CA1151187A - Process for preparing 1-methyl-5-(p-toluoyl)pyrrole-2- acetic acid - Google Patents
Process for preparing 1-methyl-5-(p-toluoyl)pyrrole-2- acetic acidInfo
- Publication number
- CA1151187A CA1151187A CA000379120A CA379120A CA1151187A CA 1151187 A CA1151187 A CA 1151187A CA 000379120 A CA000379120 A CA 000379120A CA 379120 A CA379120 A CA 379120A CA 1151187 A CA1151187 A CA 1151187A
- Authority
- CA
- Canada
- Prior art keywords
- toluoyl
- methyl
- acetic acid
- pyrrole
- 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
Links
Landscapes
- Pyrrole Compounds (AREA)
Abstract
ABSTRACT
A process is disclosed for preparing 1-methyl-5-(p-toluoyl)-3-carboxypyrrole-2-acetic acid which is an intermediate for 1-methyl-5-(p-toluoyl)pyrrole-2-acetic acid a known analgesic and anti-inflammatory agent.
A process is disclosed for preparing 1-methyl-5-(p-toluoyl)-3-carboxypyrrole-2-acetic acid which is an intermediate for 1-methyl-5-(p-toluoyl)pyrrole-2-acetic acid a known analgesic and anti-inflammatory agent.
Description
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
(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.
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 tIII) (IV) CH3 ~ CO ~ ,~ [C~12COOC2H5 (V) ~- ~ ~ CO ~ COOH
(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-
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
(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.
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 tIII) (IV) CH3 ~ CO ~ ,~ [C~12COOC2H5 (V) ~- ~ ~ CO ~ COOH
(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).
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).
Claims (4)
1. A process for preparing 1-methyl-5-(p-toluoyl)-3-carboxypyrrole-2-acetic acid which comprises hydrolyzing 1-methyl-5-(p-toluoyl)-3-ethoxycarbonyl-pyrrole-2-acetate.
2. The process of claim 1 wherein 1-methyl-5-(p-toluoyl)-3-ethoxycarbonylpyrrole-2-acetate is prepared by reacting p-toluoyl chloride with 1-methyl-3-ethoxycarbonylpyrrole-2-acetate.
3. The process of claims 1 or 2 wherein 1-methyl-5-(p-toluoyl)pyrrole-2-acetic acid is prepared by heating 1-methyl-5-(p-toluoyl)-3-carboxypyrrole-2-acetic acid in the presence of a base.
4. 1-Methyl-5-(p-toluoyl)-3-carboxypyrrole-2-acetic acid whenever prepared or produced by the process of claims 1 or 2 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP76827/1980 | 1980-06-06 | ||
| JP7682780A JPS572270A (en) | 1980-06-06 | 1980-06-06 | Preparation of 1-methyl-5- p-toluoyl pyrrole-2-acetic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1151187A true CA1151187A (en) | 1983-08-02 |
Family
ID=13616503
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000379120A Expired CA1151187A (en) | 1980-06-06 | 1981-06-05 | Process for preparing 1-methyl-5-(p-toluoyl)pyrrole-2- acetic acid |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS572270A (en) |
| AT (1) | AT374794B (en) |
| CA (1) | CA1151187A (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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4947752A (en) * | 1972-03-24 | 1974-05-09 |
-
1980
- 1980-06-06 JP JP7682780A patent/JPS572270A/en active Granted
-
1981
- 1981-06-05 AT AT253581A patent/AT374794B/en not_active IP Right Cessation
- 1981-06-05 CA CA000379120A patent/CA1151187A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ATA253581A (en) | 1983-10-15 |
| AT374794B (en) | 1984-05-25 |
| JPS572270A (en) | 1982-01-07 |
| JPH0135825B2 (en) | 1989-07-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |