IE45967B1 - Phenoxyacetic acid derivatives - Google Patents

Phenoxyacetic acid derivatives

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Publication number
IE45967B1
IE45967B1 IE1933/77A IE193377A IE45967B1 IE 45967 B1 IE45967 B1 IE 45967B1 IE 1933/77 A IE1933/77 A IE 1933/77A IE 193377 A IE193377 A IE 193377A IE 45967 B1 IE45967 B1 IE 45967B1
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IE
Ireland
Prior art keywords
acid
dichloro
compound
process according
alkyl
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IE1933/77A
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IE45967L (en
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Rolland Sa A
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Application filed by Rolland Sa A filed Critical Rolland Sa A
Publication of IE45967L publication Critical patent/IE45967L/en
Publication of IE45967B1 publication Critical patent/IE45967B1/en

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    • 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
    • C07D333/26—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C07D213/20—Quaternary compounds thereof
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (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)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

2,3-Dichloro-4-(2-thenoyl)phenoxyacetic acid is a drug possessing a diuretic effect. It is prepared by acylating thiophene with 2,3-dichloro-4-carboxyphenoxyacetic acid or its alkyl ester. In the latter case, the resulting ester is hydrolysed.

Description

The present invention is concerned with processes for the preparation of 2,3-dichioro-4-(2-thenoyl)phenoxyacetic acid (tienilic acid), a diuretic and uricosuric agent used in human therapy.
French Pateiit Specification 2,058,403 describes the preparation of tienilic acid which involves the reaction of a derivative of 2-thiophenecarbdxylic acid with either 2,3-dichloroanisole or 2,3-dichlorophenoxyacetic acid in the presence of a Lewis catalyst.
According to this invention there is provided a process for the preparation of 2,3-dichloro-4-(2-thenoyl)phenoxyacetic acid and alkyl esters thereof, which comprises acylating thiophene with a compound of the formula: (where R is hydrogen or an alkyl group and X is hydroxy or chloro) (a) in the presence of a dehydration agent when X is hydroxy and R is hydrogen or an alkyl group, or (b) in the presence of stannic chloride when X is chloro and R is an alkyl group, and if desired subjecting the product to hydrolysis when R is alkyl in the compound produced.
R is conveniently a C^-C^ alkyl group, for example an ethyl group.
The dehydration agent is polyphosphoric acid or trifluoroacetic anhydride, for example. A solvent is preferably used, for example benzene, methylene chloride or di chloroethane. The reaction is usually complete in from 1-8 hours. It is also possible to use the product of the action of phosphoric anhydride on methane sulfonic acid, as described in J. Org.
Chem. 38 4071 (1973), as the dehydration agent. However, the yields of the reaction have been lower in this latter case.
Alternatively, the compound of formula I wherein R represents an alkyl group can be converted into the corresponding acid chloride by reaction with thionyl chloride and then condensed with thiophene in the presence of stannic chloride and in a solvent such as 1-,2-dichloroethane. - 2 45967 In the above formula I, R preferably represents an alkyl group of C-j-C^ and more particularly an ethyl group.
The compound of formula I can be prepared from 2,3-dichloroanisole by carrying out, for example, the following reactions: Cl Cl Cl Cl O-CHo + Cl-CHp-CO-Cl A1C13 > ci-CH„- C , O-CH, ch2ci2 I! This sequence of reactions is described in British Patent Specification from No. 1,568,320, and/(2,3-dichloro-4-hydroxy)benzoic acid,(2,3,-dichloro-420 carboxy)phenoxyacetic acid can be obtained for such by reaction with monochloroacetic acid in the presence of sodium hydroxide or by reaction with ethyl monochloroacetate followed by hydrolysis. It is possible to transform (Z,3-dichloro-4-carboxy)phenoxyacetic acid into its ethyl ester, which has a significantly higher solubility in organic media than the free acid, for example, by monoesterification. (2,3-Dichloro-4-carboxy)phenoxyacetic acid, in addition to having utility as an intermediate in preparing tienilic acid has a diuretic and uricosuric activity as demonstrated in standard pharmacological procedures summarized as follows.
Diuretic and Uricosuric Activity.
The diuretic and uricosuric activity of (2,3dichloro-4-carboxy)phenoxyacetic acid is determined by intraveneous admin- 3 45967 istration to the phosphate-mannitol infused mongrel dog.
From renal clearance studies,the effect of the test compound upon kidney function is determined by measurement of effective renal plasma flow, glomerular filtration rate and filtration fraction. Urine volume, pH, electrolyte and uric acid excretion are also determined. In this study, (2,3-diehloro-4carboxy) phenoxyacetic acid at a dose of 60 mg/kg i.v. increased sodium and potassium excretion and increased uric acid filtered by 116%.
The following example illustrates the invention.
