Benzopyran derivatives, their preparation and pharmaceutical compositions containing them

New benzopyran derivatives of general formula (I) in which: PA1 R.sub.1 represents a hydrogen or halogen atom or a hydroxy, alkyloxy, nitro, amino, alkylsulphonamido or acylamino radical, PA1 R represents PA2 (1) radical ##STR1## R.sub.2 and R.sub.3, which may be identical or different, being H, halogen, OH, alkyl, alkyloxy, NH.sub.2, alkylsulphonamido or NO.sub.2, or PA2 (2) a radical ##STR2## n being 0 or 1, R.sub.4 being H, alkyl or optionally substituted phenyl and Q is acyl, alkylsulphonyl or ##STR3## Y being --CO-- or --SO.sub.2 -- and Z being a single bond, --CH.sub.2 -- or --NH--, or PA2 (3) a radical ##STR4## n being 0 or 1, m being 0 or 2, X being C or N (if n=0), W being a bond or --NH-- and AR being pyridyl, indolyl, quinolyl, 2-alkylquinolyl or phenyl optionally substituted with R.sub.2 and R.sub.3, provided that n=0 when X equals N, or PA2 (4) a radical of general formula: ##STR5## R.sub.7 being H or alkyl, or alternatively (5) a radical ##STR6## R' and R" are identical and represent hydrogen atoms or alkyl radicals, their isomeric forms and the mixtures thereof, and their addition salts with acids. These new products are useful as anti-arrhythmic and antifibrillating agents. ##STR7##

DETAILED DESCRIPTION OF THE INVENTION 
The present invention relates to new benzopyran derivatives of general 
formula: 
##STR8## 
to their salts, to their preparation and to pharmaceutical compositions 
containing them. 
In German Patent Application No. 3,330,004, a description has been given of 
4-(aminomethyl)benzopyran derivatives which are active as hypotensives and 
muscle relaxants, and corresponding to the formula: 
##STR9## 
in which A represents, in particular, a single bond, 
R.sub.1, R.sub.2, R.sub.8, R.sub.9, R.sub.10 and R.sub.11 can represent 
hydrogen atoms, 
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 can be hydrogen atoms or alkyloxy 
radicals, 
R.sub.12 to R.sub.16 can be inter alia, hydrogen atoms or alkyloxy 
radicals, or 2 of these adjacent radicals can form a methylenedioxy 
radical, 
and --NR.sub.7 --CR.sub.8 R.sub.9 --CR.sub.10 R.sub.11 --X-- can represent 
a piperazinyl radical. 
It has been found that the products of general formula (I) in which 
R.sub.1 represents a hydrogen or halogen atom or a hydroxy, alkyloxy, 
nitro, amino, alkylsulphonamido or acylamino radical, 
R represents 
1) a radical of general formula: 
##STR10## 
in which R.sub.2 and R.sub.3, which may be identical or different, 
represent hydrogen or halogen atoms or hydroxy, alkyl, alkyloxy, amino, 
alkylsulphonamido or nitro radicals, or alternatively 
2) a radical of general formula: 
##STR11## 
in which n equals 0 or 1, R.sub.4 is a hydrogen atom, an alkyl radical or 
a radical of structure: 
##STR12## 
in which R.sub.5 and R.sub.6 are hydrogen or halogen atoms or an alkyloxy 
radical, and Q represents an acyl or alkylsulphonyl radical or a radical 
of structure: 
##STR13## 
in which R.sub.2 and R.sub.3 are defined as above, Y represents a 
carbonyl or sulphonyl radical and Z represents a single bond or a 
methylene or imino radical, or alternatively 
3) a radical of general formula: 
##STR14## 
in which n equals 0 or 1, m equals 0 to 2, X is a carbon atom or X can be 
a nitrogen atom if n=0, W represents a single bond or an imino radical and 
Ar represents a pyridyl, indolyl, quinolyl or 2-alkylquinolyl radical or 
Ar represents a phenyl radical optionally substituted with radicals 
R.sub.2 and R.sub.3 as defined above, provided that m is other than 0 when 
X is a nitrogen atom, or alternatively 
4) a radical of general formula: 
##STR15## 
in which R.sub.2 and R.sub.3 are defined as above and R.sub.7 denotes a 
hydrogen atom or an alkyl radical, or alternatively 
5) a radical of formula: 
##STR16## 
and R' and R", which are identical, represent hydrogen atoms or alkyl 
radicals, 
as well as their salts, bring about an especially advantageous increase in 
the refractory periods, which corresponds to the antifibrillating effects 
of class III anti-arrhythmic products according to VAUGHAN WILLIAMS's 
classification. 
In the general formula (I), when R.sub.1 and/or R.sub.2, R.sub.3, R.sub.5 
or R.sub.6 (in the symbol R) represent a halogen atom, the letter may be 
selected from fluorine, chlorine, bromine or iodine. Furthermore, it is 
understood that the alkyl or acyl radicals and portions may be linear or 
branched and they contain 1 to 4 carbon atoms. 
It is also understood that the products of general formula (I) possess 
isometric forms, and that these isomers and the mixtures thereof fall 
within the scope of the present invention. 
According to the invention, the products of general formula (I) may be 
obtained by the action of a product of general formula: 
EQU H--R (VIII) 
or its salt, in which R is defined as above provided that n=0, on a 
benzopyran derivative of general formula: 
##STR17## 
in which R.sub.1, R' and R" are defined as above and Y.sub.1 represents a 
halogen atom or an alkylsulphonyloxy or arylsulphonyloxy radical, 
optionally followed by oxidation of the product obtained when it is 
desired to prepare a product for which n=1, or alternatively by conversion 
to oxime when it is desired to obtain a product for which R is a radical 
defined above at 4) and when the corresponding ketone for which R is a 
radical defined above at 3), m being equal to 0 and --W--Ar being an 
optionally substituted phenyl radical, has been obtained. 
It is advantageous to work in the presence of an acid-accepting agent. It 
is also possible to work without an acid-acceptor, in the presence of 2 
equivalents of the product of general formula (VIII). 
When Y.sub.1 represents a halogen atom, it may be selected from chlorine 
and bromine atoms. 
When Y.sub.1 represents an alkylsulphonyloxy radical, it represents, in 
particular, a methylsulphonyloxy radical, and when it represents an 
arylsulphonyloxy radical, it can be, inter alia, a p-toluenesulphonyloxy 
radical. 
By way of acid-acceptor, an alkali metal hydroxide or alkaline earth metal 
hydroxide (e.g. sodium hydroxide or potassium hydroxide), an alkali metal 
carbonate (e.g. sodium bicarbonate, potassium carbonate) or a nitrogenous 
organic base such as, e.g. triethylamine, is advantageously used. 
The reaction is performed in an inert solvent such as a ketone (e.g. 
acetone, butanone), an ether (e.g. tetrahydrofuran or dioxane), an alcohol 
(e.g. methanol or ethanol), a hydrocarbon (e.g. hexane or toluene), 
acetonitrile, dimethylformamide or dimethyl sulphoxide, or in a mixture of 
such solvents, at a temperature between 20.degree. C. and the refluxing 
temperature of the reaction mixture. 
It is understood that, in cases where R.sub.1, R.sub.2 and/or R.sub.3 (in 
R) represent an amino radical, the latter is protected beforehand. 
Similarly, when R.sub.2 and/or R.sub.3 represent a hydroxy radical, it is 
preferable to protect this radical prior to the reaction. 
The protection is accomplished with any compatible group whose use and 
removal do not adversely effect the remainder of the molecule. It is 
performed, in particular, according to the methods described by T. W. 
Greene, Protective Groups in Organic Synthesis, A. Wiley - Interscience 
Publication (1981), or by McOmie, Protective Groups in Organic Chemistry, 
Plenum Press (1973). 
Where appropriate, the oxidation is performed by any known method which 
does not adversely effect the remainder of the molecule. The reaction is 
accomplished, in particular, by means of an oxidizing agent such as an 
organic peracid, e.g. peracetic acid or monoperphthalic acid, in an 
organic solvent such as an ether (e.g. ethyl ether, tetrahydrofuran) or a 
chlorinated solvent (e.g. chloroform, dichloromethane), at a temperature 
of between 0.degree. and 25.degree. C. The oxidation may also be 
accomplished by means of hydrogen peroxide, working in an aqueous medium 
or in acetic acid or acetic anhydride at a temperature of between 
-50.degree. and +25.degree. C. 
