DE1941625B2 - Substituted phenyl alkanoic acids - Google Patents

Description

- C

R ₅

e) —N

wherein R ₅ and R _{6 represent} methyl groups or R _{5 represents} a hydrogen atom and R _{6 represents} a hydrogen atom, a methyl group, a cyclopropylmethyl group or a cyclopropyl group or R _{5 represents} a methyl group and R _{6 represents} a cyclopropyl group or a cyclopropylmethyl group,

mean.

2. Therapeutic preparation, characterized by a content of a compound according to Claim 1 in addition to a pharmaceutically acceptable carrier.

- (CH ₂ ), - Z

0)

and the pharmaceutically acceptable acid addition salts of the basic compounds thereof Group in which

Yi represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group;

a hydrogen atom, a methyl group or an ethyl group;

the numbers 0 or 1 and

the group

a) -COOR ₂ , in which R _{2 represents} a hydrogen atom, a methyl group, an ethyl group or an alkali-alkaline earth or ammonium cation;

10

The invention relates to substituted phenylalkanoic acids of the general formula

R ₁

CH- (CHj) _n -Z

and the pharmaceutically acceptable acid addition salts of the basic compounds of this group, wherein

Yi represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group;
Ri is a hydrogen atom or a methyl or

Ethyl group;
η the number O or 1 and
Z the group

a) -COOR ₂ , in which R _{2 represents} a hydrogen atom, a methyl or ethyl group or an alkali, alkaline earth or ammonium cation;

25th

30th

35

wherein R and R _{3 represent} methyl groups or R represents a hydrogen atom and R3 represents a hydrogen atom, a hydroxyl group, a methyl group, a cyclopropylmethyl group or a group of the formula -CH ₂ COOH; c) - OR4, in which R4 is a hydrogen atom, an acetyl group, a propionyl group or an N-methylcarbamyl group, where η denotes the number 1;

45

or also in the case that η stands for the number 1

55

60

65

b) —CON

wherein R and R _{3 are} methyl groups, or R is hydrogen and R _{3 is} a hydrogen atom, a hydroxy or a methyl group, a cyclopropylmethyl group; or represent a group of the formula -CH ₂ COOH;

c) - OR4, in which R4 is a hydrogen atom, an acetyl group, propionyl group or N-methylcarbamyl group, where η denotes the number 1;

d) N N

- C

N
H

or in the event that η stands for the number 1, also e) the group

R ₅

—N

R ₆

wherein R ₅ and R _{6 represent} methyl groups or R _{5 represents} a hydrogen atom and R _{6 represents} a hydrogen atom, a methyl, cyclopropylmethyl or a cyclopropyl group or R _{5 represents} a methyl group and R _{6 represents} a cyclopropyl group or a cyclopropylmethyl group,

mean.

Under alkali or alkaline earth cations, sodium, potassium, lithium, calcium, magnesium or Understood barium cations. The term acid addition salts refers to salts that are produced by reaction of the free amine with an organic or inorganic acid. To such salts include, for example, the hydrochlorides, hydrobromides, sulfates, bisulfates, acetates, valerates, oleates, Laurates, borates, benzoates, lactates, phosphates, tosylates, citrates, maleates, fumarates, succinates, tartrates and Napsylates (salts of 2-naphthalene sulfonic acid).

The compounds of formula I are medicaments. In particular, they make excellent anti-inflammatory properties Agents, many of which have an ED50 of 0.2 to 1.0 mg / kg in the erythema inhibition test. 15th All of the compounds according to the invention are suitable for treating inflammation in mammals The acids and amines are preferred for this. They show their anti-inflammatory activity Compounds mild analgesic and antipyretic action. The subject matter of the invention also includes therapeutic preparations containing a compound of formula I as an active ingredient in conjunction with a pharmaceutically acceptable diluents or carriers. The connections will be on 25 Mammals in general in doses from 0.2 to the formula I.

50.0 mg / kg body weight daily either in a single dose or in multiple doses over one Administered over a period of 24 hours

Both the d- and the 1-isomers of formula 1 are covered by the definition according to the invention. For example, the alpha-alkyl acids can after known methods ir, their d- and 1-isomers broken down will. The d- and the 1-isomers are practically equally effective. To treat inflammation, Pain and fever in mammals can therefore be either the racemate or the d- and 1-isomers use.

The compounds of the formula I can be prepared by processes known per se. A row the preferred reaction sequences are described below. In the following explanation, the respective substituents as defined in formula I and Ar denotes the radical

-O

A. Acids

I. Ar-CH ₃

NaCN

NBS

Ar-CH ₂

Ar-CH ₂ -Br

-H ₂ O-

• CN

Ar-CH ₂ -COOH

The methyl group of a suitable methyl diaryl ether or diaryl thioether is activated by action of N-bromosuceinimide, N-chlorosuccionimide, sulfuryl chloride or similar halogenating agents in the presence of a catalyst, for example benzoyl peroxide, or azobisisobutyronitrile, in an inert solvent, for example carbon tetrachloride or another halogenated hydrocarbon, halogenated. The halomethyldiaryl ether obtained or thioether is reacted with sodium or potassium cyanide, advantageously in dimethyl sulfoxide solution. The nitrile obtained in this way is after the action of acidic or basic reagents known methods hydrolyzed to the corresponding carboxylic acid.

B. α-alkyl acids

na. Ar-CH ₂ -CN

NaNH ₂ ZNH ₃

Ar-CH-CN Ri H ₂ O

-> Ar-CH-COOH
R ₁

n _b . Ar-CH ₂ -COOH

R1X2

Ar-CH-COOH Ri

Dc. Ar-CH ₂ C

NHR ₃

NaNH ₂ / NH ₃ HH ₂ O

³ -> Ar - CH - C - NHR ₃ - ^ - > Ar - CH - COOH

R1X2

Ri Ri

lld. Ar-CH ₂ -COOC ₂ H ₅

-> Ar-CH (COOC ₂ Hs) ₂ -

R1X2

Ar-CH-COOH
Ri

Ar-C (COOC ₂ Hs) ₂

R ₁

H ₂ O Ar-C (COOH) ₂

R ₁

Hey Ar-CH ₂ -CN

(C ₂ H ₅ O) ₂ CO

Na COOC ₂ H ₅

R, COOC ₂ H ₅

Ar-CH

CN

NaOCjH ₅
R ₁ X ₂

H, 0

Ar

CN

COOH

/ Ar-C

l \

R, COOH

Ar-CH - COOH R ₁

St. Ar-CH ₂ -CN

HCOOC ₂ Hs

nIh

H, / Pd Ar-C-CN
CHOH

Ar-ClI-CN

I. CH,

0COCI

H ₂ O

Ar-C-CN

Il

CHOC —Φ

Il ο

Ar-CH-COOH CH ₃

I \ Ar — C-CH,

NaBHj OH

- Ar-CH-CH ₃

NaCN Ar-CH-CN

CH ₃

PBr,

H ₂ O

Br
Ar-CH-CH ₃

Ar-CH-COOH CH ₃

V. Ar-C-CH ₃

NaOCl - ♦ Ar - COOH

SOCl ₂

C ₂ H ₄ -N ₂ -> Ar-C - CHN ₂

1. ^ CH ₂ OH
Ag.

2. H ₂ O '

Ii

Ar- C-Cl Ar-CH-COOH

CH ₃

VI. Ar-C (CHj) _n CH ₃

S HN O

H ₂ O

Ar-CH ₂ - (CH ₂₎ "C

N 0

Ar-CH ₂ - (CH ₂₎ "COOH

Vila. Ar-OO

Close

VIIb. Ar-C = O
R ₁

KOt-Bu

Ar-CH-CH ₂ -COOH

Ri
H ₂ / Pt

Ri R ₁

Ar-CH- (CH ₂ ) "- C00H
R ₁

The nitrile prepared according to the above scheme can with an aliphatic halide or tosylate (R] X2) in liquid ammonia in the presence of Sodium amide can be alkylated to form an aliphatically substituted nitrile. The alkylated nitrile is like hydrolyzed above to the corresponding carboxylic acid (reaction sequence Ha). Similarly, a Aryl acetic acid or an arylacetamide are alkylated in the «position to the carboxyl group, as in the reaction sequence Hb to Hc is shown. In the case of the arylacetamide can, if desired, the «-alkyl derivative obtained for corresponding carboxylic acid are hydrolyzed.

Another method, which is illustrated by the reaction sequences Hd and He, can be one Aryl acetate esters, e.g. B. the ethyl ester, or an arylacetonitrile by the action of metallic sodium and diethyl carbonate in the corresponding malonic ester or transfer cyanoacetate. Any of these derivatives can then be alkylated. To carry out such an alkylation is usually the malonic ester or cyanoacetic ester with a strongly basic one Reagent, for example sodium ethoxide, sodium methoxide, Potassium tert-butoxide or sodium hydride, converted, whereby a carbanion is formed on the carbon atom intermediate carbanions with an alkylating agent, for example an alkyl halide or tosylate (R1X2), the corresponding a-alkylmalonic ester or -cyanacetic ester derivative obtained. Both can the corresponding α-alkylarylmalonic acid hydrolyzed are, which is then decarboxylated by known methods and so the Ä-alkylarylacetic acid supplies

Bn nitrile produced according to reaction sequence I can optionally be methylated according to the following procedure (reaction sequence ΙΠ): The nitrile is converted to BeiH ₃ O with ethyl formate under basic conditions

play in the presence of sodium hydride or sodium methoxide, condensed in an inert hydrocarbon solvent such as benzene. The received Hydroxymethylene derivative is made by the action of benzoic anhydride or benzoyl chloride and Benzoylated pyridine. The benzoic acid ester is then hydrogenated in the presence of a noble metal catalyst, whereby the α-methylarylacetonitrile is obtained, which is then hydrolyzed as above.

The a-methylarylacetonitrile can optionally on the following reaction path (reaction sequence IV) are produced: The aryloxyacetophenone (produced by a Ullman ether synthesis) is either with hydrogen in the presence of a noble metal catalyst or with a metal hydride, for example Lithium aluminum hydride or lithium or sodium borohydride, reduced to the corresponding alcohol The conversion of this alcohol into the corresponding one

so bromide can be obtained by treating the alcohol with phosphorus tribromide, preferably in an inert Solvent, for example chloroform, benzene or carbon tetrachloride, take place. The thus obtained Bromide is then mixed with sodium cyanide, advantageously in dimethyl sulfoxide solution, converted to a nitrile, which is hydrolyzed to the carboxylic acid as above.

Another method for the production of «-Alkylphenoxyphenylessigsäuren uses the Arndt-Eistert reaction, as reaction sequence V shows below Use of a phenoxybenzoic acid as a starting material.

The a-alkyl acids obtained in this way can according to known methods broken down into their d- and 1-isomers will.

The phenoxyphenyl alkanoic acids can also be prepared with the help of the Wilgerodt reaction (reaction sequence VT) getting produced. A phenoxyphenyl alkyl ketone is used for this purpose for example with morpholine and sulfur

heated and the thioamide obtained to the alkanoic acid derivative hydrolyzed by treatment with two equivalents of sodium amide in liquid ammonia and subsequent addition of the alkyl halide or tosylate (R1X2) alkylated according to reaction sequence Hb can be.

The acids according to the invention, in which η denotes the number 1, can by known methods with the aid

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the known Wittig reaction can be prepared, as the reaction sequences VIIa and VIIb show. the intermediate unsaturated esters (as in VIIa) or nitriles (as in VIIb) can in the presence of a Noble metal catalyst, for example platinum, are hydrogenated. The saturated esters and nitriles obtained can be hydrolyzed to the carboxylic acids as above.

Villa. Ar-CH- _(CH2) "COOH

VIlIb. Ar-CH- (CHj) _n COOH
R,

C. Esters
R ₂ OH / HC1

Ar-CH- (CH ₂ ) "COOR ₂
R,

SOCl,

Ar-CH-R,

- (CHj) _n COCl

R ₂ OH

Ar-CH- (CHj) _n COOR ₂

R ₁

The carboxylic acids according to the above by converting the acid into the corresponding indicated reaction sequences shown methods acid chloride and subsequent conversion of acid maintenance are, according to known methods, rechlorids with an alcohol, preferably in return Example by heating the acid with a 30 wart of a hydrogen chloride acceptor (VIlIb), in the Converted alcohol in the presence of a mineral acid (Villa) or corresponding ester.

IX. Ar-CH-

R ₁

- (CH ₂ ), - C

Cl

RR ₃ NH

D. amides

-> Ar-CH- Ri

- (CH ₂ J _n -C

R ₃

The amides according to the invention are converted by carbon tetrachloride or carbon tetrachloride, in the presence of an acid

tion of the above acid chlorides with an amine acceptor, for example pyridine or H ₂ CO3, or in

obtain. This reaction is usually carried out in a tertiary amine solvent, for example

inert solvents, for example chloroform, benzene, collidine, lutidine or triethylamine, carried out.

X. Ar-CH-COOR ₂
R.

LiAlH ₄

E. Alcohols
Ar-CH-CH ₂ OH

The esters, the preparation of which has been explained above, can by known methods with a metal hydride, for example lithium aluminum hydride, can be reduced to the corresponding alcohols.

F. Ester

XIb. Ar-CH-CH ₂ -OH

Ri

Ac ₂ O

Ar-CH-CH ₂ OC-CH ₃
Ri

The alcohols obtained by reaction sequence X 65 tertiary amine such as pyridine or triethylamine in

can be converted by known methods, for example by ester derivatives. By using

Treatment of the alcohol with an acid chloride or acetic anhydride for such a reaction will

Acid anhydride, preferably obtained in the presence of, for example, the acetic acid ester.

11 12

G. Carbamates

XIc. Ar-CH-CH ₂ -OH - _{Ar CH} _ _ _ _c _ _{CH2O NHCHj}

I I

R, Ri

From the alcohols Ν, Ν-Dimethylcarbamoylchlond obtained according to reaction sequence X. These reactions are

Carbamate derivatives can also be prepared, preferably in a tertiary amine, for example

either by reacting the alcohol with an io pyridine or triethylamine, carried out as a solvent

isocyanate or by reacting the alcohol,

H. Amines

O O

XIIa. Ar— CH- C ' Ar— CH- C '

I \ I \

R, Cl R, NR ₅ R ₆

LiAlH ₄

Ar-CH-CH ₂ -N

I \

K] K ₆

XIIb. Ar-CH-CN Ar-CH-CH ₂ -NH ₂

Ri R,
XHc. _Ar _ _{c == 0> Ar} __C = CH - NO ₂ ► Ar-CH-CH ₂ -NH ₂

R, R, R.

The amine derivatives according to the invention can be (reaction sequence XIIb).

known methods can be prepared, for example · »» Where appropriate, a suitably substituted

be condensed by reducing an amide with a metal hydride aryl alkyl ketone with nitromethane,

reagent such as lithium aluminum hydride (reaction sequence The nitrostyrene derivative obtained can then

XIIa). If primary amines are desired, either catalytic or with a metal hydride reaction

this simply by hydrogenating the appropriate gens such as lithium aluminum hydride to the amine

Nitriles are reduced in the presence of ammonia and an active -r> (reaction sequence XIIc).
Catalyst, for example Raney nickel prepared

I. hydroxamic acids

XIV. Ar — CH— (CH ₂ ), —COOR ₂ > Ar — CH— (CH,) - C

I I * \

R ₁ R, NH-OH

The esters obtainable by the reaction sequences Villa and VIIIb can be converted in a known manner by reaction be converted into hydroxamic acids with hydroxylamine.

K. Tetrazoles

N N

NaN ₃ Il Il

XV. Ar - CH (CH ₂ ), - CN> Ar - _{CH - (CH 2} ) n - CN

R, R ₁ N

Nitriles which are converted by the methods of reaction sequences I, for example by reaction Ila, III or IV or other known methods with sodium azide using dimethylform are, can be used in the corresponding tetrazole amide as a reaction solvent (according to the procedure

by Finnigan, W. G, Henry, R. A-, and Lofquist, R, J. Am. Chem. Soc, 80, 3908 [1958J.

The starting materials for the reactions described above can easily be obtained by a Uilman diaryl ether synthesis as described by Bacon and Steward, J. Am. Chem. Soc, 87, 4953 (1965) and is shown in the following equation:

Ar ¹ -OH + Ar "X

Ar ¹ -O -Ar "

where Ar 'is an unsubstituted phenyl radical and Ar "is the substituted phenyl radical

from the general formula I.

The invention is further illustrated by the following examples.

example 1
Production of 2- (3-phenoxyphenyl) acetic acid

26 ml of morpholine are mixed with 42.4 g of m-phenoxyacetophenone and 9.6 g of sulfur. The reaction mixture is kept at reflux temperature with stirring for 20 hours. Then become the reaction mixture 700 ml of 15% aqueous potassium hydroxide solution and a small amount of ethyl alcohol were added. That The reaction mixture is kept at reflux temperature for a further 20 hours with stirring. It will about 200 ml of the solvent is distilled off. The remaining reaction mixture is filtered hot, with Ice partially cooled and acidified with concentrated hydrochloric acid, resulting in an oily precipitate forms and then crystallizes. The crystalline precipitate is filtered off, several times with water washed and dried to give 45.9 g of crude product as a yellow-orange solid. That The crude product is suspended in boiling hexane and ethyl acetate is added until the product dissolves. The solution is treated with charcoal, filtered and cooled. There are 22.7 g of white flakes 2- (3-Phenoxyphenyl) acetic acid with a melting point of 84 to 86 ° C. pK'a = 6.9.

Analysis:

for C ₁₄ Hi ₂ O ₃ : C, 73.66; H 5.30;
Found: C, 73.85; H 5.35.

Examples 2 - 5

Following the procedure of Example 1, the following compounds were prepared from the corresponding compounds Phenoxyacetophenones made using appropriate amounts of sulfur and morpholine.

2- (4-methyl-3-phenoxyphenyl) acetic acid,
M.p. 49 to 51 ° C; pK'a = 7.0,
from 4-methyl-3-phenoxyacetophenone.
Analysis:

for Ci ₅ HmO ₃ : C 74.36; H 5.83;

Found: C 74.45; H 5.88.

2- (4-methoxy-3-phenoxyphenyl) acetic acid,
F. 85 to 87.5 ° C; pK'a = 6.9,
from 4-methoxy-3-phenoxyacetophenone.

Analysis:

for Q ₅ H ₁₄ O ₄ : C, 69.75; H 5.46; Found: C, 69.47; H 530.

2- (2-Methoxy-5-phenoxyphenyl) acetic acid, mp 90 to 94 ° C; pK'a = 7.4,
from 2-methoxy-5-phenoxyacetophenone. Analysis:

for C ₅ H ₁₄ O ₄ : C, 69.75; H 5.46;

Found: C, 69.58; H 5.61.

2- (2-methyl-5-phenoxyphenyl) acetic acid, boiling point 153 to 163 ° C / 0.16 mm; pK'a = 6.9, from 2-methyl-5-phenoxyacetophenone. Analysis:

for C ₁₅ H ₁₄ O ₃ : C 74.36; H 5.83;

Found: C 72.08; H 5.82.

Example 6 2- (4-chloro-3-phenoxyphenyl) acetic acid

1200 ml of carbon tetrachloride are mixed with 232.7 g of 3-phenoxy-4-chlorotoluene, 196 g of N-bromosuccinimide and 1.0 g of benzoyl peroxide are added. The reaction mixture is stirred at the reflux temperature for 24 hours and then filtered. The solids are washed with carbon tetrachloride. That The filtrate is evaporated to an oil. By distillation, fractions A, B and C become crude 4-chloro-3-phenoxybenzyl bromide was obtained.

fraction

Sdp.
(mm)

Weight (g)

A 140 to 150 (0.08) 118.5 g 1.5960

B 145 to 153 (0.07) 190.6 g 1.6152

C 145 to 160 (0.07) 79.4 g 1.6250

Fractions B and C are combined and analyzed.

Analysis:

for Ci ₃ H ₁₀ BrClO: C, 52.46; H 3.38; Found: C, 52.25; H 3.44.

The combined fractions B and C are distilled again in a Vigreux column, creating fractions A, B, C, D and E can be obtained.

fraction Sdp. 145 (0.09) Weight: i " (mm) 155 (0.09) (G) A. 105 to 136 (0.07) 24.2 , 5951 B. 145 to 135 (0.07) 29.6 , 6114 C. 130 to 149 (0.06) 79.4 , 6228 D. 128 to 52.9 , 6218 E. 136 to 29.8 , 6274

NMR studies show that fractions C and D 91 or 92% of 4-chloro-3-phenoxyphenyl bromide contain.

In about 400 ml of dimethyl sulfoxide, 22.2 g of 95% sodium cyanide are dissolved, and the reaction mixture is heated to about 50 ° C. 125 g of the crude 4-chloro-3-phenoxybenzyl bromide are then added dropwise with stirring added. The temperature will

19 4!

Maintained between 50 and 60 ° C. during the addition of bromide. Immediately after adding the bromide creates a red color. After the addition of the bromide has ended, the reaction mixture is heated to 60.degree and stirred for 3 hours. The mixture is then cooled to room temperature and stirred overnight, then poured onto ice and extracted with ethyl ether and then with hexane. The extracts are with Washed with water and dried over sodium sulfate. The solvents are evaporated, leaving a Reddish brown viscous oil is obtained. Distillation of the oil provides fractions A, B and C of 2- (4-chloro-3-phenoxyphenyl) acetonitrile.

Sdp.
(mm)

Weight n "
(G)

A 0.4 (170) to 0.15 (170) 51.6 1.5916

B 163 to 174 (0.08) 16.3 1.5917

C 174 to 190 (0.10) 2.2 1.5917

Analysis:

Ber. for ChH ₁₀ CINO: C 68.99; H 4.13; N 5.74;
Found: C, 68.72; H 4.20; N 5.50.

The corresponding 2- (4-chloro-3-phenoxyphenyl) acetic acid is obtained by acid hydrolysis of the nitrus. For this purpose, 50.9 g of the nitrile are added to 500 ml of concentrated hydrochloric acid. The reaction mixture is heated to 85 ° C. for 24 hours while stirring. 500 ml of distilled water are added to the reaction mixture, whereupon the mixture is heated to 105 ° C. for 4 hours with stirring (gentle reflux). Then the reaction mixture is poured into a large volume of ice and water. It is then extracted twice with ethyl ether. The ether phases are combined, washed with water and extracted with dilute sodium carbonate solution. The extract is then washed with ethyl ether and acidified by adding dropwise 6η hydrochloric acid while stirring. The voluminous white precipitate thus obtained is filtered off, washed with water and dried in vacuo. There are g white 2- (4-chloro-3-phenoxyphenyl) acetic acid obtained crystalline 34.2 a melting point of 77 to 8O ⁰ C.

Examples 7 and 8

Example 9

Production of 2- (3-phenoxyphenyl) propionic acid
A) 3-phenoxyacetophenone

A mixture of 908 grams (6.68 moles) of m-hydroxyacetophenone, 4500 grams (28.6 moles) of bromobenzene, 996 grams (7.2 moles) of anhydrous potassium carbonate, and 300 grams of copper bronze is made with stirring using a Dean-Stark trap heated to reflux temperature until the evolution of water has ceased. The mixture is then kept at reflux temperature with stirring for 24 hours. After cooling to room temperature, the reaction mixture is _{diluted with an equal volume of CHCl 3} and filtered. The filtrate is washed with 5% HCl, then with 5% NaOH and with water, _{dried over Na 2} SO ₃ and evaporated in vacuo. The oily residue is distilled in a 15-cm Vigreux column to give 918 g of 3-phenoxyacetophenone, bp 120 (0.09 mm) can be obtained up to 121 ⁰ C, ni ¹ = 1.5868.

Analysis:

for Ci ₄ Hi ₂ O ₂ : C 79.22; H 5.70;
Found: C 79.39; H 5.79.

25th

30th

35

40

45

50

The following compounds were prepared from the corresponding ones by the method of Example 6 Toluene derivatives using appropriate amounts of N-bromosuccinimide, lenzoyl peroxide and sodium cyanide manufactured:

2- (2-chloro-5-phenoxyphenyl) acetic acid,
F.88bis90 ⁰ C; pK'a = 6.8;

Analysis:

for ChH ₁₁ CIO ₃ : C 64.00; H 4.22;
Found: C 63.73; H 4.32.

2- (2-fluoro-5-phenoxyphenyl) acetic acid,
80-82 ° C; pK'a = 6.65;

Analysis:

for ChHhFO ₃ : C, 68.28; H 4.50;
Found: C, 68.08; H 4.43.

60

65

B) «-Methyl-3-phenoxybenzyl alcohol

A solution of 700 g of m-phenoxyacetophenone in 3000 ml of anhydrous methanol is cooled ^{to 0 ° C. in an ice-acetone bath while stirring.} 136 g (3.6 mol) of sodium borohydride are added to this solution in small portions at such a rate that the temperature never ^{rises above 10 °} C. After the addition of the borohydride has ended, the reaction mixture is allowed to warm to room temperature and stirred for 18 hours. It is then heated to reflux temperature for 8 hours while stirring. About 400 ml of methanol are distilled off, and the remaining solution is ^{evaporated in vacuo to about 1} hour of its original volume and poured into ice water. This mixture is extracted twice with ether, acidified with 6N HCl and extracted again with ether. The ether extracts are combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The remaining oil is distilled in a 15-cm Vigreux column to give 666 g "-methyl-3-phenoxybenzylalkohoI of boiling point 132 to 134 ⁰ C (0.35 mm) can be obtained, π" = 1.5809.

Analysis:

for C ₁₄ H ₁₄ O ₂ : C, 78.48; H 6.59;
Found: C 78.75; H 6.31.

C) «-Methyl-3-phenoxybenzyl bromide

A solution of 1357 g of methyl-3-phenoxybenzyl alcohol in 5000 ml of anhydrous CCl ₄ (previously dried over a molecular sieve) is cooled to ^{0 ° C. with stirring.} Then, 1,760 g of _PBr3 are added, being stirred and then cooled so that the temperature remains during the addition at 0 to 5 ⁰ C. The reaction mixture is then allowed to warm to room temperature and stirred overnight (about 12 hours) at room temperature. The reaction mixture is then poured into ice water and the organic phase is separated off. The aqueous phase is extracted with CCU, and the extracts are combined, washed three times with water, dried over anhydrous sodium sulfate

Fat dried and evaporated to dryness in vacuo, whereby 1702 g «-Methyl-3-phenoxybenzyl bromide are obtained as a heavy viscous oil. iil ⁵ = 1.5993.

Analysis:

for CnHi ₃ BrO: C, 60.44; H 4.71; Br 28.73;
Found: C, 60.62; H 4.89; Br 28.47.

D) 2- (3-phenoxyphenyl) propionitrile

A suspension of 316 g of 98% sodium cyanide in 5000 ml of anhydrous dimethyl sulfoxide (previously over a molecular sieve-dried) is heated and with good stirring at 50 to 60 ⁰ C slowly at this temperature g 1702 "-methyl-3-phenoxybenzylbromid added After completion Addition of the bromide, the temperature is increased to 75 ° C. and the mixture is stirred at this temperature for 1.5 hours. The mixture is then cooled to room temperature, stirred at room temperature overnight and then poured into ice water. The aqueous suspension obtained is extracted twice with ethyl acetate and then with ether. The organic extracts are washed twice with a sodium chloride solution and once with water and dried over anhydrous sodium sulfate. Vigreux column is distilled. This gives 1136g 2- (3-phenoxyphenyl) -propionitriI of boiling point 141-148 ⁰ C (0.1 mm), ni = 1.5678 ^s.

Analysis:

for Ci ₅ H ₁₃ NO: C 80.69; H 5.87; N 6.27;
Found: C 80.89; H 6.10; N 6.14.

E) 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% ethanol is kept at reflux temperature with stirring for 72 hours. After cooling to room temperature, the reaction mixture is poured into ice water. The resulting solution is washed with ether, acidified with concentrated HCl and extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. By distilling the remaining oil, 203.5 g (84%) 2- (3-phenoxyphenyl) propionic acid are obtained as a viscous oil with a boiling point of 168 to 171 ° C. (0.11 mm), n% = 1.5742, pK'a = 7.3.

Analysis:

for C ₁₅ HhO ₃ : C 74.36; H 5.83;
Found: C 74.48; H 6.05.

Example 10

2- (3-Phenoxyphenyl) propionic acid sodium salt dihydrate

6460 g of 2- (3-phenoxyphenyl) propionic acid are converted into the sodium salt in a proportion of 26.7 mol 2 N sodium hydroxide solution was added with stirring and cooling. Then the aqueous solution is in vacuo concentrated almost to dryness. The semi-dry residue is then stirred with ethyl acetate and evaporated again in vacuo. The white solid residue is in the smallest possible amount dissolved in boiling ethyl acetate, in a large container

filtered (about 18 liters of solution) and overnight at 7 ° C ditched.

The crystalline mass obtained is filtered off and dried in vacuo at room temperature 6954 g of pure sodium 2- (3-phenoxyphenyl) propionate dihydrate with a melting point of 76 to 78 ° C. were obtained.

Analysis:

for C ₁₅ H ₁₇ O ₅ Na: C 59.99; H 5.70;
Found: C, 59.93; H 5.97.

Example 11
5- (4-chloro-3-phenoxybenzyl) -1H-tetrazole

A mixture of 17.0 g of 4-chloro-3-phenoxyphenylaceionitrile, 5.0 g sodium azide, 4.15 g ammonium chloride and a trace amount of lithium chloride in 80 ml Dimethylformamide (dried over a molecular sieve) is heated to 125 ° C. for 12 hours while stirring.

The reaction mixture is filtered and the solvents are evaporated until a brown oil is obtained. The oil is suspended in about 400 ml of water. After the mixture has been stirred, the pH of the suspension is adjusted to pH 2 by the dropwise addition of 3N HCl. After cooling, the precipitate obtained is filtered off, washed with ice water and dried in vacuo. The precipitate is then taken up in boiling aluminum 1,2-dichloroethane and left to crystallize slowly overnight. 14.5 g of 5- (4-chloro-3-phenoxybenzyl) -1 H-tetrazole are obtained in fine white needles with a melting point of 157 to 158 ° C., pK'a = 5.7.

Analysis:

for C ₁₄ H ₁ IClNO ₄ : C, 58.64; H 3.86; N 19.54;
Found: C, 58.66; H 4.07; N 19.84.

Example 12
2- (3-phenoxyphenyl) propionamide

A solution of 0.5 mole of 2- (3-phenoxyphenyl) propionyl chloride in 300 ml of dry ethyl ether is added dropwise with stirring to 2 l of liquid ammonia given. After the addition has ended, the reaction mixture is stirred for 1 hour and then with 500 ml Diethyl ether added. The reaction mixture is stirred overnight, whereby the excess Ammonia is evaporated. Dilute hydrochloric acid is then added to the reaction mixture. the The ether layer is separated off, washed with sodium hydroxide and water and dried over sodium sulfate. After evaporation of the ether in vacuo, a gummy residue remains, which after trituration crystallized with cold hexane. Recrystallization from ethyl acetate and hexane gives 76.2 g of 2- (3-phenoxyphenyl) propionamide obtained from melting point 67 to 69 ° C.

Analysis:

Calcd. for C ₁₅ H ₁₅ NO _2: C 74.66; H 6.27; N 5.81;
Found: C 74.01; H 6.30; N 6.15.

Example 13
N, N-dimethyl-2- (3-phenoxyphenyl) propionamide

400 ml of dry chloroform are mixed with 72.6 g of 2- (3-phenoxyphenyl) propionic acid and 36.9 g of thionyl chloride offset. The reaction mixture is under

Stirring is maintained at reflux temperature for about 3 hours. Then the chloroform is evaporated and with the residue was twice azeotroped with benzene. The residue was converted into ethyl ether dissolved and added with stirring and cooling to a solution of 45 g of dimethylamine in ethyl ether. the Temperature is maintained at about 0 ° C or below during the addition. The reaction mixture will Allowed to warm to room temperature, kept at gentle reflux for 1.5 hours, in ice and water Ό poured and acidified. The ethyl ether layer is separated. The aqueous layer is washed with ethyl ether The ether extracts are combined, washed with water, dried over sodium sulfate and evaporated to a white solid. The solid is dissolved in boiling hexane and the solution becomes slowly allowed to cool to room temperature, yielding 67.6 g of N, N-dimethyl-2- (3-phenoxyphenyl) propionamide from melting point 73.5 to 76 ° C can be obtained.

Analysis:

for C ₁₇ H ₁₉ NO ₂ : C 75.80; H 7.11; N 5.20;
Found: C 75.93; H 6.90; N 5.27.

Example 14

N, N-dimethyl-2- (3-phenoxyphenyl) propylamine hydrochloride

A flask dried in the flame is placed under jo Nitrogen charged with 6.08 g of lithium aluminum hydride and 500 ml of ethyl ether. The mixture will be about 30 Stirred for minutes at room temperature and thinly added dropwise with a solution of 67.3 g of N, N-dimethyl-2- (3-phenoxyphenyl) propionamide (produced by the method of Example 13) in 800 ml of ethyl ether The reaction mixture is kept at reflux temperature overnight with stirring. then 4.65 ml of water, 3.5 ml of 20% sodium hydroxide solution and 16.5 ml of water are added. Then will the reaction mixture poured onto ice, mixed with further sodium hydroxide solution and with ethyl ether extracted The ether layer is washed with water and extracted with dilute hydrochloric acid. Of the acid extract is washed with ethyl ether, with τ> Made sodium hydroxide alkaline and extracted twice with ethyl ether. The ether extracts are with Washed water, dried over sodium sulfate and evaporated to an oil. By distilling the oil 39.2 g of N, N-dimethyl-2- (3-phenoxyphenyl) pro 5 « pylamine with a boiling point of 114 to 120 ° C / 0.1 mm received, M.G. 255.

Analysis:

Calcd. WrC ₁₇ H ₂₁ NO: C 79.96; H 8.29; N 5.49;
Found: C 79.76; H 8.06; N 5.38.

34 g of this amine are dissolved in about 800 ml of dry ethyl ether. Hydrogen chloride gas is introduced into the solution initiated until saturated. The white solid precipitate obtained is filtered off, with ethyl ether t> o washed, partially dried and from boiling ethyl alcohol to give 34.3 g of N, N-dimethyl-2- (3-phenoxyphenyl) propylamine hydrochloride recrystallized from melting point 215 to 217 ° C.

Analysis: ' ^b '

for C ₁₇ H ₂ INO · HCl: C 69.96; H 7.60; N 4.80;
Found: C, 69.68; H 7.40; N 4.90.

Example 15

N-Cyclopropylmethyl-2- (3-phenexyphenyl) propionamide

350 ml of chloroform are mixed with 60.5 g of 2- (3-phenoxyphenyl) propionic acid and 30.4 g of thionyl chloride are added. The reaction mixture is kept at reflux temperature with stirring overnight and evaporated Azeotropic distillation with benzene is carried out three times with the residue The oily acid chloride obtained is taken up in chloroform. 40 g of aminomethylcyclopropane hydrochloride are dissolved in a small amount of water, made alkaline with 5N sodium hydroxide solution and extracted with chloroform. The aqueous layer is saturated with sodium chloride and again with chloroform extracted. The chloroform extracts are combined and dried over sodium carbonate and sodium sulfate. The extracts are filtered and 50 ml of triethylamine are added. The mixture is in one The ice-acetone bath is cooled. The chloroform solution of the acid chloride is then added dropwise. While the addition is cooled and stirred.

The reaction mixture is allowed to warm to room temperature, stirred for 30 minutes, heated to reflux temperature, allowed to cool to room temperature and stirred overnight. Then the solution is partially evaporated and poured into an ice-water mixture. The chloroform layer is washed with dilute hydrochloric acid, dried over sodium sulfate and evaporated to an oily residue. The residue is covered with hexane and scratched, whereby a crystalline solid forms. The crystalline solid is taken up in boiling ethyl acetate and hexane is added until the solution is cloudy. After the solution has cooled, 50.6 g of crystalline N-cyclopropylmethyl-2- (3-phenoxyphenyl) are added ) propionamide with a melting point of 94.5 to 96 ^° C. is obtained.

Analysis:

ber.IUrOqH ₂₁ NO ₂ :
found:

C 77.26; H 7.17; N 4.74;
C 77.14; H 7.17; N 4.71.

Examples 16 and 17

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

N-methyl-2- (3-phenoxyphenyl) butyramide,

F. 84 to 86 ° C.

Analysis:

for CH ₁ QNO ₂ : 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,

F. 57 to 58 ° C.

Analysis:

for C, _b H ₁₇ NO ₂ : C 75.27; H 6.71; N 5.49;

Found: C 75.51; H 6.86; N 5.61.

Examples 18-20

The following compounds were prepared by the method of Example 14 from the corresponding Amides produced using suitable starting materials.

N-methyl-2- (3-phenoxyphenyl) butylamine hydrochloride, m.p. 124 to 126 ° C.
Analysis:

for Ci ₇ H ₂ iNO · HCl: C 69.96; H 7.60; N 4.80;

Found: C, 69.83; H 7.80; N 4.87.

N-methyl-2- (3-phenoxyphenyl) propylamine-

hydrochloride, m.p. 160 to 162 ° C.

Analysis:

for C ₁₆ H ₁₉ NO · HCl: C 69.17; H 7.25; N 5.04;

Found: C, 69.21; H 7.02; N 5.30.

N-Cyclopropylmethyl ^ S-phenoxyphenyOpropyl-

amine hydrochloride, m.p. 115 to 117 ° C.

Analysis:

for C ₁₉ H ₂₃ NO · HCl: C, 71.79; H 7.61; N 4.40;

Found: C, 71.96; H 7.46; N 4.39.

Example 21

Separation of
<% - dl-2- (3-phenoxyphenyl) propionic acid

200 g of dl-2- (3-phenoxyphenyl) propionic acid (prepared according to Example 9) are dissolved in 3000 ml of hot ethyl acetate. 100 g of d- (+) -a-methylbenzylamine are added to the solution. After cooling, a crystalline mass separates out which, after filtering off, gives 229 g of dl-2- (3-phenoxyphenyl) propionic acid-d- (+) - «- methylbenzylamine salt with a melting point of 115 to 126 ° C. By recrystallizing five times from hot ethyl acetate 63.5 g of d- (+) -2- (3-phenoxyphenyl) -propionic acid-d- (+) -a-methylbenzylamine salt of melting point 142 to 144 ° C were obtained, [λ] "+ 14.5 ° (C = 1%, CHCl ₃ ), [*] "+ 3.74 (C = 1%, CH ₃ OH).

Analysis:

for C ₂₃ H ₂₅ NO ₃ : C 76.00; H 6.93; N, 3.85;
Found: C 75.72; H 6.80; N 3.63.

1- (-) - 2- (3-Phenoxyphenyl) propionic acid 1 - (-) - «- methylbenzylamine salt with a melting point of 141 to 142 ° C. is prepared in the same way. [λ] ^? ₀ ^; -3.63 (C = io / o.CHjOH).

52 g of d- (-1-) -2- (3-phenoxyphenyI) propionic acid-d- (+) -Λ-methylbenzylamine salt are suspended in a mixture of 1.5 1 H ₂ O and 0.5 I Et ₂ O and acidified by adding 6N HCl. The ether layer is washed with water, dried over sodium sulfate and evaporated in vacuo to give d- (+) -2- (3-phenoxyphenyl) propionic acid [a] i ⁵ + 46.0 (C = 1 %, CHCl ₃ ).

In the same way, l- (-) - 2- (3-phenoxyphenyl) propionic acid, [λ]? - 45.7 (C = 1%, CHCl ₃ ) is obtained from 1 - (-) -2- (3-phenoxyphenyl) propionic acid 1 - (-) -a-methylbenzylamine salt

Example 22
A) 2- {3-phenoxyphenyl) propylamine

100 g of 2- {3-phenoxyphenyl) propionitrile (prepared according to Example 9D), 10 g of RaneynickeL, 250 ml of ethyl alcohol and 150 g of ammonia are combined in a pressure vessel under an initial hydrogen pressure of 70 kg / cm ^2. The reaction mixture is kept under pressure and while shaking Heated to 70 to 80 ^° C. for 4 hours, whereby a hydrogen uptake of 91% is achieved. After cooling and filtering off the catalyst, the reaction mixture is poured into ice water, acidified with hydrochloric acid, washed with ethyl ether, made alkaline with 10% sodium hydroxide solution and extracted with ethyl ether. Di Äthylätherschicht practice sodium sulfate is washed with water, dried and evaporated to an oil which was distilled 78.9 g of 2- (3-phenoxyphenyl) propyl ^r> amine of boiling point 158-161 ° C / 0.08 mm ran n'i = 1, 5752.

Analysis:

for C ₁₅ Hi ₇ NO: C 79.26; H 7.54; N 6.16;
_{| 0} Found: C 79.18; H 7.29; N 6.07.

B) 2- (3-phenoxyphenyl) propylamine hydrochloride

20 g of the 2- (3-phenoxyphenyl) propyl amines obtained above are dissolved in ethyl ether and the solution wire saturated with hydrogen chloride gas, creating a solid Precipitate is formed. The precipitate is filtered off, washed with ethyl ether and poured into hot Ethyl alcohol dissolved. After adding ethyl ether bi to turbidity, the reaction mixture is cooled and scratched, whereby 18.9 g of 2- (3-phenoxyphenyl) per pylamine hydrochloride of melting point 147 bi 147.5 ° C can be obtained.

Analysis:

for C ₁₅ H ₁₇ NO
found:

HCl: C, 68.30; H 6.88; N 5.31;
C 68.11; H 6.58; N 5.32.

Example 23
2- (3-phenoxyphenyl) butyric acid
^J0 A) 2- (3-phenoxyphenyl) butyronitrile

To 4 1 liquid ammonia in a 5-1 flask, de contains a catalytic amount of ferric chloride, 23 g of sodium are added. The reaction mixture wire Stirred for about 30 minutes Then 209 g of 2- (3-phenoxyphenyl) acetonitrile (corresponding to Reac tion sequence I prepared) added The reaction mixture is stirred for 30 minutes and then with a stirrer 187.2 g of ethyl iodide are added. The mixture is then stirred overnight so that ammonia can evaporate The residue is treated with anhydrous ethyl acetate and the mixture is treated with 6N hydrochloric acid « acidified and stirred for about 1 hour. It is then extracted with ethyl ether. The ether layer becomes mil Water and sodium thiosulphate solution washed and evaporated by distillation of the oily obtained 155.2 g of 2- (3-phenoxyphenyl) -buty are left behind ronitrile with a boiling point of 138 to 140 ° C / 0.14 mm.

B) 145 g of the 2- (3-phenoxyphenyl) butyronitrile obtained are hydrolyzed to the corresponding acid according to the method of Example 9E. 953 g 2- (3-Phenoxyphenyl) butyric acid with a melting point of 73 to 77 ° C.

Analysis:

for Ci ₆ Hi ₆ O ₃ : C 74.98; H 6.29;

found:

C 74.70; H 633.

Example 24
Ethyl 2- (3-phenoxyphenyl) propionate

2XX) g 2- (3-PhenoxyphenyT) propionic acid (according to example 9) are dissolved in 1500 ml of ethanol. Hydrogen chloride gas is introduced into the ethanol solution it until saturated. The reaction mixture is then stirred overnight at reflux temperature held. A large part of the ethanol is then in the Vacuum evaporated and the remaining reaction mixture

Schung poured into ice water. The reaction mixture is made alkaline with 10% sodium hydroxide solution and extracted twice with ethyl ether. The ether extracts are combined and washed twice with water and dried over sodium sulfate. After the ethyl ether has evaporated, crude ethyl 2- (3-phenoxyphenyl) propionate remains as an oily residue. This procedure is repeated with a further 200 g of 2- (3-phenoxyphenyl) propionic acid. The crude products are combined and distilled in a 15 cm Vigreux column, whereby 339.9 g of ethyl 2- (3-phenoxyphenyl) propionate with a boiling point of 128 to 134 ° C / 0.15 mm are obtained, nl * = 1.5458 .

Analysis:

for Ci ₇ H ₁₈ O ₃ : C 75.53; H 6.71; Found: C 75.75; H 6.70.

Example 25 2- (3-phenoxyphenyl) propanoI

27.4 g of lithium aluminum hydride, which are in a flame-dried, nitrogen-flushed flask, are mixed with about 11 ethyl ether. The mixture is stirred vigorously for 45 minutes. Then the lithium aluminum hydride suspension is added dropwise with a solution of 300 g of ethyl 2- (3-phenoxyphenyl) propionate (prepared according to Example 41) in 500 ml of ethyl ether at such a rate that there is constantly a gentle reflux After the addition of the ether has ended, the reaction mixture is stirred overnight and kept under gentle reflux. After the reaction mixture has cooled to room temperature, it is decomposed by the careful dropwise addition of 44.5 ml of water, 333 ml of 20% sodium hydroxide solution and 155 ml of water. The reaction mixture is then extracted with ethyl ether. The ether layer is separated off and the aqueous layer is extracted again with ethyl ether. The ether extracts are combined, washed with water and dried over sodium sulfate and a little sodium carbonate. The dried ether solution is then evaporated to an oily residue 241.6 g of 2- (3-phenoxyphenyl) propanol with a boiling point of 128 to 131 ° C./0.1 mm are obtained, nl '= \ , 5771.

Analysis:

for Ci ₅ H ₁₆ O ₂ : C 78.92; H 7.06; Found: C 78.65; H 7.17.

Example 26

2- (3-phenoxyphenyQpropyl-N-methylcarbamate A solution of 2 ^> 1 g of methyl isocyanate in 75 ml dry benzene is added dropwise with stirring at room temperature with a solution of 10 g of 2- (3-phenoxyphenyQpropanol (prepared according to Example 25) in 25 ml of benzene are added. The resulting reaction mixture is kept at the reflux temperature for 5 hours with stirring. Thereupon the reaction mixture evaporated to an oil, the distillation of which is 8.7 g of 2- (3-phenoxyphenyT) propyl-N-methylcarbarnate from Boiling point 170 to 180 ° C / 0.1 mm gives iif = 1.5615.

Analysis:

for Ci ₇ H ₁₉ NO ₃ : C 71.56; H 6.71; N 4.91; Found: C, 71.64; H 6.90; N 4.77.

Example 27

2- (3-phenoxyphenyl) propyl acetate

11.4 g 2- (3-phenoxyphenyl) propanol (according to Example 25 prepared), 7 ml of acetic anhydride and about 100 ml of pyridine

ίο are combined and stirred for 18 hours Maintained reflux temperature. Most of the pyridine is evaporated in vacuo and the residue is dissolved in chloroform, washed with dilute hydrochloric acid and water and dried over anhydrous sodium dried sulphate. After evaporation of the chloro forms in vacuo and distillation of the oily residue obtained, 10.6 g of 2- (3-phenoxyphenyl) propyl acetate with a boiling point of 138 to 145 ° C./0.1 mm are obtained, / JOM, 5478.

. ,

Analysis:

for Ci ₇ Hj ₈ O ₃ : C 75.53; H 6.71; Found: C, 75.40; H 6.59. ·

B e i s ρ i e 1 28

2- (3-phenoxyphenyl) propyl propionate

In the same way as in Example 27, 2- (3-phenoxyphenyl) propylpropionate with a boiling point of 142 to 149 ° C./0.1 ^{mm is prepared from suitable starting materials, nO s} = 1.5420.

Analysis:

for Ci ₈ HmO ₃ : C 76.03; H 7.09; Found: C 75.73; H 7.32. ·

Example 29 2- (3-phenoxyphenyl) propionohydroxamic acid

By adding 5 g of sodium metal to 150 ml

Methanol is produced sodium methoxide. The cooled sodium methoxide solution is mixed with a solution of 7 g of hydroxylamine hydrochloride in 100 ml Methanol is added and the precipitated sodium chloride is filtered off. Then the filtrate is stirred while stirring with 25.6 g of methyl 2- (3-phenoxyphenyl) propionate (prepared according to the method of Example 24) added The reaction mixture is stirred for 1/2 hour at room temperature and then stirred for IV2 hours Maintained reflux temperature. The reac tion mixture cooled and by dropwise Addition of 6η-hydrochloric acid, acidified. After removing part of the solvent in vacuo, a formation forms yellow oil which then crystallizes by recrystallizing from a small amount of ethyl acetate and methylcyclohexane are 12 pounds of 2- {3-phenoxyphenyl) propionohydroxamic acid of melting point 121 bis 122 ° C obtained.

Analysis:

for Ci ₅ Hi ₅ NO ₃ : C 70.02; H 5.88; N 5.44; Found: C 6935; H 5.96; N 5.41.

Example 30

3- (3-phenoxyphenyr) butyric acid A) Ethyl 3- (3-phenoxyphenyl) crotonate

224 g of triethylphosphonoacetate are slowly stirred into a suspension of 48 g of 50% strength

Sodium hydride dispersion added to 500 ml of ethylene glycol monomethyl ether. A solution of 212 g of m-phenoxyacetophenone in 1500 ml of ethylene glycol monomethyl ether is then added dropwise to the reaction mixture and the mixture is stirred for 1 hour. The reaction mixture is then kept at reflux temperature overnight, cooled to room temperature and decomposed by adding water. After evaporation of the solvent in vacuo, the crude product is dissolved in ethyl acetate, washed twice with water and dried over sodium sulfate. After evaporation of the ethyl acetate, an oily residue is left behind which was distilled 52,6 g of ethyl-3- (phenoxyphenyl) crotonate provides a boiling point of 163 to 170 ⁰ C / 0.2 mm, s "= 1.5770.

B) ethyl 3- (3-phenoxyphenyl) butyrate

A solution of 197 g of the ethyl 3- (phenoxyphenyl) crotonate thus obtained in 400 ml of ethanol is hydrogenated in the presence of 5 g of platinum oxide. After evaporation of the ethanol an oily residue remains, the distillation of which gives 160 g of ethyl 3- (3-phenoxyphenyl) butyrate with a boiling point of 137 to 139 ° C / 0.06 mm, n'i = 1.5401.

C) 3- (3-phenoxyphenyl) butyric acid

106 g of the ethyl 3- (3-phenoxyphenyl) butyrate thus obtained are hydrolyzed according to the method of Example 9E. 117.2 g of 3- (3-phenoxyphenyl) butyric acid with a boiling point of 193 to 195 ° C. / 0.23 mm are obtained, n'i = 1.5687, pK'a = 7.2.

Analysis:

for C ₁₆ Hi ₆ O ₃ : C 74.98; H 6.29;
Found: C 75.18; H 6.41.

Within the scope of the invention are pharmaceutical agents which, as an active ingredient, are one of the substances according to the invention Compounds contained in association with a pharmaceutical carrier or diluent. The invention Compounds are effective both orally and parenterally and can be used as dosage forms be prepared for oral, parenteral, rectal or topical administration.

Solid dosage forms for oral administration are, for example, capsules, tablets, pills, powders and granules. In such solid preparation forms, the active compound is inert with at least one Diluents, e.g. B. sucrose, lactose or starch mixed. Such dosage forms can furthermore, as usual, contain other substances in addition to inert diluents, e.g. B. Lubricants, such as Magnesium stearate For capsules, tablets and pills, the dosage forms may also contain buffering agents contain. In addition, tablets and pills can be provided with enteral layers.

Liquid preparations for oral administration include pharmaceutically acceptable emulsions, Solutions, suspensions, syrups and elixirs that are inert Diluents as are customary for this purpose, included, e.g. B. water. Except inert diluents such preparations can also include auxiliaries, e.g. B. wetting agents, emulsifiers and suspending agents and Contain sweeteners, flavorings and fragrances.

The preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or carriers are PropylengrycoL Polyethylene GlycoL vegetable oils,

z. Olive oil, and injectable organic esters, e.g. B. ethyl oleate. Such dosage forms can also Contain auxiliaries, e.g. B. preservatives, wetting agents, emulsifiers and dispersants. she can, for example, by filtration through a bacteria-retaining filter, by adding sterilizing agents on the preparations, by irradiating the preparations or by heating of the preparations are sterilized. You can also

ίο Manufactured in the form of sterile solid preparations be placed in sterile water or in another sterile injectable immediately before use Medium can be dissolved.

Preparations for rectal administration are suppositories which, in addition to the active ingredient, carriers such as Can contain cocoa butter or a suppository wax.

The dosage of the active ingredient in the agent according to the invention can vary, but it is necessary that the active ingredient is contained in such an amount that a suitable dosage form is achieved. the chosen dosage depends on the desired therapeutic effect, the route of administration and on the duration of treatment. In general, dosages between 0.2 and 50 mg / kg of body weight will be used administered per day to mammals for effective relief of inflammation, pain and fever achieve.

The following examples illustrate the pharmaceutical

JO zeutischen means according to the invention further explained.

Example 31

Tablets are made with a weight of 500 mg and with the following composition:

2- (3-phenoxyphenyl) propionic acid

sodium salt dihydrate 250 mg

Strength 190 mg

Colloidal silica 50 mg

_w Magnesium stearate 10 mg

Example 32

Tablets are made with a weight of 200 mg and with the following composition:

2- (3-Phenoxyphenyl) acetic acid 50 mg

Strength 120 mg

Colloidal silica 27 mg

Magnesium stearate 3 mg

Example 33

Tablets are made with a weight of 500 mg and with the following composition:

2- (3,5-dichloro-4-phenoxyphenyl) -

acetic acid sodium salt 250 mg

Strength 190 mg

Colloidal silica 50 mg

Magnesium stearate 10 mg

^e0 Example 34

Tablets are made with a weight of 200 mg and with the following composition:

2- (3-methyl-4-phenoxyphenyi) - 50 mg propionic acid 120 mg strength 27 mg Colloidal silica 3 mg Magnesium stearate

For the production of tablets analogous to those described in Examples 32 to 35, the abovementioned active ingredients by the same amount by weight of another compound according to the invention be replaced. Such tablets can be provided with enteral layers and also buffer agents contain.

Example 35

A number of compounds according to the invention were tested for their anti-inflammatory effectiveness tested. The experimental set-up is described below.

To determine the anti-inflammatory activity of the compounds, a modification of the Method by Winder, C. V., Wax, J., Burr, V. and Posiere, C. E .: A Study of Pharmacological Influences on Ultraviolet Erythema in Guinea Pigs ", Arch. Int. Pharmacodyn., 116, 261, 1958, applied. Male and female albino guinea pigs weighing 225-300 g were shaved on the back and Depilated with a chemical 18 to 20 hours before exposure to ultraviolet light. the Animals were left without food overnight. Immediately after treating the guinea pigs gummed notebook paper reinforcements were attached to their backs with a test connection, whereupon they were exposed to high intensity ultraviolet light for 7 seconds. As an ultraviolet light source dieme a lamp that came into contact with the skin of the back of the guinea pig became. Then the reinforcements were removed and the backs of the animals with a water-soaked one Gauze sponge cleaned. The unexposed areas under the reinforcements served as comparison areas to assess the erythema. The animals were placed in clear plastic containers with the

) Dimensions 10 20 χ 15 cm introduced. 1 hour after the irradiation and then at half-hour intervals for a further 1½ hours The extent of the erythema is determined with the help of a rating system based on the severity of the redness and

in the contrast to the non-irradiated area. Anti-inflammatory agents delay development of the erythema and therefore show their greatest effect in the first evaluations. For this The reason was an additional weight by a factor of 4, 3, 2 or 1 for the ratings Determination given after 1.0, 1.5, 2.0 and 2.5 hours. The erythema grades were rated as follows:

Erythema scoring system

valuation

0 no redness and no contrast

1 slight reddening with an indistinct border line to the non-irradiated area

²⁾ 2 weak to moderate redness with more pronounced

Boundary line

3 pronounced reddening with sharp borders

tongue

3d The overall ratings of each treatment group of 5 or 6 guinea pigs were compared with those of the control animals and the percentage Inhibition was calculated as follows:

100

Control Animals - Treated Animals Control Animals Inhibition.

The test compounds were obtained in a suspension with 50 percent inhibition of the erythema reaction of 1% methyl cellulose in water in amounts of -in was calculated (ED50). The received 1.0 ml / kg administered orally to guinea pigs. The control animals received 1.0 ml / kg of the 1 percent Methyl cellulose suspension alone. The dose with the one

EDw values in mg / kg are compiled in the following table.

-O

Eryihem blocking example
exam, oral. ED511 No.

(mg / kg)

CH-CH ₂ NH ₂ HCl

CH ₃

CH-CH ₂ NHCH ₃ - HCl

CH ₃

CH-CHjNiCH ^ - HCl

CH ₃

22nd

19th

14th

29

Continued 30

Erylhem Blocking Sample Exam, Oral, ED ₅₀ No.

(mg / kg)

CH,

/ CH-CH ₂ NHCHX ¹ H

i \

CH ₃ CH ₂

CH-CH ₂ OH CH ₃

(I.

CH-CH ₂ OC-CH ₂ CH ₃ CH ₃

Il

CH-CH ₂ OC-NHCH ₃

CH ₃

Il

CH-C-NH ₂

CH ₃ CH-COONa CH ₃ CH-COOCa / 2 CH ₃ CH-COOCH ₃ CH ₃ CH-COOC ₂ H ₅ CH ₃ CH-CONHCH ₂ COOh CH ₃

Ch ₂ CH ₂ -NHCH ₃ HCI CH ₂ -CH ₂ N (CHj) ₂ - HCI CH ₂

■ HCl

CH-CH ₂ NH-CH

CH ₃ CH ₂

HCl

0.9

1.0

1.0

1.5

20th

25th

28

26th

10

1941
31
continuation CH ₃ O
Μ XT XI 625
32 Example 36 example
No. R. CH-CH ₂ N (
I \ /
CH ₃ CH ₂ -CH
\ CH-CH ₂ -O-CCH ₃ Il Il
CH-C N
I \ /
CH ₃ N
H Erythema blocking
exam, oral, ED ₅₀
(mg / kg) The inhibition of the acetic acid-induced 65
Seizure syndrome in mice is used to detect the
relative analgesic effects of to be tested
Links. To prove the analgesic efficacy CH ₃
CH-CH ₂ N (
\ \ /
CH ₃ CH
\
C. : h ₂
• HCl
■ STT I.
CH ₃ O
H 3 : H ₂ · HCl
: h ₂ Il
CH-C - NHCH ₃ I.
CH ₃ 3 0 CH ₃
Il /
CH-C - N
I \
CH ₃ CH ₃ 27 O
Μ 8th Il
CH-C - NHOH
I. I.
CH ₃ Acetylsalicylic acid 10 Phenylbutazone 17th 30th 13th 25th 29 2 50 5 of compounds according to the invention
applied a method similar to that of Koster, R., et al.,
"Acetic Acid for Analgesic Screening" Fed. Proa, 18:
412 (1959), is comparable.

method

Male albino mice weighing 16 up to 18 g, the compounds to be tested were either subcutaneously or through a gastric tube administered. At various times after the administration were given by intraperitoneal administration 60 mg / kg acetic acid (0.6 percent) induced convulsions. Each test group consisted of 6 mice. the The total number of convulsions in a test group was recorded during an observation period of 10 minutes, starting 5 minutes after the administration of acetic acid, the total numbers of the test groups were counted were used with those of control groups to calculate percent inhibition:

% Inhibition = 100 total number of test group]
Total number of control group

• 100

The following table shows the doses in mg compound / kg body weight that are to be used lead to a 50 percent inhibition of the frequency of convulsions (ED50).

2- (3-phenuxyphenyl) -R
Meaning of R ED ₅₀

mg / kg

(subcutaneous)

example
No.

CHCH ₂ NH ₂ - HCl 20

22nd

CH ₃

CH-CH ₂ NHCH ₃ -HCl 20

CH ₃

CH-CH ₂ N (CHj) ₂ -HCI 10

i
CH ₃ 19

14th

Acetylsalicylic acid

The drawing shows the results of this investigation with the calcium salt of 2- (3-phenoxy-20

greater inhibition of the cramps caused at significantly lower doses than the comparative

phenyl) propionic acid. It can be seen 40 substances phenylbutazone and acetylsalicylic acid. that the substance of the invention is an essential

Example 37

Some of the compounds of the invention have been shown to inhibit erythema as a percentage

The following table is compiled in the following table, described in Example 36. The ones from the

subject to examination. The compounds tested, the results are calculated values for the ED ₅₀

the dose administered, the number of test animals and the number also stated.

link

2- (3-phenoxyphenyl) propionic acid

2- (3-phenoxyphenyl) acetic acid

dose Number of animals InI (mg / kg) % 0.25 5 9 0.75 5 41 2.25 5 74 0.33 6th 25th 1.00 6th 72 3.00 6th 87 10 5 37 20th 5 52 40 5 90 10 6th 49 20th 6th 64 40 6th 88

Example no.

0.8

13.9

35 36

continuation

Compound Dose Number of Animals Inhibition of EDs ₁ , example

(mg / kg)% ^No.

2- (3-phenoxyphenyl) butyric acid 0.33 5 24-23

0.33 5 24 1.00 5 47 3.00 5 70 9.00 5 87 0.33 5 22nd 1.00 5 44 3.00 5 68 9.00 5 79

1,2 The other compounds falling under the general formula show a comparable effect.

1 sheet of drawings

Claims (1)

Patent claims: ! Substituted phenylalkanoic acids of the general formula I ^Rl b) —CON N- -N