EXAMPLE A) Preparation of (2,3-dichloro-4-methoxyphenyl) chloromethyl ketone ~ ~ g. of aluminum chloride is added in small portions to a solution, kept at 0°C., of 53 g. of 2,3-dichloroanisole and 37 g. of chloracetyl chloride in 400 ml. of methylene chloride. After 2. hours at 0°C., the mixture is kept for 12 hours at 25°C. and then poured over a mixture of ice and concentrated hydrochloric acid. The organic phase is decanted and the aqueous phase is once again extracted with chloroform. The residue obtained after evaporating the organic solvents is recrystallized in a mixture of benzene and petroleum ether (1/1) to give in 80% yield, the ketone which melts at 90°C.
B) Preparation of N-[(2,3-dichloro-4-hydroxyphenyl) carbonylmethyl) pyridinium chloride A mixture of 231 g. of pyridine hydrochloride and 77 g. of the previously obtained ketone is kept for 10 minutes at 170°C. and then cooled to 100°C.; then 3 volumes of ice water and 10· ml. of IN aqueous solution of hydrochloric acid are added. - 4 45867 The precipitate is isolated and then washed with boiling methanol to obtain in 75% yield, the pyridine derivative which melts higher than 250°c.
C) Preparation of (2,3-dichloro-4-hydroxy) benzoic acid 49.6 g. Of the preceding compound is suspended in 400 ml. of water containing 20 g. of sodium hydroxide and the mixture is kept at the reflux temperature until the solid has completely disappeared, i.e., about 4 hours. The solution is acidified by adding concentrated hydrochloric acid. The precipitate formed is separated out and recrystallized from dichloroethane to give in 95% yield, the acid which melts at 205°C.
D) (2,3-Dichloro-4-carboxy) phenoxyacetic acid is then prepared by the action of sodium monochloracetate on the phenol compound prepared in (C)., in the presence of sodium hydroxide in aqueous or alcoholic solution, or also by the action of ethylmonochloracetate on the compound prepared in (C) in alcohol solution, followed by hydrolysis in a basic aqueous medium.
METHOD 1 g. of (2,3-dichloro-4-hydroxy) benzoic acid is added to 100 ml. of a 3 N aqueous solution of sodium hydroxide, followed by the addition of 9.45 g. of monochloracetic acid. After 2 hours of reflux, 5 g. of sodium hydroxide and 4.7 g. of monochloracetic acid is added once again and the reflux is extended for 2 hours.
The aqueous solution is then acidified and the precipitate is filtered and recrystallized in a dioxane/water mixture (50/50) to give the acid product which melts at more than 250°C., with 70% yield.
METHOD 2 4.8 g. of (2,3-dichloro-4-hydroxy) benzoic acid is heated for 1 hour at the reflux temperature in 50 ml. of ethyl alcohol containing 2.55 g. of potassium hydroxide and 3.9 g. of potassium iodide. Then 5.9 g. of ethyl monochloracetate is added and the mixture is kept at the reflux temperature until it becomes neutral. 50 ml. of water and 5 g. of potassium hydroxide are then added and the mixture refluxed for another 1-1/2 hours. The reaction mixture is cooled, poured into water, and acidified with hydrochloric acid, separating the precipitated diacid (yield 75%).
Ethyl (2,3-dichloro-4-carboxy) phenoxyacetate is obtained by monoesterification of the diacid. Thus 20 g. of the diacid is dissolved in 250 ml. of benzene,and 250 ml. of ethyl alcohol and 1.2 ml. of concentrated sulfuric acid are added. The solution is kept at the reflux temperature for f hours. After neutralization by adding sodium bicarbonate, the solvents are evaporated and the residue is dissolved in an aqueous solution of sodium carbonate. The aqueous phase is then acidified and the precipitate is filtered and recrysfcallized from 1,2-dichloroethane by filtering hot; the precipitate obtained melts at 166°C. (yield 50%).
E) Preparation of tienilic acid METHOD 1: .12 g. of ethyl(2,3-dichloro-4-carboxy)phenoxyaceta.teand 1.68 g. of thiophene are added to a mixture of 40 g. of polyphosphoric acid and 200 ml. of benzene, while vigorously agitating. The reaction mixture is kept for 10 hours at the reflux temperature of benzene and then is poured into 2 volumes of water. The benzene phase is decanted and the aqueous phase is extracted with ether. The organic phases are washed with an aqueous solution of sodium hydroxide, dried, and the solvents evaporated. 1.2 g. of ethyl 2,3-dichloro-4-(2-thenoyl) phenoxyacetateis isolated, which is hydrolyzed by the action of potassium hydroxide in ethyl alcohol at the reflux temperature in order to obtain tienilic acid with a yield of 90%.
During this reaction it is also possible to use as a solvent methylene chloride or 1,2-dichloroethane. Also, thiophene may be added in portions during the course of heating.
Furthermore, it is also possible to use the same procedural method to acylate the (2,3-dichloro-4-carboxy ) phenoxyacetio acid.
METHOD 2 g, of ethyl (2,3-dichloro-4-carboxy) phenoxy15 acetate and 30 ml. of thionyl chloride are heated 3 hours at about 80°C. Benzene is added and the liquid distilled under reduced pressure.
The crude product (2,3-dichloro-4-oarbethoxymethoxy) benzoylchloride remains as a solid, m.p. 80°C. 2.8 g. of thiophene and 8.5 g. of the acid chloride obtained above are dissolved in 100 ml. of 1,2-dichloroethane.
At about 0°C., 3.2 ml. of stannic chloride is introduced in the solution. The mixture is slowly heated to 60°C. and this temperature is maintained 2 hours. Ice water and hydrochloric acid are poured in, the organic phase decanted and the solvent from evaporated. The crude product is recrystallized / a mixture of ethanol/water (75/25) to give 6 g. of the pure ester.

Claims (13)

1, A process for the preparation of 2,3-dichloro-4-(2-thenoyl) phenoxyacetic acid and alkyl esters thereof, which comprises acylating thiophene with a compound of the formula: Cl Cl XC (where R is hydrogen or an alkyl group and X is hydroxy or chloro) a) in the presence of a dehydration agent when X is hydroxy and R is hydrogen or an alkyl group, or b) in the presence of stannic chloride when X is chloro and R is an alkyl group, and if desired subjecting the product to hydrolysis when R is alkyl in the compound produced.
2. A process according to Claim 1, where R is a C-|-C^ alkyl group.
3. A process according to Claim 1 or Claim 2, wherein the dehydration agent is polyphosphoric acid or trifluoroacetic anhydride.
4. A process according to Claim 3, wherein the reaction is carried out in the presence of a solvent.
5. A process according to Claim 4, wherein the third solvent is benzene, methylene chloride or di chloroethane.
6. A process according to Claim 1, wherein the compound of formula I is prepared by reacting (2,3-dichloro-4-hydroxy) benzoic acid with monodhloroacetic acid or an alkyl monochloroacetate, respectively, optionally followed by hydrolysis.
7. A process according to Claim 1, substantially as herein described.
8. A process for the preparation of 2,3-dichloro-4-(2-thenoyl)phenoxyacetic acid and its alkyl esters, substantially as herein described in the Example. -3 5
9. 2,3-Dichloro-4-(2-thenoyl)phenoxyacetic acid and its alkyl esters, when prepared by a process according to any of the preceding claims.
10. A compound of the formula: Cl Cl HOOC where R represents hydrogen or alkyl containing from one to four carbon 10 atoms.
11. The compound according to Claim 10, where R represents hydrogen.
12. The compound according to Claim 10, where R represents ethyl.
13. 15 Dated this 20th day of September 1982.
IE1933/77A 1976-09-21 1977-09-21 Phenoxyacetic acid derivatives IE45967B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR7628274A FR2364916A1 (en) 1976-09-21 1976-09-21 PROCESS FOR OBTAINING DICHLORO-2,3 (THENOYL-2) -4 PHENOXYACETIC ACID

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IE45967L IE45967L (en) 1978-03-21
IE45967B1 true IE45967B1 (en) 1983-01-12

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JP (1) JPS5340758A (en)
BE (1) BE858848A (en)
CA (1) CA1092132A (en)
CH (1) CH632754A5 (en)
CS (1) CS194693B2 (en)
DD (1) DD132870A5 (en)
DE (1) DE2742126A1 (en)
ES (1) ES462472A1 (en)
FR (1) FR2364916A1 (en)
GB (2) GB1568320A (en)
GR (1) GR63570B (en)
HU (1) HU172875B (en)
IE (1) IE45967B1 (en)
IL (1) IL52881A (en)
IT (1) IT1086083B (en)
NL (1) NL7710353A (en)
PL (1) PL200937A1 (en)
PT (1) PT67035B (en)
RO (1) RO72173A (en)
SU (1) SU736871A3 (en)
YU (1) YU222077A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2916980C2 (en) * 1979-04-26 1981-06-19 Ludwig Heumann & Co GmbH, 8500 Nürnberg Process for the preparation of thenoyl-phenoxyacetic acid esters

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2458520A (en) * 1945-11-08 1949-01-11 Socony Vacuum Oil Co Inc Acylation of thiophene

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ES462472A1 (en) 1978-07-16
HU172875B (en) 1978-12-28
YU222077A (en) 1983-02-28
RO72173A (en) 1981-06-26
FR2364916A1 (en) 1978-04-14
IL52881A0 (en) 1977-11-30
GB1568319A (en) 1980-05-29
PL200937A1 (en) 1978-05-22
CH632754A5 (en) 1982-10-29
NL7710353A (en) 1978-03-23
CS194693B2 (en) 1979-12-31
FR2364916B1 (en) 1979-08-17
PT67035B (en) 1979-02-15
SU736871A3 (en) 1980-05-25
IL52881A (en) 1981-05-20
BE858848A (en) 1978-03-20
DE2742126A1 (en) 1978-08-03
IT1086083B (en) 1985-05-28
PT67035A (en) 1977-10-01
GB1568320A (en) 1980-05-29
JPS5340758A (en) 1978-04-13
CA1092132A (en) 1980-12-23
IE45967L (en) 1978-03-21
GR63570B (en) 1979-11-20
DD132870A5 (en) 1978-11-15

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