US3832354A - 4-hydroxy-5-phenyl-3-thiophene acetic acids and their derivatives - Google Patents

Abstract

THE INVENTION CONCERNS SUBSTITUTED OR NON-SUBSTITUTED 4-HYDROXY-5-PHENYL-3-THIOPHENE ACETIC ACIDS WHICH ARE USEFUL AS ANTIPHLOGISTICS AND ANTI-ARTHRITS AGENTS.

Description

United States Patent Oihce 3,832,354 Patented Aug. 27, 1974 US. Cl. 260-3321 A 29 Claims ABSTRACT OF THE DISCLOSURE The invention concerns substituted or non-substituted 4-hydroxy-5-pheny1-3-thiophene acetic acids which are useful as antiphlogistics and anti-arthritis agents.

This application is a continuation-in-part of Ser. No. 277,126, filed August 1, 1972, now abandoned.

The present invention relates to heterocyclic compounds and more specifically to substituted 2-phenylthiophene compounds.

The present invention provides compounds of formula COR:

wherein R is hydrogen or alkyl of 1 to 4 carbon atoms, R is hydroxy, alkoxy of 1 to 4 carbon atoms, cycloalkyloxy of 3 to 6 carbon atoms, cycloalkylalkoxy of 3 to 6 ring carbon atoms and 1 to 4 alkoxy carbon atoms, amino, monoalkylamino of 1 to 4 carbon atoms or dialkylamino, each alkyl substituent having 1 to 4 carbon atoms, or R and R together denote a single bond, R is hydrogen, chlorine or alkyl of 1 to 4 carbon atoms, or when R is hydrogen, or when R and R together denote a single bond, then K, may be hydroxy, or when R is alkyl of 1 to 4 carbon atoms, then R may be alkoxy of 1 to 4 carbon atoms,

I R, is hydrogen, chlorine, bromine or alkyl of 1 to 4 carbon atoms,

or when R is hydrogen, or when R, and R together denote a single bond, then R, may be hydroxy, or when R, is alkyl of 1 to 4 carbon atoms, then R, may be alkoxy of 1 to 4 carbon atoms, or when R, is hydrogen, then R, may be fluorine or trifluoromethyl, R is hydrogen or alkyl of 1 to 4 carbon atoms, and R is hydrogen or methyl.

It is to be understood that when any of the above groups is or includes a non-cyclic alkyl group of more than 2 carbon atoms, this may be straight or branched chain.

The present invention also provides a process for producing a compound of formula I, which comprises (a) Solvolysing CN to COR wherein R is hydroxy, amino, primary or secondary alkoxy of l to 4 carbon atoms or cycloalkylalkoxy of 3 to 6 ring carbon atoms and 1 to 4 alkoxy carbon atoms, or cycloalkyloxy of 3 to 6 carbon atoms,

in a compound of formula H,

wherein R is hydrogen or alkyl of 1 to 4 carbon atoms, R is hydrogen, chlorine, or alkyl of 1 to 4 carbon atoms,

or when R is hydrogen, then R may be hydroxy, or when R is alkyl of 1 to 4 carbon atoms, then R; may be alkoxy of 1 to 4 carbon atoms, R is hydrogen, chlorine, bromine, or alkyl of 1 to 4 carbon atoms,

or when R is hydrogen, then R,, may be hydroxy, or when R is alkyl of 1 to 4 carbon atoms, then R} may be alkoxy of 1 to 4 carbon atoms, or when R is hydrogen, then R may be fluorine or trifluoromethyl, and R and R are as defined above, to produce a compound of formula Ia,

wherein R5, R6, R1I, R21, and R41 are as defined above, or

(b) Hydrolyzing a compound of formula I0,

R,- R! 0R1 ll s s wherein R R R R and R are defined above, and

R is alkoxy of 1 to 4 carbon atoms, cycloalkyloxy of 3 to 6 carbon atoms or cycloalkylalkoxy of 3 to 6 ring carbon atoms and 1 to 4 alkoxy carbon atoms,

to produce a compound of formula Ib,

COOH

wherein R R R R and R are as defined above, or

(c) Esterifying an acid of formula lb, or a reactive acid derivative thereof, to produce a compound of formula Ic, or

(d) Reacting a compound of formula Ie, Ia, 10, or

with a compound of formula III,

III wherein R is alkyl of 1 to 4 carbon atoms, and X is iodine, chlorine, bromine, R 80; wherein R is as defined above, or an organic sulphonate group,

to produce a compound of formula Id,

omm

R5 C-Ro Bi wherein R is alkyl of 1 to 4 carbon atoms, R is alkoxy of 1 to 4 carbon atoms, cycloalkylalkoxy of 3 to 6 carbon atoms, cycloalkylalkoxy of 3 to 6 ring carbon atoms and 1 to 4 alkoxy carbon atoms, or dialkylamino, each alkyl substituent having 1 to 4 carbon atoms,

R is hydrogen, chlorine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms,

R is hydrogen, chlorine, bromine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms,

or when R is hydrogen, then R," may be fluorine or trifluoromethyl, and R, and R 1 are as defined above, or

(e) Reacting an acid of Formula lb, or a reactive acid derivative thereof, with a compound of formula IV,

mm W

wherein R is amino, monoalkylamino of 1 to 4 carbon atoms or dialkylamino, each alkyl substituent having 1 to 4 carbon atoms,

to produce a compound of formula I),

C O R a a 0 R1 wherein R R RJ, R R and Rz are as defined above,

(f) Splitting the ether groups to form hydroxy groups in a compound of formula Ih,

wherein R R R R R and R are as defined above,

to produce a compound of formula Ig,

CORZIV a wherein R R and R are as defined above, R is hydrogen, chlorine, alkyl of 1 to 4 carbon atoms or hydroxy, and R is hydrogen, chlorine, bromine, alkyl of 1 to 4 car- -bon atoms or hydroxy, or when R is hydrogen, then R may be fluorine or trifluoromethyl, or

(g) Cyclizing a compound of formula If,

COOH

R5- Ru OH IL m wherein R R R and R are as defined above, to produce a compound of formula Ii,

00 RAJ-R, o

wherein R R R and R are as defined above.

The compounds of formula I, wherein R is hydroxy and/or R is hydrogen, may exist either in free acidic form or in salt form. Salt forms may be formed from free acidic forms in manner known per se and vice versa.

The compounds of formula I wherein R is different to R exist in optical isomeric forms. It is to be understood that formula I embraces the optically pure forms as well as the racemic forms of such compounds.

Process (a) may be effected according to the standard methods for solvolysing cyanides. As will be readily appreciated, the nature of the resulting compound, i.e. acid, amide or ester, will depend on the reaction conditions and solvolysing agent employed.

As will also be appreciated, the choice of the appropriate hydrolysis conditions is determined by the reactivity of the nitrile substituent of the compound of formula II, which is dependent on the degree and nature of the substituents on the carbon atom a to the nitrile substituent.

Thus, for example, an amide of formula Ia may be produced by alkaline or acid hydrolysis of the cyanide of formula II. Alkaline hydrolysis may be effected in i the presence of a dilute aqueous alkali metal hydroxide solution, e.g. 0.5 to 5 N caustic soda solution at a temperature of between room temperature and 100 C. Alternatively, alkaline hydrolysis may be effected with hydrogen peroxide in the presence of a dilute aqueous alkaline solution. Acid hydrolysis may be effected by employing the required amount of aqueous mineral acid at about room temperature.

A carboxylic acid of formula Ia may be produced, for example, by hydrolysis in the presence of a strong basic catalyst, e.g. 2 N to 50% alkaline solution, or in the presence of a strong acid catalyst, e.g. a strong mineral acid, such as concentrated hydrochloric acid or 20 to 75% sulphuric acid. The hydrolysis may be effected at a temperature between 60 and 160 C., optionally in a bomb tube.

A carboxylic acid ester of formula Ia may be produced by solvolysis with an aqueous alcohol (containing 1 to 3 mols of water per mol of the compound of formula II) of formula Vb,

wherein R is primary or secondary alkyl of 1 to 4 carbon atoms or cycloalkylalkyl of 3 to 6 ring carbon atoms and 1 to 4 side chain alkyl carbon atoms, or cycloalkyl of 3 to 6 carbon atoms,

in the presence of an acid, e.g. hydrogen chloride gas or sulphuric acid. Preferably, however, the reaction is effected by first converting a compound of formula II, with an alcohol of formula Vb in the presence of an acid catalyst, into an imino ether of formula VI,

wherein R R R}, R R and R are as defined above,

and then hydrolysing the resulting compound with the required amount of water. Thus the reaction may, for example, be effected by passing hydrogen chloride gas through a solution of a compound of formula II in an alcohol of formula Vb, at a reduced temperature, preferably at a temperature between 10 and +10 0., subsequently allowing reaction at a temperature between and 100 C. for 10 to 25 hours, and then hydrolysing the resulting compound of formula VI, optionally after evaporating excess solvent which may have been used, with 1 to 3 mols of water calculated on one mol of the compound of formula VI, for approximately 1 to hours at a temperature of approximately 50 to 100 C., preferably at the boiling temperature of the reaction mixture. As will be readily appreciated, the solvolysis reactions hereinbefore described may, if desired, be effected in the presence of a water-miscible inert organic solvent.

Process (b) may be carried out in accordance with the usual methods for ester hydrolysis. For example, the compounds of formula Ic may be allowed to react with water, optionally in an inert water-miscible organic solvent, e.g. an alkanol such as methanol or ethanol, acetone, tetrahydrofuran or dioxane, in the presence of a basic catalyst, e.g. an alkali metal or alkali earth metal hydroxide, or in the presence of an acid catalyst, e.g. a mineral acid such as hydrochloric or sulphuric acid, or an organic sulphonic acid, at a temperature between room temperature and approximately 100 C. for 1 to 50 hours. Hydrolysis is preferably effected in an alkaline medium, e.g. with at least one equivalent amount of an aqueous alkali metal hydroxide, at room temperature or at slightly elevated temperature, whereby an alkali metal salt of a compound of formula Ib is obtained. Alkaline hydrolysis is particularly preferred when R in the compounds of formula Ib is hydrogen, since lactone formation, which may otherwise occur as side reaction in an acid medium, is avoided or reduced.

Process (c) may be carried out in accordance with the usual processes for ester formation. For example, a solution of an acid of formula Ib in an excess of an alcohol of formula V,

RqOH V wherein R is alkyl of l to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 3 to 6 ring carbon atoms and 1 to 4 side chain alkyl carbon atoms,

may be allowed to react in the presence of an acid condensation agent, e.g. sulphuric acid, hydrogen chloride gas, an organic sulphonic acid or an acid ion exchange substance, optionally with the addition of an inert organic solvent, e.g. an ether or an aromatic hydrocarbon such as benzene or toluene, at a temperature between room temperature and approximately C. Removal of the water formed during esterification by azeotropic distillation may generally be found to be advantageous.

Production of a tertiary ester may be effected by using the ester form of the alcohol of formula V, preferably an ester thereof with a carboxylic acid, especially the formate. Reactive derivatives of the acid of formula lb may also be employed. Suitable reactive derivatives of an acid of formula Ib are, for example, the acid halides thereof, the mixed anhydrides of an acid of formula Ib with a suitable organic carboxylic acid, or a suitable alkyl ester of an acid of formula Ib. Thus, for example, the acid of formula Ib may first be converted into its acid chloride by reaction with a suitable inorganic acid chloride, e.g. phosphorus trichloride, phosphorus pentachloride or thionyl chloride, and the resulting acid chloride may subsequently be esterified with an alcohol of formula V, optionally in the presence of an acid-binding agent, e.g. an organic base such as pyridine or a tertiary amine. It is also possible to react the alcohol in the form of a Grignard derivative of formula Va,

R OMgY Va wherein R; is as defined above, and Y is chlorine or bromine,

with an acid chloride or an acid of formula Ib. The latter reaction is particularly applicable to the production of esters of tertiary alcohols. The exchange of ester radicals of an alkyl ester of an acid of formula Ib with a tertiary alcohol is likewise particularly suited to the production of esters of tertiary alcohols. This reaction is preferably effected in the presence of a catalytic amount of metallic sodium, at a temperature between approximately 80 and C., by melting. The production of a methyl ester may, for example, also be effected by reacting the acid of formula Ib with diazomethane in conventional manner.

The alkylation of process (cl) may, for example, be effected by converting a compound of formula Ie, in the presence of an inert solvent, e.g. liquid ammonia, an organic aprotic, prefer-ably polar, solvent, e.g. dimethyl formamide, dimethyl sulphoxide or hexamethyl phosphoric acid triamide, a suitable ether such as 1,2-dimethoxyethane or tetrahydrofuran, or an aromatic hydrocarbon such as benzene or toluene, into its anion, with a strong basic condensation agent, e.g. an alkali metal, an alkali metal amide such as sodamide, an alkali metal hydride such as sodium hydride, or an alkali metal alcoholate, and reacting the resulting compound with a compound of formula III at a temperature of approximately -50 to approximately +60 C. When R is hydrogen or any of R R or R are hydroxy in the compounds of formula Ie, these are converted into alkoxy groups, and when R is amino or monoalkylamino, this is alkylated to a dialkylamino group. When R in the compounds of formula Ie denotes hydrogen, and it is desired to obtain a monoalkylation on the carbon atom to which it is attached, the reaction is preferably effected in liquid ammonia, in the presence of an equivalent amount of sodamide, at a reduced temperature, and the alkylating agent is added slowly. When R in formula Ie denotes hydrogen, the reaction is preferably effected in a polar organic solvent, e.g. dimethyl formamide or dimethyl sulphoxide, using sodium hydride as condensation agent, in order to obtain complete etherification.

Process (e) may be carried out in accordance with the usual methods of acid amide production. Thus, for example, an acid of formula Ib may be allowed to react at a temperature between approximately 100 and 250 C., with a compound of formula IV, preferably with excess of the latter. The reaction may, for example, be effected by melting, or effected in an inert solvent, e.g. an aromatic hydrocarbon such as benzene or toluene, conveniently with the removal of the resulting water by azeotropic distillation. In place of the free acids of formula Ib it is also possible to react reactive derivatives thereof, e.g. acid halides, suitably alkyl esters or mixed anhydrides of an acid of formula Ib with a suitable carboxylic acid, with a compound of formula IV. The reaction with acid halides or mixed anhydrides of an acid of formula Ib may, for example, be effected by using an excess of a compound of formula IV, or in the presence of an acidbinding agent, e.g. an alkali metal hydroxide or an organic base, e.g. pyridine or a tertiary amine, in the presence of water, and optionally in an inert water-miscible organic solvent, preferably at room temperature or at a slightly elevated temperature. An alkyl ester of an acid of formula Ib may be reacted with a compound of formula IV, for example at a temperature between approx. 100 and 250 C., optionally in an autoclave, optionally with the addition of an inert organic solvent, e.g. an alkanol.

Process (f) may be carried out in accordance with the usual methods for ether splitting. Thus, for example, a compound of formula II: may be allowed to react with a Lewis acid, e.g. boron tribromide or aluminium chloride, in an inert organic solvent, e.g. a halogenated hydrocarbon such as methylene chloride or carbon tetrachloride, or an aromatic hydrocarbon such as toluene or benzene, at -80 to +70 C. It is also possible to treat the compound of formula Ih for a short time with a strong mineral acid, e.g. hydrobromic or hydriodic acid, optionally at an elevated temperature, e.g. at approx. 20 to 100 C., optionally with the addition of glacial acetic acid. Any ester or amide groups in the compounds of formula Ih are thus simultaneously hydrolyzed to the carboxyl group. The ether splitting of the compounds of formula Ih with an alkali metal alkyl mercaptide, or an 'alkali metal or alkali metal hydride/alkyl mercaptane combination, e.g. sodium hydride/ethyl mercaptane, in an inert polar organic solvent, e.g. dimethyl formamide, at a temperature between approx. 50 and 150 C., preferably 80 to 120 C., has been found to be specially convenient. In this r eaction any ester and amide groups in the compounds of formula II: are also split when using an excess of reagent. However, such groups are generally not affected when using an equimolar amount of reagent. In accordance with a further process variant, lithium iodide may be allowed to react with a compound of formula Ih in the presence of 2,4,6-trimethyl pyridine at a temperature between 100 and 150 C.

The cyclization of the invention in accordance with process (g) may, for example, be effected by heating a compound of formula If to a temperature of approx. 80 to 180 C. The reaction is preferably effected in the presence of an acid condensation agent, optionally with the addition of an inert organic solvent, e.g. an aromatic hydrocarbon such as benzene or toluene. Acetic anhydride is preferred as acid condensation agent, optionally with benzene as solvent. Examples of other suitable condensation agents are strong mineral acids, e.g. polyphosphoric acid or sulphuric acid.

The compounds of formula I may be isolated from the reaction mixture and purified in known manner; the

free acidic compounds of formula I, wherein R is hydroxy and/or R is hydrogen, may be converted into salt form in conventional manner. Such salt forms include alkali metal salts, e.g. sodium and potassium salts. If desired, the racemates of the compounds of formula I, wherein R is different to R may be separated into their optical isomers in known manner, e.g. the racemic acids of formula I may be converted into a mixture of their diastereoisomeric salts with optically active bases, the salts separated by physical methods, and the optical isomers of the acids of formula I isolated therefrom.

The starting materials may, for example, be obtained as follows:

(a') A compound of formula Ila,

wherein R R R and R are as defined above,

may, for example, be obtained by splitting the ether groups into hydroxy groups in a compound of formula IIb,

IIc

wherein R R R R and R are as defined above,

may, for example, be obtained by alkylating a compound of formula IId,

ON H--Ru 0R1 ll s IId wherein R R R and R are as defined above,

with a compound of formula III. The reaction may, for example, be effected under the reaction conditions described in relation to process ((1).

(c') A compound of formula 112,

wherein R R and R are as defined above,

may, for example, be obtained by reacting a compound of formula II wherein R R and R are as defined above,

in liquid ammonia, with methyl iodide in the presence of sodamide in manner known per se.

(d') A compound of formula III may, for example, be obtained by reacting a compound of formula VII,

CI-hX IL i n VII wherein R R and RJ are as defined above, and X is chlorine or bromine,

with a metal cyanide. An alkali metal cyanide such as as sodium or potassium cyanide, or copper-(I) cyanide, is preferably used. The reaction may, for example, be effected in an inert organic solvent, or in a mixture of water and an organic solvent, e.g. acetone or a suitable alcohol, optionally with the addition of a metal iodide such as sodium iodide. The reaction temperature may be between 50 and 100 0., preferably the boiling temperature of the reaction mixture. The reaction may have a duration between approx. 2 and 24 hours.

(e) A compound of formula VII may, for example, be obtained by treating a compound of formula VIII,

OH: OH

VIII

wherein R R and R are as defined above,

10' (f') A compound of formula VIII may, for example, be obtained by reducing a compound of formula IX,

COOK; 0R

wherein R R and R are as defined above, and R is alkyl of 1 to 4 carbon atoms.

The reduction may, for example, be effected with a complex metal hydride, e.g. lithium aluminum hydride or sodium dihydro-bis)2 methoxyethoxy) aluminate, in an inert organic solvent, e.g. an ether such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or in an aromatic hydrocarbon such as benzene, and is preferably effected at room temperature.

(g') A compound of formula IX may, for example, be obtained in conventional manner, erg. for the production of phenol ethers by etherifying a phenolic compound of formula X,

coon. on

i l I 11,11

wherein R R, and R are as defined above,

preferably in the form of a salt thereof, with a compound of formula XIa,

Ri -X XIo or XIb,

Bi -O R -O XIb wherein R and X are as defined above,

in the presence of a basic condensation agent. Examples of basic condensation agents which may be'used are alkali metal hydroxides, alkali metal alcoholates, sodamide or sodium hydride, in a suitable solvent. Examples of solvents which may bej-used are alcohol, dimethyl formamide or an excess of the alkylating agent. The reaction with an alkyl halide in the presence of sodium hydride in dimethyl formamide and the reaction with dimethyl sulphate with the addition of a 50% sodium hydroxide solution have been found to be specially convenient.

(h') A compoundof formula X may, for example, be produced by oxidizing a compound of formula XII,

COORI O R4" XII wherein R R, and R are as defined above.

Oxidation of the'compounds of. formula XII is conveniently effected in an inert polar solvent, e.g. an aliphatic alcohol such as ethanol. In such a solvent a compound 11 of formula XH is probably partially present in the enol form of formula XI-Ia,

. XIIa wherein R R," and R are as defined above.

Examples of oxidizing agents which may be used are atmospheric oxygen, hydrogen peroxide, chlorine, bromosuccjnimide, manganese dioxide, potassium permanganate or lead dioxide.

(i') A compound of formula XII may, for example, be obtained by cyclization of a compound of formula XIII,

R41! wherein R R, and R are as defined above,

in conventional manner.

A compound of formula XIH may, for example, be produced by reacting a fl-mercaptopropionic acid alkyl ester of formula XIV,

R OOC-CH CI-I -SH wherein R is as defined above,

with a compound of formula XV,

XIII

XIV

wherein R R R and X are as defined above,

in the presence of a basic condensation agent e.g. an alkali metal alcoholate, in an inert organic solvent.

(k') A compound of formula XV may, for example,

wherein R R," and R are as defined above,

with bromosuccinimide in an inert organic solvent, in the presence of an organic peroxide, or by chlorinating a compound of formula XVII,

wherein R R, and R are as defined above,

with a chlorinating agent, e.g. thionyl chloride or phosphorus pentachloride, in conventional manner.

XVII

Insofar as the production of the starting materials is not described, these are known or may be produced in accordance with known processes, or in a manner analogous to the processes described herein or to known processes.

The compounds of formula I have hitherto not been described in the literature. They are useful because they exhibit pharmacodynamic properties in animals, e.g. mammals. In particular, they are useful as antiphlogistics for the inhibition of exudation in inflammations or edemas, as indicated by standard tests, e.g. the Carrageen paw edema test in the rat, wherein inhibition of edma formation is observed at a dose of 5 to 30 mg./kg. animal body weight, or in the subchronic granuloma cyst test in the rat, wherein inhibition of cyst formation is observed at a dose of approximately 20 to mg./kg. animal body weight. For the abovementioned use, doses to be used will naturally vary depending on the compound used, the mode of administration and the condition to be treated. However, in general satisfactory results are obtained when administered orally or parenterally at a daily dosage of from 1 to 80 mg./kg. animal body weight, conveniently given in divided doses 2 or 3 times a day or in sustained release form. For the larger mammals the total daily dosage amounts to from 50 to 300 mg. and dosage forms siutable for oral administration contain approximately 15 to 150 mg. of the compounds, aside from solid or liquid pharmaceutical carriers or diluents.

The compounds 4 methoxy 5 phenyl 3 thiophene acetic acid and 2 (4 methoxy 5 phenyl 3 thienyl) propionic acid and pharmaceutically acceptable salts thereof, especially 2 (4 methoxy 5 phenyl 3 thienyl) propionic acid, have been found to be particularly effective. Specific daily doses suitable for oral administration are as follows, viz: g

(i) 4-methoxy-5-phenyl-3-thiophene acetic acide: about 1 to 22 mg./ kg. animal body weight.

(ii) 2-(4-methoxy-5-phenyl-3-thienyl) propionic acid:

about 1 to 40 mg./kg. animal body weight and (iii) (+)-2-(4-methoxy-5-phenyl-3-thienyl) propionic acid: about 1 to 40 mg./kg. animal body weight.

The compounds of formula I are also useful as arthritisinhibiting agents as indicated by standard tests. Thus, for example, in the Freund adjuvant arthritis latent period test in rats, they inhibit swelling at a dose of approximately 30 to mg./kg. animal body weight. For such use the dosage to be used will naturally vary depending on the compound used, the mode of administration and the condition to be treated. However, in general, satisfactory results are obtained when administered orally or parenterally at a daily dosage of from about 1 to 100 mg./kg. animal body weight, conveniently given in divided doses 2 or 3 times a day, or in sustained release form. For the larger mammals, the total daily dosage is in the range of from about 100 to 500 mg. and dosage forms suitable for oral administration, contain from about 30 to 250 mg. of the new compounds, aside from solid or liquid pharmaceutical carriers or diluents.

The compounds 2-(4-methoxy-5-phenyl-3-thienyl) propionic acid and pharmaceutically acceptable salts thereof, especially (+)-2-(4-methoxy-5-phenyl-3-thienyl) propionic acid, have been found to be particularly effective. Specific daily doses suitable for oral administration are as follows, -viz:

(i) 2-(4-methoxy-5-phenyl-3-thienyl) propionic acid: 1 to 100 nag/kg. animal body weight and (ii) 2 (4 methoxy 5 phenyl 3 thienyl) propionic acid: 1 to 100 mg./kg. animal body weight.

The new compounds or where appropriate their watersoluble, pharmaceutically acceptable salts, e.g., the sodium or potassium salts, may be used as medicaments on their own or in the form of a pharmaceutical composition comprising a compound of formula I, where appropriate 13 in free acidic or pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent. Suitable forms of composition for oral administration are tablets and capsules which may be produced in conventional manner and contain, aside from pharmaceutical 14 extracted with benzene. Drying is elfected over magnesium sulphate, the solvent is evaporated, and the resulting 4-methoxy-5-phenyl-3-thiophene acetic acid is recrystallized from ether/petroleum ether. M.P. 88-94.

The starting material may be obtained as follows:

carriers or diluents, conventional adjuvants. (a) g. of 4-hydroxy-5-phenyl-3-thiophene carbox- One preferred group of compounds are the compounds ylic acid ethyl ester are heated to 60 for minutes with of formula I wherein 0.97 g. of sodium hydride dispersed in 40 cc. of dimethyl formamide. 5.5 g. of methyl iodide dissolved in cc. $33225 to 4 carbon atoms partlculafly methyl 10 of dimethyl formarnide are then added dropwise to the Z and R4 areeach independently hydrogen alkyl of 1 to 4 reactlon mixture which has agaln been cooled to room preferably 1 to 3, carbon atoms or alkoxy of 1 to 4 temperature, and stlrrlng ls effected at room temperature preferably 1 to 3, carbon atoms, particularly hydrogen, for The i fi f ls fif i pourfid methyl or methoxy, and/or one of R and R is hydroon 18 extracted wlt met y ene onde and t gen. 15 methylene chloride layer 1s extracted with a 2 N caustic soda solution cooled wlth we. The crude 4-methoxy-5- When 2 15 mono" dialkylamine, e eaeh alkyl phenyl-S-thiophene carboxylic acid ethyl ester, obtained snbstitnent Preferably has 1 to 2 Carbon atoms, y after evaporating the methylene chloride phase which When e is alkyl, this Preferably has 1 t0 3 carbon has been washed with sodium chloride solution and dried atoms, Pattlenlatly 1 2 carbon atoms, y 20 over magnesium sulphate, is distilled in a Hickmann flask when 5 is different to s in the Compounds of formula (B.P. 144/ 0.09 mm. Hg) and crystallizes upon cooling. I, e.g. 2-(4-methoxy-5-phenyl-3-thienyl) propionic acid, M P 55. 57 then the compounds possess an asymmetric centre, i.e. the (b) A l i f 542 of 4- h .5- 3 Fatben atom 9 Whleh 5 and e are bonded, and as herethiophene carboxylic acid ethyl ester in 1.5 litres of tetralnhefore e e the Compounds y exist in Optically hydrofuran is added dropwise in an atmosphere of nitro- P e 1n the form of h Optical isomers, as Well gen to a suspension of 100 g. of lithium aluminium hyas In raeetnle fofm- Of'the nptleally P forms, in dride in 1.5 litres of tetrahydrofuran within 2 hours, and er the Preferred t 15 that form having a configuration the reaction mixture is stirred at room temperature for a at the abovementloned asymmetric centre identiea1 t further 16 hours. The slightly exothermic reaction can be (-l Y- -P Y h P p aeldkept at a reaction temperature of 20-35 by occasional T1115 f the compounds W111 heremafte1' he referred cooling with ice water. The excess lithium aluminium hy- 9 as the form of the eenlponnds and Is to be dride is subsequently decomposed by the addition of a tlngnlshed the he that form having identisaturated aqueous sodium sulphate solution while cooling eel eenfiglgratlen t y- -p y well. Dilution is effected with 2 litres of benzene, the rey P P O C acid. Determlnatlon of the relatlve consulting precipitate is filtered off, washing is effected with figurailon lsomers of P of formula benzene, and the combined filtrates are concentrated by Whereln 5 1s dlfierenlf to e h e p t to evaporation. The resulting crude 4-methoxy-5-phenyl-3- g -p yly p p aeld y be thenyl alcohol is distilled in a Hickmann flask. B.P. 139- fected ln conventlonal manner 0 mm Yeuow il,

