Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
33~
The present invention relates to a new process for
~he preparation of 2,4-dichloro-5-fluoro~benzoic acid,
~hich is an intermediate product for the preparation of anti-
bacterial agents~
It is already known that trihalogenobenzo;c acids
can be prepared by saponificat;on of a tr;haLogeno-tri-
halogenomethyl~benzene. Thus~ 2,4-dichloro-5-fluoro-
benzoic acid is formed ;n the saponi~;ca~;on of 2,4-di-
chloro-5-fluoro-trichloro~ethylben~ene (EP-OS (European
Published Specification) 78,36Z).
It is also kno~n that acylation with aliphat;c
carboxylic acid halides is very difficult ;n the case o~
dihalogenobenzenes, and it is said that it does not pro-
ceed in the case of trihalogenobenzenes (co~pared Methoden
der or~anisrhen Chem;e CMethods of or~anic chemistry~
(Houben~Weyl-Muller) Volume 7/2a, 43 t1973), Th;eme-Yerlag,
Stuttgart).
In addit;on, it i5 known that 2,4-dichloro-5-
fluoro-acetophenone ;s obtained in poor yield from 2~4-
20 dichLorofluorobenzene in the acylation ~ith carboxylicacid anhydrides, such as, for e~a~ple~ acetic anhydride,
in the presence of aluminium trichloride ~co~pare CA 58,
11243 ~
Surprisin3ly, ;t has no~ been found that 2,4~di-
chloro-5~fluoro~ben~o;c ~cid of th~ ~or~ul~
Cl ~ COOH lI)
is obtained in very 900d y;eld ~nd hi~h purity~ ~hen 2,4-
dichlorofluorobenzene is reacted ~;th acetyl chloride~
in the presence of acylation catalysts and optionally in
the presence of diluents, at temperatur~s between 10C
and 150C and the reaction product, 2~4--dichloro-5-fluoro-
Le A 23 3B5
~e
.. . . .
.
~5~33~
2 --
acetophenone of the for~ula ~II)
Cl
Cl ~ ~o-CH3 tII)
F
formed in th;s way ;s, optionally after ;solation, reacted
~;th a sod;um hypochlor;te solut;on (in the form of the
so-called chlorinated soda solut;on) at a temperature
between 0C and 140C.
Surprisingly, it is poss;ble by means of the pro-
cess according to the invention to effect an acylation of
2,4-dichlorofluorobenzene ~ith a carboxylic acid chloride,
in high yield and ~ith a high selectivity, in the m~ta-
position relative to the more electronegative halogen.
This is the more surprising since~ acrording to the
state of the art, acylation in th~ ortho-position or para-
posit;on relative to the ~ore electronegative halogen ~as
to be expected in the acylation of halogenoben~enes
~Methoden der organischen Chemie ~Methods of organic
chem;stry~ (Houben-Weyl-Muller~ volume 7t2a 43 (1973
Thieme-Verlag, Stuttgart).
The abovementioned known processes have a nu~ber
of disadvantages. Thus, in the preparation of 294-di-
chloro-5-fluoro-trichloromethylbenzene, a triazene, ~hich
is very difficult to handle because of its unfavourable
phys;olo~ical properties, ;s prepared as an înternediate
product~
~5 Moreover, this process for the preparation of
2,4-dirhloro-S-fluoro-benzoic acid requires several
sta~es.
In the acylation~ described in the literature, of
2,4-dichloro-5-fluorobenzene in the presence of acetic
anhydride, the yield of reaction product is very low.
If 2~4-dichlorofluoroben~ene and acetyl chloride
as startin0 materials, aluminium chloride as the catalyst
and chlor;nat*d soda solution are used~ the react;on
Le A 23 385
'' ~ ' `
.
' ' ~ '
3~3
-- 3 --
s~qu~nce can be reproduced by the following set of
~ua~ i OhS:
Cl~> + CH3-CO-CI AlC13 > [c~ CO-C~
Chlor;nated soda
solution ~ F ~ COOH
2,4 D;chlorofluorobenzene is a kno~n compnund of
organic chemistry.
The reaction temperature can be var;ed with;n ~
fairly wide range. ~hus, temperatures bet~een 10C and
150C, preferably bet~een 20C and 130OCD in particular
between 80C and 130c, are ~eneralLy used in the acy-
~ation. The subsequent oxidation ~ith the so-called chlo-
rinated soda solution is in general carried out at tempera-
tures bet~een 0C and 140C, preferably bet~een 20C
and lZ0C~ In general, the reaction is carried out
under normal pressure.
The process according to the invention is prefer-
ably carried out ~ithout a diluent.
Catalysts ~hich can be used for the process
according to the invention are acylation ca~alysts, sush
as, for example, irontIII) chloride~ zinc chlor;de or
Z0 aluminium chloride~ preferably alum;nium chloride.
So-called chLorinated soda solution~ ~hich ;s a
sodium hypochlorite solution in ~ater, can be used as the
oxidising a~ent for the process accord;ng to the inven-
tionO
~hen carry;ng out the process ac~ording to the
;nvention, 1 to 3 mol of acetyl chloride and 1 to 3 mol
of aluminium chloride are in general empLoyed per 1 mol
of 2~4-dichlorofluorobenzene. After the reaction has
ended, the reaction m;xture is poured onto ice and taken
L~ ~ 23_~85
- '
,
'
up in a diluent which is immiscible with ~ater, such as,
for example, methylene chloride or chloroform. However,
the reaction product can also be separated off ~ithout
the use of diluents If appropriate after re00val of the
extr~ction agent, the residue is oxidised in the presence
of 2 to 4 1, preferably 2.1 to 3.3 1, of chlo~;nated soda
solut;on (150 g of active chlor;ne/1) per mol of starting
mater;al. Subsequently, the 2,4-dichloro-5-fluoro-benzene
acid is precipitated with a m;neral acid, such as, for
example, hydrochloric ac;d~ and then f;ltered off with
suc~ion.
