CA1089475A - Process for the preparation of 2,3-dichloro-4-(2-thenoyl) phenoxyacetic acid - Google Patents
Process for the preparation of 2,3-dichloro-4-(2-thenoyl) phenoxyacetic acidInfo
- Publication number
- CA1089475A CA1089475A CA286,001A CA286001A CA1089475A CA 1089475 A CA1089475 A CA 1089475A CA 286001 A CA286001 A CA 286001A CA 1089475 A CA1089475 A CA 1089475A
- Authority
- CA
- Canada
- Prior art keywords
- fact
- dichloro
- diacid
- formula
- process according
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
According to the process of the invention, a diacid or diester of the following formula is decarboxylated by heating:
in which R represents H or an alkyl group, optionally followed by hydrolysis.
The 2,3-dichloro-4-(2-thenoyl) phenoxyacetic acid pre-pared in this way is a valuable diuretic and uricosuric agent.
According to the process of the invention, a diacid or diester of the following formula is decarboxylated by heating:
in which R represents H or an alkyl group, optionally followed by hydrolysis.
The 2,3-dichloro-4-(2-thenoyl) phenoxyacetic acid pre-pared in this way is a valuable diuretic and uricosuric agent.
Description
lU~ 75 1 The present invention is co~cerned with a new process for the preparation of 2,3-dichloro-4-(2-thenoyl)-phenoxyacetic acid (tienilic acid), a diuretic and urico-suric agent used in human therapy. This process makes it possible to isolate the phenoxyacetic acid product in a highly pure state by a series of simple operations and with excellent yields. ;~
The process according to the invention consists ;
of decarboxylation by heating of a compound of formula I:
~S ~ C ~ -CH ~ (I) ;
in which:
R represents H or an alkyl group, .optionally followed by hydrolysis. In the above formula, ;
R preferably represents an alkyl group of Cl-C4 and in ~ -~articular an ethyl group.
The phenoxymalonic derivatives of formula I used as starting materials are prepared by reacting, in a basic medium, an -halogenated malonic ester with (2,3-dichloro-4-hydroxyphenyl) (2-thienyl) ketone, optionally followed by hydrolysis The diester obtained is either hydrolyzed be~ore decarbo~ylàtion or decarboxylated first, followed by hydrolysis of the phenoxyacetic ester obtained.
The decarboxylation of the diacid, which leads to `~ `~
The process according to the invention consists ;
of decarboxylation by heating of a compound of formula I:
~S ~ C ~ -CH ~ (I) ;
in which:
R represents H or an alkyl group, .optionally followed by hydrolysis. In the above formula, ;
R preferably represents an alkyl group of Cl-C4 and in ~ -~articular an ethyl group.
The phenoxymalonic derivatives of formula I used as starting materials are prepared by reacting, in a basic medium, an -halogenated malonic ester with (2,3-dichloro-4-hydroxyphenyl) (2-thienyl) ketone, optionally followed by hydrolysis The diester obtained is either hydrolyzed be~ore decarbo~ylàtion or decarboxylated first, followed by hydrolysis of the phenoxyacetic ester obtained.
The decarboxylation of the diacid, which leads to `~ `~
2,3-dichloro-4-(2-thenoyl) phenoxyacetic acid, is carried : . . . ~ .:
out according to the invention by heating in various media, the decarboxylation temperature essentially being a function of these media~ When the operation is carried out on the crude product, obtained after hydrolysis, decarboxylation . ~, .
.~ - ,, ~ ~' - 2 ~ J
, ~ 7 ~
1 begins at about i0ac. and the mixture is gradually brought to about 130C. and kept at this temperature until the CO2 has be~n completely released. The reaction may also be advantageously carried out in water; the suspension of crude diacid in water (for example ~ g/100 ml) being slowly brought to about 100C. and maintained for several hours at this temperature. One then obtains phenoxyacetic acid, recrystallized from dichloroethane, at a yield higher than 90%. This decarboxylation may also take place in a homogeneous medium by heating a solution of crude diacid in a solvent such as benzene, toluene, or methylethyl-ketone, or in pyridine whose use in these reactions is well known, and in the presence or absence of copper as a catalyst. ', If the decarboxylation is carried out on the diester, one will preferably proceed,in dimethylsulfoxide `~
in the presence of a neutral mineral salt such as NaCl and water.
The phenoxymalonic or phenoxyacetic diester is hydrol~zed in classical fashion by an alkaline salt or , hydro~ide in a water-alcohol medium. The salt obtained is then acidified, for example by means of hydrochloric ; ' acid.
