AU484455B2 - Phenylbutanol derivatives, processes for their preparation, and compositions containing them - Google Patents

Description

This invention 78.60 is 875 concerned with certain

novel phenylbutanol derivatives, with processes for

their preparation, and with compositions containing

them.

We have found that phenylbutanol derivatives

of formula I:

z-c(cr1 (OM)-ClI)-Y I

1 wherein Z is f-biphonylyl or the group

R1 ,0

2 Y is COOR 2 or CH OR3, R1 is H, F, Cl or Br, R is IH or

A, R is II or alkanoyl having I to 6 C atoms, and A is

alkyl having 1 to 6 C atoms, and their physiologically

acceptable salts have valuable pharmacological proper-

ties and are well tolerated. In particular, these

compouncds have anti-inflammato'ry activity, as can be

demonstrated on rats, for example, in the adjuvans-

arthritis test using the method of Noe;.bould (Brit. J.

Pharmacol., 21, (1963), pages 127 136). Certain

of these compounds also have cholesterol level-reducing

and triglyceride level-reducing activity, as can be

demonstrated in the serum of rats by the method of

Levine et al. (Automation in Analytical Chemistry,

Technicon Symposium 1967, Mediad, New York, pages 25

28) or by the method of Noble and Campbell (Clin. Chem.,

16 (1970), pages 166 170). The compounds also exhibit

analgesic, anti-pyrotic, enzyme-inducing or fibrinolytic

activity or are effective in inhibiting the aggregation

2 484,455

78,608 of thro;;.bocytcs as can he observed by methods which

are current for this purpose.

The foregoing compounds can, therefore, be

used as medicaments in human and veterinary medicine

and also as intermediates for the preparation of other

medicaments. For example, the biphenylyl derivatives

of formula I (Z 4-biphenylyl) can be converted by

chlorination into other valuable anti-inflammatory

agents.

The compounds of formula I and their physio-

logically acceptable salts are novel and constitute one

aspect of the present invention.

Generally similar compounds are described in

German DOS 2,162,038, but said specification does not

disclose any compound which falls within formula I.

In formula I, R is preferably I, F or Cl;

R1 is preferably in the m-nosition or, more preferably,

in the p-position, but R may also be in the o-position. 2 The radical R is preferably H, methyl or ethyl, and

the radical R is preferably iH or acetyl. The olkanoyl

group is the radical of a fatty acid having 1 to 6 C

atoms, preferably acetyl, and also, for example, formyl,

propionyl, butyryl, isobutyryl, valeryl, isovaleryi,

methylethylacetyl, trimethylacetyl, caproyl, isocaproyl

or tert.-butylacetyl.. Alkyl is preferably methyl or

ethyl and secondarily n-propyl, isopropyl, n-butyl,

isobutyl, n-pentyl or n-hexyl, but may also be, for

example, sec.-butyl, tert.-butyl, isopentyl, neopentyl

or isohexyl.

Preferred compounds according to the invention

3 484.455

78,60 8 /75 are those in which at least one of the radicals men-

tioned has one of the preferred meanings given above.

The invention also comprises a process for

the preparation of a compound of formula I, which com-

prises:

treating a compound of formula II:

Z-Q II

wherein Q is -C(C H3 (Ol)-CII 2 -W or -CX(C1 3 )-C11 2 W is

a functionally modified -COOHI or -CH 2 OIH group, but is

different from Y, X is Hal or a functionally modified

hydroxyl group, and Hal is Cl, Br or I and Y and Z

have the above-stated meanings, with a solvolysing

agent, or

(ii) reducing a compound which otherwise

corresponds to formula I, but which contains, addi-

tionally or instead of 1I atoms, at least one group which

can be reduced or can be replaced by hydrogen, or

(iii) oxidizing a compound of formula III:

Z-CHi(Cii -CIIY Ill

wherein Y and Z have the above-stated meanings, or

(iv) reacting a compound of formula IV:

q C(CHi (OfI)-CI 2-y IV

or a salt thereof, with a compound of formula V:

Q2 V

4 •484455

78.608 /75 1 2 or a salt thereof, wherein one of the groups Q or Q 1 is OHi, and the other is X, and R X, Y and Z have

the above-stated meanings, or

diazotizing a compound of formula VI:

Ar-C(O011) (CI[ -CH2-Y VI

wherein Ar is the radical Hn N

0

and Y has tlhe above-stated meaning, and reacting the

resulting diazonium salt with a halogenating agent.

The compound of formula I obtained by any of

the foregoing processes may, if desired, be treated with

a reducing, oxidizing, solvolysing, esterifying or

trans-esterifying agent to convert tlhe Y radical into

another Y radical and/or, when R in such compound,

[11

be treated with a chlorinating or brominating agent to

obtain a product in which R- Cl or 3r and/or, when

such compound contains a carboxyl group, be treated with

a base to convert it into a physiologically acceptable

salt.

The processes described above represent part-

icular applications of standard methods described in the

literature (for example, in standard works such as

l1ouben-Weyl, Methoden der organischen Chemie ("Methods

of Organic Chemistry"), Georg Thieme Verlag, Stuttgart;

Organic Reactions, John Wiley Sons Inc., New York);

in particular, the reaction conditions which are known

and suitable for the reactions concerned, can be used.

The starting materials for the preparation of

s 484,455

78,608 /75 the compounds of formula I can, if desired, be formed

in situ in such a way that they are not isolated from

the reaction mixture, but are immediately reacted

further to give the compounds of formula I. The

starting materials for the preparation of the compounds

of formula I are, in general, also new; they can,

however, be readily obtained by methods which are in

themselves known.

The compounds I can be obtained, in particular, by

solvolysis (preferably hydrolysis) of corresponding funct-

ionally modified compounds of formula II. Solvolysis of

the latter compounds may be carried out in an acidic,

neutral or alkaline medium at a temperature of from

to 300°C.

Hydrochloric acid, sulphuric acid or acetic

acid are preferably used to effect acidic solvolysis,

while sodium hydroxide, potassium hydroxide, calcium

hydroxide, sodium carbonate or potassium carbonate are

preferably used for basic solvolysis. The solvent

used is preferably water, a lower alcohol, such as

methanol or ethanol, an ether, such as tetrahydrofuran

(THF) or dioxan, an amide, such as dimethylformamide

(DMF), a nitrile, such as acetonitrile, a sulphone,

such as tetramethylenesulphone, or a mixture of two

or more of these solvents, particularly mixtures con-

taining water.

The solvolysis of an alcohol derivative of

the formula Z-CX(C1 3 )-C12-Y is preferred. In these

compounds, X is preferably a functionally modified OH

group, or Cl, Br or I. The Oil group can, for example,

6 .48 4.455

78,60 8 he functionally modified in the form of one of its

alcoholates, preferably one of its zinc alcoholates

of the formula Z-C(CHI )(OZnBr) -CI2-Y, such as are

formed as primary products in zinc organic syntheses,

particularly fhe Reformatsky reaction, and also in

the form of one of its magnesium alcoholates or lithium

alcoholates, such as are formed as reaction products in

Grignard reactions or reactions with organo-lithium

compounds, as an ester, for example a carboxylic acid

eFter, the carboxylic acid radical preferably having

up to 7 C atoms (for example, acetyl or benzoyl), as

an alkylsulphonic or arylsulphonic acid ester (wherein

the alkyl radical preferably contains 1 to 6 C atoms

and the aryl radical preferably 6 to 10 C atoms), or

as an ether, for example an alkyl ether (wherein the

alkyl group preferably contains up to 6 C atoms), an

aryl ether (wherein the aryl group preferably contains

.6 to 10 C atoms) or an aralkyl ether (wherein the

aralkyl group preferably has 7 to 11 C atoms). Boric

acid esters, which are formed as intermediates in

oxidative hydroboronation, can also be used.

Compounds of formula II (Q=-C(CH )(OZnizal)-

CH -COOA) are preferably obtained by reacting a ketone

of the formula Z-CO-CII 3 with an organo-zinc compound of

the formula IIalZn-CII 2COOA under the conditions of the

Reformatsky reaction (see, for example, Organic Reactions,

Vol. 1, page 1 et. seq.). The ketones can be obtained,

for example, by a Friedel-Crafts acetylation of compounds

of the formula Z-H on which they are based; the organo-

zinc compounds are preferably prepared in situ from the

7 4 8 4.4

78,608 corresponding haloognoacetic acid derivatives and

zinc. Bromoacetic acid esters, particularly bromo-

acetic acid methyl and ethyl esters, are preferred as

the halogcnoacetic acid derivatives. The zinc can

be employed in any desired form, for example as zinc

dust, zinc foil or zinc wool or in granulated form.

The reaction can be carried out in the absence or,

preferably, in the presence, of a solvent. Examples

of suitable solvents are hydrocarbons, such as benzene

oc toluene, and ethers, such as diethyl ether, TIIF or

dioxan, and mixtures thereof. The addition of iodine

or trimethyl borate can be advantageous. Suitable 0 reaction temperatures are from 0° to 150 C, preferably

0 from 20 C to the boiling point of the reaction mixture.

The resulting zinc complex can be hydrolysed to give

an alkyl ester of formula I (Y COOA); under more

vigorous conditions of hydrolysis, the ester is sapon-

Sificd in the reaction mixture to give the acid I

(Y COOH).

A corresponding organolithium compound or

Grignard compound of the formula M-CHI2-Y (M Li or

MgIIal) can also be reacted with a ketone of the formula

Z-CO-CH under identical or similar conditions, a metal

alcoholate of formula II (Q -C(CII )(OM)-CH2-Y) being

formed. A variant of this synthesis consists of

reacting a ketone Z-CO-CII with acetic acid in the

presence of an alkali metal, preferably Li or Na,

and an aromatic hydrocarbon, preferably naphthalene or

phenanthrene; in the course of this reaction the di-

anion of a compound of the formula MCHICOON (M alkali

8 -484.455 metal) is 78 608 formed as an intermediate.

Metal alcoholates of the formula

Z-C(CH (OM)-CII2-Y (M Li or Mg!ial) can also be

obtained by reacting a ketone of the formula Z-CO-C 2-Y

with an organo-mctal compound of the formula CHIM3 (N

Li or Ngllal), such as methyl-lithium, methylmagnesium

bromide or methylmagnesium iodide or by reacting a

ketone of the formula CH COCH Y with an organo-metal

compound of the formula Z-M (N Li or Ng!Ial), such

a:s 1l-biphenylylmagnesium bromide, 4-phenoxyphenyl-

lithium or li-p-fluorophenoxyphenyl-lithium. Ketones

of the formula Z-CO-CI{2-Y can be obtained by a Friedel-

Crafts acylation of a compound of the formula Z-II using

an acid halide of the formula Cl-CO-CT2 Y; keto-esters

of the formula Z-CO-CH2-COOA can be obtained, for example,

using malonic ester chlorides; and the corresponding

keto-acids can be obtained by subsnequent saponification.

-The Grignard reactions and the reactions with organo-

lithium compounds referred to above are preferably

carried out under the same or similar conditions as

those indicated above for the Reformatsky reaction.

The metal alcoholates mentioned, of formula

II (Q -C(CII )(OM)-CH 2 N Li, MglIal or ZnHal), are

preferably not isolated, but, after their formation,

are hydrolysed in situ using a fairly dilute acid, for

example sulphuric acid or hydrochloric acid, or aqueous

ammonium chloride solution, compounds of formula I

being obtained.

Compounds of formula I can also be prepared

by solvolysis of an acid derivative of the formula

9 48 4,455

78,60 8 175 Z-C(CII (oil)-CI[ 2W In these, W is preferia-bly one of

the following radicals (wherein the Rl' and P."1 groups

which are to be split off can be radicals of any des-

ired kind and are, for example, alkyl having preferably

1 to 4 C atoms, the alkyl groups being the same or

different or together form, for example, tetramethylene

or pentatnethylene, optionally'interrupted by 0):

CHal 3 COOP."' (wherein is a different radical

from A, particularly alkyl having 7 to 12 C atoms or

aa alkyl radical substituted in any desired way which

is, however, different from C(OT')3 COOAcyl

(wherein Acyl is the radical of a carboxylic acid

having up to 20 C atoms, preferably an acyl radical

of the formula Z-C(Cil 3 (OiW)-C J12 CN; CON11I2

CONJIR'1; CONR'R"; c6NI10OM; C(011)=NOII; CONIM-H2 CON 3

C (Olt I)=Nil; C(Nil 2 =NNH~f2 C(NI[NI 2 )=Nil; CSOH; COS11;

CSORl' CSNII 2 CSNIfl' or CSNR'R". W is preferably

a nitile g~roup rar an acid aimide group.

The compounds of th6e formulda Z-C(C!I (04) -cil 2-W

can be obtained in a known manner, and the hydi-oxy-.

esters Z-C (CHl )(OiI)-CLIO.-COOR"' can be obtained, for

examnle. by reacting a ketone of the formula Z-CO-Cll,

with an ester of the formula Hfal-Cl, 2-COOR"' in the*

pre~sence of zinc. Halogen derivatives of thc formula

Z-Clial(CI! -CH Y can. be prepared, for example, by an

addition reaction between a hydrogen hialide and a suit-

able unsaturated compound of the formula Z-C(Cii =CII-Y.

Compounds of formula II whcrein X is Cl, B3r,

I or an acylated Oil group, or wherein W is Cif, al or

Cil2 OAcyl, are preferably saponified in an aqueous or

-48 4,455

78,608 aqueous alcoholic solution or suspension, with the

addition, if desired, of a solubiliser, for example

an alcohol, glycol or glycol ether. Alkalis, such

as NaOH or KOIH, alkaline earth metal hydroxides, such

as Ca(OIl)2 or'Ba(OlI) 2 or also suspensions of Pb(Ol) 2

or AgO!!, are preferably used as the saponifying agent.

Alcohols, such as methanol, ethanol or isopropanol,

and mixtures thereof with water, are preferably used

as the solvent. The saponification is preferably

carried out at a temperature of from 20 to 100 C,

preferably from 600 to o100oC.

Halogen atoms in compounds of formula II

[Q -C(CI 3 (OH)-CII2 -CH 2 Ial] can also be converted

into the corresponding acyloxy groups by treatment

with a salt of a fatty acid, for example potassium

acetate or heavy metal acetates, in an inert solvent,

such as dimethylformamide, at a temperature of from

20° to 100°C.

Halogen atoms or ester groups which are

linked to a tertiary carbon atom in II (Q -Clal(CI{3)-

by CH 2 -Y or -C(OAcyl)(CHi3 )-CI2-Y) can also be replaced

Oil or can be removed by the action of water, preferably of a in the presence of a catalytically active amount at a mineral acid, such as sulphuric acid, preferably more preferably 110° temperature of from 20° to 100°C, 0 to 60 C.

Etherified OH groups are preferably hydrolysed such as 113r or by the action of a hydrogen halideacid, out in lI, the reaction advantageously being carried temperature of acetic acid or aqueous acetic acid at a

11 -484,455 from 60 C to the boiling point, S78,608 particularly at the boiling point. The halogen compounds. formed are generally hydrolysed subsequently using alcoholic alkali as described above.

Nitriles of formula II (W CN) and amides

of formula II (W1 CONIH2, CONHR' or CONR'R") are

preferably hydrolysed in an alkaline medium (for

example using aqueous alcoholic alkali).

The compounds I can also be obtained by,

r',ducing compounds which otherwise correspond to

formula I, but which contain additionally or instead

of H atoms, at least one group which can be reduced or

can be replaced by hydrogen. Preferred starting

materials for the reduction are compounds of formula

VII:

Z-C(CH3 )(OH)-CII 2 -E VII

-w herein E is a free or functionally modified -COOH or

-CHO group or benzyloxymethyl, but is different from

Y, and 7 has the above-stated meaning.

In detail, E is preferably COOR (wherein R

is an alkyl group having more than 7, preferably 7 to

12, C atoms), CHO1 and also COilal, CN, CONH 2 CON 3

COOAcyl (wherein Acyl has the above-stated meaning)

or another ether group which can be split by hydro-

genolysis, such as diphenylmethyloxymethyl or tri-

phenylmethyloxymethyl. Compounds which have at least

one substituent on the benzene rings which can be re-

moved reductively (for example N1i are also suitable

as starting materials for the reduction.

12 484,455

78,608 The al!<yl esters ;;f-ttioned c be oi;tained,

for exauiplec, from ketones of the formula Z-CO-C'i 3 by

means of zinc and bromoacetic acid alkyl esters; they

can be readily converted (for example by saponification,

aidisation or reduction) into thle other above-mentioned

functional derivatives of tlhe acids.

Catalytically activated hydrogen or complex

metal hydrides are preferably used for the reduction.

It is also possible to use other conventional reducing

agznts, for example metals conjointly with acids or

bases.

Examples of suitable catalysts for catalytic

hydrogenations are noble metal, nickel or cobalt cat-

alysts and also mixed catalysts, such as copper-chromniim

oxide. Suitable noble metals are, in particular,

platinum and palladium, which can be present on

supports (for example charcoal, calcium carbonate or

strontium carbonate), as oxides or in a finely divided

form. Nickel and cobalt catalysts are preferably

employed as Raney metals. The hydrogenation can be

carried out at a pressure of from I to 100 atmosl-heres

and at a temperature of from -80° to 4150° C, preferably 0 from 20° to 100 C. The hydrogenation is carried out

in the presence of an inert solvent, for example an

alcohol, such as methanol, ethanol or isopropanol;

a carboxylic acid, such as acetic acid; an ester, such

as ethyl acetate; or an ether, such as TU7 or dioxan.

Mixtures of two or more solvents, for example mixtures

containing water, can also be used.

Suitable complex metal hydrides for use as

484.455

78,60 8 '7 1 reduc itng agents inII LdICIiA11U \ah 1 1 I anII!d di1)or.an e

optionally with the addition of cattys ts such aifs Br 3

33

in particular, ethers, such its (iethyl cthert THF,

dioxan, 1, 2-dimethoxyethane or diglyme. In the case

of a reduction with NaI3!11 1 suitable solvents are, in

particular, alcohols, such as methanol or ethanol.

The reduction is preferably carried out at a temiperature

of from -800 to +150 0C, more preferably from 20 0 to

A further suitable method of reduction, for

example for the aldehydes or esters mentioned, is reac-

tion with nascent hydrogen. The latter can be generated,

for example, by treating metals urth acids or bases.

Examples of systems which can bi: used are zinc/acidj

zinc/alkali metal hydroxide solutiont iron/acid and

tin/acid. Sodium, or another alkali metal, in an

alcohol, such as ethanol, isopropcE -ol, n-butanol, amyrl

alcohol or isoamyl alcohol or phenol; an aluminium!

nickel alloy in an aqueous alkaline solution, if des-

ired with added methanol; and sodium amalgam or

aluminiun nmalgam in anuceous alcoholic solution or

aqueous solution, can also be used to generate the

nascent hydrogen. In this method, the reaction temp-

erature is suitably from 0 0to 150 0C, preferably front 0 0 to 120 C.

Amino groups present on the aromatic rings

can be removed by reduction, by first diazotising the

amino groups and then reduicing the Aresulting diazonium

salts ill situ, for example by boiling with ethanol,

48 4,455

78,608 formic acid, 1 3PO, or stannite solutions.

The compounds of formula I can also be obtained

by oxidation of compounds of formula III, for example

with Cr0O or KMnO or with air or oxygen in the presence 3 ofcatalysts such as CuO/CaCO 3 or Ca(0{) 2 The compounds

of formula III can in turn be prepared, for example, by

condensation of ketones of the formula Z-CO-CJI with 1 3 nialonic acid, subsequent decarboxylation and hydrogena-

tion and, if desired, estcrification and/or reduction

of the ester group.

The compounds of formula I can also be obtained

by reacting a compound of formula IV or a salt thereof

with a compound of formula V or a salt thereof. The

starting materials of formula IV can be obtained, for

example, by reaction of a p-Q -acetophenone with a

bromoacetic acid alkyl ester and zinc, if desired

followed by saponification and/or reduction. The

startirng materials of formula V are in most cases known.

A phenol of formula IV (Q OH) may be reacted

with a compound of formula V (Q2 X) or a compound of

formula IV (Q X) may be reacted with a phenoL of

formula V (Q Oil). In this reaction, the phenol is

preferably in the form of the corresponding phcnolate,

particularly the sodium phenolate or potassium phenolate.

The reaction is suitably carried out in the presence of

an inert solvent, such as DIF or phosphoric acid hexa-

methyltriamide (IDIPT), in the presence of a catalyst,

such as copper powder, at a tem)perature of from 50 to

2000°C, preferably from 80° to 130°C.

Compounds of formula I which contain halogen

15 S1 484.455

78,60 8 can also be obtained from the corresponding amino

compound of formula VI by first diazotising the latter,

for example with a salt or ester of nitrous acid (such

as NaNO2 or n-butyl nitrite) in qlueous hydrochloric acid

at a temperature of from -20° to +10°C, and then con-

verting the resulting diazonium salt into the halogen

compound. Fluorine compounds R1 F) are prefer-

ably obtained by reaction with IHBFi to give the diazonium

tetrafluoborate followed by thermal decomposition at

from 1000 to 200 C in the absence or presence of an

inert solvent, such as toluene, xylene or dioxan.

Decomposition may also be effected at room temperature

in an aqueous medium in the presence of copper powder.

If the diazotisation is carried out with NaNO in

anhydrous hydrofluoric acid, the desired fluorine com-

pound is obtained directly on subsequent warming.

Replacement of the diazonium group by chlorine or

,bronini is preferably carried out in hot acuccus

solution in the presence of Cu2Cl or Cu 2Br 2 The

starting materials of formula VI can be obtained, for

example, by reduction of corresponding 3-hydroxybutyric

acid esters which, however, contain a nitro group in

place of the radical R 1

The Y radical in a resulting compound of

formula I can, if desired, be converted into another

Y radical by reduction, oxidation, solvolysis, ester-

ification or transesterification, in accordance with

methods described in the literature.

In particular, an acid or ester of formula I 2 (Y COO may be reduced to the corresponding alcohol

484.455

78,60 8 of formula I (Y C!,011) preferably with LiAlHl, in

accordance with the above-mentioned methods.

Conversely, an alcohol of formula I (Y

CI 201) may be oxidized to the corresponding carboxylic

acid of formula I (Y COOH) in accordance with known

methods, for example with KNnO or Cr0 3

The R radical in a compound of formula I may

be converted into another R radical by treatment with

solvolysing agents. In particular, an ester of formula

I (Y COOA) can be saponified to the corresponding

acid I (Y COH)) or an ester of formula I (Y

can ba saponified to the corresponding

alcohol of formula I (Y CIH 2 01H). The solvolysis or

with saponification can be carried out in accordance solvolysis one of the above-mentioned methods for the

of the compounds of formula II. The esters are pref-

alcoholic alkali erably saponified by treatment with an hydroxide, solution, for example ethanolic potassium

at a temperature of from 20° to 120°C, more preferably

at the boiling temperature.

An acid of formula I (Y COOH) may be

with an alcohol of the formula A-Oil, or esterified

a diol of formula I (Y CH 2 OI!) may be esterified with

(or one of its an alkanoic acid having up to 6 C atoms or anhydride, reactive derivatives,_ for example a halide or acetic such as acetyl chloride, acetyl bromide

anhydride). The esterification is suitably carried catalyst, out in the presence of an acidic or basic or organic acid, such as IIC1, for example an inorganic

IHBr, ill, 2 SO l[ H3 PO 4, trifluoroacetic acid, benzene-

17 484,455 suiplionic acid or ptuneslhicacid, or an acidic ion exclkanger, or of a base, for examnpic of an alkali metal hydroxide, such as NaOlI or KOHU, an alkali metal carbonate, such as sodium carbonate or potassium carbonate, or an organic base, such as pyridine, if desired in the presence of an inert solvent, such as beiizene, toluene or xylene, at a 0 temperature of from 0 0 to i1 C, preferably from 200

0 of the acid I (Y= to 100 C. In the estcrification

Cr011), the alcohol is preferably used in excess. The

esterification of a (1101 I (Y CH 2 OIl) is preferably

carried out with the appropriate acid chloride or acid

anhydride in pyridine at room temperature. Esters can

also be obtained by an addition reaction between a

carboxylic acid I (Y COOII) with an olefin (for

example, isobutylcne) or by reaction of the carboxylic

acid v:ith a diazoalkhanc, for ezample diazomothane.

Furthermore, esters can be prcpared by reaction of a

metal salt of an acid I (Y C0011) prefcrably an

alk-ali4 metal salt, lead salt or silver salt, vith a

halide of the formula A-X or with the corresponding

chlcrosulphiJtcs of the formula A-OSOCl, the resulting

adducts subsequently being thermally decomposed. Thle

esterification can also be carried out in several

stages. The diols I- (Y =Clf 011) can also be ester-

ified uith keterineS. Forma tes I (Y C11[2 0-CIIO) can

suitably be obtained from the corresponding cliol by

heating with an excess of formic acid.

The desired esters of formula I COOA)

Can also be obtained by trans-esterificatiofl, particularly

48 4.48

78,60 8 by reaction of another ester with an excess of the

appropriate alcohol or by reaction of a carboxylic

acid I (Y COOHi) with any other ester of the appro-

priate alcohol (preferably alkanoates wherein the

alkanoyl radical has up to 4 C atoms), preferably in

the presence of a basic or acid catalyst, for example

sodium ethylate or sulphuric acid, and at a temperature

of from 0 C to boiling temperature, the latter being

more preferred.

A chlorine or bromine atom may be introduced

into a compound of formula I (R1 H) by halogenation

in accordance with methods described in the literature,

in order to obtain a compound of formula I (R1 Cl or

Br). Halogenation-may, for example, be effected by

direct reaction with elementary chlorine or bromine

in an inert solvent, such as ether, tetrachloromethane

or acetic acid, preferably in the presence of a catalyst,

for examl].e iron filings, iodine or AlCl 3 and at a

temperature of from -300 to 100 0 C.

The acids of formula I (Y COOH) can be

converted into a physiologically acceptable metal or

ammonium salt thereof by reaction with the appropriate

base. Salts which can be used are, in particular,

the sodium, potassium, magnesium, calcium and ammonium

salts, and also substituted ammonium salts, such as,

for example, the dimethylammonium, diethylammonium and

diisopropylammonium, monocthanolammonium, diethanol-

ammoniumi and triethanolammonium, cye lohexylammonium,

dicyclohexylammonium and dibenzyle thylenediaimmonium

salts.

9 48 4,4 5

78, 608 Conversely, an acid of formula I (Y COO1)

can be liberated from a metal or ammonium salt thereof

by treating the latter with an acid.

The compounds of formula I contain a centre

of asymmetry and are usually obtained in the racemic

form. The racemates can be separated into their

optical antipodes by any of the known mechanical or

chemical methods as described in the literature; for

example, an acid I (Y COOH) can be separated by the

use of an optically active base and a diol I (Y

CI 20H) by the use of an optically active acid via the

diastereoisomeric ester or by forming an acid ester

(for example, the phthalate) and resolving the latter

by the use of an optically active base.

The compounds according to the invention are

used in human or veterinary medicine in admixture with

solid, liquid and/or semi-liquid inert, physiologically

.acceptable carriers or excipients. Suitable carriers

are organic or inorganic substances which are suitable

for parenteral or enteral administration or topical

application and which do not react with the novel

compounds, for example water, vegetable oils, benzyl

alcohol, polyethylene glycols, gelatine, lactose,

starch, magnesium stearate, talc, petroleum jolly and

cholesterol. Compositions in the form. of tablets,

drages, capsules, syrups, elixirs or suppositories

are suitable for enteral administration. Compositions

in the form of solutions, preferably oily oraqueous

solutions, suspensions, emulsions or implants are

suitable for parenteral administration, whilst ointments,

484,455

78,608/75 creams or powders are suitable for topical application.

Such compositions may be sterilised and/or may contain

adjuvants, such as lubricants, preservatives, stabil-

isers and/or wetting agents, emulsifiers, salts for

regulating the osmotic pressure, buffer substances,

colorants, flavouring materials and/or aromas. They

may, if desired, also contain one or more other active

compounds.

The compounds of formula I and their salts

are, in general, administered similarly to known anti-

inflammatory agents, such as Indomethacin. The daily

dosage is preferably from 0.2 to 20 mg/kg of body

weight. Oral administration is preferred. When

the composition is formulated in dosage unit form,

each dosage unit preferably contains from 10 to 1000 mg,

more preferably from 30 to 300 mg, of the active com-

pOu nd( a).

In order that the invention may be more fully of understood, the following examples are given by way

illustration. In these examples, all temperatures

are in The expression "standard working up"

means: water and/or an organic solvent, such as

:benzene, chloroform or dichloromethane, is added, if

to the reaction mixture, the resulting mix- necessary,

ture is separated into two phases, the organic phase evaporated, is dried over sodium sulphate, filtered and

purified by chromatography and/or and the product is

crystallisation.

Ixam nle

21.2 g of h-phcnoNyacetophlcrione and 11.1 ml a)

484,455

78, 60 8 of bronioace tic acidi othyl ester are diss-olved in a

mnixture of 75 nil of 1-11-Z110 and 75 nil of toluene.

ml of this solution alrc added to 7, g of zinc powder

(previously washed suiccessively u;ith hydroclloric

acid, water and acetone, and then dried) and the~ iix-

ture is heated to 700 While stirring and passing in

nitrogen. After the reac tion has begun, the remain der

of the solution is added dropwise, the mixture is boiled

for one hour and cooled and 110 ml of 2M' sulphuric acid

are added dropwise in order to decompose the resulting

alcoholate of the formutla C 6 11 5 0-p-C 6 1III -C (C I 1 (OZnI11r)-

CHT -COOC 2 f1 The organic phase is separated off and

standard working up gi'ves 3-p-phenoxypllenyJ -3-hydroxy-

butyric acid eth~yl ester.

The following are obtained similarly from

the corresponding broinoacetic acid esters:

3- i-Biphenylyl) -3-liydroxybutyric acid methyl ester,

3. (k-bir4-Thenylyl) -3-hyd,(roxybutyric acidl ethy]. ester, 0 m.p. 56 57 4-biplieliylyl)1-3-hiydroxybutyri-c acid propyl ester,

3-(4-biphenrylyl)-3-iydr-oxybutyric acid isopropyl ester,

!I.biphieiylyl) -3-hiydrexybutyric acid n-butyl ester,

t -biphenylyl) -3-Ilydrioxylbutyric acid isobutyl ester,

3-(Ii-biplieniylyl) -3-hiydr-oxybutyric acid sec.-butyl ester,

!l-biph)Ienylyl)-3-hiydr-oxybutyric acid. tert. -butyl ester,

3-p)-pheno-xyplienyl-3-hydroxybutyric acid methyl ester,

3-p-phienoxNy 1 ,henyl-3-hiydroxybuttyric acid propyl ester,

3-)p-henoxyplienyl-3-hiydroxybutyric acid isopropyl ester,

3-p-phncloxYph)enyl-3--hiydroxybuttyric acid ji-butyl ester,

3-p-phenoxvphenyl-3-fhydroxyhityric acid isobutyl ester,

22 48 4,45

78,60 8 3-p-phlenoryplIwxky(l-3-1iydoxy~ttyric acid seC.-butyl ester,

and

acid tert.-butyl ester. 3-P-illiovllpeiY-3-hydroNybutyric

b) 10 g of 3--piphenox-yplyenyl--.hydroxybutyric acid

are dissolved in 50 ml of ethanol and the ethyl ester

solution is boiled for 15 minutes with 2 g of KOIT,

evaporated and subjected to standard working up to

3-plphenox-ypflnyl-3-hydiroxybutyric acid, m.p. give

1380. Cycloliexylamine salt, m.p. 188 1890. 137

3-(4-fiphcnylyl) -3-hydroxybutyric acid,. m.p.

137 1380, is obtained analogously from the corres-

ponding ethyl ester.

c) 3 g of 3-p-plpeno-yl'icnyl-3-lcIroxybuityric

acid acid ethyl ester are dissolved in 20 ml of acetic

of 0.8 of blohrine ir 20 ml of acetic and a !olution

the acid is added dropwise with stirring at 200 and

is stirred for a furthor hour, evaporatcd r.d nxture

subjected to standard working up to give 3-p-(p-

chloroplieiioxY) phelnyl-3-hydroxybutyric acid ethyl

0 ester, n 1.5456.

Example 2

a) A mixture of 20 g of bromoacetic acid ethyl and ester, 23.1 g of p-(p-fluorophclnoxy)-acetoplwnone

8 g of zinc foil is added to 100 ml of benzene and the

boiled with stirring for one hour. After mixture is

cooling, dilute sulphuric acid is added in order to

decompose the resulting alcoholate and standard work-

ing up is effected to give 3-p-(p-fluoropY.enoxy)-3

hydrcxybutyric acid ethyl ester.

