United States Patent Office Patented July 29, 1969 2 alkyl, for example, lower alkyl; nitro; alkanamido, for 3,458,565 (3-OXO-E-ALKENYL)ARYLOXYALEKANOIC ACEDS example, lower alkanamido such as acetamido; and, taken AND DERVATIVES THEREOF together, two X radicals on adjacent carbon atoms of ohn B. Bicking and Edward J. Cragoe, Jr., Lansdale, the benzene ring may be joined to form anhydrocarbylene Pa., assignors to Merck & Co., Inc., Rahway, N.J., a chain (i.e., a divalent organic radical composed solely corporation of New Jersey of carbon and hydrogen) containing from three to four No EDrawing. Filed Feb. , 1966, Ser. No. 523,908 carbon atoms between their points of attachment, for it. C. C07c63/60, 93/00, 103/20 example, trimethylene, tetramethylene, 1,3-butadienyl U.S. C. 26-529 16 Claims ene (i.e., -CH=CH-CH=CH-), etc.; Y is a member O Selected from the group consisting of alkylene and halo alkylene having a maximum of six carbon atoms and ABSTRACT OF THE DISCLOSURE which contain from one to three linear carbon atoms (3-oxo-1-alkenyl)phenoxyalkanoic acid products and between the carboxy and oxygen moieties, for example, the acid addition salts, esters and amide derivatives there methylene, ethylene, ethylidene, trimethylene, propyl of which are substituted in the phenoxy ring by from one 5 idene, isopropylidene, fluoromethylene, etc.; and n is an to four halo, alkyl, nitro, lower alkanamido, etc. sub integer having a value of one to four. stituents. The said products are diuretic and saluretic A preferred embodiment of the invention relates to agents useful in the treatment of hypertension. the I(3-oxo-1-alkenyl)phenoxyalkanoic acids having the The products are prepared by four routes: (1) via the following structural formula: condensation of a nuclear formyl substituted phenoxyal 20 kanoic acid with an appropriate aldehyde or ketone; (2) via the etherification of a (3-oxo-1-alkenyl)phenol; (3) via the hydrolysis of a (3-oxo-1-alkenyl)phenoxylal R1CC o-on-on- >-on- OOE kanoic acid ester; or (4) via the hydrolysis of an ap wherein R1 and R2 are similar or dissimilar members propriate (3-disubstituted amino-1,3-alkadien-1-yl) 25 Selected from the group consisting of hydrogen and lower phenoxyalkanoic acid ester. alkyl and X and X8 are similar to dissimilar members Selected from the group consisting of halogen, lower alkyl and, taken together, may be joined to form a 1,3- This invention relates to a new class of chemical com butadienylene chain (i.e., -CH=CH-CH=CH-). pounds which can be described generally as (3-oxo-1- 30 The foregoing class of compounds exhibits particularly alkenyl)aryloxyalkanoic acids and to the nontoxic, good diuretic and saluretic activity and represents a pre pharmacologically acceptable salts, esters and amide ferred subgroup of compounds within the scope of this derivatives thereof. invention. Also, it is an object of this invention to describe novel The (3-oxo-1-alkenyl)aryloxyalkanoic acids (I) of methods of preparation for the foregoing (3-oxo-1-al 35 the invention are conveniently prepared by one or more kenyl)aryloxylalkanoic acids, esters and amides. of four alternate processes. The first method of prepara Pharmacological studies show that the instant products tion relates to the condensation of a formyl substituted are effective diuretic and saluretic agents which can be aryloxyalkanoic acid (II) with an appropriate aldehyde used in the treatment of conditions associated with elec or ketone; the second involves the etherification of a (3- trolyte and fluid retention and hypertension. When ad 40 oXo-1-alkenyl)-phenol (IV); the third relates to the hy ministered in therapeutic dosages, in conventional vehi drolysis of an ester of a (3-oxo-1-alkenyl)aryloxy cles, the instant products effectively reduce the amount of alkanoic acid (VI, infra); and the last involves the hy sodium and chloride ions in the body, lower dangerous drolysis of a suitable (3-disubstituted amino-1,3-al eXcesses of fluid levels to acceptable limits and, in gen 45 kadien-1-yl)aryloxyalkanoic acid ester (VII, infra). eral, alleviate conditions usually associated with edema. The first of the aforementioned processes, that is, The (3-oxo-1-alkenyl)aryloxyalkanoic acids of the the conednsation process, for preparing the products (I) invention are compounds having the following structural of the invention relates specifically to the reaction of a formula: formyl substituted aryloxyalkanoic acid (II, infra) with 50 a suitable aldehyde or ketone (III). The reaction is ad RCH-CO-CR2 =CE vantageously conducted in the presence of a catalyst, for example, in the presence of an aqueous solution of an -O-Y-COOH alkali metal hydroxide such as sodium hydroxide, potas I sium hydroxide, lithium hydroxide, etc. and the alkali wherein R1 and R2 are similar or dissimilar members 55 metal salt of the product thus formed is then treated selected from the group consisting of hydrogen, alkyl, with an acid to obtain the desired (3-oxo-1-alkenyl) for example, lower alkyl such as methyl, ethyl, propyl, aryloxyalkanoic acid (I). The following equation illus isopropy, butyl, pentyl, etc. and, taken together, R and trates the reaction: (X)n R2 may be joined to form an alkylene chain containing RiCEICOCHR2 -- OCEI from one to three carbon atoms between their points of 60 Base H+ attachment to the acylvinyl group, for example, an al -O-Y-COO --> --> kylene chain of the formula -CH2m- wherein m is III I an integer having a value of one to three or, alternatively, (X)n Ri and R2 may be joined to form a mononuclear cycloal RCH2CO-CR2 eCE kylidene substituted alkylene chain wherein the chain 65 O-Y-COO contains two to three carbon atoms between its points of attachment to the acylvinyl group, for example, a cycloalkylidene substituted propylene chain of the formula wherein R, R2, X, Y and n are as defined above and -C=C(CH2)(CH2)2- wherein x is an integer having H+ is the cation derived from an organic or inorganic a value of four to five and z is an integer having a value 70 acid such as hydrochloric acid. The reaction is preferably of two to three; the X radicals are similar or dissimilar conducted at ambient temperatures but higher tempera members selected from the group consisting of halogen, tures may also be employed. 3,458,565 3 4 The second principal method by which the products flux temperatures. Acidification of the resulting mixture (I) of the invention are prepared relates to the reaction (Ic, infra) thus obtained yields the desired product (Id, of a (3-oxo-1-alkenyl)phenol (IV, infra) with a Suit infra). The following equation illustrates the reaction: able etherification reagent, in the presence of a base, (X)n R1CH-CO-CER2C followed by the conversion of the I(3-oxo-1-alkenyl) 5 MOH aryloxyalkanoic acid salt (a, infra) thus formed to the -OE -- ((R)- (R)3 --> corresponding free acid (Ib, infra) by acidification of the O bo reaction mixture. Suitable bases which may be used in IW the process include the alkali metal carbonates such as (X)n potassium carbonate, the alkali metal alkoxides such as O RCHCO-CR2-CH R3 R3 sodium ethoxide, etc. The etherification reagent is a halo -o-c-b-co OM alkanoic acid salt having the following formula: k is X1-Yi-COOM wherein Xi is halogen, for example, c chlorine, bromine, iodine, etc.; Yi is a methylene or tri methylene radical which may be appropriately substituted 5 by alkyl or halogen radicals such as a monofluoro group H. and M is hydrogen or the cation derived from an alkali (X) in metal hydroxide, an alkali metal carbonate, etc. Such as RCHCO-CR2sCE R3 R a sodium or potassium cation. The following equation -o-c-b-c O O. wherein the etherification reagent employed is an halo 20 is ki alkanoic acid and the basic reagent is potassium carbon d ate, illustrates this method of preparation; however, it wherein M, R, R2, X, n and H+ are as defined above is to be understood that the alkali metal salts of the halo and the R3 radicals are similar or dissimilar substituents alkanoic acid reactant may also be employed in an other selected from the group consisting of hydrogen and wise similar process and that other basic reagents such 25 lower alkyl. as sodium carbonate or alkali metal alkoxides may also The third principal method for preparing the products be employed: of the invention consists in the hydrolysis of an ester of (X)n an appropriate (3-oxo-1-alkenyl)aryloxyalkanoic acid RICHCO-CR2=CH KCO3 (VI, infra). The hydrolysis is conducted in the conven -OH -- Xi-Yl-COOH --> 30 tional manner by treatment of the said ester (VI) with an aqueous Solution of an acid as, for example, with an Iw W aqueous solution of hydrochloric acid, in which instance (X)n a solvent such as acetic acid can be used, or, alternatively, RICHCO-CR2-CH the hydrolysis may be conducted with an aqueous solu --O-Y1-COOH tion of a base Such as an aqueous solution of sodium bi carbonate, in which instance the use of an alcoholic solvent Ea such as a lower alkanol is advantageous; however, when an aqueous solution of a base is employed it is necessary to treat the carboxylate salt intermediate thus formed H 40 with an acid to obtain the desired product. The following (X)n equation illustrates this method