The following examples illustrate the invention, ' ' , ~
?S without nevertheless limiting its scope. ~ ~ , EXA~PLE 1 A) Preparation of 2,3-dichloro-4-(2-thenoyl) phenoxymalonic acid 10.8 g. ~0.2 mole) of sodium methylate and then ` '' 54,6 g. (0,~ mole) of 2,3-dichloro-4-hydroxyphenyl) (2-thienyl) ketone are dissolved in 100 ml, of anhydrous methanol. 120 ml. , ~;
,,: `
out according to the invention by heating in various media, the decarboxylation temperature essentially being a function of these media~ When the operation is carried out on the crude product, obtained after hydrolysis, decarboxylation . ~, .
.~ - ,, ~ ~' - 2 ~ J
, ~ 7 ~
1 begins at about i0ac. and the mixture is gradually brought to about 130C. and kept at this temperature until the CO2 has be~n completely released. The reaction may also be advantageously carried out in water; the suspension of crude diacid in water (for example ~ g/100 ml) being slowly brought to about 100C. and maintained for several hours at this temperature. One then obtains phenoxyacetic acid, recrystallized from dichloroethane, at a yield higher than 90%. This decarboxylation may also take place in a homogeneous medium by heating a solution of crude diacid in a solvent such as benzene, toluene, or methylethyl-ketone, or in pyridine whose use in these reactions is well known, and in the presence or absence of copper as a catalyst. ', If the decarboxylation is carried out on the diester, one will preferably proceed,in dimethylsulfoxide `~
in the presence of a neutral mineral salt such as NaCl and water.
The phenoxymalonic or phenoxyacetic diester is hydrol~zed in classical fashion by an alkaline salt or , hydro~ide in a water-alcohol medium. The salt obtained is then acidified, for example by means of hydrochloric ; ' acid.
The following examples illustrate the invention, ' ' , ~
?S without nevertheless limiting its scope. ~ ~ , EXA~PLE 1 A) Preparation of 2,3-dichloro-4-(2-thenoyl) phenoxymalonic acid 10.8 g. ~0.2 mole) of sodium methylate and then ` '' 54,6 g. (0,~ mole) of 2,3-dichloro-4-hydroxyphenyl) (2-thienyl) ketone are dissolved in 100 ml, of anhydrous methanol. 120 ml. , ~;
,,: `
- 3 - '~
a~ 7~
1 of anhydrous dimethylformamide is then poured into the mixture and the methanol is evaporated under reduced pressure before adding 38.92 g. (0.2 mole) of ethylchloro-malonate The mixture is kept at 55-60C., while stirring, for about 12 hours; 3/4 of the solvent is evaporated under reduced pressure, 2 volumes of water are added and the solution is extracted twice with ethyl ether. After desiccation of the organic phase and evaporation o~ the solvent, 83 g of orange oil is obtained, ethyl 2,3-dichloro-
a~ 7~
1 of anhydrous dimethylformamide is then poured into the mixture and the methanol is evaporated under reduced pressure before adding 38.92 g. (0.2 mole) of ethylchloro-malonate The mixture is kept at 55-60C., while stirring, for about 12 hours; 3/4 of the solvent is evaporated under reduced pressure, 2 volumes of water are added and the solution is extracted twice with ethyl ether. After desiccation of the organic phase and evaporation o~ the solvent, 83 g of orange oil is obtained, ethyl 2,3-dichloro-
4-(2-thenoyl)phenoxymalonate.
The hydrolysis of this oil is carried out, for example, as follows: 10.77 g. (0.025 mole) of the previously obtained phenoxymalonate is dissolved in 80 ml. of ethyl alcohol and 4.2 g, (0.05 mole) of sodium bicarbonate dissolved in 20 ml. of water is added. The solution is heated for 6 hours at the reflux temperature; the sodium salt of the diacid, which precipita~es out after cooling the reaction mixture, is isolated by filtration. In this ;~
way 7 g. of solid is obtained. This is dissolved in 150 ml. of water and the solution is acidified by slowly ~ ~
adding a 1.5 N aqueous solution of hydrochloric acid. ~ `
The hydrolysis of this oil is carried out, for example, as follows: 10.77 g. (0.025 mole) of the previously obtained phenoxymalonate is dissolved in 80 ml. of ethyl alcohol and 4.2 g, (0.05 mole) of sodium bicarbonate dissolved in 20 ml. of water is added. The solution is heated for 6 hours at the reflux temperature; the sodium salt of the diacid, which precipita~es out after cooling the reaction mixture, is isolated by filtration. In this ;~
way 7 g. of solid is obtained. This is dissolved in 150 ml. of water and the solution is acidified by slowly ~ ~
adding a 1.5 N aqueous solution of hydrochloric acid. ~ `
5.5 g. of 2,3-dichloro-4-(2-thenoyl) phenoxymalonic acid, ; - `
containing a small amount of phenoxyacetic derivative, precipitates out. The pure diacid melts at 150C., with decomposition.
B) Preparation of 2,3-dichloro-4-(2-thenoyl) phenoxyacetic ;~
acld 10 g. of 2,3-dichloro-4-(2-thenoyl) phenoxymalonic ~
acid is suspended in 250 ml. of distilled water and progress- ~ -ively heated to 100C. during this period, carbon dioxide `
] is released. After the gas has been released (a few hours), ~ ~: -- . : -- - .
. ~ . . : .
: . .
1 the suspension is cooled and the precipitate is filtered or extracted in ethyl ether In this way 9 g. of 2,3-dichloro-4-(2-thenoyl) phenoxyacetic acid is obtained, which can be recrystallized from dichlorethane.
4 g. of ethyl 2,3-dichloro-4-(2-thenoyl) phenoxy-malonate (prepared as in Example 1) is dissolved in 50 ml.
of dimethylsulfoxide. 0.5 ml of water and 0.6 g. of ~;
sodium chloride are added and the mixture is maintained at 150C. until the gas has been released, i.e. at least 8 hours. The solution is then poured in 3 volumes of ice water and extracted with ethyl ether. Following the usual treatments, one obtains 3 g. of ethyl 2,3-dichloro-4-(2-thenoyl) phenoxyacetate which is hydrolyzed by the action lS of an alkaline hydroxide in a water-alcohol medium, in order to obtain 2,3-dichloro-4-(2-thenoyl) phenoxyacetic acid. ~ -.~.
~ ~ ~
~; .,''''~
:;'; . ' ' S ,,. . ,~
, ~ ' ~ ', ' ' ,~
''' , ~
containing a small amount of phenoxyacetic derivative, precipitates out. The pure diacid melts at 150C., with decomposition.
B) Preparation of 2,3-dichloro-4-(2-thenoyl) phenoxyacetic ;~
acld 10 g. of 2,3-dichloro-4-(2-thenoyl) phenoxymalonic ~
acid is suspended in 250 ml. of distilled water and progress- ~ -ively heated to 100C. during this period, carbon dioxide `
] is released. After the gas has been released (a few hours), ~ ~: -- . : -- - .
. ~ . . : .
: . .
1 the suspension is cooled and the precipitate is filtered or extracted in ethyl ether In this way 9 g. of 2,3-dichloro-4-(2-thenoyl) phenoxyacetic acid is obtained, which can be recrystallized from dichlorethane.
4 g. of ethyl 2,3-dichloro-4-(2-thenoyl) phenoxy-malonate (prepared as in Example 1) is dissolved in 50 ml.
of dimethylsulfoxide. 0.5 ml of water and 0.6 g. of ~;
sodium chloride are added and the mixture is maintained at 150C. until the gas has been released, i.e. at least 8 hours. The solution is then poured in 3 volumes of ice water and extracted with ethyl ether. Following the usual treatments, one obtains 3 g. of ethyl 2,3-dichloro-4-(2-thenoyl) phenoxyacetate which is hydrolyzed by the action lS of an alkaline hydroxide in a water-alcohol medium, in order to obtain 2,3-dichloro-4-(2-thenoyl) phenoxyacetic acid. ~ -.~.
~ ~ ~
~; .,''''~
:;'; . ' ' S ,,. . ,~
, ~ ' ~ ', ' ' ,~
''' , ~
Claims (9)
1. Process for the preparation of 2,3-dichloro-4-(2-thenoyl) phenoxyacetic acid, characterized by the fact that a diacid or diester of the following formula is decar-boxylated by heating:
(I) in which R represents H or an alkyl group, optionally followed by hydrolysis,
(I) in which R represents H or an alkyl group, optionally followed by hydrolysis,
2. Process according to claim 1, characterized by the fact that R represents an alkyl group of C1-C4'
3. Process according to claim 1, characterized by the fact that the diacid of formula I is decarboxylated by heating from about 70 to 130°C.
4. Process according to claim 1, characterized by the fact that the diacid of formula I is decarboxylated in suspension in water at about 100°C., for several hours.
