CA1048041A - Benzalicyclic carboxylic acid derivatives - Google Patents

Abstract

Abstract of the disclosure Compounds of the formula:

Description

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The present invention relates to a novel compound of the following general formula:
coRl (j 2)n (I) COR
wherein Rl is a phenyl group which may be substituted by a lower alkyl having 1 to 4 carbon atoms, a lower alkoxy having 1 to 4 carbon atoms, a halogen, a mono- or di-alkylamino having 1 to 3 carbon atoms, an acylamino having 2 to 3 carbon atoms or an acyloxy having 2 to 3 carbon atoms, n is 1 or 2, and R
is hydroxyl, alkoxy having 1 to 6 carbon atoms, phenyloxy, benzyloxy, amino, hydroxylamino, hydrazino, mono- or di-alkylamino having 1 to 3 carbon atoms the alkyl moieties of which may be substituted by hydroxyl, phenylamino, the benzene ring of which may be substituted by methyl, a 5- to 6-membered cyclic amino containing one or two nitrogen atoms, benzylamino the benzene ring of which may be substituted by methyl, phenethylamino, mono- or di-methylhydrazino or phenylhydrazino, or when R is hydroxyl and thus forms a carboxyl group in the l-position, a salt with an alkali metal, an alkaline earth metal, aluminum or onium, or said carboxyl group may form a salt with an amine selected from : the group consisting of mono- or di-alkylamine having 1 to 3 carbon atoms the alkyl moieties, of which may be substituted by hydroxyl, phenylamine the benzene ring of which may be substituted by methyl, a 5- to 6-membered cyclic amine containing one or two nitrogen atoms, benzylamine the benzene ring of which may be substituted by methyl, phenethylamine, mono- or di-methylhydrazine and phenylhydrazine, The present inventors have made extensive study about a series of indan derivatives and lJ2,3,4-tetrahydronaphthalene derivatives and succeeded in synthesizing the novel compound of the above formula (I) and a derivative at the carboxyl function thereofl and have fDund out that the above compounds have remarkable antipyretic, analgesic and anti-inflammatory effects.
The novel compounds of the above formula (I) are useful as medicines ~i ~

such as antipyretics, analgesics and anti-inflammatory agents.
The derivatives at the carboxyl function of the compounds of the above formula may be the corresponding ester, acid amide or salt. The esters include alkyl esters whose alkyl moieties are, for example, methyl, ethyl, propyl, iso-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, n-hexyl, etc., aryl esters such as phenyl ester, etc., aralkyl es~ers such as benzyl ester, etc.
The acid amides include not only those which carboxyl moieties can be represented by -CONH2 but also the hydroxamic acids represented by -CONHOH, the hydrazides represented by -CONHNH2, the N-mono- or di-substituted acid amides corresponding to such organic amines as mono- or di-lower alkylamines of about 1 to about 3 carbon atoms whose alkyl moieties may be substituted by hydroxyl ~for example, ethanolamine, diethanolamine, methylamineJ ethylamine, dimethylamine, diethylamine, propylamine, etc.), arylamines (for example, ani-line, methylaniline, etc.), five- to six-membered cyclic amines containing 1 to 2 nitrogen atoms (for example, morpholine, pyrrolidine, piperidine, piper-azine, N-substituted piperazine, etc.), N-aralkyl-substituted amines (for exam-ple, benzylamine, alpha-methylbenzylamine, phenethylamine, etc.), alkyl-substi-tuted or aryl-substituted hydrazines (for example, methyl hydrazine, dimethyl hydrazine, phenyl hydrazine~ etc.) and the like. As the salts, there may be mentioned, among others, the salts with alkali metals (for example, sodium, potassium, etc.), alkaline earth metals (for example, calcium, magnesium, etc.) and metals such as aluminum, as well as the ammonium salts and the salts with the organic amines such as those slmilar to organic amines exemplified as those of the residue for acid amines.
The aryl group represented by Rl includes such species as phenyl, naphthyl, etc., each of which may be further substituted. The substituent or substituents on the aryl group may be any of lower alkyls having 1 to ~ carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, etc., lower alkoxy having 1 to 4 carbon atoms such as methoxy, ethoxy,propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, etc., halogens such as chlorine, bromine, fluorine etc., mono- or di-alkylamino having 1 to 3 carbon v ~ ~ -2-4~
atoms such as N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, methyl-amino~ ethylamino, propylamino, etc., acylamino having 2 to 3 carbon atoms such as acetylamino, propionylamino, etc. or acyloxy having 2 to 3 carbon atoms such as acetyloxy, propionyloxy7 etc. One or more of these substituents, either the same or different, may occur in optional positions of the aryl group.
The compounds of general formula ~I) and the derivatives at the car-boxyl function thereof have prominent analgetic, antipyretic, anti-inflammatory and other actions, and show low toxicity and less side effects. Taking ad-vantage of these properties, these compounds can safely be used aS analgesics, antipyretics, anti-inflammatory agents and other drugs. When a compound (I) is used as such a medicine, it can be administered, either as it is or in ad-mixture with a pharmaceutically acceptable vehicle, excipient or/and diluent, orally or parenterally in various dosage forms such as powders, granules, tablets, capsules, suppositories and injections. When any of the compounds is used for the purpose of treating such diseases as chronic articular rheuma-tism, arthritis deformans, spondylosis deformans, arthralgia and lumbago, it is administered orally at the normal daily dose for human adults of about 10 to 1000 mg. or non-orally in amounts of S to 500 mg. per dose for adult humans.
The compounds of formula (I) and the derivatives at the carboxyl function thereof can be prepared ~y the various process steps described belo~.

il )4~
CORI
~CH2~CH2)n COOH
(IV) ¦slepA
-COOH CORI . CHzRI
~(CH2)n stepI ~ C~)n Step K ~H2)n O (V) / o \ o (ll[-a) step ~ ~ Step8 \ 1 \ stepF
~H ~ e~Hj CORI "

tep L
~~;r(CH2)n OH OH ~(CH )n ) 1 StePC ~ tepL ¦ StepC ~C~O
R3~<R4 OH COOH St PL CO I R--<4 COOll PG ~I H (911'J . . Xl~ ~¦ Step G . . . .1 ~ ~ ¦~ s-epD ~ ~y ~ I

~C~n ~ ~CH2jn ~ ~C~n ¦ step H / CN ~ ) CN (~ Step H CN ( m - b ) tep E ~E ~ step E

Step I" ~ ~C~3)n stepK~ ~ll))n COOH (I ) I (I-a) COOH COOH (~--C ) \Step M
/ Step J
~(CH2)n CORI
cHJ ~C~)n COOH . C
( 1l ) R ~COOH
(I-b ) .

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Referring to the above formulas (I-a), (I-b~, (III-a), (III-b~, (III-c~, (IV), (V), (VI~, (VII), (VIII), (IX) and ~X), R has the meaning given above R3 and R~ in formulas ~IX), ~IX'), ~X) and ~X') are each a sub-stituted mercapto group; R3 and R4 together may form a ring. The substituted mercapto group may for example be straight-chain or branched lower alkyl mercapto groups ~e.g. methyl-, ethyl-, propyl-, butyl-mercapto, etc.), sub-stituted lower alkylmercapto group ~e.g. mercaptoalkyl-, aminoalkyl-mercapto, etc.) arylmercapto groups ~e.g. phenylmercapto, etc.~, substituted aryl mer-capto groups ~e.g. p-tolylmercapto, etc.), aralkylmercapto group ~e.g. benzyl-mercapto, etc.) or the like. The substituted mercapto groups mentioned above may take the form of S-oxide. R8 in formula (I-b~ has the same meaning as alkyl group designated by R2.
Referring to the formulas (VII) and ~VII'~, X is a hydroxyl group converted to a reactive ester. The hydroxyl group converted to a reactive ester is exemplified by halogens such as chlorine, bromine or iodine and the residues of alkyl-, substituted alkyl-, aryl- and substituted-arylsulfonic acid esters such as methanesulfonic acid ester, trichloromethanesulfonic acid ester, o-toluenesulfonic acid ester p-toluenesulfonic acid ester, o-nitroben-zenesulfonic acid ester, p-nitrobenzenesulfonic acid ester, o-chlorobenzene-sulfonic acid ester, p-chlorobenzenesulfonic acid ester, ~-naphthalenesulfonic acid ester, etc.
The reaction of Step A is carried out by subjecting a compound of general formula ~IV) or a reactive derivative at the carboxyl function thereof to intramolecular cyclization reaction.
The said reactive derivative of carboxylic acid ~IV) may be any one insofar it is instrumental in the attainment of the objects of this step.
Thus, for example, acid halides, acid anhydrides, esters, etc. may be mentioned.As the acid halidesl there may be mentioned, among others, the corresponding acid chloride, acid bromide, acid iodide and acid fluoride. As said acid an-hydride, theremay be mentioned, by way of example, the anhydride of carboxylic acid ~IV) and the mixed anhydrides of carboxylic acid ~IV) and another acid ~e.g. organic acids such as formic acid, acetic acid, etc. and inorganic acids 1~48~
such as silicic acid, boric acid, etc.). The ester may for example be the p-nitrophenyl ester of compound (IV).
The intramolecular cyclization reaction according to this invention is generally conducted with advantage in the presence of a catalyst. As said catalyst, any of the catalysts which are commonly useful in Friedel-Crafts reactions, i.e. Friedel-Crafts catalysts, can be utilized.
For example, Lewis acid ~e.g. aluminum chloride, aluminum bromide, aluminum fluoride, iron chloride, iron bromide, antimony chloride, antimony bromide, titanium chloride, tin chloride, tin bromid~, zinc chloride, zinc bromide, bismuth chloride, boron triEluoride, etc.); mineral acids such as sulfuric acid, phosphoric acid, polyphosphoric acid, etc.; and hydrogen fluo-ride to name but a few. When a Lewis acid, among said catalysts, is employed, an alkali metal halide ~e.g. potassium chloride, sodium chloride, sodium ~romide, potassium bromide, sodium iodide~ potassium iodide), for instance, may be added to the reaction system. While the proportion of such a catalyst is more or less optional, it is preferably in the range of about 1 to 10 moles to each mole of carboxylic acid ~IV) or its reactive derivative. It should, however, be understood that when said mineral acid or hydrogen fluoride is employed as the catalyst, it may be used in large excess so that the catalyst will function as the solvent as well. The reaction of this step may ba carried out in the absence of a solvent or in the presence thereof. The solvent for this purpose may be any solvent only if it is inert to the contemplated re-action. Thus, nitrobenzene and halogenated hydrocarbons ~e.g. methylene chloride, ethylene chloride, 1,1,2,2-tetrachloroethane, chlorobenzene, di-chlorobenzene, etc.) may be mentioned by ~ay of example. While the reaction conditions including the reaction temperature and time are more or less op-tional, the preferred temperature range is from room temperature to about 20~C.
The compound of general formula tV) thus obtained can be easily 3Q isolated and purified by conventional separation purification procedures such as extraction, dis~illation, recrystallization, chromatography, etc.
The reaction of Step B is carried out by reducing a compound of the general formula (V).
This reduction can be achieved by any procedure for reducing a car-bonyl group to an alcohol. For practical purposes, there may be exemplified several kinds of the reduction procedures, namely, the reduction procedure involving the use of a metal hydride such as sodium borohydride or lithium aluminum hydride, the catalytic reduction procedure which involves the use of a metal catalyst such as palladium, nickel, platinum, iron, rhodium, iridium or the like; the reduc~ion procedure involving the use of an alkali metal, e.g. sodium, lithium, potassium or the like together with a solvent which can act as hydrogen donor, e.g. alcohol, liquid ammonia or the like; and the reduc-tion procedure in which a metal complex compound of a metal such as rhodium, iridium or the like is employed. While each of these reduction procedures generally proceed under cooling to heating and the reaction temperature and time are not part;cularly critical, the preferred temperature range is from about -35 to ahout 100C.
In the case of catalytic reduction, hydrogen is introduced at normal pressure or at elevated pressure, there being no particular limitation upon the pressure of hydrogen. When lithium aluminum hydride is employed, it is preferable to use anhydrous ether solvents (e.g. ethyl ether, propyl ether, isopropyl ether, tetrahydrofuran, dioxane, ethylene glycol-dimethyl ether, ethylene glycol-diethyl ether, etc.), while,liquid ammonia and dry alcohols ~e.g. methanol, ethanol, propanol, isopropanol, butanol, isobutanol, etc.), among others, are suited when alkali metals are employed. In other cases, water, alcohols ethers, etc. are used, although there is no particular limita-tion upon the type of solvent unless such a solvent do not hinder the contem-plated reduction. The compound of general formula (VI) thus obtained can be isolated and purified by per se known procedures such as distillation, re-crystallization, column chromatography, etc.
The reaction of Step C is carried out by subjecting a compound of the formula (VI) to a reaction leading to a reactive ester to obtain a compound of formula (VII).
As regards the reaction leading to a reactive ester, there may be 1~48a~
mentioned halogenation and reactions leading to sulfonic acid esters.
The halogenation reaction may be conducted by, for example, the procedure wherein a hydrogen halide in anhydrous conditions or an aqueous solution (e.g. hydrogen chloride gas, hydrogen bromide gas, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.); a thionyl halide ~e.g. thionyl chlo-ride, thionyl bromide, thionyl iodide, etc.); a phosphorus halide (e.g. phos-phorus pentachloride, phosphorus trichloride, phosphorus tribromide, phosphorus triiodide, etc.); phosphorus oxychloride; red phosphorus and a halogen such as hromine or iodine; an alkali metal iodide (e.g. sodium iodide, potassium iodide, etc.) and phosphoric acid, among others, is/are permitted to act, either alone or in combination, upon compound (VI). The reaction may be conducted in the presence or absence of a catalyst. The catalyst is generally selected from among organic amines, e.g. pyridine, aromatic amines (e.g. dimethylaniline, diethylaniline, etc.) and aliphatic amines (e.g. triethylamine etc.).
The reaction proceeds in the presence or absence of a solvent. The solvent, if employed, may be any type of solvent insofar as it is inert to the reaction. Examples of the solvent inert to the reaction include benzene, tolu-ene, xylene, chloroben~ene, hexane, halogenated hydrocarbons (e.g. chloroform, methylene chloride, ethylene chloride, 1,1,2,2-tetrachloroethane, etc.). While the reaction temperature depends upon the reagents and solvent, if any, to be employed, the reaction generally proceeds over the temperature range of under cooling to under heating, preferably at about 0 to about 100C, there being no particular restriction on the reaction time.
When the alcohol of general formula (VI) is to be converted to a sulfonic acid ester, the sulfonic esterification reaction is employed. For example, the sulfonic acid or sulfonyl chloride corresponding to one of the sulfonic acid esters mentioned in the definition of X in compound (VII) is reacted with the alcohol of general formula ~VI). While the reaction proceeds in the absence of a catalyst, it can be conducted more advantageously in the presence of a catalyst. As the catalyst, a basic catalyst is ordinarily em-ployed. ~ore common species of the catalyst are dimethylformamide and pyridine as well as the aromatic amines and aliphatic amines mentioned in halogenation -- 8 ~

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of this step. As regards the solvent, such a basic agent may be used in a large excess so that it will function as the solvent as well. It is also pos-sible to employ solvents inert to the reaction such as benzene, toluene, xy-lene, chlorobenzene, hexane, halogenated hydrocarbons (e.g. chloroform, methy-lene chloride, ethylene chloride, 1,1,2,2-tetrachloroe~hane, etc.). While the reaction temperature and time are virtually optional, the preferred temperature range is from about 0 to about 50 C.
The compound ~VII~ thus obtained can be separated and purified by a per se known separation purification procedur0s such as recyrstallization, distillation chromatography, etc.
The reaction of Step D is carrîed out by reacting a compound of the general formula (VII) with a cyanide.
As the cyanide to be reacted with compound ~VII), there may be men-tioned the salts of metals of Group I of the Periodic Table of the Elements.
Thus, for example, the sodium salt, potassium salt, copper salt, silver salt, etc. can ~e e~ployed.
The reaction may be generally carried out in the absence or presence of a catalyst. As said catalyst, there may be mentioned quaternary ammonium halides. The quaternary ammonium ions may be substituted by alkyl groups of about 1 to 20 carbon atoms. Among them are those comprising a straight-chain or branched alkyl group including, for example tetraalkylammonium, alkylaralkyl-ammonium, tetraaralkylammonium, etc. For example, tetrabutylammonium, tri-ethylhexadecylammonium, triethylbenzylammonium, etc. may be mentioned. More common species of halide ion are chloride, bromide, etc. ~urther, instead of using a cyanide and the catalyst, use may be made of an ammonium cyanide. In this connection, the ammonium ion may be any of the above-mentioned ammonium ions.
While the reaction time, temperature and other conditions are not particularly critical, the reaction temperature is preferably in the range of about O to about 100C. As the solvent to be employed when the reaction is to be carried out without a catalyst, it is advantageous to employ, for ex-ample, the following: dimethylsulfoxide, N,N-dimethylformamide, hexamethyl^