of preparation. R1CHCO-CR2=CH (X) in --O-Y-COOE RCHCO-CR2CE Hydrolysis -O-Y-COOR rare b 45 wherein R1,R2, X, X, Y, in and Hit are as defined above. WE The choice of a suitable reaction solvent is dependent (X) largely upon the character of the reactants and, in gen R1CECO-CER2-CH eral, any solvent which is substantially inert to the re -O-Y-COO actants employed and in which the reagents are reason 50 N ably soluble may be used; however, ethanol and acetone are particularly advantageous solvents in which to con duct the process. Also, the reaction may be carried out wherein R, R2, X, Y and n are as defined above and R at ambient temperatures but, generally, it is desirable to is an hydrocarbyl radical, that is, an organic radical com conduct the reaction at temperatures slightly above am 55 posed solely of carbon and hydrogen such as an alkyl bient temperature. radical, etc. The foregoing etherification reaction is most Suitable The fourth principal method for preparing the instant for obtaining those (3-oxo-1-alkenyl)aryloxylalkanoic products also relates to the hydrolysis of a (3-disubsti acid products (Ia, supra) which contain an alkylene chain tuted amino-1,3-alkadien-1-yl)aryloxyalkanoic acid ester having a single carbon atom or three carbon atoms be 60 (VII, infra). The hydrolysis is conveniently carried out tween the carboxy group and oxygen atom; this is apparent in a mixture of acetic acid, water and a strong acid such from the definition of the etherification reagent, as hydrochloric acid, with slight heating. Preferably, the Xi-Y1-COOM (see the preceding paragraph) wherein hydrolysis mixture is heated on a steam bath for a period Y1 is defined as a methylene or trimethylene radical. of 15 minutes to one hour. The following equation illus Those (3-oxo-1-alkenyl)aryloxylalkanoic acids which 65 trates this method of preparation: contain two linear carbon atoms in the alkylene chain (X)n RCH-scC-CR2-seCH between the carboxy group and oxygen atom are also ob E tained by the etherification of a (3-oxo-1-alkenyl)phenol NR4RS -O-Y-COOR re (IV, infra) but, in lieu of employing the metal salt of a haloalkanoic acid as described in the preceding para 70 WII graphs, a propiolactone or an appropriately substituted (X)n derivative thereof, is employed. The reaction of the (3- R1CHCO-CR2s-CH oxo-1-alkenyl)phenol (IV) with the lactone is conducted -O-Y-COOH in the presence of a base such as an aqueous Solution of sodium hydroxide and, preferably, with heating at re 75 3,458,565 5 6 wherein R, R, R2, X, in and H+ are as defined above; R. Substituted aryloxyalkanoic acid (IIb). The following and R represent similar or dissimilar alkyl radicals which equation illustrates the reaction: may be joined together directly or through a hetero atom such as oxygen, to the nitrogen atom to which they are (X)n attached to form a hetercocyclic ring such as pyrrolidinyl, OCH piperidino, morpholino, piperazinyl, N-alkylpiperazinyl, 5 MOH etc. -OH + O (R)-((R).CO - The (3-oxo-1-alkenyl)aryloxyalkanoic acids (I) of WII the invention are generally obtained as crystalline solids (X)n and, if desired, may be purified by recrystallization from OCH R3 R3 a suitabe solvent. Suitable solvents include, for example, O ethyl acetate, isopropyl alcohol, nitromethane, acetic acid, -O-(-)-cooM acetonitrile, etc. or mixtures of Solvents such as a mixture is k: of ethyl acetate and hexane or a mixture of butanone and hexane, etc. 15 H. The formyl substituted aryloxyalkanoic acids (II) (X) in which are employed as starting materials in the aforemen O CH R R tioned reaction with the aldehyde or ketone reactants (III, -O-C-C-COOH supra) are prepared from their appropriate nuclear hy k is droxy substituted benzaldehyde precursors (VIII, infra) 20 by the reaction of the latter with an appropriate etherifica tion reagent. wherein M, R, X, in and H+ are as defined above. When, for example, it is desired to prepare a formyl Also, the formyl substituted aryloxyalkanoic acids (II) substituted aryloxyalkanoic acid (IIa, infra) wherein the may be prepared by hydrolysis, in an aqueous solution alkylene chain of the alkanoic acid moiety has one or 25 three linear carbon atoms in the chain between the car of an acid or a base, of the corresponding formyl sub boxy group and oxygen atoms, the etherification reagent stituted aryloxyalkanoic acid ester (IX, infra) as shown is an alkali metal or an alkaline earth metal salt of a suit by the following equation: able haloakonoic acid having the formula (X)n X-Yi -COOM 30 OCE Hydrolysis wherein M, Xi and Yi are as defined above. In general, -O-Y-COOR - - - the etherification is conducted in the presence of a base such as an aqueous solution of sodium or potassium car X X) bonate or in the presence of the corresponding hydroxide 35 och or in the presence of a sodium alcoholate such as sodium ethoxide, and the alkanoic acid salt thus obtained is then -O-Y-COOE converted to the desired formyl substituted aryloxyalk anoic acid derivative (IIa) in the convenitional manner I by treatment with an acid such as hydrochloric acid. The 40 wherein R, X, Y and n are as defined above. following equation illustrates the reaction: The (3-oxo-1-alkenyl)phenols (IV) which are used as (X)n starting materials in the second principal method for pre OCH Base H paring the instant products, that is, the etherification proc -OH - X1-Yi-COOM --> --> eSS, Supra, are prepared by either of two routes. The first 45 method of preparation consists in the reaction of a nu VIII clear hydroxy substituted benzaldehyde (VIII) with a suit (X)n able aldehyde or ketone (III). The condensation may OCE be carried out either in the presence of a base as, for ex -O-Yi-COOE ample, in the presence of an alkali metal hydroxide such 50 as sodium hydroxide or, alternatively, in the presence of IIa an acid as, for example, hydrochloric acid, However, when either the R or R radicals represents hydrogen the wherein M, X, X1, Y1, in and H+ are as defined above. choice of a suitable catalyst determines the structure of The choice of a suitable reaction solvent for the process the (3-oxo-1-alkenyl)phenol (IV). When, for example, a is dependent largely upon the character of the reactants 55 basic catalyst is employed, the point of condensation on employed; however, in general, it can be stated that any the ketone reactant (III) is at the methylene carbon bear solvent which is substantially inert with respect to the ing the alkyl group, whereas, when an acid catalyst is used, reactants employed and in which the reagents are reason the point of condensation is at the methylene carbon bear ably soluble may be used. Solvents which have proved to ing the hydrogen atom. The reaction is advantageously be particularly advantageous include ethanol and dimeth 60 conducted at ambient temperatures and, usually, over a ylformamide. Also, the reaction may be carried out at ambient temperatures but, generally, it is desirable to con period of from 24-27 hours: duct the reaction at temperatures slightly above ambient temperature. OCH (X):X Those formyl substituted aryloxyalkanoic acid starting 65 materials (IIb, infra) wherein the alkylene chain contains -OH -- R1CHCO CHR -) two linear carbon atoms between the carboxy group and oxygen atom are prepared from their corresponding nu WII III clear hydroxy substituted benzaldehydes (VIII) by the re (X)n action of the latter with propiolactone or with an appro 70 R1 CHCO-CR2=CE priately substituted propiolactone, in the presence of a -OH base such as an aqueous solution of sodium hydroxide, preferably, while heating the solution at reflux tempera W tures; followed by the acidification of the carboxylate in termediate thus formed to obtain the corresponding formyl 5 wherein R, R, X and n are as defined above. 3,458,565 7 8 The second method of preparation for the (3-oxo-1- The condensation process (b) for preparing the ester alkenyl)phenols (IV) consists in the hydrolysis of an ap derivatives (VI) involves the reaction of a formyl sub propriate (3-disubstituted amino-1,3-alkadien-1-yl)phenol stituted aryloxyalkanoic acid ester (IX) with a suitable (X, infra). The hydrolysis is conducted in a mixture of aldehyde or ketone (III) in the presence of an acid cat acetic acid, water and a strong acid such as hydrochloric alyst such as hydrogen chloride or boron trifluoride. The acid and, preferably, with the application of heat as, for reaction may be conducted in the absence of a solvent but, example, by heating on the steam bath for approximately if desired, an excess of an aldehyde or ketone may be used 15 minutes to one hour: as the reaction medium. The application of heat is not necessary to the reaction and, in general, the synthesis is 0. advantageously conducted at ambient temperatures: (X)n R1C-C-CR2-e-CE H+ NRRS -OH --> (X)n R1CHCO CHR2 - O CH H+ X 5 O-Y-COOR - (X)n R1CHCO-CR-CH I IX -OE (X)n R1 CHCO-CR2-CH IV 20 -O-Y-COOR WI wherein R, R2, R, R5, X, n and H+ are as defined above. The (3-oxo-1-alkenyl)aryloxyalkanoic acid esters (IV) which have been described above in connection with 25 wherein R, R, R2, X, Y and n are as defined above. the third principal method for preparing the products of The synthesis of the (3-oxo-1-alkenyl)aryloxyalka the invention (I) are useful not only as chemical inter noic acid esters (VI) by way of the Schiff base interme mediates but are themselves active as diuretics. The said diates (c) consists in treating an ester of a suitable (N-Sub esters may be prepared by one or more of four different stituted iminomethylaryloxy) alkanoic acid (XI, infra) methods: (a) by the etherification of a (3-oxo-1-alkenyl) 30 with an appropriate aldehyde or ketone (III) in the pres phenol (IV, infra) by reaction of the said phenol (IV) ence of an acid catalyst such as hydrochloric acid and, with a suitable haloalkanoic acid ester; (b) by the con preferably, in a solvent such as dimethylformamide. The densation of a formyl substituted aryloxyalkanoic acid ester (VI) thus obtained may be isolated and purified for ester (IX, infra) with a suitable aldehyde or ketone; (c) use as a diuretic or, alternatively, for use as a chemical by the reaction of an appropriate Schiff base intermediate 35 intermediate, but, as a practical matter, when the said ester (XI, infra) with a suitable aldehyde or ketone and (d) by (VI) is to be employed as an intermediate in the syn the esterification of a (3-oxo-1-alkenyl)aryloxyalkanoic thesis of the carboxylic acid products (I) of this invention, acid (I) according to conventional methods. These meth it is advantageous to omit the isolation and purification ods of preparation are discussed further below. step and, instead, hydrolyze the ester (VI) directly to the The etherification process (a) for preparing the said 40 desired acid (I). The following equation illustrates this ester derivatives relates specifically to the reaction of a method of preparation: (3-oxo-1-alkenyl)phenol (IV) with an appropriate halo alkanoic acid ester having the formula X-Y-COOR wherein R, Xi and Yi are as defined hereinabove. The foll lowing equation illustrates the reaction: 45 Rich,cocH.R.: + RN=CH if O-Y-COOR -

I IX R1CHCO-CR2=CH 50 (X)n -OH + X-Y-COOR -} RICHCO-CR2-CH -O-Y-COOR IV (X)n WI RCH-CO-CR2=CH 55 -O-Y-COOR wherein R, R, R2, X, Y and n are as defined above and w R is an alkyl radical, aryl, etc. The esterification method (d) for the preparation of the 60 I(3-oxo-1-alkenyl)aryloxyalkanoic acid esters (VI) con wherein R, R, R2, X, X, Y and n are as defined above. sists in converting the corresponding (3-oxo-1-alkenyl) In general, the reaction is conducted in the presence of a aryloxyalkanoic acids (I) to their corresponding esteri base such as sodium or potassium carbonate, Sodium or fied derivatives by either of two alternate methods of prep potassium hydroxide or in the presence of a sodium al aration. According to one method a (3-oxo-1-alkenyl) coholate such as sodium ethoxide. The choice of a suit 65 aryloxyalkanoic acid (I) is treated with an appropriate able reaction solvent is dependent largely upon the char lower alkanol, preferably, in the presence of a catalyst acter of the reactants employed but, in general, any solvent such as an acid for example, sulfuric acid, to obtain the which is substantially inert with respect to the reactants corresponding esterified product (VI); or, alternatively, and in which the reagents are reasonably soluble may be according to the second method the (3-oxo-1-alkenyl) used. For example, ethanol and dimethylformamide have 70 aryloxyalkanoic acid (I) is converted to the correspond proved to be particularly advantageous solvents in which ing acid halide (XII, infra) by treating the said acid with to conduct the reaction. The process may be carried out at an appropriate halogenating agent such as thionyl chlo ambient temperatures but, generally, it is desirable to con ride, followed by the reaction of the acid halide thus duct the process at temperatures above ambient tempera formed with an appropriate alcohol as, for example, with ture. 75 a lower alkanol or with a dialkylamino substituted lower 3,458,565 9 10 alkanol such as 2-diethylaminoethanol, to prepare the cor gen cyanide and hydrogen chloride(gas) in the presence responding esterified product (VI). The following equa of anhydrous aluminum chloride. This reaction is prefer tions illustrate these processes: ably conducted in an inert solvent as, for example, in a

(X) RCECO-CR2-cC -O-Y-COC XII sock/ M (X) in RiCCO-CR-CE -O-Y-COOH NoH R1CHCO-CR2e CH w-O-Y COOR

WI

wherein R, R, R2, X, Y and n are as defined above. benzene solution. The following equation illustrates these The 3-(disubstituted amino - 1,3 - alkadien-1-yl)- methods of preparation: aryloxyalkanoic acid esters (VII) which are also em ployed as starting materials in the preparation of the in (X) (X)n 30 OC stant products (I) are prepared by the reaction of a Base/HO Acid formyl substituted aryloxyalkanoic acid ester (IX) with -OH -- CHCl3 re-- - - an enamine (XIII, infra) derived from the reaction of a secondary amine with an appropriate aldehyde or ketone HCN VIII -- (i.e., III, supra) and, preferably, in a water-immiscible HC (gas) Solvent in which the reactants and products are reason 35 -- ably soluble, such as toluene or benzene. Also, it is advan AlCl3 tageous to add a small amount of a carboxylic acid such X)n as acetic acid or the amine salt of a carboxylic acid och if wherein the amine is identical to the secondary amine which is used in the preparation of the enamine reactant. 40 Also, it is desirable to remove the water formed during WI the reaction as, for example, by the use of molecular sieves, azeotropic distillation, chemical dehydrating wherein X and n are as defined above. agents, etc. The following equation illustrates this method The formyl substituted aryloxyalkanoic acid esters of preparation: 45 (IX) which are intermediates in the preparation of the (3-oxo-1-alkenyl)aryloxyalkanoic acid esters (VI) are prepared by one of three methods: (a) by the etherifica tion of an appropriate nuclear hydroxy substituted ben (X)n Zaldehyde (VIII); (b) by the esterification of a formyl RICH-i-CHR -- O CH 50 Substituted aryloxyalkanoic acid (II); or (c) by the form NRR5 -O-Y-COOR. -- ylation of an aryloxyalkanoic acid ester (XII, infra). The etherification process (a) for preparing the formyl XII IX Substituted aryloxyalkanoic acid esters (IXa, infra) is (X)n conducted in a manner similar to that described above for RCH-i-c R2-CH 55 the etherification of the (3-oxo-1-alkenyl)phenols (IV), NR4RS -O-Y-COOR i.e., by treating a nuclear hydroxy substituted benzalde hyde (VIII, infra) with an haloalkanoic acid ester of the VII formula: X-Y-COOR. The following equation illus trates the reaction: 60 wherein R, R, R2, R4, R5, X, Y and n are as defined X above. The nuclear hydroxy substituted benzaldehyde inter --OH -- X-Yi-COOR - mediates (VIII) are either known compounds or may be 65 prepared by methods which are known to those skilled in WII the art. Thus, for example, by treating a phenol or an ap X propriate nuclear substituted derivative thereof with chlo roform in the presence of an aqueous solution of a base -O-Y-COOR and then treating the resulting mixture with an acid such O as hydrochloric acid, the corresponding nuclear hydroxy Xa substituted benzaldehyde is obtained. Alternatively, the said hydroxy substituted benzaldehyde intermediates may Wherein R, X, X, Y and n are as defined above. The also be obtained by the reaction of a phenol, or an appro reaction is conducted in the presence of a base such as priate nuclear substituted derivative thereof, with hydro 75 Sodium or potassium carbonate or sodium or potassium 3,458,565 11 12 hydroxide or in the presence of a sodium alcoholate such soluble and in the presence of a small amount of car as sodium ethoxide. Suitable reaction solvents may be boxylic acid catalyst such as a lower alkanoic acid, for ex employed but ethanol or dimethylformamide have proved ample, acetic acid or in the presence of an amine salt of to be particularly advantageous reaction medium. Also, a lower alkanoic acid. Also, it is desirable to remove the the process may be conducted at ambient temperatures water formed during the process as, for example, by the but, generally, it is desirable to conduct the reaction at use of molecular sieves, azeotropic distillation, chemical temperatures above ambient temperature. dehydrating agents, etc. The following equation illustrates The esterification process (b) for the preparation of the reaction: the formyl substituted aryloxyalkanoic acid esters (IX) (X)n is effected by the reaction of an appropriate formyl sub O Rich,--OHR -- O CH stituted aryloxyalkanoic acid (II) with an appropriate NR4R5 - O -) lower alkanol, substituted lower alkanol, etc., to obtain the corresponding esterified product or, alternatively, by XIII WII the reaction of a formyl substituted aryloxyalkanoic acid (X)n (II) with a suitable halogenating agent to form the cor 5 responding acid halide and then treating the said formyl Rich--CR-csNR4RS m-OH substituted aryloxyalkanoic acid halide (XIV) thus formed with a lower alkanol or with a substituted lower X alkanol to prepare the corresponding esterified product wherein R, R2, R1, R5, X and n are as defined above. (IX). The following equation illustrates the reaction: 20 The Schiff base intermediates (XI), which are