It is understood that, in the case where the molecule bears amino 
substituents, the oxidation is performed before the liberation of the 
protective radicals. 
Where appropriate, the conversion to a product for which R is a radical of 
general formula (VI) in which R.sub.7 is a hydrogen atom or an alkyl 
radical is performed by the action of hydroxylamine hydrochloride or 
O-alkylhydroxyamine. 
The reaction is generally performed in the presence of a base (e.g. sodium 
hydroxide), in an alcohol (absolute ethanol), at a temperature of between 
20.degree. and 80.degree. C. 
According to the invention, the products of general formula (I) for which 
the radicals R.sub.1, R.sub.2 and/or R.sub.3 represent a hydroxy radical 
may also be obtained from the corresponding product of general formula (I) 
for which the radical R.sub.1, R.sub.2 and/or R.sub.3 to be converted 
represents an alkyloxy radical, by treatment in a concentrated acid 
medium. 
The reaction is generally performed by treatment with hydrobromic acid, or 
a mixture of acids, e.g. by treatment with a hydrobromic acid/acetic acid 
mixture, at the refluxing temperature of the reaction mixture. 
According to the invention, the products of general formula (I) for which R 
is defined as above at 1) and 2) and the symbols R.sub.1, R.sub.2 and/or 
R.sub.3 represent an amino or alkylsulphonamido radical, or for which 
R.sub.1 represents an acylamino radical, may also be obtained by catalytic 
hydrogenation in an acid medium of the corresponding benzopyran derivative 
of general formula (I) for which the radical R.sub.1, R.sub.2, and/or 
R.sub.3 to be converted represents a nitro radical, and then, when it is 
desired to obtain a product of general formula (I) for which R.sub.1, 
R.sub.2 and/or R.sub.3 represent an alkylsulphonamido radical, or for 
which R.sub.1 is an acylamino radical, the amino derivative obtained is 
converted by sulphonylation or by acylation, respectively. 
The hydrogenation is advantageously performed at a temperature of between 
20.degree. and 50.degree. C., in an acid such as, e.g., acetic acid or 
hydrochloric acid, in an organic solvent such as an alcohol (e.g. 
methanol, ethanol, isopropanol), in a mixture of solvents or in an 
aqueous-organic medium (e.g. alcohol/water). It is also possible to work 
directly in the acid without the further addition of a solvent. 
By way of a catalyst, palladium, platinum oxide or Raney nickel is 
generally used. 
The reaction is optionally performed under pressure. 
The sulphonylation or acylation is accomplished, respectively, by the 
action of an activated form of an acid alkSO.sub.3 H or alk'COOH (alk and 
alk' being alkyl radicals), in particular the acid halide (e.g. acid 
chloride) or anhydride, and the reaction is carried out in the presence of 
an acid-acceptor, e.g. a nitrogenous organic base such as a trialkylamine 
(e.g. triethylamine) or such as pyridine, in an inert organic solvent such 
as a chlorinated solvent (e.g. dichloromethane, chloroform) or an ether 
(e.g. ethyl ether, tetrahydrofuran), or in a mixture of these solvents, at 
a temperature of between -70.degree. and +40.degree. C. 
The reaction is optionally performed under nitrogen. 
According to the invention, the products of general formula (I) for which R 
is defined as above at 1) and 3) when X is a nitrogen atom may also be 
prepared by the action of a halide of structure: 
##STR18## 
EQU or 
EQU Hal--(CH.sub.2).sub.m --CO--W--Ar (Xb) 
in which R.sub.2, R.sub.3, W, Ar and m are defined as above and Hal is a 
halogen atom selected from chlorine or bromine, on a benzopyran derivative 
of general formula: 
##STR19## 
in which R.sub.1, R' and R" are defined as above. 
It is understood that, when R.sub.1, R.sub.2 and/or R.sub.3 denote amino or 
hydroxy radicals, the latter are protected prior to the reaction. 
The protection and removal of the protective radicals are performed under 
the conditions described above for the process which consists in reacting 
the products of general formula (VIII) and (IX). 
When a product of general formula (Xa) or (Xb) in which m=0 is reacted, the 
reaction is performed either in an organic medium, optionally in the 
presence of an acid-acceptor such as a nitrogenous organic base (e.g. a 
trialkylamine or a pyridine), in the solvent as mentioned above or a 
mixture of these solvents, at a temperature of between 0.degree. and 
20.degree. C., or in an aqueous-organic medium in the presence of an 
alkaline condensing agent such as an alkali metal carbonate or bicarbonate 
or alkaline earth metal carbonate or bicarbonate, at a temperature of 
between 5.degree. and 20.degree. C. 
When a product of general formula (Xb) for which m is 1 or 2 is reacted, 
the reaction is performed under the conditions described above for 
preparing a product of general formula (I) from the products of general 
formulae (VIII) and (IX). 
The products of general formula (VIII) may be prepared: 
when R is defined as above 1) or 3), X being a nitrogen atom: by the action 
of a halogenated derivative of formula (Xa) or (IXb) on piperazine under 
the conditions described above for the reaction of the products of general 
formula (VIII) with a benzopyran derivative of general formula (IX) in the 
presence of an excess of piperazine, without the further addition of an 
acid-acceptor; 
when R is defined as at 2): according to the method described in French 
Patent M 2430, or according to the methods mentioned by Anwer Basha, Tet. 
Lett., 29(21), 2525 (1988); 
when R is defined as at 3), X being a nitrogen atom and W an imino radical: 
from a benzylpiperazine, by application of the methods mentioned by Anwer 
Basha, Tet. Lett., 29(21), 2525 (1988) followed by removal of the radical 
protecting the piperazine; 
when R is defined as at 3), X being a carbon atom, 
a) if a W is a bond: by a Friedel-Crafts reaction between an acid chloride 
of general formula: 
##STR20## 
in which m equals 1 or 2, and the product of general formula: 
##STR21## 
in which R.sub.2 and R.sub.3 are identical or different and represent 
hydrogen or halogen atoms or an amino radical protected beforehand, or by 
application of the method described by P. Rabbe, Ber., 55, 532 (1922); 
b) if W is an imino radical: by application of the method described by L. 
D. Wise et al., J. Med. Chem., 28, 606 (1985); 
when R is defined as at 5): according to the method described by A. 
Quevauviller et al., Ann. Pharm. Franc., 24, 39 (1966). 
The products of general formula (IX) may be obtained by the action of a 
halogenating agent or an activated form of an alkylsulphonic or 
arylsulphonic acid or a 4-(hydroxyalkyl)benzopyran of general formula 
##STR22## 
in which R.sub.1, R' and R" are defined as above. 
When it is desired to prepare a product of general formula (IX) for which 
Y.sub.1 is a halogen atom, the halogenating agents may be selected from 
thionyl chloride or halogenated phosphorus derivatives such as phosphorus 
oxychloride or phosphorus tribromide. It is also possible to react allyl 
bromide in the presence of N,N'-carbonyldiimidazole. 
When it is desired to prepare a product of general formula (IX) in which 
Y.sub.1 is alkylsulphonyloxy or arylsulphonyloxy, the anhydride or halide 
of the corresponding acid is advantageously reacted. 
The reaction is generally performed in the presence of a nitrogenous 
organic base such as triethylamine or pyridine, in an organic solvent such 
as a chlorinated solvent (e.g. methylene chloride) or an ether (e.g. 
tetrahydrofuran, dioxane), working at a temperature between 0.degree. C. 
and the refluxing temperature of the reaction mixture. 
The products of general formula (IX) in which R.sub.1 is a nitro radical 
may be obtained by nitration of a derivative of general formula (IX) in 
which R.sub.1 is a hydrogen atom. 
It is advantageous to work using a nitric acid/acetic acid mixture at a 
temperature of between 0.degree. and 20.degree. C. 
The products of general formula (IX) in which R.sub.1 is a hydroxy radical 
may also be obtained from a product of general formula (IX) in which 
R.sub.1 is an alkyloxy radical, by treatment in a concentrated acid 
medium. The reaction is performed under the conditions described above for 
the production of a product of general formula (I) for which R.sub.1 
represents a hydroxy radical from the corresponding product for which 
R.sub.1 is an alkyloxy radical. 
The 4-(hydroxyalkyl)benzopyran derivative of general formula (XIV) may be 
prepared by reduction of the corresponding ester of general formula: 
##STR23## 
in which R.sub.1, R' and R" are defined as above. 
The reaction is generally performed using lithium aluminum hydride in an 
organic solvent such as an ether (e.g. tetrahydrofuran) at a temperature 
of between 0.degree. and 30.degree. C. 
The ester of general formula (XVII) may be obtained by reduction of the 
benzopyran derivative of general formula: 
##STR24## 
in which R.sub.1, R' and R" are defined as above. 
The reaction is performed by catalytic hydrogenation in the presence of 
palladium, in an organic solvent such as an alcohol (e.g. methanol, 
ethanol), at a temperature of between 10.degree. and 50.degree. C. 
The benzopyran derivative of general formula (XVI) may be prepared by a 
WITTIG reaction, from a 4-chromanone derivative of general formula: 
##STR25## 
in which R.sub.1, R' and R" are defined as above. 
The reaction is advantageously performed using ethyl 
diethylphosphonoacetate in the presence of sodium hydride, in an organic 
solvent such as an ether (e.g. tetrahydrofuran or dimethoxyethane), at a 
temperature between 0.degree. C. and the refluxing temperature of the 
reaction mixture. 
The 4-chromanone derivative of general formula (XVII) in which R.sub.1 is 
other than hydrogen may be prepared by application of the method described 
by PFEIFFER et al., Chem. Ber., 58 (1954), or according to the methods 
described in G. P. Ellis, Heterocyclic compounds, chromenes, chromanones, 
and chromones, John Wiley and Sons (1977). 
The 4-chromanone derivative of general formula (XVII) in which R.sub.1 is a 
fluorine atom may be prepared according to the method described in French 
Patent Application 2,588,860. 
The 4-chromanone derivatives of general formula (XVII) in which R.sub.1 is 
an amino, alkylsulphonamido or acylamino radical may be obtained from the 
4-chromanone derivative of general formula (XVII) for which R.sub.1 is a 
nitro radical, by a procedure similar to the methods described for the 
preparation of the products of general formula (I) for which radical 
R.sub.1 is defined as above. 
2,2-Dimethyl-4-chromanone may be obtained according to the method described 
in Belgian Patent 844,943. 
The products of general formula (Xb) may be prepared: 
when W is a bond, by a Friedel-Crafts reaction between an acid chloride of 
general formula: 
EQU Hal(CH.sub.2).sub.m COCl (XVIII) 
in which m is equal to 0 or 1, and a product of general formula (XIII), or 
when W is an imino radical, according to the method described by L. D. Wise 
et al., J. Med. Chem., 28, 206 (1985). 
The benzopyran derivatives of general formula (XI) may be obtained by the 
action of piperazine on a benzopyran derivative of general formula (IX). 
The reaction is performed under the conditions described above for the 
reaction of the products of general formula (VIII) with the benzopyran 
derivatives of general formula (IX), in the presence of an excess of 
piperazine (2 equivalents), without further addition of an acid-acceptor. 
The enantiomers of the products according to the invention may be separated 
according to known methods. 
The procedure is performed, in particular, by preparation of the enantiomer 
of the hydroxyethylbenzopyran derivative of general formula (XIV), which 
is converted to a product of general formula (I) according to the process 
described above. 
The optically active derivative of general formula (XIV) is obtained by 
preparation of an optically active amide of general formula: 
##STR26## 
in which R.sub.1, R' and R" are defined as above, separation of the 
isomers by chromatography, hydrolysis of the desired isomer and then 
reduction of the acid obtained. 
The hydrolysis of the isomer of the product of general formula (XIX) may be 
performed by any known method which does not adversely effect the 
remainder of the molecule; it is advantageous to work in an acid medium 
(mixtures of acetic acid and hydrochloric acid) at the refluxing 
temperature of the reaction mixture. 
The reduction of the acid to the alcohol is carried out according to the 
usual methods. In particular, diborane is used by way of a reducing agent, 
and it is advantageous to work in an ether such as tetrahydrofuran at 
temperatures of between 0.degree. and 30.degree. C. 