_ g _ ~8~
phosphoric triamide, alcohols (e.g. methanol, ethanol, propanol, isopropanol, etc.), acetone and water. When use is made of an ammonium cyanide or a cata-lyst, it is advantageous to use water as the solvent.
The resultant compound of general formula (VIlI) can be separated and purified by p se known procedures such as distillation, recrystalliza-tion, chromatography, etc.
The reaction of Step E is carried out by subjecting a compound of the general formula ~VIII) to solvolysis.
The solvolysis may generally be hydrolysis with water as the solvent or alcoholysis with an alcohol as the solvent.
Aside from them, there are cases in which a phenol, for instance, is used as the solvent. The solvolysis is generally conducted in the presence of a catalyst, examples of which include hydrogen halides (e.g. hydrogen chlo-ride, hydrogen bromide, hydrogen iodide), mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuri'c acid, phosphoric acid, poly-phosphoric acid, etc.; organic acids such as formic acid, acetic acid, p-toluenesulfonic acid, ~-naphthalenesulfonic acid, etc.; Lewis acids mentioned in the explanation of Step A; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc.; alkaline earth metal hydroxide such as calcium hydroxide, ~arium hydroxide, etc.; metal alcoholates made up of lower alcohols comprising alkyls of about 1 to 4 carbon atoms ~e.g. methanol, ethanol, pro-panol, isopropanol, butanolJ isobutanol, sec.butanol, tert-butanol, etc.) with alkali metals such as sodium, potassium, etc.; hydrogen peroxide, per-acids such as peracetic acid, perben~oic acid, etc. These catalysts are at times used alone and at other times used in combination. While the reaction tempera-ture varies with the type of catalyst used, the reaction may generally be car-ried out under cooling, at room temperature or under heating, preferably at about 0 to about 100C. The reaction time is virtually optional. The struc-ture of product (I-a) depends upon the reaction conditions used and the reac-tion conditions may be selected according to the contemplated compound.
For example, when use is made of an alcohol as the solvent for com-pound of general formula (VIII) and of a hydrogen halide, e.g. hydrogen chlo-ride, hydrogen bromide, e~c., sulfuric acid, p-toluenesulfonic acid or the like as the catalyst, there is obtained a compound (l-a) whose carboxyl group is converted to the ester corresponding to alcohol used. When a compound ~VIII) is hydrolyzed with water, there is obtained a compound (I-a) whose car-boxyl group is converted to an carbamoyl group (-CONH2), and under severe con-ditions, the acid amide is further hydroly7ed to give a compound (I-a) whose carboxyl group is in the form of free acid. In this procedure, one may of course isolate the acid amide formed and, then, hydrolyze it into carboxylic acid.
The acid amide is obtained when concentrated sulfuric acid, a con-centrated solution of hydrogen halide or the like is employed as the catalyst under cooling, when polyphosphoric acid is used as the catalyst under heating;
or when boron trifluoride is employed at room temperature, to name but a few instances. There is obtained a compound (I-a) whose carboxyl group is free when use is made of sul~uric acid, an alkali metal hydroxide or the like under heating. When compound CVIII) is solvolyzed with a solvent other than water, there are cases, according to the conditions used, in which the free acid is directly produced, bypassing the formation of acid amide.
The compound of general formula ~I-a) which has been produced by the reaction of this step can be purified by per se known separatory procedures such as recrys~allization, distillation, chromatography, etc.
When the resultant product compound is a free carboxylic acid of general formula (I-a), the resultant product compound can be converted to derivatives at its carboxyl function by procedures which are known per se (e.g. the production of salts by neutralization or other procedure; esterifi-cation by means of an alcohol in the presence of acid, amidation which com-prises reacting the compound with an amine; and amidation which comprises the steps of converting the compound to an acid halide and, then, reacting the latter with an amine). Conversely, such a derivative at the carboxyl function 3a can be converted to the free carboxylic acid by procedures which are known per se (e.g. hydrolysis in the presence of base or acid). Said derivative at the carboxyl function can be further converted to other types of derivatives by procedures which are known per se (e.g. amidation which comprises reacting the ester with an amine; esterification which comprises reacting the amide with an alkyl polyphosphate; etc.).
The cyclic carboxylic acid of general formula (I-a) which is ob-tainable by the method hereinbefore described has an asymmetric carbon atom in l-position of its molecule and, therefore, can be resolved through a method known per se into optical isomers, i.e. d- and Q-compounds.
Thus, optically active forms of the free carboxylic acid derivatives can be isloated by the steps of dissolving the racemic free acid in a suitable inert solvent such as chloroform, acetone, benzene, hexane, ether, water, methanol, ethanol, acetonitrile or the like, reacting the same with an optical-ly active base, separating the resultant salt or amide into diastereoisomers by taking advantage of their dissimilarity in solubility and, then, treating them with an acid~ The optically active free carboxylic acid can also be isolated by the steps of preparing an ester from the racemic free acid and a suitable optically active alcohol, resolving the ester into diastereoisomers by a procedure which is known per se such as recrystallization, distillation or chromatography and, then, hydrolyzing the ester with an acid or a base.
The optically active base ~o be thus used is exemplified by basic amine such as quinine, brucine, cinchonidine, cinchonine, dehydroabietylamine, hydroxy-hydrindamine, menthylamine, morphine, ~-phenylethylamine, phenyloxynaphthyl-methylamine, quinidine, strychnine, etc., basic amino acid such as lysine, arginine, etc., ester of amino acid, etc.
The optically active alcohol is exempli~ied by borneol, methanol,

2-octanol 9 etc.
The cyclic carboxylic acid derivative of general formula ~I-a) which has been obtained by an optical resolution procedure such as those described above can be converted to an optically active derivative at its carboxyl func-tion by the above-mentioned procedures which are known per se.
The Steps B', C', D' and E' are carried out by taking the similar procedures to those of Steps B, C, D and E, respectively. In these cases, the compounds (V'), (VI'), (VII') and (VIII') used as starting compounds in ~ 12 -4~
each of Steps B', C', D' and E' may be derivati~es at the carboxyl function thereof. As the derivatives at the carboxyl function, there are mentioned ~hose defined in the definition of the derivatives at the carboxyl function of compound (I).
The Step E" is carried ou~ by taking the similar procedures to those of Step E.
The reaction of Step F is carried out by reacting a compound (V) with a compound of general formula:
R3 - CH2 - R~ ~XI) wherein R3 and R4 have the meanings given above.
As compounds of formula ~XI), there are mentioned 1,3-dithian, 1,3,5-trithian, methyl methylthiomethylsulfoxide, methyl methylthiomethylsul-fide, ethyl ethyl~hiomethylsulfoxide, ethyl ethylthiomethylsulfide and the like.
This reaction is conveniently conducted in the presence of a base.
As said base, there may be mentioned, by way of example, alkali metal hydrox-ide ~sodium hydroxide, potassium hydroxide, etc.), alkali metal hydride (e.g.
sodium hydride, lithium hydride, etc.), alkali metal alcoholate (e.g. sodium methylate, sodium ethylate, sodium tert-butylate, potassium, tert.-butylate, sodium tert.-amylate, etc.), alkali metal amide ~e.g. sodium amide, potassium amide, lithium amide, sodium piperidide, potassium piperidide, lithium pipe-ridide, sodium diethyl amide, potassium diethylamide, lithium diethylamide, sodium diisopropylamide, potassium diisopropylamide, lithium diisopropylamide, lithium bis-trimethylsilylamide, lithium dicyclohexylamide, etc.), n-butyl lithium, triton-B, etc.
This reaction is generally conducted in the presence of a solvent.
Virtually any solvent can be used for this purpose, only if it is inert to the reaction. For example, ethers ~e.g. diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl 3Q ether, etc.), benzene, toluene, xylene, methanol, ethanol and ~ater can be employed with advantage.
~hile the amount of compound ~XI) and that of the base are largely 80'~
optional, it is desirable to each of them in the proportion of about 1 to about 2 moles per mole of compound (V).
The reaction temperature may preferably range from about -30C to the boiling point of the solvent used and the reaction time is preferably about 5 to 25 hours.
The compound (IX) thus obtained can easily be isolated by a conven-tional method known per se.
The reaction of Step G is carried out by subjecting a compound (IX) to dehydration.
In the dehydrationl use may be made of dehydrating agent with ad-vantage. As the dehydrating agent for this reaction, there may be used, with advantage, mineral acids (e.g. sulfuric acid, phosphoric acid, phosphorus acid~ hydrochloric acid, etc.), phosphorus oxychloride, thionyl chloride, arylsulfonic acids (e.g. benzensulfonic acid, p-toluenesulfonic acid, ~-naphthalenesulfonic acid, etc.), acetic acid and its derivatives (e.g. tri-fluoroacetlc acid, trichloroacetic acid, etc.) and lower alkylsulfonic acid (e.g. methanesulfonic acidJ ethanesulfonic acidJ propanesulfonic acid, etc.), to name but a few. The solvent to be used for the purpose may be virtually any type of solvent insofar as it does no~ interfere with the reaction. The reaction temperature may be a reduced temperature, i.e. under cooling, to about 150C, the reaction temperature being more or less optional.
The compound of formula ~X) thus obtained may assume the two struc-tures shown below as (X-a) and ~X-b).
coRl coRl 2)n ~ ~ H2)n (X-a) (X-b) The reaction of Step H is carried out by subjecting a compound (X) to solvolysis.

8~4~
The solvolysis generally refers to hydrolysis with water as the sol-vent, or alcoholysis which employs as the solvent an alcohol (e.g. methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec.-butanol, tert.-butanol, benzyl alcohol, etc.), although phenol, for one, may also be used as the solvent.
The solvolysis is generally conducted in the presence of a catalyst.
As said catalyst, there may be employed hydrogen halide ~e.g. hydrogen chlo-ride, hydrogen bromide, hydrogen iodide, etc.); mineral acids such as hydro-chloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, polyph~sphoric acid, etc.; organic acids such as formic acid, acetic acid, p-toluenesulfonic acid, ~-naphthalenesulfonic acid, etc.; heavy metal salts te.g. mercury chloride, mercury bromide, mercury fluoride, mercury sul-fate, copper chloride, copper bromide, etc.); to name but a few. These cata-lyst are at times used alone or used at other times in a combination of two or more. While the reaction temperature depends upon such reaction conditions as the types of solvent and catalyst, the reaction may generally be carried out under cooling, at room temperature or under heating, preferably at about 0 to about 120C.
The reaction time is optional for all practical purposes. The de-sired compound (I-a) of ~his reaction is obtained in various forms at the carboxyl function thereof under the influence of reaction conditions. The de-; sired compound ~I-a) having the desired species of derivative at the carboxyl function can be obtained by selecting the proper reaction conditions. For ex-ample, when compound ~X) is hydrolyzed, the resultant product ~I-a) is in the form of free acid. Alcoholysis of compound ~X) gives a compound ~I-a) whose carboxyl group is an esterified carboxyl group corresponding to the alcohol used. Further by selecting reaction conditions of said solvolysis, there can be obtained contemplated compound ~I-a) such that the carboxyl group in com-pound (I-a) has been esterified or de-esterified.
The compounds ~I-a) can be resolved into optical isomers by per se kno~n procedures which may be referred to those mentioned in Step E.
The Steps F', G' and H' are carried out by taking the similar pro-11;)48~1 cedures to those of Steps F, G and H, respectively. In these cases, the com-pounds (V'), (IX') and (X') used as starting compounds in each of Steps F', G' and H' may be derivatives at the carboxyl function thereof. As the deriva-tives at the carboxyl function, there are mentioned those defined in the defi-nition of the derivatives at the carboxyl function of compound (I).
The reaction of Step I is carried out by reacting a compound of formula (V') with a compound of general formula Rl H (XII) wherein Rl has the meaning given above.
The starting compound ~V') may be a reactive derivative at the car-boxyl function thereof. As the reactive derivative at the carboxyl function, there are mentioned a derivative at the carboxyl function defined in the start-ing compounds in Step B' as well as p-nitrophenyl ester and acid halide such as acid chloride, acid bromide, acid iodide, etc. When compound (V') is a free carboxylic acid, it may first be converted to a reactive derivative at the carboxyl function and, then, the derivative be subjected to the contemplated reaction. When compound (V') is a reactive derivative, it may first be con-verted to the free carboxylic acid which, in turn, is subjected to the contem-plated reaction. This reaction is generally conducted with advantage in the 2Q presence of a catalyst which may be any of the agents that can ordinarily be u~ed as catalysts in Friedel-Crafts reactions, that is to say any of the so-called Fried~l-Crafts catalysts. Thus, metal halides ~e.g. aluminum chloride, aluminum bromide, aluminum fluoride9 iron chloride, iron bromide, antimony chloride, antimony bromide, titanium chloride, tin chloride, tin bromide, zinc chloride, ~inc bromide, bismuth chloride, etc.); Lewis acids such as boron fluoride; mineral acids such as sulfuric acid, phosphoric acid, polyphosphoric acid, etc.; hydrogen fluoride; etc. may be mentioned by way of example. The reaction is advantageously conducted in the presence of a solvent which may be an aromatic compound of general formula (XII) or any of the solvents inert to the reaction. Said solvents inert to the reaction include, among others, car-bon disulfide, nitrobenzene, halogenated hydrocarbons ~e.g. methylene chloride, ethylene chloride, l,lj2,2-tetrachloroethane, etc.), etc.

When sulfuric acid, polyphosphoric acid or hydrogen fluoride, for instance, is used as the catalyst, it can be used in a large excess so that it will function as the solvent as well. When a Friedel-Crafts catalyst is employed, its proportion is ordinarily about 1 to 6 moles per mole o-f the carboxylic acid of general formula (V') or its reactive derivative. While the reaction conditions such as temperature and time are not particularly critical, the practically desirable reaction temperature is somewhere between -15C and the neighborhood of the boiling point of the solvent used. The tem-pera~ure may be increased or decreased within the above range. The reaction time ordinarily ranges from about 1 to 5 hours, although it depends upon the species of starting compound, catalyst and solvent. The resultant compound of general formula (V) can be separated and purified by procedures which are known ~ se, such as distillation, recrystallization, column chromatography, etc.
The Steps I' and I" is carried out by taking a similar procedure to that of Step I.
In these Steps, the starting compounds may be reactive derivatives at the carboxyl function on benzene ring of compound (VIII') or (I'). As the reactive derivatives, there are mentioned those defined in the starting com-pound in Step I. Further, the starting compound (I') of Step I" may be a derivative at the carboxyl function other than that on benzene ring. As the derivative, there are mentioned those defined in compound ~I).
Though, in the reaction of Step I", there is produced a mixture of compound (I-a) and compounds of follo~ing formula:

COOH COR

H
COR COR
wherein Rl has the meanings given above, the contemplated compound ~I-a) can be separated and purified by per se known separatory procedures such as re-crystallization, distillation, chromatography, etc.

The compounds ~I-a) can be obtained in a suitable form such as free acid, es~er, sal~ and the like by taking the procedures mentioned in Step E.
Further, the compounds (I-a) can be resolved into optical isomers by a similar manner to that described in Step E.
The reaction of Step J is carried out by reacting a compound of general formula ~II) with a compound of general formula;
R - COOH (XIII) wherein Rl has the meaning given above.
The compound ~II) may be a derivative a~ the carboxyl function there-of. As the derivative at the carboxyl function, there are mentioned those defined in compound (I). The compound (XIII) may be a reactive derivative at the carboxyl function thereof. As the reactive derivative at the carboxyl function, there are mentioned those defined in the starting compound (IV) of Step A. The proportion of said carboxylic acid of general formula (XIII) or said reactive derivative of (XIII) is preferably about 1 to about 10 moles to each mole of said carboxylic acid of general formula (II) or derivative at the carboxyl function of (II) for practical purposes.
Generally speaking, the reaction is advantageously conducted in the presence of a solvent and a catalyst. The solvent may be any solvent that is inert to the reaction; for example, carbon disulfide, nitrobenzene, halogenat-ed hydrocarbons (for 0xample, methylene chloride, ethylene chloride, 1,1,2,2-tetrachloroethane, chlorobenzene, dichlorobenzene, etc.) and so forth. As the catalyst for this reaction, use may be made of the substances which can be ordinarily used as catalysts in Friedel-Crafts reactions, i.e. the so-called Priedel-Crafts catalysts. While the proportion of such catalyst usual-ly need not be over about 1 to 1.5 moles per mole of said carboxylic acid of general formula (XIII) or said reactive derivative thereof, any of the above-mentioned mineral acids, hydrogen halide, etc. may be used in large excess so that it will function as the solvent as well. The reaction conditions such as temperature and time are largely optional.
Houever, for practical purposes, the reaction temperature ordinari-ly ranges from -15C to the boiling point of the solvent employed and the re-action sys~em may be cooled or heated to a suitable extent within said tem-perature range. Ordinarily the reaction time is about 1 to about 4 hours, although it depends upon the species of starting compounds, catalyst and sol-vent used.
The reaction of this invention gives rise not only to the contem-plated compound ~I-a) or a derivative at the carboxyl function of (I-a) but at times to a compound of general formula:

RlCO ~ ~H2)n (XIV) COOH

wherein R and n have the meanings given above.
The compounds (I-a) can be separated and purified by a per se known separatory procedures such as recrystallization, distillation and chromatog-raphy.
The compound ~I-a) can be obtained in a suitable form such as free acid, ester, sal~, etc. by taking the procedures mentioned in Step E.
Further, the compound ~I-a) can be resolved into optical isomers by a similar manner to that described in Step E.
The reaction of Step K is carried out by oxidizing a compound a).
As the procedures of oxidation, use may be made of any procedure by which a methylene group can be oxidized to a carbonyl group. Thus, oxida-tion procedures utilizing for example, chromic acid, permanganic acid, manganese dioxide, selenium dioxide, cerium, N-bromosuccinimido3 etc. as the oxidizing agents may be used to advantage. More particularly, in the chromic acid oxidation process, use may be made, with advantage, of any of such oxidizing agents as chromic anhydride, chromic acid, dichromates ~e.g.

ammonium dichromate, potassium dichromate, sodium dichromate, etc.), chromates ~e.g. ammonium chromate, potassium chromate, silver chromate, cobalt chromate, cesium chromate, sodium chromate, barium chromate, etc.), - i9 -chromic acid chloride (e.g. chromyl chloride), etc. The solvent for use in this process may for example be an acid, e.g. sulfuric acid, acetic acid or the like; water; and an organic solvent, e.g. acetone, benzene, ether, acetic anhydride or the like. These solvents are used either alone or as a mixture.
In the permanganic acid oxidation, use is desirably made of such oxidizing agents as permanganates (e.g. potassium permanganate, sodium permanganate, - barium permanganate, calcium permanganate, magnesium permanganate, zinc per-manganate, etc.). As the reaction solvent, a basic, neutral or acid aqueous solution is desirable and, in certain cases, an organic solvent such as ace-tone, benzene or toluene may be concomitantly present. In the manganese di-oxide oxidation, manganese dioxide and sulfuric acid are desirably used as the oxidizing agent and solvent, respectively. The selenium dioxide oxidation is desirably carried out with selenium dioxide as the oxidizing agent in water, acetic anhydride, acetic acid, dioxane or the like as the solvent. In the case of cerium oxidation, cerium ammonium nitrate [Ce(NH4)2(NO3)6~ is used as ~he oxidizing agent, the solvent being either a single-component solvent or a solvent mixture, for example, water, mineral acids (e.g. perchloric acid, nit-ric acid, sulfuric acid, etc.), organic acids (e.g. formic acid, acetic acid, propionic acid, etc.), acetonitrile, tetrahydrofuran, acetone, dioxane, etc.
may be employed for this purpose.
In these oxidizing reactions, the reaction temperature is somewhere within the range of under cooling with ice to about 100C, the reaction time being more or less optional.
The contemplated compound thus obtained can be separated and purified by procedures which are known ~ se. such as distillation, recrystallization, column chromatography, etc.
The Steps K' and K" are carried out by taking the procedures similar to those of Step K:
In the reaction of Step K", the starting compound may be a derivative at the carboxyl function of compound (III-c). As the derivative, there are mentioned those defined in compound (I).
The objective compounds of these reactions can be separated and ~4~4~
purified by the per se kno~n separatory procedures such as recrystallization, distillation and chromatography.
The compound (I-a) can be recovered in a suitable form such as free acid, es~er, salt, etc. by taking the procedures mentioned in Step E.
Further, the compound ~I-a) can be resolved into optical isomers by such a per _ known manner as described in Step E.
The reaction of Step L is carried out by reacting a compound of general formula (V) with sulfonylmethylisonitrile compound.
Said sulfonylmethylisonitrile compound may for example be a compound represented by general formula R S02C~2NC (XV) wherein R9 means an aryl, aralkyl or alkyl group. The aryl group stands for, for example, phenyl or naphthyl whose aromatic nucleus may be substituted by alkyls (e.g. methyl, ethyl, etc.), halogens (e.g. chlorine, bromine, etc.), alkoxyls ~e.g. methoxy, etc.), etc. in optional positions. Particularly ad-vantageous for practical purposes are phenyl, p-tolyl, etc. The aralkyl group represented by R9 may for example be henzyl or phenethyl; the alkyl group which is also represented by R9 may for example be methyl, ethyl n-propyl, isopropyl n-butyl, isobutyl, sec.-butyl, tert.-butyl or the like.
This reaction consists in reacting 1 to 1.5 moles of (XV) with each mole of (V) in the presence of subs~antially 1 to 3 moles per mole of ~V) of a base in a solvent. Preferred species of the solvent are mixtures o~ ethers such as dimethoxyethane, diethoxyethane, tetrahydrofuran, etc., with lower alcohols such as methanol, ethanol, tert.-butanol, etc., and the mixing ratio is preferably 2 ~o 20 parts of such an ether to each part of an alcohol and, for better results, within the range of 5 to 10 parts to 1 part. The base is exemplified by metal alcoholates which are obtainable from lower alcohols, e.g. methanol, ethanol, t-butanol, etc., and alkali metals, e.g. sodium, potassium, etc. In the presence of such a base, the reaction proceeds with increased advantage.
The reaction temperature is selected from within the range of 0 to 100C according to the reactivity of the starting compounds and the types of solvent, base, etc. to be used. Particularly preferred is a temperature which lies somewhere between 10 and 40C.
Generally, the reaction goes to conclusion in I to 6 hours.
The desired product (VIII) can be isolated 6y per se known procedures.
The Steps L' and L" are carried out by taking the procedures similar to those of Step L.
The starting compound of Step L' may be a derivative at the carboxyl function of compound ~V'). As the derivative at the carboxyl function, there are mentioned those defined in the starting compound (V') of Step B'.
The reaction of Step M is carried out by subjecting a compound of general formula tI-a) to alkylation.
The alkylation is conducted by reacting with the compound ~I-a) with a compound of general ~ormula R - X (XVI) wherein R8 is an alkyl having 1 to 4 carbon atoms and X has the meaning given a60ve.
As the alkyl shown by R8, there are mentioned methyl, ethyl, propyl, i-propyl, allyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, etc.
This reaction proceeds with advantage in the presence of a base. As the base, there are mentioned alkali metal hydroxide (e.g. sodium hydroxide and potassium hydroxide), alkali metal hydride (e.g. sodium hydride and lithium hydride), alkali metal alcoholate (e;g. sodium methylate, sodium ethylate, so-dium tert.-6utylate, potassium tert.~butylate and sodium tert.-amylate), alkali metal amide (e.g. sodium amide, potassium amide, lithium amide, sodium piperi-dide, potassium piperidide, lithium piperidide, sodium diethylamide~ potassium diethylamide, sodium diisopropylamide and lithium diisopropylamide), etc. As the solvent to be used, there are mentioned alcohols (e.g. methanol, ethanol, propanol, butanol and tert.-butanol), ethers ~e.g. diethylether, tetrahydro-furan, dioxane, methoxyethane, ethoxyethane, 1,2-dimethoxyethane, dimethyl-3Q ether), ben~ene, toluene, xylene, dimethylsulfoxide, N,N-dimethyl~ormamide, hexamethylphosphoric triamide, liquid ammonia, diethylamine, diisopropylamine, etc.

The base is usually used in an amount of l to lO moles per mole of compound (I-a) and compound ~XVI) is usually used in an amount of l to 3 moles per mole of a base. While the reaction conditions such as temperature and time are largely optional, the preferred temperature range is about 0 to about 50C.
The compound (I-b) thus obtained can be separated and purified by per se known separation-purification procedures such as recrystallization, dis-tillationj chromatography, etc.
The compounds (I-b) can be recovered in a optional form such as free acid, ester, salt and the like by taking similar procedures to those mentioned in Step E.
Further, the compounds ~I-b) can be resolved into optical isomers by a similar manner to that described in Step E.
Throughout the present specification the abbreviations "mg.", "g.", "mQ." and ~&~, respectively refer to "milligram~s)", "gram~s)", "milliliter~s)"
and "degree~s) centigrade".
Although the following examples are further illustrative of this in-vention, these do not have any meaning of limiting or restricting the scope of this invention at all.
`Reference example l To lO0 mQ. of methylene chlorid~ is added 50 g. of dry aluminum chloride. The mixture is stirred and 28 g. of benzoyl chloride is added drop-wise. While the solution is stirred at 30 - 40C, 16.4 g. of methyl ~-phenyl-propionate is added dropwise over a period of about l hour. After the drop by drop addition has been completed, the solution is stirred at 30 - 40C for 2 hours. After cooling, the solution is poured into ice-hydrochloric acid and extracted with methylene chloride. The extract is washed with dilute hydro-chloric acid, water, dilute aqueous sodium hydroxide and water in the order mentioned3 followed by drying. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography ~l kg. of silica gel; eluted with benzene). The described procedure gives methyl p-benzoyl-~-phenylpropionate and methyl o-benzoyl-~-phenylpropionate.

To a solvent mixture of 20 mQ. of ethanol and 100 mQ. of water are added 20 g. of the methyl o-benzoyl-~-phenylpropionate thus obtained and 15 g.
of potassium hydroxide. The mixture is refluxed for 2 hours. After cooling, the solvent is distilled off and the residue is diluted with water and washed with ether. The aqueous layer is acidified with hydrochloric acid and extract-ed with ether. The extract is washed with water and dried. Then, the solvent is distilled off and the residue is crystallized from benzene-hexane. The procedure gives o-benzoyl-~-phenylpropionic acid.
Reference examples 2 - 6 By the similar manner to Reference 1, following compounds are pro-duced.
. _ Reference example Produced-compound Starting compound _ 2 o-(p-toluoyl)-~-phenyl- p-toluoyl chloride propionic acid +
methyl ~-phenylpropionate . . . _ .

3 o-(p-chlorobenzoyl)-~- p-chlorobenzoyl phenylpropionic acid chloride methyl ~-phenylpropionate _