used in X the preparation of the (3-oxo-1-alkenyl)aryloxyalka O CE (X) noic acid esters (VI, supra), are prepared by the con -O-Y-COC densation of a formyl substituted aryloxyalkanoic acid ester (IX) with a primary amine such as an alkylamine OCH (X)X s soc/ XIV 25 or an arylamine. It is usually desirable to conduct the re action in a water-immiscible solvent such as benzene or k -O-Y-COOH N ROH toluene and to remove the water formed during the reac ROHN tion by azeotropic distillation or other conventional means IE Y (X) as, for example, by the use of chemical dehydrating OCH 30 agents or molecular sieves. Also, it is advantageous to add -O-Y-COOR a catalytic amount of a carboxylic acid to the reaction mixture as, for example, a lower alkanoic acid such as IX acetic acid and to conduct the reaction at the reflux tem wherein R, X and n are as defined above. perature of the solvent system. The following equation The formylation process (c) for preparing the formyl 35 illustrates this method of preparation: substituted aryloxyalkanoic acid ester intermediates (IX) (X)n is conducted by treating an appropriate aryloxyalkanoic R8NH -- O CH acid ester (XV, infra) with formaldehyde and concen O-Y-COOR. --> trated hydrochloric acid to obtain the corresponding chlo romethyl substituted aryloxyalkanoic acid ester (XVI, 40 IX infra) and the chloromethyl derivative thus obtained is X)n then treated with hexamethylenetetramine and concen RNaCB ( trated hydrochloric acid under reflux to obtain the desired -O-Y-COOR formyl substituted compound (IX). The following equa tion illustrates the process: 45 XI (X)n wherein R, R, X, Y and n are as defined above. Included within the scope of this invention are the non toxic, pharmacologically acceptable acid addition salts -O-Y-COOR -- CEO -- HCl - of the instant products (I). In general, any base which will 50 form an acid addition salt with the I(3-oxo-1-alkenyl)- aryloxylalkanoic acids (I) and whose pharmacological ClCH properties will not cause an adverse physiological effect -O-Y-COOR when ingested by the body system is considered as being within the scope of this invention; suitable bases thus in XVI 55 clude, for example, the alkali metal and alkaline earth Hexamethylene metal hydroxides, carbonates, etc., ammonia, primary, tetramine secondary and tertiary amines such as monoalkylamines, dialkylamines, trialkylamines, nitrogen containing hetero cyclic amines, for example, piperidine, etc. Hol 60 Also included within the scope of this invention are X)n the amide derivatives of the instant (3-oxo-1-alkenyl)- och aryloxyalkanoic acids (I) which may be prepared by -O-Y-COOR Several methods. According to one method the amide de rivatives may be prepared by converting a (3-oxo-1- IX alkenyl)aryloxyalkanoic acid (I) to the corresponding wherein R, X, Y and n are defined as above. acid halide or ester in the manner described hereinabove, The (3-disubstituted-1,3-alkadien-1-yl)phenols (X, in and treating the said acid halide or ester derivative with fra), from which the (3-oxo-1-alkenyl)phenol intermedi ammonia, methoxyamine or with an appropriate mono ates (IV, Supra) are obtained, can be conveniently synthe alkylamine, dialkylamine, dialkylaminoalkylamine or sized by the reaction of a nuclear hydroxy substituted 70 with an heterocyclic amine such as pyrrollidine, piperi benzaldehyde (VIII) with an enamine (XIII, infra) de dine, morpholine, etc. to produce the corresponding amide rived from the reaction of a secondary amine with an ap derivative. Another method of preparation consists in the propriate aldehyde or ketone (i.e., III, supra). The reac reaction of a (3-oxo-1-alkenyl)aryloxyalkanoic acid (I) tion is advantageously conducted in a water-immiscible with a special reagent such as dicyclohexylcarbodiimide, Solvent in which the reactants and products are reasonably N-ethyl-5-phenylisoxazolium - 3'-sulfonate, 1,1'-carbon 3,458,565 13 14 yidiimidazole, 1,1'-thionyldiimidazole, etc. and treating Step C: 2,3-dichloro - 4 - (2-methyl-3-oxo-1-butenyl)- the intermediate thus formed with ammonia or a suitable phenoxyacetic acid. To a solution of 2,3-dichloro-4-(2- amine to form the corresponding amide product. Still an methyl-3-oxo-1-butenyl)phenoi (2.68 g., 0.0109 mole) in other method for preparing the amide derivatives of the dimethylformamide (11 ml.) is added potassium car instant products (I) comprises the etherification of a (3- bonate (3.32 g.: 0.0240 mole). Then ethyl bromoacetate oxo-1-alkenyl)phenol (IV) with an haloalkanoic acid 5 (4.01 g., 0.0240 mole) is added and the reaction mixture amide of the formula: X-Y-CONRTR8 wherein X is heated at 55-60° C. for 1.5 hours with stirring. and Y are as defined above and R and R8 are selected The reaction mixture is cooled in ice and treated with from the group consisting of hydrogen, alkyl, hydroxy water (55 ml.). The resulting solid ester is collected by alkyl, haloalkyl, aralkyl, alkoxyalkyl and dialkylamino O filtration and washed with water. alkyl. These and other equivalent methods for the prep The ester is treated with a mixture of acetic acid (18 aration of the amide derivatives of the instant products ml.) and 5% hydrochloric acid (9 ml.) and heated on (I) will be apparent to those having ordinary skill in the a steam bath for 0.5 hour with stirring. The cooled reac art and to the extent that the said derivatives are both tion solution is diluted with water (27 ml.) and a white nontoxic and physiologically acceptable to the body sys 5 solid separates. There is obtained 3.15 g. (95.4%) of tem, the said amides are the functional equivalent of the material, M.P. 164-169 C. Recrystallization from nitro corresponding (3-oxo - 1-alkenyl)aryloxylalkanoic acid methane gives 2.45 g. (74.3%) of 2,3-dichloro-4-(2- products (I). methyl-3-oxo-1-butenyl)phenoxyacetic acid in the form The examples which follow illustrate the (3-oxo-1- of white needles, M.P. 173.5-174.5 C. alkenyl)aryloxyalkanoic acids (I) of the invention and 20 the methods by which they are prepared. However, the Analysis.-Calculated for CHClO4: C, 51.51; H, examples are illustrative only and it will be apparent to 3.99; C1, 23.39. Found: C, 51.43; H, 4.06; C1, 23.32. those having ordinary skill in the art that all of the prod In a manner similar to that described in Example 1 for ucts embraced by Formula I, supra, may also be pre the preparation of 2,3-dichloro- 4-(2-methyl-3-oxo-1- pared in an analogous manner by substituting the appro 25 butenyl)phenoxyacetic acid, the products 2-methyl-3- priate starting materials for those set forth in the ex chloro-4-(2-methyl-3-oxo-1-butenyl)phenoxyacetic acid amples. and 2-chloro-3-methyl - 4 - (2 - methyl-3-oxo-1-butenyl) EXAMPLE phenoxyacetic acid, respectively, are prepared by sub stituting 2-methyl-3-chlorophenol and 2-chloro-3-methyl 2,3-dichloro-4-(2-methyl-3-oxo-1-butenyl)phenoxy 30 phenol for the 2,3-dichlorophenol recited in Example 1, acetic acid Step A, and following substantially the procedure de Step A: 2,3-dichloro-4-hydroxybenzaldehyde.-In a 5 Scribed in Steps A, B and C of that example. liter, three-necked flask, equipped with a mechanical stir EXAMPLE 2 rer, condenser, thermometer and dropping funnel, is placed water (2000 ml.), calcium hydroxide (280 g., 3.78 35 (2,3-dichloro-4-(2-methyl-3-oxo-1-pentenyl)phenoxy moles), sodium carbonate (320 g., 3.02 moles) and 2,3- acetic acid dichlorophenol (142.6 g., 0.875 mole). The resulting sus pension is heated on a steam bath to 65 C. and to it is Step A: 2,3 - dichloro-4-(2-methyl-3-oxo-1-pentenyl)- added chloroform (208 g., 1.75 moles), dropwise, with phenol-A finely ground suspension of 2,3-dichloro-4- stirring, while maintaining the temperature at 60-70° C. 40 hydroxybenzaldehyde (3.82 g., 0.020 mole) in diethyl After addition is complete, the mixture is stirred and ketone (13.35 g., 0.155 mole) is chilled in an ice bath and heated at 60-70° C. for one hour. treated with dry hydrogen chloride gas for 45 minutes. The reaction mixture is chilled in an ice bath and acidi The resulting dark solution then is stirred at room tem fied with concentrated hydrochloric acid. The mixture is perature. extracted with ethyl acetate (approximately 3 liters) and 45 After 42 hours the volatile materials are removed under the extract is dried over magnesium sulfate. The solvent reduced pressure. The residue is dissolved in ether and is removed by distillation under reduced pressure and the washed with water. After drying over anhydrous mag solid residue is recrystallized from toluene to obtain 37.8 nesium sulfate, the ether is removed under reduced pres g. (23%) of 2,3-dichloro-4-hydroxybenzaldehyde, M.P. Sure to give an oil which is triturated with butyl chloride 177-182 C. Two additional recrystallizations from ace 50 to yield 2.00 g. (38.6%) of a solid, M.P. 101-105° C. tonitrile give 28.4 g. (17%) of 2,3-dichloro-4-hydroxy Recrystallization from butyl chloride gives 1.37 g. benzaldehyde in the form of White prisms having a melt (26.4%) of 2,3-dichloro-4-(2-methyl-3-oxo-1-pentenyl) ing point of 184-185 C. phenol in the form of white rods, M.P. 112-113 C, Analysis.-Calculated for CHCl2O: C, 44.01 H, 55 Analysis.-Calculated for C12H12Cl2O: C, 55.62; H, 2.11; C1, 37.12. Found: C, 44.22; H, 2.30; C1, 37.02. 4.67; C1, 27.36. Found: C, 55.90; H, 4.63; C1, 27.34. Step B: 2,3 - dichloro- 4 - (2-methyl-3-oxo-1-butenyl) Step B: 2,3-dichloro-4-(2-methyl-3-oxo-1-phentenyl)- phenol-A finely ground suspension of 2,3-dichloro-4- phenoxyacetic acid.--To a solution of 2,3-dichloro-4-(2- hydroxybenzaldehyde (3.82 g., 0.020 mole) in methyl methyl-3-oxo-1-pentenyl)phenol (2.59 g., 0.010 mole) in ethyl ketone (11.18 g.; 0.155 mole) is chilled in an ice 60 dimethylformamide (10 ml.) is added potassium car bath and treated with dry hydrogen chloride gas for 45 bonate (3.04 g., 0.022 mole). Then ethyl bromoacetate minutes. The resulting dark solution is stirred at room (3.67 g., 0.022 mole) is added and the reaction mixture temperature. is heated at 55-60° C. for 1.5 hours with stirring. After 65 hours the volatile materials are removed under The reaction mixture is cooled in ice and treated with reduced pressure. The residue is dissolved in ether and 65 Water (50 ml.). The resulting solid ester then is collected washed with Water. After drying over anhydrous mag by filtration and washed with water. nesium sulfate, the ether is removed under reduced pres The ester is treated with a mixture of acetic acid (17 sure to give an oil which is triturated with butyl chloride ml.) and 5% hydrochloric acid (8.5 ml.) and heated on to yield 2.20 g. (45%) of solid, M.P. 155-156 C. Re a steam bath for 0.5 hour with stirring. The cooled re crystallization from butyl chloride gives 1.87 g. (38%) 70 action solution is diluted with water (25 ml.) and a white of 2,3-dichloro-4-(2-methyl-3-oxo-1-butenyl)phenol in the solid separates. There is thus obtained 3.17 g. (100%) of material, M.P. 152-154 C. Recrystallization from form of white prisms, M.P. 157-159 C. nitromethane yields 2.71 g. (85.5%) of 2,3-dichloro-4- Analysis.-Calculated for CHCl2O: C, 53.90; H, (2-methyl-3-oxo-1-pentenyl)phenoxyacetic acid in the 4.11; Cl, 28.93. Found: C, 53.61; H, 4.00; C1, 28.93. 75 form of white needles, M.P. 157-158° C. 3,458,565 15 16 Analysis.-Calculated for C14H14CI2O: C, 53.02; H, water (90 ml.). The resulting solid ester is collected by 4.45; Cl, 22.36. Found: C, 53.37; H, 4.52; Cl, 22.24. filtration and washed with water. The ester is treated with a mixture of acetic acid (30 EXAMPLE 3 ml.) and 5% hydrochloric acid (15 ml.) and heated on I2,3-dichloro-4-(2-methyl-3-oxo-1-pentenyl)phenoxy a steam bath for 20 minutes with stirring. The cooled re acetic acid action mixture is diluted with water (45 mi.) and the re Step A: Ethyl (2,3 - dichloro - 4 - formylphenoxy)- sulting yellow solid is collected by filtration. There is thus obtained 5.23 g. (94.6%) of material, M.P. 207-211. C. acetate.-A mixture of 2,3-dichloro-4-hydroxybenzalde Recrystallization from acetic acid yields 4.08 g. (73.8%) hyde (708 g., 0.37 mole), potassium carbonate (112 g., of 2,3-dichloro-4-(2-oxocyclobutylidenemethyl)phenoxyl 0.81 mole), ethyl bromoacetate (135 g., 0.81 mole) and O dimethylformamide (285 ml.) is stirred and heated at 55 acetic acid in the form of yellow needles, M.P. 218 60° C. for 1.5 hours. The reaction mixture then is cooled 219 C. in an ice bath and water (900 ml.) is added. The crystal Analysis.-Calculated for C18H10Cl2O4: C, 51.85; H, line produce which separates is collected on a filter and 3.35; C1, 23.55. Found: C, 52.03; H, 3.47; Cl, 23.41. washed with water. Recrystallization from cyclohexane 15 gives 97 g. (95%) of ethyl (2,3-dichloro-4-formylphe EXAMPLE 5 noxy)acetate, M.P. 89.5-91.5° C. After two more recrys 2,3-dichloro-4-(2-oxocyclopentylidenemethyl)phenoxy tallizations from cyclohexane the ethyl (2,3-dichloro-4- acetic acid formylphenoxy)acetate 87.3 g. (85%) melts at 92-93 C. Step A: 2,3-dichloro-4-(2-oxocyclopentylidenemeth Analysis.-Calculated for CH10Cl2O4: C, 47.68; H, 20 yl)phenol.--To a solution of 2,3-dichloro - 4 - hydroxy 3.64; C1, 25.59. Found: C, 47.67; H, 3.58; Cl, 25.40. benzaldehyde (5.73 g., 0.03 mole) in toluene (50 ml.) is Step B: 2,3-dichloro-4-(2-methyl-3-oxo-1-pentenyl)- added 4-(1-cyclopenten-1-yl)morpholine (5.52 g., 0.036 phenoxyacetic acid.--To a solution of ethyl (2,3 - di mole). Acetic acid (0.6 ml.) then is added and the reac chloro-4-formylphenoxy)acetate (11.08 g., 0.040 mole) tion solution is heated under reflux until the evolution of in toluene (50 ml.) is added 4-(1-ethylpropenyl)mor 25 Water Ceases. pholine (7.45 g., 0.048 mole). Then acetic acid (3 ml.) After four hours, the reaction mixture is concentrated and morpholine (1 ml.) are added and the reaction solu to dryness under reduced pressure. The residue is treated tion solution is heated under reflux until the evolution with a mixture of water, concentrated hydrochloric acid of water ceases. and chloroform and stirred vigorously. The chloroform After 11 hours the reaction mixture is concentrated to 30 layer is separated, washed with water and dried over an dryness under reduced pressure. The residual ester is hydrous magnesium sulfate. The solvent is removed under treated with a mixture of acetic acid (70 ml.) and 5% reduced pressure and the residual solid is dissolved in hot hydrochloric acid (35 ml.) and heated on a steam bath aqueous sodium carbonate solution, treated with decolor for 0.5 hour with stirring. The cooled reaction solution izing carbon and filtered. The filtrate is acidified with 6 N is diluted with water and a gum separates. The gum is dis 35 hydrochloric acid to give a solid, 1.87 g. (24%), M.P. solved in ethanol (70 ml.) and treated with a solution of 180-183° C. Recrystallization from acetonitrile yields sodium bicarbonate (6.72 g., 0.08 mole) in water (140 1.11 g. (15%) of 2,3-dichloro-4-(2-oxocyclopentylidene ml.). The resulting solution is heated on a steam bath methyl)phenol in the form of yellow needles, M.P. 185 for 0.5 hour with stirring and then concentrated to dryness 187° C. under reduced pressure. The residue is dissolved in hot 40 Step B: 2,3-dichloro-4-(2-oxocyclopentylidenemeth water, treated with decolorizing carbon and filtered. The yl)phenoxylacetic acid.--To a solution of 2,3-dichloro filtrate then is acidified with 6 N hydrochloric acid where 4-(2-oxocyclopentylidenemethyl)phenol (1.81 g., 0.007 upon a solid separates. Recrystallization from nitro mole) in dimethylformamide (7 ml.) is added potassium methane yields 3.06 g. (24%) of 2,3-dichloro - 4 - (2- carbonate (2.13 g., 0.0154 mole). Ethyl bromoacetate methyl-3-oxo-1-pentenyl)phenoxyacetic acid, M.P. 157 45 (2.57 g., 0.0154 mole) then is added and the reaction 158° C. mixture is heated at 55-60° C. for 1.5 hours with stirring. EXAMPLE 4 The reaction mixture is cooled in ice and treated with (2,3-dichloro-4-(2-oxocyclobutylidenemethyl)phenoxy water (35 ml.). The resulting solid ester is collected by acetic acid filtration and washed with water. 50 The ester is treated with a mixture of acetic acid (12 Step A: 2,3-dichloro - 4 - (2-oxocyclobutylidenemeth ml.) and 5% hydrochloric acid (6 ml.) and heated on a yl)phenol. To a solution of 2,3-dichloro-4-hydroxybenz steam bath for 0.5 hour with stirring. The cooled reaction aldehyde (7.64 g., 0.04 mole) in 12% aqueous sodium solution is diluted with water (18 ml.) whereupon a hydroxide solution (26.67 ml, 0.08 mole) is added cyclo solid separates. The solid is dissolved in ethanol (12 butanone (5.60 g., 0.08 mole) and the resulting solution 55 ml.) and treated with a solution of sodium bicarbonate is allowed to stir at room temperature. (1.18 g., 0.014 mole) in water (24 ml.). The resulting After 24 hours, the reaction mixture is triturated with solution is heated on a steam bath for 0.5 hour with water (200 ml.) and the insoluble solid is collected by stirring and then concentrated to dryness under reduced filtration. This solid is dissolved in hot water (200 ml.) pressure. The residue is dissolved in hot water, treated and acidified by the addition of 6 N hydrochloric acid. 60 with decolorizing carbon and filtered. The filtrate is acidi There is thus obtained 6.44 g. (66%) of yellow solid, fied with 6 N hydrochloric acid whereupon a solid sepa M.P. 203-205 C. Recrystallization from acetonitrile rates. There is thus obtained 2.07 g. (94%) of material, yields 5.4 g. (55.6%) of 2,3-dichloro - 4 - (2-oxocyclo M.P. 212-214 C. Recrystallization from acetic acid butylidenemethyl)phenol in the form of yellow prisms, yields 1.75 g. (80%) of 2,3-dichloro-4-(2-oxocyclo M.P. 210.5-21.15° C. 65 Analysis.-Calculated for CHCl2O: C, 54.35; H, pentylidenemethyl)phenoxyacetic acid in the form of 3.32; Cl, 29.17. Found: C, 54.22; H, 3.44; Cl, 29.17. orange needles, M.P. 226-227 C. Step B: 2,3-dichloro-4-(2 - oxocyclobutylidenemeth EXAMPLE 6 yl)phenoxyacetic acid.--To a solution of 2,3-dichloro 4-(2-oxocyclobutylidenemethyl)phenol (4.48 g., 0.0184 70 2,3-dichloro-4-(2-oxocyclopentylidenemethyl) mole) in dimethylformamide (18 ml.) is added potassium phenoxyacetic acid carbonate (5.60 g., 0.04.05 mole). Then ethyl bromo Step A: 2,3-dichloro-4-(2-oxocyclopentylidenemethyl)- acetate (6.76 g., 0.04.05 mole) is added and the reaction phenol.