The product of general formula (XIX) may be prepared from the acid of 
general formula: 
##STR27## 
in which R.sub.1, R' and R" are defined as above, by any known method for 
preparing an amide from an acid. 
The reaction is advantageously performed using the acid chloride of general 
formula (XX) (which may be prepared in situ), in an inert organic solvent 
such as a chlorinated solvent (e.g. dichloromethane), in the presence of 
an acid-acceptor agent such as a nitrogenous organic base (e.g. 
triethylamine), at a temperature of between 0.degree. and 30.degree. C. 
The acid of general formula (XX) may be obtained from the corresponding 
ester by any known method for obtaining an acid from an ester without 
affecting the remainder of the molecule. 
Saponification of the ester of general formula (XIV) is performed, in 
particular, with potassium hydroxide in methanol at the refluxing 
temperature of the reaction mixture. 
The acid chloride is prepared by treating the corresponding acid with 
thionyl chloride at the refluxing temperature of the reaction mixture. 
The new benzopyran derivatives according to the invention may be purified, 
where appropriate, by physical methods such as crystallization or 
chromatography. 
The products according to the invention may be converted to addition salts 
with acids. The salt formed precipitates after concentration, where 
appropriate, of the solution, and is separated by filtration, decantation 
or lyophilization. According to the process of the present invention, the 
products are generally obtained in the state of an oxalate. These salts 
may be liberated and converted to salts of other acids according to the 
usual methods. 
As examples of pharmaceutically acceptable salts, there may be mentioned 
the addition salts with inorganic acids (hydrochlorides, hydrobromides, 
sulphates, nitrates, phosphates) or organic acids (succinates, fumarates, 
acetates, propionates, maleates, methanesulphonates, p-toluenesulphonates, 
isethionates) or substitution derivatives of these compounds. 
The products according to the invention exhibit anti-arrhythmic properties. 
In particular, their especially advantageous antifibrillating properties, 
characteristic of VAUGHAN WILLIAM's class III, result in prolongation of 
the refractory periods. 
They produce, in vitro on guinea pig papillary muscle, an increase of 
between 5% and values above 30% in the duration of the initial action 
potential, according to the intracellular action potential recording 
measurement technique described by E. CORABOEUF and S. WEIDMANN, C. R. 
Soc. Biol., 143, 1329 (1949). 
Moreover, the benzopyran derivatives according to the invention exhibit low 
toxicity. They have been generally shown to be non-toxic at 300 mg/kg when 
administered orally to mice. 
Of special importance are the products of general formula (I) for which: 
R.sub.1, R' and R" are hydrogen atoms, and R represents a radical as 
defined at 1) for which R.sub.2 and R.sub.3 are hydrogen atoms, or 
R represents a radical as defined at 2) for which n equals 0, R.sub.4 is 
hydrogen atom, an alkyl radical or a radical of structure (IVa) in which 
R.sub.5 and R.sub.6 are hydrogen or halogen atoms or alkyloxy radicals and 
Q represents an acetyl or methylsulphonyl radical or a radical of general 
formula (IVb) in which Y is a carbonyl or sulphonyl radical and Z is a 
bond or a methylene or imino radical, and R.sub.2 and R.sub.3 are hydrogen 
or halogen atoms or alkyl or methylsulphonamido radicals, or 
R represents a radical as defined at 3) for which n equals 0, m equals 0 to 
2, W is bond or an imino radical, Ar is pyridyl, indolyl or phenyl 
optionally substituted with a halogen atom or alkyl or alkyloxy radicals 
and X is a carbon or nitrogen atom, or R represents a radical as defined 
at 4) for which R.sub.7 represents a hydrogen atom. 
And among these more especially active products are the products of general 
formula (I) given below: 
N-{1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-piperidyl}acetanilide 
and its salts; 
1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-nicotinoylpiperazine and 
its salts; 
N-{1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-piperidyl}-N-phenyl-4-fl 
uorobenzamide and its salts; 
4-benzoyl-1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]piperidine and its 
salts; and 
{1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-piperidyl}phenylmethanoxim 
e and its salts. 
The examples which follow, given without implied limitation, illustrate the 
present invention. 
EXAMPLES 
In the examples which follow, except where otherwise stated, chromatography 
is carried out on silica gel (60-200 .mu.).