Novel phenylacetic acid derivatives

Phenylacetic acid derivatives of the formula ##STR1## wherein n is an integer of 2 to 5; ##STR2## R.sub.1 is hydrogen, halogen, trifluoromethyl, nitro or amino; R.sub.2 and R.sub.3 each independently is hydrogen or lower alkyl; or together form an ethylene group; PA0 X.sub.1 represents two hydrogen atoms or an oxo group; and PA0 Y.sub.1 is cyano, hydroxyamidocarbonyl, carbamoyl, 5-tetrazolyl or carboxyl; and for derivatives wherein Y is carboxyl, salts thereof with physiologically compatible bases, esters thereof from physiologically acceptable alcohols and amides thereof from physiologically acceptable amines have valuable pharmacological activity, e.g., as antiinflammatory agents.

BACKGROUND OF THE INVENTION 
The present invention relates to novel phenylacetic acid derivatives, a 
process for the production thereof, and pharmaceutical preparations 
containing the same derivatives as active agent. 
SUMMARY OF THE INVENTION 
It is an object of this invention to provide new compounds which are 
pharmacologically active, e.g., as antiinflammatory agents. 
Upon further study of the specification and appended claims, further 
objects and advantages of this invention will become apparent to those 
skilled in the art. 
These objects have been achieved by providing novel phenylacetic acid 
derivatives of Formula I 
##STR3## 
wherein n is an integer of 2 to 5; 
##STR4## 
R.sub.1 is hydrogen, halogen, trifluoromethyl, nitro, or amino; R.sub.2 
and R.sub.3 each independently is hydrogen or lower alkyl, or together 
form an ethylene group; 
X.sub.1 represents two hydrogen atoms or an oxo group; and 
Y.sub.1 is cyano, hydroxyamidocarbonyl, carbamoyl, 5-tetrazolyl, or 
carboxyl; 
and for the derivatives wherein Y is carboxyl, the salts thereof with 
physiologically compatible bases, the esters thereof from physiologically 
acceptable alcohols and the amides thereof from physiologically acceptable 
amines. 
DETAILED DISCUSSION 
Suitable halogens for R.sub.1 include chlorine, bromine and preferably 
fluorine. 
Suitable lower alkyl groups for R.sub.2 or R.sub.3 preferably are those 
containing 1-4 carbon atoms, e.g., ethyl, propyl, isopropyl and especially 
methyl. 
The present invention also includes where appropriate, the racemic 
phenylacetic acid derivatives of Formula I, as well as the optically 
active antipodes thereof. 
Suitable physiologically compatible salts of the carboxyl group Y.sub.1 
include the alkali metal or alkaline earth metal salts, e.g., the sodium 
or calcium salts; the ammonium salt; the copper (II) salt; the piperazine 
salt; or the methylglucamine salt; as well as the salts of these compounds 
with amio acids such as glycine, alanine, phenylalanine, leucine alanine, 
leucine, lysine and valine. 
Physiologically acceptable alcohols with which the carboxyl group Y.sub.1 
can be esterified include, for example, straight-chain, branched or 
cyclic, saturated or unsaturated, hydrocarbon residues which can 
optionally be interrupted by an oxygen atom or a nitrogen atom, or which 
can be substituted by hydroxy groups, amino groups, or carboxyl groups, 
e.g., alkanols (especially those of 1-6 carbon atoms); C.sub.2-6 alkenols, 
C.sub.2-6 alkynols, C.sub.3-8 cycloalkanols, C.sub.3-7 cycloalkyl 
C.sub.1-6 alkanols, phenyl C.sub.2-6 alkanols, phenyl C.sub.2-6 alkenols, 
C.sub.1-6 alkanediols, C.sub.3-8 cycloalkenols, amino C.sub.1-6 alkanols, 
C.sub.1-4 alkylamino C.sub.1-6 alkanols, dialkylamino C.sub.1-6 alkanols 
of 1-4 carbon atoms in the alkyl residue, and hydroxycarboxylic acids such 
as the foregoing alcohols substituted by a carboxy group. 
Such alcohols suitable for the esterification of the carboxyl group 
include, for example, those having the following residues: 
methylcarboxymethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl 2-aminoethyl, 
2-dimethylaminoethyl, 2-carboxyethyl, propyl, allyl, cyclopropylmethyl, 
isopropyl, 3-hydroxypropyl, propynyl, 3-aminopropyl, butyl, sec-butyl, 
tert-butyl, butyl-(2), cyclobutyl, pentyl, isopentyl, tert-pentyl, 
2-methylbutyl, cyclopentyl, hexyl, cyclohexyl, cyclohex-2-enyl, 
cyclopentylmethyl, heptyl, benzyl, 2-phenylethyl, octyl, bornyl, 
isobornyl, menthyl, nonyl, decyl, 3-phenylpropyl, 3-phenylprop-2-enyl, 
undecyl, or dodecyl. Also suitable for esterification are those alcohols 
resulting in labile esters, i.e., esters which can be split under 
physiological conditions, such as 5-hydroxyindan, acyloxymethanols, 
especially acetoxymethanol, pivaloyloxymethanol, 
5-indanyloxycarbonylmethanol, glycolic acid, dialkylaminoalkanols, 
especially dimethylaminopropanol, as well as hydroxyphthalide. 
Preferred physiologically acceptable amines with which the carboxyl group 
can be amidated include C.sub.1-6 alkylamines, diC.sub.1-6 alkylamines, 
C.sub.1-6 alkanolamines, diC.sub.1-6 alkanolamines, or five- or 
six-membered N-heterocycles. Examples of suitable such amines include: 
methylamine, ethylamine, isopropylamine, ethanolamine, dimethylamine, 
diethylamine, diethanolamine, pyrrolidine, piperidine, morpholine, or 
N-methylpiperazine. 
The process of this invention for the preparation of the novel phenylacetic 
derivatives of Formula Ia 
##STR5## 
wherein n, &gt;A-B-, X.sub.1, R.sub.1, R.sub.2, and R.sub.3 have the 
above-indicated meanings and 
Y.sub.2 has the same meanings as Y.sub.1, but does not represent a cyano 
group or a 5-tetrazolyl group, 
is characterized in that, conventionally, 
(a) a nitrile of general Formula II 
##STR6## 
wherein n, &gt;A-B-, X.sub.1, R.sub.1, R.sub.2, and R.sub.3 have the 
above-indicated meanings, is hydrolyzed; or 
(b) a compound of general Formula III 
##STR7## 
wherein n, &gt;A-B-, X.sub.1, R.sub.1, R.sub.2 and R.sub.3 have the 
above-indicated meanings and 
Y.sub.3 is an alkoxycarbonyl group, a dithianylidene group, or a 
4,4-dimethyl-2-oxazolinyl group, 
is hydrolyzed; or 
(c) an aldehyde of general Formula IV 
##STR8## 
wherein n, &gt;A-B-, X.sub.1, R.sub.1, R.sub.2 and R.sub.3 have the 
above-indicated meanings, 
is oxidized; or 
(d) an acetophenone of general Formula V 
##STR9## 
wherein n and R.sub.1 have the above-indicated meanings and 
R.sub.4 represents a hydrogen atom or a lower alkyl group, is rearranged 
into the phenylacetic acid of general Formula VI 
##STR10## 
wherein n, R.sub.1, and R.sub.4 have the above-indicated meanings, 
and this compound is optionally alkylated in the .alpha.-position; or 
(c) a malonic acid derivative of general Formula VII 
##STR11## 
wherein n, &gt;A-B-, X.sub.1, R.sub.1, R.sub.2, and R.sub.3 have the 
above-indicated meanings, 
is decarboxylated; or 
(f) the oxo group of a compound of general Formula VIII 
##STR12## 
wherein n, &gt;A-B-, X.sub.1, R.sub.1, R.sub.2, and R.sub.3 have the 
above-indicated meanings, at least one of the groups &gt;A-B- or 
C.dbd.X.sub.1 signifying a carbonyl group, 
is reduced by thermal treatment with hydrazine; or 
(g) a Grignard reagent of general Formula IX 
##STR13## 
wherein &gt;A-B-, n, R.sub.1, R.sub.2 and R.sub.3 have the above-indicated 
meanings and 
Hal represents a halogen atom, 
is reacted with carbon dioxide; or 
(h) a compound of general Formula X 
##STR14## 
wherein 
n, &gt;A-B-, X.sub.1, Y.sub.2, R.sub.1, and R.sub.2 have the above-indicated 
meanings and 
R.sub.5 represents a lower alkylidene group or, if &gt;A-B- is the grouping 
&gt;C.dbd.CH-, also two hydrogen atoms or one hydrogen atom and a lower alkyl 
group, 
is hydrogenated; or 
(i) a compound of general Formula XI 
##STR15## 
wherein R.sub.1, R.sub.2, and R.sub.3 have the above-indicated meanings 
and 
R.sub.6 represents a hydrogen atom or an alkyl residue of 1-6 carbon atoms, 
is condensed in the presence of a Friedel-Crafts catalyst with a 
cycloalkanoyl chloride of general Formula XII 
##STR16## 
wherein n has the above-indicated meanings; or 
(j) a compound of general Formula XIII 
##STR17## 
wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.6 have the above-indicated 
meanings, 
is condensed with a Wittig reagent of general Formula XIV 
##STR18## 
wherein n has the above-indicated meanings, or with a carbonyl compound of 
general Formula XV 
##STR19## 
wherein n has the above-indicated meanings; or 
(k) a compound of general Formula XVI 
##STR20## 
wherein R.sub.1, R.sub.2, R.sub.3, and Y.sub.3 have the above-indicated 
meanings and 
Z represents a formyl group or a cyano group, is reacted with an 
organometallic compound of general Formula XVII 
##STR21## 
wherein n has the above-indicated meanings and 
M represents a lithium atom or a magnesium halide group; or 
(l) a compound of general Formula XVIII 
##STR22## 
wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.6 have the above-indicated 
meanings, is condensed with a .beta.-keto ester of general Formula XIX 
##STR23## 
wherein n has the above-indicated meanings and 
R.sub.7 represents a lower alkyl group, 
the ester groups are saponified, and the thus-produced .beta.-keto acid is 
decarboxylated; 
and optionally compounds of general Formula Ia with R.sub.1 being a halogen 
atom are dehalogenated, compounds of general Formula Ia with R.sub.1 being 
a hydrogen atom are halogenated or nitrated and the thus-produced nitro 
compounds are reduced to amino compounds, and optionally the thus-obtained 
carboxylic acids or reactive derivatives thereof are converted into the 
salts, esters, amides, or hydroxamic acids thereof. 
The process of this invention for preparing the novel phenylacetic 
derivatives of general Formula Ib 
##STR24## 
wherein n, &gt;A-B-, R.sub.1, R.sub.2, and R.sub.3 have the above-indicated 
meanings and 
Y.sub.4 represents a cyano group, a carbamoyl group, or a 5-tetrazolyl 
group, 
is characterized in that, conventionally, 
(m) a ketone of general Formula XX 
##STR25## 
wherein n, X.sub.1, R.sub.1, R.sub.2, and R.sub.3 have the above-indicated 
meanings and 
&gt;A.sub.1 -B.sub.1 - represents the groupings &gt;CH-CH.sub.2 -, 
##STR26## 
is reacted with an arylsulfonylmethylisocyanide; or (n) a halogenide of 
general Formula XXI 
##STR27## 
wherein n, X.sub.1, &gt;A.sub.1 -B.sub.1 -, R.sub.1, R.sub.2, R.sub.3, and 
Hal have the above-indicated meanings, 
is reacted with an alkali metal cyanide; or 
(o) a compound of general Formula XXII 
##STR28## 
wherein R.sub.1, R.sub.2, and R.sub.3 have the above-indicated meanings, 
is condensed, in the presence of a Friedel-Crafts catalyst with a 
cycloalkanoyl chloride of general Formula XXIII 
##STR29## 
wherein n has the above-indicated meanings; any thioketalized oxo groups 
present are hydrolyzed and optionally the thus-obtained cyanides of 
general Formula Ib are saponified to the corresponding amides or converted 
to the corresponding tetrazolyl compounds. 
The process of this invention according to process variant (a) takes place 
under conditions well-known to those skilled in the art. Thus, the 
nitriles can be hydrolyzed, for example, with strong mineral acids (such 
as hydrochloric acid or sulfuric acid) or with strong bases (such as 
aqueous sodium hydroxide solution or potassium hydroxide solution) 
partially to the corresponding amides or, under more vigorous conditions, 
to the corresponding carboxylic acids. 
The aqueous mineral acid of base itself can be used as the solvent for this 
reaction. However, on the other hand, it is also possible to conduct the 
reaction in the presence of polar solvents, e.g. lower alcohols methanol, 
ethanol, isopropanol, etc.), carboxylic acids (acetic acid, propionic 
acid, etc.), polar ethers (glycol monomethyl ether, dioxane, 
tetrahydrofuran, etc.), or dipolar aprotic solvents (dimethyl sulfoxide, 
etc.). 
Customarily, the hydrolysis is effected at a reaction temperature of 
20.degree.--160.degree. C. 
The starting compounds of general Formula II utilized for this reaction 
can, as mentioned above, be produced in accordance with variants (m) 
through (o) of the process of this invention. 
The process of this invention according to process variant (b) can likewise 
be conducted in a conventional way by hydrolyzing the compounds of general 
Formula III by means of dilute mineral acids (e.g. hydrochloric acid, 
sulfuric acid, phosphoric acid). This hydrolysis can be conducted in the 
absence of additional solvents. On the other hand, however, it is likewise 
possible to effect this reaction in the presence of polar solvents (e.g. 
those solvents mentioned in the description of process varient [a]) or in 
the presence of nonpolar solvents, such as chlorinated hydrocarbons 
(dichloromethane, chloroform, tetrachloride, etc.). 
Moreover, the esters of general Formula III can also be hydrolyzed with the 
aid of alkaline catalysts (potassium bicarbonate, potassium carbonate, 
potassium hydroxide, potassium ethylate, sodium carbonate, sodium 
hydroxide, sodium methylate, etc.); this hydrolysis can be conducted in 
the presence of the same solvents as the acidic hydrolysis. 
The process of this invention according to process varient (b) is usually 
carried out at a reaction temperature of -20.degree. to +100.degree. C. 
The preparation of the starting compounds of general Formula III wherein 
Y.sub.3 means an alkanoyloxy group is included in the description of 
process variant (i). 
The compounds utilized as the starting materials defined by general Formula 
III with Y.sub.3 meaning a dithianylidene group can be produced, for 
example, from the ketones of general Formula XX by reacting these ketones 
with dithiane under the conventional conditions (J. Med. Chem. 15 
[1972]:1297). 
The compounds of general Formula III used as starting materials with 
Y.sub.3 meaning a 4,4-dimethyl-2-oxazolinyl group can be prepared, for 
example, under the conditions indicated in the following practical 
examples. 
The process of this invention according to process variant (c) is likewise 
conducted under conditions well-known to persons skilled in the art. Thus, 
it is possible, for example, to oxidize the aldehydes of general Formula 
IV to the corresponding carboxylic acids in inert solvents, e.g. lower 
ketones (acetone etc.) or lower carboxylic acids (acetic acid etc.) or 
water with the use of oxidizing heavy metal oxides [chromium (VI) oxide, 
sodium dichromate, potassium permanganate, etc.]. The aldehydes of general 
Formula IV required for this modification of the process can be produced 
from the ketones of general Formula XX by reacting the latter under 
conventional conditions (J. Org. Chem. 35 [1970]:1600) with the ethyl 
ester of chloroacetic acid, and cleaving the thus-formed epoxide by means 
of bases. 
The process of this invention according to process variant (d) is 
preferably conducted by heating the acetophenones of general Formula V 
with morpholine and sulfur to 50.degree.-150.degree. C. (Willgerodt 
reaction: Newer Methods of Preparative Organic Reactions 3 [1946]:83). 
The optionally following alkylation of the compounds of general Formula VI 
is preferably conducted by esterifying these acids and reacting them with 
alkyl halogenides in the presence of proton acceptors (such as sodium 
hydride, lithium diisopropylamide, butyllithium, sodium, or lithium) in an 
inert solvent (ammonia, triethylamine, tetrahydrofuran, dioxane, 
dimethoxyethane, etc.), and saponifying the thus-formed esters in 
accordance with process variant (b). 
The production of the acetophenones of general Formula V necessary for this 
process variant is mentioned in the description of process variant (m). 
The process of this invention according to process variant (e) is likewise 
conducted under conditions well-known to those skilled in the art. This 
reaction is accomplished by thermal heating of the malonic acid 
derivatives of general Formula VII to 50.degree.-150.degree. C., wherein 
the decarboxylation can be conducted in the absence of a solvent, or also 
in the presence of a high-boiling solvent (such as xylene, chlorobenzene, 
or decahydronaphthalene). 
The malonic acid derivatives of general Formula VII can be prepared, for 
example, under the conditions described in the publication "J. Med. Chem. 
17 (1974):491" from the corresponding carboxylic acids of general Formula 
VI. 
The process of this invention according to process variant (f) is effected 
under the conditions known to those skilled in the art under the names of 
Wolff-Kishner reduction and Huang-Minlon reduction. 
Thus, the compounds of general Formula VIII can be heated, for example, in 
a high-boiling solvent (ethylene glycol, triethylene glycol, etc.) in the 
presence of alkali metal hydroxides (sodium hydroxide or potassium 
hydroxide) with hydrazine to 100.degree.-250.degree. C., thus obtaining 
the compounds of general Formula Ia. 
The compounds of general Formula VIII required as the starting materials 
for process varient (f) can be prepared, for example, under the conditions 
set forth in process variants (i) through (m), as well as in the following 
examples. 
The process of this invention according to process variant (g) is conducted 
under the conditions conventional for Grignard reactions. 
Thus, it is possible, for example, to react halogenides of general Formula 
XII in an ether (diethyl ether, diisopropyl ether, di-n-butyl ether, etc.) 
with magnesium to obtain the Grignard reagent of general Formula IX, and 
then treat this product with solid carbon dioxide. 
The process of this invention according to process variant (h) is likewise 
effected in a conventional manner. 
It is possible, for example, to hydrogenate the compounds of general 
Formula X in an inert solvent in the presence of hydrogenation catalysts 
(Raney nickel, platinum oxide catalysts, palladium catalysts, etc.) with 
hydrogen. Suitable inert solvents are, for example, lower esters (acetic 
acid ethyl ester etc.), lower carboxylic acids (acetic acid etc.), lower 
alcohols (methanol, ethanol, isopropanol, etc.), cyclic ethers (dioxane, 
tetrahydrofuran, etc.), or water. 
The compounds of general Formula X required as the starting materials can 
be prepared, for example, in accordance with variant (j) or from the 
ketones of general Formula XX, by reacting the latter with 
p-toluenesulfonic acid hydrazide, treating the thus-formed hydrazone with 
butyllithium, and decomposing the thus-formed lithium salt with carbon 
dioxide (Tetrahedron Letters 34 [1976]: 2947). 
The process of this invention according to variant (i) is conducted under 
the usual conditions of the Friedel-Crafts reaction (Houben-Weyl, vol. 
VII/2a [1973]: 38). 
Thus, the compounds XI and XII can be reacted, for example, in an inert 
solvent, carbon disulfide, nitromethane, or nitrobenzene with a 
Friedel-Crafts catalyst, such as aluminum chloride, iron(III) chloride, 
tin(IV) chloride, titanium(IV) chloride, boron trifluoride, or zinc 
chloride. 
For this reaction, the starting materials employed are preferably those 
compounds of general Formula XI which carry a hydrogen atom or a halogen 
atom as substituent R.sub.1. 
The process of this invention according to process variant (j) is 
accomplished under the conditions customarily used in Wittig reactions. 
("Organikum"--Basic Course in Organic Chemisty, VEB [=People-Owned 
Factories], publishers: Deutscher Verlag der Wissenschaften, Berlin, 1976, 
492). It is thus possible, for example, to produce from a cycloalkyl 
triphenylphosphonium halogenide the corresponding triphenylphosphine 
cycloalkylene in an inert solvent--such as diethyl ether, diisopropyl 
ether, tetrahydrofuran, or dimethyl sulfoxide--with the use of bases, such 
as sodium hydride or butyllithium; and the thus-obtained solution can be 
reacted at -20.degree. to +120.degree. C. with the aldehyde of general 
Formula XIII. 
The reaction of the aldehydes with the carbonyl compounds of general 
Formula XV takes place under the conditions customary for aldol 
condensations ("Organikum"[1976]: 563), for example in an 
aqueous-alcoholic solution in the presence of bases--such as potassium 
hydroxide--or acids--such as sulfuric acid, hydrochloric acid, or acetic 
acid. 
The process of this invention according to variant (k) takes place under 
the usual conditions, by producing the organometallic compounds of Formula 
XVII from the corresponding halogenides by reaction with lithium or 
magnesium in an inert solvent, such as diethyl ether, diisopropyl ether, 
dibutyl ether, or tetrahydrofuran, and treating the thus-obtained 
solutions with compounds of Formula XVI. 
The process of this invention according to variant (1) likewise takes place 
under conditions known per se, for example by reacting the keto ester of 
general Formula XIX and the compounds of Formula XVIII in an inert 
solvent, such as methanol, ethanol, dioxane, glycol momomethyl ether, or 
dimethylformamide, with bases--especially sodium or potassium 
alcoholates--and subsequently saponifying and decarboxylating with the aid 
of acids (sulfuric acid, p-toluenesulfonic acid, etc.). 
The optionally following dehalogenation likewise takes place in the usual 
way, for example by splitting off the halogen by hydrogenation. This can 
be accomplished by hydrogenating the compounds, for example in ethanol or 
acetic acid, in the presence of platinum or palladium catalysts. 
The racemate separation of the acids, which may follow as an optional step, 
takes place as usual by reacting these acids with optically active bases 
and separating the thus-obtained diastereomeric mixtures by fractional 
crystallization. 
Suitable optically active bases are, for example, optically active amino 
acids, d- or 1-1-phenylethylamine, d-or 1-naphthylethylamine, brucine, 
strychnine, or quinine. 
The optionally following halogenation of compounds of general Formula Ia 
with R.sub.1 meaning hydrogen is conducted in the usual way by treating 
these compounds with halogens (chlorine or bromine) in an inert solvent 
(dichloroethane, methylene chloride, chloroform, nitrobenzene, etc.) in 
the presence of a Friedel-Crafts catalyst [iron(III) chloride, iron(III) 
bromide, aluminum chloride, etc.]. 
The nitration of compounds of Formula Ia with R.sub.1 meaning hydrogen, 
which can follow as an optional step, takes place in the usual way by 
treating these compounds with nitric acid, or with nitric acid-sulfuric 
acid mixtures. 
The reduction of a nitro group, which can follow, if desired, is 
accomplished under the conditions well-known to those skilled in the art 
(Houben-Weyl, vol. XI/1 [1957]:360). 
The optionally following esterification of the free acids likewise takes 
place according to known operating methods. Thus, the acids can be 
reacted, for example, with diazomethane or diazoethane, obtaining the 
corresponding methyl or ethyl esters. A generally applicable method is the 
reaction of the acids with the alcohols in the presence of carbonyl 
diimidazole or dicyclohexylcarbodiimide. 
It is furthermore possible, for example, to react the acids in the presence 
of copper(I) oxide or silver oxide with alkyl halogenides. 
Another method resides in that the free acids are converted into the 
corresponding acid alkyl esters with the corresponding dimethylformamide 
alkyl acetals. Furthermore, the acids can be reacted, in the presence of 
strongly acidic catalysts such as hydrogen chloride, sulfuric acid, 
perchloric acid, trifluoromethylsulfonic acid, or p-toluenesulfonic acid, 
with the alcohols or the lower alkanecarboxylic acid esters of the 
alcohols. 
However, it is also possible to convert the carboxylic acids into the acid 
chlorides or mixed acid anhydrides and to react these products with the 
alcohols in the presence of alkaline catalysts, such as pyridine, 
collidine, lutidine, or 4-dimethylaminopyridine. 
The salts of the carboxylic acids are formed, for example, during the 
saponification of the esters by means of alkaline catalysts or during the 
neutralization of the acids by means of alkali carbonates or alkali 
hydroxides, e.g. sodium carbonate, sodium bicarbonate, sodium hydroxide, 
potassium carbonate, potassium bicarbonate, or potassium hydroxide. 
It is furthermore possible to react esters of general Formula I in the 
presence of acidic or alkaline catalysts with the finally desired alcohol. 
In this connection, preferred acidic or basic catalysts are hydrogen 
chloride, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 
trifluoroacetic acid, other examples being alkali, alkaline earth, 
aluminum alcoholates. 
The optionally following amide formation or hydroxamic acid formation from 
the free carboxylic acids or the reactive derivatives thereof likewise 
takes place according to the methods conventional for this purpose. It is 
possible, for example, to react the carboxylic acids, under the 
conventional conditions, with amines or hydroxylamine in the presence of 
dicyclohexylcarbodiimide, thus obtaining the corresponding aminocarbonyl 
compounds. 
Furthermore, it is possible, for example, to convert the acid chlorides, 
mixed anhydrides, or esters corresponding to the carboxylic acids into the 
corresponding amides or hydroxamic acids under the conventional conditions 
by treatment with ammonia, with amines, or with hydroxylamine. 
The process of this invention according to process variant (m) can be 
conducted under the conditions known to persons skilled in the art under 
the name TOSMIC reaction (Tetrahedron Letters 1973:1357). 
The ketones of general Formula XX can thus be reacted with 
arylsulfonylmethylisocyanides (especially 
p-toluenesulfonylmethylisocyanide), for example, in a polar ether (glycol 
dimethyl ether, dioxane, tetrahydrofuran, etc.) or in a dipolar aprotic 
solvent (dimethylformamide, dimethyl sulfoxide, N-methylmorpholine, 
hexamethylphosphoric triamide, etc.) in the presence of an alkali metal 
alcoholate (sodium methylate, potassium ethylate, potassium 
tert.-butylate, etc.): in this way, the compounds of Formula Ib are 
obtained. 
The ketones of general Formula XX required for the process of this 
invention according to variant (m) can be prepared, for example, by 
condensing a cycloalkanoyl chloride of Formula XII in the presence of 
Friedel-Crafts catalysts under the conditions of process variant (i) with 
benzene or halobenzene, reducing the thus-obtained ketone according to the 
Huang-Minlon method, or thioketalizing this ketone with thioglycols 
(ethanedithiol, 1,3-propanedithiol, etc.), and then acylating the product 
with an alkanoyl chloride under the conditions of the Friedel-Crafts 
reaction. 
The process of this invention according to variant (n) can be conducted 
under the conditions customarily employed for the exchange of halogen 
atoms against a cyano group. 
For this process variant, those compounds are preferably used as the 
starting materials of general Formula XXI which carry a chlorine, bromine, 
or iodine atom as the substituent. 
This reaction is preferably carried out in a dipolar aprotic solvent (such 
as dimethylformamide, N-methylacetamide, N-methylpyrrolidone, 
acetonitrile, dimethyl sulfoxide, or hexamethylphosphoric triamide). 
Preferred alkali metal cyanides for this reaction are sodium cyanide or 
potassium cyanide. 
During this reaction the reaction speed can be significantly accelerated by 
effecting the step in the presence of a Kronen ether. 
The starting compounds of general Formula XXI can be produced in the usual 
way from the ketones of general Formula XX by reducing the same, for 
example, with sodium borohydride and reacting the evolving carbinols with 
hydrogen halide, thionyl chloride, phosphorus oxychloride, phosphorus 
pentachloride, etc. 
The process of this invention according to process variant (o) is conducted 
under the same conditions as the process according to variant (i). 
The optionally following saponification of the cyanides to the 
corresponding amides has been mentioned in the description of process 
variant (a). 
To produce the tetrazolyl compounds, conventional operating methods can 
also be employed. Thus, it is possible, for example, to react the nitriles 
under the conventional conditions with alkali azides, such as sodium 
azide, to the corresponding tetrazolyl compounds in polar aprotic 
solvents, such as dimethylformamide, N-methylacetamide, 
N-methylpyrrolidone, or hexamethylphosphoric triamide. 
With the aid of the process according to this invention, it is possible, 
for example, to produce the following compounds of general Formula I: 
2-(3-chloro-4-cyclohexylmethylphenyl)propionic acid 
6-chloro-5-cyclopentylcarbonyl-indan-1-carboxylic acid 
6-chloro-5-cyclohexylidenemethyl-indan-1-carboxylic acid 
5-cyclopentylmethyl-6-nitro-indan-1-carboxylic acid 
6-amino-5-cyclopentylmethyl-indan-1-carboxylic acid 
5-cyclopentylmethyl-6-fluoro-indan-1-carboxylic acid 
6-chloro-5-cycloheptylmethyl-indan-1-carboxylic acid 
2-(3-chloro-4-cycloheptylmethylphenyl)propionic acid 
2-(3-chloro-4-cycloheptylidenemethylphenyl)propionic acid 
6-chloro-5-cycloheptylidenemethyl-indan-1-carboxylic acid 
2-(3-chloro-4-cyclopentylidenemethylphenyl)propionic acid 
2-(3-chloro-4-cyclobutylmethylphenyl)propionic acid 
6-chloro-5-cyclobutylmethyl-indan-1-carboxylic acid 
6-chloro-5-cyclobutylidenemethyl-indan-1-carboxylic acid 
6-chloro-5-cyclopentylmethyl-indan-1-carbohydroxamic acid 
2-(3-chloro-4-cyclopentylmethylphenyl)propiohydroxamic acid 
6-chloro-5-cyclopentylmethyl-indan-1-carboxylic acid 2-dimethylaminoethyl 
ester 
6-chloro-5-cyclopentylmethyl-1-tetrazolyl-indan 
1-(3-chloro-4-cyclopentylmethylphenyl)-1-tetrazolyl-ethane 
The novel phenylacetic acid derivatives of general Formula I are, as 
mentioned above, pharmacologically active compounds or intermediates for 
the production of such compounds. The pharmacologically active compounds 
are especially distinguished in that they possess a pronounced 
antiinflammatory activity upon systemic application to mammals, including 
humans; they show good compatibility with the stomach and only a 
relatively low toxicity. Moreover, these compounds are frequently 
distinguished by a rapid onset of activity, a high intensity of 
effectiveness, and a long duration of effectiveness; they show favorable 
resorbability. 
The antiphlogistic activity of the compounds of this invention can be 
determined with the aid of the conventional adjuvant arthritis test which 
is conducted as follows: 
Female and male rats of the Lewis strain (LEW) with a weight range of 
between 110 g. and 190 g. are utilized. The animals receive drinking water 
and "Altromin" pressed feed ad libitum. 
Ten rats are used for each dosage group. 
The irritant employed in Mycobacterium butyricum by Difko, Detroit. A 
suspension of 0.5 mg. of M. butyricum in 0.1 ml. of thinly fluid paraffin 
(DAB [German Pharmacopcial 7) is injected in a subplantar fashion into the 
right hind paw. 
The test compounds are administered starting with the 11th day of the 
experiment daily over 4 days orally. The substances are administered as a 
clear, aqueous solution or as a crystalline suspension with the addition 
of Myrj 53 (85 mg. %) in isotonic sodium chloride solution. 
Test Setup: 
The rats are distributed with regard to their body weight as uniformly as 
possible into various groups. After plethysmographic volume measurement of 
the right hand paw, 0.1 ml. of adjuvant is injected into this hind paw in 
a subplantar manner. The right hind paws are measured from the 14th day of 
the experiment until the end of the experiment. The duration of the test 
is 3 weeks. 
The dose of test compound is determined at which a 40% healing effect is 
observed (=ED.sub.40). 
A frequent complication in therapy with non-steroidal antiinflammatory 
agents is the occurrence of gastric ulcerations. These side effects can be 
proven in an animal experiment; as the dose, the amount of test compound 
is employed at which in the adjuvant arthritis test a 40% healing effect 
is observed. The ulcer test is conducted as follows. 
Male Wistar rats (SPF) are employed. The animals have a weight range of 
130.+-.10 g. The animals are made to fast starting with 16 hours prior to 
the beginning of the experiment; they receive water ad libitum. 
Five animals are used per dose. The compounds are administered once orally, 
dissolved in sodium chloride or as a crystal suspension with the addition 
of 85 mg.% Myrj 53. 
Three hours after administration of the compound, 1 ml. of a 3% solution of 
diphenyl pure blue dye is injected intravenously and the animal is 
sacrificed. The stomach is resected and examined under a microscope for 
the number of epithelial lesions and ulcers which become apparent by 
accumulations of the dye. 
The following table shows the results obtained in these tests with the 
compounds of this invention numbered 5 to 8 as compared to the prior-art 
compounds 1 to 4. 
______________________________________ 
Adjuvant 
Arthritis 
Test: Number of 
Test Com- Gastric 
pound in Ulcers at 
mg./kg. the Same 
No. Compound Animal Dose 
______________________________________ 
1 2-(4-Isopropyl- 
100 6.8 
phenyl)propionic 
acid 
(= Ibuprofen).sup.1 
2 2-(4-Cyclohexyl- 
40 7.6 
phenyl)propionic 
acid.sup.2 
3 5-Cyclohexyl- 50 8.3 
indan-1-carboxy- 
ic acid.sup.3 
4 6-Chloro-5-cyclo- 
4.0 7.8 
hexyl-indan-1- 
carboxylic acid.sup.3 
5 2-(4-Cyclopropyl- 
90 5.4 
methyl-phenyl)- 
propionic acid.sup.4 
6 2-(4-Cyclopentyl)- 
10.0 0.6 
methylphenyl)pro- 
pionic acid 
7 2-(3-Chloro-4-cy- 
3.0 0.6 
clopenylmethylphe- 
nyl)propionic acid 
8 6-Chloro-5-cyclo- 
30 2.2 
pentylmethyl- 
indan-1-carboxylic 
acid 
9 6-Chloro-5-cyclo- 
40 0.7 
pentylidenemethyl- 
indan-1-carboxylic 
acid 
______________________________________ 
.sup.1 U.S. Pat. No. 3.385.886 
.sup.2 German published application No. 1.443 429 
.sup.3 J. Med. Chem. 1972, Vol. 15, 1297 
.sup.4 J. Med. Chem. 1973, Vol. 16, 487 
The novel compounds are suitable in combination with the vehicles customary 
in galenic pharmacy for the treatment of, for example, acute and chronic 
polyarthritis, neurodermitis, bronchial asthma, hay fever, and others. 
The special drugs are produced as usual by converting the active agents 
together with suitable additives, carrier substances, and 
flavor-ameliorating agents into the desired forms of application, such as 
tablets, dragees, capsules, solutions, inhalants, etc. 
Especially suitable for oral administration are tablets, dragees, and 
capsules which contain, for example, 1-250 mg. of active agent and 50 mg. 
to 2 g. of pharmacologically ineffective vehicles, e.g. lactose, amylose, 
talc, gelatin, magnesium stearate, and similar materials, as well as the 
customary additives. 
The pharmacologically active compounds of Formula I can be processed in 
accordance with conventional methods of galenic pharmacy to produce 
medicinal agents, especially for oral administration. Conventional 
excipients are pharmaceutically acceptable organic or inorganic carrier 
substances suitable for parenteral, enteral or topical application which 
do not deleteriously react with the active compounds. Suitable 
pharmaceutically acceptable carriers include but are not limited to water, 
salt solutions, alcohols, vegetable oils, polyethylene glycols, gelatine, 
lactose, amylose, magnesium stearate, talc, silicic acid, viscous 
paraffin, perfume oil, fatty acid monoglycerides, and diglycerides, 
pentaerythritol fatty acid esters, hydroxy-methylcellulose, polyvinyl 
pyrrolidone, etc. The pharmaceutical preparations can be sterilized and if 
desired mixed with auxiliary agents, e.g., lubricants, preservatives, 
stabilizers, wetting agents, emulsifiers, salts for influencing osmotic 
pressure, buffers, coloring, flavoring and/or aromatic substances and the 
like which do not deleteriously react with the active compounds. 
For parenteral application, particularly suitable are solutions, preferably 
oily or aqueous solutions, as well as suspensions, emulsions, or implants, 
including suppositories. Ampoules are convenient unit dosages. 
For enteral application, particularly suitable are tablets, dragees, or 
capsules having talc and/or a carbohydrate carrier or binder or the like, 
the carrier preferably being lactose and/or corn starch and/or potato 
starch. A syrup, elixir or the like can be used wherein a sweetened 
vehicle is employed. Sustained release compositions can be formulated 
including those wherein the active compound is protected with 
differentially degradable coatings, e.g., by microencapsulation, multiple 
coatings, etc. 
Typical daily dosages of the compound as antiinflammatory agents are from 
1-50 mg/day/kg of body weight when administered to human patients. They 
can be administered analogously to the conventional antiinflammatory 
compound

The following examples serve for explaining the process of the present 
invention. 
Without further elaboration, it is believed that one skilled in the art 
can, using the preceding description, utilize the present invention to its 
fullest extent. The following preferred specific embodiments are, 
therefore, to be construed as merely illustrative, and not limitative of 
the remainder of the disclosure in any way whatsoever. In the following 
examples, all temperatures are set forth uncorrected in degrees Celsius; 
unless otherwise indicated, all parts and percentages are by weight. 
EXAMPLE 1 
(a) A mixture of 25 g. of cyclopentanecarbonyl chloride, 20 ml. of absolute 
benzene, and 50 ml. of carbon disulfide is cooled to 0.degree., combined 
in incremental portions with 66.6 g. of aluminum chloride, and stirred for 
one hour at 0.degree. as well as for 16 hours at room temperature. The 
carbon disulfide is then distilled off under vacuum, and the residue is 
poured into an ice-hydrochloric acid mixture. After decomposition of the 
aluminum chloride, the mixture is extracted with chloroform, the organic 
phase is washed with dilute sodium hydroxide solution and water, and dried 
over sodium sulfate. The organic phase is separated by vacuum 
distillation, thus obtaining 25 g. of cyclopentylphenyl ketone, b.p. 
120.degree. at 0.3 torr [mm. Hg]. 
(b) 15 g. of cyclopentylphenyl ketone is combined with 12.9 g. of hydrazine 
hydrate, 260 g. of sodium hydroxide, and 400 ml. of triglycol and heated 
for 2 hours to 200.degree.-220.degree.. 
The reaction mixture is allowed to cool down, then combined with 500 ml. of 
water, acidified with dilute hydrochloric acid, and extracted with 
chloroform. The organic phase is washed with water, dried over sodium 
sulfate, and separated by vacuum distillation, thus obtaining 8.7 g. of 
cyclopentylmethylbenzene, b.p. 80.degree. at 2.4 torr. 
(c) 4 g. of cyclopentylmethylbenzene is combined with 9.42 g. of acetyl 
chloride and 40 ml. of carbon disulfide, cooled to 0.degree., and mixed in 
incremental portions with 13.3 g. of aluminum chloride. The mixture is 
stirred for 30 minutes at 0.degree. and for 3 hours at room temperature; 
the carbon disulfide is withdrawn under vacuum, and the residue is poured 
into an ice-hydrochloric acid mixture. After decomposing the aluminum 
chloride, the mixture is extracted with chloroform, the organic phase is 
worked up as set forth in Example 1(a), and the product is 3.2 g. of 
4-(cyclopentylmethyl)acetophenone, b.p. 80.degree. at 0.2 torr. 
(d) A solution of 7 g. of potassium tert.-butylate, 20 ml. of 
dimethoxyethane, and 20 ml. of tert.-butanol is added dropwise to a 
solution, cooled to 0.degree., of 5 g. of 
4-(cyclopentylmethyl)acetophenone and 8 g. of 
p-toluenesulfonylmethylisocyanide in 100 ml. of dimethoxyethane. The 
reaction mixture is stirred for 45 minutes at 0.degree., another hour at 
room temperature, and then 50 ml. of water is added to the mixture. 
The mixture is extracted with pentane, the pentane phase is dried over 
sodium sulfate and concentrated under vacuum. 
The thus-obtained crude product is chromatographed with chloroform-pentane, 
6+4, over silica gel, thus obtaining 1.7 g. of 
2-(4-cyclopentylmethylphenyl)propionitrile as a colorless oil. 
(e) 150 mg. of 2-(4-cyclopentylmethylphenyl)propionitrile is combined with 
0.9 ml. of water and 0.7 ml. of concentrated sulfuric acid and heated 
under reflux for 5 hours. Then 3 ml. of water is added to the reaction 
mixture, and the latter is extracted with chloroform, washed with water, 
and the chloroform phase is concentrated under vacuum, thus obtaining 85 
mg. of 2-(4-cyclopentylmethylphenyl)propionic acid as a colorless oil. 
NMR spectrum in deuterochloroform: 
Signals at 1.5 p.p.m. (d,J=7 Hz, CH.sub.3); 1.5 p.p.m. (mc, 9H); 2.6 p.p.m. 
(d,J=7 Hz, CH.sub.2); 3.7 p.p.m. (q,J=7 Hz, 1 Hz, 1H); and 7.1 p.p.m. (mc, 
4H). 
(f) 50 mg. of 2-(4-cyclopentylmethylphenyl)propionic acid is dissolved in 2 
ml. of methanol, titrated with a 3% methanolic sodium methylate solution, 
concentrated under vacuum, and 50 mg. of sodium 
2-(4-cyclopentylmethylphenyl)propionate, m.p. 206.degree. is obtained in 
this way. 
EXAMPLE 2 
10 g. of 4-(cyclopentylmethyl)acetophenone, 8.6 g. of morpholine, and 3.1 
g. of sulfur are heated for 6 hours to 140.degree.. The still warm 
solution is then combined with 15 ml. of hot ethanol and thereafter cooled 
for 16 hours at 0.degree.. 
The thus-separated crystals are filtered off, combined with a solution of 
20 g. of potassium hyroxide in 70 ml. of ethanol and 20 ml. of water, and 
heated under reflux for 6 hours. The ethanol is then distilled off under 
vacuum, the residue is acidified with concentrated hydrochloric acid, the 
thus-separated crude product is filtered off, recrystallized from 
methanol/water, and the yield is 2 g. of 4-(cyclopentylmethyl)phenylacetic 
acid, m.p. 93.degree.. 
EXAMPLE 3 
(a) At 60.degree., 1 g. of 4-(cyclopentylmethyl)acetophenone is added 
dropwise to 1.33 g. of aluminum chloride, finely distributed in water; 
thereafter, 14 ml. of 1,2-dichloroethane is added dropwise to the reaction 
mixture. The latter is then cooled to -10.degree., dried chlorine gas is 
introduced for 15 minutes, and the mixture is decomposed with hydrochloric 
acid-ice mixture. The mixture is then extracted with chloroform, the 
chloroform phase is washed with sodium bicarbonate solution and water, 
dried over sodium sulfate, and concentrated under vacuum, thus obtaining 
900 mg. of 3-chloro-4-(cyclopentylmethyl)acetophenone as a colorless oil. 
(b) 800 mg. of 3-chloro-4-(cyclopentylmethyl)acetophenone is reacted with 
p-toluenesulfonylmethylisocyanide under the conditions described in 
Example 1(d); the mixture is worked up, thus yielding 100 mg. of 
2-(3-chloro-4-cyclopentylmethylphenyl)propionitrile as a yellowish oil. 
(c) Under the conditions of Example 1(e), 100 mg. of 
2-(3-chloro-4-cyclopentylmethylphenyl)propionitrile is hydrolyzed and 
worked up, thus obtaining 40 mg. of 
2-(3-chloro-4-cyclopentylmethylphenyl)propionic acid as a colorless oil. 
NMR spectrum in deuterochloroform: 
Signals at 1.5 p.p.m. (mc, 9H); 1.5 p.p.m. (d,J=7 Hz, CH.sub.3 2.7 p.p.m. 
(d,J=7 Hz, CH.sub.2); 3.6 p.p.m. (q, J=7 Hz, 1H); 7.2 p.p.m. (mc, 3H). 
EXAMPLE 4 
(a) Under the conditions of Example 1(a), 20 g. of cyclohexanoyl chloride 
is reacted with benzene and worked up, yielding 18 g. of cyclohexylphenyl 
ketone. 
(b) As described in Example 1(b), 15 g. of cyclohexylphenyl ketone is 
reduced and worked up, yielding 7 g. of cyclohexylmethylbenzene. 
(c) Under the conditions of Example 1(c), 5 g, of cyclohexylmethylbenzene 
is acylated and worked up, thus producing 3.5 g. of 
4-cyclohexylmethylacetophenone, b.p. 90.degree. at 0.2 torr. 
(d) As set forth in Example 1(d), 3.0 g. of 4-cyclohexylmethylacetophenone 
is reacted with p-toluenesulfonylmethylisocyanide and worked up, thus 
obtaining 1.2 g. of 2-(4-cyclohexylmethylphenyl)propionitrile as an oil. 
(c) As described in Example 1(c), 1.0 g. of 
2-(4-cyclohexylmethylphenyl)propionitrile is hydrolyzed and worked up, 
yielding 650 mg. of 2-(4-cyclohexylmethylphenyl)propionic acid as a 
colorless oil. 
NMR spectrum in deuterochloroform: 
Signals at 1.5 p.p.m. (d,J=7 Hz, CH.sub.3); 1.5 p.p.m. (mc, 11H); 2.6 
p.p.m. (d,J=7 Hz, CH.sub.2); 3.7 p.p.m. (q,J=7 Hz, 1H); 7.1 p.p.m. (mc, 
4H). 
(f) This compound is converted analogously to Example 1(f) into the sodium 
salt thereof, m.p. 225.degree.. 
EXAMPLE 5 
(a) A solution of 7.1 g. of 2,2-dimethylaziridine and 12.1 g. of 
triethylamine in 100 ml. of benzene is cooled to +10.degree. and combined 
with 1.94 g. of 2-(4-cyanophenyl)propionic acid chloride in 100 ml. of 
benzene. The mixture is stirred for 15 hours at room temperature, 
filtered, and concentrated under vacuum. The residue is dissolved in 350 
ml. of dichloromethane, combined with 0.1 ml. of concentrated sulfuric 
acid, and agitated for 15 hours at room temperature. 
The solution is then neutralized by adding sodium bicarbonate, filtered, 
concentrated under vacuum, and the yield is 
1-(4,4-dimethyl-2-oxazolinyl)-1-(4-chlorophenyl)ethane as an oily crude 
product. 
(b) A solution of 5.7 g. of crude 
1-(4,4-dimethyl-2-oxazolinyl)-1-(4-cyanophenyl)ethane in 30 ml. of ether 
is introduced dropwise within 20 minutes into a refluxing solution of 4.75 
g. of cyclopentylmagnesium bromide in 30 ml. of ether. 
The reaction mixture is stirred for 6 hours under reflux, then decomposed 
with hydrochloric acid-ice mixture, extracted with chloroform, the 
chloroform phase washed with water, dried over sodium sulfate, and 
concentrated under vacuum. The thus-obtained crude 
1-(4,4-dimethyl-2-oxazolinyl)-1-(4-cyclopentanoylphenyl)ethane is 
introduced into 200 ml. of 5% aqueous hydrochloric acid and heated under 
reflux for one hour. The reaction mixture is allowed to cool, extracted 
with ether, the ether phase washed with water, dried over sodium sulfate, 
and concentrated under vacuum, thus obtaining 
2-(4-cyclopentanecarbonylphenyl)propionic acid as a colorless oil. 
NMR spectrum in deuterochloroform: 
Signals at 1.5 p.p.m. (d,J=J=7 Hz, CH.sub.3); 1.8 p.p.m. (mc, 8H); 3.7 
p.p.m. (mc, 2H); 7.3 p.p.m. (d,J=7 Hz, 2H); 7.9 p.p.m. (d,J=7 Hz, 2H). 
EXAMPLE 6 
(a) A mixture of 0.29 ml. of 68% nitric acid and 0.34 ml. of concentrated 
sulfuric acid is added dropwise into an ice-cooled solution of 1 g. of 
2-(4-cyclopentylmethylphenyl)propionic acid in 50 ml. methylene chlorid. 
The reaction mixture is then stirred for one hour at 0.degree. and for 
another hour at room temperature, poured into an ice-water mixture, and 
extracted with chloroform. The chloroform phase is washed with water, 
dried over sodium sulfate, concentrated under vacuum, and 
2-(4-cyclopentylmethyl-3-nitrophenyl)propionic acid is thus obtained as an 
oily crude product. 
(b) 2 g. of 2-(4-cyclopentylmethyl-3-nitrophenyl)propionic acid is 
dissolved in 20 ml. of ethanol and 10 ml. of glacial acetic acid, combined 
with 500 mg. of 10% palladium animal charcoal catalyst, and hydrogenated 
under normal pressure. The catalyst is then filtered off, the filtrate is 
combined with 50 ml. of water and extracted with ether. The ether phase is 
dried over sodium sulfate and concentrated, thus obtaining 
2-(3-amino-4-cyclopentylmethylphenyl)propionic acid as an oil. 
NMR spectrum in deuterochloroform: 
Signals at 1.5 p.p.m. (mc, 9H); 1.5 p.p.m. (d,J=7 Hz, CH.sub.3) 2.5 p.p.m. 
(d,J=7 Hz, CH.sub.2); 3.6 p.p.m. (J=7 Hz, 1H); 7.1 p.p.m. (mc, 3H). 
EXAMPLE 7 
(a) 10 g. of 6-chloroindan-1-carboxylic acid is combined in 100 ml. of 
absolute dichloromethane with 12 g. of aluminum chloride and cooled to 
-40.degree.. During a period of 30 minutes, a solution of 8.0 g. of 
1,1-dichloromethyl methyl ether in 50 ml. of dichloromethane is added 
dropwise to this mixture. The reaction mixture is stirred for 30 minutes 
at -40.degree., then allowed to warm up, and poured under stirring onto 
100 g. of ice. Then the dichloromethane phase is separated, concentrated 
under vacuum, and the residue recrystallized from toluene, thus yielding 
8.9 g. of 6-chloro-5-formyl-indan-1-carboxylic acid, m.p. 162.degree.. 
(b) 5 g. of 6-chloro-5-formyl-indan-1-carboxylic acid is combined with 20 
ml. of absolute ethanol and 1.5 ml. of concentrated sulfuric acid and 
heated under reflux for 4 hours. The reaction mixture is then poured into 
50 ml. of water, extracted with chloroform, the chloroform phase washed 
with water, dried over sodium sulfate, concentrated under vacuum, and the 
residue purified by distillation in a bulb tube, thus obtaining 4.2 g. of 
6-chloro-5-formyl-indan-1-carboxylic acid ethyl ester, b.p. 150.degree. at 
0.04 torr. 
(c) 304 mg. of the ethyl ester of 6-chloro-5-formyl-indan-1-carboxylic acid 
is dissolved in 10 ml. of ethanol and added dropwise under agitation to a 
mixture of 21 mg. of sodium borohydride and 10 ml. of ethanol. The 
reaction mixture is stirred for 4 hours at 80.degree. and combined with 50 
ml. of 10% sulfuric acid. The mixture is extracted with chloroform, the 
chloroform phase is washed with water, dried over sodium sulfate, and 
concentrated under vacuum, thus obtaining 200 mg. of 
6-chloro-5-hydroxymethyl-indan-1-carboxylic acid ethyl ester in the form 
of an oil. 
(d) A mixture of 6.5 g. of thionyl chloride, 5 ml. of benzene, and one drop 
of pyridine is added dropwise to a solution of 1.2 g. of 
6-chloro-5-hydroxymethyl-indan-1-carboxylic acid ethyl ester. The reaction 
mixture is then heated for one hour under reflux, allowed to cool, and 
poured into ice water. The benzene phase is washed with water, dried over 
sodium sulfate, concentrated under vacuum, and the yield is 300 mg. of the 
ethyl ester of 6-chloro-5-chloromethyl-indan-1-carboxylic acid in the form 
of an oil. 
(e) 2.2 g. of the ethyl ester of 6-chloro-5-chloromethyl-indan-1-carboxylic 
acid is dissolved in 20 ml. of absolute ethanol, combined with 1.38 g. of 
the potassium salt of the cyclopentan-2-one-1-carboxylic acid ethyl ester, 
and heated under reflux for 6 hours. Then, 40 ml. of water is added to the 
reaction mixture, and the latter is extracted with ether, the ether phase 
washed with water, dried over sodium sulfate, and concentrated under 
vacuum. 
The residue is heated under reflux for 8 hours in 20 ml. of 10% aqueous 
sulfuric acid. The reaction mixture is allowed to cool, combined with 
dilute sodium hydroxide solution until the reaction is alkaline, and then 
the mixture is extracted with ether, the aqueous phase is acidified and 
once again extracted with ether. The ether extract of the acidic 
extraction is washed with water and dried over sodium sulfate, thus 
obtaining 6-chloro-5-(2-oxocyclopentylmethyl)-indan-1-carboxylic acid, 
m.p. 126.degree. (from petroleum ether). This product is combined with 15 
ml. of triglycol, one gram of sodium hydroxide, and 10 g. of hydrazine 
hydrate, heated for 2 hours to 200.degree., acidified with hydrochloric 
acid, and extracted with chloroform. The chloroform phase is washed with 
water, dried over sodium sulfate under vacuum, and 
6-chloro-5-cyclopentylmethyl-indan-1-carboxylic acid is thus obtained as 
an oil. 
NMR spectrum in deuterochloroform: 
Signals at 1.5 p.p.m. (mc, 9H); 2.6 p.p.m. (mc, 6H); 3.9 p.p.m. (t,J=7 Hz, 
1H); 7.0 p.p.m. (s, 1H); 7.3 p.p.m. (s, 1H). 
EXAMPLE 8 
2.31 g. of 2-(4-cyclopentylmethylphenyl)propionic acid is combined with 3 
ml. of chloroform and 860 mg. of piperazine, the mixture is heated, and 
the thus-produced precipitate is vacuum-filtered. The crude product is 
washed with ether and recrystallized from ethanol, thus obtaining 2.1 g. 
of the piperazine salt of 2-(4-cyclopentylmethylphenyl)propionic acid, 
m.p. 151.degree.. 
EXAMPLE 9 
(a) Under agitation, 1.18 kg. of AlCl.sub.3 is suspended in 2.40 l. of 
methylene chloride, cooled to 0.degree., and combined within one hour with 
a mixture of 790 g. of oxalic acid ethyl ester chloride, 895 g. of 
cyclopentylmethylbenzene, and 3.36 l. of methylene chloride. The mixture 
is then agitated for another 2 hours at 20.degree., poured on 9 kg. of 
ice/water (pH must be tested and set to 3), and the organic phase is 
separated. The aqueous phase is extracted twice with respectively 2.5 l. 
of methylene chloride, the combined organic phases are washed neutral with 
sodium chloride solution, dried, and concentrated, thus obtaining 1,476 g. 
of the ethyl ester of (4-cyclopentylmethylphenyl)glyoxylic acid in the 
form of an oil. 
(b) 1,016 g. of potassium hydroxide is dissolved under agitation in 5 l. of 
methanol, and then 1,355 g. of the ethyl ester of 
(4-cyclopentylmethylphenyl)glyoxylic acid is added thereto and the mixture 
is stirred at 20.degree. until a salt is precipitated. This salt is made 
to dissolve with 8 l. of water, the entire solution is concentrated to 
half its volume and washed three times with respectively 2 l. of ether. 
The aqueous phase is acidified with concentrated hydrochloric acid and 
extracted three times with respectively 2 l. of ether. The organic phase 
is washed with sodium chloride solution, dried, and concentrated, thus 
obtaining 1,026 g. of (4-cyclopentylmethylphenyl)glyoxylic acid as an oil. 
(c) A Grignard solution of 259 g. of magnesium and 820 ml. of methyl iodide 
in 4.5 l. of ether, freshly prepared under argon, is added dropwise under 
vigorous agitation to 519 g. of (4-cyclopentylmethylphenyl)glyoxylic acid, 
dissolved in 4 l. of ether within 2 hours at 0.degree. to +5.degree.. The 
mixture is stirred for another 2 hours at 20.degree., then added dropwise 
to 10 kg. of ice water, acidified with 4 l. of concentrated hydrochloric 
acid, and the phases are separated. The aqueous phase is extracted four 
times with respectively 2 l. of ether, the combined organic phases are 
washed neutral with water, dried, and concentrated. This dry residue is 
furthermore washed with petroleum ether and finally agitated in 2 l. of 
petroleum ether for one hour at 0.degree. and then vacuum-filtered, thus 
obtaining 404 g. of 2-(4-cyclopentylmethylphenyl)-2-hydroxypropionic acid, 
m.p. 111.degree.. 
(d) 726 g. of 2-(4-cyclopentylmethylphenyl)-2-hydroxypropionic acid is 
refluxed for 2 hours in 15 l. of dioxane with 1 l. of concentrated 
sulfuric acid. After cooling to 20.degree., the mixture is gradually 
introduced into 35 kg. of ice water by inoculation. After a few hours of 
agitation under cooling, the mixture is vacuum-filtered, dried, and 
recrystallized from petroleum ether, thus obtaining 376 g. of 
2-(4-cyclopentylmethylphenyl)acrylic acid, m.p. 100.degree.. 
(e) 320 g. of 2-(4-cyclopentylmethylphenyl)acrylic acid is dissolved in 3 
l. of dioxane, and the solution is hydrogenated under normal pressure with 
30 g. of palladium charcoal (10%). After the filtrate has been filtered 
off from the catalyst, it is concentrated to an oil, thus obtaining 322 g. 
of 2-(4-cyclopentylmethylphenyl)propionic acid. 
EXAMPLE 10 
(a) 2.18 g. of 4-(cyclopentylmethyl)phenylacetic acid is refluxed in 6.9 g. 
of ethanol with 0.39 g. of concentrated sulfuric acid for 5 hours. After 
the mixture is concentrated, it is combined with water, extracted with 
ether, and the ether phases are washed neutral and concentrated. Yield: 
2.0 g. of 4-(cyclopentylmethyl)phenylacetic acid ethyl ester in the form 
of a yellowish oil. 
(b) 5.13 g. of 4-(cyclopentylmethyl)phenylacetic acid ethyl ester is 
combined in 17 ml. of diethyl carbonate under boiling heat dropwise with a 
solution of 0.52 g. of sodium in 12 ml. of ethanol; during this process, 
ethanol is removed by distillation. Once the distilling over of ethanol 
ceases, the mixture is cooled, poured on water, and extracted with ether. 
The ether phases are washed with water and concentrated. Distillation with 
the use of a bulb tube at a jacket temperature of 180.degree. and a 
pressure of 0.06 torr yields 4.9 g. of the diethyl ester of 
2-(4-cyclopentylmethylphenyl)malonic acid. 
(c) 3.39 g. of tetrabutylammonium hydrogen sulfate and 0.80 g. of sodium 
hydroxide are dissolved in 10 ml. of water, and this solution is combined 
at 20.degree. with a solution of 3.08 g. of the diethyl ester of 
2-(4-cyclopentylmethylphenyl)malonic acid and 2.84 g. of methyl iodide in 
10 ml. of methylene chloride. The initially clear solution becomes 
milky-opaque. Thereafter, the mixture is stirred for 20 minutes. The 
organic phase is separated and concentrated, the residue is combined with 
ether; the mixture is filtered off from salts, and the filtrate is 
concentrated. Yield: 3.04 g. of the diethyl ester of 
2-(4-cyclopentylmethylphenyl)-2-methylmalonic acid in the form of an oil. 
(d) 3.0 g. of the diethyl ester of 
2-(4-cyclopentylmethylphenyl)-2-methylmalonic acid is refluxed in a 
solution of 1.4 g. of potassium hydroxide in a small amount of water for 3 
hours. The mixture is acidified under boiling heat with hydrochloric acid, 
cooled, extracted with ether, and the ether phases are concentrated, 
yielding an oil which is heated for another 15 minutes to complete the 
decarboxylation. Yield: 1.9 g. of 2-(4-cyclopentylmethylphenyl)propionic 
acid. 
EXAMPLE 11 
(a) 7.45 g. of cyclopentyl bromide and 19.7 g. of triphenylphosphine are 
heated in a pressure pump under argon for 6 hours in a bath having a 
temperature of 160.degree.. After cooling, the solid reaction product is 
extracted by boiling several times with benzene and finally dried. Yield: 
15.7 g. of cyclopentyltriphenylphosphonium bromide. 
(b) 4.11 g. of cyclopentyltriphenylphosphonium bromide is suspended in 
tetrahydrofuran under argon and combined at 20.degree. with 4.3 ml. of a 
3-molar solution of butyllithium in n-hexane. After 2 hours of agitation 
at 20.degree., a solution of 2.24 g. of 
6-chloro-5-formyl-indan-1-carboxylic acid in 15 ml. of tetrahydrofuran is 
added thereto at 5.degree.. The stirring is continued for 16 hours at 
20.degree., then the mixture is concentrated, the residue is combined with 
dilute hydrochloric acid, and extracted with ether. The ether phases are 
washed and concentrated. The remainder (2 g.) is chromatographed over a 
silica gel column (eluent:cyclohexane 325 parts+toluene 160 parts+ethyl 
acetate 190 parts+acetic acid 19 parts). Recrystallization from petroleum 
ether yields 1 g. of 6-chloro-5-cyclopentylidenemethyl-indan-1-carboxylic 
acid, m.p. 112.degree.. 
(c) 1.58 g. of 6-chloro-5-cyclopentylidenemethylindan-1-carboxylic acid is 
hydrogenated at 20.degree. and 760 torr in 32 ml. of ethanol after adding 
158 mg. of platinum dioxide. The catalyst is filtered off, the filtrate is 
concentrated, and the residue is recrystallized from petroleum ether, 
yielding 0.89 g. of 6-chloro-5-cyclopentylmethyl-indan-1-carboxylic acid, 
m.p. 126.degree.. 
EXAMPLE 12 
(a) 0.50 g. of cyclopentanone and 1.35 g. of 
6-chloro-5-formyl-indan-1-carboxylic acid are agitated in a mixture of 6.2 
ml. of acetic acid and 2 ml. of concentrated sulfuric acid for 1 hour at 
20.degree.. The mixture is then poured on ice water and extracted with 
ether. The ether phases are washed neutral and concentrated; the remainder 
is chromatographed over a silica gel column (cyclohexane 325 parts+toluene 
160 parts+ethyl acetate 190 parts+acetic acid 19 parts). Yield: 0.41 g. of 
6-chloro-5-(2-oxopentylidenemethyl)indan-1-carboxylic acid, m.p. 
170.degree.. 
(b) 2.5 g. of 6-chloro-5-(2-oxopentylidenemethyl)indan-1-carboxylic acid is 
combined with 1.3 g. of hydrazine hydrate, 26 g. of sodium hydroxide, and 
40 ml. of triglycol, and heated for two hours to 200.degree.-220.degree.. 
After cooling, the mixture is combined with water, acidified with dilute 
hydrochloric acid, and extracted with ether. The ether phases are washed 
with water, concentrated, and the residue recrystallized from petroleum 
ether, yielding 0.9 g. of 6-chloro-5-cyclopentylmethyl-indan-1-carboxylic 
acid, m.p. 126.degree.. 
EXAMPLE 13 
As described in Example 12(a), 
2-[4-(2-oxopentylidenemethyl)phenyl]propionic acid, m.p. 158.degree., is 
obtained from cyclopentanone and 2-(4-formylphenyl)propionic acid. This 
product yields, as described in Example 12(b), by reduction of the 
carbonyl group, 2-(4-cyclopentylidenemethyl)phenylpropionic acid, m.p. 
87.degree.. 
EXAMPLE 14 
(a) A solution of 22.4 g. of the ethyl ester of 6-chloro-indan-1-carboxylic 
acid in 100 ml. of 1,2-dichloroethane is added dropwise at 0.degree. to a 
mixture of 28.4 g. of cyclohexanecarboxylic acid chloride, 26.6 g. of 
aluminum chloride, and 200 ml. of 1,2-dichloroethane. After 16 hours of 
agitation at 20.degree., the mixture is poured on ice water, and the 
organic phase is separated and concentrated. The remainder (49.2 g. of 
oil) is chromatographed over silica gel (eluent:cyclohexane 95 parts+ethyl 
acetate 5 parts). Yield: 3.7 g. of the ethyl ester of 
6-chloro-5-cyclohexylcarbonyl-indan-1-carboxylic acid in the form of an 
oil. 
(b) 3.3 g. of the ethyl ester of 
6-chloro-5-cyclohexylcarbonyl-indan-1-carboxylic acid is refluxed with a 
mixture of 1.06 g. of sodium carbonate, 2 ml. of water, and 6 ml. of 
ethanol for 2 hours. Acidification with dilute hydrochloric acid at 
0.degree. and vacuum-filtering yield 2.9 g. of 
6-chloro-5-cyclohexylcarbonyl-indan-1-carboxylic acid, m.p. 67.degree.. 
(c) 1.3 g. of 6-chloro-5-cyclohexylcarbonyl-indan-1-carboxylic acid is 
combined with 0.65 g. of hydrazine hydrate, 13 g. of sodium hydroxide, and 
20 ml. of triethylene glycol and heated for 2 hours to 
200.degree.-220.degree.. The mixture is then cooled, combined with water, 
acidified with dilute hydrochloric acid, and extracted with ether. 
Concentration of the ether phases and recrystallization of the residue 
from hexane yield 0.4 g. of 6-chloro-5-cyclohexylmethyl-indan-1-carboxylic 
acid, m.p. 131.degree.. 
(d) At 20.degree. and 761 torr, 0.36 g. of 
6-chloro-5-cyclohexylmethyl-indan-1-carboxylic acid is hydrogenated over 
44 mg. of palladium-charcoal (10%) in 10 ml. of alcohol and 1 ml. of 
water. After the catalyst has been removed by filtration and the mixture 
has been concentrated, 0.27 g. of an oil is obtained. Preparative layer 
chromatography on silica gel (system: cyclohexane-ethyl acetate 1:1) 
yields 0.19 g. of 5-cyclohexylmethyl-indan-1-carboxylic acid, m.p. 
54.degree. (from petroleum ether). 
The preceding examples can be repeated with similar success by substituting 
the generically and specifically described reactants and/or operating 
conditions of this invention for those used in the preceding examples. 
From the foregoing description, one skilled in the art can easily ascertain 
the essential characteristics of this invention, and without departing 
from the spirit and scope thereof, can make various changes and 
modifications of the invention to adapt it to various usages and 
conditions.