--To a solution of 2,3-dichloro-4-hydroxybenzal mixture is heated at 55-60° C. for 1.5 hours with stirring. dehyde, Example 1, Step A, (3.82 g., 0.20 mole) in 12% The reaction mixture is cooled in ice and treated with 5 aqueous sodium hydroxide solution (13.3 ml, 0.040 3,458,565 17 18 mole) is added cyclopentanone (3.36 g., 0.040 mole) and After 20 hours the reaction mixture is concentrated to the resulting solution is allowed to stand at room tem dryness under reduced pressure and the residue is dis perature. solved in acetic acid (9 ml.) and heated on a steam bath After 19 hours, the reaction mixture is dissolved in for 10 minutes. The cooled reaction solution then is water (100 ml.) and acidified by the addition of 6 N hy treated with water to give a solid. The product is dis drochloric acid. There is thus obtained 5.14 g. (100%) solved in ethanol (10 ml.) and treated with a solution of of yellow solid, M.P. 159-166° C. Recrystallization from sodium bicarbonate (1.0 g., 0.012 mole) in water (20 acetonitrile yields 1.17 g. (22.8%) of 2,3-dichloro-4-(2- ml.). The resulting solution is heated on a steam bath oxocyclopentylidenemethyl)phenol in the form of yellow for one hour with stirring and then concentrated to dry needles, M.P. 185-187 C. 0. ness under reduced pressure. The residue is dissolved in Analysis.-Calculated for C12H10Cl2O2: C, 56.06; H, hot water, treated with decolorizing carbon and filtered. 3.92; Cl, 27.58. Found: C, 56.16; H, 3.96; Cl, 27.42. The filtrate is acidified with 6 N hydrochloric acid and a Step B: 2,3-dichloro-4-(2-oxocyclopentylidenemethyl)- solid separates. There is thus obtained 1.40 g. (74%) of phenoxyacetic acid-By following the procedure de material, M.P. 205-212° C. Recrystallization from acetic scribed in Example 5, Step B, 2,3-dichloro-4-(2-oxocyclo 5 acid yields 1.19 g. (63%) of 2,3-dichloro-4-(2-oxocyclo pentylidenemethyl)phenol is converted to 2,3-dichloro pentylidenemethyl)phenoxyacetic acid in the form of 4 - (2 - oxocyclopentylidenemethyl)-phenoxylacetic acid, orange needles, M.P. 226-227 C. M.P. 226-227 C. EXAMPLE 9 EXAMPLE 7 20 2,3-dichloro-4-(2-oxocyclopentylidenemethyl)phenoxy) (2,3-dichloro-4-(2-oxocyclopentylidenemethyl) acetic acid phenoxyacetic acid To a solution of 2,3-dichloro-4-(2-oxocyclopentylidene To a solution of ethyl (2,3-dichloro-4-formylphenoxy)- methyl)phenol (1.00 g., 0.00389 mole) in acetone (50 acetate (4.16 g., 0.015 mole) in toluene (20 ml.) is added ml.) is added potassium carbonate (1.06 g., 0.00778 4-(1-cyclopenten-1-yl)morpholine (2.75 g., 0.18 mole). 25 mole) and iodoacetic acid (1.45 g., 0.00778 mole) and Acetic acid (0.3 ml.) then is added and the reaction solu the resulting mixture is heated under reflux for 24 hours tion is heated under reflux until the evolution of water with stirring. CeaSeS. The reaction mixture is filtered and the collected solid After 2.25 hours the reaction mixture is concentrated is washed with boiling acetone. This solid is dissolved in to dryness under reduced pressure. The residual ester is 30 water (100 ml.) and made acid to Congo red paper by treated with a mixture of acetic acid (25 ml.) and 5% the addition of 6 N hydrochloric acid. There is thus hydrochloric acid (12.5 ml.) and heated on a steam bath obtained 1.14 g. (93%) of an orange solid. Recrystal for 0.5 hour with stirring. The cooled reaction solution is lization from acetic acid gives 0.53 g. (43%) of 2,3- diluted with water and a solid separates. The solid is dis dichloro - 4 - (2 - oxocyclopentylidenemethyl)phenoxy solved in ethanol (25 ml.) and treated with a solution of 35 acetic acid in the form of orange needles, M.P. 226 sodium bicarbonate (2.52 g., 0.03 mole) in water (50 227 C. ml.). The resulting solution is heated on a steam bath EXAMPLE 10 for 0.5 hour with stirring and then concentrated to dry ness under reduced pressure. The residue is dissolved in 2,3-dichloro-4-(2-oxocyclohexylidenemethyl)phenoxyl hot water, treated with decolorizing carbon and filtered. 40 acetic acid The filtrate then is acidified with 6 N hydrochloric acid To a solution of ethyl (2,3-dichloro-4-formylphenoxy)- whereupon a solid separates. There is thus obtained 4.25 acetate (5.54 g., 0.02 mole) in toluene (25 ml.) is added g. (90%) of material, M.P. 190-212° C. Recrystalliza 4-(1-cyclohexen-1-yl)morpholine (4.01 g., 0.024 mole). tion from acetic acid yields 3.43 g. (72.7%) of 2,3-di Acetic acid (1 ml.) then is added and the reaction solu chloro - 4-(2-oxocyclopentylidenemethyl)phenoxyacetic 45 tion is heated under reflux until the evolution of water acid in the form of orange needles, M.P. 226-227 C. CaSCS Analysis.--Calculated for C14H12OlO4: C, 53.35; H, After three hours, the reaction mixture is concentrated 3.84; Ci, 22.50. Found: C, 53.37; H, 3.94; Cl, 22.36. to dryness under reduced pressure. The residual ester is treated with a mixture of acetic acid (35 ml.) and 5% EXAMPLE 8 50 hydrochloric acid (17.5 mi.) and heated on a steam bath 2,3-dichloro-4-(2-oxocyclopentylidenemethyl) for 0.5 hour with stirring. The cooled reaction mixture phenoxyacetic acid then is diluted with water whereupon a gum separates. Step A: Ethyl (2,3-dichloro-4-(phenyliminomethyl)- The gum is dissolved in ethanol (35 ml.) and treated with phenoxyacetate.--To a solution of ethyl (2,3-dichloro 55 a solution of sodium bicarbonate (3.36 g., 0.04 mole) in 4-formylphenoxy)acetate (9.70 g., 0.035 mole) in ben water (70 ml.). The resulting mixture is heated on a zene (50 ml.) is added aniline (3.59 g., 0.0385 mole). steam bath for 0.5 hour with stirring, filtered and the Then acetic acid (1 ml.) is added and the reaction solu filtrate concentrated to dryness under reduced pressure. tion is heated under reflux until the evolution of Water The residue is dissolved in hot water, treated with de CSCS 60 colorizing carbon and filtered. The filtrate is acidified with After 1.5 hours, the reaction mixture is concentrated 6 N hydrochloric acid and 3.91 g. (61%) of a solid to dryness under reduced pressure to give 12.3 g. (100%) separates. Recrystallization from benzene and then from of a yellow solid, M.P. 117.5-120.5 C. Recrystallization acetonitrile yields 1.81 g. (28%) of 2,3-dichloro-4-(2- from butyl chloride yields 10.6 g. (86%) of 2,3-di oxocyclohexylidenemethyl)phenoxyacetic acid in the chloro - 4 - (phenyliminomethyl)phenoxyacetate in the 65 form of yellow prisms, M.P. 161-162 C. form of needles, M.P. 119.5-120.5 C. Analysis.-Calculated for CHCl2O: C, 54.73; H, Analysis.-Calculated for CH15Cl2NO3: C, 57.97; H, 4.29; Cl, 21.54. Found: C, 55.05; H, 4.52; C1, 21.85. 4.29; N, 3.98. Found: C, 57.66; H, 4.45; N, 3.92. EXAMPLE 11 Step B: 2,3-dichloro-4-(2-oxocyclopentylidenemethyl)- 2,3-dichloro-4-(2-oxo-3-cyclopentylidenecyclopentyli phenoxyacetic acid.--To a solution of ethyl 2,3-di 70 chloro-4-(phenyliminomethyl)phenoxyacetate (2.11 g., denemethyl)phenoxyacetic acid 0.006 mole) in dimethylformamide (7.2 mi.) is added Step A: 2,3-dichloro-4-(2-oxo-3-cyclopentylidenecyclo cyclopentanone (0.50 g., 0.006 mole) and concentrated pentylidenemethyl)phenol.--To a solution of 2,3-dichloro hydrochloric acid (0.05 ml.). The resulting solution is 4-hydroxybenzaldehyde (5.73 g., 0.03 mole) in 12% allowed to stand at room temperature. 75 aqueous sodium hydroxide solution (20 ml, 0.06 mole) 3,458,565 19 20 is added a solution of cyclopentanone (15.81 g., 0.188 precipitate the solid product. Recrystallization from iso mole) in ethanol (20 ml.) and the resulting Solution is propyl alcohol yields pure N-methoxy-2-(2,3-dichloro-4- heated under reflux for three hours with stirring. (2-methyl-3-oxo-1-butenyl)phenoxyacetamide. The cooled reaction solution is diluted with water (40 ml.) and acidified by the addition of 6 N hydrochloric EXAMPLE 14 acid. An oil separates which then is solidified by tritu 2,3-dichloro-4-(2-oxocyclopentylidenemethyl)phenoxyl rating with acetonitrile to yield 3.21 g. (33%) of ma acetamide terial, M.P. 196-198° C. Recrystallization from acetic A mixture of 2,3-dichloro-4-(2-oxocyclopentylidene acid yields 2.17 g. (22.4%) of 2,3-dichloro-4-(2-oxo-3- methyl phenoxyacetic acid (3.2 g., 0.01 mole), thionyl cyclopentylidenecyclopentylidenemethyl)phenol in the O chloride (4.8 g., 0.04 mole) and benzene (30 ml.) is re form of yellow prisms, M.P. 214.5-215.5 C. fluxed for 45 minutes whereupon a clear solution is ob Analysis.--Calculated for CH16Cl2O2: C, 63.17; H, tained. Volatile materials are removed by vacuum distilla 499; Cl, 21.94. Found: C, 63.43; H, 4.98; Cl, 22.10. tion leaving (2,3-dichloro-4-(2-oxocyclopentylidenemeth Step B: 2,3-dichloro-4-(2-oxo-3-cyclopentylidenecyclo yl)phenoxyacetyl chloride as a viscous oil. pentylidenemethyl)phenoxy)acetic acid. To a solution Anhydrous ammonia is added during 15 minutes to a of 2,3-dichloro-4-(2-oxo-3-cyclopentylidenecyclopentyli solution of the acid chloride in benzene (50 ml.). After denemethyl)phenol (3.51 g., 0.0109 mole) in dimethyl removal of ammonium chloride by filtration, the filtrate formamide (28 ml.) is added potassium carbonate (3.22 is concentrated to yield 2,3-dichloro-4-(2-oxocyclopentyl g., 0.0240 mole). Then ethyl bromoacetate (4.01 g., idenemethyl)phenoxyacetamide. 