Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
3~
1 The present invention is concerned with a new
process for the preparation o~ 2,3-dichloro-4-(2-thenoyl)
phenoxyacetic acid (tienilic acid), diuretic and uricosuric
agent used in human therapy.
S In contrast to the synthesis described in French
Patent 2,068,403 the carbonyl function is no longer created
by the reaction of a derivative of 2-thiophenecarboxylic acid
on a benzene base (2,3-dichloroanisole or 2,3-dichloro-
phenoxyace~ic acid), in the presence of a Lewis catalyst.
According to this invention the ketone function is
created by alkylation of thiophene by a compound of the
formula:
Cl Cl
~OOC ~ O-CH2-COOR ~I~
L5 in which R represents a hydrogen atom or an alkyl group, in
the presence of a dehydration agent such as polyphosphoric acid
or trifl~oroacetic anhydride and preferably wi~h a third sol-
vent which is, for example, benzene, methylene chloride or
dichloroethane. The reaction is carried out until comple-
tion, and conveniently for from about 1-8 hours. It is
possible to use as another dehydration agent the result of
the action of phosphoric anhydride on methane sulfonic
acid, as described in J. Org. chem. 38 4071 (1973). Never-
theless the yields of the reaction are lower in the latter case.
Alternatively, the compound of formula I wherein R
represents an alkyl group is converted to the corresponding
acid chloride by reaction with thionyl chloride and th~n
condensed with thiophene in the presence of stannic chloride
and in a solvent such as 1,2-dichloroethane.
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2:~3Z
1 In the above formula I, R preferably represents
an alkyl group of Cl-C4 and more particularly an ethyl
group.
The compound of formula I is prepared from 2,3-
dichloroanisole by carrying out, for example, the followingreactions:
Cl ~ O-CH3 + Cl-cH2-co-cl ~ CH2 ~ ~ 0-CH3
Cl Cl C~ Cl
CH3-~- ~ g-CH2-Cl + Cl HN ~ H ~ Cl ~
HO ~ ~ 2 ~ + NaCH + ~0 - > HO ~ COoH
Cl-
From (2,3-dichloro-4-hydroxy) benzoic acid one
obtains (2,3-dichloro-4-carboxy) phenoxyacetic acid by the
action of monochloracetic acid in the presence of sodium
hydroxide or also by the action of e~hyl monochloracetate
2~ followed by hydrolysis. It is possible to transform (2,3-
dichloro-4-carboxy) phenoxyacetic acid into its ethyl ester,
whose better solubility in an organic medium is significant,
for example by monoesterification.
The compound described above, namely (2,3-dichloro-
4-carboxy) phenoxyacetic acid, in addition to utility as an
intermediate has diuretic and uricosuric activity as demon-
strated in standard pharmacological procedures summarized as
f ollows .
Diuretic and Urlcosuric Activity
3~ The diuretic and uricosuric activity of (2,3-dichloro-
4-carboxy)phenoxyacetic acid i~ determined by intravenous admin-
Zl~
I istration to the phosphate-mannitol infused mongrel dog.
From renal clearance s~udies the effect of the test compound
upon kidney function is determined by measurement of effective
renal plasma flow, glomerular filtration rate and filtration
S fraction. Urine volume, pE, electrolyte and uric acid excre-
tion axe also determined. In this study, (2,3-dichloro-4-
carboxy) phenoxyacetic acid at a dose of 60 mg/kg i.v. in-
creased sodium and potassium excretion and increased uric acid
filtered by ll6~.
~he following example illustrates the invention
without nevertheless limiting its scope.
EXAMPLE
A~ Preparation of (2,3-dichloro-4-methoxyphenyl) chloromethyl
ketone - ~~~~~ ~
_
40 g. of aluminum chloride is added in small portions
to a solution, kept at 0C., of 53 g. of 2,3-dichloroanisole
and 37 g. of chl~racetyl chloride in 400 ml. of methylene
chloride. After 2 hours at 0C., the mixture is kept for 12
hours at 25C. and then poured over a mixture of ice and con-
centrated hydrochloric acid. The o~rganic phase is decanted
and the aqueous phase is o~ce again extracted with chloroform.
The residue obtained after evaporating the organic solventsis recrystallized in a mixture of benzene and petroleum ether
(l/l) to give in 80% yield, the ketone which- melts at 90C.
~) Prehal]a~ion~df N ~(2hl di.dhloro-~-hydroxyphenyl?_ca bonyl-
met y pYrl lnlum c orl e
A mixture of 231 g. of pyridine hydrochloride and 77
g. of ~he previously obtained ketone is kept for lO minutes at
170C. and then cooled to 100C.t then 3 volumes of ice water
and lO ml. of lN aqueous solution of hydrochloric acid is added.
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1 The precipitate is isolated and then washed with
boiling methanol to obtain in 75~ yield, the pyridine deriva-
tive which melts higher than 250C.
C) Preparation of (2,3-dichloro-4-hydroxy) benzoic acid
49.6 g. of the preceding compound is suspended in
400 ml. of water containing 20 g. of sodium hydroxide and the
mixture is kept at the reflux temperature until the solid has
completely disappeared, i.e., about 4 hours. The solution is
acidified by adding concentrated hydrochloric acid. The
precipitate formed is separated out and recrystallized from
dichloroethane to give in 95% yield, the acid which melts
at 205C
D) (2,3-Dichloro-4-carboxy) phenoxyacetic acid is then
, _ . . .
prepared by the action of sodium monochloracetate on the
phenol compound prepared in (C), in the presence of sodium
hydroxide in aqueous or alcoholic solution, or also by the
action of ethylmonochloracetate on the compound prepared in
(C) in alcohol soiution, followed by hydrolysis in a basic
aqueous medium.
METBOD 1
17 g. of (2,3-dichloro-4-hydroxy) benzoic acid is added
to 100 ml. o~ a 3 N aqueous solution of sodium hydroxide,
followed by the addition of 9.45 g. of monochloracetic acid.
After 2 hours of reflux, 5 g. of sodium hydroxide and 4.7 g.
of monochloracetic acid is added once again and the reflux is
extended for 2 hours
The aqueous solution is then acidified and the
precipitate is filtered and recrystallized in a dioxane/water
mixture (50/50) to give the acid product which melts at more
than 250C., with 70~ yield.
Z~2
1 METHOD 2
4.8 g. of ~2,3-dichloro-4-hydroxy) banzoic acid
is heated for 1 hour at the reflux temperature in 50 ml. of
ethyl alcohol containing 2.65 g. of potassium hydroxide
and 3.9 g. of potassium iodide. Then 5.9 g. of ethyl mono-
chloracetate is added and the mixture is kept at the reflux
temperature until it becomes neutral. 50 ml. of water and
5 g. of potassium hydroxide is then added and the mixture
refluxed for another 1-1/2 hours. The reaction mixture is
cooled, poured into water, and acidified with hydrochloric
acid, separating the precipitated diacid (yield 75%).
Ethyl (2,3-dichloro-4-carboxy) phenoxyacstate is
obtained by monoesterification of the diacidO Thus 20 g. of the
diacid is dissolved in 250 ml. of benzene and 250 ml. of
ethyl alcohol and 1.2 ml. of concentrated sulfuric acid is
added. The solution is kept at ~he reflux temperature for
.3 hours. After neutralization by adding sodium bicarbonate,
the solven~s are e~aporated and the residue is dissolved in
an aqueous solution of sodium carbonate. The aqueous phase
~0 is then acidified and the precipitate is filtered and recry
stallized from l,2-dichloroethane by filtering hot; the
precipitate obtained melts at 166C. (yield 50%).
E) Preparation of tienilic acid
METHOD 1:
5.12 g. of Ethyl(2,3-dichloro-4-carboxy)phenoxy-
~5
acetic and 1.68 g. of thiophene are added to a mixture of
40 g. of polyphosphoric acid and 200 ml. of benzene, while
vigourously agitating. The reaction mixture is kept for 10
hours at the reflux temperature of benzene and then is
poured into 2 volumes of water. The benzene phase is decanted
and the aqueous phase is extracted with ether. The organic
~2~32
1 phases are washed with an aqueous solution of sodium
hydroxide, dried, and the solvents evaporated. 1.2 g. of
Ethyl 2,3-dichloro-4-(2-thenoyl) phenoxyacetic is isolated,
which is hydrolyzed by the action of potassium hydroxide
in ethyl alcohol at the reflux ~emperature in order to
ob~ain tienilic acid with a yield of 90~.
During this reaction it is also possible to
use as a olvent methylene chloride or 1,2-dichloroethane.
Also, thiophene may be added in portions during the course
of heating.
Furthermore, it is also possible to use the
same procedural method to acylate the (2,3-dichloro-4-car-
boyx) phenoxyacetic acid.
METHOD 2
6 g. of Ethyl (2,3-dichloro-4-carboxy) phenoxy-
acetate and 30 ml. of thionyl chloride are heated 3 hours at
about 80C. Benzene is added and the liquid distilled under
reduced pressure. ~ -
The crude product (2,3-dichloro-4-carbethoxymethoxy)
benzoylchloride remains as a solid, m.p. 80C.
2.8 g. of Thiophens and 8.5 g. of the acid chloride
obtained above are dissolved in 100 ml. of 1,2-dichloroethane.
At about 0C., 3.2 ml. of stannic chloride is introduced in
the solution. The mixture is slowly heated to 60C. and this
tsmperature is maintained 2 hours. Ice water and hydrochloric
acid are poured in, the organic phase decanted and the solvent
evaporated. The crude pr~duct is recrystallized in a mixture
of ethanol/water (75/25) to give 6 g. of the pure ester.
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