 or 2, wherein aluanniun trichloride is used as the acylation catalyst. 4. A process according to any one of Claims 1 to 3, 2o wherein the reaction with acetyl chloride is carried out at a temperature between 20°C and 130°C. 5. A process according to any one of Claims 1 to 4, wherein the reaction with the sodium hypochlorite solution Cch lor i nated soda solution) "Is carried out at a 25 temperature between 20°C and 120°c. 6 . A process according to any one of Claims 1 to 5, wherein the 2,4-dichloro-5-fluoro-acetophenone forced is, without isolation, reacted with the sodium hypochlorite solution (chlorinated soda solution). 7. A process according to Claim 1 for the preparation of 2f,4-dichloro~5-fluoro-benzoic acid? substantially as hereinbefore described with particular reference to the accompanying Preparation Example. 8. 2^4-Dichloro-5-fluoro-benzoic acid whenever prepared by a process claimed in a preceding claim. Dated this the 26th day of September, 19 85 F. R„ KEJ^fc/Z & // i EXECUTIVE 27 Clyde Road,/Ballsbridge, Dublin 4 AGENTS FOR TIJEf APPLICANTS