DK145778B - ANALOGY PROCEDURE FOR PREPARING 3-PHENOXYPHENYLALKANIC ACID DERIVATIVES - Google Patents

Description

(19) DENMARK

® | (12) PUBLICATION OR 145778 Β

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 4 ^ 61/69 (51) IntCI.3 C 07 C 59/68 (22) Filing Day 1 ^ ·· ®dg * 19 ^ 9 C 07 C 69/736 (24) Running Day l4aug . 1969 C 07 C 83/10 (41) Aim. available Feb 16 1970 C 07 C 103/00 (44) Submitted Feb 28 19¾ (86) International Application No. ~ (86) International Filing Day (85) Continuation Day - (62) Master Application No. -

(30) Priority 15 Aug 1968 * 752800, US Aug 15 1968, 752801, US May 28, 1969 * 828756, US

(71) Applicant ELI LILLY AND COMPANY, Indianapolis, US.

(72) Inventor Winston Stanley Marshall, US.

(74) Associate Engineer Hofman-Bang & Boutard.

(54) Analogous process for the preparation of 5-phenoxyphenylalkanoic acid derivatives.

The present invention relates to an analogous process for the preparation of novel 3-phenoxyphenylalkanoic acid derivatives of the general formula I set forth in the preamble of the claim, and the process of the invention is characterized by the characterizing part of the claim.

Many people and animals are known to suffer from various rheumatic D disorders that cause inflammation, swelling, tenderness, reduced mobility, pain and fever. There are a number of available anti-inflammatory agents that have been shown to be effective in the symptomatic treatment of disorders such as rheumatoid arthritis, rheumatoid spondylitis and osteoarthritis of the hip, but these agents have a number of undesirable side effects.

3 2 145778

U.S. Patent No. 3,385,886 discloses a number of related compounds having anti-inflammatory effect. Only para-substituted compounds are referred to, while the present invention relates to meta-substituted compounds.

By comparison between a number of the compounds of the invention with unsubstituted p-phenoxyphenylacetic acid as well as with known para-substituted acids and certain ortho-substituted acids, it has been found that the compounds of this invention are as active as the compounds of the above-mentioned United States patent, but causes much less irritation to the stomach.

Thus, the present invention relates to a process for the preparation of novel compounds which are excellent anti-inflammatory agents and which, in addition to their anti-inflammatory action, exert a mild, aspirin-like analgesic and antipyretic effect.

The disclosed 3-phenoxyphenylalkanoic acids and their pharmaceutically acceptable derivatives may be designated by the general formula II: wherein the symbols used have the meaning given in the preamble of the claim.

The compounds of general formula I are excellent anti-inflammatory agents, many of which have an ED, of 0.9-5.0 mg / kg in the erythema-blocking test. The present compounds are useful in the treatment of inflammatory diseases in mammals. In addition to their anti-inflammatory effect, the compounds have a mild analgesic and antipyretic effect. They can be used in therapeutic mixtures containing as active ingredient one or more of the compounds of formula I together with a pharmaceutically acceptable diluent or carrier. The compounds are usually administered in mammals at doses of 0.2-50.0 mg / kg body weight daily, either in one or in multiple doses over 24 hours. It is to be understood that both the d- and the 1-isomer of the o-alkyl compounds are encompassed by the invention. Thus, e.g. The C 1 -alkyl acids are cleaved into their d and 1 isomers by well known methods, and the two isomers have been found to have essentially identical effect. Thus, both the racemic mixture and the d- and 1-isomer can be used in the treatment of inflammation, pain and fever in mammals.

Some of the compounds of the present invention, especially those wherein and Y 2 represents hydrogen, n is 0, is hydrogen, methyl or ethyl and Z is C00H, or salts thereof, has surprisingly been found to increase the analgesic effect of certain analgesic agents such as the esters of 1,2-diphenyl-2-hydroxy-3-methyl (substituted 4-amino) butanes, in particular α-d-propoxypheu (chemically identified as adl, 2-diphenyl-2-propionoxy-3-methyl-4- dimethylaminobutane) as well as certain narcotic analgesics such as morphine and codeine when administered therewith. The increase in the analgesic effect occurs when approx. 1 part by weight of the compound prepared by the method of the invention is administered substantially simultaneously with or from 1 hour before to 1 hour after the administration of 0.005-20 parts by weight of the analgesic agent. In general, it can be said that to obtain a greater analgesic effect, one must administer 0.5-50 mg / kg of one of the compounds prepared by the method of the invention together with the usual therapeutic dose of the analgesic agent.

The present compounds are prepared by methods known per se for the preparation of phenylacetic acids, phenylpropionic acids and derivatives thereof, the methods of which are illustrated below. In the following, R-R has the same meaning as in the preamble of claim and "Ar" denotes the group set forth in Formula I: 4 145778

Yo ___ Α. Acids

I * Year-GH: 3 Ar-GH2-Br FaCFj Ar-CH2-0F H20 Year-CH2-C00H

The methyl group in a suitable methyl diaryl ether is halogenated by reaction with N-bromosuccinimide (NBS), N-chlorosuccinimide, sulforyl chloride or a similar halogenating agent, using a suitable catalyst such as benzoyl peroxide or azo-bis-isobutyronitrile in an inert solvent such as carbon tetrachloride or another halogenated hydrocarbon. The resulting halomethyl diaryl ether is reacted with sodium or potassium cyanide, preferably in a dimethyl sulfoxide solution. The nitrile thus obtained is hydrolyzed to the corresponding carboxylic acid by treatment with either acidic or basic reagents in known manner.

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The nitrile prepared according to Scheme I, as shown above, can be alkylated with an aliphatic halide or tosylate (R-xXg) in liquid ammonia in the presence of sodium amide to form an α-aliphatic substituted nitrile. The alkylated utryl is hydrolyzed to give the corresponding carboxylic acid (reaction sequence IIa). Similarly, one can alkylate an arylic acetic acid at the ot position with respect to the carboxyl group, - as shown in reaction sequence IIb.

By another method, as shown in nc and Ild, an aryl acetate ester such as the ethyl ester or an aryl acetonitrile can be converted to the corresponding malone ester or cyanoacetic acid ester by the action of metallic sodium and diethyl carbonate. Any of these derivatives can then be alkylated. Such alkylation is usually carried out by reacting the malone ester or cyanoacetic acid ester with a strong base such as sodium ethoxide, sodium methoxide, potassium tert-butoxide or sodium hydride, thereby forming a carbanion at the α-carbonator network. A subsequent treatment of the carb anion intermediate with an alkylating agent such as an alkyl halide or tosylate (¾¾) gives the corresponding α-alkylmalon ester or cyanoacetic acid ester derivative. Each of these can be hydrolyzed to a corresponding ος-alkylaryl malonic acid, which is then decarboxylated in known manner to give the desired o-alkylaryl acetic acid.

A nitrile prepared according to reaction sequence I can, if desired, be methylated as follows (III): The nitrile is condensed with ethyl formate in basic medium, e.g. in the presence of sodium hydride or sodium methoxide in an inert hydrocarbon solvent such as benzene. The resulting hydroxymethylene derivative is benzoylated by the action of either benzoic acid anhydride or benzoyl chloride and pyridine and the benzoic acid ester are then hydrogenated in the presence of a noble metal catalyst to form the desired α-methyl arylaeetonitrile, which is then hydrolyzed as above.

Optionally, the desired α-methylarylacetonitrile may be prepared by the following reaction series (IV): Aryloxyacetophenone 9 145778 (prepared by a Ullman ether synthesis) is reduced either by hydrogen in the presence of a noble metal catalyst or by a metal hydride such as lithium aluminum hydride, lithium boron or uranium boron. hydride, to the corresponding carbinol. Conversion of this carbinol to the corresponding bromide can be accomplished by treating the carbenol with phosphorus tribromide, preferably in an inert solvent such as chloroform, benzene or carbon tetrachloride. The bromide thus obtained is reacted with sodium cyanide, preferably in a dimethyl sulfoxide solution to form a nitrile, which is then hydrolyzed as above to the desired carboxylic acid.

The α-alkyl acids thus obtained can be cleaved into their d- and 1-isomers in known manner.

The desired phenoxyphenylalkanoic acids can also be prepared by the Willgerodt reaction (V). In this reaction, a suitable -phenoxyphenylalkyl ketone is heated with morpholine and sulfur and the resulting thioamide is hydrolyzed to form the desired alkanoic acid derivative which can be alkylated by treatment with two equivalents of sodium amide in liquid ammonia, followed by the addition of alkyl halide or tosylate (11 x X 2) as illustrated in Ilb.

The acids prepared according to the invention, wherein n is different from 0, can be prepared in known manner by the Wittig reaction as shown in Schemes Via and VIb. The unsaturated esters (as in Via) or nitriles (as in VIb) arising as intermediates can be hydrogenated in the presence of a precious metal catalyst such as platinum, and the resulting saturated esters and nitriles can be hydrolyzed, as shown above, to the desired carboxylic acids .

10 U577 «C. Estere, 7IIIa. Ar-CH- (GH,) COOH IUOH / HCl Ar-CH- (CHJgOOR, ~ L - * S1

VIIIb. Ar-CE- (CH,) COOH SOGI, Ar-CH- (CH,) COG1- I ^ C \ I ^ U- R1 R1 s2oh

V

Ar-CH- (CH 2) uC00R2

A

The garboxylic acids prepared by the process described above can be converted to the corresponding esters in known manner, such as by heating the acid with an alcohol in the presence of a mineral acid (Villa) or by converting the acid to the corresponding acid chloride, and then reacting this with an alcohol, preferably in the presence of a compound which can take up HG1 (VIHb).

D. Amider.

IX. Ατ-0Η- (0Η2) η-ς ^ (Sj) 2KH Ar-CH- (CH

Ri Xl S?

The amides are prepared by reacting the above acid chloride with an amine. The reaction is usually carried out in an inert solvent such as chloroform, benzene or carbon tetrachloride, in the presence of a substance capable of binding the acid such as pyridine or C

The starting materials for the foregoing reactions are readily prepared by a Ullman diaryl ether synthesis, as described by Bacon and Stevard, J. Am. Chem. Soc., £ 8, 4953 (1965) and indicated by the following reaction:

Ar * -OH + Ar »X. ------ ^ Ar * -O-Year« wherein Ar 'represents an unsubstituted phenyl group and Year' represents the substituted phenyl group

11 14S77S

T1 * 2a from the general formula I ·

Typical intermediates prepared by the above reaction are the following: 3- Phenoxyacetophenone, b.p., 117-126 ° C / 0.08 mm; njp = 1.5865, 4- Chloro-5-methyl diphenyl ether, b.p., 105-113 ° C / 0.06 mm; n = 4'5 = 1.5850, 2-J-Chloro-5-methyl diphenyl ether, b.p., 120-123 ° C / 0.08 mm; n? 5 »5 = 1.5850, 4-Fluoro-5-methyl dip] enyl ether, b.p., 75-85 ° C / 0.05 mm; n ^ 4 = 1.5565, 4-Methyl-5-phenoxyyaetophenone, b.p., 120-132 ° C / 0.05 mm; ζξ5 = 1.5888, 2-Methoxy-5-phenoxyyaetophenone, b.p., 132-140 ° C / 0.15 mm; n £ 5 = 1.5864.

The invention is further illustrated by the following examples. EXAMPLE 1

Preparation of 3-Nhenoxyphenyl Acetic Acid

To 26 ml of morpholine were added 42.4 g of m-phenoxyacet ophenone and 9 »6 g of sulfur. The reaction mixture was heated under reflux and stirred for 20 hours. To the reaction mixture was then added 700 ml of 15 µl of aqueous potassium hydroxide and a small amount of ethyl alcohol. The reaction mixture was refluxed and stirred for a further 20 hours. There distilled approx. 200 ml of the solvent. The residual reaction mixture was filtered hot, partially cooled with ice and acidified with concentrated hydrochloric acid to precipitate an oily precipitate which then crystallized. The crystalline precipitate was filtered off, washed several times with water and dried to give 45.9 g of crude product as a yellow-orange solid. The crude product was suspended in boiling hexane and ethyl acetate was added until the product was dissolved. The solution was treated with activated charcoal, filtered and cooled to give 22.7 g of white flakes of 3-phenoxyphenylacetic acid, m.p. 84 - 86 ° C, pK'a = 6.9.

Calcd. For C 14 H 2 O 3: C, 3.66; H, 5.30,

Found: C, 73.85; H, 5.35.

EXAMPLES 2-6

The following compounds were prepared according to the procedure of Example 1. From suitably corresponding phenoxyacetophenone using appropriate amounts of sulfur and morpholine.

(4-Methyl-3-phenoxy) phenylacetic acid, m.p. 49-51 ° C, pK'a = 7.0 from 4-methyl-3-pb-enoxyacetophenone.

Analysis calculated for Ο- ^ Η- ^ Ο ^: 0.74.36; H, 5.83;

Pound: C, 74.45; H, 5.88.

(4-Methoxy-3-pyreneoxy) phenylacetic acid, m.p. 85-87.5 ° C, pK'a = 6.9 from 4-methoxy-3-phenoxyacetophenone.

For C ^ forH-jO O: C, 69.75; H, 5.46;

Pound: 0, 69.47; H, 5.30.

(2-Methoxy-5-phenoxy) phenylacetic acid, m.p. 90-94 ° C, pK'a = 7.4 from 2-me thoxy5-phenoxya ce tophenone.

Analysis calculated for O 2 H- O O: c> 9.75; H, 5.46,

Pound: 0, 69.58; H, 5.61 · (2-Methyl-5-phenoxy) phenylacetic acid, b.p., 153-163 ° C / 0.16 mm; pK'a = 6.9 from 2-methyl-5-phenoxyacetophenone.

Analysis calculated for Ο ^ Ξ ^ Ο ^: 74.36; H, 5.83,

Pound: C, 72.08; H, 5.0 + EXAMPLE 7 13

U577B

(4- chi or ~ 3-phenoxy) phenylacetic acid

To 1200 ml of carbon tetrachloride were added 232.7 g of 3-phenoxy-4-chloro-toluene, 196 g of E-bromosuccinimide and 1.0 g of benzoyl peroxide. The reaction mixture was stirred and heated under reflux for 24 hours, then filtered and the solid washed with carbon tetrachloride. The filtrate was evaporated to an oil and distilled to give fractions A, B and C of crude 4-chloro-3-pheo-benxy-benzyl bromide: n n25 fraction K.P. ° 0 (mm) _ Frosty (g) _ A 140-150 (0.08) 118.5 1.5960 B 145-153 (0.07) 190.6 1.6152 G 145-160 (0, 07) 79.4 1.6250 The fractions B and C were combined and analyzed.

Analysis calculated for C C CH ^ øBrClO: C, 52.46; Ξ, 3.38; found: 0, 52.25; H, 3.44.

The combined fractions B and C were redistilled through a Tigreux column to give fractions A, B, C, D and E.

n? 5 fraction K.P. ° C (mm) Cover (g) O_ A 105-145 (0.09) 24.2 1.5951 B 145-155 (0.09) 29.6 1.6114 0 130-136 (0.07) 79 , 4 1.6228 D 128-135 (0.07) 52.9 1.6218 E. 136-149 (0.06) 29.8 1.6274 MR studies indicated that fractions C and D contained 91 and 92% of 4-chloro-3-phenoxybenzyl bromide, respectively.

For approx. 400 ml of dimethyl sulfoxide were dissolved in 22.2 g of 955% sodium cyanide and the reaction mixture was heated to ca. 50 ° C. The crude 4-chloro-3-phenoxybenzyl bromide (125 g) was added dropwise with stirring. The temperature was maintained at 50-60 ° 0 during the bromide addition. A red color formed immediately after the addition of the bromide. After the addition, the reaction mixture was heated to 60 ° C and stirred for 3 hours. The mixture was allowed to cool to room temperature and stirred overnight, then poured over ice and extracted with ethyl ether and then with hexane. The extracts were washed with water and dried over sodium sulfate. The solvents were evaporated to give a reddish-brown viscous oil, which was distilled to give fractions A, B and C of (4-ehloro-3-phenoxyphenyl) acetonitrile.

25

Eraktion K.P. ° C (mm) _ Weight (g) _ ^ D_ A 170 (0.4) -170 (0.15) 51.6 1.5916 B 163-174 (0.08) 16.3 1.5917 0 174 -190 (0.10) 2.2 1.5917

Analysis calculated for C ^ HH- qCIM): C, 68.99; Η, 4.13r N, 5i74;

Found: 0 »68.72; Ξ, 4.20; R, 5.50.

Purified hydrolysis of the nitrile gave the corresponding (4-chloro-3-phenoxy) phenylacetic acid. To 500 ml of concentrated hydrochloric acid was added 50.9 g of the above nitrile. The reaction mixture was stirred and heated to 85 ° C for 24 hours. 500 ml of distilled water was added to the reaction mixture, which was then heated with stirring and refluxed to 105 ° C for 4 hours. The reaction mixture was poured into a large volume of ice water. Extract twice with ethyl ether. The combined ether phases were washed with water and extracted with dilute sodium carbonate. The extract was then washed with ethyl ether and acidified by dropwise addition of 6H hydrochloric acid with stirring. The volatile white precipitate formed was filtered and washed with water and dried in vacuo to give 34.2 g of white crystalline (4-chloro-3-phenoxy) phenylacetic acid, m.p. 77-80 ° C.

EXAMPLES 8-9 The following compounds were prepared according to the procedure of Example 7 from the corresponding toluene using appropriate amounts of N-bromosuccinimide, benzoyl peroxide and sodium cyanide.

(2-Chloro-5-phenoxy) phenylacetic acid, m.p. 88τ90 ° C, pK'a = 6.8.

Analysis calculated for C- HH- ^ ClO₂: 0.64.00; H, 4.22; ^ Low: 0, 63.73; H, 4.32.

145778 (2-Fluoro-5-phenoxy) phenylacetic acid, snip. 80-82 ° C, pK + α = 6.65.

Analysis calculated for: C, 68.28; H, 4> 50;

Found: C, 68.08 H, 4.43.

EXAMPLE 10

Preparation of 2- (3-phenoxyphenyl) propionic acid A. 5-Phenoxyaceto-phenone. A mixture consisting of 908 g (6.68 mole) of m-hydroxyacetophenone, 4500 g (28.6 mole) of bromobenzene, 996 g (7.2 mole) of anhydrous potassium carbonate © g 300 g of copper bronze was heated at reflux until the formation of water was complete, below use of a Dean-Stark water separator. The mixture was stirred and heated under reflux for 24 hours. After cooling to room temperature, the reaction mixture was diluted with an equal volume of chloroform and filtered. The filtrate was washed with 5% hydrochloric acid and then with 5% sodium hydroxide and water, dried over sodium sulfate and evaporated in vacuo. The oily residue was distilled through a 15 cm Tigreux column to give 918 g of 3-phenoxyacetophenone, m.p. 120-121 ° C (0.09 mm), ηψ = »1.5868.

Analysis calculated for 79.22; H, 5.70;

Found: C, 79.39; H, 5.79.

B, g-Methyl-3-nhenoxybenzyl alcohol

A stirred solution of 700 g of m-pheuoxyyaetophenone in 3000 ml of anhydrous methanol was cooled to 0 ° C on an ice-acetone bath. 136 g (3.6 moles) of sodium borohydride were added in small portions to the solution at such a rate that the temperature did not rise above 10 ° C. After the borohydride addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. Then it was heated under reflux and stirring for 8 hours. There were distilled approx. 400 ml of methanol and the remaining solution evaporated to ea. one third of the original volume in vacuo and poured into ice water. This mixture was extracted twice with ether, acidified with 6N hydrochloric acid and extracted again with either. The ether extracts were mixed, washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was distilled through a 15 cm Vigreux column to give 666 g of α-methyl-3-phenoxybenzyl alcohol, b.p. 132-134 ° C. (0.35 mm) njp = 1.5809.

Analysis calculated for c »78.48; 6,5, 6.59;

Pound: C, 78.75; H, 6.31.

0. g-Me thyl-5-phenoxybenzyl bromide

A stirred solution of 1357 g of α-thyme 1-3-phenoxybenzyla Ikoho 1 in 5000 ml of anhydrous CCl 2 (dried over a molecular sieve) was cooled to 0 ° C. To this was added 1760 g of PBr 2, and the stirring and cooling

D Q

was maintained so that the temperature remained at 0-5 0 during the addition. The reaction mixture was then allowed to warm to room temperature and stirred overnight (about 12 hours). The reaction mixture was then poured into ice water and the organic phase separated. Pure aqueous phase was extracted with 001 and the combined extracts were washed 3 times with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 1702 g of α-methyl-3-phenoxybenzyl bromide as a heavy viscous oil, n 5 = 1.5393;

Analysis calculated for C C ^H BrO Br BrO: 0.60.44; H, 4.71; Br, '28, 73;

Pound: - 0, 60.62; H, 4.89; Br, 28.47.

D. 2- (5-Phenoxyphenyl) prorionitrile

A vigorously stirred suspension of 316 g of 98 µl sodium cyanide in 5000 ml of anhydrous dimethyl sulfoxide (dried over a molecular sieve) was heated to 50-60 ° G and maintained at this temperature while 1702 g of α-methyl-3-phenoxybenzyl bromide was slowly added. After the bromide addition was complete, the temperature was raised to 75 ° C and the mixture was stirred at this temperature for 1.5 hours. The mixture was allowed to cool to room temperature and stirred overnight at room temperature, then poured into ice water.

Pure resulting aqueous suspension was extracted twice with ethyl acetate and then with ether. Pure organic extract was washed twice with a sodium chloride solution and once with water, and then dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo left an oily residue which was distilled through a 15 cm Tigreux column to give 1136 g of 2- (3-pbenoxyphenyl) propionitrile, bp, 141-148 ° C (0.1 17 145778 mm), ujjp = 1.5678.

Analysis calculated for G 2 E 2 W: 0.80.69; H, 5.87; H, 6.27?

Pound: 0, 80.89 H, 6.10; I, 6.14.

S. 2- (3-Phenoxyphenyl) propionic acid

A mixture of 223 g of 2- (3-phenoxyphenyl) propionitrile and 400 g of sodium hydroxide in 1600 ml of 50 $ 6 ethanol was heated under reflux and stirring for 72 hours. After cooling to room temperature, the reaction mixture was poured into ice water. A resulting solution was washed with ether, acidified with concentrated HCl and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. An oily residue was distilled to give 203.5 g (84 1 °) of 2- (3-phenoxyphenyl) propionic acid as a viscous oil, bp, 168-171 ° C, (0.11 mm), n , 5742, pK'a = 7.3.

For C-forH H ^O O: C, 74.36: H, 5.83;

Pound: C, 74 »48; H, 6.05.

EXAMPLE 11 2- (3-Phenoxyphenyl) propionic acid, sodium salt. dihydrate 6460 g of 2- (3-Phenoxyphenyl) propionic acid was converted to the sodium salt by portion addition to 26.7 moles of 2SF sodium hydroxide with stirring and cooling. Aqueous solutions were evaporated to near dryness in vacuo. One half-dry residue was stirred with ethyl acetate and evaporated again in vacuo. One white solid residue was dissolved in the smallest amount of boiling ethyl acetate, filtered into a large vessel (about 18 liters) and left overnight at 7 ° C. A resulting crystalline mass was filtered and dried in vacuo at room temperature to give 6954 g of pure sodium 2- (3-phenoxyphenyl) propionate, dihydrate, m.p. 76-78 ° C.

Analysis calculated for: C, 59.99? H, 5.70?

Pound: 0, 59.93; H, 5.97.

EXAMPLE 12 2- (5-Phenoxyphenyl ·) nitro-pionamide

A solution of 0.5 µl of 2- (3-pbeuoxyphenyl) propionyl chloride in 300 ml of dry ethyl ether was added dropwise to 2 liters of liquid ammonia with stirring. After the addition was complete, the reaction mixture was stirred for 1 hour and 500 ml of diethyl ether was added.

The reaction mixture was allowed to stand overnight, thereby evaporating excess ammonia. Dilute hydrochloric acid was added to the reaction mixture and the ether layer was separated, washed with sodium hydroxide and water and dried over sodium sulfate. Evaporation of the ether in vacuo left a gummy residue which crystallized after trituration with cold hexane. Recrystallization from ethyl acetate and hexane gave 76.2 g of 2- (3-phenoxyphenyl) propionamide, m.p. 67-69 ° 0.

Analysis calculated for: C, 74.66: Ξ, 6.27; E, 5.81;

Pound: C, 74.01; H, 6.50; E, 6.15.

EXAMPLE 15

II, IT-Dime thy 1-2 - (5-nhenoxyphenyl) oropionamide

To 400 ml of dry chloroform were added 72.6 g of 2- (3-phenoxyphenyl) propionic acid and 56.9 g of thionyl chloride. The reaction mixture was heated under reflux and stirring for ca. 5 hours. The chloroform was then evaporated and the residue was subjected twice to azeotropic distillation with benzene. The residue was dissolved in ethyl ether and added with stirring and cooling to a solution of 45 g of dimethylamine in ethyl ether. The temperature was kept at approx.

0 ° 0 or below during the addition. The reaction mixture was allowed to warm to room temperature, then gently heated under reflux for 1.5 hours, poured into ice and water and acidified and the ethyl ether layer separated. The aqueous layer was extracted with ethyl ether. The ether extracts were combined, washed with water, dried over sodium sulfate and evaporated to a white solid. The solid was dissolved in boiling hexane and allowed to cool to room temperature to give 67.6 g of IT, lt-dimethyl-2- (5-phenoxyphenyl) propionamide, m.p.

73.5-76 ° C.

19 145778

Analysis calculated for c17 H19 NO2: C, 75.80; H, 7.11; N, 5.20;

Found: C, 75.93; H, 6.90; N, 5.27.

EXAMPLES 14-15

The following compounds were prepared analogously to the method of Example 13 from appropriate starting materials.

N-Methyl-2- (3-phenoxyphenyl) butyramide, m.p. 84 - 86 ° C.

Analysis calculated. for C ^H ^ NCN₂O: C, 75.81; H, 7.11; N, 5.20.

Found: C, 75.60; H, 7.11; N, 5.00.

N-Methyl-2- (3-phenoxyphenyl) propionamide, m.p. 57 - 58 ° C.

Analysis calculated. for c15 H17 NO2: c '75.27; H, 6.71; N, 5.49.

Found: C, 75.51; H, 6.86; N, 5.61.

EXAMPLE 16

Cleavage of dl-2- (3-phenoxyphenyl) propionic acid 200 g of dl-2- (3-phenoxyphenyl) propionic acid prepared as in Example 10 was dissolved in 3000 ml of hot ethyl acetate and 100 g of d - (+) - ^ - methyl-benzylamine. was added to the solution. A crystalline mass is separated by cooling. This was filtered to give 229 g of dl-2- (3-phenoxyphenyl) propionic acid, d- (+) - α-methylbenzylamine salt, m.p. 115-126 ° C. 5 successive recrystallizations from hot ethyl acetate gave 63.5 g of d - [+) - 2- (3-phenoxyphenyl) propionic acid, d - (+) - α-methyl-benzylamine salt, m.p. 142-144 ° C, + 14.5 ° (C = 1 $, OHOl +), ZT + + 5.74 (C = ltf, CH 3 OH).

Analysis. Ber. for C ^H ^ NONO:: C, 76.00; H, 6.93; Η »3.85 ·

Pound: C, 75.72; H, 6.80; N, 3.63- Similarly, 1 - (-) - 2- (3-phenoxyphenyl) propionic acid, 1- (~) -α-methylbenzylamine salt, m.p. 141-142 ° C - 3.63 (C = 1 / o, CH 3 OH).

52 g of d - (+) - 2- (3-phenoxyphenyl) propionic acid, d- (+) - α-methylbenzylamine salt were suspended between 1.5 L of K 2 O and 0.5 L of EtgO and acidified by addition. of 6R H01. The ether layer was washed with water, dried over ITagSO 4 and evaporated in vacuo to give d - (+) - 2- (3-phenoxyphenyl) propionic acid, + 46.0 (0 = 1 $, CHCl 3).

In a similar manner, 1 - (-) - 2- (3-phenoxyphenyl) propionic acid, δ - 45.7 (O = 1 $, OHOl , 1- (-) - α-methylbenzylamine salt.

EXAMPLE 17 2- (5-Phenoxyphenyl) butyric acid A. 2- (3- Phenoxyphenyl) butyr onit in 23 g of sodium was added to 4 liters of liquid ammonia in a 5-liter flask containing a catalytic amount of iron (III) chloride. The reaction mixture was stirred in ea. 30 minutes. To the resulting mixture was added 209 g of 2- (3-phenoxyphenyl) acetonitrile prepared as above under Scheme I. The reaction mixture was stirred for 30 minutes and 187.2 g of ethyl iodide was added with stirring. The reaction mixture was stirred overnight, evaporating the ammonia. Per anhydrous ethyl ether was added to the residue, and the mixture was acidified with 6R hydrochloric acid and stirred for approx. 1 hour. The reaction mixture was then extracted with ethyl ether. The ether layer was washed with water and sodium thiosulfate solution and the ether was evaporated.

Pen resulting oily residue was distilled to give 155.2 g of 2- (3-phenoxyphenyl) butyronitrile, b.p. 138-140 ° C / 0.14 mm.

B-145 g of the 2- (3-phenoxyphenyl) butyronitrile prepared above was hydrolyzed to the corresponding acid, following the procedure of Example 10E to give 95.9 g of 2- (3-phenoxyphenyl) butyric acid, m.p. 73-77 ° 0th

Analysis. Ber. for O ^ H ^ O ^: 0, 74.98; H, 6.29

Pound: C, 74.70; H, 6.33 · 21 EXAMPLE 18

Ethyl 2- (5-phenoxyphenyl) propionate 200 g of 2- (3-phenoxyphenyl) propionic acid, prepared as in Example 10, was dissolved in 1500 ml of ethanol and hydrogen oxide of gas was poured into the ethanolic solution until saturated. The reaction mixture was then heated under reflux and stirring overnight, after which a large part of the ethanol was evaporated in vacuo and the remaining reaction mixture was poured into ice water. The mixture was basified with 10 $ sodium hydroxide and extracted twice with ethyl ether. The combined ether extracts were washed twice with water and dried over sodium sulfate. The ethyl ether was evaporated leaving crude ethyl 2- (3-phenoxyphenyl) propionate as an oily residue. The preparation was repeated with an additional 200 g of 2- (3-phenoxy-phenyl) propionic acid. The crude residues were combined and distilled through a 15 cm Vigreux column to give 339.9 g of ethyl 2- (3-phenoxyphenyl) propionate, b.p. 128-134 ° 0 / 0.15 mm, = 1.5458.

Analysis. Ber. for C17H1803: 0.75.53i H, 6.71.

Found: C, 75.75} H, 6.70.

EXAMPLE 19 3- (5-Phenoxyphenyl) Butyric Acid A. Ethyl 3- (3-Phenoxyphenyl) Crotonate 224 g of triethylphosphonoacetate was slowly added to 48 g of 50 percent sodium hydride dispersion suspended in 500 ml of dimethoxyethane relieving stirring. 212 g of m-phenoxyacetophenone dissolved in 1500 ml of dimethoxyethane were added dropwise and stirred for 1 hour. The reaction mixture was then heated at reflux overnight, cooled to room temperature and decomposed by adding water. After evaporation of the solvent in vacuo, the crude product was dissolved in ethyl acetate, washed twice with water and dried over sodium sulfate. Evaporation of the ethyl acetate left an oily residue which was distilled to give 52.6 g of ethyl 3- (3-phenoxyphenyl) crotonate, b.p., 163-170 ° C / 0.2 mm, τι2 = 1.5770.

Ethyl 3- (3-phenoxyphenyl) butyrate 197 g of the above-prepared ethyl 3- (3-phenoxyphenyl) crotonate dissolved in 400 ml of ethanol was hydrogenated in the presence of platinum oxide. The ethanol was evaporated in vacuo leaving an oily residue which was distilled to give 160 g of ethyl 3- (3-phenoxyphenyl) butyrate, k, p. , 137-139 ° C / 0.06 mm, n ^ 5 = 1.5401.

C. 3- (5-phenoxyphenyl) butyric acid 160 g of the above-prepared ethyl 3- (3-phenoxyphenyl) butyrate was hydrolyzed as in Example 10E to give 117.2 g of 3- (3-phenoxyphenyl) butyric acid. k, P. f 193-195 ° C / 0.23 mm, nD25 = 1.5687, pK'a = 7.2. Analysis, Ber. for C16 H15 Cl2 C * 74.98; H, 6.29

Found: C, 75 »18; H 6.41 Example 20

Preparation of 2- (3-phenoxyphenyl) propionic acid by decarboxylation of a dicarboxylic acid A. Preparation of ethyl 2- (3-phenoxyphenyl) acetate.

Dry HCl gas is bubbled through a solution of 257 g of 3-phenoxyphenylacetic acid, prepared as in Example 1, in 1500 ml of ethanol until saturation. The mixture was heated under reflux and stirring for 3 hours and then saturated with HCl gas again. It was refluxed overnight. After cooling, the mixture was partially evaporated in vacuo and poured into ice water. The oily product was extracted into ether and the ether solution was washed with water and a 5% sodium bicarbonate solution and dried over sodium sulfate. Evaporation of the ether in vacuo and distillation of the oily residue yielded 256 g of ethyl 2- (3-phenoxyphenyl) acetate at boiling point 140-146 ° C (10.1 mm). N§ 5.5 = 1.5520.

Analysis calculated for C-y-yO ^: C, 74.98; H, 6.29

Found: C, 75.16; H 6.21 B. Preparation of diethyl-2-methyl-2- (3-phenoxyphenyl) malonate.

A mixture of 128 g of ethyl 2- (3-phenoxyphenyl) acetate and 300 ml of diethyl carbonate was stirred and heated to about 110 ° C, while 11.5 g of metallic sodium in pea-sized chunks was added over 90 minutes. Some ethanol and diethyl carbonate distilled away during the addition of sodium. After complete addition of sodium, the reaction temperature was increased until the vapor temperature reached 130 ° C. The mixture was cooled to 15 ° C in an ice bath and 60 ml of methyl iodide was added dropwise over 15 minutes. The mixture was heated to 80 ° C for one hour. After cooling, a small amount of water was added and the mixture was poured into ice water, acidified with HCl and extracted with ether. The ether extract was dried over sodium sulfate and evaporated in vacuo. The remaining liquid was distilled through a 15 cm Vigreux column to give 100.2 g of diethyl-2-methyl-2 (3-phenoxyphenyl) malonate at boiling point 155-175 ° C (10.1 mm); Ng3'5 = l, 5337th

Analysis calculated for ^ 20 ^ 22 ^ 5; c, 70.16; H, 6.48

Found; C, 70.40; H, 6.27.

C. Preparation of 2-methyl-2- (3-phenoxyphenyl) malonic acid.

A solution of 57 g of diethyl-2-methyl-2- (3-phenoxyphenyl) malonate and 40 g of sodium hydroxide in 300 ml of 50% (v / v) aqueous ethanol was stirred and heated under reflux overnight. The mixture was poured into ice water and washed with ether to remove non-hydrolyzed ester. The aqueous phase was acidified with concentrated HCl and extracted with ether. The ether extract was dried over sodium sulfate and evaporated in vacuo to give 44 g of 2-methyl-2- (3-phenoxyphenyl) malonic acid. Melting point: 138-143 ° C (decomposition during gas evolution).

Analysis calculated for C C CHHO O: C, 67.13; H, 4.93

Found: C, 67.37; H, 5.23.

D. Preparation of 2- (3-phenoxyphenyl) propionic acid.

15 g of 2-methyl-2- (3-phenoxyphenyl) malonic acid were heated to 130-160 ° C and stirred until the violent (ling evolution ceased. After cooling to room temperature, 12.2 g of 2- (3-phenoxyphenyl) was obtained). propionic acid having an NMR spectrum identical to the spectrum of the compound prepared in Example 10E N = 1.5729.

Analysis calculated for C, 74.36; H, 5.82

Found: C, 74.07; H, 5.81.

24 145778

The present compounds may be used to prepare pharmaceutical agents in known manner. At least one of the compounds of this invention is used in combination with a suitable carrier or diluent. The compounds exhibit both oral and parenteral action and may be formulated appropriately for oral, parenteral, rectal or topical administration.

A number of the compounds of this invention have been tested for anti-inflammatory action in an erythema-blocking test as follows:

A method is used which is a modification of that of C.V.Winder et al. described method (CV Winder, V. Burr and C. Posiere; "A Study and Pharmacological Influences on Ultraviolet Erythrea in Guinea Pigs", Arch. Int. Pharmacodyn., 116, 261, 1958). This method uses guinea pigs (albinos) by Both sexes weigh 2.25-300 g. The guinea pigs are shaved on the back and chemically distilled (NAIR Lotion Hair Remover, Carter Products, NY, NY) After 18 to 20 hours, the animals are exposed to ultraviolet radiation after fasting overnight. Immediately after the treatment with one of the compounds of the present invention, a protective piece of adhesive paper is applied to the animals' backs and then exposed to high-intensity ultraviolet radiation for 7 seconds, and the ultraviolet light source is placed in contact with the skin on the backs of the animals. paper, and the guinea pigs' back is cleaned with a gauze tampon dipped in water. hema. The animals are placed in transparent plastic holders. After 60, 90, 120 and 150 minutes, the degree of the resulting erythema is judged by an arbitrary point system based on the degree of contrast and redness formed. Anti-inflammatory agents delay the development of erythema and therefore have the greatest effect on initial assessments. Therefore, the judgments are weighed by a factor of 4, 3, 2 and 1 when judged after 60, 90, 120 and 150 minutes respectively. The erythema formed is evaluated as follows:

Erythema Assessment System Assessment Appearance of treated area 0 No redness and no contrast 1 Light redness with slight outline of the protective paper 2 Light to moderate redness with clear outline 3 Distinct redness with clear circular outline

The total assessment from each group of treated animals (5 or 6 guinea pigs in each group) was compared to a control group and the percentage inhibition calculated according to the following formula: 100 x Control - Treated. prooent lnhlberlng control

The test compounds are prepared in a suspension of 1% methyl cellulose in water and administered orally. Guinea pigs are treated orally with 1 ml suspension per. kg body weight. Control animals are treated with 1 ml per day. kg. body weight of a 1% suspension of methyl cellulose. The dosage in mg per kg, which causes a 50% inhibition of the erythemic response (ED ED q) is listed in the following Table I for a number of the compounds concerned:

TABLE I

26 145778 "Y r_ Z Erythema block insertion Y1 2 1 Oral ED50 _ (mg. Bandage per kg body weight)

TV! > \ - / ch-z Y2 ~ Η H CH ^ COONa 0.9 Η H CH ^ COOCa 1.0 0 Η H CH3 -CNH2 3 0 Η H CH3 -CNHCH3 30 0 Η H CH3 -CN (CH3) 2 25 0 Η H CH 3 -CNHOH 2

ISLAND

Η H CH3 -CNHCH2C00H 5

Aspirin 50 p-phenoxyphenylacetic acid (U.S. Patent No. 3,385,886) 29 2-p-Phenoxypropionic Acid n (U.S. Patent No. 3,385,886)

The sodium salt of 2- (4-phenoxyphenyl) propionic acid (Compound A) and the sodium salt of dl-2- (3-phenoxyphenyl) propionic acid (Compound B) were examined for the effect on the acid secretion and gastric mucosal learning of pylorus-laced rats; see e.g.

H. Shay et. al., "A Simple Method for the Production of Gastric Ulceration in the Rat", Gastroenterology 5, 43-61 (1945) and T. Lin et. al., "3-β-Aminoethyl-1,2,4-triazole, A potent Stimulant of Gastric Secretion", J. Pharmacol, and Exp. Therapy 154, 88-94 (1961).

27 145778

The above compounds were tested on male Harlan rats weighing 150 g. After fasting for 48 hours, the rats had their abdomen cut along the middle and the pylorus was laced - under light ether anesthesia. The compounds were administered orally at doses of 5 »10 and 25 mg / kg to 10 rats for each dose immediately after surgery. Each animal was sacrificed 3 hours after administration of the drug.

Stomach contents were sampled and analyzed for volume and total acidity (up to pH 7), and the stomachs were immediately examined for lesions and ulcerations.

Wound formation was assessed according to an arbitrary point system that takes into account the following characteristics: 1. size and number of wounds 2. degree of degradation 3. bleeding and edema 4. percentage of rats with wounds and the like.

The points awarded for treated rats were compared with the allocated points for the control rats and the following results were obtained: 1. Impact on the acid secretion:

The percent changes in secretion (volume) over a period of 3 hours and the acid concentration in control animals and treated animals are shown in Table II:

TABLE II

dose Number of rats bandaged. conn.

(mg / kg P.O.) per group A B

5 10 + 9% - 9%) 10 10 -15% -20% r volume 25 10 0% 1%) 5 10 - 5% - 5%) acid 10 10 - 6% -15 concentration 25 10 - 3 % -7% J tration 28 145778 2. Impact on the lining of the gastric mucosa.

TABLE III

dose Number of rats compound A compound B

(mg / kg P.O.) per group points% change points% change 5 10 9.41 + 6.7 8.56 - 2.9 10 10 12.46 +41.2 8.18 - 7.3 25 10 15.01 +70.1 6, 93 -21.5 control 10 8.82 8.82

Finally, comparisons were made between meta-pbenoxyphenyl-1-alkanoic acids and the corresponding para compounds, these acids being pairwise examined by the method described above for the evaluation of erythema induced by ultraviolet radiation. Table IV lists the compounds studied and the results obtained are shown in Table V.

TABLE IV

29 145778

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CH = COOH CH

70391 PARA Propionic acid C-H-COOH

~ CH3 53488 META Acetic Acid

'== TH2C00H

33656 PARA Acetic Acid _CHgCOOH

69II5 META Butyric acid

^ CH-COOH

_ ^ CH2-CH3

62792 PARA Butyric Acid ft \ ~ Often y — CH-CQOH

ch2-ch3 69353 META Valerian Acid ft \

'^' CH-COOH

CH2-CH2-CH3

62813 PARA Valeric Acid ft \ W) - // ^ _CH-COOH

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Claims (1)

32 145778 Analogous Process for Preparation of 3-Phenoxyphenylalkanoic Acid Derivatives of the General Formula Y 2 Y1 - (σιΛ "ζ (« wherein: Y "* · represents hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C represents hydrogen, halogen, methyl or ethyl, Y being hydrogen if Y 1 is alkoxy, R * is hydrogen or C 1 -C 6 alkyl, n is 0 or 1, and Z is: 2 2 ( a) -COOR wherein R represents hydrogen, C 1 -C 4 alkyl or an alkali metal or alkaline earth metal, or (b) R 3 -COH 2 X 3 wherein each R is the same or different and represents hydrogen, hydroxy, methyl or -CH COOH, in racemic or in d or 1 form, characterized in that for the preparation of compounds wherein Z is -COOH, (a) hydrolyzes a nitrile of the formula: R 1 in Ar-CH- (CH 2) n-CN Wherein R1 and n have the meaning given above, while Ar here and hereinafter represents the group Y2 γ! J-, (b) decarboxylates a dicarboxylic acid of the formula: Ar - C (C00H) · Has it on top for specified meaning, for the preparation of a compound in which n is 0; (c.) heats a ketone of the formula: 0 n Ar-C- (CH 2) n-CH 3 with sulfur and morpholine, and hydrolyzes the resulting thioamide to produce a compound wherein R 1 is hydrogen, or (d) converts an aldehyde or a ketone of the formula: Ar-C = O in R 1 wherein R 1 is as defined above, with triethyl phosphone acetate, catalytically hydrogenates the product thus formed and hydrolyzes the resulting ester to the corresponding acid wherein n is 1,