Note: Descriptions are shown in the official language in which they were submitted.
This invention relates to a novel process Eor preparing 5-(p-
chloroben~oyl)-1,4-dimethylpyrrole-2-acetic acid.
:.
5-(p-Chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid is the analgesic
and anti-inflam~atory agent generically known as "zomepirac". Some
methods of preparing it are described in Japanese Patent Publication
(unexamined) No. 418/19719 et al.
The above Japanese Patent Publication discloses the process for
preparing 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid,
which is illustrated by the following reaction scheme:
..'.~
-- 1 --
:
:
8~
CH3 2 5
~ ~ .
Cl- ~COCl + llN~L CH2cooc2H5
CH3
(I) (II)
CH3~ COOC2H5 3~ COOH
Cl~CO I CH2COOC2H5 Cl~CO I CH2COOH
CH3 CH3
(III) (IV)
Cl~CH3~ COOH CO ~ CH2COOC2H5
(V) (VI)
Cl~ 3
(VII )
According to this method, 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-
acetic acid (VII) can be prepared by subjecting the compound (I) and the
compound (II) to a Friedel-Crafts reaction to yield the diester compound
(III), hydrolyzing the compound (III) to yield the dicarboxylic acid
(IV), esterifying only the carboxy group of the acetic acid moiety at
the 2-position of the compound (IV) to yield the monoethyl ester compound
(V), subjecting the compound (V) to decarboxylation by heating it in a
-- 2 --
basic organic solvent such as quinoline or in the molten state to yield
the ethyl ester compound (VI) and hydrolyzing the compound (VI).
The inventor investigated extensively to find more excellent processes
for preparing 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid on
an industrial scale and found that the decarboxylation of the carboxy
group at the 3-position occurs ln pre~erence to the decarbo~ylation of
the carboxy group of the acetic acid moiety at the 2-position when the
dicarboxylic acid compound (IV) is heated in the presence of a base and
hence 5-(p-chlorobenzoyl)-1,4-dimethyl-pyrrole-2-acetic acid can be
obtained in a good yield.
In accordance with this invention, 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-
2-acetic acid (VII) can be obtained in a good yield by heating 5-(p-
chloroben~oyl)-1,4-dimethyl-3-carboxypyrrole-2-acetic acid (IV~ in the
presence of a base.
The method of this invention can be carried out by heating 5-(p-chlorobenzoyl)-
1,4-dimethyl-3-carboxypyrrole-2-acetic acid and a base in a solvent.
Inorganic and organic bases can be used. The preferred inorganic bases
include an alkali metal hydroxide such as lithium hydroxide, sodium
hydroxide or potassium hydroxide, an alkali metal carbonate such as
lithium carbonate, sodium carbonate or potassium carbonate, an alkali
metal bicarbonate such as lithium bicarbonate, sodium bicarbonate or
potassium bicarbonate, ammonium hydroxide and the like. The preferred
organic bases include a tertiary amine such as trimethylamine,
triethylamine, tri-n-propyl-amine, tri-n-butylamine, N-methylpiperidine,
N-methylmorpholine or N,N,N',N'-tetramethylethylenediamine, a
secondary amine such as dimethylamine, diethylamine, di-n-propylamine
-- 3 --
$~
or di-n-butylamine, a primary amine such as methylamine, ethylamine, n-
propylamine or n-butylamine and the like. The base is preferably used
in 1 to 1.3 equivalents per 1 mole of 5-(p-chlorobenzoy])-1,4-dimethyl-
3-carboxypyrrole-2-acetic acid. In the case of a tertiary amine, it can
be used in a larger amount. The preferred solvents are those in which a
mixture of 5-(p-chlorobenzoyl)-1,4-dimethyl-3-carboxypyrrole-2-acetic
acid and a base is dissolved and include water, aqueous dioxane, aqueous
lower alcohol (e.g., methanol, ethanol, isopropanol or butanol) and
aqueous diethylene glycol. The reaction temperature may range from
about 140C to about 230C and preferably about 180C to about 200C.
The reaction time is generally 1 to 4 hours. The reaction may be optionally
conducted at higher pressure than atmospheric pressure. A-Eter the
reaction is complete, the desired product can be isolated and purified
in a conventional manner.
In accordance with this invention, two steps can be reduced compared
with the method disclosed in Japanese Patent Publication (une~amined)
No. 418/1971, and the decarboxylation of 5-(p-chlorobenzoyl)-1,4-dimethyl-
3-carboxypyrrole-2-acetic acid (IV) can be conducted subsequent to the
hydrolysis of the diester compound (III) without isolating the former.
Those merits of this invention serve for the industrial scale production
of 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid.
