Note: Descriptions are shown in the official language in which they were submitted.
106003~
The present invention relates to a process ~or
producing 5-carboxy-2-acetylthiophene.
5-Carboxy-2-acetylthiophene has been known to
be a useful intermediate ior the production of the thienyl-
thiazole derivative of the formula:
H2NCO - ~ N CH3
S JJ- s CH2 - a~ - CH2 - ~H - c - C1~3
OH CH~
which is useful as a potent therapeutic agent for the treat-
ment of heart diseases such as arrhythmia and coronary heart
diseases(U.S. Patent No. 3,932,400).
With respect to the preparation of 5-carboxy-2-
acetylthiophe~e, there have been proposed the following
processes:
(1) Xydrolysis of 5-cyano-2-acetylthiophene, ~instead7
Noble and Wright; J. Chem. Soc., 1937, 911. Dann; Ber.,
B76, 419 (1943)~
(2) Cxidation of 2,5-diacetylthiophene, ~Hartough and
Kosak; J. Am. Chem. ~oc., 69, 1012 (1947)~
(3) Acylation of thenoic acid ester, ~K. Schoe~el and
H. Pelonsek; Ann., 1 (1962)3
(4) Carboxylation of 2-methyl-2'-thienJl-1,3-dioxolane
(acetylthiophene ketal). ~'~hames and McClesky; J. Hetero-
cyclic Chem., 3, (1), 104 (1966)~ -
These knoum processes areS however, unsatisfactory
for the commercial production of said compound.
As the result of study, it has now been found that
5-carboxy-2-acetylthiophene can advantageously be prepared
_ 2 -
...
~O~iO030
in a high yield by the selective oxidation of 5-acetyl-2-
thienylacetic acid or its derivative with a chromic acid
derivative or a hypohalite.
So far, it has been quite difficult, or rather
impossible to expect whether oxidation occurs at the acetyl
methyl group or at the methylene group linked to the thio-
phene ring when 5-acetyl-2-thienylacetic acid or its deriva-
tive is subjected to the oxidation;re~action~
According to the present invention, however, 5-
carboxy-2-acetylthiophene can advantageously be prepared by
the selective oxidation of the methylene group linked to the
thiophene ring of 5-acetyl-2-thienylacetic acid or its
derivative. Specifically, 5-carboxy-2-acetylthiophene can
be prepared by the oxidation of 5-acetyl-2-thienylacetic acid,
which has the following ~ormula (II):
~3C - C _ ~ - CH2~00H (II)
with a chromic anhydride-solvent complex or a dichromate, or
by the oxidation of a compound of the formula (III):
H3C C - ~ - CH2COOR (I~I)
X S
wherein X is a conventional carbonyl protecting group, and
R is a conventionalester residue, with a hypohalite.
~ he term 1'conventional carbonyl protecting group"
as used herein means any carbo~yl protecting group which does
not disturb the progress of the oxidation reaction and which
is removable. ~xamples of such carbonyl protecting group are
106003Q
ketal, hemithioketal, dithioketal, thiazolidine, imidazoli-
dine and oxazolidine. ~'he term "conventional ester residue"
means any ester residue which does not disturb the progress
of the oxidation reaction. Examples of such ester residue
are lower alkyl (e.g. methyl, ethyl, etc.) and phenyl groups.
With respect to the oxidation of 5-acetyl-2-thienyl-
acetic acid with said chromic acid derivatives, it can gene-
rally be conducted in a solvent at a temperature from 0C.
to a boiling point of the solvent employed, preferably 0 to
100C.
Examples of preferred chromic anhydride-solvent
complex are chromic anhydride-acetic acid complex, chromic
anhydride-pyridine complex, chromic anhydride-dimethylform~
amide complex and the like. ~xample~ of preferred dichromate
are potassium dichromate, sodium dichromate, etc.
In carrying out the process using said chromic
anhydride-solvent complex, the use of the solvent which,
together with chromic anhydride, forms the chromic anhydride-
solvent oomplex is particularly preferable, but the process
can also be carried out in other inert solvent such as dichloro-
methane, carbontetrachloride and hydrocarbons such as light
petroleum and petroleum benzine.
While, when a dichromate i~ used, the process can
be carried out in organic acid solvents, water or a mixture
thereof. Examples of preferred organic acid solvent are ali-
phatic acids or anhydrides thereof such as acetic acid,
propionic acid, butyric acid, or acetic anhydride.
The chromic anhydride-solvent complex and the di-
chromate may be used in an amount of 2 to 3 moles per 1 mole
of 5-acetyl-2-thienylacetic acid.
