Note: Descriptions are shown in the official language in which they were submitted.
This .invention relates to a novel process for preparing l~methyl-5-
(p-toluoyl)py~role-2-acetic acid, which is the analgesic and anti-
inflammatory agent generically known as "tolmetin", and to a novel
intermediate for preparation thereof. More particularly, it relates
to a process for preparing l-methyl-5-(p-toluoyl)pyrrole-2-acetic
acid which is characteri~ed by heating l-methyl-5-~p-toluoyl)-3- .
carboxypyrrole-2-acetic acid in the presence of a base and to 1-
methyl-5-(p-toluoyl)-3-carboxypyrrole-2-acetic acid.
The method of this invention is illustrated by the following reaction
scheme:
3 ~ CO ~ I[CU2COOH C2 ~ CH3 ~ CO- ~ LCH2COOH
CH3 CH3
(II) (I)
- 1 - .
., . -
-
, .
The method of this invention can be carried out by heating 1-
methyl-5-(p-toluoyl)-3-carboxypyrrole-2-acetic acid (II) (hereinafter
referred to as the dicarboxylic acid (II in the presence of 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-propylamine, tri-n-
butylamine, N-methylpiperidine, N-methylmorpholine, or N,N7~1',N'-
tetramethylethylenediamine, a secondary amine such as dimethylamine,
diethylamine, di-n-propylamine 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
l mole of the dicarboxylic acid (II). In the case of a ~ertiary
amine, it can be used in a larger amount. The preferred solvents
are those in which a mixture of the dicarboxylic acid (II) 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 optionally be conducted at higher pressure than atmospheric
pressure. After the reaction is complete, the desired product can
be isolated and purified in a conventional manner.
-- 2 --
In accordance with the method of this invention, l-methyl-5-(p-
toluoyl)pyrrole-2-acetic acid (I) can be obtained from the dicarboxylic
acid (II) in a good yield.
The dicarboxylic acid (II) is novel and can be prepared by, for
example, the method illustrated by the followlng reaction scheme:
3 ~ COCl ~ ~ 2H5
CH3
tIII) (IV)
CH3 ~ CO ~ ,~ [C~12COOC2H5
CH3
(V)
~- ~ ~ CO ~ COOH
CH3
(II)
The reaction of the compound (III) with the compound (IV) can be
perfarmed under ordinary Friedel-Crafts reaction conditions. For
example, it is conducted at about 0C to about 9~C in the presence
of a Lewis acid such as aluminum chloride in a salvent such as
methylene chloride, ethylene chloride, carbon disulfide or nitrobenzene.
The hydrolysis of the compound (V) to the dicarboxylic acid (II)
can be performed in a conventional manner, for example, by heating
the compound (V) in the presence of a base such as sodium hydroxide
or potassium hydroxide in a solvent such as aqueous ethanol.
This invention is illustrated more speciEically by the following
examples but not li~ited thereto:
Example 1
To a refluxing solution of 9.6 g of ethyl 1-methyl-3-ethoxycarbonylpyrrole-
2-acetate in 30 ml of ethylene chloride was added dropwise over a period
of 30 minutes a solution of 6.80 g of p-toluoyl chloride and 5.85 g of
aluminium chloride in 30 ml of ethylene chloride. After the addition,
the reaction mixture was refluxed for an additional 6 hours and then
poured into ice-hydrochloric acid. The ethylene chloride layer was
separated, washed with 10% aqueous sodium carbonate and then with water,
and dried over anhydrous sodium sulfate. The ethylene chloride was
distilled off. The oily residue was dissolved in a small amount of
methylene chloride and chromatographed on silica gel. The eluates with
methylene chloride-n-hexane (2:1) gave ethyl 1-methyl-5-(p-toluoyl)-3-
ethoxycarbonylpyrrole-2-acetate (6.27 g), which was recrystalli~ed from
isopropanol to show the melting point of 99-100C.
Analysis - Calcd- for C20H23N05: C, 67.21; H, 6.49; N, 3.92.
Found: C, 67.28; H, 6.59; N, 3.90.
NMR (CDC13) ~: 1.28 (6H, t), 2.42 (3H, s), 3.95 (3H, s), 4.00-4.60
(6H, m), 7.15 (lH, s), 7.32 (2H, d), 7.80 (2H, d).
Example 2
To a mixture of 20 ml of 25% aqueous sodium hydroxide and 10 ml of
ethanol was added 2.0 g of ethyl 1-methyl-5-(p-toluoyl)-3-ethoxycarbonylpyrrole-
2-acetate. The resulting mixture was heated at 95C for 2 hours and
acidifled with concentrated hydrochloric acid. Crystals precipitated
were collected by Eiltration and recrystallized from isopropanol to give
l-methyl-5-(p-toluoyl)-3-carboxypyrrole-2-acetic acid tl.43 g), m.p.
255-257~C (decomposition).
Analysis - Calcd. for C16H15N05:C, 63.78; H, 5.02; N, 4.65.
Found: C9 63.89; H, 5.03; N, 4.61.
Example 3
To 30 ~1 of water solution containing 0.13 g of sodium hydroxide was
added 0.9 g of 1-methyl-5-tp-toluoyl)-3-carboxypyrrole-2-acetic acid.
The resulting mixture was heated at 200C in a sealed tube for one hour,
allowe~ to cool, and extracted with 10 ml of methylene chloride. The
aqueous layer was acidified with dilute hydrochloric acid~ Crystals
precipitated were collected by filtration, dissolved with heating in
10 ml of 10~ aqueous sodium hydroxide, and the solution was allowed to
stand. Crystals precipitated were collected by filtration and dried to
give sodium l-methyl-5-(p-toluoyl)pyrrole-2-acetate dihydrate (0.66 g),
m.p. above 300C.
A~alysis - Calcd. for C15H14N03Na-2H20: C, 57.14; H, 5.75; N, 4.44.
Found: C, 56.82; ~, 5.76; N, 4.34.
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 l-methyl-5-~p~toluoyl)pyrrole-
2-acetic acid, m.p. 158-160C ~decompostion).
The IR spectrum of this product was identical to that of the authentic
sample prepared by the method described in Japanese Patent Publication
No. 37668/1975.
ExamPle 4
A mixture of 1.0 g of 1-methyl-5-(p-toluoyl)-3-carboxypyrrole-2-acetic
acid and 0.34 g of triethyl~mine in 40 ml of water was heated at 200C
in a sealed tube for one hour. A small amount of the precipitate was
removed by filtration and the filtrate was acidified with concentrated
hydrochloric acid. Crystals precipitated were collected by filtration,
dissolved with heating in 10 ml of 10% aqueous sodium hydroxide, and the
solution was allowed to stand. Crystals precipitated were collected by
filtration and dried to give sodium l-methyl-5-(p-toluoyl)pyrrole-2-
acetate dihydrate (0.80 g).
Example 5
A mixture of 0.9 g of 1-methyl-5-(p-toluoyl)-3-carboxypyrrole~2-acetic
acid and 3.3 ml of 1~l 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 ~ to give sodium 1-
methyl-5-(p-toluoyl)pyrrole-2-acetate dihydrate (0.76 g).
The following reference examples show the experimental results obtained
by treating l-methyl-S-(p-toluoyl)-3-carboxypyrrole-2-acetic acid under
ordinary decarboxylation reaction conditions.
~:~5~ 7
Reference Example 1 (comparative example)
A mixture of 0.50 g of 1-methyl-5-(p-toluoyl)-3-carboxypyrrole-2-acetic
acid and 8 ml of quinoline was heated at 160C for 8 hours, allowed to
cool, and acidified with dilute hydrochloric acid. Crystals precipitated
were-rollected by filtration, dried and recrystallized from ethanol to
give 1,2-dimethyl-5-(p-toluoyl)pyrrole-3-carboxylic acid (0.32 g), m.p.
248-249C (decomposition).
Analysis - Calcd. for C15H15N03: C, 70.02; H, 5.88; N, 5.44.
Found: C, 69.87; H, 5.89; N, 5.63.
Reference Example 2 (comparative example)
A mixture of 0.50 g of 1-methyl-5-(p-toluoyl)-3-carboxypyrrole-2-acetic
acid and 50 mg of copper chromite in 8 ~1 of quinoline was heated at
140C for 3 hours and allowed to cool. The reaction mixture was treated
in substantially the same manner as in Reference Example 1 to give 1,2-
dimethyl-5-(p-toluoyl)pyrrole-3-carboxylic acid (0.34 g).