E p of the Pt' lnventlen W111 now be 40 (c) 316 g. of thionyl chloride are added dropwise at 3 the followlqg examples all temperatures are 2o to a solution of 533 g. of 4-methoxy-5-phenyl-3- mdlcated m degrees Cemlgradethenyl alcohol in 1.5 litres of chloroform. The reaction Example 1: 4-Methoxy-5-phenyl-3-thiophene acetic acid mixture is stirred at a further 2 hours, the

(A) 2 g of 4 methox hen h vent is evaporated and the residue 1s divided between t H b d t fl 1 me acetom' chloroform and water. The chloroform phase, whlch has r 6 e re i or .Q m 40 of 2 N been washed with dilute sodium hydrogen carbonate socaustlc Soda 501mm *Y the afldltlPn of a Small f lution and dried over magnesium sulphate, is concentrated of ethanol. The reaction solution is then rendered acid b eva oration and the resultin crude 4-1ncthox -5- to Con 0 red with 2 N sul huric acid is extra t d 'th V p y g P c 6 W1 phenyl-3-thenyl chlorlde ls dlstllled m a Hlckmann flask. ether, and e ethereal Phase Washed Wlth a Saturated B.P. us /0.1 mm. Hg. 4-methoxy-S-phenyl-3-thenyl chlochlonde solutlon- Drymg 1S effected Over ride is obtained as a viscous oil which crystallizes upon neslum sulphate, the ether is evaporated and the resultstanding for a long time figptit; (impound is recrystallized from ether/pentane. (d) A Solution of 5 f 5 henyl chloride in 200 cc. of acetone is added dropwise (B) A solution of 100 g. of 4-methoxy-5-phenyl-3-thlor t phene acetonitrile in 500 cc. of ethanol is saturated with 50 e g Sodium g ag andfls of hydrochloric acid gas while cooling with ice. The reacso mm 10 1 m wa er an 0 acetone tion solution is then boiled at reflux for 8 hours, is cooled thefeficnon mixture 15 Subsequently .heated at reflux and is diluted with 50 cc. of water while cooling. The whlle for 20 hours i 18 then removed reaction mixture is kept at for 1 hour, is evaporated 60 by evaporatl'on and resldue i dlvlded between bento dryness, and the flask residue is heated to 50 for 3 Zena and Water After evaP1:atmg the f i hours in a solution of 20 g. of potassium hydroxide in crude Y' -Ph Y Ph n aeetomtflle ls 250 cc. of water and cc. of ethanol. The reaction 50- tained as Yellow resldue and 1s dlstllled m Hlckmann lution is evaporated to dryness, and the residue is divided flask- 8- between benzene and water. The aqueous layer is ren- 65 The following compounds y he Pfedneed in a dered acid to Congo red with 2 N sulphuric acid and is ner analogo s to that described in Example 1A Produced Ex. analog. to No. Substance Ex. No. Physical constants, observations 2-..--- 5-(4-fiu0rophenyl)-4-methoxy-3-thiophene acetic acid 1A M-P- (ether/Petroleum ether)- Starting material:

(a) 5-(4-fiuorophenyl)-4-methoxy-3-thlophena carboxylic acid ethyl ester... 1a

(b) 5-(4-fiuorophenyl)-4-methoxy-3-thenyl alcohol -(4 fluorophenyl)+rnethoxy3-thenyl chloride fl0r0pheny1)-4-metlloxy-3-thlophene acetonitn'le 1d TABLE-Continued Produced Ex. analog. to No. Substance Ex. No. Physical constants, observations 3 -(4-ch1oropheny1)-4-methoxy-3-thiophene acetic acid .l 1A M.P. 85-87 (ether/petroleum ether).

Starting material:

(a) 5-(4-chlorphenyl)-4-methoxy-3-thlophene carboxylic acid ethyl ester 1a M.P. 98101 (ethanol). (b) 5-(4-chlorpheny1)-4-methoxy-3-thenyl alcohol 1b Unpurlfied. (c) 5-( l-chlorophenyl)-4-methoxy-3-thenyl chlorlde 1c D0. (d) 5-(4-ch1orphenyl)-4-methoxy-3-thiophene acetonltrlle 1d Do.

4...-.;. 4-methoxy-5(4- ethoxyphenyD-B-thlophene acetic acid 1A. M.P. 101-104" (ether, sinters trom 80).

Starting material- (a) 4-methoxy-5-(4-methoxyphenyl)-3-thiophene carboxylic acid ethyl 1a ester. 4-methoxy-6-(4 methoxyphenyI)-3-thenyl alcohol (c) 4-methoxy-5-(4-methoxyphenyl)-3-thenyl 0111011416. (d) 4-methoxy-5-(4-rnethoxyphenyl)-3-thiophene acetomtnld.

Example 5 5-(3-Ch1orophenyl)-4-methoxy-3-thiophene acetic acid 5 (3 chlorophenyl) 4 methoxy-3-thiophene acetonitrile is reacted in accordance with the process described in Example 1A. M.P. of the title compound: 101-103 (from acetone/petroleum ether).

The starting material may be obtained as follows:

(a) 160.0 g. of ,B-mercaptopropionic acid ethyl ester are added dropwise at 60 within 90 minutes to a mixture of 58 g. of a 50% sodium hydride dispersion and 500 cc. of toluene in an atmosphere of nitrogen, the mixture is stirred at 90 for a further 30 minutes, is allowed to cool to 25, and a solution of 330 g. of a-bromo- 3-chlorophenyl acetic acid ethyl ester in 500 cc. of toluene is added dropwise. The reaction mixture is stirred at room temperature for 18 hours and is subsequently extracted with water while cooling with ice. Upon concentrating the toluene phase, a-[2-(carbethoxy)ethylthio]-3-chlorophenyl acetic acid ethyl ester is obtained as yellow viscous oil and is used for the next reaction without purification.

(b) A solution of 358 g. of crude a-[2-(carbethoxy) ethylthio]-3-chlorophenyl acetic acid ethyl ester in 500 cc. of toluene is added dropwise within 60 minutes to a sodium ethylate suspension produced from 55 g. of sodium in 1 litre of toluene, the reaction mixture is stirred at room temperature for 1 hour and is heated at reflux for a further 2 hours. After cooling, the reaction mixture is poured on a mixture of ice and 1 litre of 2 N sulphuric acid. The organic phase, which has been washed with an aqueous sodium hydrogen carbonate solution and water, is concentrated, whereby crude 5-(3-chlorophenyl)tetrahydro-4-oxo-3-thiophene carboxylic acid ethyl ester is obtained and used for the next reaction without purification.

(0) 400 cc. of a 40% hydrogen peroxide solution are added dropwise at 60 to a solution of 315 g. of 5-(3- chlorophenyl)tetrahydro 4-oxo-3-thiophene carboxylic acid ethyl ester in 500 cc. of ethanol, the reaction mixture is kept at 60 for a further hour, is cooled in an ice bath, is diluted by the addition of 2 litres of water and is extracted with benzene. The 5-(3-chlorophenyl)-4-hydroxy-3-thiophene carboxylic acid ethyl ester, obtained after concentrating the benzene phase, is recrystallized from methanol. M.P. 8487.

(d) 5 (3 chlorophenyl) 4-methoxy-3-thiophene carboxylic acid ethyl ester, produced in a manner analogous to that described in Example 1 (a). After recrystallization from ethanol/petroleum ether the product has a M.P. of 74-76".

(e) 5 (3 chlorophenyl) 4 methoxy 3 thenyl alcohol, produced in a manner analogous to that described in Example 1(b), colourless viscous oil. B.P. 154-155 0.1 mm. Hg.

(f) 5 (3 chlorophenyl) 4-methoxy-3-thenyl chloride, produced in a manner analogous to that described in Example 1(c). The crude product is obtained as yellow viscous oil and is used as such for the next reaction.

(g) 5 (3 chlorophenyl) 4 methoxy-3-thiophene acetonitrile, produced in a manner analogous to that described in Example 1(d). B.P. 164166/0.08 mm. Hg, yellow viscous oil.

B.P.ua 160, oil which solidifies in crystalline form; UnpIigrified.

0. M.P. 75-77 (irom petroleum ether).

1b 1c 1d Example 6: 4-Methoxy-5-0-tolyl-3-thiophene acetic acid 4-methoxy-5-0-tolyl-3-thiophene acetonitrile is reacted in accordance with the process described in Example 1B. The crude compound is purified by chromatography on silica gel, eluant: toluene. M.P. of the title compound: 60-62 (from pentane).

The starting material may be obtained as follows:

(a) g.. of ,B-mercaptopropionic acid ethyl ester are added dropwise at 5-10 to a solution of 18 g. of sodium in 400 cc. of ethanol, in an atmosphere of nitrogen, 157 g. of a-chloro-o-tolyl acetic acid ethyl ester are then added dropwise, whereby the temperature should not exceed 40"; the reaction mixture is stirred at room temperature for 2 hours and is boiled at reflux for 1 hour, is concentrated and divided between water and ether. The crude 2-[2-(carbethoxy) ethylthio]-o-tolyl acetic acid ethyl ester, obtained as orange-coloured oil after concentrating the organic phase which has been washed with sodium chloride solution, is used for the next reaction without purification.

(b) Tetrahydro-4-oxo-5-o-tolyl-3-thiophene carboxylic acid ethyl ester, produced in a manner analogous to that described in Example 5 (b). The crude compound is obtained as orange-coloured oil and is used for the next reaction without purification.

(c) 4-hydroxy-5-o-tolyl-3- thiophene carboxylic acid ethyl ester, produced in a manner analogous to that described in Example 5 (c). Working up is efiected by dividing the reaction mixture between an ice-cold 5% sodium chloride solution and chloroform, concentrating the organic phase which has been washed with sodium chloride solution and an iron II sulphate solution, and subjecting the resulting oil to chromatography on silica gel, whereby the compound is eluted with toluene. M.P. 4345 (from pentane).

(d) 4-methoxy-5-a-tolyl-3-thiophene carboxylic acid ethyl ester, produced in a manner analogous to that described inn Example 1(a). The crude product is purified by chromatography on silica gel (eluant: toluene), and the resulting oil is used for the next reaction without further purification.

(e) A solution of 87 g. of the ester described above in 400 cc. of toluene is added dropwise at 60 in an atmosphere of nitrogen to a mixture of 185 cc. of a 70% benzene solution of sodium dihydro-bis(Z-methoxyethoxy) aluminate and 400 cc. of toluene, the mixture is stirred at 60 for 2% hours, cc. of a 30% caustic soda solution are subsequently added dropwise while cooling with ice, dilution with 400 cc. of water and extraction with toluene are effected. Upon concentrating the toluene phase which has been washed with a 2 N caustic soda solution and sodium chloride solution, crude 4-methoxy-5-0-tolyl- B-thenyl alcohol is obtained as an oil which is used as such for the next reaction.

(f) 4-methoxy-5-0-tolyl-3-thenyl chloride, produced in a manner analogous to that described in Example 1(c). The crude compound obtained as an oil is used for the next reaction without purification.

(g) 4-methoxy-5-o-tolyl-3-thiophene acetonitrile, produced in a manner analogous to that described in Example 1(d). Reaction time 7 hours. The crude product is chromatographed on silica gel and the compound, ob-

tained as yellow oil after elution with toluene, is used as such for the next reaction.

The following compounds may be produced in a man concentrating. The resulting oily crude compound (R, value 0.3, adsorbent: silica gel, eluant: benzene, n =1.5330) is used for the next reaction without purificaner analogous to that described in Example 1A or 1B. tron.

Produced Ex. analog. to No. Substance Ex. N 0. Physical constants, observations 7 4methoxy-5-m-tolyl-3 thiophene acetic acid 1B M.P. 8990 (ether/pentane).

Starting material:

(a) 2-[2-(carbethoxy) ethylthio1-m-tolyl acetic acid ethyl ester"; 6a Unpun'fied oil. (b) tetrahydro-ibxo-5-m-tolyl-3-thiophene carboxylic acid ethyl ester 5b Do. 4-hydroxy-5-m-toly1-3thiophene carboxylic acid ethyl ester- 60 Do. (d) 4-methoxy-5-m-tolyl-3-thiophene carboxylic acid ethyl ester 6d Do. (e) 4-methoxy-5-m-tolyl-3 thenyl almhni 6e Do. (I) 4-methoxy-5-m-tolyl-3-thenyi chloride 10 D (g) 4 methoxy--mtolyl-3-thiophene acetomtrrle.... 6g Unpurified.

8..;... 4-methoxy-fi-p-tolyl-3-thiophene acetic acid 1B M.P. 8890 (ether/pentane).

Starting material:

(a) 2-[2-(carbethoxy)ethylthio1-p-tolyl acetic acid ethyl ester 6a Unpurlfied oil. (b) tetrahydro4-oxo5-p-tolyi-3-thiophene carboxylic acid ethyl ester 5b M.P. g57fisi(lpentalne), purification by chromatograp yon cage (c) 4-hydroxy5-ptolyl-3-thi0phene carboxylic acid ethyl ester 6c M.P. 7475 (pentane). (d) 4-methoxy-5-p-tolyl-3-thiophene carboxylic acid ethyl ester 6d Unpurified oil. (e) 4-methoxy-5-p-tolyl-3-thenyl alcohol 6e Do. (i) 4-methoxy-5-p-tolyl3-thenyl chloride Do. (g) e-methoxy-5-p-tolyl-3-thiophene acetomtrrle 6g Do.

9 5-(2-chloro henyl)-4-methoxy-3-thiophene acetic acid 1B M.P. 97-100 (pentane).

