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US3681365A - Derivatives of acetic acid - Google Patents

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US3681365A
US3681365A US768881A US3681365DA US3681365A US 3681365 A US3681365 A US 3681365A US 768881 A US768881 A US 768881A US 3681365D A US3681365D A US 3681365DA US 3681365 A US3681365 A US 3681365A
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Prior art keywords
acetic acid
ester
mixture
piperidyl
ethyl
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Rudolf G Griot
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Sandoz AG
Sandoz Wander Inc
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Sandoz AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C07C59/70—Ethers of hydroxy-acetic acid, e.g. substitutes on the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4

Definitions

  • This invention relates to derivatives of acetic acid.
  • the invention pertains to bis-(substituted phenoxy) acetic acids and derivatives thereof which possess hypocholesteremic/hypolipemic activity.
  • the invention further relates to pharmaceutical compositions containing the above compounds as anactive ingredient thereof and the use of such compositions for the treatment of hypercholesteremia/hyperlipemia.
  • the compounds of the present invention are of the structural formula wherein R represents hydrogen or the residue of a monohydric alcohol capable of forming an ester by reaction with an acid,
  • a saturated aliphatic alcohol preferably a saturated lower aliphatic alcohol such as aliphatic alcohol having 1-5 carbon atoms, e.g. methanol, ethanol, propanol, isopropanol, butanol and the like;.an unsaturated aliphatic alcohol such as alkyl alcohol; a substituted aliphatic alcohol such as ethanolamine; an aromatic alcohol other than a phenol such as 'benzyl or phenylethylalcohol; an alicyclic alcohol such as cyclohexanol; a heterocyclic alcohol such as furfuryl alcohol an alcohol of the formula B-Ol-l where B represents piperidino, cyanomethyl or di[carb(lower)alkoxymethyl, where lower qualifies the alkoxy moiety to mean one containing l-S carbon atoms, an alcohol of the formula A-Ol-l wherein A (the point of attachment being at either the 2- of 3- positions);
  • each R independently, represents hydrogen or lower alkyl, preferably containing from one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl;
  • R represents hydrogen; halo, preferably bromo or chloro; or lower alkyl, preferably containing from one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl; R represents lower alkyl, preferably containing from one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl; propargyl; phenyl; halophenyl, the halo substitutent preferably being bromo or chloro; or phenyl(lower)alkyl, the lower alkyl substituent preferably containing from one to four carbon atoms, e.g., benzyl and phenethyl;
  • R represents hydrogen; lower alkyl, preferably containing from one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl; cycloalkyl containing from five to seven ring carbon atoms, e.g., cyclopentyl, cyclohexyl and cycloheptyl; phenyl; phenyl(lower) alky1, the lower alkyl substituent preferably containing from one to four carbon atoms, e.g., benzyl and phenethyl; lnaphthyl; or Z-naphthyl; and R represents lower alkyl, preferably containing from one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl; cycloalkyl containing from five to seven ring carbon atoms, e.g., cyclopentyl, cyclohexyl and cycl
  • R R R and R each independently, represents hydrogen, chloro, iodo or bromo, and
  • R and R each additionally, independently, represents trifluoromethyl or phenyl (which term for purposes of the definition of the compounds of formula (I) in the specification and in the claims is also intended to include p-chlorophenyl, p-iodophenyl and pbromophenyl), provided 1. at least one of the R, and r is other than hydrogen,
  • R R R and R each, independently, may represent only chloro or hydrogen only when R represents other than hydrogen, a residue of a saturated aliphatic alcohol, the basic radical A defined above, piperidino, cyanomethyl or di[carb(lower)alkoxy]methyl,
  • R R R and R each, independently, represents only hydrogen, chloro, iodo or bromo, provided at least one represents other than chloro, only when R represents other than hydrogen or a residue of a saturated aliphatic alcohol,
  • R and R each, independently, represents trifluorornethyl or phenyl only a. when at least one of R R R and R represents chloro, fluoro or iodo,
  • R represents a trifluorornethyl or phenyl group and the other of 5 R, and R represents the second group, or
  • R represents other than hydrogen, A as defined above, or the residue of a saturated aliphatic alcohol.
  • residue of a monohydric alcohol is meant that moiety of the alcoho] other than the -OH portion.
  • l-lower alkyl-4-piperidyl e.g., l-methyl-4-piperidyl and l-ethyl4-piperidyl
  • l-lower alkyl-3-piperidyl e.g., --methyl-3-piperidyl and l-ethyl-3-piperidyl
  • l-lower aIkyl-Z-piperidyl e.g, l-methyl-Z-piperidyl and lethyI-Z-piperidyl
  • l-phenyl-4-piperidyl l-phenyl-3- piperidyl
  • l-phenyl-Z-piperidyl l-benzyl-4-piperidyl
  • l phenethyl-4-piperidyl i phenethyl-3-piperidyl
  • the compounds of formula (I) may be prepared according to the processes indicated below.
  • Method A pertains to the reaction of a substituted phenoxy halo acetic acid derivative (II) and an ap intestinaltely substituted phenol (lil) as the phenolate.
  • This reaction is conveniently effected in a suitable inert organic solvent such as dimethylacetamide; diethylacetamide; dimethylforrnamide; and tetramethylurea.
  • a suitable inert organic solvent such as dimethylacetamide; diethylacetamide; dimethylforrnamide; and tetramethylurea.
  • the reaction is initially carried out at room temperature and then allowed to continue at elevated temperatures up to about 80C.
  • the particular solvent employed is not critical, nor is the temperature employed critical provided it does not exceed about 80C.
  • the resulting acetic acid derivative (I) is readily recovered employing conventional techniques.
  • the substituted phenol (III) is converted to the phenolate using standard techniques, such as treating the phenol with either a strong alkali metal hydroxide, e.g., KOH or NaOH, and water or sodium hydride in dimethylacetamide.
  • a strong alkali metal hydroxide e.g., KOH or NaOH
  • Method B involves the reaction of the substituted phenol (IV) as a phenolate and a dihalocarboxylic acid or derivative thereof (V) and the solvents and temperatures which may be used are substantially as discussed with respect to method A.
  • the compounds (I) where R represents the basic radical A earlier described may be preferably obtained by treating the compounds of formula (I) where R H or lower alkyl with an alcohol A OH, where A is as earlier defined, under conventional transesterification conditions.
  • this procedure may be performed in an inert organic solvent such as benzene, toluene or xylene, in the presence of an alkali metal alkoxide, preferably sodium methoxide or ethoxide, at a temperature of about 50l50C, preferably at reflux temperature.
  • the compounds of formula (I) where R represents piperidino are preferably prepared from the acid halide of the compounds (I) by treatment with l-hydroxypiperidine or an appropriate salt thereof in inert solvent, e.g., benzene or toluene, at about room temperature.
  • inert solvent e.g., benzene or toluene
  • R represents cyanomethyl or di[carb(lower)alkoxy] methyl
  • the free acid is treated with a haloacetonitrile or a dialkylhalomalonate, respectively, in inert solvent such as tetrahydrofuran or ethyl acetate in the presence of a tertiary amine such as triethylamine, preferably at the reflux temperature of the system.
  • the substituted phenoxy haloacetic acid ester starting materials (ll) used for process A described above may be prepared as indicated according to processes C and D.
  • Method C concerns treatment of the phenolate of compound (IV) with a monohaloacetic acid (VI), e.g., chloro acetic acid, to obtain the substituted phenoxy acetic acid of formula (VII).
  • VI monohaloacetic acid
  • the same solvents and reaction conditions discussed respecting processes A and B apply here as well.
  • the compounds of formula (VII) are then halogenated to provide the compounds of formula (ll) (method D). Conventional halogenating agents such as bromine or chlorine may be employed.
  • the halogenation is conveniently carried out in a suitable inert organic solvent such as a halocarbon, for instance a chloralkane, e.g., dichloromethane, chloroform, carbontetrachloride, and the like.
  • a suitable inert organic solvent such as a halocarbon, for instance a chloralkane, e.g., dichloromethane, chloroform, carbontetrachloride, and the like.
  • a suitable inert organic solvent such as a halocarbon, for instance a chloralkane, e.g., dichloromethane, chloroform, carbontetrachloride, and the like.
  • a halocarbon for instance a chloralkane, e.g., dichloromethane, chloroform, carbontetrachloride, and the like.
  • the reaction is initially carried out at room temperature and then allowed to continue at reflux temperature.
  • neither the choice of solvent nor the temperature used is critical
  • the compounds of formula (I) are useful because they possess pharmacological properties in animals.
  • these compounds are useful as hypocholesteremics/hypolipemics, as indicated by activity in sodium hexobarbital anesthetized rat tested by extracting serum or plasma with isopropanol and noting the cholesterol content.
  • the compounds may be administered orally as such or admixed with conventional pharmaceutical carriers or administered orally in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs.
  • compositions may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation.
  • adjuvants such as sweetening agents, flavoring agents, coloring agents and preserving agents
  • Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc.
  • the tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastro-intestinal tract and thereby provide a sustained action over a longer period.
  • suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preservatives (ethyl-p 'hydroxybenzoate).
  • suspending agents methylcellulose, tragacanth and sodium alginate
  • wetting agents lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate
  • preservatives ethyl-p 'hydroxybenzoate
  • Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin.
  • the compounds of formula (I) where R H may also be utilized as hypocholesteremics/hypolipemics in the form of non-toxic pharmaceutically acceptable salts thereof.
  • the aluminum salt more specifically, that aluminum salt wherein two hydroxyl groups of Al(OH) have been replaced by the acid radical; non-toxic alkali metal salts, e.g., potassium and sodium salts; non-toxic alkaline earth metal salts, e.g., magnesium and calcium salts; salts with N-containing bases such as ammonium salts and pharmaceutically acceptable primary, secondary and tertiary amine salts, e.g., ethanol amine salts, diethanol amine salts, and the like.
  • the compounds (I) are basic esters, such as when R represents A as defined above, the compounds may also be used as the non-toxic acid addition salt thereof or quaternary salts.
  • the salts are prepared using conventional techniques.
  • the dosage of active ingredient employed for the alleviation of hyperlipemia may vary depending on the particular compound employed and the severity of the condition being treated. In general, satisfactory results are obtained when these compounds are administered at a daily dosage of from about 0.5 milligrams to about 50 milligrams per kilogram of animal body weight. This daily dosage is preferably given in divided doses and administered two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 50-2000 mg, and dosage forms suitable for internal use comprise from about 12.5 milligrams to about 500 milligrams of active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.
  • the preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly hard-filled capsules and tablets containing from 25 milligrams to about 250 milligrams of the active ingredient.
  • EXAMPLE 1 (p-trifluoromethylphenoxy)-(p-chlorophenoxy)acetic acid, ester with l-hydroxypiperidine
  • a mixture of 20.2 g. of l-hydroxypiperidine and 800 ml. of absolute diethyl ether is stirred and cooled to about C. in an ice-salt bath.
  • To the cooled mixture is then added dropwise with stirring a solution of 33 g. of (p-trifluoromethylphenoxy-(p-chlorophenoxy) acetyl chloride in 400 ml. of absolute diethyl ether, while maintaining the temperature of the reaction mixture between to 0C. with external cooling.
  • EXAMPLE 2 acid CIICOOCIIzCN A mixture of 50 g. of (p-biphenylyloxy)-(pchlorophenoxy) acetic acid, 24.2 g. of triethylamine and 18 g. of chloroacetonitrile and 240 ml. of ethyl acetate is refluxed on a steam bath for 24 hours, then filtered and the ethyl acetate solution extracted once with 500 ml. of water and then twice with 500 ml. (each) of 2N hydrochloric acid. The ethyl acetate layer is then dried over sodium carbonate, filtered with charcoal and then evaporated.
  • EXAMPLE 3 (p-iodophenoxy)-(p-chlorophenoxy)acetic acid dicarbethoxymethyl ester A mixture of 50 g. of (p-iodophenoxy)-(pchlorophenoxy) acetic acid, 24.2 g. of triethyiamine, 57.3 g. of diethylbromomalonate and 240 ml. of ethyl acetate is refluxed on a steam bath for 24 hours, then filtered and the ethyl acetate solution extracted once with 500 ml. of water and then twice with 500 ml. of 2N hydrochloric acid.
  • Step 1 (p-bromophenoxy)-( acetic acid methyl ester Sodium hydride (56.7 percent in mineral oil) (47 g.) is washed free from the mineral oil with low boiling petroleum either and suspended in 750 ml. of dimethylacetamide. To the suspension is added g. of p-bromophenol in 500 ml. of dimethylacetamide as the temperature is maintained at l0-20C. The mixture is stirred for 2 hours and methyl chloro acetate is added. The resulting mixture is stirred for 5 hours at 80 C. and then at room temperature for 72 hours. The resulting mixture is then poured over 2 liters of ice water, extracted with 750 ml. of isopropyl ether.
  • Step 2 a-bromophenoxy acetic acid methyl ester
  • l80 g. of (p-bromophenoxy)acetic acid methyl ester To 1 liter of carbon tetrachloride is added l80 g. of (p-bromophenoxy)acetic acid methyl ester. With stirring at room temperature bromine g.) is added dropwise and the mixture is stirred for l7 hours at room temperature. The mixture is washed with 1,500 ml. of water and then 500 ml. of cold lpercent aqueous sodium bicarbonate.
  • Step 3 (p-bromophenoxy)-(2-chloro-4- trifluoromethylphenoxy acetic acid methyl ester
  • dimethylacetamide 15 g. of 2- ehloro-4-trifluoromethylphenol
  • the resulting mixture is added dropwise, with stirring, to a suspension of 4.6 g. of 56.7 percent sodium hydride (which had been washed free of mineral oil with petroleum ether) in 100 ml. of dimethylacetamide.
  • the resulting mixture is stirred at room temperature for 90 minutes and 26 g.
  • Step B Preparation of bis-(p-bromophenoxy)acetic acid l-methyl-4-piperidyl ester
  • Bis-(p-bromophenoxy)acetic acid methyl ester 10 grams, is mixed with 10 grams of B-hydropyethylpiperidine, 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 1 10C., the reaction mixture is cooled to 65C. and then evaporated on a rotary evaporator employing 12 mm. vacuum and maintaining the temperature between 657OC.
  • the crude product thus obtained is treated with an excess of a 20 percent aqueous solution of tartaric acid to yield the tartrate salt of bis-(pbromophenoxy)acetic acid ,B-piperidinoethyl ester.
  • the free base is obtained by treating the washed tartrate salt with 2N sodium hydroxide and extracting the base with dichloromethane.
  • the dichloromethane extract is dried over magnesium sulfate, the solvent evaporated and the residue neutralized with an isopropanolic solution of hydrogen chloride (10 percent hydrogen chloride gas in isopropyl alcohol).
  • Step 1 (p-trifluorornethylphenoxy)acetic acid Sodium hydride (56.7 percent in mineral oil) (47 g.) is washed free from the mineral oil with low boiling petroleum ether and suspended in 750 ml. of dimethylacetamide. To the suspension is added 81 g. of trifluoromethylphenol in 500 ml. of dimethylacetamide as the temperature is maintained at l0-20C. The mixture is stirred for 1 hour and 38 g. of chloroacetic acid is added. The resulting mixture is stirred for 5 hours at C. and then at room temperature for 72 hours.
  • Step 2 a-bromo-p-trifluoromethylphenoxy acetic acid.
  • Step 3 (p-trifluoromethylphenoxy)-(2,4- dichlorophenoxy)acetic acid
  • dimethylacetamide To 200 ml. of dimethylacetamide is added 16.3 g. of 2,4-dichlorophenol and the resulting mixture is added dropwise, with stirring, to a suspension of 9.2 g. of 56.7 percent sodium hydride (which had been washed free of mineral oil with petroleum ether) in 100 ml. of dimethylacetamide.
  • the resulting mixture is stirred at room temperature for minutes and 22 g. of abromo-pJrifluoromethylphenoxy acetic acid in 50 ml. of dimethylacetamide is added gradually.
  • the mixture is stirred at room temperature for 72 hours, then at 50C.
  • R represents n represents a whole number of from 1 to 4, inclusive
  • each R independently, represents hydrogen or lower alkyl
  • R represents hydrogen, halo or loweralkyl
  • R represents lower alkyl, propargyl, phenyl,
  • R,, R R and R each independently represents hydrogen, chloro, iodo or bromo, and R and R additionally each, independently, represents trifluoromethyl or phenyl, provided I. at least one of R and R is other than hydrogen, 2.
  • R R R and R each, independently, may not represent only chloro or hydrogen, 3.
  • R and R each, independently, represents trifluoromethyl or phenyl only a. when at least one of R R a R and R represents chloro, bromo or iodo, or b. when one of R and R represents a trifluoromethyl or phenyl group and the other of R and R represents the second group; or a non-toxic acid addition or quaternary salt thereof.

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Abstract

This disclosure relates to derivatives of acetic acid, e.g., (pbiphenylyloxy)-(p-chlorophenoxy)acetic acid methyl ester. These compounds are useful as hypocholesteremics/hypolipemics.

Description

United States Patent Griot 5] *Au l, 1972 [54] DERIVATIVES OF ACETIC ACID [56] References Cited [72] Inventor: Rudolf G. Griot, Florham Park, NJ. UNITED STATES PATENTS [731 Assignw Hanover 3,462,446 8/1969 De Wald ..260/295 Notice; The onion of the term of this 3,470,234 9/1969 Bencze ..260/473 patenlasubsequem to 8 1987, 3,476,767 11/1969 Bencze ..260/326.3
l has been dlsc almed Primary Examiner-Henry R. Jiles Flledl 06L 1963 Assistant Examiner-G. Thomas Todd Attorney-Gerald D. Sharkin, Frederick H. Weinfeldt, [21] Appl' 768381 Robert S. Honor, Walter F. Jewell and Richard E.
Villa [52] US. Cl.....260/293.82, 260/239 D, 260/239 BF,
260/247.2 B, 260/268 R, 260/268 PH, [57] ABSTRACT g f igg g This disclosure relates to derivatives of acetic acid, 424/267 424/274: 424/308 e.g., (p-biphenylyloxy)-(p-chlorophenoxy)acetic acid I C67! 29 24 methyl ester. These compounds are useful as [51] C o u hypocholesteremicslhypolipemicsl [58] Field of Search ..260/294.3 A
3 Claims, No Drawings DERIVATIVES OF ACETIC ACID This invention relates to derivatives of acetic acid. In particular, the invention pertains to bis-(substituted phenoxy) acetic acids and derivatives thereof which possess hypocholesteremic/hypolipemic activity. The invention further relates to pharmaceutical compositions containing the above compounds as anactive ingredient thereof and the use of such compositions for the treatment of hypercholesteremia/hyperlipemia.
The compounds of the present invention are of the structural formula wherein R represents hydrogen or the residue of a monohydric alcohol capable of forming an ester by reaction with an acid,
e.g. a saturated aliphatic alcohol, preferably a saturated lower aliphatic alcohol such as aliphatic alcohol having 1-5 carbon atoms, e.g. methanol, ethanol, propanol, isopropanol, butanol and the like;.an unsaturated aliphatic alcohol such as alkyl alcohol; a substituted aliphatic alcohol such as ethanolamine; an aromatic alcohol other than a phenol such as 'benzyl or phenylethylalcohol; an alicyclic alcohol such as cyclohexanol; a heterocyclic alcohol such as furfuryl alcohol an alcohol of the formula B-Ol-l where B represents piperidino, cyanomethyl or di[carb(lower)alkoxymethyl, where lower qualifies the alkoxy moiety to mean one containing l-S carbon atoms, an alcohol of the formula A-Ol-l wherein A (the point of attachment being at either the 2- of 3- positions);
CHCOOR (the point of attachment being at either the 2-, 3- i or 4-p0sitions) (the point of attachment being at either the 2- or 3- positions);
(the point -of attachment being at either the 2- or 3- l 0 positions) (the point of attachment being at either the 2-, 3- or 4-positions) or 2-dimethylamine-:2-methyl propyl; represents (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) 0 4E R5 NJ (the point of attachment being at, either the 2- 01' 3- positions) nrepresents a whole number from 1 to 4 inclusive;
each R, independently, represents hydrogen or lower alkyl, preferably containing from one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl;
nrepresents 2, 3 2,3 4;
R represents hydrogen; halo, preferably bromo or chloro; or lower alkyl, preferably containing from one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl; R represents lower alkyl, preferably containing from one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl; propargyl; phenyl; halophenyl, the halo substitutent preferably being bromo or chloro; or phenyl(lower)alkyl, the lower alkyl substituent preferably containing from one to four carbon atoms, e.g., benzyl and phenethyl;
R represents hydrogen; lower alkyl, preferably containing from one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl; cycloalkyl containing from five to seven ring carbon atoms, e.g., cyclopentyl, cyclohexyl and cycloheptyl; phenyl; phenyl(lower) alky1, the lower alkyl substituent preferably containing from one to four carbon atoms, e.g., benzyl and phenethyl; lnaphthyl; or Z-naphthyl; and R represents lower alkyl, preferably containing from one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl; cycloalkyl containing from five to seven ring carbon atoms, e.g., cyclopentyl, cyclohexyl and cycloheptyl; phenyl; or phenyl(lower)alkyl, the lower alkyl substituent preferably containing from one to four carbon atoms, e.g., benzyl and phenethyl; provided that when R is hydrogen R is phenyl,
R R R and R each independently, represents hydrogen, chloro, iodo or bromo, and
R and R each additionally, independently, represents trifluoromethyl or phenyl (which term for purposes of the definition of the compounds of formula (I) in the specification and in the claims is also intended to include p-chlorophenyl, p-iodophenyl and pbromophenyl), provided 1. at least one of the R, and r is other than hydrogen,
2, R R R and R each, independently, may represent only chloro or hydrogen only when R represents other than hydrogen, a residue of a saturated aliphatic alcohol, the basic radical A defined above, piperidino, cyanomethyl or di[carb(lower)alkoxy]methyl,
3. R R R and R each, independently, represents only hydrogen, chloro, iodo or bromo, provided at least one represents other than chloro, only when R represents other than hydrogen or a residue of a saturated aliphatic alcohol,
4. R and R each, independently, represents trifluorornethyl or phenyl only a. when at least one of R R R and R represents chloro, fluoro or iodo,
b. when one of R, and R represents a trifluorornethyl or phenyl group and the other of 5 R, and R represents the second group, or
c. when R represents other than hydrogen, A as defined above, or the residue of a saturated aliphatic alcohol.
It will be clear that the term residue of a monohydric alcohol" is meant that moiety of the alcoho] other than the -OH portion.
As illustrative of the substituents represented by A there may be mentioned the following:
l-lower alkyl-4-piperidyl, e.g., l-methyl-4-piperidyl and l-ethyl4-piperidyl; l-lower alkyl-3-piperidyl, e.g., --methyl-3-piperidyl and l-ethyl-3-piperidyl; l-lower aIkyl-Z-piperidyl, e.g,, l-methyl-Z-piperidyl and lethyI-Z-piperidyl; l-phenyl-4-piperidyl; l-phenyl-3- piperidyl; l-phenyl-Z-piperidyl; l-benzyl-4-piperidyl; l -benzyl-3-piperidyl; l phenethyl-4-piperidyl; i phenethyl-3-piperidyl; l-propargyl- 4-piperidyl; l-propargyl-3-piperidyl; 1-[B-(p-chlorophenoxy)ethyl1-4- piperidyl; 3-quinuclidinyl; Z-quinuclidinyl; B-pyrrolidinoethyl; y-pyrrolidinopropyl; B-piperidinoethyl; "y-piperidinopropyl; fi-morpholinoethyl; ymorpholinopropyl; fi-dimethylaminoethyl; ydiethylaminopropyl', B-anilinoethyl; 'y-anilinopropyl; [3- (N-rnethylanilino)ethyl; B(l-lower alkyl-2-pyrrolidinyl)ethyl, e.g., B-( l-methyl-2-pyrrolidinyl)ethyl; y-( 1- lower alkyl-2-pyrrolidinyl)propyl, e.g., 'y-( l-methyl-Z- pyrrolidinyl)propyl, B-( l-phenyl-3-pyrrolidinyl)ethyl; B-( l-phenyl-2-pyrrolidinyl)ethyl; B-( l-beyzyl-3-pyrrolidinyl)ethyl; B-(l-benzyl-2-pyrrolidinyl)ethyl; B-( lphenethyl-3-pyrrolidinyl)ethyl; B l-phenethyl-Z-pyrrolidinyl)ethyl; fi-( l-propargyl-3-pyrrolidinyl)ethyl; B- (l-propargyl-2-pyrrolidinyl)ethyl; and [H l-[B-(pchlorophenoxy)ethyl]-3-pyrrolidinyl]ethyl.
The compounds of formula (I) may be prepared according to the processes indicated below.
(VII) halogenatiou CH0 0 OR CHCOUR where R, R R R and R, are as defined above, and X represents halo, preferably chloro or bromo.
Method A pertains to the reaction of a substituted phenoxy halo acetic acid derivative (II) and an ap propriately substituted phenol (lil) as the phenolate. This reaction is conveniently effected in a suitable inert organic solvent such as dimethylacetamide; diethylacetamide; dimethylforrnamide; and tetramethylurea. Preferably, the reaction is initially carried out at room temperature and then allowed to continue at elevated temperatures up to about 80C. The particular solvent employed is not critical, nor is the temperature employed critical provided it does not exceed about 80C. The resulting acetic acid derivative (I) is readily recovered employing conventional techniques. The substituted phenol (III) is converted to the phenolate using standard techniques, such as treating the phenol with either a strong alkali metal hydroxide, e.g., KOH or NaOH, and water or sodium hydride in dimethylacetamide.
Method B involves the reaction of the substituted phenol (IV) as a phenolate and a dihalocarboxylic acid or derivative thereof (V) and the solvents and temperatures which may be used are substantially as discussed with respect to method A.
The compounds (I) where R represents the basic radical A earlier described may be preferably obtained by treating the compounds of formula (I) where R H or lower alkyl with an alcohol A OH, where A is as earlier defined, under conventional transesterification conditions. For instance, this procedure may be performed in an inert organic solvent such as benzene, toluene or xylene, in the presence of an alkali metal alkoxide, preferably sodium methoxide or ethoxide, at a temperature of about 50l50C, preferably at reflux temperature.
The compounds of formula (I) where R represents piperidino are preferably prepared from the acid halide of the compounds (I) by treatment with l-hydroxypiperidine or an appropriate salt thereof in inert solvent, e.g., benzene or toluene, at about room temperature. Preferably also, when R represents cyanomethyl or di[carb(lower)alkoxy] methyl, the free acid is treated with a haloacetonitrile or a dialkylhalomalonate, respectively, in inert solvent such as tetrahydrofuran or ethyl acetate in the presence of a tertiary amine such as triethylamine, preferably at the reflux temperature of the system.
The substituted phenoxy haloacetic acid ester starting materials (ll) used for process A described above may be prepared as indicated according to processes C and D. Method C concerns treatment of the phenolate of compound (IV) with a monohaloacetic acid (VI), e.g., chloro acetic acid, to obtain the substituted phenoxy acetic acid of formula (VII). The same solvents and reaction conditions discussed respecting processes A and B apply here as well. The compounds of formula (VII) are then halogenated to provide the compounds of formula (ll) (method D). Conventional halogenating agents such as bromine or chlorine may be employed. The halogenation is conveniently carried out in a suitable inert organic solvent such as a halocarbon, for instance a chloralkane, e.g., dichloromethane, chloroform, carbontetrachloride, and the like. Preferably, the reaction is initially carried out at room temperature and then allowed to continue at reflux temperature. However, neither the choice of solvent nor the temperature used is critical.
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.
Various of the phenolates and alcohols employed as reactants above are known and are prepared according to methods disclosed in the literature. Those others not specifically described in the literature are prepared by analogous methods from known materials.
As previously indicated, the compounds of formula (I) are useful because they possess pharmacological properties in animals. In particular these compounds are useful as hypocholesteremics/hypolipemics, as indicated by activity in sodium hexobarbital anesthetized rat tested by extracting serum or plasma with isopropanol and noting the cholesterol content. For such usage, the compounds may be administered orally as such or admixed with conventional pharmaceutical carriers or administered orally in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs. Such compositions may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastro-intestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preservatives (ethyl-p 'hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin.
The compounds of formula (I) where R H may also be utilized as hypocholesteremics/hypolipemics in the form of non-toxic pharmaceutically acceptable salts thereof. As illustrative of such salts there may be included the aluminum salt, more specifically, that aluminum salt wherein two hydroxyl groups of Al(OH) have been replaced by the acid radical; non-toxic alkali metal salts, e.g., potassium and sodium salts; non-toxic alkaline earth metal salts, e.g., magnesium and calcium salts; salts with N-containing bases such as ammonium salts and pharmaceutically acceptable primary, secondary and tertiary amine salts, e.g., ethanol amine salts, diethanol amine salts, and the like.
When the compounds (I) are basic esters, such as when R represents A as defined above, the compounds may also be used as the non-toxic acid addition salt thereof or quaternary salts. The salts are prepared using conventional techniques.
The dosage of active ingredient employed for the alleviation of hyperlipemia (hypercholesteremia) may vary depending on the particular compound employed and the severity of the condition being treated. In general, satisfactory results are obtained when these compounds are administered at a daily dosage of from about 0.5 milligrams to about 50 milligrams per kilogram of animal body weight. This daily dosage is preferably given in divided doses and administered two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 50-2000 mg, and dosage forms suitable for internal use comprise from about 12.5 milligrams to about 500 milligrams of active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent. The preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly hard-filled capsules and tablets containing from 25 milligrams to about 250 milligrams of the active ingredient.
The following examples serve to further illustrate the present invention. However, it is to be understood that the examples are for purposes 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 (p-trifluoromethylphenoxy)-(p-chlorophenoxy)acetic acid, ester with l-hydroxypiperidine A mixture of 20.2 g. of l-hydroxypiperidine and 800 ml. of absolute diethyl ether is stirred and cooled to about C. in an ice-salt bath. To the cooled mixture is then added dropwise with stirring a solution of 33 g. of (p-trifluoromethylphenoxy-(p-chlorophenoxy) acetyl chloride in 400 ml. of absolute diethyl ether, while maintaining the temperature of the reaction mixture between to 0C. with external cooling. After the addition is completed, the mixture is stirred for an additional minutes and then, while cooling, 400 ml. of a cold saturated solution of sodium carbonate is added and the phases separated. The aqueous phase is extracted with 500 ml. of absolute diethyl ether. The combined organic phases are then washed twice with 400 ml. (each) of cold water, dried over anhydrous potassium carbonate and evaporated to dryness. The residue is recrystallized from absolute diethyl ether, using some charcoal as a decolorizing agent, to obtain (p-trifluoromethylphenoxy p-chlorophenoxy )acetic acid, ester with l-hydroxypiperidine.
EXAMPLE 2 acid CIICOOCIIzCN A mixture of 50 g. of (p-biphenylyloxy)-(pchlorophenoxy) acetic acid, 24.2 g. of triethylamine and 18 g. of chloroacetonitrile and 240 ml. of ethyl acetate is refluxed on a steam bath for 24 hours, then filtered and the ethyl acetate solution extracted once with 500 ml. of water and then twice with 500 ml. (each) of 2N hydrochloric acid. The ethyl acetate layer is then dried over sodium carbonate, filtered with charcoal and then evaporated. The residue is crystallized and recrystallized from diethyl ether-petroleum ether (1:1) and washed with isopropyl ether to obtain (pbiphenylyloxy)-(p-chlorophenoxy)acetic acid cyanomethyl ester.
EXAMPLE 3 (p-iodophenoxy)-(p-chlorophenoxy)acetic acid dicarbethoxymethyl ester A mixture of 50 g. of (p-iodophenoxy)-(pchlorophenoxy) acetic acid, 24.2 g. of triethyiamine, 57.3 g. of diethylbromomalonate and 240 ml. of ethyl acetate is refluxed on a steam bath for 24 hours, then filtered and the ethyl acetate solution extracted once with 500 ml. of water and then twice with 500 ml. of 2N hydrochloric acid. The ethyl acetate layer is then dried over sodium carbonate, filtered with charcoal and then evaporated. The residue is distilled using a high vacuum diffusion pump and a maximum oil bath temperature of 250C. to obtain (p-iodophenoxy)-(pchlorophenoxy) acetic acid dicarbethoxymethyl ester.
EXAMPLE 4 (p-bromophenoxy 2-chloro-4- trifluoromethylphenoxy) acetic acid methyl ester CHCOOCH:
Step 1. (p-bromophenoxy)-( acetic acid methyl ester Sodium hydride (56.7 percent in mineral oil) (47 g.) is washed free from the mineral oil with low boiling petroleum either and suspended in 750 ml. of dimethylacetamide. To the suspension is added g. of p-bromophenol in 500 ml. of dimethylacetamide as the temperature is maintained at l0-20C. The mixture is stirred for 2 hours and methyl chloro acetate is added. The resulting mixture is stirred for 5 hours at 80 C. and then at room temperature for 72 hours. The resulting mixture is then poured over 2 liters of ice water, extracted with 750 ml. of isopropyl ether. The organic layer is separated, extracted with cold 1N sodium hydroxide, dried over anhydrous sodium sulfate, filtered and evaporated to provide (p-bromohenoxy)- (acetic acid methyl ester. Step 2. a-bromophenoxy acetic acid methyl ester To 1 liter of carbon tetrachloride is added l80 g. of (p-bromophenoxy)acetic acid methyl ester. With stirring at room temperature bromine g.) is added dropwise and the mixture is stirred for l7 hours at room temperature. The mixture is washed with 1,500 ml. of water and then 500 ml. of cold lpercent aqueous sodium bicarbonate. The organic layer is separated, dried over anhydrous sodium sulfate and evaporated to provide a-bromo-p-bromophenoxy acetic acid methyl ester. Step 3. (p-bromophenoxy)-(2-chloro-4- trifluoromethylphenoxy acetic acid methyl ester To 200 ml. of dimethylacetamide is added 15 g. of 2- ehloro-4-trifluoromethylphenol and the resulting mixture is added dropwise, with stirring, to a suspension of 4.6 g. of 56.7 percent sodium hydride (which had been washed free of mineral oil with petroleum ether) in 100 ml. of dimethylacetamide. The resulting mixture is stirred at room temperature for 90 minutes and 26 g. of a-bromo-p-bromophenoxy acetic acid methyl ester in 50 ml. of dimethylacetamide is added in several portions. The mixture is stirred at room temperature for 72 hours, then at 50 C. for 30 minutes, poured over 1,500 ml. of ice water and extracted with 500 ml. of isopropylether. The ether layer is extracted with 100 ml. of cold lN sodium hydroxide, dried over anhydrous sodium sulfate, filtered and evaporated to yield (pbromophenoxy)-(2-chloro-4-trifluoromethylphenoxy) acetic acid methyl ester.
EXAMPLE 5 (p-biphenylyloxy)-(p-chlorophen0xy) acetic acid 1- methyl-4-piperidyl ester A mixture of g. of (p-biphenylyloxy)-(pchlorophenoxy) acetic acid methyl ester, 3.2 g. of lmethyl-4-hydroxypiperidine, 100 ml. of toluene and 0.2 g. of sodium methoxide is atmospherically distilled until the sump temperature reaches 150 C. (approximately 30 minutes). The sump temperature is maintained at 150 C. for an additional 15 minutes and then with the heat off water-aspirator vacuum is carefully applied until distillation ceases. The resulting mixture is cooled to 50 C. and 200 ml. of benzene is added thereto. The resulting mixture is further cooled to C. and then 200 ml. of water is added thereto. The top oily layer is separated, washed first with 200 ml. of water, then with 100 ml. of a saturated solution of sodium chloride and then dried over magnesium sulfate and evaporated on a rotary evaporator at approximately 100 mm vacuum. The residue is crystallized from 50 ml. of isopropanol to obtain (p-biphenylyloxy)-(pchlorophenoxy) acetic acid l-methyl-4piperidyl ester.
EXAMPLE 6 Bis-(p-bromophenoxy)acetic acid l-methyl-4-piperidyl ester \CHC o O-O-Cm Br 0 Step A. Preparation of bis-(p-bromophenoxy)acetic acid methyl ester A solution of 25 grams of 4-bromophenol in 200 ml. of dimethylacetamide is slowly added to a stirring slurry of 9.5 grams of sodium hydride (56 percent in mineral oil) in 250 ml. of dimethylacetamide and the mixture stirred at 20 C. for 1 hour.
To the resulting clear solution is added 14 grams of methyldichloroacetate in 200 ml. of dimethylacetamide and a catalytic amount of potassium iodide. The reaction mixture is stirred at 20C. 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 1N 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 produce from methanol yields bis-(pbromophenoxy)acetic acid methyl ester; m.p. 79.5-8 0.5C.
Step B. Preparation of bis-(p-bromophenoxy)acetic acid l-methyl-4-piperidyl ester Bis-(p-bromophenoxy)acetic acid methyl ester, 10 grams, is mixed with 10 grams of B-hydropyethylpiperidine, 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 1 10C., the reaction mixture is cooled to 65C. and then evaporated on a rotary evaporator employing 12 mm. vacuum and maintaining the temperature between 657OC. The crude product thus obtained is treated with an excess of a 20 percent aqueous solution of tartaric acid to yield the tartrate salt of bis-(pbromophenoxy)acetic acid ,B-piperidinoethyl ester. The free base is obtained by treating the washed tartrate salt with 2N 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 percent hydrogen chloride gas in isopropyl alcohol).
EXAMPLE 7 (p-biphenylyloxy)-( p-chlorophenoxy )acetic anilinoethyl ester (p-biphenylyloxy)-(p-chlorophenoxy)acetic acid methyl ester, 10 grams, is mixed with 10 grams of B- anilinoethanol, 50 mg. of sodium methoxide and 10 ml. of toluene. The resulting mixture is slowly heated to distill very slowly through a Vigreux Column. When the temperature at the distilling head reaches 1 10C., the reaction mixture is cooled to 65C. and then evaporated on a rotary evaporator employing 12 mm. vacuum and maintaining the temperature between 657OC. The crude product is chromatographed on a Silica Gel Column and the product recovered by washing the column with benzene. The benzene is then evaporated off to obtain (p-biphenylyloxy)-(pchlorophenoxy)acetic acid ,B-anilinoethyl ester.
ester /CHC O O CH2CH2N To a mixture of 120 g. of bis-(p-bromophenoxy)acetic acid methyl ester, 50 g. 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 100C. for 1 hour and then cooled to about lS-20C. 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 isopropanol. To the cooled alcohol solution (5C.) is added, with stirring, a solution of ll percent hydrochloric acid in isopropanol until the pH thereof is l. The resulting mixture is filtered, the filtrate cooled overnight at -5C. 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 C. with 100 g. of carbon tetrachloride and filtered off to obtain hisp-bromophenoxy )acetic acid B-pyrrolidinoethyl ester.
EXAMPLE 9 Bis-(p-iodophenoxy)acetic ethylanilino)ethyl ester To a mixture of 160 g. of bis-(p-iodophenoxy)acetic acid methyl ester, 80 g. of N-ethyl-N-phenylethanolamine and [,000 ml. of toluene is added, with stirring 2 g. of sodium methoxide. The resulting mixture is heated at 120C. for 1 hour and then cooled to about 20C. 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 5C., filtered and the solids washed with 200 ml. of cold isopropanol. The washed solids are dissolved in 500 ml. of isopropanol and the resulting solution treated at reflux with 10 g. of charcoal, then cooled and filtered. The filtrate is allowed to stand for 2 weeks at room temperature. The resulting crystalline material is recovered by decanting off 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-iodophenoxy)acetic acid [3-( N-cthylanilino) ethyl ester.
EXAMPLE l() (p-trilluoromethylphenoxy 2,4-dichlorophcnoxy)acetic acid acid B-(N- CHC OOH CF; 0
Step 1. (p-trifluorornethylphenoxy)acetic acid Sodium hydride (56.7 percent in mineral oil) (47 g.) is washed free from the mineral oil with low boiling petroleum ether and suspended in 750 ml. of dimethylacetamide. To the suspension is added 81 g. of trifluoromethylphenol in 500 ml. of dimethylacetamide as the temperature is maintained at l0-20C. The mixture is stirred for 1 hour and 38 g. of chloroacetic acid is added. The resulting mixture is stirred for 5 hours at C. and then at room temperature for 72 hours. The resulting mixture is then poured over 2 liters of ice water, made acidic with a slight excess of hydrochloric acid and is extracted with 750 ml. of isopropyl ether. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to provide (p-trifluoromethylphenoxy)- acetic acid.
Step 2. a-bromo-p-trifluoromethylphenoxy acetic acid.
To 1 liter of'carbon tetrachloride is added 10 g. of (p-trifluoromethylohenoxy)acetic acid. With stirring at room temperature bromine (160 g.) is added dropwise and the mixture is stirred for 17 hours at room temperature. The mixture poured onto 2 kilograms of crushed ice, stirred for 30 minutes and then separated. The organic layer is washed repeatedly with water and then dried over anhydrous sodium sulfate and evaporated to provide a-bromo-ptrifluoromethylphenoxy acetic acid.
Step 3. (p-trifluoromethylphenoxy)-(2,4- dichlorophenoxy)acetic acid To 200 ml. of dimethylacetamide is added 16.3 g. of 2,4-dichlorophenol and the resulting mixture is added dropwise, with stirring, to a suspension of 9.2 g. of 56.7 percent sodium hydride (which had been washed free of mineral oil with petroleum ether) in 100 ml. of dimethylacetamide. The resulting mixture is stirred at room temperature for minutes and 22 g. of abromo-pJrifluoromethylphenoxy acetic acid in 50 ml. of dimethylacetamide is added gradually. The mixture is stirred at room temperature for 72 hours, then at 50C. for 30 minutes, poured over 1,500 ml. of ice water, acidified with hydrochloric acid, and extracted with 500 ml. of isopropylether. The ether layer is extracted with ml. of water, dried over anhydrous sodium sulfate, filtered and evaporated to yield (ptrifluoro-methylphenoxy 2,4-dichlorophenoxy)acetic acid.
When the above procedure is carried out and pchlorophenyl, p-iodophenol, p-bromophenol, p-phenylphenol, p-(p-chlorophenyl phenol or 2,4- dibromophenol is used in place of 2,4-dichlorophenol, there is obtained (p-trifluoromethylphenoxy)-(p-chlorophenoxy)acetic acid,
(p-trifluoromethylphenoxy acetic acid,
( p-trifioromethylphenoxy acetic acid, (p-trifluromethylphenoxy acetic acid, (p-triflouromethylphenoxy p-(p-chlorophenyi )phcnoxy] acetic acid, or (p-trifluoromethylphenoxy 2,4-dibromophcnoxy acetic acid,
respectively.
What is claimed is: l. A compound of the formula R CHCOOA wherein A represents (CHR) R,
R represents n represents a whole number of from 1 to 4, inclusive;
each R, independently, represents hydrogen or lower alkyl;
R represents hydrogen, halo or loweralkyl; and
R represents lower alkyl, propargyl, phenyl,
halophenyl or phenyl(lower)alkyl;
R,, R R and R each independently represents hydrogen, chloro, iodo or bromo, and R and R additionally each, independently, represents trifluoromethyl or phenyl, provided I. at least one of R and R is other than hydrogen, 2. R R R and R each, independently, may not represent only chloro or hydrogen, 3. R and R each, independently, represents trifluoromethyl or phenyl only a. when at least one of R R a R and R represents chloro, bromo or iodo, or b. when one of R and R represents a trifluoromethyl or phenyl group and the other of R and R represents the second group; or a non-toxic acid addition or quaternary salt thereof.
2. The compound of claim 1 which is bis-(pbromophenoxy) acetic acid 1-methyI-4-piperidyl ester.
3. The compound of claim 1 which is (p-biphenylyloxy)-(p-chlorophenoxy) acetic acid l-methyl-4- piperidyl ester.

Claims (4)

  1. 2. The compound of claim 1 which is bis-(p-bromophenoxy) acetic acid 1-methyl-4-piperidyl ester.
  2. 2. R2, R2, R3 and R4 each, independently, may not represent only chloro or hydrogen,
  3. 3. R1 and R2 each, independently, represents trifluoromethyl or phenyl only a. when at least one of R1, R2, a R3 and R4 represents chloro, bromo or iodo, or b. when one of R1 and R2 represents a trifluoromethyl or phenyl group and the other of R1 and R2 represents the second group; or a non-toxic acid addition or quaternary salt thereof.
  4. 3. The compound of claim 1 which is (p-biphenylyloxy)-(p-chlorophenoxy) acetic acid 1-methyl-4-piperidyl ester.
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Publication number Priority date Publication date Assignee Title
US4051170A (en) * 1973-12-15 1977-09-27 Merck Patent Gesellschaft Mit Beschrankter Haftung Diphenoxyacetic acid derivatives
EP0107640A1 (en) * 1982-09-30 1984-05-02 Monsanto Company Dialkyl glyoxylate surfactants

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KR101679108B1 (en) 2010-06-21 2016-11-23 에이비비 슈바이쯔 아게 Phase control thyristor with improved pattern of local emitter shorts dots

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US3462446A (en) * 1966-11-25 1969-08-19 Parke Davis & Co Substituted beta-amino-2-stilbazole compounds
US3470234A (en) * 1965-08-23 1969-09-30 Ciba Geigy Corp Diaryl substituted benzocycloalkanes
US3476767A (en) * 1965-10-11 1969-11-04 Ciba Geigy Corp 1,2-diaryl - 6 - tertiary amino lower-alkoxy-3,4-dihydro naphthalenes

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3470234A (en) * 1965-08-23 1969-09-30 Ciba Geigy Corp Diaryl substituted benzocycloalkanes
US3476767A (en) * 1965-10-11 1969-11-04 Ciba Geigy Corp 1,2-diaryl - 6 - tertiary amino lower-alkoxy-3,4-dihydro naphthalenes
US3462446A (en) * 1966-11-25 1969-08-19 Parke Davis & Co Substituted beta-amino-2-stilbazole compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4051170A (en) * 1973-12-15 1977-09-27 Merck Patent Gesellschaft Mit Beschrankter Haftung Diphenoxyacetic acid derivatives
EP0107640A1 (en) * 1982-09-30 1984-05-02 Monsanto Company Dialkyl glyoxylate surfactants

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