CA1151188A - 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
- CA1151188A CA1151188A CA000379152A CA379152A CA1151188A CA 1151188 A CA1151188 A CA 1151188A CA 000379152 A CA000379152 A CA 000379152A CA 379152 A CA379152 A CA 379152A CA 1151188 A CA1151188 A CA 1151188A
- Authority
- CA
- Canada
- Prior art keywords
- pyrrole
- methyl
- toluoyl
- compound
- formula
- 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)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT
A process is disclosed for preparing a compound of the formula
A process is disclosed for preparing a compound of the formula
Description
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 ,~
- ~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
- ~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:
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 (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.
N a condensing agent 3 Na catalyst (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.
Claims (5)
1. A process for preparing a compound of the formula which comprises reacting in the presence of a catalyst 1-methyl-5-(p-toluoyl)pyrrole with a compound of the formula wherein R1 and R2 are identical or different and each represens a lower alkyl.
2. The process of claim 1 wherein the 1-methyl-5-(p-toluoyl)pyrrole is prepared by reacting in the presence of a condensing agent 1-methyl pyrrole with a compound of the formula wherein R3 and R4 are identical or different and each represents a lower alkyl or R3 and R4 may be combined with the nitrogen atom present to form a heterocyclic group.
3. The process of claim 1 wherein the 1-methyl-5(p-toluoyl)pyrrole is prepared by methylation of 5-(p-toluoyl)pyrrole.
4. The process of claims 1, 2 or 3 wherein the compound wherein R1 and R2 are as previously defined, is hydrolyzed and decarboxylated to prepare 1-methyl-5-(p-toluoyl)pyrrole-2-acetic acid.
5. The compound of the formula wherein R1 and R2 are identical or different and each represents a lower alkyl whenever prepared or produced by the process of claims 1, 2 or 3 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7682680A JPS572269A (en) | 1980-06-06 | 1980-06-06 | Preparation of 1-methyl-5- p-toluoyl pyrrole-2-acetic acid |
| JP76826/1980 | 1980-06-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1151188A true CA1151188A (en) | 1983-08-02 |
Family
ID=13616476
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000379152A Expired CA1151188A (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) | JPS572269A (en) |
| AT (1) | AT374793B (en) |
| CA (1) | CA1151188A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4873340A (en) * | 1986-05-29 | 1989-10-10 | Syntex (U.S.A.) Inc. | Process for preparing 5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-A]pyrrole-1,1-dicarboxylates |
| US4988822A (en) * | 1986-05-29 | 1991-01-29 | Syntex (U.S.A.) Inc. | Intermediates for preparing 5-aroyl-1,2-dihydro-3H-pyrrolo(1,2-A)pyrrole-1,1-dicarboxylates |
-
1980
- 1980-06-06 JP JP7682680A patent/JPS572269A/en active Granted
-
1981
- 1981-06-05 AT AT253481A patent/AT374793B/en not_active IP Right Cessation
- 1981-06-05 CA CA000379152A patent/CA1151188A/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4873340A (en) * | 1986-05-29 | 1989-10-10 | Syntex (U.S.A.) Inc. | Process for preparing 5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-A]pyrrole-1,1-dicarboxylates |
| US4988822A (en) * | 1986-05-29 | 1991-01-29 | Syntex (U.S.A.) Inc. | Intermediates for preparing 5-aroyl-1,2-dihydro-3H-pyrrolo(1,2-A)pyrrole-1,1-dicarboxylates |
Also Published As
| Publication number | Publication date |
|---|---|
| AT374793B (en) | 1984-05-25 |
| ATA253481A (en) | 1983-10-15 |
| JPS572269A (en) | 1982-01-07 |
| JPS649987B2 (en) | 1989-02-21 |
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| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |