Note: Descriptions are shown in the official language in which they were submitted.
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HOECHS~ AKTlENGESELLSCHAFT HOE 85~F 206 Dr.MA/mU
A PROCESS FOR THE PREPARATION ~F HALOTHIOPHENE-2-
CARBOXYLIC ACIDS
The invention relates to a process for the preparation of
halothiophene-2-carboxylic acids of the general formula
(Hal)n ~ ~here n = 1 or 2
S ~OOH Hal = halogen
Halothiophene-2-carboxyl;c acids are known as valuab~e
intermediates for the preparation of pharmaceutical prepar-
ations. For example, a series of heterocyclic compounds
which can be used, inter alia, as analgesic agents, is
synthesized from 3-chlorothiophene-2-carboxylic acid (US
Patent 4,230,873 = German Offenlegungsschrift 2,706,873).
S-Chlorothiophene-2-carboxyLic acid serves as a synthesis
component for the preparation of compounds having a chol-
esterol- and lipid-reducing action (US Patent 4,017,514).
Heterocyclic compounds having a s~eetener character have
also already been prepared from halothiophene-2-carboxy~ic
acids tUS Patent 4,028,373).
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; ~ 20 It is kno~n that halothiophene-2-carboxylic acids can be
prepared by oxidation of the appropriate halo-2-acetylthio-
phene - also known as 1-(halo-t2)-thienyl)-ethanone - using
aqueous permanganate solution or using alkaline, aqueous
sodium hyperchlorite solution tJ. Am. Chem. Soc., 69, 3098,
(1947)). In this case, ho~ever, considerable problems are
caused by the production of inorganic salts in the liquid
~aste, since the hypochlorite solution must be used in 3-
fold excess and destroyed after the oxidation using
bisulfite solution ~Org. Synth., Coll. Vol. II, 428 (1943)).
~" 30 The reaction mixture is finally acidified to precipitate
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the free thiophene-2-carboxylic acids.
The object ~3S to convert halo-2-acylthiophenes, ~hich are
generally easily accessible by acylation of halothiophenes
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2 23221-4282
(J. Am. Chem. Soc~, 69, 3093-3097, (1947)), to the halothiophene-
2-carboxylic acids by means of a technically simple oxidation
method, avolding the problems mentioned.
The invention relates to a process for the preparation of
halothiophene-2-carboxylic acids of the general formula
tHal )n ~3~
S COOH
in which Hal denotes halogen and n denotes 1 or 2, by oxidation of
the appropriate halo-2-acylthiophenes of the general formula
( Hal ) n~
.~., S C-(CH2)~C-C~3 .
where x - O to 3, wherein the oxidation is carried out in a
solvent stable towards oxygen in the used temperature range using
oxygen in the presence of salts of manganese, cobalt, chromium or
~ 20 iron as a catalyst.
.,
; The novel process allows the preparation of halothiophene-2-
carboxylic acids in high yields using a widely available oxidant.
~Furthermore, it has the advantage that virtually no
environmentally polluting waste salts or liquid wastes are
produced and the isolation of the halothiophene-2-carboxylic acids
is achieved in a particularly simple fashion.
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2a 23221-4282
It is surprising here that formation of sulfones only occurs to a
limited extent under the reaction conditions used in the process
according to the invention.
All mono-and dihalo-2-acylthiophenes are suitable as starting
materials for the oxidation according to the invention.
The followlng can be used as halogen derivatives: fluorine,
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chlorine, bromine and iodine der;vatives. ~ecause of the
thermal lability of the iodine derivatives and the poor
accessibility of the fluorine derivatives, the der;vatives
of chlorine and bromine are particularly i~portant, above
all the chlorine derivatives.
The acyl radical in the halo-2-acylthiophenes used as
starting material can be acetyl, propionyl, butyryl or
pivaly~. ~ecause of the wide availability of acetic an-
hydride, the acyl radical is preferably acetyl.
All solYents which are stable toward oxygen ;n the tempera-
ture range used are suitable as solvent ~hen carrying out
the oxidation. Ho~ever, al;phatic carboxylic acids having
up to five carbon atoms, such as, for example, acetic acid,
propionic ac;d or pival;c acid, are preferred. Acetic
acid is particularly preferred.
The weight ratio of solvent to halo-2-acy~thiophene is not
of overriding importance and is, in general, about 4:1 to
20:1. The range 6:1 to 12:1 is particularly favorable.
In general, salts of manganese, cobalt, chromium or iron
can be used as catalysts, above all the halides, carboxy-
lates, carbonates or sulfates of these metals.
Manganese and cobalt are preferred, particularLy mixtures
thereof, a ~eight ratio of manganese:cobalt of 10:1 to 20:1
having proven favorable.
,
The metal salts are dissolved in the solvent. In the case
of the preferred use of aliphatic carboxylic acids as
solvents, it has proven favorable to use the carboxylates
of the metals, preferably those metal carboxylates ~hich
are derived from the carboxylic acid used as solvent. The
~ 30 acetates are therefore particularly preferred metal salts.
