CA1151189A - Process for preparing: 5-(p-chlorobenzoyl)-1, 4- dimethylpyrrole-2-acetic acid - Google Patents
Process for preparing: 5-(p-chlorobenzoyl)-1, 4- dimethylpyrrole-2-acetic acidInfo
- Publication number
- CA1151189A CA1151189A CA000379162A CA379162A CA1151189A CA 1151189 A CA1151189 A CA 1151189A CA 000379162 A CA000379162 A CA 000379162A CA 379162 A CA379162 A CA 379162A CA 1151189 A CA1151189 A CA 1151189A
- Authority
- CA
- Canada
- Prior art keywords
- chlorobenzoyl
- acetic acid
- dimethylpyrrole
- dimethyl
- carboxypyrrole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT
A process is disclosed for the preparation of 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid which is effected by heating 5-(p-chlorobenzoyl)-1,4-dimethyl-3-carboxypyrrole-2-acetic acid in the presence of a base. The compound is a known analgesic and anti-inflammatory agent.
A process is disclosed for the preparation of 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid which is effected by heating 5-(p-chlorobenzoyl)-1,4-dimethyl-3-carboxypyrrole-2-acetic acid in the presence of a base. The compound is a known analgesic and anti-inflammatory agent.
Description
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:
..'.~
:
:
8~
~ ~ .
Cl- ~COCl + llN~L CH2cooc2H5 (I) (II) CH3~ COOC2H5 3~ COOH
Cl~CO I CH2COOC2H5 Cl~CO I CH2COOH
(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 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-
:.
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:
..'.~
:
:
8~
~ ~ .
Cl- ~COCl + llN~L CH2cooc2H5 (I) (II) CH3~ COOC2H5 3~ COOH
Cl~CO I CH2COOC2H5 Cl~CO I CH2COOH
(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 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 $~
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-
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 $~
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 ~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.
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 ~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.
Claims
l. A process for preparing 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid which is characterized by heating 5-(p-chlorobenzoyl)-
1,4-dimethyl-3-carboxypyrrole-2-acetic acid in the presence of a base.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP76825/1980 | 1980-06-06 | ||
| JP7682580A JPS572268A (en) | 1980-06-06 | 1980-06-06 | Preparation of 5- p-chlorobenzoyl -1,4-dimethylpyrrole- 2-acetic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1151189A true CA1151189A (en) | 1983-08-02 |
Family
ID=13616447
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000379162A Expired CA1151189A (en) | 1980-06-06 | 1981-06-05 | Process for preparing: 5-(p-chlorobenzoyl)-1, 4- dimethylpyrrole-2-acetic acid |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS572268A (en) |
| AT (1) | AT374176B (en) |
| CA (1) | CA1151189A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0230110A1 (en) * | 1985-11-30 | 1987-07-29 | FISONS plc | Pharmacologically active pyrrole and pyrazole derivatives |
-
1980
- 1980-06-06 JP JP7682580A patent/JPS572268A/en active Pending
-
1981
- 1981-06-05 AT AT253381A patent/AT374176B/en active
- 1981-06-05 CA CA000379162A patent/CA1151189A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ATA253381A (en) | 1983-08-15 |
| AT374176B (en) | 1984-03-26 |
| JPS572268A (en) | 1982-01-07 |
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| MKEX | Expiry |