5. Process according to claim 1, characterized by the fact that the diacid of formula I is decarboxylated dissolved in a solvent.
6. Process according to claim 1 ro 2, characterized by the fact that the diester of formula I is decarboxylatad in solution in dimethylsulfoxide.
7. Process according to claim 1, characterized by the fact that the diacid or diester of formula I is prepared by reacting a lower alkyl ester of .alpha.-halogenated malonic acid with (2,3-dichloro-4-hydroxyphenyl) (2-thienyll ketone, optionally followed by hydrolysis.
8. A chemical intermediate having the following formula:
in which R represents hydrogen or lower alkyl of from one to four carbon atoms whenever prepared or produced by the process of claim 7 or by any obvious chemical equivalent thereof.
in which R represents hydrogen or lower alkyl of from one to four carbon atoms whenever prepared or produced by the process of claim 7 or by any obvious chemical equivalent thereof.
9. A chemical intermediate according to claim 8, characterized by the fact that R represents hydrogen whenever prepared or produced by the process of claim 7 or by any obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7628272A FR2364914A1 (en) | 1976-09-21 | 1976-09-21 | PROCESS FOR THE PREPARATION OF DICHLORO-2,3 (THENOYL-2) -4 PHENOXY-ACETIC ACID |
| FR76/28272 | 1976-09-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1089475A true CA1089475A (en) | 1980-11-11 |
Family
ID=9177879
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA286,001A Expired CA1089475A (en) | 1976-09-21 | 1977-09-01 | Process for the preparation of 2,3-dichloro-4-(2-thenoyl) phenoxyacetic acid |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5340756A (en) |
| CA (1) | CA1089475A (en) |
| CH (1) | CH623048A5 (en) |
| ES (1) | ES462470A1 (en) |
| FR (1) | FR2364914A1 (en) |
| GR (1) | GR63627B (en) |
| HU (1) | HU173514B (en) |
| IL (1) | IL52879A (en) |
| IT (1) | IT1086081B (en) |
| PL (1) | PL200936A1 (en) |
| PT (1) | PT67033B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI60005C (en) * | 1979-11-27 | 1981-11-10 | Farmos Oy | ETT NYTT FOERFARANDE FOER FRAMSTAELLNING AV (2,3-DICHLORO-4- (2-THIENYLCARBONYL) PHENOXY) -AETHYXY MED THERAPEUTIC ACTIVITIES SAMT (2,3-DICHLORO-4- (2-THIENYL CARBONYL) FENOXYAN) FOERFARANDET |
| JPH0632887B2 (en) * | 1986-08-29 | 1994-05-02 | 株式会社日立製作所 | Chamfering method |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1793212C3 (en) * | 1967-08-31 | 1974-02-21 | Egyt Gyogyszervegyeszeti Gyar, Budapest | Process for the preparation of 2,3-dichloro-4-butyryl-phenoxyacetic acid |
-
1976
- 1976-09-21 FR FR7628272A patent/FR2364914A1/en active Granted
-
1977
- 1977-09-01 CA CA286,001A patent/CA1089475A/en not_active Expired
- 1977-09-02 IL IL52879A patent/IL52879A/en unknown
- 1977-09-07 IT IT27347/77A patent/IT1086081B/en active
- 1977-09-15 PT PT67033A patent/PT67033B/en unknown
- 1977-09-19 PL PL20093677A patent/PL200936A1/en unknown
- 1977-09-19 GR GR54372A patent/GR63627B/en unknown
- 1977-09-20 HU HU77RO943A patent/HU173514B/en unknown
- 1977-09-20 JP JP11389877A patent/JPS5340756A/en active Pending
- 1977-09-20 CH CH1150977A patent/CH623048A5/en not_active IP Right Cessation
- 1977-09-20 ES ES462470A patent/ES462470A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| PT67033A (en) | 1977-10-01 |
| JPS5340756A (en) | 1978-04-13 |
| IL52879A (en) | 1981-09-13 |
| GR63627B (en) | 1979-11-27 |
| IT1086081B (en) | 1985-05-28 |
| PT67033B (en) | 1979-02-15 |
| FR2364914A1 (en) | 1978-04-14 |
| FR2364914B1 (en) | 1980-07-25 |
| PL200936A1 (en) | 1978-05-22 |
| ES462470A1 (en) | 1978-07-16 |
| IL52879A0 (en) | 1977-11-30 |
| HU173514B (en) | 1979-05-28 |
| CH623048A5 (en) | 1981-05-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |