DE1941625A1 - Substituted phenylalkanoic acids and derivatives thereof - Google Patents

Description

. i

Eli Lilly and Company, Indianapolis, Indiana, Y.St.A. n = S = 3SS = SS = i = 3S = SSSS3 = a == S = SSSSS3S3SSS3SSSS8SSSSBSSSS

Substituted phenylalkanoic acids and derivatives thereof

SSSSSSSSSSSSSSSSSSSSSSiSSSSSSSSSSSSSSSSSSiSSSSSSSSSS

The invention relates to new 3- or 4-Pheßoxyphenyl- and 3- or 4-Phenylthiophenylalkansäuren, their pharmaceutically acceptable cationic salts and the corresponding ester, amide, amine, alcohol, ether, tetrazole, car. 'bamate and urea derivatives with anti-inflammatory activity and mild aspirin-like analgesic and antipyretic activity. :

It is known that many people and animals at different suffer from rheumatic symptoms, including inflammation, swelling. Weakness, decreased mobility, Pain and fever include. Although there is a number of currently available anti-inflammatory products Agents that are used for the symptomatic treatment of conditions such as rheumatoid arthritis, rheumatoid spondylitis or hip degeneration (osteoarthritis) have been shown to be effective, but these remedies have different ones unwanted side effects. There is

009847/2014

BATH ORIGINAL

forth a need for better anti-inflammatory Means.

The invention relates to new compounds that are excellent Anti-inflammatory agents are and, in addition to their anti-inflammatory activity, mild aspirin-like have analgesic and antipyretic activity.

The invention relates to compounds of the formula

(CH ₂ ) _n -Z Formula I.

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

X oxygen or sulfur

Y _{1 is} a hydrogen atom, a hydroxyl group, an amino group, a nitro group, a halogen atom, a methyl radical, an ethyl radical, a C ₁ -C, alkoxy group, a methanesulfonyl group, a methanesulfonamido group, a trifluoromethyl radical, an acetamido group, a methyl mercapto group o

BATH ORIGINAL

R _{1 is} a hydrogen atom, a Cj-Cc-alkyl radical, Cg-Cc-alkenyl radical, C ₂ -Cc -alkynyl radical or C, -Cg -cycloalkyl radical

and if I do the rest /. Λ-X- in the p-graduation is located,

η the number 0,

Y _{2 represents} a hydrogen atom, a hydroxyl group, a chlorine atom, a fluorine atom, a bromine atom, an iodine atom, a C ₁ -C ₅ -AlCy! Radical or a C ₁ -C -alkoxy group

where only one of the radicals Y ₁ and Yg can be a water off atom, if

R _{1 is} a hydrogen atom or a methyl group, Z is either

(A) the group -COOR ₂₁ in B _{2 is} ^a hydrogen atom, a C ^ -Cc-alkyl radical, a di (C ₁ -C - alkyl) amino C ₁ -C.-alkylreet or an alkali »alkaline earth, Ammonium or substituted ammonium cation,

(b) the group -COH

in which the radicals R, which can be identical to or different from one another, hydrogen atoms, hydroxyl groups, Cj-Cc-alkyl radicals, cyclopropylnethyl radicals or groups -CH ₂ -COOR ₂

represent, ■

(c) the group -CH ₂ OR. in R. represents a hydrogen atom, a C -Cu. alkyl, acetyl, ^ ropionylrest, ¹ 00% 847 / 20U

Carbamyl radical, N-methylcarbamyl radical, Ν, Ν-dimethylcarbamyl radical or CU-Gg-Alkoxyalkylrest., dar- ' represents, or

(d) the group

Il

and if the H _e st { _v // "* ^x is in m-graduation,

η is an integer from 0 to 3 _t

Yg is a hydrogen atom, a hydroxyl group is a halogen atom, a methyl radical or an ethyl radical, but a hydrogen atom, if Y., a hydroxyl group or represents a Cj-C, alkoxy radical,

Eg in addition to the best mentioned above, a 2- (3-phenoxyphenyl) propylene radical and

Z additionally, if η is an integer from 1 to 3,

(e) the group

mean, in which the radicals S ₅ , which may be the same or different from one another,

009847/2014

(1) Hydrogen atoms, Cj-Cc-alkyl radicals, cyclo- ' prbpylreste or cyclopropylmethylreste or

(2) Acetyl residues, propionyl residues, N-methylcarbamyl residues or represent N, N-dimethylcarbamyl radicals.

The new 2- (3- or 4-phenoxyphenyl) - or 2- (3- or 4-Phenylthiophenyl) alkanoic acids, their pharmaceutically acceptable cationic salts and the related ones Esters, amides, amines, alcohols, ethers, tetrazoles, carbamates and and ureas are used as pharmaceutical agents for treatment of inflammation, pain and fever in humans and animals beneficial. Through some of the invented

compounds according to the invention is also the analgesic Significantly increased activity of a number of analgesic agents.

The new 3-phenoxyphenyl and 3-Phenylthiophenylalkansäuren, their pharmaceutically acceptable cationic S _a LZE and the corresponding esters, amides, amines, alcohols, ethers, carbamates, ureas and tetrazoles can be represented by the following general formula II

ρ "

CH- (CH ₂ ) _n -2

II

009847 / 20U '^;

X oxygen or sulfur,

Y- a water st off atom, a hydroxyl group ,. an amino group, a nitro group, a halogen atom, a ^ e thy Ire st, an ethyl radical, a CL-Cz-alkoxy radical, a methanesulfonyl-: group »a methanesulfonylamido group, a rifluoromethyl radical, an acetamido group or ^ a methyl mercapto group,

Yg represents a hydrogen atom, a hydroxyl group, a halogen atom, a methyl radical or an ethyl radical, but a hydrogen atom when Y _{1 represents} a hydroxyl group or a Cj-C ^ -alkoxy radical,

Lj a hydrogen atom, a Cj-Cc-alkyl radical, a € 2 »G ₅ -alkenyl radical _t a Cg-Cc-alkynyl radical or a CU-Cg-cycloalkyl radical,

an integer from 0 to 3 and

Ca) the group -COOB-, in which R _{0 is} a hydrogen atom, a Cy-C _.- alkyl radical _{s is} a di-C ₁ -C, -! Cj-G ^ -alkyl radical, a 2- (3-phenoxyphenyl) propylreet or an alkali, alkaline earth, aluminum, ammonium or substituted ammonium cation represents,.

di® Srupp®, .--. ' -COH

009847/2014

in which the radicals R », which can be identical to or different from one another, represent hydrogen atoms, hydroxyl groups, Cj-Cc-alkyl radicals, cyclopropylmethyl radicals or groups -CH ₂ -COOR ₂ ,

(C) the _{group.-CH 2} OR., in which R represents a hydrogen atom, a C.

(d) the group

N -Έ

c.

or, if η is a whole count from 1 bi « represents,

(e) the group

/ R ₅

means in which the radicals Rc are mutually exclusive can be the same or different from each other,

(1) Hydrogen atoms, C ₁ - Cc-Alkylreete, Cyclopropylreste or Cyclopropylmethylreste or

(2) Ac etyl groups, "Propionyl groups, S-Methy1-carbamy! Groups or Η, Ν-simethylcarbamyl groups share.

009847/2014

This also includes the pharmaceutically acceptable acid addition salts of the basic compounds of this group.

The ηβμβη 4-phenoxyphenyl and 4-phenylthio compounds according to the invention can be determined by the following general Show Formula III; -.

CH-Z

Formula III

X oxygen or sulfur,

Y _{1 is} a hydrogen atom, a hyd ^ oxy group, a halogen atom; (Chlorine, fluorine, bromine, iodine), an amino group, a nitro group, a C ₁ -C alkyl group, a C ₁ -C alkoxy group, a phenoxy group, a methanesulfonyl group, a methanesulfonamido group, a trifluoromethyl group, an acet

^ k ' or a methyl mercapto group,

Y ₂ eitn WaÄBeretoffaiiom, a hydroxyl group eln'Halpgen- ■■> -ii * iw -: i ^: iraiaa * _t ;> luör _t ^J -. ^; ÄPoiBfi- Jodf _t a Oj-C ₅ -Alkylreet or U ₁ -C ₅ ^{-AIkÖxyreet:}

a hydrogen atom, a hydroxyl group, a

, a C ₂ -Cc-alkenylreBt, a

00 9 847/2014

C ₂ -C ₅ alkynyl radical or a C ^ -Og cycloalkyl radical,

where mix one of the radicals Y

and Y _{2 is} water

is material atom when H _{1 represents} a hydrogen atom or a methyl group, and

(a) the group -COOK ", in which R _{2 is} a hydrogen atom, an aj-Gc-alkyl radical, a di-C ₁ -C ₅ -alkylamino-Cj-Gj-alkyl radical or an alkali, '.' Alkaline earth, ammonium or substituted ammonium cation dar8-files, j

(b) the group

-σου

in which the best R-, which can be identical to or different from one another, represent hydrogen atoms, hydroxyl groups, C ₁ -C 12 -alkyl radicals, cyclopropylmethyl radicals or -CH ₂ -COOR _{2 groups}

wherein R- is hydrogen-4

(c) the group -GH

atom, C ₁ -C alkyl, acetyl; Prow pionylrest, Carbamylres *, If ^ -Methylcarbämy! Rest, N, II-I) imethylearbamyires1; o4er C ^, - G _fi -J reet darteil *, or

(d) the group

-0 009t47 / 2Q1

ORlQfNAL

a / ■

means. This also includes the pharmaceutical - ■ " acceptable acid addition salts of the basic Connections in this group.

The term "alkali metal", as used herein, denotes sodium, potassium and lithium.

The term "alkaline earth metal" refers to calcium, Magnesium and barium.

The term "substituted ammonium" includes methylammonium, Diethylammonium, Benzylammonium, Triathaholammonium and like ·.

The term "acid addition salts" refers to salts ''' ■ which are prepared by reacting the free amine with an organic or inorganic acid. Such salts include, for example, the hydrochlorides, hydrobromides, sulfates, bisulfates, acetates, valerates, oleates, laurates, borates, benzoates, lactates, phosphates, tosy-. 'Late, would occur citrates, Malea.te, fumarates, Sucelnäte, Tar and napsylates (S _a LZE of 2-naphthalenesulfonic acid).

The term "Cj-Cc-alkyl radical" denotes both straight-chain and branched alkyl radicals, for example methyl, ethyl, n- ^ ropyl, isopropyl, n-butyl, see-butyl, tert-butyl, isobutyl, n -Amyl, isoamyl or neopentyl. '' ■■ -

The term "Gg-Ct-alkenyl radical" denotes how pbeii defi- ^

nierie G2-C ^ -alkyl groups from which at 2 adjacent r ';

Carbon atoms each have a hydrogen atom, below \% Λ

Formation of an ethylenically unsaturated bond -;

,, ziui example vinyl, allyl,! iethaiIyI or "\ ~, _ ΐ \

* m

The term "halogen atom" includes chlorine, fluorine, bromine and iodine.

The term “Cg-Cc-alkynyl radical” denotes as above defined Cp-Cc-alkyl groups, from which on two adjacent carbon atoms each have 2 hydrogen atoms below Formation of an acetylene bond are removed, for example Ethynyl, Frogargyl, 2-Butynyl or 1-Pentiny1 «

The term "C ^ -Cg-Cycloalkylreet" includes cyclopropyl, Cyclobutyl, cyclopentyl and cyclohexyl

The term "C ₁ -C, -alkoxy radical ¹¹ refers to methoxy, ethoxy and propoxy.

The compounds of the general formula I are excellent anti-inflammatory agents, many of which have an ED ₅₀ ^{of 2 0} A ^{8 1 01} SAg in the erythema inhibition test. All of the compounds according to the invention are suitable for treating inflammation in mammals. The acids and amines are preferred for this. In addition to their anti-inflammatory activity, the compounds show mild analgesic and antipyretic activity. The subject of the invention also includes therapeutic agents which contain one or more compounds of the general formula I as active ingredient or active ingredients in conjunction with a pharmaceutically acceptable diluent or carrier. The compounds are administered to mammals in general in doses of 0.2 to 50.0 mg Ag body weight daily either in a single dose or in multiple doses over a period of 24 hours.

It will be dr <rn. Γ pointed out that both the d and dl · l-Ieoaeren of the a-alkyl compounds according to the invention

009847/2 0il ^%; V ^

ORfQfNAL fNS

lie within the scope of the invention. For example the »cr-alkyl acids according to known methods in their d- and l-isomers are broken down. It was found that the d- and l-isomers have practically the same activity i Therefore, for the treatment of inflammation, Pain and Fever in Mammals Either the racemate or the d- and l-isora can be used.

Surprisingly, it has been found that some of the compounds according to the invention, especially those in which Y ₁ and Y _{2 are} hydrogen atoms, η is the number 0, R _{1 is} a hydrogen atom, a methyl radical or an ethyl radical and Z is the group COOH or a salt thereof, the reinforce analgesic effects with certain analgesics, r »-Ji * T3 'pi - ^' if-« · ^ * · ^^ - »"! / 3 <-t * Ίΐ "J ***** "f"f!> * ΐ "»> \ ϊγλμ Ί O ... Χ * ·! irxi · * y-Λ ΐ "* t *" \ _r ... ** ^ -% - »ϊγ / ^ - r * Γ: "** - ·· r - ^ ', _w ! vi> _w ,

ο *% Λ * ϋ & U ** · *** y ^ - &> - -fc iitwei JUl ^ W * - »4 ^ Vi * * ^ e-- '4 / -JWi ₁ ^ tS ₁ Jr ₁ S ₁ * - λ * ^ ν, * ^ **, / "-ί * ·» --- "thy1 ~ (substituted 4 ~ amino) butanes, especially a ~ d - propoxyphene (chemical name a ~ dl, ■ 2- Diphenyl'-2-propionoxy- ⁱ 3-methyl-4-dimethylaminobutane) and certain narcotic analgesic agents, for example morphine. or codeine when administered concomitantly with these agents.

An intensification of the analgesic effect occurs, if you do about 1 part by weight of a compound according to the invention practically at the same time as 0.005 to 20 parts by weight of the analgesic agent, i.e. at the same time as this agent or one hour before to one hour after it is used deduction is given. To achieve a stronger analgesic Effect will generally be 0.5 to 50 mg / kg a compound according to the invention with the usual thera » A small dose of the analgesic administered.

Examples of the compounds according to the invention are:

2-Cyolohexylr; 2- (3-phenoxyphenyl) acetic acid 2-vinyl-2 "(4 * chloro-5" phenylthihiophenyl} acetic acid

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BATH

Ar ₁ : ■

2-propargyl ~ 2 -. (3-phenoxyphenyl) acetic acid ~ natrii * m- ·

5 ~ { 3-? Lieuüxybenzyl) -lH-tetrazul 2- (2,5-dichloro ~ 3-phenoxyphenyl) es.8etic acid 2- (2,5 ~ dimethyl-3-phenylthiophenyl) acetic acid _λ 2- (2-fluoro- 5-ethyl-3-phenoxyphenyl) acetic acid 2- (4-iodo-6-hydroxy-3-phenylthipphenyl) propionic acid 2- (2,5-dibromo-3-plienylthiophenyl) butyric acid 2- (4-ethoxy-3-phenoxyphenyl) .yl) propionic acid d-2- (3-phenylthiophenyl) propionic acid d-2 ~ (3 ~ phenoxyphenyl) propionic acid 2- (1-pentyl) -2- (3-phenoxyphenyl) acetic acid 2-cyclopropyl-'2 ~ (2, 5-diciilor-3-piienoxyphenyl) acetic acid

2 ~ (3-Phenoxyplienyl) acetic acid 2- (3-phenoxyphenyl) propionic acid sodium salt dihydrate 2- (3-phenoxyphenyl) propionic acid calcium sala-dihydrate 2 ~ (4 - »methyl-3-phenoxyphenyl) acetic acid 2- ( 4-Hydroxy-3-phenOxyphenyl) acetic acid 2- (4-Nitro-3-piienoxyphenyl) acetic acid 2 ~ {4-methoxy-3-piienoxyphenyl) acetic acid 2- (4-chloro-3-piienoxyphenyl) propionic acid 2- (4- Chlor-3-ph.enoxyphenyl) acetic acid 1 -2 ~ (3-phenoxyphenyl) propionic acid sodium salt 2 ~ (2 ~ iodo-5-plienylthiophenyl) acetic acid 2- (5-chloro-3-plienoxyphenyl) acetic acid 2- (2- Ch.lor-3-phenoxyphenyl) acetic acid 2- (^ -Methanesulfonamido - ^ - piienoxyplaenyl) butyric acid 2- (2-Amino-3-phenoxyphenyl) "butyric acid 2- (2-methyl-5-phenoxyphenyl) acetic acid 2- ( 3-Ph.enoxy phenyl) propionic acid 2- (5-propoxy ~ 3-piienylthiopheriyl) butyric acid 2- (2-fluoro-5-pjienoxyphenyl) acetic acid 2 ~ (2-ethyl-3 ~ phenoxyph.enyl) propionic acid calcium salt 2- (5-olilor-3 ™ piienoxyp2ienyl 5 propionic acid

009847/2014 BAD

2- (3-phenoxyplienyl) propanol.

Ethyl 2- (3 ^<i -phenoxyphenyl) acetate

Ethyl 2- (3- phenoxyphenyl) propionate. '

2 ~ Gyclopropyl-2 ~ (3 ~ phenoxyphenyl) acetic acid 2- (diethylamino) ethyl-.2- (3-ph8n.oxyphe'nyl) propionate 2- (3-phenoxyphenyl) propyl-2- (3 ~ plienoxyphenyl) propionate 2- (3 ~ phenoxyphenyl) propionamide 2- (3-phenoxyphenyl) ethyl carbamate N-methyl ~ 2- (3 ~ plienoxy phenyl) propion.ami <i N-methyl ~ 2- (3- phenoxy phenyl) propylcarbainate I, N-bimethyl-2- (3-phenoxyphenyl) propionamide N-, N-dimethyl- 2- (3-phenoxyphenyl) -n-pentyl-carbama t N-glyclopropylmethyl-2r (3-phenoxyphenyl) propionamide 2- (5 ~ methylmercapto-3-phenoxyphenyl) acetic acid 2- (3-phenylthiophenyl) acetic acid 2-ethiny1-2- (4-methanaulfonyl-3-phenoxyphenyl) acetic acid 2 - (^ 3- * phenyl thiophenyl) propionic acid 2- (3-Phenylthiophenyl) butyric acid 2- (3-phenylthiophenyl) valeric acid 2- (3-phenylthiophenyl) acetic acid ammonium salt 2- (4 ~ hydroxy-3-phenylthiophenyl) acetic acid 2- (4-methyl-3-phenylthiophenyl) propionic acid natriuinsaiz 2- (2-trifluoromethyl-5-plienoxyphenyl) propionic acid 2- (4-chloro-3-phenylthiophenyl) propionic acid 2- (4-chloro-3-phenylthiophenyl) e Acetic acid 2- (5-chloro-3-piienylthiophenyl) acetic acid benEylamine salt 2- (2-chloro-3-phenylthiophenyl) propionic acid

2- {2-Methylr-5-phenylthiophenyl) acetic acid. '

2- (2-Fluoro ~ 5-phenylthiophenyl) propionic acid 2- (3-> Phenoxyphenyl) ethylamine F-Gyclopropyl-2- (3 "-phenoxyphenyl5butylamimnalea1; 2- {5" -BroiB ~ 3-pto.enyltbi © phenyl) esaetic acid -calcium salt 2 ". (J-Phaaylthioplienyl) propanol

47/2014

bad ^

Methyl 2- (5-phenylthiophenyl) p: rapiQnat Ethyl 2- (3-phenylthiophenyl) propionate, 2-diethylaminoethy1-2- (3-phenylthiophenyl) propionate 2 ^ (3-phenylthiophenyl) propyl-2- (3-phenylthiophenyl) acetate

2- (3-phenylthiophenyl propionamide 2- (3-phenoxy phenyl-propionohydroxanic acid N-Cyclopropylmethy1-2- (3-phenoxyphenyl) propylamine hydrochloride

N-methyl-2- (3-phenoxyphenyl / propylamine sulfate N, N-dimethyl-2- (3-phenoxyphenyl) propylamine hydrochloride 2- (3-phenoxyphenyl) butteric acid 2- (3-phenoxyphenyl) valeric acid 2- (3 ^ phenoxyphenyl) caproic acid 2- (3-Phenoxyphenyl) oenanthic acid 3- (3-Phenoxyphenyl) butyric acid 2- (3-Phenoxyphenyl) propylamine hydrochloride 2- (3-Phenoxyphenyl) butylamine sulfate 1 -Methyl-3-Z ~ ² - (5 ~ Pne ⁿ ° xyphenyl) propyl J ^ naxastoff 1 _t -dimethyl-3-Z ~ 2- (3-phenoxyphenyl} propy £ 7harnetoff Xthyl-3- (3-phenoxyphenyl) butyrate 3- (3-phenoxyphenyl) butanol. "3- (3 -Pflenoxyphenyl) butyl acetate 2- (3-phenoxyphenyl) propylpropionate N- / r3- (3 ~ phenylthiophenyl) butyl7acetajnId 5_ (a-methyl-'3-phenoxybenzyl) -lH-tetrazole N-Zr ^^ (3-phenoxyphenyl) propyl / acetamid N- / T "2- (3-phenoxyphenyl) propy l / propioaamld 4 - (3 ^ Phe noxyphenyi) raleraiaid 5- (3-phenoxyphenyl) caproic acid alufflinium al2 2- (3-phenylthiophenyl) acetamide

2- (3-phenylthiophenyl) butyramide,

N'-Methyl-2- (3-phenyl thiophenyl) propionamide N-Cyclopropylae thyl-2- (3-phenylthiophenyl) propionamide 2- (2, 3-di _t "ethyl-4-phtnoxyphenyl) propion * äure

009847 / 20U

^BATH

2- (3j 5-Dimethyl-4-phenoxyphenyl) propionic acid, sodium salt 2- (S-iodo-4-phynylthiophenyl) acetic acid 2- (3-methoxy-4-phenoxyphenyl) propionic acid 2- (3-methoxy-4-phenoxyphenyl ) acetic acid 2-cyelohexyl-2- (2-isopropyl-4-phenoxyphenyl) acetic acid 2- (2-methoxy-4-phenoxyphenyl) acetic acid 2- (2-methoxy-4- ^i- phenylthiophenyl) propionic acid t-buty1-2- (2-methyl-4-phenoxyphenyl) propionate 2- (3-methyl-4-phenoxyphenyl) acetic acid ethyl 2- (3-bromo-4-phenoxyphenyl) propionate 2- (3-methyl-4-phenoxyphenyl) propionic acid '2 - (2,3-Dimethyl-4-phenoxyphenyl) acetic acid 2-vinyl-2- (3-chloro-4-phenoxyphenyl) acetic acid 2- (2,3-dimethyl-4-phenoxyphenyl) propionic acid 2- (2-ethyl- 4-phenylthiophenyl) acetic acid methyl 2- (3-t-butyl-4-phenoxyphenyl) acetate 2- (3-hydroxy-4-phenoxyphenyl) acetic acid-benzylammonium 2-cyclopropyl-2- (2-fluoro-4-phenylthiophenyl) acetic acid 2- (3 1 5-dimethoxy-4-phenoxyphenyl) acetic acid 2- (3-methylmercapto-4-phenoxyphehyl) valeric acid 2- (2,5-dimethoxy-4-phenoxyphenyl) acetic acid 2- (2,4-diphenoxyphenyl) ess igsäure 2- (3-Methanesulfonyl-4-phenoxyphenyl) acetic acid 2- (3 f 4-Mphenoxyphenyl) acetic acid 2- (2-Pluoro-4-phenylthiophenyl) acetic acid 2- (2-Pluoro-4-phen9xyphenyl) propionic acid Methyl- 2- (2-fluoro-4-phenoxyphenyl) propionate ethyl 2- (3-trifluoromethyl-4-phenoxyphenyl) acetate ethyl 2- (2-acetamido-4-phenoxyphenyl) propionate 2- (3-methyl-4-phenoxyphenyl ) propionamide 2- (2-chloro-4-phenoxyphenyl) propionaraid K-methyl-2- (2-fluoro-4-phenoxyphenyl) propionamide H-methyl-2- (3-methoxy-4-phenoxyphenyl) propylcarbamate H, N- Dimethyl-2- (3-ethyl-4-phenoxyphenyl) propionamide H, Η-dimethyl-2- (2,5-dlchlor-4-phenoxyphenyl) -n-pentylca.r bamate

009847/2014

- 17 -

N-Cyclopropylmethyl-2- (3-methyl-4-phenoxyphenyl) propionamide

2- (Ethynyl-2- (3-nitro-5-methanesulfonyl-4-phenoxyphenyl) -acetic acid

2- (2-propoxy-4-phenylthiophenyl) propanol Methyl 2- (2-amino-4-phenylthiophenyl) propionate Ethyl 1-2- (3-nitro-4-phenylthiophenyl) propionate 2-diethylaminoethyl 2- (2-iodo-4-phenylthiophenyl) propionate 2- (3-methanesulfonyl-4-phenylthiophenyl) propyl-2- (3-chloro-4-phenylthiophenyl) acetate

2- (2-methylmercapto-4-phenylthiophenyl) propionamide 2- (3-Bromo-4-phenylthiophenyl) acetamide 2- (3-chloro-4-phenylthiophenyl) butyramide N-Methy1-2- (3-phenoxy-4-phenylthiophenyl) propionamide N, N-Dimethyl-2- (2-chloro-4-phenylthiophenyl) propionamide N-Cyclopropylmethyl-2- (2-fluoro-4-phenylthiophenyl) propionamide.

The compounds according to the invention can be prepared by known methods for the preparation of phenylacetic acid, phenylpropionic acids and their derivatives. Although various routes can be used to prepare the compounds according to the invention, a number of the preferred reaction sequences are shown and described below. In the following e _r refining the radicals H

means the rest

to R-. as defined in formula I and "Ar"

009847/2014 INSPECTED

^r - ■ ν ■

'■' ti;

the formula I.

A. Acids I. Ar-CH, HBSv Ar-CH ₀ -Br NaCN. Ar-CH ₉ -CN -H ₉ O-

• *

Ar-CH ₂ -COOH

The methyl group of a suitable methyl diaryl ether or diarylthioether is produced by the action of N-bromosuccinimide, N-chlorosuccinimide, sulfuryl chloride or similar halogenating agents in the presence of a suitable catalyst, for example benzoyl peroxide, or azobisiso-butyronitrile, in an inert solvent, for example carbon tetrachloride or another halogenated hydrocarbon, halogenated. The halomethyl diaryl ether or thioether obtained is made to react with sodium or potassium cyanide * preferably in dimethyl sulfoxide solution. The nitrile obtained in this way is by the action of acidic or basic reagents are hydrolyzed to the corresponding carboxylic acid by known methods.

009847/2014

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009847/2014

BATH

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009847 / 2Ö14

BATH

The -Nifcril prepared according to the above scheme can be treated with an aliphatic halide or tosylate (R ₁ X ₂ ) ⁱⁿ liquid ammonia in the presence of sodium hydroxide. oc-aliphatically substituted nitrile-alkyl Ie rt. The alkylated nitrile is hydrolyzed to the corresponding carboxylic acid as above (reaction sequence Ha). In a similar way, an arylacetic acid or an arylacetamide can be alkylated in the α-position to the carboxyl group, as shown in the reaction sequence Hb to lic . '',.-.- ■ ". ■

According to another method, which is illustrated by the reaction sequence Hd and He, an aryl acetate ester, for example the ethyl ester, or an arylacetonitrile can be carried out by '. - Exposure to metallic sodium and diethyl carbonate, converted into the corresponding malonic ester or cyanoacetic ester. Each of these derivatives can then be alkylated. To carry out such an alkylation, the malonic ester or gyanacetic ester is usually reacted with a strongly basic reagent, for example sodium ethoxide, sodium ethoxide, potassium tert-butoxide or potassium hydride, whereby am α-carbon atom forms a carbanion. By subsequent treatment of the ^; ~ ^J intermediate carbanions with an alkylating agent, for example an alkyl halide or tosylate (R ^ Xp), the corresponding α-alkylmalonic ester or -cyanoacetic ester derivative is obtained. Both can be hydrolyzed to the corresponding α-alkylarylmalonic acid, which is then decarboxylated by known methods and thus gives the desired α-alkyl- arylacetic acid. -

A Mtril prepared according to reaction sequence I can be methylated, if necessary, according to the following procedure (reaction sequence III)? The hitrile is treated with ethyl formate .'- {

009847/2014
BATH

under basic conditions, for example in-.present of sodium hydride or sodium methoxide, in an inert Carbon dioxide solvent, for example benzene, condensed. The obtained hydroxymetbylene derivative is through Benzoylated by action of benzoic anhydride or of benzoyl chloride and pyridine. The benzoic acid ester is then used in Hydrogenated presence of a noble metal catalyst, whereby. the desired a-methylarylacetonitrile is obtained, the is then hydrolyzed as above.

The desired α-kethylarylaeetonitrile can optionally be prepared in the following reaction path (reaction sequence IV): The aryloxy- or arylthioacetophenone (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 borohydrides to your "Corresponding carbinol reduced * The conversion of this carbinol into the corresponding. Bromide can be achieved by treatment of carbinol with phosphorus tribromide, preferably in an inert solvent, for example chloroform, benzene or carbon tetrachloride, take place »The thus obtained Bromide is then combined with sodium cyanide, advantageously in Dimetbylsulfoxidlosung »converted to a Mtril, the hydrolyzed to the desired carboxylic acid as above.

A ^N others. Method for the production of α-alkyl-phenoxyphenyl- or -phenyltbiophenyl-acetic acids uses the ArndtpiBistert reaction, as reaction sequence V shows, using a phenoxy- or phenyltfaiobenzoic acid as the starting material.

The 80 α-alkyl acids obtained can be broken down into their d-vind 1-IeoEeren by known methods

009847/2014

BATH

The desired phenoxyphenylalkanoic acids can also be prepared with the aid of the Wilgerodt reaction (reaction sequence VI). For this purpose, a phenoxypbenyl or phenylthiophenyl alkyl ketone, for example with morphol "in and sulfur, is heated and the thioamide obtained is hydrolyzed to the desired alkanoic acid derivative, which is obtained by treatment with two equivalents of sodium amide in liquid ammonia and subsequent addition of the alkyl halide or tosylate (RX ₀ ) according to the reaction sequence Hb can be alkylated,.

The acids according to the invention, where η is a number other than O means _f can be prepared as the reaction sequences show VIIa and VIIb according to known methods with the aid of well-known Wittig reaction. The intermediate unsaturated esters (as in VIIa) or nitriles (as in VIIb) can be hydrogenated in the presence of a noble metal catalyst, for example platinum. The saturated esters and nitriles obtained can be used as above. Carboxylic acids are hydrolyzed "

C_. _m _Bster

ι. Ar-CH- (GH ₉ ) GOOH R _o 0H / HC1 Ar-CH- (CH ₀ LCOQR ₀

' £ _mi ν I & Ti C.

R- ■ "■ ■ R

VIIIb. Ar-CH- (CH ₉ -Y COQH.-SOCl ₉ - Ar-CH- (CH ₀ ) CQCl-

R ₂ QH V

Ar-CH -. (CH ₂ ), _a "B-

00-9847 / 2014
BATH

The Carla on acids, which are obtained by the methods shown in the above -Eeaktionssequences, are prepared by known methods, for example by Er-. warm the acid with an alcohol in the presence of a mineral acid (Villa) or by converting the acid into the corresponding acid chloride and subsequent reaction of the acid chloride with an alcohol, preferably in the presence of an HCl trapping agent (VIIIb) _{f converted} into the corresponding ester.

D. amides

O ' , 0

IX. Ar-CH- (CH ₉ LC ^ ( R- ) ₀ NH Ar-CH- (CH ₉ ) -C _Ώ

^{d n} \ $ * y ι * ⁿ \ Al

R ₁ Cl R ₁ F

The amides according to the invention are obtained by reacting the abovementioned acid chlorides with an amine. These The reaction is usually carried out in an inert solvent, for example chloroform, benzene or carbon tetrachloride, in the presence of an acid peak septor, for example pyridine or HgCO. ,, or in a tertiary amine as solvent, for example colliding lutidine or triethylamine. . ■

E. Alcohols

X. ' · Ar-CH- (GH ₀ ) ^ - COOE ₀ LiAlH, Ar-CH- (CH ₀ LCH ₀ OH

J <· U έ. 4- ^ j = ■ "■ £ U iC

Ελ R ».

003847/2014
BATH

2ο -

The esters, the preparation of which has been explained above., - can according to "known methods with a metal hydride, for example Lithium aluminum urohydride, to the corresponding alcohols be reduced.

P. "Ether

XIa, Ar-GH- (CH ₀ -K-CH ₉ -OH 1) NaH. Ar-GH- (GH ₉ ) -, CH ₉ OR,

4 2

The alcohols obtained above can be prepared by reacting the alcohol with a basic salt-forming reagent, for example an alkali metal, alkoxide or hydride, preferably in dimethylformamide or dimethyl acetamide solution, and reacting the salt thus obtained with an alkyl halide or tosylate (R ^ X ₂ ) are transferred into the corresponding ethers.

G, ester

XIb ₈ Ar-CH- (CHg) _n -CH ₂ -OH Ac ₂ O Ar-CH- (CH ₂ ) _n -

The alcohols obtained after reaction sequence X can after known methods, for example by treating the alcohol with an acid chloride or acid anhydride, preferably in the presence of a tertiary amine such as pyrldine or Triethylamine can be converted into eater derivatives. By Use of acetic anhydride for such a reaction is made for example, the desired acetic ester obtained.

009847/2014

■ '■ \. ' ^: BATH

H, carbamates

XI 0. "Ar-CH- (GH ₉ ) -CH ₉ -OH CH, N = C = Q Ar-CH- (CH ₉ J-CH ₉ OC-IiHCH,

Carbamate derivatives can also be prepared from the alcohols obtained according to reaction sequence X, either by reacting the alcohol with a cyanate or by reacting the alcohol with a carbamoyl halide
Example N, N-dimethylcarbaraoyl chloride. These reactions
are preferably carried out in a tertiary amine, for example pyridine or triethylamine, as the solvent.

I. Amines

XIIa. Ar-CH- (CH ₂ ) _n -C

R ₁

XIIb. Ar-CH-

, 0

KH Ar-CH- (CHg) ₁₁ -G ^

LiAlH,

Ar- CH- «

"R,

Hg / EaKi Ar-CH- (CH ₂ ^ -

XIIo. Ar-C = O

.Ar-CeGH-NO ₉ '* - ^ Ar-CH-CH ₉ -KiL

Ö0984 7 / 20U "

BATH

1341625

The amine derivatives according to the invention can according to known. Methods are prepared, for example by reducing an amide with a metal hydride _{reagent such as lithium aluminum%} minluinhydride (reaction sequence XIIa). If primary amines are desired, these can be prepared simply by hydrogenation of the corresponding nitriles in the presence of ammonia and an active catalyst, for example Raney-Niekel- (reaction sequence XIIb).

If appropriate, a suitably substituted aryl alkyl ketone can be condensed with nitromethane. The nitrostyrene derivative obtained can su then reduced either catalytically or with a metal hydride such as Lithiumaluminiuinbydriä the desired Amiri v / ground (Reaktious- follow XIIc). · "- .. '.

XIIIa; Ar-CH- (CHgJ _n -CH ₂ -NH ₂

R ₁ R ₁

XIIIb, Ar-CH- (CH ₂ J _n -CH ₂ ^ IH ₂ Ac ^ O Ar-CH- (CH ₂ ) _a -0H ₂ -NH-C-.CH

R ₁ R ₁

Derivatives of amines by ueen above methods available can be produced by conventional _methods? like the consequences of the reaction. XIIIa and ZIIIb show. The amiirkaim be reacted with an isocyanate, for example methyl cyanate, vorzweiee in ? Yridine solution, to a urea derivative (reaction sequence ■ XIIIa ). ·. Aging & tiy hardly any AmIn if needed according to well-known processes.

009847 / 2014- - ■ = '/

BATH ORIGINAL

be converted into an amide derivative (reaction sequence XIIIb). For example, if the amine with acetic anhydride in Treating pyridine solution forms the corresponding N-acetyl derivative.

K. Hydroxamic Acids

XIV. Ar-CH- (CH ₀ ) -000R ₀ H ₀ NOH Ar-CH- (CH ₀ ) ι c τι c cs ι t η.

nnh-

Those obtainable according to the reaction sequences Villa and VIIIb Esters can be converted into hydroxamic acids in a known manner by reaction with hydroxylamine.

L. Tetrazole ""

XV. Ar-CH (CH ₀ ) -CN NaN, Ar-CH- (CH ₉ ) -CN

ⁿ - h \ _w /

R ₁ R ₁ ST

^{1 1} H

Nitriles that are obtainable by the methods of reaction sequences I, Ha, III or IV or by other known methods can be converted into the corresponding tetrazoles, for example by reaction with sodium azide using dimethylformamide as the reaction solvent (according to the method of Pinnigan, W, G., Henry, RA, and Lofquist, R., S. Am. Chem. Soc., 80, 3908 (1958)).

009847/20 14

■. ■ 1941525

The starting materials for the reactions described above can easily be determined by a Ullman diaryl ethynthesis inherited as described by Bacon and Steward, J. Am. Cbera. 3oc, 87, 4953 (1965) and in the following Equation is shown j

. Ar '-OH + Ar ¹¹ X -——-—— $> Ar'-0-Ar "

where Ar 'is an unsubstituted phenyl radical and Ar "den substituted pbenyl radical

from the general formula I.

Typical intermediates made after this reaction are %

3-phenoxyacetophenone., Bp »117-126 ° c / 0 _f 08 mm; n ^ ⁵ = 1.5665., 4 ~ chloro-5 ~ methyl phenyl ether, bp 105-113 ° C / 0.06 mm;

n | ⁴ ' ⁵ »1.5850,. .

2-chloro-5-methyldiphenyl _{ether s} bp, 120-123 ° C / 0.08 mm;

n | ⁵ ' ⁵ = 1.5850, ■ ■'. -.- ■ -. ■ .. '

4-fluorine-5-methyldiphenyl ether, b.p. 75, ^ 85 ^o d / 0.05 mm;

ⁿ D ³ ^ »5565 j
4 ™ methyl ~ 5 ~ phenoxyaoetopbenony bp. 120-132 ° G / OJO5 mm;

n * ⁵ > 1.5828, '_

00 9847/20 14

BATH

2- ^ ethoxy-5-phenoxyacetophenone _!! Sap., 132 - HO ° C / O _f 15-nan; n ^ ⁵ = 1.5864.

The invention is further developed by the following examples explained.

example 1

Production of 2 ~ { 3- ?henoxyphenyl Jgj

26 ml of thiorpholin are mixed with 42.4 g of ifc-Pbenoxyaeetopherion and 9f6 g of sulfur. The reaction mixture is kept under stirring for 20 hours at the reflux temperature. 00 ml of aqueous potassium hydroxide solution and a small amount of kenge ethyl alcohol are then added to the reaction mixture. The reaction mixture is kept at reflux temperature for a further 20 hours with a stirrer. About 200 ml of the solvent are distilled off. The remaining reaction mixture is filtered, partially cooled with 3is and acidified with concentrated hydrochloric acid, whereby an oily precipitate forms and then crystallizes. The crystalline precipitate is filtered off, washed several times with kit water and dried, whereby 45-9 g of Rob product are obtained as a yellow-cream-colored solid. The crude product is suspended in boiling hexane and Atnylacetax is added until the product is dissolved. The solution is treated with throat, filtered and cooled. There are 22.7 g of white flakes of 2- (3-phenoxyphenyl) acetic acid obtained ⁰ C of melting point 84-86. pK'a = 6.9 «analysis _v be.r. for C ₁₄ H ₁₂ O ₃ SC 73.66; H 5.30. Found C 73.85; H 5.55.

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BATH ORIGINAL

B e ί s ρ i e 1 e 2-6

The following compounds were made according to the procedure of Example 1 from the corresponding phenoxyacetophenones made using appropriate amounts of sulfur and morpholine.

2- (4-methyl-3-phenoxyphenyl) acetic acid, mp 49-51 ⁰ C; pK'a = 7 »0, from 4-methyl-3-pbenoxyacetophenone. Analysis calculated for O ₁₅ H ₁₄ O ₅ -. C 74.36; H 5.83. Found: C 74.45; H 5.88.

2- (4-methoxy-3-phenoxyphenyl) acetic acid, 85 to 87.5 ⁰ P. C; pK'a = 6.9 »from 4-methoxy-3-phenoxyacetopbenone. Analysis calculated for C ₁ CH ₁₄ O ₄ : C, 69.75; H 5.46. found C 69.47; H 5.30.

2- (2-methoxy-5-phenoxyphenyl) acetic acid, P. 90-94 ° C; pK'a β 7.4, from ^ -methoxy-S-phenoxyacetophenone. Analysis over. for C ₁₅ H ₁₄ O ₄ SC 69.75; H 5.46. found! C 69.58 H 5.61.

2- (2-methyl-5-P ⁿ enoxyphenyl) acetic acid, bp. 153-163 ° C / 0.16 MMJ pK'a »6.9, from ^ -methyl-S-phenoxyacetophenone. Analysis calculated for C ₁₅ H ₁₄ O ₅ SC 74.36; H 5.83. found C 72.08; H 5.82.

2- (3-Phenylthiophenyl) acetic acid, P. 82-84 ° C, pK'a = 7.1 from 3-Phenylthiophenylacetophenön. Analysis calculated for C ₁₄ H ₁₂ O ₂ Ss G 68.86; H 4.95; S 13.12. Found: C, 69.09; H 5.17; S 13.06.

■ 009847/201 A

- 33 Examples 7-13

The following compounds were made according to the method of Example 1 from the corresponding phenoxyacetophenories using appropriate amounts of sulfur and morpholine manufactured!

2- (2-Ethyl-3-phenoxyphenyl) acetic acid from 2-ethyl-3-phenoxyacetopbenone.

2- (4-n-Propyl-3-pbenoxypbenyl) acetic acid from 4-n-Propyl-3-phenoxyacetophenone.

2- (5-iso-propyl-3-pbenoxyphenyl) acetic acid from 5-iso-propyl-3-pbenoxyacetopbenone.

2- (4-Trifluoromethyl-3-phenoxyphenyl) acetic acid from 4-trifluoromethyl-3-phenoxyacetophenone.

2- (2-Ethyl-5-pbenyltbiophenyl) acetic acid from 2-ethyl-5-pbenyltbioacetopbenone. . ■

2- (2-n-Pentyl-3-pbenyltbiopbenyl) acetic acid from 2-n-pentyl-3-pbenyltbioacetophenone.

2- (2,5-Diethyl-3-phenylthiopbenyl) acetic acid from 2,5 ethyl-3-pbenyltbioaoetopbenone.

Example 14 2- (4-chlorof-3-phenoxyphenyl) acetic acid

1200 ml of carbon tetrachloride are mixed with 232.7 g of 3-phenoxy-4-cblortoluene, 196 g of N-bromosucoinimide and 1.0 g of benzoyl peroxide offset. The reaction mixture is stirred

009847 / 20U

- 34 - ...- .. ■ .. ■■■■■■

Maintained 24 hours at BÜokfluss Temperatur and then filtered · The solids are washed with carbon tetrachloride. The filtrate is evaporated to an oil. By Fractions A, B and 0 of crude 4-CblQr- »3-pbenoxybenzylbroiside are obtained by distillation.

fraction Sdp. (Mm) (0 , 08) weight , 5 S. (G) . * ■■■ 1V 5960 A. 140-150 (0 , 07) 118 , 6 S. 1.6152 B. 145-153 (b , 07) 190 A. S. 1.6250 C. 145-160 79

Fractions B and 0 are - «cleaned and analyzed.

Analysis bar. for O ₁₃ H ₁₀ BrGlOs G 52.46 | H 3.38 s 0 52.25 i H 3.44

The combined fractions B and 0 are redistilled in a Vigreux column, whereby fractions A, B _g Oj D and E are obtained.

fraction Sdp. (Mi a) Weight (g) ⁿ D _A. ■
105-145 (0.09) 24.2 1.5951 B. 145-155 (0.09) 29.6 1.6114 G 130-136 (0.07) 79.4 1.6228 D. 128-135 (0.07) 52.9 1.6218 £ 136-149 (0.06) 29.8 1.6274

009847/2014

t * * ί

NMR Untersuobungen revealed that the fractions C and D 91 or 92 io containing 4-chloro-3-phenoxyphenyrbromid.

In about 400 ral Dimethylsulföxid 22.2 g 95 # Iiatriumcyanid sodium are dissolved, and the reaction mixture is heated to about 50 ⁰ C. 125 g of the crude 4-chloro-3-pbenoxybenzyl bromide are then added dropwise with stirring. The temperature is maintained during the bromide addition between 50 uid 60 ⁰ C. Immediately after adding the bromide, a red color appears. After complete addition of the bromide the reaction mixture is heated to 60 ⁰ C and gorührt 3 hours. The mixture is then allowed to cool to room temperature and stirred overnight, then poured onto ice and extracted with ethyl ether and then with hexane. The extracts are washed with water and dried over sodium sulfate. The solvents are evaporated to give a reddish brown viscous oil. Distillation of the oil yields fractions A ₁ B and C of, 2- (4-Cblor-3-pnenoxypnenyl) aeetcmitril.

Fraction Sdp. (Mm) Weight (g) t &

A 17O (0.4) -17O (0.15) 51.6 1.5916 B 0.08 (163-174) 16.3 1.5917 C 0.10 (174-190) 2.2 1.5917

Analysis calculated for C ₁₄ H ₁₀ ClNO: C 68.99? H 4.13; N 5.74 ^ 0.68.72 H 4.20; N 5.50.

Acid hydrolysis of the nitrile produces the corresponding 2- (4-chloro-3-phenoxyphenyl) acetic acid was obtained. For this purpose, 500 ml of concentrated hydrochloric acid are added with 50.9 g of the nitrile

009847 / 20-14

added »The reaction mixture is heated to 85 ° C. for 24 hours while stirring. The reaction mixture is treated with 500 ml of distilled water, whereupon heated with stirring for 4 hours at 105 ⁰ O (gentle reflux), then the Eeaktionsmischung is poured into a large amount of volume of ice and water. It is then extracted twice with ethyl ether. The ether phases are pre-cleaned, washed with water and extracted with dilute sodium carbonate solution. The extract is then washed with ethyl ether and acidified by adding 6 η hydrochloric acid dropwise while stirring. The voluminous white precipitate obtained in this way is filtered off, washed with water and dried in vacuo. There are 34.2 g of white crystalline. 2 - * (4-chloro-3-phenoxyphenyl) acetic acid of melting point 77 - 8O ⁰ C preserver th "; -. ^: ■■ - --------

Examples 15-16

The following compounds were made by the method of Example 14 from the corresponding toluene derivatives below Use of suitable amounts of N-bromosuccinimide, benzoyl peroxide and Matrlumcyanid produced:

2- (2-chloro-5-phenoxyphenyl) acetic acid, P. 88-90 ⁰ C; pK'a = 6.8j

Analysis calculated for C ₁₄ H _{11 GlO 5} : C, 64.00; H 4.22.

; Found: C63.73j H 4.32.

2- (2-Pluor-5-pbenoxyphenyl) acetic acid, P. 80-82 ° C; V pK'a · 6.65i

Analysis calculated for C ₁₄ H ₁₁ PO ₅ : C, 68.28; H 4.50.

Found: 068.08; H 4.43.

0098 47 / 20U

Examples 17-24

The following compounds were made by the method of Example 14 produced from corresponding starting materials;

2- (2-iodo-3-phenylthiopbenyl) acetic acid

2- (2,5-Dimethoxy-3-phenoxyphenyl) acetic acid .- * · ..

2- (5-chloro-3-phenylthiophenyl) acetic acid (,, j.

2- (2-chloro-3-phenoxyphenyl) acetic acid £% "'

2- (5-i ^l luor-3-phenylthiophenyl) essigsäur e 2- (5-bromo-3-phenoxyphenyl) acetic acid

2- (2-chloro-5-methyl-3-phenoxyphenyl) acetic acid

2- (4,6-dichloro-3-phenoxyphenyl) acetic acid

Example 25 . '' * \

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

A mixture of 908 grams (6.68 moles) of m-hydroxyacetophenone, 4500 grams (28.6 moles) of bromohenzene, 996 grams (7.2 moles) of anhydrous potassium carbonate, and 300 grams of copper bronze is stirred 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 OHGl and filtered. The filtrate is washed with 5% HGL, then with 5% NaOH and with water, dried over NapSO ^ and evaporated in vacuo. The oily residue is distilled on a 15 cm Vigreux column to give 918 g of 3-phenoxyacetophenone, b.p. 120-121 ⁰ Verden obtained (0.09 mm) C, n ^ = 1.5868.

009847/2014

-.38 -.

Analysis calculated for C ₁₄ H ₁₂ Q ₂ : C-79.22; H 5.70. "found * s ^: C 79.39; H 5.79.

B. a-Meth _| yl ~ 5- ' phenoxyben2yl alcohol

Ethylene solution of 700 g of m-phenoxyacetophenone in 3000 ml of anhydrous methanol is cooled to ^{0 ° C. in an ice-acetone bath with 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. When the addition of the borohydride is complete, 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 1/3 its original volume and poured into ice water. This mixture is extracted twice with ether, acidified with 6 η HCl and extracted again with ether. The ether extracts are combined, washed with saturated UaGl solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The remaining oil is distilled in a 15 cm Vigreux column, whereby 666 g of a-methyl-3-phenoxybenzyl alcohol with a boiling point of 132-134 ° C. (0.35 mm) are obtained, rijy = 1.5809.
Analysis calculated for C ₁₄ H ₁₄ O ₂ SC 78.48; H 6.59. found. C 78.75 6.31.

G. α-methyl-3-phenoxybenzyl bromide

A solution of 1357 g of a-methyl-3-ph.enoxybenzyl alcohol in 5000 ml of anhydrous CGI. (previously dried over a molecular sieve) is cooled ^{to 0 ° C. with stirring.} 1760 g of Pbr, are then added, stirring and cooling in such a way that the temperature is from 0 to 5 ^° C. during the addition

19U625

remain. 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 CCl, and the extracts are combined, washed three times with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 1702 g of a-methyl-3-phenoxybenzyl bromide as a heavy viscous oil.

nl ³ m 1.5993; '

Analysis about; for C ₁₄ H ₁₃ BrOi C 60.44i H 4.71j Br 20.75.

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 diffiethyl sulfoxide (previously dried over a molecular sieve) is heated to 50-60 ° C. with thorough stirring and 1702 g of α-methyl-3-phenoxybenzyl bromide are slowly added at this temperature. After complete addition of the bromide the temperature is increased to 75 ⁰ C and the mixture stirred for 1.5 hours at this temerature. The mixture is then allowed to cool to room temperature, stirred at room temperature overnight and then poured into ice water. The. 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. After evaporation of the solvent in vacuo, an oily residue remains , which is distilled through a 15 cm Vigreux column. It werdenM136 g of 2- (3-phenoxyphenyl) propionitrile of boiling point 141 - 148 receive ⁰ C (0.1 mm), n ^ ■ "1.5678"

009847/2014

Analysis calculated for C ₁ JH ₁₅ NO: C 80.69; H 5.87; N 6.27. Found: G 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 4 ^ 0 g of sodium hydroxide in 1600 ml of 50 tiger ethanol turns 72! Maintained at reflux temperature with stirring for hours. After cooling to room temperature, the reaction mixture is poured into ice water. The obtained lo-; The solution is washed with ether, acidified with concentrated oil 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-ihenoxyphenyl) propionic acid are obtained as a viscous oil with a boiling point of 168 to 171 ⁰ O (0.11 mm), ηψ = 1.5742,

Anal. Calcd for C ₅ H ₁₄ O _3: C, 74.36; H 5.83. found .: C 74.48; H 6.05.

■ For SP ie 1 26 2 ^ (3 ^ phenoxyphenyI) pfopionic acid sodium salt dihydrate

6460 g of 2- (3 ^ phenoxyphenyl) propionic acid are used for the transfer

-. ■ _ solution

in the sodium salt in a proportion of 26.7 mol of 2N sodium hydroxide / ^ added with stirring and cooling. Then, "the aqueous solution in vacuo nearly evaporated to dryness, the hälbtrockne residue is then stirred with ethyl acetate and again evaporated in vacuo The white solid;... Residue is dissolved in a minimum amount of boiling ethyl acetate, filtered in a large container ~ ( about t8 he lit solution) and incubated overnight at 7 ⁰ C stehengelassetu;

009847 / 20U

The crystalline mass obtained is filtered off and dried in vacuo at room temperature. There are 6954 g of pure sodium-2- (3-phenoxyphenyl) propionate dihydrate with a melting point 76 to "-78-. ⁰ received C.

Analysis calculated for C ₁₅ H ₁₇ O ₅ Na: C 59.99; H 5.70 Measured values: C 59.93; H 5.97.

Example 27 5- (4-0hlor-3-phenoxybenzyi) -IH-tetrazo!

A mixture of 17.0 g of 4-chloro-3-phenoxyphenylacetonitrile, 5.0 g of sodium azide, 4.1-5 g of ammonium chloride and a trace amount of lithium chloride in 80 ml of dimethylformamide (dried over a molecular sieve) is heated to 125 minutes with stirring for 12 hours c heated. 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 adding 3N HGl dropwise. After cooling, the resulting precipitate is filtered off, washed with ice water and dried in vacuo. Then "the precipitate is taken up in boiling 1,2-dichloroethane and allowed to crystallize slowly overnight." 14.5 g of 5- (4-chloro-3-phenoxybenzyl) -lH-tetrazole are obtained in fine white needles with a melting point of 157-158 ⁰ C, pK'a = 5.7.

Analysis calculated for C ₁₄ H _{11 GlNO 4} : C 58.64; H 3.86; N 19.54. Found: C, 58.66; H 4.07; N 19.84.

009847/20 14

Example 28 2- (3 ~ phenoxyphenyl) propionamide

A solution of 0.5 mol of 2- (3-phenoxyphenyl) propionyl chloride in 300 ml of dry ethyl ether is added dropwise with stirring to 2 liters of liquid ammonia. Each time the addition is complete, the reaction mixture is stirred for 1 hour and then 500 ml of diethyl ether are added. The reaction mixture is stirred overnight, which evaporates the excess ammonia. Then the reaction mixture is mixed with dilute hydrochloric acid. The ether layer is separated off, washed with sodium hydroxide and water and dried over sodium sulfate. After evaporation of the ether in a vacuum, a rubbery one remains. Residue, which crystallizes after trituration with cold Hescan. By recrystallization from ethyl acetate and hexane, 76 * 2 g of 2- (3-phenoxyphenyl) propionamide with a melting point of 67 to 69 ⁰ O are obtained.

Analysis area JrUrC ₁₅ H ₁₅ NO ₂ SC 74.66; H 6.27 ", N 5.81. Get.z- C 74.01; H 6.30; N 6.15.

B e i s ρ i e 1 29 methy1-2- (3-phenoxyphenyl) acetate

2- (3-Phenoxyphenyl) acetic acid is dissolved in chloroform and slowly while stirring. Thionyl chloride in chloroform. The reaction mixture is stirred for about 3 hours: heated to gentle reflux and then evaporated to dryness, whereby the corresponding acid chloride is obtained, The acid chloride is taken up in chloroform, and the obtained solution becomes one dropwise with stirring ■ Given an excess of cold methyl alcohol. The responses -

009847 / 2OH

mixture is cooled ⁰ C under 1 O and then allowed to warm to room temperature. After removing the solvent in a rotary evaporator and distilling the residue, methyl 2- (3-phenoxyphenyl) acetate is obtained.

At game 30 N, N-dimethyl-2- (3-T3henoxyphenyl) 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. The reaction mixture is kept under stirring at reflux temperature for about 3 hours. The chloroform is then evaporated and the residue is twice azeotroped with benzene. The residue is dissolved in Xthyläther and, while stirring and cooling to a iösung of 45 g dimethylamine in ethyl ether * The temperature is maintained during the addition at about 0 ⁰ C or below. The reaction mixture is allowed to warm to room temperature, refluxed gently for 1.5 hours, poured into ice and water and acidified. The ethyl ether layer is separated. The aqueous layer is extracted with ethyl ether. The ether extracts are combined, washed with water, dried over sodium sulfate and evaporated to a white pest. The Peststoff is dissolved in boiling hexane and the solution is allowed to cool slowly to Räumtepmepatur, whereby 67.6 g of S "lf-Diffiethyl-2- (3-phenoxyphenyl) propionamide are obtained with a melting point _f 73 5-76 ⁰ C.

Analysis calculated for C _{1 → H 19} HO ₂ ϊ C 75.8Oi H 7.11; N 5.20. Found i C 75t93i H 6.90; Ji 5.27.

009 8 47 / 20U

• It * · I t 1 ^ ι M *

Il. · I t : >

h ii ϊ · ■

Example 31 NVlJ-Dimethyl ~ 2- (3-phenoxyphenyI) propylamine .-- hydrochloride

A flame-dried flask is charged under nitrogen with 6.08 g of lithium aluminum urahydride and 500 ml of ethyl ether. The mixture is stirred for about 30 minutes at room temperature and then added dropwise with a solution of 67.3 g of N, N-Mmethyl-2- (3 -phenoxyphenyl) -proplonamid (prepared according to the method of Example 30) added to 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. The reaction mixture is then poured onto ice, further sodium hydroxide solution is added and the mixture is extracted with ethyl ether. The ether layer is washed with water and extracted with dilute hydrochloric acid. The acidic extract is washed with ethyl ether, made alkaline with sodium hydroxide and extracted twice with ethyl ether. The ether extracts are washed with water, dried over sodium sulfate and evaporated to an oil. By distilling the oil, 39.2 g of N, N-dimethyi-2- (3-phenoxypheny1) propylamine with a boiling point IH to 120 ° C / 0.1 mm, MW 255.

Arialysis calcd for C 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 bubbled into the solution until it is saturated. The obtained white solid Precipitate is filtered off, washed with ethyl ether, partially dried and added from boiling ethyl alcohol 54,% N, N-Dimethy1-2- (3-phenoxyphenyl) propylamine-hydro-

009847/2014

öiSO nm

• ti

t r

- 45 chloride of melting point 215 - 217 ⁰ C recrystallized.

Analysis calculated for C ₁₇ H ₂₁ NCHCls C 69.96; H 7.60; N 4.80. found : 0 69.68 H 7.40; N 4.90.

B e i s ρ i e 1.: 32 N-Cyclopropylmethyl-2- (3-phenoxyphenyl) propionamide

350 ml of chloroform are mixed with 60.5 g of 2- (3-phenoxyphenyl) propionic acid and 30.4 g of thionyl chloride. The reaction mixture is kept at reflux temperature with stirring overnight and evaporated. With the residue an azeotropic distillation is carried out three times with benzene. The oily acid chloride obtained is dissolved in chloroform recorded. 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 the aqueous layer is saturated with sodium chloride and extracted again with chloroform. The chloroform extracts are combined and dried over sodium carbonate and sodium sulfate. The extracts are filtered and with 5 0 ml Triethylamine added. The mixture is cooled in an ice-acetone bath. Then the chloroform solution is added dropwise of the acid chloride added. Cool and stir during the addition.

The React ion mixture is allowed to warm to room temperature, stirred for 30 minutes, heated to reflux, 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 washed v / lrd with dilute Salsjaäuya, evaporated over sodium sulfate and an oily residue; Dar

009847 / 2GH
BADORiGlNAL

.III I lli ι,. J ι

:, - * · Ej τ r "ι> ι t

- 46 -

The residue is covered with hexane and scraped off,

ί where a crystalline solid forms. Of the

The crystalline solid is dissolved in boiling ethyl acetate.

I- taken and hexane was added until it became cloudy. After leaving

^: To cool each solution, 50.6 g of crystalline If-Cyclo-

I-propylmethyl-2 '- (3-pJienoxyphenyl) propionamide from the enamel

pünkt94 * 5 Msι | δ ^P G received.

| Ü3? C ₁ ^ ₂₁ NOgT C 7-7 »26j H 7.17s N 4.74. si C, 77.14; H 7.17; N 4.71.

B ice ρ 1 el e 33 - 34

The following compounds were made by the method of Example 30 prepared from appropriate starting materials.

K-methyl-2- (3-phenoxyphenyl} butyramide, P. 84-86 ⁰ C. Analysis calculated _{for C 17} H _{19 IiO 2} SC ■ 75.81; H 7.11; N 5.20 * found: 0 75.60, H 7.11, N 5.00.

N-methyl-2- (3-phenoxyphenyl) propionamide, P. 57-58 ⁰ G. Analysis _{calculated for C 1} → H ₁₇ NO ₂ IC 75.27; H 6.71; N 5.49. Found: C 75.51; H 6.86; N 5.61.

For games 35 - 37 '

The following compounds were made by the method of Example 31 prepared from the corresponding amides using suitable starting materials »

QG3847 / 20I4

»» II

t t i * τ t t tu r *

ι »« ι * '. «■ <· I r t t

N-Kethyl-2- (3-phenoxyphenyl) butylamine hydrochloride,

P. 124 - 126 ⁰ C.

Analysis calculated for C ₁₇ H ₂₁ NO-HCl! C 69.96} H 7.60} N 4j, 80.

Found: C 69.83} H 7.80; N 4.87.

N-methyl-2- (3-phenoxyphenyl) propylamine hydrochloride, P. 160 - 162 ⁰ C.

Analysis calculated for C ₁₆ H ₁₉ NO 3 HCls C 69.17} H 7.25; N 5.04, found: C 69.21} H 7.02} N 5.30,

N-Cyclopropylmethyl-2- (3-phenoxyphenyl) propylamine hydrochloride, P. 115 - 117 ⁰ C.

Analysis calculated for C ₁₉ H ₂₃ NO 1 HCl C 71.79; H 7.61} N 4.40. found s. C 71.96} H 7.46} N 4.39.

Be i a p ie 1 38 Separation of a-dl-g ^ fft-phenpxyphenyl) propionic acid

200 g of dl-2- (3-phenoxyphenyl) proploa8äiare (prepared according to the example) are dissolved in 3000 ml of hot ethyl acetate. 100 g of d - (+) - a-methylbenzylamine are added to the solution. (+) - - After cooling, a crystalline checkout after filtration 229 g of dl-2- {3- £ henoxyphenyl) propionic acid-d separates which a-möthylbenzylaminsalz of melting point 115 - 126 ⁰ C provides. 3) ürch five-fold recrystallization from hot ethyl acetate to 63 »5 g of d- (+) '- 2- (3-phenoxyphenyl) propionic acid, d - (+) - obtained 144 ⁰ C - a-methylben2ylaminsalz of melting point 142nd £ a J ^ ⁵ + 14.5 ° (C = T ^,

Analysis calculated for C ₂₃ H ₂₅ NO ₃ : C 76.00} H 6.93; N 3.65

It - J

ϊ »I ϊ» 3

ί f «1 t * * J

3 »f Ϊ * 1 ill

i I * J 1 t

In the same manner, 1 - (-) - 2- (3- * phenoxyphenyl) propionic acid 1 - (-) - a-methylbenzylamine produced from the melting point 141- 142 ⁰ C. f * J ^ ⁵ -3.63 (C = $ 1, CH ₃ OH).

52 g of d-C + J ^ -O-phenoxyphenylJpropionic acid-d-C + Ja-inethylbenzylamine salt are suspended in a mixture of 1.5 1 H ₂ O and 0.5 1 EtoO 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. jT & J7 -n + 46.0 (0 «1Jti

In the same way, 1 - (-) - 2- (3-phenoxyphenyl) propionic acid, faj / ψ - 45.7 (C = 1 $ CHCl ₅ ) from 1 - (-) - 2-

(J-Bheiioxyphenyr) propionic acid - (~) - a ~ methylbeuay lamifisalt. manufactured.

- ■ - '■■ Bei p iel 39 A. 2 ~ (3-pheno xyphenyl) propylamine

100 g of 2- (3-phenoxyphenyl) propioiiitrIl (prepared according to Example 25 D), - 10 g of Raney nickel, 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 (1000 psi). The Eeaktionsmischung is maintained under pressure and under shaking 4 were on 70 liis 80 ° CerwärBit _f -.v / odürch recording a hydrogen; 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. The lthy lathe rs chicht is washed with water, evaporated oil dried over Hatriumsulfat and one whose destination 78.9 g of 2- (3-phenoxyphenyl) propylamine of boiling point 158-161 ° C / 0.08 mm provides «n ^ ⁵ = 1.5752.

009847/2014

> ι π

• t ►

• et r * f

• I * ■ *

- 49'-

Analyee \ tev. for C _1i; H ₁₇ NO: O 79.26} H 7 * 54? H 6.16. found: O 79.1Si H 7.29ί K 6, Q7,

B. 2- (3-Phenoxyphen.yl) propylene amine hydrochloride

20 g of the 2- (3-phenoxyphenyl) propylamine obtained above are dissolved in ethyl ether and the solution is saturated with hydrogen chloride gas, a solid precipitate is formed. The precipitate is filtered off, washed with ethyl ether and dissolved in hot ethyl alcohol. After addition of Äthylä'uher to turbidity, the reaction mixture is cooled and scratched to give 18.9 g of 2- (3-phenoxyphenyl) propylamine hydrοchlorid of melting point 147 are obtained to 14715 ⁰ G.

Analysis calculated for C ₁₅ H ₁₇ NO-HCl: C 68.30; H 6.88, N 5.31. Found: C, 68.11; H 6.58; H 5.32.

Example 40 '

2- (3-phenoxy phenyl ") butyric acid A. 2- (3-Phenoxyphenyl) butyronitrile

To 4 1 liquid ammonia in a 5 1 flask, the one contains a catalybic amount of ferric chloride, 23 g Given sodium. The reaction mixture is about 30 minutes long stirred. Then 209 g of 2- (3-phenoxyphenyl) acetonitrile (prepared according to reaction sequence I) are added. the Reaction mixture is stirred for 30 minutes and then 187> 2 g of ethyl iodide are added while stirring. Afterward is stirred overnight so that ammonia can evaporate. The residue is mixed with anhydrous ethyl ether and the mixture is acidified with 6N hydrochloric acid and stirred for about 1 hour. It is then extracted with ethyl ether. The ether layer becomes with water and sodium thiosulphate solution

009847/2014

Il: ti Il

- 50 -

Distillation of the

butyroaitrile obtained at boiling point 138-140 ° G / 0.14 mm.

B. 145 g of the 2- (3-phenoxyphenyl) butyronitrile obtained are hydrolyzed to the corresponding acid by the method of Example 25Ξ. It werden'95,9 g of 2- (3-phenoxyphenyl) butyric acid of melting point 73 - 77 ⁰ C obtained.

Analysis calculated for C ₁₆ H ₁₆ O ₃ : C, 74.98; H 6.29. found JC 74.70; H 6.33. ·

Example 41 Ethyl 2- (3-phenoxyphenyl) propionate

200 g of 2- (3-phenoxyphenyl) propionic acid (prepared according to Example 25) are dissolved in 1500 ml of ethanol. Hydrogen chloride gas is introduced into the ethanol solution until it is saturated. The reaction mixture is then kept overnight at the reflux temperature with stirring. A large part of the ethanol is then evaporated in vacuo and the remaining reaction mixture is poured into ice water. The reaction mixture is made alkaline with 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-phenoxyphenyDprppionat from boiling point 1 ^ 8 - 134 ° C / Ö, 15 mm are obtained ^ nD ^ = 1.5458. . ^:

009847/2014

BATH

t · t

Analysis calculated for C ₁₇ Hj ₈ O. ^ C 75.53; Η 6.71. Found: C 75.75; H 6.70.

B e 1 s ρ i e 1 42 2 ~ ($ - phenoxyphenyl) propanol

27.4 g of lithium aluminum hydride, which are in a flame-dried flask flushed with nitrogen, are mixed with about 1 1 A * thy lather. The mixture is vigorously stirred for 45 minutes. Then the lithium aluminum hyäridsuspension 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, 33.3 ml of 20% sodium hydroxide solution and 155 ^ffi l of water. Then a larger amount of water is added, whereby an emulsion is formed. The emulsion becomes clear on acidification. The reaction mixture is then extracted with ethyl ether. The ether layer is separated 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. By distilling this residue, 241.6 g of 2- (3-phenoxyphenyl) propanol with a boiling point of 128-131 ^O C / 0.1 Em, n ^ ⁵ * 1.5771 are obtained. Analysis calculated for C ₁₅ H ₁₆ O ₂ JC 78.92; H 7.06

* C 78.65; H 7.17.

009847 / 2QU

BATH O.

. - 52 -

Example 43 2 - (3-Phenoxyphenyl) propyl-N-methylcarbamate

A solution of 2.51 g of methyl isocyanate in 75 ^ 1 of dry benzene is added dropwise with stirring at room temperature with a solution of 10 g of 2- (3-phenoxyphenyl) propanol (prepared according to Example 42) in 25 ml of benzene. The reaction mixture obtained is kept at reflux temperature with stirring for 5 hours. The reaction mixture is then evaporated to an oil, the distillation of which gives 8.7 g of 2- (3-phenoxyphenyl) propyl-N-methylcarbamate with a boiling point of 170 to 180 ° ^{C./0.1 mm, n * 5} = 1.5615.

Analysis calculated for C ₁₇ H ₁₉ NO ₅ : C, 71.56; H 6.71; N 4.91. Found i C, 71.64; H 6.90; N 4.77.

Example 44 2o- (3-phenoxyphenyl) propyl acetate

11.4 g of 2- (3-phenoxyphenyl) propanol (produced according to Example 42), 7 ml of acetic anhydride and about 100 ml of paridine are combined and kept at reflux temperature for 18 hours while stirring. 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 sulfate. After evaporation of the chloroform in vacuo and distillation of the oily residue obtained, 10.6 g of 2- (3-phenoxyphenyl) propyl acetate with a boiling point of 138-145 ° C./0.1 mm are obtained ^ ηψ a 1.5478.

Analysis calculated for C ₁₇ H ₁₈ O ₅ : C 75.53; H 6, 7th found: C 75.40; H 6.59.

O098A7 / 2014

i ι ι *

- 5> - ■ - ■. ■■■. ". ■ '·. ■;

For example, P i el 45 2-1 3-phenoxyphenylypropyl propionate

In the same way, 2- (3-phenoxyphenyl) propylpropionate with a boiling point of 142-149 ° C / 0.1 mm is produced from suitable starting materials, n ^ ⁵ "■» ■ 1.5420.

Analysis calculated for 0-JqH ₂₀ O ₃ ; C 76.03; H 7.09 Measured values: C 75.73} H 7.32.

B e i s ρ i el 46 2- (3 ~ phenoxyphenyl) propionic hydroxamic acid

By addition of 5 g of sodium metal to. ·! 50 ml of methanol sodium methoxide is prepared. · The cooled sodium ■ methoxide solution is added to a solution of 7 g Hydroxy1-amine hydrochloride in 100 ml of methanol and the abgesehiedene sodium chloride is iiriert ABFI ^. 25.6 g of methyl 2- (3-phenoxyphenyl) -i 'propionate (prepared according to the method of Example 41) are then added to the ' ■, filtrate while stirring. The reaction mixture is stirred for 1/2 hour at room temperature and then kept at the reflux temperature with stirring for 11/2 hours. The reaction mixture is then cooled and acidified by the dropwise addition of 6N hydrochloric acid. After removing part of the solvent in vacuo, a yellow oil forms, which then crystallizes. By recrystallization from a small ^ close ethyl acetate and methylcyclohexane 12.2 g of 2- (3-phenoxyphenyl) · propionohydroxamsäure of melting point 121 - 122 ⁰ C obtained. ";..

Analysis calculated for C ₁₃ H ₁₅ NO ₃ JG 70.02; H 5.83; 15.44,

0 59.95; H

BATH

I>

- 54 For β P ie 1 - 47

1-methyl-3 - / "2- (3-phenoxyphenyl) propyl_ / urea

A solution of 4.9 g of 2- (3-phenoxyphenyl) propylamine (prepared according to the method of Example 39) in 15 ml of pyridine is treated with a solution of 1.43 g of methyl isocyanate in 10 ml of p / ridine. The resulting mixture is heated almost to reflux temperature for 2 hours and then stirred at room temperature overnight. The reaction mixture is then briefly heated and the pyridine is removed by evaporation in vacuo. The gummy residue obtained crystallizes after trituration with cold hexane. By recrystallization from ethyl acetate and hexane, 4.5 g of 1-methyl-3- / ~ 2- (3-phenoxyphenyl) are propyleneurea melting point of 64.5 to 66 ⁰ C obtained.

Analysis calculated for Ci ₇ H ₂₀ N ₂ O ₂ : C, 71.80; H 7.09; N 9.85. · "Found i, C 71.74; H 7.08; N 9.92.

Example 48

3- (3-phenoxyphenyl) butyric acid A. Ethyl 3- '(3-phenoxyphenyl) crotonate

224 g of triethylphosphonoacetate are added slowly with stirring to a suspension of 48 g of a 50 # sodium hydride dispersion given in 500 ml of ethylene glycol monomethyl ether. Then the reaction mixture is added dropwise with a solution of 212 g of m-phenoxyacetophenone Sn 1500 ml Ethylene glycol monomethyl ether is added and for 1 hour touched. The re.action is laughed at

II
1

* I 9

• I
I f

- 55 -

"held at reflux temperature, cooled to room temperature and decomposed by the addition of water. After evaporation of the solvent in vacuo, the crude product is' ■ dissolved in ethyl acetate, washed twice with water, and I. dried over sodium sulfate. After evaporation of the ethyl acetate remains an oily residue, the distillation of 52.6 g of ethyl 3- (phenoxyphenyl) orotonate from the boiling point "

point 163 - 170 ° C / 0.2mm delivers, n £ ⁵ = 1., 577Oi i

- - ■ w

B. Ethy1-3- (3-phenoxyphenyl) butyrate ,

A solution of 197 g of the thus obtained ethyl-3t (phenoxyphenyl) crotonata in 400 ml of ethanol in the presence of 5 ^g. Hydrogenated platinum oxide. After the ethanol has evaporated, an oily residue remains, the distillation of which is 160 g ■ ^:

Ethyl-3- (3-phenoxyphenyl) butyrate of boiling point 137 to 139 ⁰ C / 0.06 mm provides, ^ ⁵ »1.5401.

0. 3- (3-Phenoxyphenyl) butyric acid

106 g of the ethyl 3- (3-phenoxyphenyl) butyrate thus obtained are hydrolyzed according to the method of Example 25E. 117.2 g of 3- (3-phenoxyphenyl) butyric acid with a boiling point of ^{193-195 ° C./0.23 mm are obtained, ^ 5} * 1.5687, pX ^f a * 7.2.

Analysis calculated for C ₁₆ H ₁₆ O ₅ : C, 74.98; H 6.29 Measured values: 0 75fi8 | H 6.41.

009847/2014

BATH. ORl0iNÄt

. '"■ Example 49 ''

Production of 2- (3-methoxy -4-pheiioxyphenyl) acetic acid:

17 ml. Morpholine are mixed with 29.2 g of 3-methoxy-4-phenoxyacetopfienone and 5 »75 g of sulfur are added. The reaction is maintained under gentle reflux with stirring for 20 hours. The reaction mixture is treated with 15 $ potassium hydroxide ■ · solution and 100 ml of ethyl alcohol diluted to 300 ml and kept under stirring overnight at reflux temperature. Then the reaction mixture is poured into ice water and acidified with 6N HCl, resulting in a guiniai-like precipitate, which "partially crystallizes, forms. The precipitate becomes filtered off, washed with water and dried in vacuo. The dried precipitate is dissolved in ethyl acetate in hexane absorbed, decolorized in the boiling point, filtered and cooled, yielding 18.4 g of dense yellow-orange crystals of 2- (3-kethoxy-4-phenoxyphenyl) acetic acid of melting point 83-85 ° C. PK'a = 6.8.

Analysis calculated for C ₁₅ H ₁₄ O ^: C, 69.75; H 5.46. Found: C 69.72; H 5.45.

Beiapi e. Ie - 50 - 56

The following connections were made using the \ on method Example 49 from the. corresponding phenoxyacetophenones prepared using appropriate amounts of sulfur and morpholine.

008847/2014

bath

_ 57 - 1 9A1

2- (2-Mebhyl-4-phenoxyphenyl) acetic acid, m.p. 71, 5 ~ 74 ° C., pK'a = 6.9.

Analysis over. for G ₁₅ H ₁₄ O ₃ : C, 74.36; H 5.83. Found: C 74.43; H 5.79.

2- (3,5-dime-thyl-4 ~ phenoxyphenyl) acetic acid, mp 124-126 ⁰ C, pK'a = 7.45.

Analysis calculated for O ₁₆ H ₁₆ O ,; C 74.98; H 6.29. Found: C 74.30; H 6.27.

2- (3 ~ Metbyl-4-pbenQxyphe-nyl) acetic acid F. 89-91 ⁰ C, pK 'a = 7.1.

Analysis calcd. For O ₁₅ H ₁₄ O,: 0 74.36; H 5.83. Found: 0 74.49; H 5.72.

2- (2 _i 3-dimethyl-4-pnenoxyp "henyl) acetic acid, F '106-108 ⁰ C, pK'a = 7.1.

Analysis calculated for C ₁₆ H ₁₆ O ₅ : C, 74.98; H 6.29. Found: G 74.95; H 6.00.

2- (2-Ethyl-4-phenoxyphenyl) acetic acid, P. 82-84 ° C, pK'a = 7.0. .

Analysis calcd. For C 1 H ₁₆ O ₅ : C 74.98; H 6.29. Found _: C 75.20; H 6.55-

2- (2-Phenoxy-4-phenoxyphenyl) acetic acid, m.p. 125 ~ 127 ° 0, pK'a = 7.0.

Analysis calculated for C ₂₀ H ₁₆ O ₄ : C, 74.99; H 5.03. found ... G 74.84; H 4.92.

2- (2-Metnoxy-4-phenoxyphenyl) acetic acid, P, 1O5-1O7 ° C, pK'a = 7.4.

Analysis calculated for G ₁₅ H ₁₄ O ₄ : C 69 _f 75; H 5.46. Found: C, 69.83; H 5.60.

009847/2014

BATH

B e i 3 ρ i e 1 57

Preparation of 2- (3-Hydroxy-4-phenoxyphgnyl) oGnl ^ 3 acid

105 ml of 48% hydrobromic acid in 175 ml of glacial acetic acid are mixed with 17.5 g of 2- (3-metboxy-4-phenoxyphenyl) acetic acid (prepared according to Example 49). The reaction mixture is kept at reflux temperature for 18 hours with stirring and nitrogen and then poured into about 3 liters of ice water. Daa Beaktionsgemisch is extracted with ethyl ether ■ and the extracts are washed twice with water overall ■ Ψ and extracted with 5 $ hydrochloric Natriumbydroxidlö3ung. The basic solution is washed with ethyl ether, heated with charcoal, filtered, cooled and acidified by adding dropwise 6N HGl while stirring, whereby 13.6 g of crude crystalline 2- (3-hydroxy-4-pbenoxypbenyl) -acetic acid with a melting point of 118 - 12O ⁰ C can be obtained. The critical 'stalline product is taken up in boiling ethyl acetate and hexane and the solution is allowed to cool to room temperature, whereby 8.6 g of 2- (3-Hydroxy-4-phenoxyphenyl) acetic acid in Porm of needles of melting point 118-120 ⁰ C. be won. Bp / mm 194-204 / 0.08, pK'a = 6.8.

Analysis bar. for C ₁₄ H ₁₂ O ₄ ^; G 68.84; H 4.99. Found: C, 68.99; H 4.92.

00 9 8 4 7 / 2Ö ti *

BATH

- 59 - Example 58

Preparation of 2 - (^ - Heth yl-4- phenpxyphenyl) propionic acid

500 ml of liquid ammonia with a trace of perrichloride contains, partially mixed with 2.48 g of sodium metal. After stirring the solution for 30 minutes 11.8 g of 2- (2-Kethyl-4-phenoxyphenyl) acetic acid in a period of 30 minutes added and the dark green solution is stirred for 45 minutes. The solution is added dropwise mixed with 11.3 g of methyl iodide. After 2.5 hours long stirring of the reaction mixture will be 500 ml drier Ethyl ether added. The reaction mixture is left overnight stirred and the ammonia is allowed to evaporate. The solution is acidified mix dilute hydrochloric acid, the ethyl ether is separated and with 10 - # - sodium hydroxide solution extracted. This extract is washed with ethyl ether, acidified and extracted with ethyl ether. Of the Ethyl ether extract is dried over sodium sulfate and evaporated. By distilling the oil obtained are 5 g of 2- (2-Kethyl-4-phenoxyphenyl) propionic acid as a yellow fluorescent oil with a boiling point of 185 - 188 ° G / 0.08 mm. won, pK'a »7.40.

Analysis calculated for C ₁₆ H ₁₆ O: C 74.98? H 6.29. fief .: C 74.73; H 6.41

009847/201 A BATH

Eg 1 e 59 - 64

The following α-alkylated compounds have been identified according to the method of Example 58 from the corresponding phenoxyphenylacetic acid (or substituted phenoxyphenylacetic acid) and the corresponding alkyl halide.

2- (2-Methy 1-4-phenoxyphenyl) propionic acid, P '. 123.5 to 125 ⁰ C, pK'a = 7.3.

Analysis calculated for C ₁₆ H ₁₆ O ₅ : C, 74.98; H 6.29.

Found: C 74.88; H 6.31. .'- »■ ·

2- (4-Phenoxyphenyl) valeric acid from 2- (4-phenoxyphenyl _a ) - ⁱ :, acetic acid and n-propyl iodide, P. 73-75 ⁰ O, pK'a = 7.45.

Analysis calculated for C ₁₇ H ₁₈ O ₃ ; C 75.73; H 6.71. Found: .C 75.92; H 6.98.

2- (2,3-dimethyl-4-phenoxyphenyl) propionic acid, P. 100 - 101 ⁰ C, Analysis calculated for C ₁₆ H ₁₆ O _3: C 74.98;. H 6.29. Γ ""

Found: C 74.88; H 6.31.

2- (2-Fluoro-4-phenoxyphenyl) propionic acid, P. 92-94 ⁰ C.

. Analysis calculated for C ₁₅ H ₁₅ PO _5: C 69.22; H 5.03.

Found i - C 68.94; H 5.28. '.-' - ^

2- (3-methoxy-4-phenoxyphenyl) propionic acid, bp. 242-250 ⁰ C / 0.08 mm.

Analysis calculated for C ₁₆ H ₁₆ O ₄ : C, 70.57; H 5.92.

Found: C, 69.92; H 6.13. ;

2-Cyclohexyl-2- (4-phenoxyphenyl) acetic acid, P. 146-149 ⁰ C, pK'a = 6.9.

Analysis calculated for C ₂₀ H ₃₂ O ₅ : C, 77.39; H 7, H; 0 15.47.

: · C, 77.52; H 6.96; 0 15.55. : "

009847/201 U

BADORFOINAL

Example 65

The following compounds were prepared from the corresponding pbenylthioacetophenones following the procedure of Example 49 produced «.

2- (2-methyl-4-phenylthiophenyl) acetic acid 2- (3,5-Dimethyl-4-phenylthiophenyl) acetic acid 2- (3-methoxy-4-phenylthiophenyl) acetic acid 2- (3-ethyl-4-phenylthiophenyl) acetic acid 2- (2-phenoxy-4-phenylthiophenyl) acetic acid 2- (2-Methoxy-4-phenyltbiophenyl) acetic acid Q 2- (2-chloro-4-phenylthiophenyl) acetic acid 2- (2-iTuor-4-pbenyl "fchiophenyl) acetic acid.

At s ρ i 'e 1 66

2- (3-Hydroxy-4-phenylthiophenyl) acetic acid is after Method of Example 57 aUa 2- (3-Methoxy-4- «pbenyltliiophenyl} · inherited acetic acid. ,

Example I 67

The following α-alkyl compounds were prepared according to the method of Example 58.

2- (2-methyl-4-phenylthiophenyl) propionic acid ',

2- (3-methyl-4-phenylthiophenyl) propionic acid 2- (4-phenylthiophenyl) butyric acid 2- (2 _f 3-dimethyl-4-phenylthiophenyl) propionic acid 2- (2-fluoro-4-phenylthiophenyl) propionic acid 2- (3 -Methoxy-4-pbenylthiophenyl) propionic acid 2- (Cyclohexyl-2- (4-phenyltbibphenyl) acetic acid.

009847 / 20U

Within the scope of the invention are pharmaceutical agents, as active ingredient at least one of 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 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 forms of preparation, the active mixture with at least one inert diluent, e.g. Sucrose, lactose or starch. Such dosage forms can also be used as usual except inert diluents contain other substances, e.g. lubricants such as magnesium stearate. In the case of capsules, tablets and pills, the posing forms also allow piiffer remedies contain. In addition, tablets and pills can be provided with an enteric label.

Liquid drinks for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as are conventional for this purpose, for example water. In addition to inert diluents, such preparations can also contain ingredients, for example dressings, emulsifiers and suspending agents and 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 propylene glycol, Polyethylene glycol, vegetable oils, e.g. olive oil, and injectable organic esters, e.g., ethyl oleate. Such Dosage forms can also contain excipients, e.g.

009847 / 2aU

BATH

preservative gowns, wetting agents, emulsifiers and dispersants. You can, for example, by filtration through a bacteria-retaining filter, by addition from sterilizing agents to the preparations, by irradiating the preparations or by heating the preparations sterilized. They can also be produced in the form of sterile solid preparations that be dissolved in sterile water or other sterile injectable medium immediately before use can.

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

The dosage of the active ingredient in the invention Means can vary, but it is necessary that the active ingredient is contained in such an amount that one appropriate dosage form is achieved. You chose Dosage "depends on the desired therapeutic effect, the route of administration and the duration of treatment away. In general, doses between 0.2 and 50 mg / kg body weight per day are administered to mammals, to provide effective relief from inflammation, pain, and fever.

The pharmaceutical compositions according to the invention are further illustrated by the following examples.

Example 68

There are tablets weighing 500 mg and manufactured with the following composition:

009847/2014

BADORJGtNAL ,,

250 mg 190 mg 50 mg 10 mg

2- (3-Phenoxyphenyl) propionic acid sodium salt « dihydrates.

Strength ,

colloidal silicon dioxide magneaium sterate & t

Example 69

There are TaTaletteii with a weight of 200 mg and with ■ divided into the following composition:

2- (3-5henoxyphenyl) acetic acid 50 mg.

Strength . . 120 mg

colloidal silicon dioxide 27 mg

Magnesium stearate 3 mg

; B is ρ ie 1 70

There are tablets weighing 500 mg and manufactured 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.

'0098477201.4 _s . . _Vi Λ. '".

BAD OBIGINAU

- 65 Example 71

There will be "tablets weighing 200 mg and made with the following composition;

2- (3-Methyl-4-phenoxyphenyl) propionic acid 50 mg

Strength 120 mg

colloidal silicon dioxide 27 mg

Magnesium stearate 3 mg.

For the production of tablets analogous to those in the examples 68 and 71 are described, the above-mentioned active ingredients can be replaced by the same amount by weight of a other connection according to the invention are replaced. Such tablets can be provided with enteric layers and also contain buffer medium or the like.

009847/2014

Claims (1)

X oxygen or sulfur}. Y | one hydrogen atom, one hydroxyl group one Jünino group, a halo group, a halogen atom, a methyl radical, an ethyl radical, a Cj-G - alkoxy radical, a methanesulfonyl group, a ketfaansulfonamido group, an irifluoromethyl radical, a Acetamido group, a methyl mercapto group or a 'phenoxy group} a hydrogen atom, a Ci-Cc-Ailtylrest, G2-C5-Alkenylrest, Cg-C ^ -alkynyl radical or C ^ -Cg cycloalkyl radical, and when the Heat located in the p- »slope, 009847/20 η the number 0; Vase material atom, a hydroxyl group, a halogen atom, a Cj-Cc-ATicylrest or a C ₁ -C, -alkoxy radical, where only one of the radicals Y ₁ and Y2 consists of a hydrogen atom when Ej represents a hydrogen atom or a methyl radical, the group (a) -CCGR ₂ , in which Rg is a hydrogen atom, a »A Di-Cj-G ^ -alkylaEinoj ^ or an alkali, brodalkali »ammonium or substituted ammonium cation represents} Cb) -CQlK ⁷ , in which the radicals R ,, are 3 identical to or different from one another can be hydrogen atoms, hydroxy groups, Cj-Cg-alkyl radicals, cyclopropylmethyl radicals or groups. "Represent -CH ₂ -COOR ₂ ; (c) -CH ₅ OR-, in which R _{A is} a hydrogen atom, a C ^ -Cc alkyl group, acetyl group, propionyl group, carbamyl group, K-methylcarbamyl group, H, Nl) imethylcarbamyl group or C ^ -Gg-altoxyalkyl group, or (d) N ■ * if Il W and »if aicb the remainder L Λ — X- is in m-graduation, 0098 47/2014 - .; λ> ■■ '' - 68 - η is an integer from 0 to 3; Yg. "A hydrogen atom, a hydroxyl group : a calogen atom, a methyl radical or an ethyl radical, but a V'aeeeretoffatom, when Y ^ is a hydroxyl group or a Represents Cj-G ^ alkoxy; Bg besides the best ones mentioned above 2- (3-pbenoxyphenyl) propyl radical, and, when η represents an integer from 1 to 3, Z as well (e) the group -H ^, in which the radicals Rc, 5 which are equal to each other or be different from each other can represent (1) hydrogen atoms, C ₁ -C -alkyl radicals, cyclopropyl radicals or cyclopropylmethyl radicals or (2) acetyl radicals, propionyl radicals, N-methylcarbamyl radicals or Ν, ΐί-dimethylcarbamyl radicals. * 2. Compound according to claim 1, characterized in that that Z means the group COORg. 3. A compound according to claim 1, characterized in that η is an integer from 1 to 3 and Z is the group, means" 009847./20U 4. 2- (3-Pbenoxyphenyl) propionic acid or a pharmaceutical acceptable cationic salt thereof " 5. 2 * (3-Pbenoxypbenyl) acetic acid or a pharmaceutic acid acceptable cationic salt thereof. 6. 2- (5-phenoxyphenyl) propylamine or a pharmaceutical acceptable acid addition salt thereof. 7 * I-Methyi-2- (3 «phenoxyphenyl) propylamine or a pharmaceutical pharmaceutical acceptable acid addition salts thereof * ! ■ 8. 2- (3- 4-phenoxyphenyi) propionic acid or a pharinazeutiseh acceptable cationic salt thereof. 9. 2- (3 «methyl-4-pbenoxyphenyl) acetic acid or a pharmaceutically acceptable cationic salt thereof * TO «2« (3 «methoxy-4-phenoxyphenyl) acetic acid or a phar Pharmaceutically acceptable national salary thereof. 11. 2- (3,5-dichloro-4-phenoxyphenyl) oesetic acid or a pharmaceutically acceptable cationic salt thereof. 12 * 2- (3r5-Öimethyl-4 * pheiiöxyphenyl) esi ^ acid or a pharmaceutically acceptable cationic saijs thereof * 13 «* iherapetttiäches means includes characterized acceptable gekennzöiöhnet _r daiJ era a compound of any of 1 to Anspriicbe as active ingredient and eifteä pharma2eutiscn * 009847 / 20U