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)pyrrole-2-acetic acid, which is the analgesic and anti-
inflammatory agent generically known as "tolmetin", and to a novel
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- ~s~
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 hydrolyzing and decarboxylating a
compound of the formula (I)
CH3 ~ ~ ~ COORl (I)
wherein Rl and R2 are identical or different, and each represents a
lower alkyl,
and to the compound of the formula (I).
In the above formula (I), it is preferred that Rl and R2 are identical
and especially preferred that each represents methyl or ethyl.
The method of this invention can be carried out by heating the
compound of the formula (I) and a base in a solvent. The base used
includes an alkali metal hydroxide such as sodium hydroxide or
potassium hydroxide, an alkali metal carbonate such as sodium
carbonate or potassium carbonate and an alkali metal bicarbonate
such as sodium bicarbonate or potassium bicarbonate. The solvent
used includes water, a lower alcohol such as methanol, ethanol or
isopropanol and a mixture thereof. The base is preferably used in
2 to 4 equivalents per 1 mole of the compound of the formula (I).
The reaction temperature is generally 50C to 120C and the reaction
time is generally 1 to 10 hours. The method of this invention can
especially preferably be performed by heating under refluxthecompound
~ :.
of the formula (I) in a mixture of a lower alcohol (e.g., e~hanol
or isopropanol) and an aqueous solution of an alkali metal hydroxide
(e.g., sodium hydroxide or potassium hydroxide) for sevcral hours
and then isolating l-methyl-S-(p-toluoyl)pyrrole-2-acetic acid in
the form of an alkali metal salt or free acid in a conventional
manner.
In accordance with the method of this invention, l-methyl-5-(p-
toluoyl)pyrrole-2-acetic acid can be obtained from the compound of
the formula (I) in a good yield.
The compound of the formula (I) is novel and can be prepared by,
for example, the method illustrated by the following reaction
scheme:
3 ~ CoN,,R3 (III) N C /COORl (V)
> CH ~ CO ~
N a condensing agent 3 Na catalyst
CH3 CH3
(II) me ~ ~ (IV)
CH3 ~ CO
(VI)
wherein Rl and R2 are as defined above and R3 and R4 are identical
or different, and each represents a lower alkyl, or the R3 and R4
may be combined with the neighboring nitrogen atom to form a heterocyclic
group such as morpholino or piperidino.
;
The conversion of the compound of the formula (II) to the compound
of the formula (IV) is generally conducted by reacting the compound
of the formula (II) with the compound of the formula (III) in the
presence of a condensing agent in a solvent. The condensing agent
includes phosphoryl chloride and ~he like, and the solvent includes
dichloromethane, dichloroethane, trichloroethylene and the like.
The reaction temperature is generally 50C to 100C. The compound
of the formula (IV) can be also obtained by methylating the compound
of the formula (VI), which is prepared by, for example, the method
described in J. Med. Chem., 16, 1298 (1973), in a conventional
manner.
The conversion of the compound of the formula (IV) to the compound
of the formula (I) is generally conducted by reacting the compound
of ~he formula (IV) with the compound of the formula (V) in the
presence of a catalyst without a solvent or in a solvent. The
catalyst includes rhodium acetate, silver acetate, copper powder,
cuprous chloride and cupric sulfate. The solvent includes benzene,
toluene and xylene. The reaction temperature is generally 80C to
140C. The compound of the formula (V) can be readily prepared by,
for example, the method described in Synthesis, 19719 658.
This invention is illustrated more specifically by the following
examples and reference examples but not limited thereto.
Reference Example
A solution of 55.3 g o~ N,N-dimethyl-p-tolua~ide and 52 g o~ phosphoryl
chloride in 200 ml of anhydrous dichloroethane was heated under re~lux
for 30 minutes. The reaction mixture was allowed to cool and thereto
was added dropwise with stirring a solution of 27.5 g of l-methylpyrrole
in 50 ml of anhydrous dichloroethane. After the addition, the resulting
mixture was refluxed for 15 minutes, then allowed to cool, and a solution
of 230 g of sodium acetate trihydrate in 200 ml of water was added
dropwise. After the addition, the reaction miæture was refluxed for 10
minutes and allowed to cool. The dichloroethane layer was separated,
dried over anhydrous sodium sulfate and evaporated to dryness. The oily
residue was chromat.ographed on silica gel, using dichloromethane-n-
hexane tl:l) as an eluent, to give l-methyl-5-(p-toluoyl)pyrrole (37.5 g),
b.p. 137C/2 mmHg. This product solidifled on standing and showed the
melting point of 51C.
Analysis - Calcd. for C13H13NO: C, 7O.36; H, 6.58; N, 7.03.
Found: C, 78.20; H, 6.44; ~, 7.12.
NMR (CDC13) ~: 2.42 (3H, s), 3.68 (3H, s), 6.68 (2H, m), 7.31 (2H, d),
7.82 (2H, d).
Example 1
To a solution of 2.6 g of 1-methyl-5-(p-toluoyl)pyrrole and 2.3 g of
dimethyl diazomalonate in 30 ml of toluene was added 20 mg of rhodium
acetate. The resulting mixture was refluxed with stirring for 30 minutes,
allowed to cool, and 10 ml of water was added. The toluene layer was
separated, dried over anhydrous sodium sulfate, and evaporated to dryness.
~5~
The residue was dissolved in a small amount of dichloromethane and
chromatographed on silica gel. The eluates with dichloromethane-n-
hexane gave dimethyl [l-methyl-5-(p-toluoyl~pyrrole-2]malonate (2.2 g~,
which was recrystallized from n-hexan~ iethyl ether to show ~he melting
point of 92-93C.
Analysis - Calcd. for C~8H19N05: C, 65.64; H, 5-82; N, 4.25.
Found: C, 65.42; H, 5.66; N, 4.10.
NMR (CDC13) ~: 2.42 (3H, s), 3.85 (6H, s), 3.95 (3H, s), 4.87 (lH, s),
6.31 (lH, d, J=4 Hz), 6.73 (lH, d, J=4 Hz), 7.27 (2H, d, J=8 Hz), 7.77
(2H, d, J=8 Hz).
Example 2
To a mixture of 10 ml of 10% aqueous sodium hydroxide and 20 ml of
ethanol was added 2.0 g of dimethyl ~1-methyl-5-(p-toluoyl)pyrrole-
2~malonate. The resulting mixture was refluxed for 2 hours and the
ethanol was distilled off under reduced pressure. Crystals precipitated
were collected by filtration and recrystallized from 80% ethanol to give
sodium l-methyl-5-(p-toluoyl)pyrrole-2-acetate dihydrate (1.5 g), m.p.
298-299C (decomposition).
Analysis - Calcd- for C15H14N03Na~2H20: C, 57.14; H, 5.75; N, 4.44.
Found: C, 56.94; H, 5.94; N, 4.48.
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 and dried to give l-methyl-5-(p-toluoyl)-pyrrole-2-acetic
acid, m.p. 158-160~C (decomposition).
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.