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16~60030
It i~ particularly advantageous to conduct the
proces~ in the following manner:
(1) by adding chromic anhydride to acetic acid, acetic
anhydride or a mi~ture thereof to give chromic anhydride-
acetic acid complex,
(2) adding thereto 5-acetyl-2-thienylacetic acid, and then
(3) reacting them at a xoom temperature for several hours.
In thi~ case, the oxidation reaction proceeds completely to
give only 5-carboxy-2-acetylthiophene as the product.
With respect to the oxidation o~ a compound of the
formula (III) with a hypohalite, the process can be conducted
in a mixture of water and an alcohol (e.g. methanol, ethanol,
etc.) at a temperature from O to 60C. and then removing
the carbonyl protecting group.
Examples o~ pre~erred hypohalite are sodium hypo-
chlorite, sodium hypobromite~ potassium hypoohlorite and
potassium hypobromite.
In carrying out the process, it is preferable to use
at least 3 moles of a hypohalite per 1 mole of the compound
of the formula (III).
After the reaction is finished, the carbonyl
protecting group can be removed by a conventional method as
disclosed in McOMIE; "Protective Groups in Organic Chemistry",
Plenum Press London and New York, (1973~. For example, ketal,
hemithioketal, oxazolidine and imidazolidine can be removed
by treating them with a dilute acid such as dil. hydrochloric
acid, dil. sulfuric acid, aqueous acetic acid, etc. LC. Djerassi,
F. Batres, J. Romo and ~. Rosenkranz; J. ~m. Chem. Soc., 74,
3634 (1952). ~. P. Goldberg and H.R. Nace; J. Am. Chem. Soc.,
779 359 ~1955). H. W. Wanzlict and W. Loechell; Chem. Ber.,
1060030
86, 1463 (1953)~ Thioketal can be removed with a mercury
salt. ~H. Zinner, K. H. Rohde and A. ~Iattheus; Ann , 677,
160 (1964). ~. J. Corey and R. ~. Mitra; J. Am. Chem. Cos.,
84, 2g38 (1962)~
The isolation of the product can be carried out
in a conventional manner. For e~ample, well-refined 5-
carboxy-2-acetylthiophene, which sometimes precipitates when
the reaction system is diluted with, for example, water and,
if necessary, acidified with a ~uitable acid such as hydro-
chloric acid, can be isolated by filtration and washing with
water, or it may be isolated by extracting with an inert solvent
such as ether or by evaporating the solvent and washing the
product with water.
5-acetyl-2-thienylacetic acid and the compound of
the formula (III) can be prepared from 2-thienylacetic acid
as follows:
AC20 ~D
S 3 4 2 3 " ~ -CH2COOH
(A)CH2C00~ S
¦ esterification
AC20
. . ~ ~ 1
I H P0 or ZnCl ' l
S~ ~-CH2COOR 3 4 2 H3C-C- S -CH2COOR
(~) / (C)
H~jC-C-1 ~ 1-CH2COOR
(III)
- 6 -
~060~30
~he compound (II) can be prepared by acylating 2-thienyl-
acetic acid (A) with acetic anhydride in the presence of
phosphoric acid or zinc chloride. The compound (C) can be
obtained in the same manner as above from the compound (~),
which can be prepared by the esterification of the compound (A).
The compound (III) can be prepared by introducing the carbonyl
protecting group by a conventional method as disclosed in
the ~'Protective Groups in Organic Chemi~try".
As mentioned previously, 5-carboxy-2-acetylthio-
phene can be used as an intermediate for the production of
a therapeutic agent, which can be prepared from 5-carboxy-
2-acetylthiophene as follows:
~ amidation ~
H3C-,C, S COOH H3C-,C, S CONH2
O O
brominatisn ~ H2NCSNH4
BrH C-C S CONH2
2 "
OH CH
al-CH2-CH-CH2-~X - C - CH3
~2~C0 ~ ~
H2~CO ~ ~ ~ OH CH3
S S-CH2- CH-CH2-NH - C - CH3
CH~
1060030
The following examples are given to illustrate
the present invention more concretely, but it is not intended
to limit the present invention thereto.
Example
To an aqueous solution (5.3 g.) of sodium hypochlorite
containing excess sodium hydroxide (prepared from a part of
chlorine and 2.5 parts of sodium hydroxide) was added a solu-
tion of 0.204 g. of 5-acetyl-2-thienylacetic acid methyl
ester ketal in 5 ml of ethanol dropwise at such a rate that
the temperature could be maintained below 40C. by means of
cooling bath. After the addition was completed, stirring was
continued until the temperature fell to 25 - 30C. without aid
of cooling bath (0.5 - 4 hrs.). ~odium bisulfite was added to
destroy an excess o~ sodium hypochlorite. ~he resulting solu-
tion was made acidic with conc. hydrochloric acid (pH 1),
diluted with 30 ml of water and extracted with ether. ~ther
layer was washed with water~ dried and stripped to provide the
residue, which was recrystallized from water to afford 0.12 g.