This invention is illustrated more specifically by the following examples
but not limited thereto:
: .
L5~
Example l
To 30 ml of water solution containing 0.13 g of sodium hydroxide was
added 1.0 g of 5-~p-chlorobenzoyl)-1,4 dimethyl-3-earboxypyrrole-2-
aeetic acid and the mixture was heated at 200C in a sealed tube for one
hour. The reaction mi~ture was allowed to cool and extraeted with 10 ml
of methylene chloride. The aqueous layer was acidified with dilute
hydrochloric acid. Crystals precipitated were eolleeted by filtration,
dissolved with heating in 10 ml of 10~ aqueous sodium hydroxide, and the
solution was allowed to stand. Crystals preeipitated were eollected by
filtration and dried to give sodium 5-(p-chlorobenzoyl)-1,4-d:imethylpyrrole-
2-acetate dihydrate (0.68 g), m.p. above 300C.
Analysis - Calcd- for C15H13ClN03Na-2H20: C, 51.51; H, 4.90; N, 4.00.
Found: C, 51.62; H, 4.63; N, 3~70.
The above sodium salt was dissolved in a proper amount of water, and the
solution was acidified with dilute hydrochloric acid. Crystals precipitated
were collected by filtration and dried to give 5-(p-chlorobenzoyl)-1,4-
dimethylpyrrole-2-acetic aeid, m.p. 178-179C.
The IR spectrum of this product was identical with that of the authentic
sample prepared by the method described in Japanese Patent Publication
(unexamined) No. 418/1971.
Example 2
A mixture of 1.5 g oE S-(p-chlorobenzoyl)-1,4-dimethyl-3-carboxypyrrole-
2-acetic acid and 0.46 g of triethylamine in 60 ml of water was heated
at 200C in a sealed tube for one hour. A small amount of the precipitate
-- 5 --
~a5~
was removed by filtration, and the filtrate was acidified with concentrated
hydrochloric acid. Crystals precipitated were collected by filtration
and dissolved with heating in 15 ml of 10% aqueous sodium hydroxide, and
the solution was allowed to stand. Crystals precipitated were collected
by filtration and dried to give sodium 5-tp-chlorobenzoyl)~1,4-dimethylpyrrole-
2-acetate dihydrate (1.09 g).
Example 3
A mixture of 1.0 g of 5-(p-chlorobenzoyl)-1,4-dimethyl-3-carboxypyrrole-
2-acetic acid and 3.3 ml of lN aqueous ammonia in 40 ml of water was
heated at 200C in a sealed tube for one hour. The reaction mixture was
treated in substantially the same manner as in Example 2 to give sodium
5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2~acetate dihydrate (0.83 g).
The following reference examples show the experimental results obtained
by treating 5-(p-chlorobenzoyl)-1,4-dimethyl-3-carboxypyrrole-2-acetic
acid under conventional decarboxylation conditions.
Reference Example 1 (com~arative examDle)
To 8 ml of quinoline was added 0.50 g of 5-(p-chlorobenzoyl)-1,4-dimethyl-
3-carboxypyrrole-2-acetic acid, and the mixture was heated at 180C for
2 hours. The reaction mixture was allowed to cool and acidified with
dilute hydrochloric acid. Crystals precipitated were collected by
filtration, dried and recrystallized from ethanol to give 5-(p-chlorobenzoyl)-
1,2,4-trimethylpyrrole-3-carboxylic acid (0.31 g), m.p. 219-221C (decomposition).
Analysis - Calcd. for C15H14ClNO3: C, 61.76; H, 4.84; N, 4.80. Found:
C, 61.66; H, ~.80; N, 4.65.
Reference Exam~le 2 (comParatiVe examDle)
A mixture of 0.50 g of 5-(p-chlorobenzoyl)-1,4-dimethyl-3-carboxypyrrole-
2-acetic acid and 50 mg of copper chromite in 8 ml of quinoline was
heated at 150C for 3 hours. The reaction mixture was treated in substantially
the same manner as in Reference Example l to give 5-(p chlorobenzoyl)-
1,2,4-trimethylpyrrole-3-carboxylic acid (0.32 g).
Reference Example 3 (comparative examPle)
5-(p-Chlorobenzoyl)-1,4-dimethyl-3-carboxypyrrole-2-acetic acid (0.50 g)
was heated at 270-280C for 20 minutes. After cooling, the residue was
recrystallized from isopropanol to give 5-(p-chloroben~oyl)-1,2,4-
trimethylpyrrole (0.30 g), m.p. 103-104C.
Analysis - Calcd. for Cl4Hl4ClNO: C, 67.88; H, 5.70; N, 5.65.
Found: C, 67.59; H, 5.52; N, 5.75.
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