Starting material:

(a) 2-[2-(carbethoxy)ethylthiol-Z-chlorophenyl acetic acid ethyl ester 6a Unpunfied 011. (b) 5-(2-chlorophenyl)tetrahydro-4-ox0-3-thiophene carboxylic acid ethyl 5b Do.

ester. (0) 5-(2-chlorophenyl)-4-hydroxy-3-thiophene carboxylic acid ethyl ester... 60 (d) 5-(2-cl1lorophenyl) -4-methoxy-3-thiophene carboxylic acid ethyl ester- 1a (e) 5-(2'ch1orophenyl)-4methoxy-3-thenyl alcohol 69 (t) 5-(2-chlorophenyl)+methoxy-3-thenyl chloride (g) 5-(2-chlorophenyl)4-methoxy-3-thi0phene acetonitrile 6g Example 10: 5-(2,4-Dichlorophenyl)4-methoxy- 3-thiophene acetic acid 5-(2,4-Dichlorophenyl)4-methoxy-3-thiophehe acetonitrile is reacted in accordance with the process described in Example 1A. M.P. of the title compound: 107-109 (from diethyl ether/pentane) The starting material may be obtained as follows:

(a) A solution of 310 g. of 2,4-dichlorobenzyl chloride in 600 cc. of ethanol is added dropwise to a solution heated to 100 in an oil bath of 120.5 g. of sodium cyanide in 96 cc. of water, and the mixture is heated at reflux for 1 /2 hours. The ethanol is then removed by distillation at reduced pressure, the residue is dissolved between diethyl ether and water, and the crude oily 2,4- dichlorophenyl acetonitrile, obtained after concentrating the ether extract, is distilled in a high vacuum. B.P. 140- 143/ 0.03 mm. Hg.

(b) A solution of 80.0 g. of 2,4-dichlorophenyl acetonitrile in 510 cc. of ethanol is saturated with hydrogen chloride gas at room temperature, is heated at reflux for 20 hours, cc. of water are added, and heating at reflux is efiected for a further 3 hours. The reaction mixture is subsequently completely concentrated at reduced pressure, the residue is taken up in benzene, is extracted with water, and the dried benzene phase is concentrated. The resulting crude 2,4-dichlorophenyl acetic acid ethyl ester is distilled in a high vacuum. B.P. 90/ 0.05 mm. Hg.

(0) 95.0 g. of 2,4 dichlorophenyl acetic acid ethyl ester, 80.3 g. of N-bromosuccinimide and 0.6 g. of dibenzoyl peroxide are heated at reflux for 16 hours in 350 cc. of carbon tetrachloride. After cooling to 20, the succinimide is filtered off, and the filtrate is completely concentrated at reduced pressure. The resulting oily crude a-bromo-2,4-dichlorophenyl acetic acid ethyl ester is distilled in a high vacuum. B.P. 113-115/0.06 mm. Hg.

(d) a-[2-(carbethoxy)ethylthio] 2,4 dichlorophenyl acetic acid ethyl ester, produced in a manner analogous to that described in Example 5(a). Solvent: benzene. Reaction time minutes at room temperature, and 1 hour at Working up is effected by pouring the reaction mixvture on ice/water, neutralizing the same with 0.5 N hydrochloric acid, separating the benzene phase, washing this with a saturated sodium chloride solution, drying and M.P. 47-49". Unpurified oil.

Do. Do.

(e) 5-(2,4-dichlorophenyl)tetrahydro 4 oxo-3-thiophene carboxylic acid ethyl ester, produced in a manner analogous to that described in Example 5 (b). Reaction time 16 hours at room temperature. Working up is effected by pouring the reaction mixture on a mixture of ice water/hydrochloric acid having a pH of 3, extracting the aqueous phase with diethyl ether, concentrating the combined organic phases which have been washed with saturated sodium chloride solution, and recrystallizing the resulting compound from ethanol. M.P. 69-71.

(f) 5-(2,4-dichlorophenyl) 4 hydroxy-S-thiophene carboxylic acid ethyl ester, produced in a manner analogous to that described in Example 5(0). Reaction time 18 hours in an oil bath at 60. After cooling the reaction mixture to -10, the compound precipitates in crystalline form, is filtered olf and is washed twice with cold ethanol. M.P. -107.

(g) 5-(2,4-dichlorophenyl) 4 methoxy-3-thiophene carboxylic acid ethyl ester, produced in a manner analogous to that described in Example 1(a). Reaction time 20 hours at room temperature. Working up is effected by pouring the mixture on ice water, adjusting the pH to 4 with 1 N hydrochloric acid, extracting with diethyl ether and concentrating the organic phase which has been washed with a saturated sodium chloride solution and purified over animal charcoal. The resulting compound is recrystallized from diethyl ether/pentane 1:2. M.P. 78- 80.

(h) 5-(2,4-dichlorophenyl) 4 methoxy 3 thenyl alcohol, produced in a manner analogous to that described in Example 6(e). The crude compound (R; value 0.65, adsorbent: silica gel, eluant: chloroform/ethanol 9:1) is used for the next reaction without purification.

(i) 5-(2,4-dichlorophenyl) 4 methoxy 3 thenyl chloride, produced in a manner analogous to that described in Example 1(c). B.P. 160/0.06 mm. Hg.

(j) 5-(2,4-dichlorophenyl) 4 methoxy-3-thiophene acetonitrile, produced in a manner analogous to that described in Example 1(d) Reaction time four hours at 60. The crude oily compound (R; value 0.35, adsorbent: silica gel, eluant: chloroform) is used for the next reaction without purification.

The following compounds may be produced in a manner analogous to that described in Example 1A or 1B.

Produced Ex. analog. to N 0. Substance Ex. No. Physical constants, observations 11 5 (3-fluorophenyl)4-methoxy-3-thiophene acetic acid 1A M.P. 90-92" (diethyl ether/pentane).

Starting material:

(a) a-Bromo-Zi-fiuorophenyl acetic acid ethyl ester 10c B.P. 138-140. (b) a-[2-(carbethoxy)ethylthiol-Ii-fluorophenyl acetic acid 10d Unpurified oil (Ri value 0.3, adsorbent: silica gel, eluant:

ethyl ester. chloroform). (c) 5 (3-fluorophenyl)tetrahydro--oxo-3-thiophene carboxylic 10o Unpurified oil (Rf value 0.5, adsorbent: silica gel, eluant:

acid ethyl ester. chloroform). (d) 5-(3-fluorophenyl)-4-hydroxy-3-thiophenecarboxylic acid 10f M.P. 60 (pentane) (Rf value 0.6, adsorbent: silica gel, eluant:

ethyl ester. chlorofonn (e) ti-(i-flliiorophenyl)4-methoxy-3-thiophenecarboxylic acid 10g M.P. 62-64" (diethyl ether/pentane).

e y es er. (i) 5-(3-fluorophenyl)-4-methoXy-3-thenyl alcohol 6e Unpur/iffild oil1(R1f)value 0.65, adsorbent: silica gel, eluant: chloroorm'e ano 9: (g) 5-(3-fluorophenyl)-4-methoxy-3-thenyl chloride 1c Unlpluriiied )oil (Rf value 0.6, adsorbent: silica gel, eluant:

c ore orm (h) 5-(3-fluorophenyl)4-methoxy-3-thiophcne acetonitrila.-. 1d Unfiilurified ell (Rf value 0.45, adsorbent: silica gel, eluant:

c oro orm 12 5-(3,4-dichlorophenyl)4-methoxy-3-thiophenc acetic acid 1A Starting material:

(a) 3,4-dichlorophenyl acetic acid ethyl ester 10b (b) a-Bromo3,4-dichlorophenyl acetic and ethyl ester .t 2500 ace re a (c) a-[2-(carbethoxy)ethylthio]-3,4-dichlorophenyl acid eth ester. ((1) 5-(3A dichlorgpherzyl)tetrahydro-4-oxo-3-thiopheue car- 5b es er boxylic acid et yl (e) 5-(3,4-dichlorophenyl)4-hydroxy-3-thiophene carboxylic 5c Starting material.

(a) a-[z-ggarlnigthoxrtr)ethylthio]-3,4-dimethoxyphenyl acetic 62.

a y es er.

(b) 5-(3,4-dimethoxyphenyl)tetrahydro-4-oxo-3-thiophenc 5b carboxylic acid ethyl ester.

(c) 5-(3,4-dimethoxyphenyl)-4-hydroxy-3-thiophene carbox- 5c ylic acid ethyl ester.

(d) 5-(3,4-dimethoxyphenyl)4-methoxy-3-thiophene carbox- 1a ylic acid ethyl ester.

(e) 5-(3,4-dimethoxyphenyl)-4-methoxy-3-thenyl alcohol... 1b

(f) 5-(3,4-dimethoxyphenyl)-4-methoxy-3-thenyl chloride. 1c

(gag-(3A-dimethoxyphenyl)4-methoxy-3-thiophene actoni- 1d 14..-; 4-1sopropoxyophenyl-a-thiophene acetic acid.

St ng materl e (b) 4-1sopropoxy-5-pl1enyl-3-thenyl alcohoL.

1A i-isopropoxy-5-phenyl-3-thiophene carboxylic acid ethyl 1a s or M.P. 125127 (diethyl ether/pentane).

B.P. .1 115, no 1.5310. B.P.0 1 146, HD 15550. Unpurified, B.P.o.o4 155.

(Rf value 0.3, adsorbent: silica gel, eluant: benzene/ethanol] concentrated ammonia 75:15:10).

M.P. 103105 (chloroform/pentane).

M.P. 87-89 (diethyl ether/pentane).

B.P.o.1 l70l80, M.P. ill-02 (ether/pentane). M.P. 67-68 (chloroform/pentane).

Unpurgfied (Rf value 0.4, adsorbent: silica gel, eluant: chloroorm M.P. 9497 (ether/petroleum ether). Unpurified oil.

M.P. 63 (ether/petroleum ether).

Unpurified oil, B-PJl-OE 140.

Unpurified oil. (c) 4-isopropoxy-5-phenyl-3-thenyl chloride Do. (d) 4-isopropoxydphenyl-ii thiophene acetoni Do.

15...:- 4-ethoxy-5-phenyl-3-thiophene acetic acid-.--.- 1A M.P. 53-57 (pentane).

Starting material:

(agst-ethoxy--phenyl-3-thiophone carboxylic acid ethyl 1a Unpurified.

er. (b) 4-ethoxy-5-phenyl-3-thenyl alcohol. 1b Do. (c) 4-ethoxy-5-phenyl-3-thenyl chloride..-.- D (d) 4-ethoxy-5-phenyl-4-thiophene acetonitril 1d D Example 16: 2-(4-Methoxy-5-phenyl-3-thienyl) cinchonidine salt crystallized above, are acidified with 2 N prop1omc acid sulphuric acid and extracted with ether. The residue obtained after concentrating the ether phase, and which con- 2 (4-methoxy-5-phenyl-3-thienyl)propionitrile is reacted in accordance with the process described in Example 1A, using a 50% caustic soda solution. Reaction time 16 hours. M.P. of the title compound (raccmate): 10l102 (from ether/petroleum ether).

M.P. of the sodium salt of the title compound: 236 55 238 -(decomp., from ethanol/acetone).

The optical antipodes may be obtained from the racemic compound as follows:

(A) 2-(4-Mcthoxy-5-phenyl-3-thienyl)propionic acid: The racemate of 2-(4-methoxy-5-phenyl-3-thienyl) propionic acid is dissolved in a 12-fold quantity of acetone, and the calculated amount of cinchonidine is added. After 3 hours, the crystalline precipitate, which contains the cinchonidine salt of 2 (4-methoxy-5-phenyl-3- thienyl)propionic acid in strongly concentrated form, is filtered oif and recrystallized several times from ethanol. M.P. of the cinchonidine salt: 131-134. [a] --97 (in ethanol, c.=l).

The free acid produced from the cinchonidine salt forms a tough resin, [a] =76 (in chloroform, c.=l).

M.P. of the sodium salt of (-)-2-(4-methoxy-5-phenyl- 3-thienyl)propionic acid: 200-202 (from ethanol). [u] -19.5 (in Water, c.=l).

(B) 2-(4-Methoxy-S-phenyl-B-thienyl)propionic acid: The mother liquors obtained after filtering off the tains 2 (4-methoxy-5-phcnyl-3-thienyl) propionic acid in strongly concentrated form, is converted into a salt With the calculated amount of (--)a-methylbenzylamine, and this salt is recrystallized several times from ethanol. M.P. of the u-methylbenzylamine salt: 154-157".

[a] +26 (in ethanol, c.=l).

The free acid produced from the a-methylbenzylamine salt forms a tough resin. [a] +76 (in chloroform, c.=l).

M.P. of the sodium salt of +)-2-(4-methoxy-5-phcnyl- 3-thienyl)propionic acid: 201203 (from ethanol). [a] +195 (in Water, c.=l).

The starting material may be obtained as follows:

(a) An ethereal solution of 11.5 g. of 4-mcthoxy-5- pheny1-3-thiophene acetonitrile is added to 5.6 g. of potassium tertbutylate in cc. of ether in an atmosphere of nitrogen. 7.8 g. of methyl iodide are then slowly added dropwise, the mixture is stirred at room temperature for 1 hour and is subsequently extracted with ice water and dried over magnesium sulphate. After evaporating the solvent, crude 2 (4 mcthoxy-5-phenyl-3-thienyl) propionitrile is obtained and is used as such for the next reaction.

The following compounds may be produced in a manner analogous to that described in Example 1 or 16.

Produced Ex. arralogqto No. Substance Ex. 0. Physical constants, observations 17..... 2-[4-methoxy-5- (4-methoxyphenyl)-3-thienyl] propionic acid 16 MP. 99-101 (ether/petroleum ether).

Starting matenal: 2-[4-methoxy-5-(4-methoxyphenyl)-3-thienyl]propionitri 16a Unpurified.

18....-. 2-[5-(tchlorophenyl)-4-methoxy-3-thienyl]propionic acid 16 MP. 82 (ether/petroleum ether).

Starting material: 2-[5-(4-ch1orophenyl)+methoxy-3-thienyl]propionitrlle. 16a Unpurified.

19..... 2-[5-(4-fiuoropheny1)-4-methoxy-3-thieny1]propionic acid 16 MP. 101103 (ether/petroleum ether).

Starting material: 2-[5-(4-fluorophenyl)-4-methoxy-3-thienyl]propionit 16a Unpurified.

20"... 2-[5-(3-chlorophenyl)-4-methoxy-3-thienyllpropionic acid 16 MP. 7778 (petroleum other/ether),

Starting material: 2-[5-(3-ch1orophenyl)-4-n1ethoxy-3-thienyl1propionitril 16a Unpurified.

21...; 2-(4-methoxy-5-phenyl-3-thienyl) hexanoic acid-..- 16 MP. 68-69 (ether/petroleum th Starting material: 2-(4-methoxy-5-phenyl-8-thienyl) hexanoic acid nitrile- 16a Unpurified.

22... 2-(4-methoxy-5-0 tolyl-3-thienyl) propionic acid 1B M.P.71-72 (pentaue),

Starting material: 2-(4-methoxy-5-O-tolyl-3-thienyl)propionitrile 16a Unpurified.