(78.2 %) of 5-carboxy-2-acetyl thiophene. This product was
identified with an authentic sample prepared according to the
known procedure. (IR, ~MR and mixed m.p.)
~xample 2
In a mixture of acetic acid (8 ml) and acetic anhyd-
ride (2 ml) was dissolved 0.3 g. (0.003 mol) of CrO3 and 0.186 g.
(0.001 mol) of 5-acetyl-2-thienylacetic acid was added portion-
wise with stirring mechanically and cooling at 10C. The
resulting mixture was stirred at room temperature for 3.5 hrs.
and diluted ~ith 20 ml of water followed by e~traction with
ether. ~ther layer was washed with water, dried and evaporated.
-- ~3 --
lQ60030
The crude product was recrystallized from water to provide
0.13 g. (76 ~0) of 5~carboxy-2-acetyl thiophene, identical to
an authentic sample. (IR, NMR and mixed m.p.)
~xample 3
Chromic anhydride, 0.~42 g. (0.00342 mol) was added
portionwise to a cooled (0 - 5~.) pyridine (10 ml). After
few minutes, orange complex began to precipitate. 5-Acetyl-
2-thienylacetic acid, 0.202 g. (0.0011 mol) was added and
stirred at roo~ temperature overnight. The reaction mixture
was made acidic with conc. hydrochloric acid and extracted
with ether. Ether layer was washed with water, dried and
evaporated. Crude product was purified by recrystallization
~rom water. Yield; 0.14 g. (75.1 ~). This material was iden-
tified with an authentic sample. (IR, NMR and mixed m.p.)
Example 4
To a solution of 5-acetyl-2-thienylacetic acid,
9.985 g. (0.0543 mol) in 90 ml of acetic acid was added potas-
sium dichromate portionwise at 60C. with stirring. After
the addition was compIete, the mixture was warmed up to 80C.
and 30 ml of acetic anhydride was dropped slowly while the
temperature of the reaction mixture rose gradually to its
reflux. The resulting solution was heated moreover under
reflux for 4 hrs. and cooled to 15~. The green precipitate
was remo~ed by filtration and the filtrate was diluted with
large volume o~ water. Precipitate was collected,washed with
water and dried. Yield; 3.81 g. (41.3 %). The material was
identical to an authentic sample. (IR, NMR and mixed m.p.)
~060030
Preparation of 5-acetyl-2-thienylacetic acid methyl ester:
A mixture of 2-thienylacetic acid methyl ester,
1.41 g. (0.01 mol) and acetic anhydride, 4.2 g. (0.04 mol)
was heated at 70 - 80C. and 0.2 g. of 85% H3P04 was added
dropwise with stirring mechanically. The reaction was some-
what exothermic but cooling was not necessary. ~he mixture
was maintained between 70 - 80C. for 3 hrs., and then, poured
onto ice-water followed by extraction with ether. Organic
layer was washed with water several times 9 dried over anhyd.
MgS04 and evaporated. ~he re~idue was distilled at 2 mmHg
and a fraction between 160~. and 172C. was collected. This
material was gradually crystallized and could be recrystalli~ed
from the mixture of light-petroleum and benzene. m.p. 43 - 44C.
Yield; 1.39 g. (76~5 %)
~etallization of 5-acetyl-2-thienylacetic acid methyl ester:
A solution of ethyleneglycol, 0.997 g. (15.7 mmol)
ethyl orthoformate, 1.~07 g. ~9.47 mmol), 5-acetyl-2-thienyl-
acetic acid methyl ester, 0.572 g. (~.14 mmol) and a trace of
p-toluenesulfonic acid was allowed to stand at room temperature
for 3 hrs. ~he mixture was poured into water and organic
layer wa~ separated. An aqueous layer was extracted with
benzene (50 ml x 2). Both organic layer~ were combined, washed
with water, dried over anhyd. MgSG4 and evaporated in vacuo to
provide 0.286 g. ~91 %) of its ketal as an yellow oil. This
product can be characterized as the ethylene ketal of 5-acetyl-
~-thienylacetic acid methyl ester on the basis of disappearance
of carbonyl absorbtion at 1670 cm 1 (IR) and appearance of
singlet of dioxolane methylene at 4.00 (o) (NMR).
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'~ , ' : '