S 484,4

78,60 8 175 The fol lo-iiig are obtained analogously front

the corresponding bromoacetic acid esters:

3-P- p-Fluloraphclno\Y) -plionyl-3-l'idroxybutyric acid

methyl ester,

3-P- (p-fluorop] enoxy) -henYl-3-hydroxybuttyric acid

propyl ester,

3-P- (p-fluorophieloxy) -pheinyl-3-hiydroxylhutyric acid

isopropyl ester,

3 (p -f luo rophieno xy) -Phe nYl- 3-hydroxybu tyri c acid n-

butyl ester,

3-P- (p-flnorophienoxy-) -ph!cnY-l-ydroxy~butyric acid iso-

butyl ester,

3-p- (p-fluorophieno.xy) -phenyl-3-hyd!ro-ybutyric acid

sec. -butyl ester, and

p-fluorophienoxy) -phenyl-3-uiydroxybfltyric acid

tert. -butyl ester.

b) 1 g of 3-p- (p-fluorophenoxy) -p1icenyl-3-h'Ydroxy-

butyric acid ethyl ester is allowed to stand for 24

hours with 0.2 g of Na~il in 40 ill of isopropanol, and

standard -working up of the mixture gives 3-P-(P-fluoro.-

phenoxy) -plenYl-3-hydroxybutyric acid. Cyclohe-y laniine 0 salt, decomposition at 190

Example 3

a) 2.46 g of Ii-p-chloropenoyacntopienofle and

g of bromoacetic acid ethyl ester are addled to a

mnixtutre of 6.5 g of granulated zinc (Previously washed

with dilute hydrochloric acid, water and acetone, and

then dried) and 0.2 g of iodinie in 70 ml of benzemn and

nil of diethyl ether. The mixture is boiled for 4

48 4,455

78, 60 hours with occasional shalking, 5 9 of zinc and] a trace

of iodine being added after 1, 2 and 3 hours, and a

further 1.5 g of bromoace tic acid ethyl cster being

added after 2 hours. After cooling, acetic acid and

ethanol are added in order to decompose tlic resulting

alceholate to give a solution which is poured into

water, and standard working up ges3p(p-chloro-

phenox-y) I)phenyl-3-hiydroxybutyric acid ethyl ester;

20 n D 1.54i56. The following are ebtained analogously, using

the correspondinig broinoacetic acid esters:

acid 3-P- (p-Chiloroplienoxy) -pheny 1-3-hiydroxybutyric

methyl ester,

3-p)-(p-clilorophienoxy) -plenyl-3-hydroxybutyric acid

propyl ester,

acid 3--pclrp-eoy-pinl3hdoyiiyi

isopropyl ester,

acid 3-P- (P-clfl oropheioxy) -phieriY] .3-hydiroxyhutyric

I n-butyl ester,

-pheniyl.-3-hydroxybutyric acid 3-p- (p-clelrophen--oxyc)

isobutyl ester,

acid 3-P- (P-ciiloroplenloxy) -phrenyl-3 -hydroxybutyric

sec.-butyl ester,

acid 3-P- (p-clilorophielo.y) -plenyl-3-hydroxybttyric tert.-butyl ester, and

acid 3-P-(p)-chloroplicnoxy) -phenYl-3-tidro)Cybutyric

n-hexyl ester.

b) 1 g of p-chilorfopheino-xy) -plienyl-3-iydrOX,.y-

butvric acid ethyl ester is boiled for one hour with

carbonate in 25 nil of methanol, and g of potassium

5-.48 4.45

78,608 17 the mixture isi Subjectced to s tanclnrd wor'king tip to

give p-chj ~oropihenoxy) -phlelY-3-1i)clroxy)I~ityl-ic

acid; cyclohexyainine salt, rn.p. 183 1840.

Example

a) The following are obtained by the procedure

described in Examiple 1, using p-(o-fluorophenoxy)-

acetophienoac, p-(rn-±'luoro)hletoxy) -acetoplienione, p-(o- cilorolphienoxy) -acetophenionie, p-(mi-chilorophienoxy) a:--etophenoxne, p- (o-brornophene-ixy) -acetophenione, p-(in- h~romoplic:-iox-y) -atctophienonie or p- (p-broinopherioxy)

acetophenone, as the starting material:

3-p- (o-Fluoroplienoxy) -pleniyl-3-liydroxybutyric acid

methyl ester,

3p- -fluorophenoxy) -pheniyl-3-hiydroxybutyric acid

ethyl. ester,

(~-rluccphmoxy)-phenyl-3-hydroxybutr-ic. 3-p acir

cthy- ester,

3-p- (i-fluoropheonoxy) -phcnyl-3I-hydroxybutyric acid

ethyl ester,

3-p-(o-chilorophenoxy) -plhenyl-3-hydroxybutyric acid

methyJ. ester,

3-p- -chilorophenoxy) -phenyl-3--hydroxybutyric acid

ethyl ester,

3-p- (m-chilorophonox 1 )henyl-3 -hydroxybutyric acid

methyl ester,

3-p- (m-clilorophenoxy) -plienyl-3-hydroxybuityric acid

ethyl ester, 3p-(o-bronopmenoxy) -phenyl-3-hydroxyuyicai

methyl. ester,

R6 48 4,455

78,60 8n5 'icicI 3-1- o-hro:lophenlo-xY) phenvl-3-liYclro-xybiitYric

ethyl ester,

3-p-C n-Ibron'iophento-y) -pheiiyl-3-liydvio.xybu tyric acid

methyl. ester,

3-p-(rm-bror-oplienoxy) I)hen'Yl-3-Iiydr-o>.butyric acid

ethyl ester,

3-P- (p)-broinoplienoxy) -phenyl-3-ydi-oxybutyric acid

methyl ester, and

3-P-(p-Ihromophefloxy)>Thiel3-hydroxybutyric acid,

ethyl ester.

b) The following acids are obtained in the same

way as in Example lb), by alkaline saponification of

the previously mentioned esters:

acid, 3-p-(p-Fluoroplheo-cy) -phenyl-3-hydroxybittyric acid, 3-p-(m-fluoroplienoxy) .PlheuYl-3-hydro.%ybutyric

o-chloroplhenoxy) -phenl'Y.3-lydro~wbittyric acid,

'-c11 1 oroPlienOv-Y) -P1'eTiiy1 3-hyvdrcxybujtvric acid,

3--(or..p.kvY -11 YI 3-hydroxybu tyric acid,

acid, and 3-p,-C ,:-bror~ophienoxy) -plienyl-3-hydro-ybutyric acid, 3-P-(p-Iromopienoxv) -piienyvl-3-iiydroxvbutyric

M.P. i08 lo09

a) i ~25.6 g of naphthalene, 4i.6 g of finely

divided sodium and 150 nil of TI[F are well mixed under

nitrogen and cooled to -15 A solution of 6 g of

in 10 nil of THfF is added dropwise, the acetic acid

mixture is heated at 500for 2 hours, a solution of

g of p- (p)fltoroPhiefoxy)-ace toplenonc, in 100 ml 23.1

of ether is added and the whAole is stirred for two hours.

48 4,455

78,608 175 Water is added in order to decompose the

resulting alcoholate and the mixture is subjected to

standard working up to give 3--p-(p-fluorophelnoxy)-phenyl-

3-hydroxybutyric acid.

b) An ethereal diazomethane solution is added

at 200 to a solution of 1 g of 3-p-(p-fluorophenoxy)-

phenyl-3-hydroxybutyric acid in 20 ml of ether until

there is a permanent yellow colouration. After evap-

oration, 3-p-(p-f luorophenoxy)-phenyl-3-hydroxybutyric

acid methyl ester is obtained.

c) I g of 3 -P-(p-fluorophenoxy)-phenyl-3-hydroxy-

butyric acid is allowed to stand for 24 hours at 200

with 20 ml of ethanolic hydrochloric acid and the mix-

ture is evaporated to give 3-p-(p-fluorophenoxy)-phenyl-

3-hydroxybutyric acid ethyl ester.

Example 6

A Grignard solution obtained from 14.2 g of

methyl iodide and 2.4 g of magnesium in 100 ml of THF

is added dropwise to a solution of 28.14 g of 4-phenoxy-

benzoyl-acetic acid ethyl ester in 200 ml of THIF.

After the completion of the addition, the mixture is

heated with stirring on a water bath for a further 2

hours and cooled and the resulting alcoholate is

hydrolysed by means of ice and saturated NH14C1 solution

The ethereal phase is dried and evaporated to give 3-p-

phlenoxyphenyl-3-hydroxybutyric acid ethyl ester.

Example 7

A solution of p-phenoxy)pheniylmagrnsiium bromide

4 8 44,45

78.60 8 (obtained from 2.49 g of 4'-bromodiphenyl ether and

0.211 g of magnesium in 100 ml of ether) is added drop-

wise at 200, with stirring, to a solution of 1.3 g of

acetoacetic acid cthyl ester in I10 ml of ether, and

the mixture is stirred for a further two hours, the

resulting alcoholate is decomposed by means of ice

and saturated NHIIC1 solution, and the ethereal phase

is dried and evaporated to give 3-p-phenoxyphenyl-3-

hydroxybutyric acid ethyl ester.

Example 8

A solution of 2.26 g of 1-p-biphlnylyl-3-

hydroxypropan-1-one (obtainable by acylating biphenyl

with 3-methoxypropionyl chloride to give 1-p-biphenylyl-

3-methoxypropan-1-one and subsequent ether splitting)

in 20 ml of THF is added dropwise at 200, with stirring,

to a Grignard solution prepared from 3 g of methyl

iodide and 0.5 g of magnesi-um! in 100 i3 of Fethelr.

The mixture is stirred for a further 4 hours, the

resulting alcoholate is decomposed by means of water

and dilute sulphuric acid, and standard working up

gives 3-p-biphonylyl-1,3-butanediol, m.p. 115 117

Example 9

0.44 g of 1-hydroxy-3-butanone in 410 ml of

ether is added dropwise at 200, with stirring, to a

Grignard solution prepared from 2.33 g of 'I-bromobiphenyl

and 0.21l g of magnesium in 100 ml of ether. The mixture

is stirred for a further two hours,, the resulting

alcoholate is decomposed by means of dilute sulphuric

29 48 4,4 5

78, 608 acid, and standard %w.-orling; up gives 3-p-b ipheIylyl

1,3-biitane-diol, mi.p. 115 -1170.

Example

2.21i g of 3-p-bipihonyiyl-1-uten-1l-ol

(obtainable from p-biphenylylmagnesium bromide and

methyl vinyl ketone) arc dissolved in 5 ml of diglyme,

3 ml of a 1 M solution of NaB!It in diglyme are added

and a solution of 0.56 S of 1F etherate in 1.2 ml of 3 di.glyme is added dropwise under N 0.7 ml of water

is then added and 1.4 ml of 3N NaOI and 1.I ml of 30O, !102 are then added dropwise at 80 1000 The mixture is

cooled, treated with ice water, and standard working

up gives 3-p-biphenylyl-1,3-butanodiol, m.p. 115 1170

(the boric acid ester fortried as an intermediate being

hydrolysed)

1 g of 3-p-phenoxyphenyl-3-lydroxybityronitrile

(obtainable from 1 -bromo-2-p-pIicnoyphinyl-2 -prop--nol

and KCN) is boiled with 10 ml of 250e sodium hydroxide

solution for 10 hcurs under nitrogen. The mixture

is washed with ether and acidified to give 3-P-pienOxy-

phenyl-3-hydro-ybutyric acid, m.p. 137 1380.

Example 12

3 g of p-p!ieno-yenyl-3-hiyvdroxybutyric acid

amide (obtainable from 4-phenoxyacetophlenone and bromo-

acetaide/zinc) and 5 g of KOH in 100 ml of ethanol are

boiled for 3 hours under nitrogen. The mixture is evaporntcd adl(d 78, 60 8 uiui1'Ito u jvL 3-p-PiIcn-XYpheiIYl-37-

11-ilroxvbu tYr ic acid, 137 1380.

Exaiple 13

1 g of 3-chloro-3-p-phe.cnox-%v,,phenrlyl-butyric

acid (obtainable by an additioa reaction of IICI with

3-p-plienoxypheonyl-2-butcruic acid) and 25 m! of

potassiu. hydroxide nolution are boiled for 10 minutes,

cooled, i-ashed u-ith ether and acidified to give 37P-

phenoxyphenyl-3j-hydi-oxybutyric acid, r.p. 137 1380.

Example 14

3.55 g of 3-bromo-3-p-(p-chlorophenoxy) -phenyl- 1-butanol (obtainable by brominating 3-p-(p-clorophenoxy)-

phenyl-1-butanol) are dissolved in a mixture of 15 ml

of acetone and 15 ml of water, 1 drop of sulphuric acid

is added and the mixture is warmid at "150 for 4 boirs,

.and standard working up gives 3-P-(.-ch'Ioro 1.)hen.xy)- 20 pheny.-1,3 -butanediol; n1 2 1.5838.

Example

2.94 g of 1-chloro-3-( -p-fluoroplienoxy- 1 phenyl)-3-butanol (obtainable by reacting -(3-chloro-

propioyl)-li'-fluoroiplieiiy1, ether with CH 3 NgI and

subsequently Iiydrolysing) are boiled for 3 hours with

a solution of 2 g of Ba(Oil)2 in 40 ml of methanol,

water is added and the inixtlzr- is extracted with chloro-

form, niid the extract is evaporated to give 3-p-(p-

Il,iioIlulonoxy) -phenyl- 1, 3-biita ticd iol; 0i 1.5583.

31 484,455

16 78,608 a) 2.6 gOf -Cllero 3 p .utf 1CICiYl-3Iluano

oh tiii nib] froin -h leulyuaui;Imi, -Orlid alnd I-

cliloro-3-butanouic) are disso1Vcd ini 20 ml of UDIF, 3 g of anhydrous potassium acctate are added aid thenixture

is stirred for 3 hours at 600. After stauidard orking

up, l-acetoxy-3-p-b iphenylyl-3-butanol is obtained.

b) A solution of 2.84 g of I-acetoxy-3-p-

biphenylyl-3-butanol and 2 g of NaQll in 30 ml of 8.,4 .ethanol is boiled for 3 hours. Water is added and

the mixture is extracted with chloroform and the extract

is evaporated to give 3-p-biphienylyl-1,3-butandiol 0 m.p. 115 117

Example 17

a) 3-Bromo-3 -p-biph-enylyl- -butanol (obtainable

by brominating: 3-p-biplenylyi- l-hutarol) is reacted

.uith potassium acetate, analogously to Example 16 a),

to give 3-acetoxy-3-p-biphcnylyll-butanol.

b) 2.811. g of 3-acetoxO 3-p-bipIianyll-lbut-no

are boiled for 2 hours with 2 g of KOH iii 50 ml of

methanol, water and chloroform are added and the mixture

is worked up to give 3-p-bipeyylyl-13-butalediolInm~p

115 -'1170.

Example 18

A solution of 2.111 g of 1-amino-3-p-biplmenylyl-

3-hutanol (obtainable from 3-hydroxy-3-p-biplhcnylyl-

bmtyrammide by means of LiAl!I) in 50 nil of 13'0 aqIuous

acetic acid is treated, miile being cooled with ice,

2 484.455

78,608 with a solution of 1 g of NaNO 2 in 5 ml of water. The

tnixturo is heated at 800 for one hour and standard

working up then gives 3-p)-bipheniylyl-1,3-iitanediol,

m.p. 115 1170.

Example 19

2.56 g of 1-methoxy-3-p-biphenylyl-3-butanl

(obtainable from 3-methoxy-l-p-biplienylyl-1-proanone

and CH MgI) is boiled for 2 hours with a mixture of

ml of 48qC aqueous diLr and 5 ml of acetic acid, 10 ml

of 10W~ methanolic KOII are added and boiling is continued

for a further 2 hours and the mixture is worked up

using water and chloroform to give 3-p-biphenylyl- a 1,3-butanediol, m.p. 115 117

Exnmnle

A solution of g of 3-hydroxy-3-P-bipheylyl-

butanal (obtainable by reacting p-phenylacetophenone with

2,2-diethoxyethylmiagnesium bromide and subsequently

hydrolysiiig) in 12 ml of ethanol is added dropuise to

a solution of 0.6 of Nakid4 in 15 ml of ethanol. The

mixture is stirred for tw.o hours at 200 and standard

working u then gives 3-p-hiphenylyl-l,3-butailediol,

m.p. -115 1170.

Example 21

2 g of 1-benzyloxy-3--(p-fluorophenoxfy)-

phenyl-3-butanol (obtainable from I-p-fluorophenoxy-

phenylacctopllncofl and 2-henzyloxyethylmagnesiul bromide)

are dissolved in 50 ml of methanol and are hydrogenated

48 4.4 5 3$

78, 608 nt 200 and ioranl pressure in the nrcsenlce of 0.5 g

of 5' Pd-C catalyst until the absorption of hydrogen

ceases to give 3--(p-floro lienoxy) -j~ienyl-1,3- 200 butoncdiol; n 11,5583.

Example 22

2.89 of 3-(j-amino-k-penoxypienyl)-1,3-

butanediol (obtainable by nitrating 3-p-chlorophienyl-

1,3-butanediol to give 3-(3-nitro-1-chlorophenyl)-1,3-

buitanediol, reacting with phenol to give 3-(3-nitro-

4-p)henoxyphenyl)-1,3-btanediol and reducing the product

with Sn/lCl) arc mixed, with stirring, with 25 ml of

15"4 hydrochloric acid, 0.69 g of NaNO2 in 2 ml of 0 water are added at 0 5 30 ml of ethanol are then

added, and thc mixture is then stirred for 30 minutes

at 200 and is boiled for 30 miniutes. After cooling,

standard working up gives 3-p-phenoxyphenyl-1,3-

hbttanediol, r.P. 74 750

Exariple 23

A stream of air is passed through a solution

of 2.6 g of 3-p-(p-fluorophenoxy)-plhcnyl--butarioI

(obtainable by reducingl 3-i- (p-fluoroph lenoxy) -phlien.yl-

butyric acid ethyl ester) in 50 ml of boiling toluene,

in the presence of 1 g of a CuO/CaCO catalyst, for 8

hours. Standard i-orking up then gives 3-p-(p-fluoro-

plienoxy) -pienyl- 1, 3-butanediol, n 0 1.5583.

Example 24

A inixture of 2.22 g of p-i odofluorobcnzene

34 48 4,455

78, 60 8 and 2.1I g of the disodium salt of 3-p-hydroxyphvenyl-3-

hydroxy'2-Ktyric aci (obtainable by reacting p-hydroxy-

acetophcncii with bromloacotic acid e-thyl ester and

zinc and subsequently saponifying) is heatcd at 900

for 8 hours in the presence of 1 g of Cu powder in

ml of !QiPT. Standard working up then gives 3-

p-(p-fluoroplienox y)-ipenyl-3-hddroxybutyric acid, 0 cyclohexylamine salt, decomposition at 190

3-P-(p-Fluorophenoxy) -phenyl-1,3 -butanediol

n' 1.5583, is obtained analogously using the Na salt

of 3-p-hiydrox-yphnciyl-1, 3 -htanit."iediol (obtainable by

reducing 3-p-1ydrox.,cyphcnyl-3-lhydroxybutyric acid ethyl

ester).

Example

A solution of 3.28 g of the sodium salt of

3-p-iodophenyl3hydroxvbutyric acid and 1.34 g of

sodium p-fluorophenolate in 20 ml of DMF is heated

at 1300 for 8 hours. Standard workcing up gives

3-p- (p-fluoropherox>y -phcnyl-3-hydronybutyric acid,

cyclohcxylamine salt, decomposition at 1900.

3-p-Phenoxyphenyl- 1, 3 -butanecliol1 t. p. 74

is obtained analogously from 3-p-iodorlienyl-1,3-

butanediol (obtainable by reducing 3-p-iodophenyl-3-

hydroxybutyric acid ethyl ester) and sodium phenolate.

Example 26

3 ml of concentrated hydrochloric acid are

added at 00 to 3.15 g of 3-p-(p-1inopy l yplcl

3-!ydroxyhiltyric acid ethyl ester (obtainable by a

35.-48 44455

78,608 oformtslv roacli-on from p-acetamidophenoxyacetoplhclnnone,

and a solution of 1.11 g of' NzaNO, in (6 ml of water is

then added at 00, Wit s After addifjlg a

solution of 0.7 g of boric acid in 1.5 g of 605 hydro-

fluoric acid, the mixture is stirred for !0 aiinutes

and the product is filtered off, washed with water,

methanol and other, and then dried. The diazonjum

salt is heated to about 1500 until decomposition is

comple to. This gives 3-pl-( p-fluoroplicnoxy) -phenyl-3-

hydroxyutyric acid ethyl ester.

3-p-(P-F1.uorophcnoxy) -phoniiyl-,3 -I3ianodiol 0 n2 1.5583, is obtained analogously from 3-P-(P-

aminoplienoxy)-phenyi-1,3-hutanediol (obtainable by

hydrogenating 3-P-(p-nitrophienoxy)-penyl-3-hydroxy-

butyric acid ethyl ester over CuCr 0 ld

Example 27

3.15 g of 3-p-(p-.-,r'tinopienoxy) -plienyl.-3-

hydroxybutyric acid ethyl ester are dissolved in 30 ml

of hydrochloric acid, 0.7 g of NaNO, in 2 ml of

water are added at 0 to 5Q and the resulting dialzonium

salt solution is added dropwisc slowly to a hot solution

of Cu Cl (obtained by reducing 2.1 g of copper sulphate 2 2 with SO, in 13 ml of water in the presence of 2.6 g of

NaCi), and the mixturq is heated for a further

minutes at 90 to 950, cooled and standard working up

then gives 3-p-.(P-chioroplienoxy) -phlenyl-3-tydr-oxybutyric 20 acid etiiyl ester; 12 1.51,56.

3-p-(p-Drociopiienoxy) -ph eyl-3-hlyre-oxybutyric

acid ethyl ester is obtained analogously, using Cu 2 Br,,

36 484.455

78,608 /75 2 and 3-p)-(p-ch lorophelloy) -l~llemlyl-lI, 3-1Italecdiol, "2

1.5838, is obtained analogotisly from 3-p-(p-amino-

phenoxy)-phenyl-I 3-b)utatnedliol, using Cu Cl 2 2

Examle 28

a) A solution of 33*It g of 3-p-(p-chlorophonoxy)-

phenyl-3-hydroxybutyric acid ethyl ester in 300 ml of

TVIF is added dropwise to a solution of 4.6 g of LiAlIf 4

in 100 ml of TiIF, while stirring and passing N2 through

the mixture. The mixture is boiled for an hour and

cooled and a mixture of 20 ml of TIIF and 5 ml of water

is first added dropwise and 5 ml of 3200 sodium hydroxide

solution are then added dropwise and the mixture is

worked up with chloroform and water to giye 3-p-(p-

choropenoxy) -phenyl- 1 3-butandiol, an oil, nD

1.5838.

3-13-Bipheiylyl- 1 ,3-butanediol, m. p. 115 1170 00 3-p-plienoxyphlenyl-I ,3-himtanediolI m-P. 74+ 750; 3-p

(p-fluorophenxy)-plienyl-1,3-butnicdiol, 20 1.5583;

and 3-P-(p-bomophlcnoxy) -ph!enyl- 3-butanediel are

obtained analogously, by reduction with LiAlli4 from

3-p-biphenylyl-3b-hydroxbutyric acid ethyl ester, 3-p-

phenioxyphienyl-3-lhydroybutyric acid ethyl ester, 3-P-

(p-fluorophenoxy) -phenyl-3-hiydroxybutyric acid ethyl

ester, and 3-p-(p-bri-oropnhcoxy)-pheyl-3-hydroxybutyric

acid ethyl ester.

b) A mixture of 2.92 g of 3-p-(p-chlorophcnooy)-

phenyl- ,3-butanediol, 5 mrl of acetic aniydride and

8 ml of pyridine is allowed to s Land at 200 for 15 hours

and is poured into ice water and worked up using chloro-

37 484,4-.55

78,6088/75 form and water to give 1-aicctoXY-3-1p-( p-chiorohltoxy)

p henyl- 3 -b uta no I.

I -Ace to.\Y-3 -1-phenoxyphefl-3 -butafll, I- n acetoxY-3-P- (p-f-luoroplienoxy) -plienyl-3-buttanolI

1.5376, and 1I-ace toXY-3 p-bromnhnOXY) -pileonY1- 3-

butanol are obtained analogously by acetylating the

corresponding diols.

C) The corresponding propionates, butyrates,

is..:ibutyrates, valerates, isovalerates, trimetliyl

ai:etates, caproates, isocaproates and tort. -butyl

acetates, for example:

1 -prop ionyloxY-3 (p-chlorophenoxy) -phenyl-3-butanol,

1-butyrylox-y-3-P--(p-chlorolheloxy) -plienyl-3-butariol,

1-isobutYrylo,\Y-3-P- p-chlorophcnoxy) -phenyl-3-butanol I

1-valeryloxy-3-P- p-chlorophenoxy) -pheiiyl-3-butanol

1-isovaileryloxy-3-)-( p-chilorophenoxy) -phenyl-3-butanol,

i-isocaproylox-3-p-(p -chlorphnoxy) -phenyl-3 -but anol,

and

1-tert. -butylac etoxY-3-P- (p-chlorophienoxy) -Pho"Yl-3-

butano 1,

are obtained, analogously to using the corresponding

anhydrides.

d) 2.92 g of 3-P-(p3-chloroh)Ieox y) -Pilen'yl- 3-

butanediol are heated with 15 ml of formic acid for 2

hours at 800 and the mixture is cooled and standard

working up thien gives 1-fornmYlOXY-3-p-(p-clioro)le-oxy)

pie ny 1-3- u tano 1.