23.,..- 2-(4-methoxy-54n-tolyl-3-thienyl)propionic acid 22 MP. 82-85 (pentfln),

Starting material: 2-(4-methoxy-54n-tolyl-3-thienyl)propionitrile 16a Unpurified.

24 2-(4-methoxy-S-p-tolyl-li-thienyl)propionic acid 18 MP. 86-88 (pentane).

Starting material: 2-(4-methoxy-5-p-tolyl-3-thienyl)propionitrile..... 16a Unpurlfied.

25...... 2-[5-(2-chlorophenyl)4-methoxy-3-thienyl1propionic acid 1B M.P. 108-110 (ether/mummy Starting material: 2-[5-(2-chlorophenyl)+methoxy-3-thienyl]propionitrile- 16a Unpurified.

26 2-[5-(2,4-dichlorophenyl)4-methoxy-3-thienyl] propionic acid 16 MP. 75-77 (ether/pentan Starting material: 2-[5-(2,4dichlorophenyl)-4-methoxy-3-thienyl] propionitrile-- 16a 27. 2-[5-(3-fluorophenyl)-4-methoxy-3-thienyl] propionic acid 16 MP. 78-80 (ether/pentan Starting material: 2-[5-(3-fiuorophenyl)-4-methoxy-3-thienyl] propionitrile. 16a

23 2-[5-(3,4-dimethoxypheny1)-4-methoxy-3-thienyll propionic acid.-. 16 MP. of the sodium salt 245-247 (acetone),

Starting material: 2-[5-(3,4-dimethoxyphenyl)4-methoxy-3-thienyl] propioniduced with 1 N NaOH in methanolic solution trile. 16a dried at 70 in a high vacuum.

29 2-(4-1sopropoxy-5 phenyl-3-thienyl) propionic acid m 28 MP. of the sodium salt 213-215 (a t n Starting material: 2-(41sopropoxy-5-phenyl-3-th1enyl)propromtriie 16a 30 2-(4-cthoxy-5-phenyl-3-thienyl)propionic acid 28 MP. of the potassium salt 213 ac t h Starting material; 2-(4-ethoxy-5-phenyl-3-thienyl)propionitrile 16a e one/6t Br) 31 2-(4methoxy-5-phenyl-3-thienyl)butyric acid 16 MP. of the otassium sa1t208-210 Starting material: 2-(i-methoxy-5-phenyl-3-thienyl)butyronitrile.. 10a p (acetone/ether)" 32..." 4-methoxy-5-(m-trifiuoromethylphenyl)-3-thiophene acetic acid--. 1A M.P. 98-100" (ether/petroleum ether).

Starting material:

(a) a-Bromo-m-trifluoromethylphenyl acetic acid ethyl ester.. 10c Unpurified oil, B.P.12 133. (b) a-[2-(carbethoxy)ethylthio]err-triflnoromethyl-phenyl acetic acid ethyl 5a Unpurified oil, B.P.o.m 130-140".

es 1'. (c) ed-(ml-ltriflugromethylphenyl)tetrahydro-4-oxo3-thiophene carboxylic 5b Unpun'fied.

aci at y es er. (d)t1?-m-rifiuoromethylphenyl)-4-hydroxy-3-thiophene carboxylic acid M.P. 9899 (aqueous ethanol).

e y es er. (e) 1fli-nlietlzio2ry-5-(m'trifluoromethylphenyl)-3-thiophene carboxylic acid 1a B.P.o.os 121124, my, 1.5395.

c y es er. (1) i-methoxy-5-(mtrifluoromethylphenyl)-3-thenyl alcohol 6e B.P.o o7 129, nu", 1.5612. (g) 4-meth0xy-5-('m-trifluoromethylphenyl)-3-thenyl chloride. 1c B.P.o 05 121-123", mg 1.5620. (11) 4-methoxy-5-(m-trifluoromethylphenyl)-3-thiophene acetomtrile 1d Di s iiilation in an air bath at 130140/0.01 mm. of

g. 33 4-methoxy-5-(2-methoxyphenyl)-3-thiophenc acetic acid 1A M.P. 9395 (ether/petroleum oth Starting material:

(a) a-Ohloro-o-methoxyphenyl acetic acid ethyl ester B.P.t.o4 106-105", produced from o-methoxy mand n acid ethyl ester and thionyl chloride. (b) 2-[2-(carbethoxy)ethy1thio]-0-methoxyphenyl acetic acid ethyl ester--.. 6a Unpurified. (c) th5-1(2-r1ethoiryphenyl)tetrahydro-4oxo4i-thiophene carboxyiic acid 5b Do.

e y es er. (d) 4-hydroxy-5-(2-rnethoxyphenyl)-3-thiophene carboxylic acid ethyl ester. 50 MP. 9597 (ethanol). (e) 4-methoxy-5-(2-methoxyphenyl)-3-thiophene carboxyhc acid ethyl ester- 1a M.P. 53-55. (1) 4-methoxy6-(2-methoxyphenyl)-3-thenyl alcohol 6e 13.1m -170". (g) 4-methoxy-5-(2-methoxyphenyl)-3-thenyl chloride.-. 1c Unpurified, B.P. -190. (h) 4-methoxy-5-(2-methoxyphenyl)-3-thiophene acetonrtrile 1d B.P.o.o5 170180.

34..... 5-(2,5-dichlorophenyl)-4-methoxy3-thiophene acetic acid 1A M.P. 93-96 (ether/petroleum ether),

Starting material:

(a) 2,5dichloromandelic acid ethyl ester B.P.o.s l16 7, Produced m -dlchloromandelic acid and ethanol. (b) a-ChIoro-2,5-dichlorophenyl acetic acid ethyl ester B-P-o-r 108, produced from 2,5-dichloromandelic acid ethyl ester and phosphorus pentachloride. (c) a-[2-(carbethoxy)ethylthio]-2,5-dichlorophenyl acetlc acid ethyl ester... 5a Unpunfied, B.P. 155-165". (d)th5-1(2,5-dichlorophenyl)tetrahydro-4-oxo-3-thiophene carboxylic acid 51) MP. 84-8? (ethanol/water).

e y ester. (e) 5-(2,5-dichlorophenyl)-4-hydroxy-3-thiophene carboxylic acid ethyl 50 MP. 113-115" (80% ethanol).

es er. (i) 5-(2,5-dichlorophenyl)-4-methoxy-3-thiophene cerboxylic acid ethyl 1a M.P. 78-80.

ester. (g) 5-(2,5-dichlorophenyl)-4-methoxy-3-thenyl alcohol 6e RP 155-160. (h) 5-(2,5-dichlorophenyl)+methoxy-3-thenyl chloride.... 10 B.P. 137. (i) 5-(2,o-dichlorophenyl)-4-methoxy-3-thiophene acetonitrile 1d B.P. .or 158. 35-.-.. 2-[5-(m-trlfluoromethylphenyl)-4-methoxy-3-thienyl] propionic acid 16 Ml. 106109 (ether/petroleum ether).

Staritliirig material: 2-[5(m-triiiuoromethylphenyl)-4-methoxy-3-thienyl]propio- 16a Unpurified.

m e. 36..... 2-[5-(2-methoxyphenyl)-4-methoxy-3-thienyl]propionic acid 16 MP. 113-115 (ether/petroleum ether).

Starting material: 2-[5-(2-methoxyphenyl)-4-methoxy-3-thienyilpropionitrile. 16a Unpunfied. 37 2-[5-(2,5-dichloropheny1)-4-methoxy-3-thienyl] propionic acid 16 MP. 108-112 (ether/petroleum other).

Starting material: 2-[5-(2,5-dich1orophenyl)-4-methoxy-3-thienyl] propiomtrile- 16a Unpurrfied. 38 2-methyl-2-(4-methoxy-5-pherryl-Ztthienyl) propionic acid 16 MP. 164-137 (ether/petroleum ether).

Starting material: 2-methyl2-(4-meth0xy-5-phenyi-3-thienyl) propionitrlie 16a Unpimficd. 39..... 2-methyl-2-(4-methoxy-5-phenyl-3-thienyl) heiranoic acid 16 Ml. 126-127" (ether/petroleum ether).

Starting material: 2-methyl-2-(4-methoxy-5-phenyl-3-thienyl) hexauoic acid 16a Unpunfied, from 2-(4-methoxy-5-phenyl-3-thienyl)- rile.

propionitrile and butyl iodide.

23 Example 40: 4-Hydroxy-5-phenyl-3-thiophene acetic acid 2.5 g. of 4-hydroxy-5-phenyl-3thiophene acetonitrile are boiled at reflux for 24 hours in 12.5 cc. of a 2 N caustic soda solution. The dark solution is rendered acid to Congo red with 2 N sulphuric acid and is extracted with ether. After concentrating the ether phase by evaporation, the title compound is obtained as dark viscous oil and is characterized by its infrared spectrum. Cyclization of the title compound yields 2,3-dihydro-6-phenylthieno [3,4-b1furan-2-one which has a M.P. of 104-106" (from benzene/ petroleum ether).

The starting material may be obtained as follows:

(a) A solution of 15.2 g. of 4-methoxy-5-phenyl-3- thiophene acetonitrile is added dropwise while stirring to a sodium ethylate mercaptide solution produced from 3.2 g. of a 50% sodium hydride dispersion and 4.2 g. of ethyl mercaptan in 120 cc. of dimethyl formamide in an atmosphere of nitrogen, the dark solution is heated to 100 for 5 hours, is cooled, is poured on a mixture of ice/ 2 N hydrochloric acid and is extracted with benzene. The benzene extracts are extracted with ice-cooled 2 N caustic soda solution, the alkaline extracts are rendered acid and again extracted with benzene. Upon concentrating the benzene phase which has been washed with a saturated sodium chloride solution, 4-hydroxy-5-phenyl-3-thiophene acetonitrile crystallizes. M.P. of the crude product: 85- 92.

The following compounds may be produced in a manner analogous to that described in Example 1 or Example 40 and may be characterized by the melting point of the lactone obtained therefrom by cyclization.

Example 47: 4-Methoxy-5-pheny1-3-thiophene acetic acid amide 2 g. of 4-methoxy-5-phenyl-3-thiophene acetonitrile are boiled at reflux for 90 minutes in 100 cc. of 0.5 N caustic soda solution with the addition of a small amount of ethanol. The reaction solution is concentrated to approx. one third of its original volume, and the solution is divided between benzene and water. Upon concentrating the benzene phase which has been dried over magnesium sulphate, the title compound crystallizes. M.P. 112-1 14 (from benzene/ ether).

Example 49: 4-Methoxy-5-phenyl-3-thiophene acetic acid ethyl ester A solution of 64 g. of 4-methoxy-5-phenyl-3-thiophene acetonitrile in 600 cc. of ethanol is saturated with hydrogen chloride gas while cooling with ice water, and is subsequently heated at reflux for 24 hours. The solution is then evaporated to dryness, 11 cc. of water and 500 cc. of ethanol are added, the mixture is again boiled at reflux Ex. N 0. Substance 41".-- 5-(4-fluorophenyl)4-hydroxy-3-thiophene acetic acid Starting material: 5-(4-fluorophenyl)-4-hydroxy-3-thiophene acetonitrile 42- 5-(4-chlorophenyl)-4-hydroxy3-thie hene acetic acid Starting material: 5-(4-chloropheny] -4-hydroxy-3-thi0phene acetonitrile 44...-.. 4-hydroxy-5-o-tolyi-3-thiophene acetic mid Starting material: 4-hydroxy-S-O-toIyI-B-thiophene acetonitrile 45... 5-(Z-chlorophenyl)-4-hydroxy-3-thipohene acetic acid Starting material: 5-(2-chlorophenyl)-4-hydr0xy-3-thiophene acetonitrile-..;-.;

Example 46: 2-(4-Hydroxy-5-phenyl-3-thienyl)propionic acid 2 (4 hydroxy-5-phenyl-3-thienyl)propionitrile (produced in a manner analogous to that described in Example 40(a) is reacted in accordance with the process described in Example 40. A solution of 2.1 g. of potassium hydroxide in 50 cc. of methanol is added to 9.2 g. of the crude title compound, the mixture is evaporated to dryness and dried in a high vacuum at 60 for 18 hours. The residue is boiled with a mixture of ether and a small amount of acetone, whereby the potassium salt of the title compound crystallizes. M.P. approx. 100"; the salt is strongly hygroscopic.

Produced analog. Ex. No. M.P. of the lactone Oily- 134-136" (sinters irob 130,

benzene/petroleum ether).

Observations 84-85" Sbenzene/petroleum ether Unpurified oil- Oily 8889 (pentane). Unpurified oil.

girlgfigfiagfii. 112 113 (pentane).

for 2 /2 hours, is evaporated to dryness, and the residue is divided between chloroform and water. The title compound, obtained after concentrating the chloroform layer which has been washed with sodium hydrogen carbonate solution and dried over magnesium sulphate, is distilled in a Hickmann flask. B.'P. 144-145 0.08 mm. Hg, yellow oil.

M.P. of 4-methoxy-5-phenyl-3-thiophene acetic acid, obtained by hydrolysis of the title compound: 88-94".

The following compounds may be produced in a manner analogous to that described in Example 49 and may be characterized by the melting points of the acids obtained therefrom by hydrolysis.

Substance 5-(3-chlorophenyl)=4-methoxy-3-thiophene acetic acid ethyl ester d-methoxy-S-o-tolyl-3-thiophene acetic acid ethyl ester 4-methoxy-5-1n-tolyl-3-thiophene acetic acid ethyl ester..

4-methoxy-5-p-tolyl-3-thiophene acetic acid ethyl ester 5-(2-chlorophenyl)-4-methoxy-3-thiophene acetic acid ethyl ester 59 5-(3-fluorophenyi) 4-rnethoxy-3-thiophene acetic acid ethyl ester (l0 5-(3, 4-dichiorophenyl)-4-methoxy-3-thiophene acetic acid ethyl ester.-- 61 5-(3, 4-dimethoxyphenyl)-4-methoxy-3-thiophene acetic acid ethyl ester 62.. 4-isopropoxy-5-phenyl-3-thiophene acetic acid ethyl ester 63..:.. 't-ethoxy-5-phenyl-3-thiophene acetic acid methyl ester"..-

5-(4-fluorophenyl)-4-methoxy-3-thiophene acetic acid ethyl ester 5-(4-chlorophenyl)-4-methoxy-3-thiophene acetic acid ethyl ester 4-methoxy-5-(4-methoxyphenyl)-3-thiophene acetic acid ethyl ester- 5-(2, 4-dichlorophenyl)-4-methoxy-3-thiophene acetic acid ethyl Physical constants, observations M.P. oi the acid B.P.n.25 165-171... 114-116 (ether/petroleum ether). B.P.n. 154156 85417 (ether/petroleum ether).

