GB1568319A - Phenoxyacetic acid derivatives - Google Patents

Phenoxyacetic acid derivatives Download PDF

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GB1568319A
GB1568319A GB38258/77A GB3825877A GB1568319A GB 1568319 A GB1568319 A GB 1568319A GB 38258/77 A GB38258/77 A GB 38258/77A GB 3825877 A GB3825877 A GB 3825877A GB 1568319 A GB1568319 A GB 1568319A
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dichloro
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Laboratoires Albert Rolland SA
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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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  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (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

(54) PHENOXYACETIC ACID DERIVATIVES (71) We, ALBERT ROLLAND, S.A., of 49, Rue-Saint André des Arts, 75006 -- Paris, France, a French Corporation, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention is concerned with processes for the preparation of 2,3 dichloro - 4 - (2 - thenoyl)phenoxyacetic acid (tienilic acid), a diuretic and uricosuric agent used in human therapy.
French Patent Specification 2,068,403 describes the preparation of tienilic acid which involves the reaction of a derivative of 2-thiophenecarboxylic acid with either, 2,3-dichloroanisole or 2,3-dichlorophenoxyacetic acid in the presence of a Lewls 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 C1-C4 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 dichloroethane. 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.
In the above formula I, R preferably represents an alkyl group of C1-C4 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:
This sequence of reactions being described in our copending Application 20299/79 (Serial No. 1,568,320), (2,3 - dichloro - 4 - hydroxy) benzoic acid (2,3 dichloro - 4 - 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 (2,3 - 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 - carboy) phenoxyacetic acid, in addition to having utility as an intermediate in preparing tienilic acid has diuretic and uricosuric activity as demonstrated in standard pharmacological procedures summarized as follows.
Diuretic and Uricosuric Activity The diuretic and uricosuric acitivity of (2,3 - dichloro - 4carboxy)phenoxyacetic acid is determined by intraveneous administration 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 - dichloro - 4 - carboxy) phenoxyacetic acid at a dose of 60 mglkg 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 40 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 OOC., the mixture is kept for 12 hours at 250C.
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 900 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 1700C. and then cooled to 1000C.; then 3 volumes of ice water and 10 ml. of 1 N aqueous solution of hydrochloric acid are added.
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 2050C.
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 17 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 /n 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 2.65 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 is 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 3 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 recrystallized from 1,2dichloroethane by filtering hot; the precipitate obtained melts at 1660C. (yield 50%).
E) Preparation of Tienilic Acid Method 1 5.12 g. of ethyl(2,3 - dichloro - 4 - carboxy)phenoxyacetate and 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 phenoxyacetate is 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 can 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) phenoxyacetic acid.
Method 2 6 g. of ethyl (2,3 - dichloro - 4 - carboxy) phenoxyacetate 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 - carbethoxymethoxy) benzoylchloride remains as a solid, m.p. 800 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 into 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 evaporated. The crude product is recrystallized from a mixture of ethanol/water (75/25) to give 6 g. of the pure ester.
WHAT WE CLAIM IS: 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:
(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 C1-C4 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 dichloroethane.
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 monochloroacetic 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- (2thenoyl)phenoxyacetic acid and its alkyl esters, substantially as herein described in the Example.
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:
where R represents hydrogen or alkyl containing from one to four carbon atoms.
11. The compound according to Claim 10, where R represents hydrogen.
12. The compound according to Claim 10, where R represents ethyl.
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (12)

**WARNING** start of CLMS field may overlap end of DESC **. temperature is maintained 2 hours. Ice water and hydrochloric acid are poured in, the organic phase decanted and the solvent evaporated. The crude product is recrystallized from a mixture of ethanol/water (75/25) to give 6 g. of the pure ester. WHAT WE CLAIM IS:
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:
(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 C1-C4 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 dichloroethane.
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 monochloroacetic 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- (2thenoyl)phenoxyacetic acid and its alkyl esters, substantially as herein described in the Example.
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:
where R represents hydrogen or alkyl containing from one to four carbon atoms.
11. The compound according to Claim 10, where R represents hydrogen.
12. The compound according to Claim 10, where R represents ethyl.
GB38258/77A 1976-09-21 1977-09-14 Phenoxyacetic acid derivatives Expired GB1568319A (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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GB38258/77A Expired GB1568319A (en) 1976-09-21 1977-09-14 Phenoxyacetic acid derivatives
GB20299/79A Expired GB1568320A (en) 1976-09-21 1977-09-14 Substituted benzoic acid

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GB20299/79A Expired GB1568320A (en) 1976-09-21 1977-09-14 Substituted benzoic acid

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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) GB1568319A (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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BE858848A (en) 1978-03-20
YU222077A (en) 1983-02-28
RO72173A (en) 1981-06-26
FR2364916B1 (en) 1979-08-17
CA1092132A (en) 1980-12-23
GR63570B (en) 1979-11-20
HU172875B (en) 1978-12-28
PL200937A1 (en) 1978-05-22
IL52881A0 (en) 1977-11-30
PT67035A (en) 1977-10-01
GB1568320A (en) 1980-05-29
DD132870A5 (en) 1978-11-15
JPS5340758A (en) 1978-04-13
CS194693B2 (en) 1979-12-31
NL7710353A (en) 1978-03-23
CH632754A5 (en) 1982-10-29
ES462472A1 (en) 1978-07-16
DE2742126A1 (en) 1978-08-03
IL52881A (en) 1981-05-20
SU736871A3 (en) 1980-05-25
PT67035B (en) 1979-02-15
IE45967B1 (en) 1983-01-12
IE45967L (en) 1978-03-21
IT1086083B (en) 1985-05-28
FR2364916A1 (en) 1978-04-14

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PS Patent sealed [section 19, patents act 1949]
PCNP Patent ceased through non-payment of renewal fee