38 -484,45

78,60 8 175 forinyloxY-3-l- p-fluioroplhenoxy) -plicnyl-J--bu-tanrol and

1-formlylox-Y-3-p-( p-Irom-ontlxenoxv) -p'ienl-3-buttantol are

obtainecd analogously from the corresponding diols.

e) 2.58 g of 3-P-phenio-yph-eiiyl-1,3-buxtanedio1

are dissolved in 20 ml of acetic acid, a solution of

0.8 g of chlorine in 20 ml of acetic acid is added

dropwise with stirring at 20 0 and the mixture is

stirred for a further houar and evaporated. Standard

working up, using water and chloroform, gives 3-P-(P-

c.lorophienoxy)-phcnyl-1,31-butiAnediol, n 1538

a) 3-.P-(p-Fluorophenoxy)-phienyl-3-hydroxybutyric

acid is rcduced, analogously to Example 28 a, using

LiAlfi-,, but boiling for 8 hours. This gives 3-P-

(p-fluorophienoxy) -pheonyl- 1, 3-butanediolI an oilnD

1.5583.

The following are~ obt;,iiecl atnal orouslyv by

reducing thc corresponding ncidE or their esters:

3-P- (o-Flutorophefnoxy) -pieny-l-i, 3-buitanediol,

3-p-i m-fluorophienoxY) -phenyl-I, 3-butainediol,

3-n-.(o-ch1iLoropheLnoxv) -olinyl- 1, 3-butanediol,

3-P-(-m-clhlorophenoxcy) -plienyl-1 ,3-butainediol,

3-P-(o-bromoplieno-xy)-plienyl-1,3-butaflediolI and

3-P-(mr-hromnoplhnoxy) -phenyl- 1,3 -butanediol.

b) The following are obtained, analogously to

Fxample 28b, by acctylating the above-mnentioned diols:

1-AcetoxY-3-p)- (o-fluoroplienoxy) -plhenyl-3-buitanol,

I -acetoxY-3-p)-( in-fluioroplienioxy) -pjVcnyl-3-h)utainol,

I -ace toxy- 1 -p3- (o-cliloropherioxy) -phenyl-3 -butanol,

39. 48 4 5

78,608 1 1 -acctoxy-3-P-( m-chlorop he)oxy) -phenyl-3-butanol,

-nace toxy-3-p-( -bronmophn:oxy) -phenyl-3-'butanol, and

1-;cctoxy-3-p-(m-brornophonoxy) -phinyl-3-butanol.

The following examples of pharmaceutical

compositions containing active compounds of formula

I or physiologically acceptable salts thereof, are

given by way of illustration:

Example A: Tablets

A mixture consisting of 1 kg of the cyclo-

hexylamine salt of 3-p-(p-chlorophenoxy)-phlenyl-3-

hydroxybutyric acid, 4 kg of lactose, 1.2 kg of potato

starch, 0.2 kg of talc and 0.1 kg of magnesium stearate

is pressed into tablets in conventional manner so that

each tablet contains 100 mg of the active compound.

Example B: Dragees

Tablets are pressed in the same way as ir

Example A, and are then coated in conventional manner

with a coating consisting of sugar, maize starch, talc

and tragacanth.

Tablets and dragccs containing onc or -ore

of the other compounds of formula I or their physio-

logically acceptable salts thereof are obtainable

analogously.

40 484.455

Claims (1)

1. 78,60 8 The claims defining the invention are as follows:

   1. Phenylbutanol derivatives of formula I:

   Z-C(CH 3 )(OH)-CH 2 -Y I wherein Z is 4-biphenylyl or the group

   0

   is CORor CH 2 OR R is H, F, Cl or Br, R is H or A, R 3is H or alkanoyl having 1 to 6 C atoms, and A

   is alk-,l having 1 to 6 C atoms, and their physiologic'ally

   acceptable salts.

   2. A compound Selected from:

   3-(4-biphertylyl)-3-hydroxybutyric acid;

   3-(4-biphenylyl )-3-hydroxybutyric acid ethyl ester;

   3-p-biphenylyl-l, 3-butanediol;

   3-p-phenoxyphenyl-l, 3-butanediol;

   3-p-(p-fluorophenoxy)-phenyl-l, 3-butanediol;

   3-p-(p-chlorophenoxy)-phenyl-l, 3-butanediol;

   3-p-(p-bromophenoxy)-phenyl-l, 3-butanediol;

   1-acetoxy-3-p-phenoxyphenyl-3-butanol; l-acetoxy-3-p-(p-fluorophenoxy).phenyl3.butan-,l 3 -p-phenoxyphenyl-3-hydroxybutyric acid;

   3-p-phenoxyphenyl-3-hydroxybutyric acid ethyl ester;

   p-fluorophenoxy)-phenyl-3-hydroxybutyric acid;

   3-p-C p-fluorophenoxy)-phenyl-3-hydroxybutyric acid

   ethyl ester;

   3-p-C p-chlorophenoxy)-phenyl-3-hydroxybutyric acid;

   3-p-C p-chlorophenoxy)-phenyl-3-hydroxybutyric acid

   ethyl ester;

   41. 484.455

   78,608 p-chlorop:henoxy)-phenyl-3-hydroxybutyric acid

   n-hexyl ester;

   3-p-(p-bromophenoxy)-phenyl-3-hydroxybutyric acid;

   and

   3-p-(p-bromophenoxy)-phenyl-3-hydroxybutyric acid

   ethyl ester.

   3. A process for the preparation of a phenylbutanol

   derivative of formula I specified in claim 1, which

   comprises

   treating a compound of formula II:

   Z-Q II

   wherein Q is -C(CH )(OH)-CH 2 -W or -CX(CH 3 )-CH 2 W is

   a functionally modified -COOH or -CH 2 OH group, but is

   different from Y, X is Hal or a functionally modified

   hydroxyl group, and Hal is Cl, Br or I, and Y and Z

   have the meanings specified in claim 1, with a solvolys-

   ing agent; or

   (ii) reducing a compound which otherwise correspond!

   to formula I, but which contains, additionally or insteac

   of H atoms, at least one group which can be reduced or

   can be replaced by hydrogen; or

   (iii) oxidizing a compound of formula III:.

   Z-CH(CH 3 )-CH 2 -Y III

   wherein Y and Z have the meanings specified in claim 1;

   or

   (iv) reacting a compound of formula IV:

   Q-1 C(CH 3 )(OH)-CH 2 -Y

   or a salt thereof, with a compound of formula V:

   42 484,4

   78,60 8 1 R 2 V (Q

   or a salt thereof, wherein one of the groups QI or

   Q2 is OH, and the other is X, and R1 X, Y and Z have the meanings specified in claim 1; or

   diazotizing a compound of formula VI:

   Ar-C(OH)(CH 3)-CH 2-Y VI wherein Ar is the radical H N 2

   and Y has the meaning specified in claim 1, and

   reacting the resulting diazonium salt with a halogenat-

   ing agent. 4. A process according to claim 3 in which the

   compound of formula I obtained is treated with a reducing,

   oxidising, solvolysing, esterifying or trans-esterifying

   agent to convert the Y radical into another Y radical

   and/or, when R 1 H in such compound, the compound is treated with a chlorinating or brominating agent to obtain

   a product in which R 1 Cl or Br and/or, when such 6cmpound contains a carboxyl group, it is treated with a base to

   convert it into a physiologically acceptable salt.

   A compound as claimed in claim 1 substantially as

   herein described with reference to any one of the fore-

   going specific examples thereof.

   6. A process for the preparation of a phenylbutanol

   derivative of formula I specified in claim 1 or a salt

   thereof, substantially as herein described in any of

   Examples 1 to 29.

   43 S44

   78, 60 8 7. A pharmaceutical composition comprising at least

   one compound acccrding to any of claims 1, 2 and 5 and

   an inert, physiologically acceptable carrier. 8. A pharmaceutical composition according to claim 7

   in dosage unit form, each dosage unit containing from

   to 300 mg of said compound(s).

   9. A pharmaceutical composition substantially as

   herein described in either of Examples A or B.

   DATED this 24th day of February, 1975.

   MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG,

   By Its Patent Attorneys,

   ARTHUR S. CAVE CO.

   G

   44- 484,455