US3575988A - Piperidyl bis(parachlorophenoxy) acetates - Google Patents

Abstract

THE COMPOUNDS ARE OF THE CLASS OF BASIC ESTERS OF BIS(P-CHLOROPHENOXY)ACETIC ACID, E.G., BIS-(P-CHLOROPHENOXY) ACETIC ACID 1-METHYL-4-PIPERIDYL ESTER, WHICH ARE USEFUL AS HYPOCHOLESTEREMIC/HYPOLIPEMIC AGENTS.

Description

United States Patent C US. Cl. 260-2943 7 Claims ABSTRACT OF THE DISCLOSURE The compounds are of the class of basic esters of bis- (p-chlorophenoxy)acetic acid, e.g., bis-(p-chlorophenoxy) acetic acid 1-methyl-4-piperidyl ester, which are useful as hypocholesteremic/hypolipemic agents.

This is a continuation-in-part of my copending application Ser. No. 598,970, filed Dec. 5, 1966, which in turn is a continuation-in-part of my copending application Ser. No. 568,759, filed July 29, 1966, which in turn is a continuation-in-part of my copending application Ser. No. 549,475, filed May 12, 1966, all three now abandoned.

This invention pertains to derivatives of acetic acid. In particular, the invention is directed to basic esters of bis- (p-chlorophenoxy)acetic acid. The basic esters of the present invention may be represented structurally as follows:

CHCOOR wherein R represents -(CHR),,R

(the point of attachment being at either the 2- or 3-positions) (the point of attachment being at either the 2-, 3- or 4-p0sitions) 3,575,988 Patented Apr. 20, 1971 (the point of attachment being at either the 2- or 3-positions) (the point of attachment being at either the 2- or 3-positions);

(the point of attachment being at either the 2- or 3-positions) (the point of attachment being at either the 2-, 3- or 4-positions) or 2-dimethylamino-2-methy1 propyl; R represents (the point of attachment being at either the 2- or 3-positions) (the point of attachment being at either the 2-, 3- or 4-positions) (the point of attachment being at either 2 or 3-positions) (the point of attachment being at either the 2- or 3-positions);

(the point of attachment being at either the 2- or 3-positions) n represents a whole number of from 1 to 4, inclusive;

each R, independently, represents hydrogen or lower alkyl, preferably containing from 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl and hutyl;

n represents 2, 3 or 4;

R represents lower alkyl, preferably containing from 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl and butyl; propargyl; phenyl; halophenyl, the halo substituent preferably being bromo or chloro; or phenyl(lovver) alkyl, the lower alkyl substituent preferably containing from 1 to 4 carbon atoms, e.g., benzyl and phenethyl;

R represents hydrogen; halo, preferably bromo or chloro;

or lower alkyl, preferably containing from 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl and butyl;

R represents hydrogen; lower alkyl, preferably containing from 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl and butyl; cycloalkyl containing from 5 to 7 ring carbon atoms, e.g., cyclopentyl, cyclohexyl and cycloheptyl; phenyl; phenyl(lower)alkyl, the lower alkyl substituent preferably containing from 1 to 4 carbon atoms, e.g., benzyl and phenethyl; l-naphthyl; or Z-naphthyl; and

R represents lower alkyl, preferably containing from 1 to 4 carbon atoms, e.g,, methyl, ethyl, propyl and butyl; cycloalkyl containing from 5 to 7 ring carbon atoms, e.g., cyclopentyl, cyclohexyl and cycloheptyl; phenyl; or phenyl(lower)alkyl, the lower alkyl substituent preferably containing from 1 to 4 carbon atoms, e.g., benzyl and phenethyl; provided that when R is hydrogen R is phenyl.

As illustrative of the substituents represented by R there may be mentioned the following:

l-lower alkyl-4-piperidyl, e.g., l-methyl-4-piperidyl and l-ethyl-4-piperidyl; l-lower alkyl-3 piperidyl, e.g., l-

methyl-3-piperidyl and l-ethyl-S-piperidyl; l-lower alkyl- 2-piperidyl, e.g., l-methyl-Z-piperidyl and l-ethyl-Z-piperidyl; 1-phenyl-4-piperidyl; 1-phenyl-3-piperidyl; l-phenyl- 2-piperidyl; l-benzyl-4-piperidyl; l-benzyl-3-piperidyl; l-

phenethyl-4-piperidyl; 1-phenethyl-3-piperidyl; l-propargyl-4-piperidyl; l-propargyl 3 piperidyl; l-[B-(p-chlorophenoxy)ethyl]-4-poperidyl; 3-quinuclidinyl; Z-quinuclidinyl, fl-pyrrolidinoethyl; -pyrrolidinopropyl; ,G-piperidinoethyl; 'y-piperidinopropyl; [3-morpholinoethyl; 'y-morpholinopropyl; ,B-dimethylaminoethyl; 'ydiethylaminopropyl; ,B-anilinoethyl; -anilinopropyl; 8-(N-methylanilino)ethyl; ,B-(I-lower alkyl-Z-pyrrolidinyl)ethyl, e.g., B-(l-methyl-Z- pyrrolidinyl) ethyl; l-lower alkyl-Z-pyrrolidinyl) propyl, e.g., 'y-( l-methyl-Z-pyrrolidinyl)propyl; fl-(1-phenyl-3-pyrrolidinyl)ethyl; B (l-phenyl-Z-pyrrolidinyl)ethyl; 8-(1- benzyl-3-pyrrolidinyl) ethyl; l-benzyl-2-pyrrolidinyl) ethyl; ;9-( l-phenethyl-3-pyrrolidinyl)ethyl; ;8-( l-phenethyl- 2-pyrrolidinyl ethyl; fil-prop argyl-3-pyrrolidinyl ethyl; B-(l propargyl 2-pyrrolidinyl)ethyl; and fi-[l-[fl-(pchlorophenoxy ethyl] -3-pyrrolidinyl1 ethyl.

The above-noted compounds can be prepared by a one step process which involves the reaction of either an alkyl ester of bis-(p-chlorophenoxy) acetic acid or a dialkyl ester of bis-(p-chlorophenoxy)malonic acid with an appropriate alcohol. Alternatively, the compounds may be prepared by converting bis-(p-chlorophenoxy)acetic acid to its corresponding acid halide and reacting the latter with an appropriate alcohol or alcoholate. These processes are illustrated by the following reaction scheme:

/CHCOOB." C-(COOR)2 Cl- 0 Cl 0 II -I- III It OH CHGOOR \EOH (or aleoholate) CHCOOH CHCOX R is as previously defined;

The reaction of the monoor di-alkyl ester II or III) with the appropriate alcohol is carried out in a suitable inert organic solvent, e.g. benzene, toluene and Xylene, and in the presence of an alkali metal alkoxide, such as sodium methoxide or sodium ethoxide. The reaction is conveniently effected at an elevated temperature, preferably the reflux temperature of the system. The desired product is readily recovered in conventional manner.

In the alternative process, bis-(p-chlorophenoxy)acetic acid (IV) is converted to the corresponding acid halide (V) by reaction with thionyl chloride or other suitable reagent commonly used for this purpose, e.g., thionyl bromide, phosphorus pentachloride and phosphorus pentabromide. The reaction is conveniently carried out in a suitable inert organic solvent and at room temperature (20 C.) or elevated temperatures up to reflux temperature of the system. However, the use of a solvent is not necessary since an excess of the halide reagent can be employed for this purpose. It is generally preferred to carry out the reaction in the presence of a catalytic amount of dimethylformarnide. The reaction of the thus-obtained acid halide with the appropriate alcohol or alcoholate is conveniently effected in a suitable inert organic solvent, e.g. benzene, toluene, chloroform and diethyl ether, and at room temperature (20 C.) or below. The reaction, if desired, can be carried out at elevated temperatures; however, in such instances, external cooling should be provided since the reaction is highly exothermic. Preferably the reaction is carried out at a temperature of from about 10 to abotu C. Where the free alcohol is employed it is desirable to provide a means for taking up the liberated hydrogen halide. This can be accomplished by employing an excess of the alcohol or by carrying out the reaction in the presence of an alkali metal carbonate, e.g., potassium carbonate, or suitable inert base, e.g. pyridine. Where an alcoholate is used, the alkali metal salts, particularly the sodium and potassium salts, are preferred. The desired product thus obtained is readily recovered in conventional manner.

The monoand di-alkyl esters (II and III) employed as starting materials are readily prepared by reacting pchloro-sodium phenolate (prepared from p-chlorophenol and sodium hydride) with a lower alkyl dichloroacetate or di-(lower) alkyl dibromornalonate, respectively. The reaction is readily carried out in a suitable inert organic solvent, e.g., dimethylacetamide, diethylacetamide and dimethylformamide, and at room temperature or elevated temperature (which should not exceed about 80 C. when it is desired to prepare the esters of Formula III).

The bis-(p-chlorophenoxy)acetic acid (IV), employed as the starting material for the alternative process described above, can be readily prepared in conventional manner from either the monoor di-alkyl ester (II or III) by reacting the same in an aqueous, inert organic solvent, with a strong base, at room temperatures. The base is preferably one which will yield a water-soluble salt of the desired acid, e.g., sodium hydroxide and potassium hydroxide. The acid then is obtained by simply treating the thus-obtained salt With a mineral acid, such as hydrochloric acid, in conventional manner. The acid (IV) can also be prepared by decarboxylating the free malonic acid (III, R"=H) in conventional manner.

Many of the alcohols employed as starting materials are known and can be prepared as described in the literature. Such others which may not be specifically known can be prepared from available materials in analogous manner. The alcoholates can be prepared from the corresponding alcohols in conventional manner.

Certain of the compounds of Formula I have asymmetric centers and therefore exist as optical isomers. The respective isomers can be readily separated by conventional techniques or they can be selectively prepared employing the desired isomeric form of the alcohol reactant and accordingly are included within the scope of this invention.

Representative compounds which can be made in the manner set forth above and are included within the scope of this invention are set forth in tabular form below. For convenience only, the compounds are identified by setting forth the significance of the ester moiety represented by R in structural Formula I. However, it is to be understood that the designation of the compounds in this manner is merely in lieu of setting forth the chemical name thereof.

Compound: R

Compound Compound: R C0mp0nnd Compound The compounds of the present invention (Formula I) are useful because they possess pharmacological activity in animals. In particular, the compounds possess marked hypocholesteremic activity and can be used as hypocholestermic/hypolipemic agents.

'For such usage, the compounds may be admixed with conventional pharmaceutical carriers, and other adjuvants, if necessary, and administered orally in such forms as tablets, elixirs, suspensions or solutions. Furthermore the compounds may be similarly administered in the form of their non-toxic pharmaceutically acceptable acid addition or quaternary salts. Such salts do not materially differ from the free base in their pharmacological effects andare included within the scope of the invention. The acid addition salts are readily prepared by reacting the base with pharmacologically acceptable acids in conventional manner. Representative of such salts are the mineral acid salts such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts such as the benzoate, acetate, maleate, p-toluenesulfonate, benzenesulfonate and the like. Similarly, the quaternary salts are prepared by reacting the base with pharmaco logically acceptable quaternizing agents in conventional manner. Exemplary of the quaternary salts are those derived from common quaternizing agents such as straight-chain lower alkyl halides wherein the lower alkyl group preferably contains from 1 to 4 carbon atoms and the halide substituent is either chloride, bromide or iodide, e.g., methyl bromide, methyl chloride, ethyl bromide, methyl iodide and ethyl iodide, and straight-chain di- (lower) alkyl sulfates, e.g., dimethyl sulfate.

For the above-mentioned use, the dosage administered will, of course, vary depending on the compound employed. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 4 milligrams to about 30 milligrams per kilogram of animal body weight, preferably given in divided doses, 2 to 4 times a day, or in sustainted release form. For most mammals the administration of from about 0.25 gram to about 2 grams of the compound in divided doses of from about 62.5 milligrams to about 1000 milligrams 2 to 4 times a day, is adequate for the treatment of hypercholesteremia/hyperlipemia. A representative formulation suitable for oral administration is a tablet (prepared by standard tabletting techniques) and containing, by weight, 50 parts of bis-(p-c'hlorophenoxy)acetic acid 1-methyl-4- piperidyl ester (as the free base), 2 parts of tragacanth, 39.5 parts of lactose, 5 parts of corn starch, 3 parts of talcum and 0.5 part of magnesium stearate.

As noted hereinabove certain of the compounds of Formula I exist as optical isomers. In some instances, enhanced activity or other beneficial attribute may be found with respect to a particular isomer and in such instances administration of such isomer may be preferred.

The following examples show representative compounds contemplated by the present invention and the manner in which said compounds are made. However, it is to be understood that the examples are intended for the purpose of illustration only and are not intended as in any way limiting the scope of the invention which is defined in the appended claims.

EXAMPLE 1 Bis-(p-chlorophenoxy)acetic acid fi-piperidinoethyl ester Step A. Preparation of bis-(p-chlorophenoxy)acetic acid methyl ester: A solution of 25.6 grams of 4chlorophenol in 200 ml. of dimethylacetamide is slowly added to a stirring slurry of 9.5 grams of sodium hydride (56% in mineral oil) in 250 ml. of dimethylacetamide and the mixture stirred at 20 C. for one hour.

To the resulting clear solution is added 14.3 grams of methyl-dichloro-acetate in 200 ml. of dimethylacetamide and a catalytic amount of potassium iodide. The reaction mixture is stirred at 20 C. for 17 hours and then poured over 1 liter of ice water. The mixture is then extracted with isopropyl ether. The separated ether layer is extracted with cold 1 N sodium hydroxide and the organic phase separated, dried over magnesium sulfate and evaporated to obtain a brown oil which crystallizes upon standing. Recrystallization of the resulting product from methanol yields bis- (p-chlorophenoxy) acetic acid methyl ester, M.P. 54.5-55.5 C.

Step B. Preparation of bis-(p-chlorophenoxy)acetic acid B-piperidinoethyl ester: Bis-(p-chlorophenoxy)acetic acid methyl ester, 10 grams, is mixed with 10 grams of B- hydroxyethylpiperidine, 50 mg. of sodium methoxide and 10 ml. of toluene. The resulting mixture is then slowly heated to distill very slowly through a Vigreux column. When the temperature at the distilling head reaches C., the reaction mixture is cooled to 65 C. and then evaporated on a rotary evaporator employing 12 mm. vacuum and maintaining the temperature between 65-70 C. The crude product thus obtained is treated with an excess of a 20% aqueous solution of tartaric acid to yield the tartrate salt of bis-(p-chlorophenoxy)acetic acid [i-piperidinothyl ester. The free base is obtained by treating the washed tartrate salt with 2 N sodium hydroxide and extracting the base with dichloromethane.

To obtain the hydrochloride salt, the dichloromethane extract is dried over magnesium sulfate, the solvent evaporated and the residue neutralized with an isopropanolic solution of hydrogen chloride (10% hydrogen chloride gas in isopropyl alcohol). The thus-obtained hydrochloride salt is recrystallized from acetone/diethyl ether to yield hygroscopic bis-(p-chlorophenoxy)acetic acid piperidinoethyl ester hydrochloride, decomposition point 80 C.

EXAMPLE 2 Bis (p chlorophenoxy)acetic acid 1-rnethyl-4-piperidyl ester A mixture of 14.4 g. (0.151 mole) of 1-methyl-4-hydroxy piperidine in '70 ml. of toluene is cooled to about 5 C. in an ice-salt bath. To the cooled mixture is then added dropwise with stirring a solution of 25 g. (0.076 mole) of bis-(p-chlorophenoxy)acetyl chloride in 50 ml. of toluene, While maintaining the temperature of the reaction mixture between -5 and 0 C. with external cooling. After the addition is completed, the mixture is stirred for an additional minutes and then 50 ml. of ice water and 75 ml. of an aqueous sodium bicarbonate solution are added and the phases separated. The organic phase is then washed three times with 100 ml. (each) of water, then dried over magnesium sulfate and evaporated. The residue thus obtained is recrystallized from ethanol, using some charcoal to remove colored by-products, to obtain bis-(pchlorophenoxy)acetic acid 1-methyl-4-piperidyl ester, M.P. 92 to 93.6 C.

The fumarate salt thereof, M.P. 100112 C. (doc), is prepared in conventional manner by neutralizing the free base with furnaric acid in methanol and recrystallizing the product from methanol at C.

The hydrochloride salt thereof, M.P. 158-159 C., is prepared in conventional manner by reacting the free base with hydrogen chloride in ethanol and recrystallizing the product from ethanol.

The methiodide salt thereof, M.P. 166-l67 C., is prepared in conventional manner by treating the base with an excess of methyl iodide and recrystallizing the resulting product from ethanol.

The methobromide salt thereof, M.P. 195197 C., is prepared in conventional manner by treating a solution of the base in methylene chloride, at 0 C., with an excess of gaseous methyl bromide and recrystallizing the product from ethanol.

EXAMPLE 3 Bis-(p-chlorophenoxy)acetic acid fi-morpholinoethyl ester onoooornom N o A mixture of 15.8 g. (0.12 mole) of 4-(6-hydroxyethyl) morpholine in 100 ml. of toluene is cooled to about 5 C. in an ice-salt bath. To the cooled mixture is then added dropwise with stirring a solution of g. (0.06 mole) of bis-(p-chlorophenoxy) acetyl chloride in 50 ml. of toluene, While maintaining the temperature of the reaction mixture between 5 C. to 0 C. with external cooling. After the addition is completed, the mixture is stirred for an additional ten minutes and then 50 ml. of ice-water and 75 ml. of an aqueous sodium bicarbonate solution are added and the phases separated. The organic phase is then washed three times with 100 ml. (each) of water, then dried over magnesium sulfate and evaporated. The residue thus obtained is recrystallized from cyclohexane, using some charcoal to remove colored by-products, to obtain bis-(pchlorophenoxy) acetic acid B-morpholinoethyl ester, M.P. 75 to 76.5 C.

1 2 EXAMPLE 4 Bis-(p-chlorophenoxy)acetic acid l-[B-(p-chlorophenoxy) ethyl] -4-piperidyl ester Step A. Preparation of 4-hydroxy-l-[fl-(p-chlorophenoxy)ethyl]piperidine: A mixture of 30.45 g. (0.3 mole of 4-hydroxypiperidine, 20.6 g. (0.15 mole) of anhydrous p0- tassium carbonate, 5 g. of potassium iodide and 300 ml. of methanol is heated to reflux on a water bath and then treated with a solution of g. (0.15 mole) of [ET-(pchlorophenoxy)-ethyl bromide in 100 ml. of methanol. The resulting mixture is then refluxed for 64 hours, filtered and the filtrate evaporated. To the solid residue thus obtained is added 100 ml. of petroleum ether. The resulting mixture is then filtered and the solid material suspended in 700 ml. of distilled water. The insoluble material is then filtered ofi", dissolved in 400 ml. of chloroform and the resulting solution dried over magnesium sulfate and evaporated. The residue is recrystallized from 250 ml. of hexane and 80 ml. of ethyl acetate and filtered, with the aid of charcoal, through Celite to obtain 4-hydroxy-l-[ 8- (p-chlorophenoxy)ethyljpiperidine, M.P. 111-112 C.

Step B. Preparation of bis-(p-chlorophenoxy)acetic acid 1 [B-(p-chlorophenoxy)ethyl] 4-piperidyl ester: To a solution of 11.2 g. (0.0438 mole) of 4-hydroxy-l-[fi-(pchlorophenoxy)ethyl]piperidine in 1400 ml. of dry toluene is added 4.5 g. (0.044 mole) of triethylamine. The resulting mixture is stirred at room temperature and then there is added thereto, dropwise, a solution of 19 g. (0.057 mole) of bis-(p-chlorophenoxy)acety1 chloride in ml. of toluene. The resulting mixture is then stirred overnight at room temperature, filtered and the filtrate extracted three times with 100 ml. (each) of cold 10% aqueous sodium bicarbonate solution and then washed three times with 100 ml. (each) of water and the organic phase evaporated to obtain bis-(p-chlorophenoxy)acetic acid 1- [/3-(p-chlor0phenoxy)ethyl]-4-piperidyl ester, M.P. 106.5- 107 C.

EXAMPLE 5 Bis-(p-chlorophenoxy)acetic acid l-propargyl-4-piperidyl ester Step A. Preparation of 4 hydroxy-l-propargylpiperidine: A mixture of 35.4 g. (0.35 mole) of 4-hydroxypiperidine, 5 g. of potassium iodide, 24.4 g. of (0.175 mole) of anhydrous potassium carbonate and 300 ml. of methanol is heated to reflux on a water bath and then treated dropwise with a solution of 41.7 g. (0.35 mole) propargyl bromide in ml. of methanol. The resulting mixture is then refluxed overnight, filtered and the filtrate evaporated. The residue thus obtain is recrystallized three times from ethyl acetate (using charcoal as an aid) to obtain 4 hydroxy l-propargylpiperidine, M.P. 102.5- 103.5 C.

Step B. Preparation of his (p-chlorophenoxy)acetic acid 1-propargyl-4-piperidyl ester: To a solution of 11.5 g. of 4-hydr0xy-l-propargylpiperidine in 1200 m1. of anhydrous diethyl ether is added, dropwise and at room temperature, a solution of 29 g. of bis-(p-chlorophenoxy) acetyl chloride in 60 ml. of anhydrous diethyl ether. The resulting mixture is stirred overnight at room temperature and then several small pieces of ice and ml. of 2 N sodium carbonate are added with stirring. The organic phase is separated, Washed three times with ml. (each) of a saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The resulting viscous oil is dissolved in a minimum amount of chloroform and the resulting solution passed through silica gel and the silica gel then eluted first with 1 liter of petroleum ether, then with 1 liter of isopropyl ether and finally with 1 liter of benzene. The solvents are then evaporated off and the residues dissolved in anhydrous diethyl ether. Hydrogen chloride gas is bubbled through the ether solution and the resulting solid material filtered otf and recrystallized from ethyl acetate (employing charcoal as an aid) to obtain hygroscopic bis-(p-chlorophenoxy) acetic acid l-propargyl-4-piperidyl ester hydrochloride, M.P. 115.5118 C.

EXAMPLE 6 Bis-(p-chlorophenoxy)acetic acid Z-dimethylamino-Z- methylpropyl ester CH3 CH3 A mixture of 23.4 g. (0.2 mole) of 2-dimethylamino-2- methylpropanol-l and 100 ml. of toluene is cooled to C. and then there is added thereto, dropwise with stirring, a solution of 33.15 g. of 0.1 mole) of bis-(p-chlorophenoxy)acetyl chloride in 40 ml. of toluene. After the addition is completed the mixture is stirred for an additional /2 hour, filtered and the filtrate extracted twice with 100 ml. (each) of a aqueous solution of sodium bicarbonate. The organic phase is then washed three times with 100 ml. (each) of water, dried over potassium carbonate and evaporated. The residue is dissolved in anhydrous diethyl ether and hydrogen chloride gas is bubbled through the ether solution. The solid material thus obtained is filtered OE and recrystallized from 300 ml. of ethyl acetate (employing charcoal as an aid) to obtain bis-(pchlorophenoxy)acetic acid 2 dimethylamino-Z-methylpropyl ester hydrochloride, M.P. 148-148.5 C.

EXAMPLE 7 /CHC O O CHzCHzCH2-N Cl CH:

A mixture of 20.6 g. (0.2 mole) of 3-dimethylaminopropanol-l in 100 ml. of toluene is cooled to 0 C. and there is added thereto, dropwise with stirring, a solution of 33.15 g. (0.1 mole) of bis-(p-chlorophenoxy)acetyl chloride in ml. of toluene. After the addition is completed the reaction temperature is allowed to rise to room temperature and the mixture stirred for an additional 2 hours. The mixture is then filtered, the filtrate treated twice with 100 ml. (each) of cold 10% aqueous sodium bicarbonate, washed three times with 100 ml. (each) of a saturated aqueous sodium chloride solution and then dried over potassium carbonate and evaporated. The residue is dissolved in anhydrous diethyl ether and hydrogen chloride gas bubbled through the ether solution. The solid material thus obtained is filtered oil and recrystallized twice from 750 ml. (each) of ethyl acetate (employing charcoal as an aid) to obtain bis-(p-chlorophenoxy) acetic acid 'y-dimethylaminopropyl ester hydrochloride, M.P. 131.7132 C.

Bis-(p chlorophenoxy)acetic acid methyl ester, 10 grams, is mixed with 10 grams of S-anilinoethanol, 50 mg.

of sodium methoxide and 10 ml. of toluene. The result-- ing mixture is slowly heated to distill very slowly through a Vigreux column. When the temperature at the distilling head reaches C., the reaction mixture is cooled to 65 C. and then evaporated on a rotary evaporator employing 12 mm. vacuum and maintaining the temperature between 6570 C. The crude product is chromatographed on a silica gel column and the product recovered by wash-' ing the column With benzene. The benzene is then evaporated off to obtain bis-(p-chlorophenoxy)acetic acid ,8- anilinoethyl ester, M.P. 9196 C.

EXAMPLE 9 Bis-'(p-chlorophenoxy)acetic acid fi-pyrrolidinoethyl ester oHoooomom-N To a mixture of 122 g. (0.313 mole) of bis-(p-chlorophenoxy)acetic acid methyl ester, 50 g. (0.435 mole) of l-(B-hydroxyethyl) pyrrolidine and 200 ml. of benzene is added with stirring 1 g. of sodium methoxide. The resulting mixture is heated at 100 C. for 1 hour and then cooled to about 15-20 C. To the cooled mixture is added 500 ml. of benzene and 500 ml. of water. The aqueous phase is then extracted with 500 ml. of benzene and the combined organic layers washed twice with 500 ml. (each) of water and then evaporated on a rotary evaporator. The residue is dissolved in 200 ml. of isopropauol. To the cooled alcohol solution (5 C.) is added, with stirring, a solution of 11% hydrochloric acid in isopropanol until the pH thereof is 1. The resulting mixture is filtered, the filtrate cooled overnight at -5 C. The resulting solid material is filtered off and then slurried at reflux with 50 ml. ligroin. The solids are recovered by filtration, then slurried at 20 C. with 100 g. of carbon tetrachloride and filtered off to obtain bis-(p-chlorophenoxy)acetic acid fi-pyrrolidinoethyl ester hydrochloride, M.P. -130 C.

EXAMPLE 10 Bis-(p-chlorophenoxy)acetic acid l-benzyl-4-piperidyl ester f /CH0 0 0 CH2- To a mixture of 38 g. (0.2 mole) of 1-benzyl-4-hydroxypiperidine, 22 g. (0.22 mole) of triethylamine and 100 ml. of toluene is added, while stirring and maintaining the reaction temperature at about 20-25 C., a solution of 66 g. (0.2 mole) of bis-(p-chlorophenoxy)acetyl chloride in 200 ml. of toluene. The resulting mixture is stirred for an additional 2 hours at 25 C. and then cooled to 5 C. To the cooled mixture is added 500 ml. of water. The aqueous phase is extracted with 500 ml. of benzene and the combined organic layers are then Washed successively with 500 ml. of 1 N hydrochloric acid, 1 liter of water, 200 ml. of 5% aqueous sodium bicarbonate solution and then dried over magnesium sulfate and evaporated on a rotary evaporator at 100 mm. vacuum. The residue thus obtained is crystallized from 300 m1. of

methanol and then recrystallized from 500 ml. of methanol to obtain hygroscopic bis-(p-chlorophenoxy)acetic acid 1-benzyl-4-piperidyl ester, M.P. 4749 C.

EXAMPLE ll Bis-(p-chlorophenoxy) acetic acid {3-( 1-methyl-2- ethyl ester To a mixture of 163 g. (0.5 mole) of bis-(p-chlorophenoxy)acetic acid methyl ester, 83 g. (0.5 mole) of N-ethyl-N-phenylethanolamine and 1000 ml. of toluene is added, with stirring 2 g. of sodium methoxide. The resulting mixture is heated at 120 C. for 1 hour and then cooled to about 20 C. To the cooled mixture is added 500 ml. of benzene and 500 ml. of water. The resulting mixture is stirred for 15 minutes, the organic phase separated and washed twice with 500 ml. (each) of Water and then evaporated on a rotary evaporator at 100 mm. vacuum. The residue is dissolved in 500 ml. of isopropanol and the resulting solution cooled to 5 C., filtered and the solids washed with 200 ml. of cold isopropanol. The washed solids are dissolved in 500 m1. of isopropanol and the resulting solution treated at reflux wtih 10 g. of charcoal, then cooled and filtered. The filtrate is allowed to stand for two weeks at room temperature. The resulting crystalline material is recovered by decanting olf the solvent, then ground in a mortar and slurried at room temperature with 500 ml. of isopropanol. The resulting mixture is filtered and the solids washed with 200 ml. of isopropanol to obtain bis-(p-chlorophenoxy)acetic acid {3-(N-ethylanilino) ethyl ester, M.P. 56- 60 C.

EXAMPLE l2 Bis- (p-chlorophenoxy acetic acid [3- 1-methyl-2- pyrrolidinyl)ether ester To a mixture of 2.50 g. (0.022 mole) of l-l-methyl-Z- (fi-hydroxyethyl)pyrrolidine, 2.50 g. (0.025 mole) of triethylamine and 10 ml. of toluene, cooled to C., is added dropwise 55 ml. of a toluene solution containing 0.03 mole of bis-(p-chlorophenoxy)acetyl chloride at a rate such that the reaction temperature does not exceed about 5 C. After the addition is completed, the mixture is stirred overnight at 20 C., then 50 ml. of chloroform is added and the resulting mixtures extracted with 50 ml. of aqueous sodium carbonate solution. The organic phase is dried over potassium carbonate and evaporated to obtain l-bis-(p-chlorophenoxy)acetic acid fi-(l-methyl-Z- pyrrolidinyl)ethyl ester as a viscous oil.

The fumarate salt thereof, M.P. 149-150.? C., is obtaned by treating the oily base with a methanolic solution of fumaric acid, precipitating the salt by the addition of diethyl ether and recrystallizing the thus obtained salt from methanol-diethyl ether (1:1).

EXAMPLE l3 Bis(p-chlorophenoxy)acetic acid 1-phenyl-4-piperidyl To a mixture of 8.80 g. (0.05 mole) of 1-phenyl-4- hydroxypiperidine, 6.0 g. (0.06 mole) of triethylamine and 20 ml. of toluene, cooled to 0 C., is added dropwise 50 ml. of a toluene solution containing 0.06 mole of bis- (p-chlorophenoxy)acetyl chloride at such a rate that the reaction temperature does not exceed about 5 C. After the addition is completed, the mixture is stirred overnight at 20 C., then 300 ml. of chloroform is added and the resulting mixture extracted twice with ml. (each) of 10% aqueous sodium carbonate solution. The organic phase is dried over potassium carbonate and evaporated. The residue is crystallized from acetone at -5 C. to obtain bis-(p-chlorophenoxy)acetic acid l-pheny-4-piperidyl ester, M.P. 117-119.5 C.

EXAMPLE 14- Bis-(p-chlorophenoxy)acetic acid S-quinuclidinyl ester To 20 ml. of methylene chloride containing 3.80 g. (0.03 mole) of 3-quinuclidinol is added 3.50 g. of triethylamine and 10 ml. of methylene chloride containing 10.0 g. of bis-(p-chlorophenoxy)acetal chloride while maintaining the reaction temperature between 0 and 5 C. The mixture is then stirred overnight at room temperature, then 300 ml. of chloroform is added and the resulting mixture extracted twice with 100 ml. (each) of,

10% aqueous sodium carbonate solution. The organic phase is dried over potassium carbonate and evaporated. The residue is crystallized from benzene/c-hexane(1:l) to obtain bis-(p-chlorophenoxy)acetic acid 3-quinuclidinyl ester, M.P. 114-115 C.

What is claimed is:

1. A compound selected from the group consisting of compounds of the formula CHCOOR Cl O and the non-toxic addition and quaternary salts thereof,

wherein R represents 4. The compound of claim 1 which is bis-(p-chlorophenoxy)acetic acid 1-propargy1-4-piperidyl ester.

5. The compound of claim 1 which is bis-(p-chlorophenoxy)acetic acid 1-benzyl-4-piperidyl ester.

6. The compound of claim 1 which is bis-(p-chlorophenoxy)acetic acid 1-pheny1-4-piperidyl ester.

7. The compound of claim 1 which is bis-(p-chlorophenoxy)acetic acid 3-quinuclidiny1 ester.

No references cited.

US. Cl. X.R.