B.P. .m) 170-173"... 101-104 (ether/petroleum ether). Bl. c179 (1501103(ether/Jetroleum ether).

.. -127 (ether/pentane).

123126 (benzene/petroleum ether). B.P.0.l5 -145"-.- 63 (ether/petroleum other).

. an" 53-57 (pentane).

TABLE-Continned Physical Ex. constants, No. Substance observations M.P. of the acid 64.-..- 2-(4-methoxy-5-phenyl-3-thienyl) propionic acid methyl ester B.P.g .111g%58, 101102 (ether/petroleum ether).

my 65...-. 2-[4-methoxy-5-(4-methoxyphenyl)-3-thienyl] propionic acid ethyl ester 3.1 4 173-175-.. 99-101" (ether/petroleum ether). 66..... 2-[5-(4chlorophenyl)-4-methcxy-3-thienyl] propionic acid ethyl ester.. B.P.o.a 192 61-62" (petroleum ether). 67-. 2-[5-(4-fluorophenyl)-4-methoxy-3thienyl] propionic acid ethyl ester.. B.P.o.1 164 101-103 (ether/petroleum ether). 68...-. 2-[5-(3-ch1or0phenyl)-4-Inethoxy-3-thienyl] propionic acid ethyl ester B.P. ,1 159-161"--.- 7778 (petroleum ether/ether). 69-.-.. 2-(4-methoxy-5-phenyl-3'thienyl) hexanoic acid ethyl ester BiPs-gis 146, up 68-69" (ether/petroleum ether). 70.... 2-(i-mothoxy-5-0-toly1'3-thienyl) proplonic acid ethyl ester Oily... 71-72, (pentane).

... do 8285 (pentane). 86*88' (pentane). .do..... 108110 (ether/pentane).

7577 (ether/pentane).

71..-.. 2-(4methoxy-5-1n-tolyl-3-thlenyl) propionic acid ethyl ester..- 72...-. 2-(4-methoxy-5-p-tolyl-3-thienyl) propionic acid ethyl ester 73..- 2- -(2-chlorophenyl)-4-rnethoxy-3thienyl] propionic acid ethyl ester 74..- 2- 5-(2, kdichlorophenyl)-4-1neth0xy-3-thienyl] propionic acid ethyl ester 75....- 2-[5-(3-fluorophenyl)-4-methoxy-3-thienyl] propionic aicd ethyl ester ..do 78*80 (ether/pentane).

76..--. 2-[5-(3,i dimethoxyphenyl)-4-methoxy-3-thienyl] propionic acid ethyl esterdo MP. of the sodium salt 245-247 (acetone).- 77..-.. 2-(4-isopropoxy-5-pheny1-3-thienyl) propionic acid ethyl ester B.P.o. 140 MP. of the sodium salt 213215 (acetone). 78..... 2-(4-ethoxy-5-phenyl-3-thienyl)propionic acid methyl ester.. Oily 218 (acetone/ether).

79.-... 2-(4-methoxy-5-phenyl-3-thienyl) butyric acid ethyl ester B.P.om 135 7981 (ether/petroleum ether).

80...-. 4-methoxy-5-(m-trifluoromethylphenyl)-3-thiophene acetic acid ethyl ester....- B-P.l;.?l11303 218() 98-103 (ether/petroleum ether).

81..... 4-methoxy-5-(2-1nethoxyphenyl)-3-thlophene acetic acid ethyl ester 13.515 93-95 (ether/petroleum ether). 82..... 5-(2,5-dich1orophenyl)-4-methoXy-3thiophene acetic acid ethyl ester Bi tislsgj, 93-96 (ether/petroleum ether). 83.-." 2-ggrtrifluoromethylphenyl)-4-methoxy-3-thienyl] propionic acid ethyl B.P. 0.0a 127l30 106109 (ether/petroleum ether). 84...-. 2-[5-(Z-methoxyphenyl)-4-methoxy-3-thienyl]propionic acid ethyl ester 312 1112534 113-115 (ether/petroleum ether). 85.---. 2-[5-(2,5-dichlorophenyl)4-methoxy-3-thienyl] propionic acid ethyl ester Big e; 517070-170 108112 (ether/petroleum ether). 86....- 2-methyl-2-(4-methoxy-5-pheny1-3-thelnyl) propionic acid ethyl ester Bil IF. iii-739,

series 87....- 2-methyl-2-(4-methoxy-5-phenyl-3-thlenyl) hexanoic acid ethyl ester 126-127 (ether/petroleum ether).

88...-- 4-methoxy-5-phenyl-3-thiophene acetic acid isopropyl ester 58 89. 2-(4methoxy-5-pheny1-3-thienyl) propionic acid methyl ester 13.1 41: 1455b 101-102.

n0 90.-- 2-(4-methoxy-5-phenyl-3-thienyl) propionlc acid isopropyl ester B.P. 135 l01-l02. 91. 2-(4-meth0xy-5-phenyl3-thienyl) propionic acid cyclopentyl ester- B P 0 in 152 l01102 92. 2-(4-methoxy-5-phenyl-3-thienyl) propionic acid cyclohexyl ester 2-(4-methoxy6-phenyl-3-thienyl) propionic acid n-octyl ester 0 94 2-(4-meth0xy-5-phenyl-3-thienyl) propionic acid (2-cyclohexylethyl) es Produced Ex. analog rto Obser- No. Substance Ex. 0. vations 96 5-(4fluorophenyl) 4-hydroxy-3-thiophene 95 Oily. 4O acetic acid ethyl ester.

97.... 5-(4-chloropheny1)+hydroxy-3-thiophene 95 Do.

acetic acid e ester. 98 2-[5-(4-iluorophgny;%fi-hadroxy-thienyl] 95 Do. IO 101110 801 e 65 61. Example 95: 4-Hydroxy-5-phenyl-3-th1ophene 99-.-. e-h ydglixy-5ftolyl-3- t hlophene acetic acid 95 Do 8 Y 85 6!. acetlc acld ethyl ester 100... 5-(2-chlorophenyl)-4-hydroxy-3-thiophene 95 Do.

4a acetic acid ethyl ester. A solution of 6 g. of 4-hydroxy-5-phcnyl-3-thiophcne 101--- 2-(4-hyd 9 Y- -p -t y D p 95 omc acid ethyl ester. acetomtrile m 35 cc. of ethanol 1s saturated with hydrogen chloride gas while cooling with 166, 1.2 cc. of Water Example 102: 4 Methoxy s phenyl 3 thiophene are subsequently added, and the mixture 1s bolled at reflux acetic acid for 24 hours. The reaction mixture s evaporated to dry- 68.5 of 4 methoxy 5 phenyl-3-thiophcne acetic ness, the residue is taken up in ether, is washed with water, acid ethyl ester are boiled for a Short time in a Solution the residue obtained after concentrating the ether phase of 15.3 g. of potassium hydroxide in 250 cc. of water and by evaporation is again taken up in ethanol, and the 250 of methanol, and the mlxmfe 18 Subsequently solution is saturated with hydrogen chloride gas and .stmed at room temperature 24 hours methancfl is then removed by evaporatlon, the reaction mixture is agam boned at reflux for 18 hours The ethanol 15 then rendered acid with 2 N hydrochloric acid, and extraction evaporated. the residue is taken p in ether, Washed is effected with ether. Upon concentrating the ether phase, with water, the ether phase is concentrated, and the rewhich has been washed with saturated sodium chloride d u fied b solution and dried over magnesium sulphate, the title Sultmg crude Olly mle Compoun ls p n y 1 compound crystallizes. M.P. 88-94 (from ether/petrotion in a bulb tube. B.P. 165/0.01 mm. Hg. leum ether) The following compounds may be Obtained in a The following compounds may be produced in a manner analogous to that described in Example 95. net analogous to that described in Example 102.

Ex. No. Substance Physical constants, observations M.P. 114 116 (ether/petroleum ether).

. M.P. 87 (ether/petroleum ether).

. M.P. 104 (ether/petroleum ether, slnters from 80).- M.P.81) 19693 (acetone/petroleum ether).

103.... fi-(e-fiuorophenyl)-4-methoxy-3-thiophene acetic acid. 104.... 5-(4-chlorophenyl)4-methoxy-3-thiophene acetic ac1d. 105.-.. 4-methoxy-5-(4-methoxyphenyl)-3-thiophene acetic 9.01 106.... 5-(3ehlorophenyl)-4-methoxy-3-tbiophene acetic acid. 107.... 4-rnethoxy-5-m-tolyl-3-thiophene acetic acid 108.... 4-methoxy-5-p-tolyl-3 thiophene acetic acid. M.P. 88-90.

109.... 4-methoxy-5'o-tolyl-3-thiophene acetic acid. M.P. 60-62 (pentane).

110.... 5-(2-chlorophenyl)-4-methoxy-3-thiophene acetic ac M.P. 97100 (pentane).

111..-. 5-(2,4-dichlorophenyl)4-methoxy-3-thiophene acet c aci M.P. 107109 (diethyl ether/pentane). 112..-- 5-(3-iluorophenyl)+methoxy-3-thiophene acetic and... M. 90-92 (ether/pentane).

P 1 5- 3,4-dichloro hen l -i-inethox -3-thio hene acetic acid.- M.P. -l27 (diethyl ether/pentane). 1 3 p y Y p Ml. 123-126" (benzene/petroleum ether).

TABLECon tinued Ex. No. Substance Physical constants, observations 115...- 4-isopropoxy-5-phenyl-3-thiophene acetic acid M.P. 63 (ether/petroleum ether).

116.... 4-etl1oxy-5-phenyl-3-thiophene acetic acid M 117... 2-(i-mothoxy-S-phenyI-B-thienyl) propionic H616. I I I I I I I:

.1. 53-57 (pentane). M.P. 101102 (ether/petroleum ether).

MP. of the sodium salt 236238 (decomp.) Th2 racemate may be separated into the 118.... 2-[4-methoxy-5-(4-methoxyplhenyl)-3-thienyl] propionic acid..-- M.P. 119-... 2-[5-(4-chloropl1enyD-4-met oxy-3-thienyl1propionic acid M. 120...- 2-[5-(4-fluorophenyl)-4-methoxy-3-thienyl] propionic acid M. 121.... 2-[5-(3-chlorophenyl)+methoxy-3-thienyl] propionic acid M. 122 2-(4-mcthoxy-S-phenyl-ii-thienyl) hexanoic acid M. 123. 2-(4-methoxy-5o-tolyl-3-thienyl) Dl'opionic acid.- M. 124.... 2-(4-methoxy-5-m-tolyl-3-thienyl) propionic acid. M.

125...- 2-(4-methcxy-5-p-tolyl-3-thienyl) propionic acid.. M. 126.... 2-[5-(Z-chlorophenyl)-4methoxy-3 thienyl] propionic acid. M. 127.... 2-[5-(2A-dlchlorophenyl)4-methoxy-3-thienyl] propionic acid... M. 128..-. 2-[5-(3-fluorophenyl)-4-methoxy3-thienyl] propionic acid M.

129.... 2-[5-(3,4-dimethoxyphenyl)-4-methoxy-3-thienyl] ropionic acid.

130..-- 2- 4-isopropoxy-5-pl1enyl-3-thienyl) propionic acid.

131.... 2-(4-ethoxy-5-phenyl-3-thienyl) propionic acid.

132...- 2-(4-methoxy-5-phenyl-3-thienyl) butyric acid.

133.-.. 4-methoxy-5-(m-trifluoromethylphenyl)- S-thiophene acetic acid. 134.... 4-methoxy-5-(Z-methoxyphenyl)-3-thiophene acetic acid M 135.... 5-(2,5-dichlorophenyl)+methoxy-3-thiophene acetic acid M 136...- 2-[5-(m-trifluoromethylphenyl)4-methoxy43-thienyl] M propionic acid.

137...- 2-[5-(2,5-dichlorophenyl)-4-methoxy-3-thienyl] propionic acid-.. 138.... 2-[5-(2-methoxyphenyl)+methoxy-3-thienyl] propionic acid-... 139...- 2-methyl-2-(i-methoxy-5-phenyl-3thienyl) propionic acid Example 140: 2-Methyl-2-(4-methoxy-5-phenyl-3- thienyl) hexanoic acid g. of 2 methyl-2-(4-methoxy-S-phenyl-3-thienyl) hexanoic acid ethyl ester are boiled at reflux for 48 hours with 10 g. of potassium hydroxide in 3 cc. of water and cc. of methanol. The methanol is subsequently removed by evaporation, the residue is diluted with a small amount of water, is washed 'with ether, is then rendered acid to Congo red with sulphuric acid and extracted with ether. Upon concentrating the ether phase by evaporation the title compound is obtained. M.P. 126-127" (from ether/petroleum ether).

Example 141: 4-Hydroxy-5-phenyl-3-thiophene acetic acid (A) 4 hydroxy 5 phenyl 3 thiophene acetic acid ethyl ester is reacted in accordance with the process described in Example 102. The crude title compound obtained as viscous oil is purified by distillation in a bulb tube in a high vacuum. B.P. 140-145/0.08 mm. Hg. The compound is obtained as yellow oil.

(B) 1 g. of 4 hydroxy 5-phenyl-3-thiophene acetic acid ethyl ester is boiled at reflux for 24 hours in 6 cc. of 2 N caustic soda solution. The solution is subsequently rendered acid with 2 N sulphuric acid and is extracted with ether. The title compound is isolated from the ether phase as described in section A.

The 2,3 dihydro 6-phenylthieno[3,4-b]furan-2-one, obtained by cyclization of the title compound, has a M.P. of 104-106 (from benzene/petroleum ether).

The following compounds may be produced in a manner analogous to that described in Example 141 and may be characterized by the melting points of the lactones obtained therefrom by cyclization.

Ex. Obser- No.

145 4-hydroxy-5-o-tolyl-3- thiophene acetic acid.

146 5-(2chlorophenyl)+ hydroxy-a-thiophene acetic acid.

...do..... 88-89 (pentane).

-..do..... 112-113 (pentane).

optical antipodes as described in Ex. 16

P. of the soidum salt of the acid 200-202, [a]n= 19.5. of the sodium salt of the acid 201-203", [a]n=+19.5. 99101 (ether/petroleum ether).

82 (ether/petroleum ether).

101103 (ether/petroleum ether).

7778 (petroleum ether/ether).

(its-69 (ether/petroleum ether).

7l72 (pentane).

82-85 (pentane).

8688 (pentane).

108-110 (cther/pentane).

7577 (ether/pentane).

7880 (ether/pentane).

of the sodium salt 245247 (acetone), produced with 1 N NaOH in methanolic solution, dried at 70 in a high vacuum.

of the sodium salt 213215 (acetone/ether).

oi the potassium salt 218 (acetone/ether).

7981 (ether/petroleum ether).

98100 (ether/petroleum ether).

9395 (ether/petroleum ether). 93-9c (ether/petroleum ether). 106109 (ether/petroleum ether).

108-112 (ether/petroleum ether). 113l15 (ether/petroleum ether). 134-137 (ether/petroleum ether).

Example 147: 2-(4-Hydroxy-5-phenyl-3-thienyl) propionic acid 2 (4-hydroxy-5-phenyl-3-thienyl)propionic acid ethyl ester is reacted in accordance with the process described in Example 102. A solution of 2.1 g. of potassium hydroxide in 50 cc. of methanol is added to 9.2 g. of the oily crude title compound, the solution is evaporated to dryness, and the resulting crude potassium salt of the title compound is dried in a high vacuum at 60 for 18 hours and is then boiled with a small amount of acetone and a large quantity of ether, whereby the strongly hydroscopic potassium salt of the title compound is obtained in crystalline form. M.P. approx. 100.

Example 148: 4-Methoxy-5-phenyl-3-thiophene acetic acid 68.5 g. of 4-methoxy-5-phenyl-3-thiophene acetic acid ethyl ester are stirred at for 16 hours in a mixture of 250 cc. of water and cc. of dimethyl sulphoxide with the addition of 300 cc. of concentrated hydrochloric acid. The reaction mixture is then diluted with a large quantity of water and is extracted with chloroform. Upon concentrating the chloroform phase which has been washed with saturated sodium chloride solution and dried over magnesium sulphate, the title compound crystallizes. M.P. of the title compound: 88-94 (from ethyl/petroleum ether).

Example 149: 2-(4-Methoxy-5-phenyl-3-thienyl) propionic acid methyl ester 119 g. of 2 (4-methoxy-5-phenyl-B-thienyl)propionic acid chloride are added dropwise at 10 to a mixture of 80 cc. of pyridine and cc. of methyl alcohol in 250 cc. of chloroform, and the mixture is stirred at room temperature for 3 hours. The reaction solution is then successively extracted with 1 N hydrochloric acid, with sodium hydrogen carbonate solution and with saturated aqueous sodium chloride solution and is concentrated. The resulting crude oily title compound is purified by distillation in a Hickmann flask. B.P. /0.1 mm. Hg. n =1.5822.

The starting material may be obtained as follows:

(a) 18 g. of thionyl chloride are poured over 20 g. of 2-(4-methoxy-5-phenyl-3-thienyl)propionic acid, and this is allowed to stand at room temperature for 18 hours. The resulting 2-(4-methoxy-5-phenyl-3-thienyl)propionic acid chloride is purified by distillation in a Hickmann flask and forms a yellow viscous oil. B.P. 159/0.2 mm. Hg.

The following compounds may be obtained in a manner tion is allowed to stand at room temperature for 24 hours. analogous to that described in Example 149. The reaction mixture is subsequently concentrated, and the residue is divided between water and ether the ether Ex. Physical substance constants phase is successively washed with sodium hydrogen carbonate solution and with saturated sodium chloride solu- 150. 2-(4-methox -5- hen l-3-thien 1 r ionic acid 13.19. 135.

iso listi y y) p p 5 tron, 1S dried and concentrated. The resulting crude title -g gg g g ggg y y propionic acid s compound is purified by distillation in a Hickmann flask 152... 2-(4-methoxy-5-phei1yl-3-thlenyl) propionic acid B.P.0.05175- in a high Vacuum- 156-158/ cyclohexyl ester. n 25 1 5695 153-.. 2-(4n1ethoxy-5-phenyl3thienyl) propionic acid B.P.u.i 170. D

n-octyl ester. The following compounds may be produced in a mano 154- 2-ggfisgrfligialfigytgghienyl) propionic acid B.P.u.o518 1161' analogous to that described 111 Example 157. 155..- 4-methoxy-5-phenyl-3-thiophene acetic acid iso- M.P. 5358.

propyl ester.

Ex. No. Substance Physical constants, observations 158.-.. 4methoxy-5-pheny1-3-thiophene acetic acid ethyl ester B.P.u.us 144-145.

B.P.o.25 165-171.

159--.. 5-(4-fluorophenyl)4-methoxy 3-thiophene acetic acid ethyl ester- B.P.o.o5 il56.

160---. 5-(4chlorophenyl)-4-methoxy-3-thiophene acetic acid ethyl ester.

161---. 4-methoxy-5-(-methoxyphenyl)-3-thiophene acetic acid ethyl ester. B.P.o.oo 170173.

162---. 5-(3-chlorophenyl)-4-methoxy-3-thiophene acetic acid ethyl ester.. .om

163---. 4methoxy-5-0-toly1'3-thiophene acetic acid ethyl ester Oily, R; value 0.29 (adsorbent: silica gel, eluant: chloroform).

164--.- 4-methoxy-5-m-tolyl-3-thiophene acetic acid ethyl ester Oily, R: value 0.22 (adsorbent: silica gel, eluant: toluene, repeat 165-... 4-methoxy-5-p-tolyl-3-thiophene acetic acid ethyl ester Oily.

16 5-(2-cblorophenyl)-4-methoxy-3-thiophene acetic acid ethyl ester..-- D

. o. Oily, Rf value 0.5 (adsorbent: silica gel, eluant: chloroform).

. 5-(2, 4-dichlorophenyl)4-methoxy-3-thiophene acetic acid ethyl ester..

. 5-(3-fluorophenyl)-4-methoxy-3-thiophene acetic acid ethyl ester Oily, Ri value 0.3 (adsorbent: silica gel, eluant: chloroform).

. 5-(3,tdiehlorophenyl)4-methoxy-3-thiophene acetic acid ethyl ester 011st!1 litr tval)ue 0.7 (adsorbent: silica gel, eluant: acetic acid e y es er 5-(3, 4-dimethoxyphenyl)-4-methoxy-3-thiophene acetic acid ethyl ester B.P.o.oo 198.

. B.P.n.i5 140-145".

- 4-isopropoxy-5-phenyl-3'tbiophene acetic acid ethyl ester B.P. 150, an 1.5812.

17 4-ethoxy-5-phenyl-3-thiophene acetic acid methyl ester 173.-.- 2-(4-methoxy-5-phenyl-3-thienyl) ropionic acid methyl ester B.P.u.i 145", an 1.5822. 174.-.. 2-4-[methoxy-5-(4-methoxyphenyl -3-thienyl] propionic acid ethyl ester- B.P.o.o1 173l75. 175.-.. 2-5-[(4-chlorophenyl)-4-methoxy-3-thienyl] propionic acid ethyl ester.. B-P-O,B 192 (M. 61-62", petroleum ether). 176.-.. 2-5-[(4-fluorophenyl)-4-methoxy-3-thienyl] propionic acid ethyl ester 177--.- 2-5-l(3-chlorophenyl)+methoxy-3-thienyl] propionic acid ethyl ester B.P.o 1 159-161".

B.P.o.os 146, 1213 1.552.

178--.- 2-(4-methoxy-5-phenyl-3-thienyl) hexanoic acid ethyl ester Oily, R; value 0.18 (adsorbent: silica gel, eluant: toluene, repeat 179..-. 2-(4-methoxy-5-0-to1yl-3-thienyl) propionic acid ethyl este t wice 180...- 2-(4-methoxy-5-m-tolyl-3-thienyl) propionic acid ethyl ester Oiiliy R): value 0.24 (adsorbent: silica gel, eluant: toluene, repeat \VICB 'ly.

181-... 2-(4rmethoxy-5-p-tolyl-3-thienyl) propionic acid ethyl ester Oi 182.... 2-[5-(2-chlorophenyl)-4-n1ethoxy-3-thienyl] propionic acid ethyl ester.. Do. 183--.. 24542,4-dichlorophenyl)-4methoxy-3-thienyl] propionic acid ethyl est Oily, R; value 0.55 (adsorbent: silica gel, eluant chloroform). 184.... 2-[5-(3-fiuorophenyl)4-methoxy-3 thienyl] propionic acid ethyl ester Oily, Rf value 0.7 (adsorbent: silica gel, eluant: chloroform). 185.-.. 2[5-(3, 4-dimethoxyphenyl)-4-methoxy-3-thienyl] propionic acid ethyl es Oily. 186.-.. 2-(4-isopropoxy-5-phenyl-3-thienyl) propionic acid ethyl esterg:11-o.oi 140.

1 y. B.P.0 o1 135. B.P-0.01 160-180", an 1.5332.

187--.. 2-(4-ethoxy-5-phenyl-3-thienyl) propionic acid methyl ester- 188..-. 2-(4-methoxy-5-phenyl3-thienyl) butyric acid ethyl ester 189.... 4-methoxy-5-(mrifiuoromethylphenyl)-3-thiophene acetic acid et 190--.- 4-methoxy-5-( -methoxyphenyl)-3-thiophene acetic acid ethyl ester---.- B.P.o.05 l140, my 1.5808.

191-... 5-(2, S-dichlorophenyl)-4-rnethoxy-3-thiophene acetic acid ethyl ester B.P.o n4 149, up 1.5863.

192.... 2-[5-(m-trifluoromethylphenyl)-4-methoxy-3-thieriyl] propionic acid ethyl ester. B.P.o.0a 127130.

193--.. 2-[5-(2-n1ethoxyphenyl)4-methoxy-3-thienyl] propionic acid ethyl ester B.P.u.i 152, no 1.5704.

194.... 2-[5-(2, 5-dichlor0phenyl)-4-methoxy-3-thienyl] propionic acid ethyl ester.. B.P.o.oa 160-170, an 1.5771.

195.-.. 2-methy1-2-(4-methoxy-5-phenyl-3-thienyl) propionic acid ethyl ester B.P.o.i 140-142", M.P. 68-70 (ether/petroleum ether).

Example 156: 2-(4-Methoxy-5-phenyl-3-thienyl) Example 196: 2-(4-Methoxy-5-phenyl-3-thienyl) propionic acid tert.buty1 ester propionic acid ethyl ester A solution of 29.2 g. of 4-methoxy-5-phenyl-3-thioof tert'butyl alcohol are added dropwlse at room 55 phene acetic acid ethyl ester in 100 cc. of absolute ether temperature to a Grignard compound produced from 0.86 is added dropwise at to to a Suspension of of magnesium Shavings and of methyl iodide in sodium amide in liquid ammonia, produced from 2.43 g. ether, and a solution of 10.0 g. of 2-(4-methoxy-5-phenylof sodium, 150 cc. of liquid ammonia and a small amount of iron III nitrate, the reaction mixture is stirred at the same temperature for /2 hour, and a solution of 16.6 g. of methyl iodide in 50 cc. of ether is subsequently added 3-thienyl)propionic acid cholride in 15 cc. of chloroform is subsequently added dropwise, and the reaction mixture is boikd at for 18 hours- The reactio? mixture is dropwise within 50 minutes, and stirring is continued for lihfill Pouted 011 1C6 Water, the ether layer 18 separated. a further hour. 6.3 g. of ammonium chloride are then washed with saturated sodium chloride solution, dried and carefully added, the ammonia is evaporated at room temconcentrated. The title compound obtained as a viscous Para/lure and is simultanfiously replaced by the addition of ether. The ammonia-free ethereal suspension is stirred on i Purified by distillation in a bulb tube 170- at room temperature for a further 1% hours and is then 175 Hg batmdivided between 2 N hydrochloric acid and ether. The oily title compound, obtained after concentrating the ether Example z i phase which has been washed with aqueous sodium hydro- Proplomc am at y ester gen carbonate solution and with water and dried, is puri- A solution of 10 g. of 2-(4-methoxy-5-phenyl-3-thienyl) g f f fig zggs g flask 156458 propionic acid in 40 cc. of ethanol is saturated with hy- The 2-(4.methoXy 5 pheny1 3 thieny1) propionic acid, drogell Chloride gas While Cooling W t and t e $0111- obtained by hydrolysis of the title compound, has a M.P.

31 of 103l04 (sintering from 95, from ether/petroleum ether).

The following compounds may be produced in a manner analogous to that described in Example 196.

32 Example 220: 2-(4-Methoxy-5-phenyl-3-thienyl) propionic acid methyl amide 2-(4-methoxy-5-phenyl-3-thienyl)propionic acid chloride is reacted with a 33% aqueous monomethyl amine Physical Ex. constants, N 0. Substance observations M.P. of the acid 197-.-. 2-[5-(4-chlorophenyl)-4-methoxy-3-thienyl] propionic acid ethyl ester B.P. 192 til-62 (petroleum ether).

198---. 2-[5-(4-fluor0phenyl)-4-methoxy-3-thienyl] propionic acid ethyl ester 199--.- 2-[5-(3-chlorcphenyl)-4-methoxy-3-thienyl] propionic acid ethyl ester 200--.- 2-(4-1nethoxy-5-phenyl-3-thienyl] hexanoic acid ethyl ester B.P. 164 101103 (ether/petroleum ether). B.P. 159161. 7778 (petroleum ether/ether). B.1P5.g.2o 146, m 68-69 (ether/petroleum ether).

201..-- 2-(4-methoxy-5-o-tolyl-3-thienyl) propionic acid ethyl ester-.- Oily 7172 (pentane).

202..-. 2-(4-methoxy-fi-m-tolyl-3-thienyl) propionic acid ethyl ester dn 82-85 (pentane).

203.-.- 2-(4-methoxy-5-p-tolyl-3-thienyl) propionic acid ethyl esterdo 86-88 (gentane).

204-... 2-[5-(2-chl0rophenyl)-4-methoxy-3thienyl] propionic acid ethyl ester .do 108-110 (ether/pentane).

205.-.- 2-[5-(2,4-dichlorophenyl)-4-methoxy-3-thienyl] propionic acid ethyl ester ..do.. 7577 (ether/pentane).

206.... 2-[5-(3-fluorophenyl)-4-methoxy-3-thienyl] propionic acid ethyl ester .do.. 78-80" (ether/pentane).

207-... 2-[5-(3,4-dimethoxyphenyl)-4-methoxy-3-thienyl] propionic acid ethyl ester do..-.- M.(P. (if the sodium salt 245-247 ace one 208.... 2-(4-lsopropoxy-5-phenyl-3-thlenyl) propionic acid ethyl ester B.P. 140 M.(P. otf the sodium salt 213-215 ace on 209--.- 2-(4-ethoxy-5-phenyl-3-thienyl) propionic acid methyl ester Olly 218 (acetone/ether).

210-... 2-(4-methoxy-5-phenyl-3-thienyl) butyric acid ethyl ester B.P.Mw 135 79-81" (ether/petroleum ether).

211-... 2-[4-methoxy-fi-( i-methoxyphenyl)-3-thienyl] propionic acid ethyl este B.P.om 173175 99-101 (ether/petroleum ether).

212.... 2-[5-(m-trifluoromethylphenyl) -4-methoxy-8-thienyl] propionic acid ethyl este B.P.Ma 127130 106109 (ether/petroleum ether).

213.--. 2-[5-(2-methoxyphenyl)-4-methoxy-3-thienyl] propionic acid ethyl ester Bil5.;. 4152, n1) 113-115 (ether/petroleum ether).

. 0 214.-.. 2-[5-(2,5-dichl0rophenyl)-4-methoxy-3-thienyl] propionic acid ethyl ester B.P.osogl 1567()71170 108-112 (ether/petroleum ether).

my 215...- 2-(4-methoxy-5-phenyl-3-thienyl) propionic acid isopropyl ester B.P.M 135 103-104 (ether/petroleum ether).

Example 216: 2-Methy1-2-(4-methoxy-5-phenyl-3- thienyl) hexanoic acid ethyl ester g. of 2-(4-methoxy-5-phenyl-3-thienyl) propionic acid ethyl ester are added at room temperature, in a at mosphere of nitrogen, to 0.85 g. of finely dispersed sodium hydride suspended in dimethyl formamide, the mixture is heated to 60 for 30 minutes, is cooled, and 5 cc. of butyl iodide are added dropwise. The mixture is stirred at room temperature for 2 hours, is heated to 60 for a short time, is cooled, a 3-fold quantity of ice water and approx. 2 N hydrochloric acid are added, and extraction is effected with ether. After concentrating the ether phase which has been washed with sodium hydrogen carbonate solution and with water and dried, the title compound is obtained as an oil.

The 2 methyl 2-(4-methoxy-5-phenyl-3-thienyl)hexanoic acid, obtained by hydrolysis of the title compound, has a M.P. of 126-127 C. from ether/ petroleum ether).

Example 217: 2-Methyl-2-(4-methoxy-5-phenyl-3- thienyl)propionic acid ethyl ester 2 (4-methoxy-5-phenyl-3-thienyl)propionic acid ethyl ester is reacted with methyl iodide in accordance with the process described in Example 216. The title compound is purified by distillation. B.P. 140142/ 0.1 mm. Hg. The compound is obtained as yellow oil which gradually solidifies in crystalline form. M.P. 6870 (from ether/ petroleum ether).

Example 218: 2-(4-Methoxy-5-phenyl-3-thieny1) propionic acid amide 40 cc. of a aqueous ammonia solution are added dropwise within minutes to 20 g. of 2-(4-methoxy-5- phenyl-3-thienyl)propionic acid chloride, and the reaction mixture is allowed to stand at room temperature for 2 hours. The mixture is then extracted with chloroform, the chloroform layer is washed with 2 N hydrochloric acid, water, saturated sodium carbonate solution and water, is dried and concentrated. The title compound obtained in crystalline form is recrystallized from benzene/petroleum ether. M.P. 134137.

Example 219: 4-Methoxy-5-phenyl-3-thiophene acetic acid amide 4-methoxy-5-phenyl-3-thiophene acetic acid chloride [produced in a manner analogous to that described in Example 149(a)] is reacted with ammonia in accordance with the process described in Example 218. M.P. of the title compound; 112-1 14 (from benzene/ether).

solution in accordance with the process described in Example 218. M.P. of the title compound: 102-104 (from benzene/ petroleum ether) Example 221: 2-(4-Methoxy-5-phenyl-3-thienyl) propionic acid dimethyl amide 2-(4-methoxy-5-phenyl-3-thienyl)propionic acid chloride is reacted with a 40% aqueous dimethyl amine solution in accordance with the process described in Example 218. The title compound is purified by distillation and is obtained as a yellow viscous oil. B.P. 195-200/ 0.05 mm. Hg.

Example 222: 4-Hydr0xy-5-phenyl-3-thiophene acetic acid ethyl ester A solution of 10.5 g. of ethyl mercaptan in cc. of dimethyl formamide is added dropwise at room temperature in an atmosphere of nitrogen to 8.2 g. of sodium hydride in 100 cc. of dimethyl formamide. A solution of 46.6 g. of 4-methoxy-5-phenyl-3-thiophene acetic acid ethyl ester in 150 cc. of dimethyl formamide is then added dropwise, and the reaction mixture is heated to 100 for 2% hours. The reaction mixture is then cooled, water is added, the mixture is rendered acid to Congo red with 2 N hydrochloric acid, the separated oil is extracted with benzene, the benzene phase is extracted with 2 N caustic soda solution while cooling with ice, and the caustic soda solution phase is again rendered acid to Congo red by the addition of 4 N hydrochloric acid, is extracted with benzene, and the dried benzene phase is concentrated. The resulting title compound is purified by chromatography and distilled.

The following compounds may be produced in a manner analogous to that described in Example 222.

A solution of 2.50 g. of ethyl mercaptan in 20 cc. of dimethyl formamide is added dropwise at room temperature to a suspension of 1.92 g. of a 50% sodium hydride dispersion in 20 cc. of dimethyl formamide, in an atmosphere of nitrogen. A solution of 5.8 g. of 4-methoxy-5-0- tolyl-3-thiopl1ene acetic acid ethyl ether in 15 cc. of dimethyl formamide is then added dropwise, and the reaction mixture is subsequently heated to 100 for 2 /2 hours. The cooled reaction mixture is then rendered acid with 70 cc. of ice-cold 1 N hydrochloric acid, the separated oil is extracted with toluene, the toluene layer is extracted at with a l N caustic soda solution, and the caustic soda solution extract is subsequently rendered acid to Congo red with hydrochloric acid while cooling with ice. The acid solution is again extracted with toluene, and the toluene phase, which has been washed with aqueous sodium chloride solution and dried, is concentrated by evaporation, whereby the title compound is obtained as an oil. The 2,3 dihydro-6-0-tolylthieno[3,4-b]furan-2-one, obtained by cyclization of the title compound, has a M.P. of 8889 (from pentane).

Example 227 2-Chlorophenyl) -4-hydroxy-3- thiophene acetic acid A solution of 1.24 g. of ethyl mercaptan in 12 cc. of dimethyl formamide is added dropwise at room temperature in an atmosphere of nitrogen to a suspension of 0.96 g. of a 50% sodium hydride dispersion in 12 cc. of dimethyl formamide, a solution of 6.2 g. of S-(Z-chlorophenyl)-4-methoxy-3-thiophene acetic acid ethyl ester is then added dropwise, the reaction mixture is heated to 100 for 3 /2 hours and is worked up as described in Example 226, whereby the title compound is obtained as an oil.

The 6-(2-chlorophenyl)-2,3-dihydrothieno [3,4-b] furan-Z-one, obtained by cyclization of the title compound, has a M.P. of 112-113 (from pentane).

Example 228: 2-(4-Hydroxy-5-phenyl-3-thienyl) propionic acid 6.5 g. of ethyl mercaptan are added dropwise in an atmosphere of nitrogen to a suspenion of 2.6 g. of sodium hydride in 75 cc. of dimethyl forma-mide, a solution of 15.3 g. of 2-(4-methoxy-5-phenyl-3-thienyl)propionic acid ethyl ester in 25 cc. of dimethyl formamide is then added dropwise, the reaction mixture is heated to 100 for 3 hours and is worked up as described in Example 223. A solution of 2.1 g. of potassium hydroxide in 50 cc. of methanol is added to 9.2 g. of the crude title compound obtained as an oil, the mixture is evaporated to dryness and the resulting crude potassium salt of the title compound is dried in a high vacuum at 60 for 18 hours, whereupon it is boiled with a mixture of ether and a small amount of acetone, whereby the strongly hygroscopic potassium salt of the title compound crystallizes. M.P. approx. 100.

Example 229: 2,3-Dihydro-6-phenylthieno [3,4-b] fuIan-2-one Ex. Physical constants, No. Substance observations 230.... 6-(4'fluorophenyl)-2,3-dihy- M.P. 134-136 (benzene! drothieno[3,4-b]furan-2-one. petroleum ether, sinters from 130). 231- 6-(4-chlorophenyl)-2,3-dihy- M.P. 159-160 (decomp-,

drothieno[3,4-b]furan-2-one. benzene 232... fi-(t-fluorophenyl)-2,3-dlhydro-3- M.P. 8485 (benzene/petromethylthieno[3,4-b]furan-2- leum ether).

M.P. 88-89 (pentane).

M.P. 112-113 (pentana).

one.

233 2,3-dihydro-6-0-tolylthieno[3,4-

blfuran-Z-one.

234. 6-(2-ehlorophenyl) -2,3'dihydrothieno [8,4-b1furan-2-one.

The compounds of the Examples that possess an asymmetric centre, e.g. the acids of Examples 17, 21 to 27, may be obtained in optically pure form thereof in manner known per se. Determination of the relative configuration thereof with respect to (+)-2-(4-methoxy-S- pheny1-3-thienyl) propionic acid may also be eifected in manner known per se, e.g. by O.R.D. (optical rotary dispersion) complemented, if necessary, by CD. (circular dichroism).

What is claimed is:

1. A compound of the formula:

COR:

wherein R is hydrogen or alkyl of 1 to 4 carbon atoms, R is hydroxy, alkoxy of 1 to 4 carbon atoms, cycloalkyloxy of 3 to 6 carbon atoms, cycloalkylalkoxy of 3 to 6 ring carbon atoms and 1 to 4 alkoxy carbon atoms, amino, monoalkylamino of 1 to 4 carbon atoms or dialkylamino, each alkyl substituent having 1 to 4 carbon atoms, 7 or R and R together denote a single bond, R is hydrogen, chlorine or alkyl of 1 to 4 carbon atoms,

or when R is hydrogen, or when R and R together denote a single bond, then R, may be hydroxy, or when R is alkyl of 1 to 4 carbon atoms, then R may be alkoxy of 1 to 4 carbon atoms, R, is hydrogen, chlorine, bromine or alkyl of 1 to 4 carbon atoms,

or when R is hydrogen or when R and R together denote a single bond, then R, may be hydroxy, or when R is alkyl of 1 to 4 carbon atoms, then R may be alkoxy of 1 to 4 carbon atoms, or when R is hydrogen, then R, may be fluorine or trifiuoromethyl, R is hydrogen or alkyl of 1 to 4 carbon atoms, and R is hydrogen or methyl.

2. A compound of Claim 1, wherein R is hydrogen or alkyl of 1 to 3 carbon atoms.

3. A compound according to Claim 1, wherein R is hydrogen.

4. A compound of Claim 1, wherein R is methyl. 5. A compound of Claim 1, wherein R is hydroxy. 6. A compound of Claim 1, wherein R is difiierent to R6.

7. A compound of Claim 6, in optically pure isomeric form.

8. A compound of Claim 7, in D' form. 9. The compound of Claim 1, which is 2-(4-methoxy-5- phenyl-3-thienyl) propionic acid.

10. The compound of Claim 1, which is 4-methoxy-5- phenyl-3-thiophene acetic acid.

11. The compound of Claim 1, which is 2,3-dihydro- 6-phenylthieno[3,4-b] furan-Z-one.

12. The compound of Claim 1, which is 5-(4-fluorophenyl)-4-methoxy-3-thiophene acetic acid.

13. The compound of Claim 1, which is 5-(4-chlorophenyl)-4-methoxy-3-thiophene acetic acid.

14. The compound of Claim 1, which is 2-[5-(4-fluorophenyl)-4-methoxy-3-thienyl] propionic acid.

15. The compound of Claim 1, which is 4-methoxy-5- (4-methoxyphenyl)-3-thiophene acetic acid.

16. The compound of Claim 1, which is 2-[4-methoxy- 5-(4-methoxyphenyl) 3-thienyl] propionic acid.

17. The compound of Claim 1, which is 2-[5-(4-chlorophenyl)-4-methoxy-3-thienyl] propionic acid.

18. The compound of Claim 1, which is 2-[5-(3- chlorophenyl)-4-methoxy-3-thienyl] propionic acid.

19. The compound of Claim 1, which is 2-(4-methoxy- 5-m-tolyl-3-thienyl) propionic acid.

20. The compound of Claim 1, which is 5-(2-ch1orophenyl)-4-methoxy-3-thiophene acetic acid.

21. The compound of Claim 1, which is 2-(4-methoxy- 5-o-tolyl-3-thieny1) propionic acid.

22. The compound of Claim 1, which is 2,3-dihydro- 6-0-toly1thieno [3 ,4-b] furan-Z-one.

23. The compound of Claim 1, which is 2- (4-methoxy- 5-phenyl-3-thienyl) propionic acid amide.

24. The compound of Claim 1, which is 4-methoXy-5- pheny1-3-thiophene acetic acid amide.

25. The compound of Claim 1, which is 2-(4-ethoXy-5- phenyl-3-thienyl) propionic acid.

26. The compound of Claim 1, which is 2-(4-hydroxy- 5-phenyl-3-thienyl) propionic acid.

27. The compound of Claim 1, which is (+)-2-(4- methoxy-5-phenyl-3-thienyl) propionic acid.

28. A compound of Claim 1, wherein R is hydroxy and/or R is hydrogen, in pharmaceutically acceptable salt form.

29. A compound of Claim 28, in sodium or potassium salt form.

References Cited UNITED STATES PATENTS HENRY R. JILES, Primary Examiner C. M. S. I AISLE, Assistant Examiner US. Cl. X.R.

260332.2 H, 332.3 R, 332.2 C; 424-275