0.0240 mole) is added and the reaction mixture is heated 20 at 55-60 C. for 1.5 hours with stirring. The reaction EXAMPLE 1.5 mixture then is cooled in ice and treated with water 3-(2-methyl-3-oxo-1-pentenyl)-4-chlorophenoxylacetic (140 ml.). The resulting solid ester is collected by filtra acid tion and washed with water. Step A: Ethyl (3-formyl-4-chlorophenoxy)acetate.-A The ester is dissolved in ethanol (85 ml.) and treated 25 SSupension of 3-hydroxy-6-chlorobenzaldehyde (7.6 g., with a solution of sodium bicarbonate (1.83 g., 0.0218 0.0396 mole) and potassium carbonate (13.2 g., 0.1 mole) in water (50 ml.). The resulting mixture is heated mole) in dimethylformamide (30 ml.) is treated with on a steam bath for one hour with stirring and then ethyl bromoacetate (16.7 g., 0.1 mole). This mixture is concentrated to dryness under reduced pressure. The resi stirred at 55° C. for 1.5 hours and then cooled, diluted due is dissolved in boiling water (1100 ml.), treated with 30 with water and extracted with ether. The ethereal solution decolorizing carbon and filtered. The filtrate is acidified is washed with water, dried and concentrated in vacuo with 6 N hydrochloric acid whereupon a solid separates. to produce an oil which then is distilled to yield an oily There is thus obtained 3.91 g. (94%) of material, M.P. product having a boiling point of 155-175 C./.05 mm. 210-212° C. Recrystallization from acetic acid yields This product crystallizes to give 3.6 g. (38%) of ethyl (3- 1.98 g. (48%) of 2,3-dichloro-4-(2-oxo-3-cyclopentyli 35 formyl-4-chlorophenoxy)acetate having a melting point denecyclopentylidenemethyl)phenoxyacetic acid in the of 54-56 C. After recrystallization from butyl chloride form of yellow needles, M.P. 217-218 C. the ethyl (3-formyl-4-chlorophenoxy)acetate has a melt Analysis.-Calculated for C19HaClO4: C, 59.86; H, ing point of 58-60° C. 4.76; Cl, 18.60. Found: C, 59.78; H, 4.96; Cl, 18.70. 40 Analysis.-Calculated for CHClO4: C, 54.44; H, EXAMPLE 12 4.57. Found: C, 54.67; H, 4.76. Step B: 3-(2-methyl-3-oxo-1-pentenyl)-4-chlorophen 2-diethylaminoethyl (2,3-dichloro-4-(2-methyl-3-oxo-1- oxy)acetic acid-By substituting ethyl (3-formyl-4-chlo butenyl)phenoxyacetate hydrochloride rophenoxy)acetate for the ethyl (2,3-dichloro-4-formyl A mixture of 2,3-dichloro-4-(2-methyl-3-oxo-1-bute phenoxy)acetate recited in Example 3, Step B, and fol nyl)phenoxylacetic acid (3.0 g., 0.01 mole), thionyl chlo 45 lowing the procedure described therein, the product 3-(2- ride (4.8 g., 0.04 mole) and benzene (30 ml.) is refluxed methyl-3-oxo-1-pentenyl)-4-chlorophenoxyacetic acid is for 35 minutes whereupon a clear solution is obtained. obtained. Volatile materials are removed by vacuum distillation leaving 2,3-dichloro - 4-(2-methyl-3-oxo-1-butenyl)phe EXAMPLE 16 noxyacetyl chloride as a viscous residue. The acid chlo 50 2-(2-methyl-3-oxo-1-pentenyl)-4-chlorophenoxyacetic ride is added to a solution of 2-diethylaminoethanol (2.8 acid g., 0.024 mole) in ether (50 ml.). The resulting mixture Step A: Ethyl (2-formyl-4-chlorophenoxy)acetate-By is extracted with water and the ether solution is dried and substituting 5-chlorosalicylaldehyde for the 2,3-dichloro treated with hydrogen chloride to precipitate the hydro 4-hydroxybenzaldehyde of Example 3, Step A, and fol chloric acid salt of the product. The crude product is 55 lowing the procedure described therein, ethyl (2-formyl recrystallized from isopropyl alcohol to obtain pure 2 4-chlorophenoxy)acetate is obtained. The product then diethylaminoethyl 2,3-dichloro-4-(2-methyl-3-oxo-1-bu is recrystallized from a mixture of benzene and cyclohex tenyl)phenoxyacetate hydrochloride. ane to yield ethyl (2-formyl-4-chlorophenoxy)acetate in 71% yield, M.P. 51-54.5° C. EXAMPLE 1.3 60 Step B: 2-(2-methyl-3-oxo-1-pentenyl)-4-chlorophen N-methoxy-2-2,3-dichloro-4-(2-methyl-3-oxo-1-butenyl) oxyacetic acid-By substituting ethyl (2-formyl-4-chlo phenoxyacetamide rophenoxy)acetate for the ethyl (2,3-dichloro-4-formyl A mixture of 2,3-dichloro-4-(2-methyl-3-oxo-1-bute phenoxy)acetate of Example 3, Step B, and following the nyl)phenoxyacetic acid (1.5 g., 0.005 mole), thionyl 65 procedure described therein, the product. 2-(2-methyl-3- chloride (2.4 g., 0.02 mole) and benzene (15 ml.) is oxo-1-pentenyl)-4-chlorophenoxyacetic acid is obtained, refluxed for 35 minutes whereupon a clear solution is EXAMPLE 17 obtained. Then the volatile materials are removed by vacuum distillation leaving 2,3-dichloro-4-(2-methyl-3- I2-(2-methyl-3-oxo-1-pentenyl)-4-acetamidophenoxy oxo-1-butenyl)phenoxyacetyl chloride as a viscous oil. 70 acetic acid A solution of methoxyamine is prepared by adding By substituting 5-acetamidosalicylaldehyde for the 2,3- methoxyamine hydrochloride (1.3 g., 0.015 mole) to a dichloro-4-hydroxybenzaldehyde of Example 3, Step A solution of sodium (0.35 g., 0.015 g.-atom) in ethanol (8 and following the procedure described in Steps A and B ml.). To this solution, the acid chloride is added and, after of that example, the product. 2-(2-methyl-3-oxo-1-pen 10 minutes, the mixture is diluted with water (30 ml.) to 75 tenyl)-4-acetamidophenoxyacetic acid is obtained. 3,458,565 21 22 EXAMPLE 8 Analysis.-Calculated for CHCIO: C, 51.98; H, 3.49; C1, 30.69. Found: C, 51.94; H, 3.49; C1, 30.60. 3-chloro-4-(3-oxo-1-butenyl)phenoxyacetic acid Step B: 2,3 - dichloro-4-(3-oxo-1-butenyl)phenoxy Step A: (3-chloro-4-formylphenoxy)acetic acid-A acetic acid.--To a solution of 2,3-dichloro-4-(3-oxo-1- solution of 2-chloro-4-hydroxybenzaldehyde (15.0 g., butenyl)phenol (5.11 g., 0.0221 mole) in dimethylform 0.096 mole) in 1,2-dimethoxyethane (50 ml.) is added to amide (20 mi.) is added potassium carbonate (6.72 g., a Suspension of sodium hydride (2.9 g, 0.12 mole) in 1, 0.0486 mole). Then ethyl bromoacetate (8.12 g., 0.0486 2-dimethoxyethane (35 ml.). Ethyl bromoacetate (20.0 g., mole) is added and the reaction mixture is heated at 55 (). 12 mole) then is added dropwise during 20 minutes with 60° C. for 1.5 hours with stirring. stirring. The mixture is stirred and refluxed for one hour. The reaction mixture is cooled in ice and treated with The precipitated sodium bromide is filtered off and the O Water (100 ml.) whereafter the resulting solid ester is co solvent is distilled in vacuo leaving ethyl (3-chloro-4- lected by filtration and washed with water. The esterified formylphenoxy)acetate as a residual oil. product then is treated with a mixture of acetic acid (35 To the residual ethyl (3-chloro-4-formylphenoxy) ml.) and 5% hydrochloric acid (17.5 ml.) and heated on acetate, ethanol (40 ml.) and 10% sodium hydroxide solu 5 a steam bath for 0.5 hour with stirring. The cooled reac tion (100 ml.) are added and the resulting solution is tion solution then is diluted with water (55 ml.) to yield heated 10 minutes on the steam bath. The solution then 6.53 g. of a yellow solid having a melting point of 198 is acidified with concentrated hydrochloric acid to precipi 202° C. Recrystallization from isopropyl alcohol gives tate the product, which is recrystallized from aqueous acid 2,3-dichloro-4-(3-oxo-1-butenyl)phenoxyacetic acid in to yield 15.5 g. (78%) of (3-chloro-4-formylphenoxy) 20 the form of yellow needles, M.P. 204-205 C. acetic acid, M.P. 174-176.5 C. Analysis.-Calculated for C19H10ClO4: C, 49.85; H, Analysis.--Calculated for CHClO4: C, 50.37; H, 3.29. 3.49; Cl, 24.53. Found: C, 50.00; H, 3.79; C1, 24.55. Found: C, 50.39; H, 3.47. Step B: 3-chloro-4-(3-oxo-1-butenyl)phenoxyacetic EXAMPLE 21 acid.-A solution of (3-chloro-4-formylphenoxy)acetic 25 2,3-dichloro-4-(3-oxo-1-pentenyl)phenoxyacetic acid acid (4.3 g., 0.02 mole) in 5% sodium hydroxide solution Step A: (2,3-dichloro-4-formylphenoxy)acetic acid (12 mi.) and acetone (40 ml.) is allowed to stand at A solution of ethyl (2,3-dichloro-4-formylphenoxy)ace room temperature for 30 minutes and then is diluted with tate (50 g., 0.151 mole) and sodium bicarbonate (25.5 water (30 ml.) and acidified with 5% hydrochloric acid. g., 0.3 mole) in ethanol (450 ml.) and water (900 mi.) is The solid product which precipitates is recrystallized from 30 heated two hours on a steam bath and the solution then is isopropyl alcohol to yield 2.4 g (47%) of 3-chloro-4-(3- cooled. The sodium salt of the product which precipitates oxo-1-butenyl)phenoxyacetic acid, M.P. 169.5-172.5 C. is collected by filtration, dissolved in boiling water (1500 Analysis.-Calculated for C12H11ClO4: C, 56.59; H, ml.) and the solution acidified with concentrated hydro 4.35. Found: C, 56.52; H, 4.39. chloric acid to precipitate 40 g. (94%) of (2,3-dichloro-4- EXAMPLE 19 35 formylphenoxy)acetic acid, M.P. 204-210° C. Recrys tallization from acetonitrile gives pure (2,3-dichloro-4- 3-(2,3-dichloro-4-(3-oxo-1-butenyl)phenoxylpropionic formylphenoxy)acetic acid, M.P. 210-212° C. acid Analysis.--Calculated for CHClO: C, 43.40; H, Step A: 3 - (2,3-dichloro-4-formylphenoxy) propionic 2.43; C1, 28.47. Found: C, 43.22; H, 2.69; C1, 28.28. acid.--2,3-dichloro-4-hydroxybenzaldehyde (38.2 g., 0.2 40 Step B: 2,3-dichloro-4-( 3-oxo-1-pentenyl)phenoxy mole) is dissolved in a 10% sodium hydroxide solution acetic acid. A mixture of (2,3-dichloro-4-formylphen (200 mi.). The solution is heated to boiling and beta-pro Oxy)acetic acid (12.5 g., 0.05 mole), methyl ethylketone piolactone (144 g., 2.0 moles) is added dropwise at such (30.2 g., 0.42 mole), 5% sodium hydroxide solution (50 a rate as to keep the solution boiling. During the addition ml.) and water (100 ml.) is stirred 30 minutes at room 10% sodium hydroxide solution is added in portions to 45 temperature. The sodium salt of the acid which initially maintain an alkaline mixture. Then the solution is cooled precipitates gradually goes into solution. The solution is and acidified. The precipitated material is dissolved in acidified with concentrated hydrochloric acid to precipi ether and the product is extracted into a 5% sodium bi tate a Solid product which then is stirred with sodium bi carbonate solution. Acidification of the aqueous solution carbonate solution to obtain the Sparingly soluble sodium precipitates 3 - (2,3-dichloro-4-formylphenoxy) propionic 50 salt of 2,3-dichloro-4-(3-oxo-1-pentenyl)phenoxyacetic acid, which is purified by recrystallization from ethyl acid. The salt is collected on a filter, dissolved in boiling acetate. Water (200 ml.) and the solution acidified with concen. Step B: 3-2,3-dichloro-4-(3-oxo-1-butenyl)phenoxy trated hydrochloric acid. The product which precipitates propionic acid-By substituting 3-(2,3-dichloro-4-form is collected, dried and recrystallized three times from iso ylphenoxy) propionic acid for the (3-chloro-4-formylphen propyl alcohol to obtain 1.5 g. (10%) of 2,3-dichloro oxy)acetic acid of Example 18, Step B, and following the 4(3-oxo-1-pentenyl)phenoxyacetic acid, M.P. 1935 procedure described therein, the product 3-2,3-dichloro 1945° C. 4-(3-oxo-1-butenyl)phenoxypropionic acid is obtained. Analysis.--Calculated for C18H12Cl2O4: C, 51.50; H, 3.99; Cl, 23.39. Found: C, 51.91; H, 4.14; Cl, 23.45. EXAMPLE 2.0 60 In a manner similar to that described in Example 1, Steps B and C, supra, for the preparation of 2,3-dichlo 2,3-dichloro-4-(3-oxo-1-butenyl)phenoxyacetoxy acid ro - 4 - (2 - methyl-3-oxo-1-butenyl)phenoxyacetic acid, Step A: 2,3-dichloro-4-(3-oxo-1-butenyl)phenol-Ace most of the I(3-oxo-1-alkenyl)aryloxylalkanoic acid tone (7.25 g., 0.125 mole) is added to a solution of 2,3- products (I) of the invention may be obtained. Thus, by dichloro-4-hydroxybenzaldehyde (3.82 g., 0.020 mole) in 65 substituting an appropriate nuclear hydroxy substituted 12% aqueous sodium hydroxide (7 ml, 0.021 mole) and benzaldehyde, an appropriate ketone and a suitable alkyl the resulting solution is allowed to stand at room temper haloalkenoate for the 2,3-dichloro-4-hydroxybenzalde ature. hyde, the methyl ethyl ketone and the ethyl bromoacetate After two days the reaction mixture is diluted with recited in Example 1, Steps B and C, and following sub water (25 ml.) and acidified by the addition of 6 N hydro O stantially the procedure described therein, all of the (3- chloric acid. There is thus obtained 4.18 g. of an orange OXO-1-alkenyl)aryloxylalkanoic acid products (I) of this solid having a melting point of 182-183° C. Recrystal invention may be obtained. The following equation illus lization from acetonitrile gives 2,3-dichloro-4-(3-oxo-1- trates the reaction of Example 1, Steps A and Band, to butenyl)phenol in the form of yellow prisms, M.P., 188.5- gether with Table I, depict the nuclear hydroxy substi 189.5 C, 5 tuted benzaldehyde and alkyl haloalkanoate starting ma 3,458,565 23. 24 terials of the process and the corresponding products and then lactose and magnesium stearate are passed produced therefrom: through a No. 60 bolting cloth onto the powder and the combined ingredients admixed for 10 minutes and then X3, X2 filled into No. 1 dry gelatin capsules. Similar dry-filled capsules can be prepared by replac RCCO-CER2 -- on-s-on arenewala} ing the active ingredient of the above example by any of the other novel compounds of this invention. X 5 X6 It will be apparent from the foregoing description that X 3 X.2 the (3-oxo-1-alkenyl)aryloxylalkanoic acid products (I) of this invention constitute a valuable class of compounds RiCHCO-CR2=CE -O O which have not been prepared heretofore. One skilled in X X6 the art will also appreciate that the processes disclosed X-Y -COOR in the above examples are merely illustrative and are -- capable of a wide variation and modification without de Base parting from the spirit of this invention. X8 15 What is claimed is: 1. A member selected from the group consisting of a RiCECO-CR2=CH- O-Y-COOR compound having the formula:

20 R1CHCO-CER2-CH Hydrolysis O-Y-COOH X3, X2 wherein R1 and R2 are similar or dissimilar members selected from the group consisting of hydrogen, lower RCHCO-CR2scCE- --O-Yl-COOH 25 alkyl and, taken together, R1 and R may be joined to form an alkylene chain containing from one to three carbon atoms between their points of attachment to the TABLE Rl R2 X2 X3 X6 Yi -CH3 -CH3 H -NO2 -CH H -C3 E B E. -CE -CH3 -CH -CE E H -CH3 -CE -C-C- H C H -(CH2)3- H --CE3 -CH3 -CH3 -CE CE -CHCH -CH2- H F. -CH E. -CH H -C -CH -(CH2)3- -CH3 -CH3 -(CH2)4- H -CH E. -CH3 -CEast CH-CH=CH -CH -CH3 -CH3 -CH3 EI -CEI A suitable unit dosage form of the products of this acylvinyl group, or, R1 and R2 may be joined to form an invention can be administered by mixing 50 mg. of a alkylene chain containing from two to three carbon atoms (3-oxo-1-alkenyl)aryloxyalkanoic acid (I) or a suitable between its points of attachment to the acylvinyl group acid addition salt, ester or amide derivative thereof, with and which said alkylene chain is substituted with a cyclo 144 mg. of lactose and 6 mg. of magnesium stearate and pentylidene radical; the X radicals are similar or dis placing the 200 mg. mixture into a No. 1 gelatin capsule. similar members selected from the group consisting of Similarly, by employing more of the active ingredient 45 halogen, lower alkyl, nitro, lower alkanamido and, taken and less lactose, other dosage forms can be put up in No. together, two X radicals on adjacent carbon atoms of 1 gelatin capsules and, should it be necessary to mix more the benzene ring may be joined to form anhydrocarbylene than 200 mg. of ingredients together, larger capsules may chain selected from trimethylene, tetramethylene and 1,3- be employed. Compressed tablets, pills or other desired butadienylene; Y is a member selected from the group unit dosages can be prepared to incorporate the com 50 consisting of alkylene and haloalkylene and n is an in pounds of this invention by conventional methods and, teger having a value of one to four; and the nontoxic, if desired, can be made up as elixirs or as injectable Solu pharmacologically acceptable acid addition salts, lower tions by methods well-known to pharmacists. alkyl esters, di-lower alkylamino lower alkyl esters and It is also within the scope of this invention to combine the amide and methoxyamide derivatives thereof. two or more of the compounds of this invention in a 55 2. A compound having the formula: unit dosage form or to combine one or more of the com pounds with other known diuretics and saluretics or with other desired therapeutic and/or nutritive agents in dosage unit form. 60 RCEICO-C non->-oo-oor The following example is included to illustrate the preparation of a representative dosage form: wherein R1 and R2 are similar or dissimilar members EXAMPLE 32 selected from the group consisting of hydrogen and lower alkyl and X2 and X3 are similar or dissimilar members Dry-filled capsules containing 50 mg. of active ingredient selected from the group consisting of halogen, lower per capsule 65 alkyl and, taken together, may be joined to form a 1,3- Per capsule, mg. butadienylene chain. 2,3 - dichloro - 4 - (2 - methyl - 3 - oxo - 1 - bute 3. The compound of claim 2 wherein R and R are nyl)phenoxylacetic acid ------50 lower alkyl and X and X8 are halogen. Lactose ------144 4. The compound of claim 2 wherein R is lower alkyl, Magnesium stearate ------6 70 R is hydrogen and XP and X are halogen. 5. The compound of claim 2 wherein R and R are Capsule size No. 1 ------200 lower alkyl, X is hydrogen and X3 is halogen. The 2,3 - dichloro - 4 - (2 - methyl-3-oxo - 1 - bute 6. The compound of claim 2 wherein R and R are nyl)phenoxyacetic acid is reduced to a No. 60 powder 5 lower alkyl and X and X are lower alkyl. 3,458,565 25 26 7. The compound of claim 2 wherein Ri and R2 are 14. (2-methyl-3-chloro-4-(3-oxo-1-butenyl)phenoxy lower alkyl and X and X are combined to form a acetic acid. - 1,3-butadienylene chain. 15. 2,3 - dichloro - 4-(3-oxo-1-butenyl)phenoxyacetic 8. The compound of claim 2 wherein R and R2 are acid. joined to form an alkylene chain of the formula 16. (2-methyl-3-oxo-1-butenyl) naphthoxyacetic acid. -CH2- wherein m is an integer having a value of one to three. References Cited 9. (2,3-dichloro-4-(2-methyl-3-oxo-1-butenyl)phenoxyl acetic acid. UNITED STATES PATENTS 10. 2,3-dimethyl-4-(2-methyl-3-oxo-1-butenyl)phenoxy O 3,255,241 6/1966 Schultz et al. ------260-56 acetic acid. 11. 2,3 - dichloro - 4 - (2 - oxocyclobutylidenemethyl) LORRAINE A. WEINBERGER, Primary Examiner phenoxyacetic acid. J. NIELSEN, Assistant Examiner 12. 2,3-dichloro - 4 - (2-oxocyclopentylidenemethyl) phenoxyacetic acid. 5. U.S. C. X.R. 13. 2,3-dichloro - 4 - (2 - oxocyclohexylidenemethyl) 260-247.2, 268, 294, 326.3, 471, 473, 501.1, 519, 521, phenoxyacetic acid. 559, 590, 600; 424-317, 324