-~ The weight ratio of catalyst (calculated as the metal) to
halo-2-acylthiophene is, in general, 0.4:100 to 20:100,
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preferably 1:100 to 10:100.
Oxygen serves as oxidant, either in pure form or in mix-
tures with inert gases, such as, for example, nitrogen or
carbon dioxide. Air ~hich has been enriched ~ith oxygen,
particularly containing about 50% by volume of oxygen, is
preferably used.
The reaction temperature is, in general, 50 to 200C.
The ideal reaction temperature depends, inter alia, on the
thermal stability of the acyl derivatives employed and of
the carboxylic acid derivat;ves produced, and can be deter-
mined by a simple preliminary experiment. For example,
uhen monohalo-2-acetylthiophenes are employed, a tempera-
ture range of 80 to 140C proves advantageous.
The oxidation is, in general, carried out in the pressure
range of 1 to 20 bar. Ho~ever, it is an advantage of the
process according to the invention that, in general, high
conversions of at least 90~ and good yields of about 90%
can be achieved in reaction times of up to about 6 hours,
even in the case of a non-pressurized procedure.
~20 The oxidation can be carried out both in batches and also
- continuously in conventional reactors such as kettles,
kettle cascades or bubble column reactors.
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The reaction product is vorked up in a simple fashion, by
distilling off the solvent, ~hich, after further distill-
ative purification, can be reused. The crude reaction
product obtained in this fashion as a distillation residue
is washed ~ith water to remove adherent salts. The halo-
thiophene-2-carboxylic acids uhich are produced trom this
as solid products can easily be purified by recrystalliza-
tion.
EXAMPLE 1
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The reaction is carried out in an unjacketed reaction tube,
~ith a base frit, of 3.1 liter capacity, a length of 110 cm
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and an internal diameter ot 60 mm. The reaction tube is
filled ~ith a solution of 240 9 ~1.5 mol) of 1-~5-chloro-~2)-
thienyl)-ethanone ~m.p. 48C), 1.5 9 of cobalt acetate . 4
H20 and 24.0 9 of manganese acetate . 4 H20 in 1.8 liters of
glacial acetic acid, and the solution is heated to 105-106C
by means of oil-circulation heating while a gas stream of 25
liters of oxygen per hour is passed through the solution.
The internal temperature then increases within an hour to
108-110C and is kept constant in this range for the further
duration of the experiment. Approximately 4 hours after the
start of the experiment, the reaction solution ~2116 9) is
let out while still hot and concentrated to dryness in a rot-
ary evaporator. The dry crude product of carboxylic acid,
220 9 ~90.2X yield), is recrystallized from 10% strength
aqueous methanol; 196 9 of crystalline 5-chlorothiophene-2-
carboxylic acid of melt-ing point 152C remain.
EXAMPLE 2
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The reaction is carried out in the same apparatus as in
Example 1.
A solution of 120 9 ~0.75 ol) of 1-t3-chloro-(2)-thienyl)-
ethanone (b.p. 85C/2 bar), 0.5 9 of cobalt acetate .
; 4 H20 and 18.0 9 of anganese acetate . 4 H20 in 1.2 liters
of glacial acetic acid is introduced into the reaction tube
-~ and heated to a tenperature of 105-106C. A gas stream of 25
liters of oxygen per hour is simultaneously passed through
the solution, so that the internal temperature rises to 108-
110C within one hour and is kept constant at this temper-
ature for the further duration of the experinent. Approxi-
oately 3.5 hours after the start of the experi-ent, the
reaction solution (1322 9) is let out while still hot and
~orked up as in Example 1. ~he 88 9 of crude product which
; ~ remain are recrystalli2ed fro- 3X strength acetic acid. 68 9
~- ~ of 3-chlorothiophene-2-carboxylic acid, corresponding to a
ield of 55.8X, relative to the starting material employed,
renain as crystals. Howe~er, since the ketone mixture
; e-ployed only contains bout an 80X by weight of
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1-(3-chloro-~2)-thienyl)-ethanone, a selectivity of 70X is
calculated for the 3-chlorothiophene-2-carboxylic acid ob-
tained~ After recrystallization from water, the product
melts at 188-190C.
EXAMPLE 3
The procedure as in Example 1 is carried out, but with the
difference that, in place of pure oxygen, a gas mixture of 15
liters of oxygen and 15 liters of nitrogen per hour is passed
through the solution. After an experimental duration of
about 4.5 hours, the hot reaction solution is let out and
- worked up as in Example 1. 228 9 of dry crude product and
after recrystalli2ation from 15% strength methanol, 205 9 of
crystalline 5-chlorothiophene-2-carboxylic acid, corres-
ponding to a pure yield of 84.0%, are finally obtained.
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