CA1119613A - Process for preparing benzylidene derivatives - Google Patents

Abstract

ABSTRACT

A process for preparing compounds corresponding to the formula (I) (I) in which X1, X2, X3 and X4 each represent, independently of one another, a hydrogen or halogen atom or a radical CH3, CH3O, NO2, CF3, C(CH3)3 or CH3CONH, n represents an integer ranging from 1 to 10, n is a radical OH, OM
(M = alkali metal), NH2, NH-cycloalkyl, NH-phenyl, NH-benzyl, NH-alkyl, N-(alkyl)2 or N-(alkyl)-(benzyl) and R' represents a hydrogen atom or an alkyl, the alkyls having from 1 to 4 carbon atoms, with the exception of the compounds in which R' = H when X1, X2 and X3 are each, independently of one another, H, Hal, CH3 or CH3O and X4 = H, and with the exception of the compound in which R' = H, X1 = X3 = x4 = H, X2 = 5-Cl, n = 1 and R = OH, which process comprises reacting a ketone of the formula (II) with the a compound of the formula NH2-CnH2n-COR (III) in the form of the base or the hydrochloride, and, if desired, then alkylating the resulting compounds (I) in which R' = H, in order to prepare the compounds (I) in which R' = alkyl; or comprises reacting the ketone (II) with a compounds of formula H2N(CH2)nCH.HCl and carrying out a solvolysis the the nitrile (IV) obtained by condensation.
The compounds are anti-convulsants and are useful in treating disorders of the central nervous system e.g. epilepsy.

Description

DESCRIPTION
PROCESS FOR PREPARING BENZYLIDENE DERIVATIVES
. .

The present invention relates to a process for preparing benzylidene derivatives.
Our Patent No. 256882 describes and claims a process for preparing the compounds corresponding 5 to the formula:

1 ~ H

N ~CnH2n-coR

~ X3 in which Xl, X~ and X3, which are identical or different, :
each represent, independently of one another, a hydrogen or halogen atom, especially chlorine or fluorine, or a ;
10 methyl or methoxy radical, n represents an integer equal to at least 1 and at most 10 and R represents a hydroxyl radical or a radical OM, NH2, NH(CH2)3-COOH, ~H(CH2)3-COOM tM representing an alkalimetal atom, in particular sodium) NH(CH2)3-COOC2H5, NH-cycloalkyl, 15 NH-phenyl, NH-benzyl (it being possible for the benzyl radical to carry a substituent chosen from amongst halogen atoms and the trifluoromethyl radical), ~H-alkyl, n-(alkyl)2 or N-(alkyl)-(benzyl), the linear - ~, ' ' : ' ~ ' ~

or branched alkyl radicals having from 1 to 4 carbon atoms and the cycloalkyl radicals having from 3 to 6 carbon atoms, with the exception of the compound in Xl X3 = H, X2 = 5-Cl, n = 1 and R = OH
The compounds of the present application correspond to the formula (I) 1 ~ OR' ~/\ :
X2 ~ = N-cnH2n-co-R (I) ~ 4 in which Xl, X2, X3 and X4 each represent, independently of one another, a hydrogen or halogen atom or a radical 10 CH3, C~30, NO2, CF3, C(CH3)3 or CH3CONH, n representS an integer ranging from 1 to 10, R is a radical OH, OM
(M = alkali metal), NH2, NH-cycloalkyl, ~H-phenyl, NH-benzyl, NH-alkyl, N-(alkyl)2 or N-(alkyl)-(benzyl3, and R' represents a hydrogen atom or an alkyl, the alkyls ~ ' : :

having from 1 to 4 carbon atoms, with the exception of the compounds in which R' = H when Xl, X2 and X3 are each, independently of one another, H, Hal, CH3 or CH30 and X4 = H, and with the e~ception of the compound in which R -- H, Xl = X3 = X4 = H, X2 = 5-Cl n = 1 and R = OH. A group of preferred compounds comprises those in which R = OH, OM or NH2 when n is 3.
Accordinc~ to the invention, the compounds are i, prepared by reacting a ketone of the formula (II) OH
xl~
~ (II) X2 c = o ~ ':
~ X3 ~ .

with a compound of the formula (III) NH2 CnH2n - CO-R (III) in the form of the base or the hydrochloxide, and, if desired, the resulting compounds (I) in which R' - H
are then alkylated.
The reaction is carried out in an alcoholic . _ 3 _ . . ~

:

solvent, such as methanol or ethanol, at a temperature ranging from 10C to the boili:n~ poin-t of the solvent, in the presence of an aikali metal or an alkali metal alcoholate.
A variant of the preparation of the compounds (I) in which R' = H and R is ~2 consists in reacting a hydroxybenzophenone of the formula ~II) with a compound H2N(CH2)n-C~.HCl (the intermediate obtained during the preparation of the compound (III) of the formula H2N-(CH2)n-CO-NH2) and then in carrying out a solvolysis of the nitrile (IV) obtained by condensationO in accordance with the following reaction scheme:

OH

1 ~ + H2N-(CH2)n-C~- HCl ~~~

X4~

,: ' . :~:

OH either Xl ~ Na OH

X2 ~-(CH2)nCN o:r x3 ~ l ~ C~O U _ . _ --~Xl ~ OH
~ .
X2 1 ~- ( C~2)n~0-MH2 ~X3 ~

The starting compounds (III) and their preparation are already described in the literature, The starting ketones ~II)Jare prepared 1) either from the compounds Xl~ ~

_ 5 _ ..

:. . :

l3 by reaction with a compound:

~ CO Cl followed by d~nylation of th~e resulting intermediate with aluminium chloride or boron trichloride,

2) or from the compounds ~ 3 Xl~ . :

X2 c~
which are reacted with a compound X~Mg Br - and the intermediate is hydrolysed in order to obtain a compound ~ OCH3 ~ = O ~ :

Xg~

. :.~'.

. . : .

,- , . : :: . . .
: ~

~ 3 which is demethylated uslng aluminium chloride or boron trichloride to give the compou:nd (II).
The ketones (II) are :new with the exception of those in which Xl, X2 and X3 a:re each, independently of one another, H, Hal, CH3, CH30 or (CH3)3 when X4 = H.
The new ketones (II) form part of the invention.
The preparation of the ketones (II) is illustrated in the Examples for the preparation of the final compounds (I).
The following Examples illustrate the invention.
The analyses and the IR and NMR spectra confirm the structure of the compounds.
The present application also gives examples of several new compounds which correspond to the general formula of the earlier patent (compounds 24 to 47~.

Sodium 4-N-[a-phenyl-2-hydroxy~5-trifluoro-methylbenzylidenyl]-aminobutyrate.

[Xl 5 CF3~ X2 = X3 = X4 = H, R~= H, R = ONa, n = 3]
1. 2-Hydroxy-5-trifluoromethyldiphenylmethanone.
1.1 1~68 g (0.0691 moll of magnesium, 25 ml of anhydrous ' '. . ' ' ' :
, : .~:

ether and 1 crystal of iodine are introduced into a 250 ml three-necked flask equipped with a reflux condenser and a dropping funnel. The mixture is heated to the reflux temperature and about 10 % of a solution of 19.52 g (0.1243 mol) of bromobenzene in 30 ml of anhydrous etner is introduced. When the reaction is well established, the remainder is introduced in such a way as to maintain reflux.
After the introduction, the mixture is heated under reflux until all the magnesium disappears. 9.5 g (0.0472 mol) of 2-methoxy-5-trifluoromethylbenæonitrile in 80 ml of anhydrous ether are then introduced in such a way as to maintain reflux and the mixture is subsequently heated at the reflux temperature for 4 hours. It is then hydrolysed, in the cold and - under nitrogen, with 40 ml of 2N HCl. A precipitate forms which is filtered off, washed with ether and dried. The product is the imine hydrochloride ~H . HCl , ..... . . . . .
.' ' ': ' ~ :

' This hydrochloride is taken up in 50 ml of ~oluene and 50 ml of 25 % strength H2S04 and the mixture is heated at the reflux temperature for 8 hours. The organic phase is then decanted, washed several times with water, dried over MgS04 and filtered, and the toluene is evaporated off. 2-Methoxy-5-trifluoromethyldiphenylmethanone is obtained.
Boiling point (0.07 mm Hg) = 170C.
1.2 2.8 g (1/100 mol) of 2-methoxy-5-trifluoromethyl-diphenylmethanone and 100 ml of me-thylene chloride are introduced into a 250 ml reaction flask and the mixture is cooled to -60C. 10 g of boron trichloride are then introduced and the mixture is subsequently stirred at ambient temperature for 1 hour. It is 15 poured into 1.5 litres of ice-cooled water, 250 ml of methylene chloride are added, the mixture is stirred, the organic phase is decanted, washed twice with water, dried over MgS04 and filtered, and the solvent is evaporated off~
This yields pale yellow crystals which are recrystallised from petroleum ether with vegetable charcoal treatmen-t. This yields 2-hydroxy-5-trifluoro-methyldiphenylmethanone which melts at 84-85C.

- -: ~ -:

2- 1.15 g of 97 % pure 4-aminobutyrlc acid, 3~ ml of methanol and 0 62 g o~ sodium methylate are introduced into a 1 litre round-bottomed flask and the mixture is stirred for 2 to 3 minutes. 2.8 g of 2-hydroxy-5-trifluoro-methyldiphenylmethanone and ~00 ml o~ ethanol are thenintroduced. The mixture is evaporated a-t atmospheric pressure (100~. Finally, all the solvent is evaporated off (in vacuo) and the residue is cooled and dissolved in 1 litre of cold water. The solution is acidified to pH 1 10 with citric acid and ex-tracted with chloro~orm, the chloro-form phase is dried over MgS04 and filtered,and the chloro-form is evaporated off. This yields an oil which crystal-lises in petroleum ether. The crystals are filtered off, drained, washed with petroleum ether, drained and 15 recrystallised from ether with vegetable charcoal treatment.
This yields the acid which melts at 154-155C. 2.5 g of ~he acid are dissolved in 150 ml of methanol, and 0,38 g of ~odium methylate is added. The mixture is evaporated to dryness to yield the sodium salt which is dried in a 20 desiccator for 1 hour at 80C.
Melting point = 216-217C.
Example 2 4-N-[-(2',4'-Dichlorophenyl)-5-chloro-2-hydroxy-benzylidenyl]-aminobutyramide, [Xl = 5-Cl, X2 = H, X3 = 2'-Cl, X~ = 4'-Cl~
R = NH2, R' = H, n = 3]

' .

g6~3 1. 2-Hydroxy-2',4',5-trichlorodiphenylmethanone.
1.1 A solution of 2,4-dichlorobenzoyl chloride in e-ther is added slowly to a stirred solution, which has been heated to the reflux temperature~ of 25.7 g o~ p-chlorophenol and 30.3 g of triethylamine in 1.2 litres of ether. The mix-ture is then heated at the reflux temperature for 3 hours, whilst stirring, and the products are le~t in contact over-night. The precipitate of Et3N.HCl is filtered of~ and washed with ether. The organic phase is washed with 10 water, bicarbonate solution and water. It is dried over MgS04 and filtered~and the filtrate is concentrated to about 3/4 of its original volume. p-Chlorophenyl 2,4-dichlorobenzoate precipitates. The mixture is cooled and the precipitate is filtered off, drained and dried in a 15 heated desiccator at 60C.
Melting point = 124-125C.
1.2 35.5 g of the above ester are heated to the melting point. The liquid is stirred and 35.5 g of hlC13 are added.. The mixture is then heated to 190 and stirred 20 for 15 minutes at this temperature. After cooling, the residue is ground and hydrolysed. It is poured into 800 g of a mixture of water ~ ice ~ 100 m~ of concentrated hydrochloric acid, whilst stirring. The mixture is then extracted with chloroform, the extract is dried over MgS04 25 and filtered~and the filtrate is evaporated to dryness.
m e residue is recrystallised from petroleum ether, filtered off and dried in a desiccator. The product melts at .

.:

- .

_ ~2 -96-97C.
20 4-N-[x-(2',4'-Dichlorophenyl)-5-chloro-2-hydroxybenzyli-denyl]-aminobutyramide.
A solution of 12.8 g of the ketone obtained under 1, 5.8 g of Y-aminobutyramide in the form of -the hydrochloride and 2.4 g of MeONain500 ml of methanol is evaporated to dry-ness.
m ereafter, 350 ml of alcohol are added to the resi-due and evaporated o~f, this is performed 4 times in succession and the last 2 evaporations are completed under reduced pressure. The residue is dissolved in CHC13~
The solution is washed with water, dried over MgS04 and fil-tered~and the filtrate is evaporated to dryness. The residue crystallises in ether. me crystals are ~iltered of~ on a frit and drained. The product is then treated with charcoal in methanol, the mixture is filtered and the ~iltrate is evaporated to dryness. ~he residue is recry-stallised from alcohol and the crystals are filtered o~f, washed with ether, drained and dried in a heated desiccator.
Melting point = 141-142Co EXAMæLE 3 4-N-~a-(4'-Chlorophenyl)-5-tert -butyl-2-hydroxy benzylidenyl]-aminobutyric acid.
[Xl = 5-C(CH3)3, X2 = H~ X3 = 4'-Cl, X~ = H~ n = 3 R' = H, R - OH]
1. 5-Tert.-butyl-4'-chloro-2~hydroxydiphenylmethanone.
1,1 128 g of p-chlorobenzoyl chloride and 0.25 g of freshly melted and grolmd ZnC12 are added, whilst stirring, to 120 g ,. . ,.. . . . .
, _ 13 _ of p-tert.-butylanisole in 180 ml of tetrachloroethane.
The mixture is then heated`at 140C for 40 hours, whilst stirring. me solvent is then evaporated off and the residue is distilled under reduced pressure. me distil-5 late crystallises in petroleum ether. The 5-t-butyl-4'-chloro-2-methoxydiphenylmethanone is recrystallised from petroleum ether with vegetable charcoal trea-tment.
Melting point = 46-47C
1.2 46.3 g of AlCl~ are added, whilst stirring, to 88 g of 10 the previously obtained compound in 150 ml of benzene and the mixture is heated at 70 for 12 hours. After cooling, it is then hydrolysed by pouring it onto ice and concentrated hydrochloric acid and stirring. The organic phase is decanted, washed with water, dried over MgS04 and 15 filtered~and the filtrate is evaporated to dryness. The residue crystallises in petroleum ether. The crystals are filtered off on a frit, drained and recrystallised from methanol with vegetable charcoal treatment. The product is dried in a desiccator.
Melting point = 64-65C
2. 4-N-[a-(4'-Chlorophenyl)-5-tert.-butyl-2-hydroxybenzyli-denyl]-aminobutyric acid.
A solution of 5.4 g of 4-aminobutyric acid, 3 g of MeONa and 15.4 g of the previously obtained ketone in 500 ml 25 ofmethanol and 300 ml of alcohol is evaporated to dryness 600 ml of alcohol are added and the mixture is evaporated to dryness, ul-timately under reduced pressure. This oper-- 13 - ~

.. . . .:

`

ation is repeated twice. me residue is dissolved in water which has been acidi~ied -to pH 4 with citric acid.
The solu-tion is extracted with chloroform, the extract is dried over MgS04 and filtered,and the filtra-te is evaporated to dryness. The precipitate ob-tained is transferred onto a frit with petroleum ether. It is recrystallised from ethyl aceTate with vegetable charcoal treatment. The product is dried in a heated desiccator.
Melting point = 140- ll~lC
-EXAMPLE 4 4-N-~a-(4'-Chlorophenyl)-5-fluoro-2-methoxybenzy-lidenyl]-aminobu-tyramide.
~Xl = 5-F, X3 = 4'-Cl, X2 = X4 = H, R = NH2, R' = CH3, n = 3]
A solution of 3.4 g of 4-N-[~-(4'-chlorophenyl)-5-fluoro~2-hydroxybenzylidenyl]-aminobutyramide and 0.55 g of sodium methylate in 150 ml o~ methanol is evaporated to dryness. The residue is then dried in a heated desic cator at 120.
After cooling, the residue is dissolved in 100 ml o~
DMS0 (dimethylsulphoxide).
The solution is stirred and 3 g o~ methyl iodide in !!
~5 ml of DMS0 are introduced dropwise into the stirred solu-tion. The mixture is -then stirred at ambient temperature ~or 30 minutes.
The mixture is evapora-ted to dryness under reduced pressure, the residue is dissolved in 200 ml o~ chloroform and the solution is washed with water, dried and evaporated - -. . .. ..

, . . . , ~

.

to dryness. The residue is ~transferred onto a frit with ether. The product is recrystallised from alcohol and the crystals are washed with,acetone and ether, drained and dried in a hea-ted desiccator~
Melting point = 1~4.5 - 155.5C.
The following table shows the compounds which have been prepared by way of example,s and illustrate the ~ormula (I).

.
. .

TABLE I
. ..._ Com- X1 X2 X3 X4- n R R' ¦Me1tin~
... . _ . __ . . l , 1 5-No2 H 4~-C1 H 3 OH H 240 (dec, 2 5-CH3CONH H H H 3 NH2 H 240 (dec.

3 5-CF3 H 4'-CF3 H 3 ONa H238 ( dec .

4 5-CF3 H 3'-CF3 H 3 ONa H218 ( dec .

5-CF3 H 4'-CF3 H 3 NH2 H119.6

6 5-CF3 H 3,'-CF3 H 3 NH2 Hi98,7

7 5-CF3 H 4l-F H 3 OH H173.5 ONa H ~ 250

8 5-No2 H 4~-C1 H 3 NH2 H172.5

9 5-CF3 H 4'-F H 3 NH2 H120.6 5-F H 4'-No2 H 3 OH H169-70 ONa H180 ( de c, 11 5-F H 4'-No2 H 3 NH2 H190-1 ONa H216 ( dec .

145-C(CH3)3 H 4'-C1 H 3 OH H140-1 .
155-C(CH3)3 H L~r_Cl H 3 NH2 H121-2 ONa H227 ( de c .

185-C(CH3)3 H H H 3 NH2 H135-6 195-C(CH3)3 H H H 3 OH H131-2 5-C1 H 4'-C1 2-C1 3 NH2 H141-2 21 5-C1 H 4i-C1 2-C1 3 OH H172-4 . ._ ~ ONa H245 (dec. `
_ _ ' ' ' , ' ' ' ' ~ ' " ' , "' ~ '''' TABLE I ( continued) pound XlX2 X3 X~l n R R ' :1e I t i~y 22 5-F H4 ' -CF3 H 3 OH H 140-1 23 5-F H4 ' -Cl H 3 NH2 CH3 155 24 5-Cl H4 ' -Br H 3 NH2 H 169-170 5-Br H4 ' -Cl H 3 NH2 H 156-157 26 5-Br H H H 3 NH2 H 134-135 27 5-Br H4 ' -Br H 3 NH2 H 16664 5-28 5-F H2 ' -Cl H 3 OH H 85.5-87 29 5-Cl H4 ' -Cl H 3 NH2 H 161-3 5-Br H H H 3 ONa H 247-8 31 5-Br H4 ' -Cl H 3 ONa H 230 32 5-Cl H4 ' -Cl H 3 ONa H 250 33 5-Br H4 ' -Br H 3 O~ia H > 250 34 5-Cl H4 ' -Br H 3 ONa H > 235 5-F H4 ' -Cl H 2 ONa H > 240 36 5-F H4 ' -Cl H 2 NH2 H 157-8 37 5-Cl H H H 3 NH2 H 125--6 38 H H2 '-CE~30 H 3 NH2 H 119-20 39 5-P HL r L 1 OH H 192- 3 " ' '' , ' .
.
.

.~ . ': . , - ,' ' , TABLE I ( continu~d ) pound Xl X2 --~ l~G~r: ~
5-F H 4 ' -Cl H 4 ONa H > 300 41 5-F H 4 ' -Cl H 3 OH H 98-9 42 5-F H 4 ' -Cl H 4 NH2 H 140-1 43 5-Cl H 4 ' -F H 3 NH2 H 140-1 44 5-Cl H 4 ' -F H 3 OH H 127-8 5-F H 4 ' -CF H 3 ONa H > 250 46 5-Cl H 2 ' -Cl H 3 OH H 102 47 5-Cl H 2 ' -Cl H 3 NH2 H 104 48 5-Br H 2 ' -Br H 3 NH2 H 133 49 5-Br H 2'-Br H 3 ! OH H 138 5-Br H 2'-Cl 4'-Cl 3 OH H 118-119 51 5-Br H 2 ' -Cl 4'-Cl 3 NH2 H 131-132 52 5-Br H 2 ' -Cl H 3 OH H 130-131 53 5-Br H 2'-Cl H 3 NH2 H 125-126 54 5-Cl H 2 ' -Br H 3 NH2 H 118-119 Z--Cl 5{~1 2 ' -Cl H 3 NH2 H 135--136 56 z-Cl S--Cl 2'Cl H 3 OH H 149-150 -- 1% --' .

~.

.. . .. . . .
, - . ~ -. . . : : -. . . . . . .

- 19 _ The compounds of the invention have been subjected to pharmacological tests sho-Ying their activity on the central nervous system.
The acute toxicity was determined in mice by intra-peritoneal administration~ The LD 50 (50 /0 le-thal dose), namely the dose which causes death in 50 % o~ the animals, varies from 700 to.more than 1,000 mg/kg.
The activity of the compounds was.shown by the antagonism towards -the mortality induced by bicucullinein mice.
Bicuculline is a relatively selective blocking agent for GABA-ergic post-synaptic receptors and its convulsive and lethal effects are antagonised by compounds which raise the .cerebral concentration of GABA or possess a GABA-mimetic activity;
The 50 ~o active dose (AD 50), namely the dose which protects 50 ~ of the animals against the effect of bicucul-line, was evaluated for the substances studied.
The AD 50 of the compounds o~ the invention varies from 20 to 80 mglkg, administered in-t.raperitoneally, The compounds of the invention are active as anti--convulsive agents. They can be used in human and veter-inary therapy for the treatment of various diseases of the central nervous system, for example for the treatment of psychoses and certain neurological diseases such as eFi~
The invention consequently comprises all pharma-ceutical compositions which con-tain the compounds (I) as , ~ ~

.

- .

g~
- 20 _ active principles, in association with any excipients suit-able for their administration, in par~ticular their oral administration ~tablets, dragees, sugar-coated pills, CQp-sules, cachetsand solutions or suspensions which can be taken orally), or parenteral administration.
The daily dosage can range from 100 to 1,500 mg.

. . . ., : :

,

Claims (11)

The embodiments of the invention, in which an exclusive privilege or property is claimed, are defined as follows:

1. A process for preparing compounds corresponding to the formula (I) (I) in which X1, X2, X3 and X4 each represent, independently of one another, a hydrogen or halogen atom or a radical CH3, CH3O, NO2, CF3, C(CH3)3 or CH3CONH, n represents an integer ranging from 1 to 10, R is a radical OH, OM
(M = alkali metal), NH2, NH-cycloalkyl, NH-phenyl, NH-benzyl, NH-alkyl, N-(alkyl)2 or N-(alkyl)-(benzyl), and R' represents a hydrogen atom or an alkyl, the alkyls having from 1 to 4 carbon atoms, with the exception of the compounds in which R' = H when X1, X2 and X3 are each, independently of one another, H, Hal, CH3 or CH3O and X4 = H, and with the exception of the compound in which R' = H, X1 = X3 = X4 = H, X2 = 5-Cl, n = 1 and R = OH, which process comprises reacting a ketone of the formula (II) with a compound of the formula NH2-CnH2n-COR (III) in the form of the base or the hydrochloride, and, if desired, then alkylating the resulting compounds (I) in which R' = H, in order to prepare the compounds (I) in which R' = alkyl, or comprises reacting the ketone (II) with a compound of formula H2N(CH2)nCN.HCl and carrying out a solvolysis of the nitrile (IV) obtained by condensation.

2. A process according to claim 1, wherein the compound (III) is used.

3. A process according to claim 1, wherein the compound H2N(CH2)nCN.HCl is used.

4. A process according to claim 3, wherein solvolysis is carried out using sodium hydroxide and hydrogen peroxide.

5. A process according to claim 3, wherein the solvolysis is carried out using HCOOH and HCl gas.

6. A process according to claim 1,2 or 3, wherein a compound (I) in which n = 3 and R = OH, OM (M is alkali metal), or NH2 is produced.

7. A process according to claim 1, 2 or 3, wherein a compound (I) in which R' = H is produced.

8. A process according to claim 1, 2 or 3, wherein sodium 4-N-[.alpha.-phenyl-2-hydroxy-5-trifluoro-methylbenzylidenyl]-aminobutyrate is produced.

9. A process according to claim 1, 2 or 3, wherein 4-N-[.alpha.-(2',4'-Dichlorophenyl)-5-chloro-2-hydroxybenzylidenyl]-aminobutyramide is produced.

10. A process according to claim 1, 2 or 3, wherein 4-N-[.alpha.-(4'-Chlorophenyl)-5-tert.-butyl-2-hydroxybenzylidenyl]-aminobutyric acid is produced.

11. A process according to claim 1, 2 or 3, wherein 4-N-[.alpha.-(4'-Chlorophenyl)-5-fluoro-2-methoxy-benzylidenyl]-aminobutyramide is produced.