204-Dichloro-5-fluoro-benzoic acid, ~hich ;s
read;ly accessible by the process according to the inven-
tion~ can be used, for example, for the synthesis of anti-
bacterial agents. Thus, substi~ut*d oxoquinsline-carboxy-
lic acids, which are compounds of high bac~ericidal
potency~ can be prepared from this acid, for example in
accordance ~ith the follo~ing equations (compare, for
example, EP OS CEuropean Published Spec;f;cat;on) 78,362).
Cl ~ COOH SOCl~ > Cl ~ COCl CH2(COOC2HC)~ >
F F
F ~ C0-CH(COOC2Hs)2 > Cl ~ C0-CH2-COOC2Hs
Le A Z3 385
.. . .
::
.
.. ..
, .
.: .
3~
-- 5 --
OC 2H5
HC(OC2~s)3 > Cl~CO-~-COOC2H5 D~H2
HN~ o
Cl CH F~J~Cooc2H5
F~CO-~-COOC2H5 , !ICl~
~.
O ~ O
F ~ COOH RN ~H F - ~ ~COOH
Cl ~ r~~ / ~ N
~ RN~_~N
R = Ho alkyl
Cl
Cl ~ -COOH ~I)
23.6 9 ~0.3 mol) of acetyl chloride are added at
20C to 40C to a m;xture of 33 g (0.2 mol) of 204-
dichlorofluorobenzene and 66.8 ~ (0.5 mol) of aLum;n;um
chloride, ~nd the m;xture is then stirred for 2 hours at
120C. While still hot, the mixture is poured onto
250 9 of ice, and the o;l ~hich separates ou~ is taken up
in methylene chloride. The solvent is eYaporated off~
450 ~l of chlorinated soda solution ~150 9 of active
chlorine/13 are added to the residue and the m;xture ;s
first stirred for 1 hour u;thout heat;ng and then bo;led
for 2 hours under reflux. After the result;ng chloroform
has been separated off, 300 ml of water are added~ and the
Le A 23 385
33~)
/s
mlY~tUre lS treated ~ith 10 Ml of 40 ~ strength sodium bi-
su~pnile solution and then with concentrated hydrochloric
acid, until a pH value of 1 is reached.
I~l this way, 33.5 ~ (80X of theory) of 204-di-
chloro-5-fluoro~benzoic acid ar~ obtained as a colourless
po~der of melt;ng point 139C.
Le A 2~ 385
__.
,
:
3~2~
~,he e~ dimc-n~s of the inver~tion in which an e~clusiv~ prG~-rty
or privilege ~re clai~ed are defined as follows:
1- ~ compound of the formula:
R3 COR4
R ~ (
2 ~ COR4
[wherein n is an integer of 0 to 2; Rl and R3 which may be
the same or different each represents a hydrogen atom, a
halogen atom, a lower alkyl group, a lower alkoxy group or
a nitro group; R~ ;.s a hydroxyl group or the group -NHZ (Z
is a hydro~en atom or a lower alkyl group), e~cepting both
the case where n i5 0 or 1, any one of Rl to R3 is 5-chloro,
5-methoxy or 5~nitro and the remainder is a hydrogen atom,
and R4 is a hydroxyl group, and the case where n is 0 or 1,
any two of Rl to R3 axe 3,5-dichloro or 3,5-dinitro and the
remainder is a hydrogen atom, and R4 is a hydroxyl group]
or an alkali metal salt thereof.
2. A compound of the formula
R
3 ~ S
R ~ ()n
2 Rl COOH
[wherein n is a~ integer o~ 0 t~ 2; Rl to R3 which may be
the same or di~ferent each represents a hydrogen atom, a
halo~en atom, a lower alkyl group, a lower alkoxy group or a
nitro group, excepting both the case where n is 0 or 1, any
one of Rl to R3 is 5-chloro, 5-methoxy or 5-nitro, and the
remainder is a hydrogen atom, and the case where n is 0 or
1, two substituents of Rl to R3 are 3,5 dichloro or 3,5-
dinitro and the remainder is a hydrogen atom] or an alkali
metal salt thereof.
3. A compound of the formula:
CONHZ
R2 ~ (~)
Rl CONHZ
~,;
- ~.
.:
~: .
. . .
[wherein n is an integer of 0 to 2; Z is a hydrogen
atom or a loweralkyl group; R1 to R3 which may be the
same or differen-t each represents a hydrogen atom, a
halogen atom, a lower alkyl group, a lower alkoxy
group or a nitro group].
4. A pharmaceu-tical compositlon for controlling
infectious diseases, which comprises an effective
amount of a compound of the formula:
COR4
S ~ >
R1 COR4
wherein n ~s an integer of 0 to 2; Rl to R3 which may
be the same or different each represents a hydrogen
atom, a halogen atom, a lower alkyl group, a lower
alkoxy group or a nitro group; and R4 is a hydroxyl
group or the group - NHZ, Z being a hydrogen atom or
a lower alkyl group or an alkali metal salt thereof,
together with a pharmaceutically acceptable carrier.
~P
i ~ '' I I