4 o-benzoyl-r-phenyl- ethyl r-phenYlbutYlic butylic acid acid benzoyl chloride .....
o-(p-toluoyl)-y- ethyl y-phenylbutylic phenylbutylic acid acid p-toluoyl chloride 6 o-(p-chlorobenzoyl)- ethyl r-phenylbutylic y-phenylbutylic acid acid p-chlorobenzoyl chloride Referenee example 7 To 700 mQ. of ice-cooled dry ether is added 15 g. of lithium aluminum hydride, followed by the addition of 61.8 g. of crystalline o-~p-chlorobenzyl) benzoic acid. The mixture is refluxed with stirring for 5 hours, after which it is allo~ed to stand at room temperature overnight and, then, the excess reagent is decomposed with ice-water. The organic layer is separated, washed with water and dried. The solvent is distilled off under reduced pressure and the residue is distilled under reduced pressure. The procedure gives o-~p-chlorobenzyl)benzyl alcohol is a fraction boiling at 145 - 155 C/0.1 mm mer-cury.
In 400 mQ. of chloroform is dissolved ~6.5 g. of o-~p-chlorobenzyl) benzyl alcohol and, under stirring and cooling with ice, l9 g. of phosphorus tribromide is added dropwise. After the drop-by-drop addition has been com-pleted, the mixture is stirred under cooling with ice for 1 hour and, then, at room temperature for 1 hour. The solution is allowed to stand overnight and washed three times with ice cooled water, followed by drying over calcium chloride. The solvent is distilled off under reduced pressure, whereupon o-(p-chlorobenzyl)benzyl bromide is obtained as an oily residue. This product is used in the next reaction without purification.
In 100 mQ. of ethanol is dissolved 4.8 g. of sodium metal and while the solution is stirred at room temperature, 64 g. of diethyl malonate is added dropwise. After ~he drop-by-drop addition has been completed, the mixture is heated at 80 - 90C for 15 minutes and, then, cooled. Under stirring~ a mix-ture of 5g g. of o-(p-chlorobenzyl)benzyl bromide and 150 mQ. of dry benzene is added dropwise. After the dropwise addition has been completed, the mix-ture is refluxed with stirring for 2 hours. The solvent is distilled off under reduced pressure and the residue is diluted with water and extracted with benzene. The extract is washed with water and dried. The solvent is then distilled off under reduced pressure and the residue is further distilled under reduced pressure.
The described procedure gives diethyl o-(p-chlorobenzyl)-benzyl-malonate as a fraction boiling at 175 - 185C/0.2 mm mercury.
In 70 mQ. of water is dissolved 25 g. of potassium hydroxide, fol-lowed by the addition of 62.5 g. of diethyl o-(p-chlorobenzyl)benzylmalonate.
The mixture is refluxed under stirring for 6 hours and, then, allowed to stand at room temperature overnight. To the reaction mixture is added 300 m~. of water and, after the mixture is rendered acidic by the addition of hydrochloric acid, it is cooled with ice.
The precipitate is collected and dissolved in a solvent mixture of ethyl acetate and ether. The solution is washed with aqueous sodium chloride ~480~
and dried. The solvent is distilled off under reduced pressure, whereupon o-~p-chlorobenzyl)benzylmalonic acid is obtained.
Without purificationJ this product is decarboxylated by heating at 160 - 170C for 3 hours, after which it is cooled. Recrystallization from cyclohexane gives 3-~o-~p-chlorobenzyl)phenyl)propionic acid as crystals melt-ing at 107 - 109C.
To stirred polyphosphoric acidJ prepared from 100 g. of phosphorus pentoxide and 70 mQ. of phosphoric acid, 5.0 g. of 3-~o-~p-chlorobenzyl)phenyl) propionic acid is added. The mixture is stirred at 110 - 120C for 2 hours.
Upon addition of ice-waterJ yellow crystals separate out. These crystals are collected by filtrationJ washed with water and dried. The crystals are puri-fied by column chromatography ~silica gel; eluted with a 40 : 1 mixture of benzene and ethyl acetate. The described procedure gives 4-~p-chlorobenzyl)-indan-l-one as crystals melting at 87 - 88C.
Refere ce examples 8 - 10 By a similar manner to Reference example 7J the following compounds are produced.

Reference _ _ ~
example Produced-compound Starting compound 8 4-benzylindan-1-one o-benzylbenzoic acid /n-hexane/

9 4-~p-methylbenzyl- o-~p-methylbenzyl)-indan-l-one benzoic acid /cyclohexane/
. ~
4-~p-methoxybenzyl)- o-~p-methoxybenzyl)-indan-l-one benzoic acid . ~__ L~yclohexane/ ... __~
Example 1-~1) Five g. of o-benzoyl-~-phenylpropionic acid, 13 g. of anhydrous aluminum chloride and 1.3 g. of sodium chloride are admixed together and heated at 160C for 1 hour. After coolingJ water is added to the mixture, followed by extraction with chloroform. The extract is washed with a 5% aqueous solution ~4E~
of sodium bicarbonate and water in that order and, then, dried. The solvent is distilled off under reduced pressure and the residue is dissolved in ethanol. The solution is decolorized with activated carbon and recrystallized from ethanol. The procedure yields 4~benzoylindan-1-one as crystals melting at 86 - 88C.
By a similar manner to Example 1-~1), the following compounds are produced.
Example produced-compound starting compound ~ .
1-(2) 4-(p-toluoyl)indan-1- O-(p-toluoyl)-~-phenyl-one O propionic acid m~. 106 - 108 C aluminum chloride /cyclohexane/ sodium chloride . _ _ 1-(3~ 5-benzoyl-1-tetrOalone 0-benzoyl-r-phenylbutylic m p. 72.5 -_73.5 C acid Lcyclohexane/ aluminum chloride sodium chloride _ . .__ .
1-(4) 5-(p-toluoyl)-1- 0-(p-toluoyl)-r-tetralone O phenylbutylic acid m~p. 86 - 87 C aluminum chloride /cyclohexane/ sodium chloride Example 1-~5) To 5.8 g. of o-~p-chlorobenzoyl)-~-phenylpropionic acid is added 50 mQ. of thionyl chloride and the mixture is allowed to stand at room tem-perature overnight.
The excess thionyl chloride is distilled off under reduced pressure, and 13 g. of anhydrous aluminum chloride and 1.3 g. of sodium chloride are added to the resultant crude o-(p-chlorobenzoyl)-~-phenylpropionyl chloride.
The mixture is heated at 160C for 1 hour. After cooling, water is added, followed by extraction with chloroform. The extract is washed with a 5%
aqueous solution of sodium bicarbonate and water in the order mentioned and, then, dried.
The solvent is distilled off under reduced pressure and the residue is crystallized from a 1:1 mixture of benzene and cyclohexane. The described procedure gives 4-(p-chlorobenzoyl)-indan-1-one as crystals melting at 145.5 -146C.

~48(1 g~
Example l 16) By a similar manner to Example l-(5)9 6 g. of o-(p-chlorobenzoyl)-~ -phenylbutyric acid is converted to o-(p-chlorobenzoyl)- ~-phenylbutyryl chloride which9 in turn, is reacted with 13 g. of anhydrous aluminum chloride and l.3 g.
of sodium chloride to prepare 5-(p-chlorobenzoyl)-l-tetralone.
melting point 96 98C (recrystallization solvent cyclohexane).

Exam~le 2~
To 120 m~. of ethanol is added 5.7 g. of methyl l-oxo-indan-4-carboxylate and the mixture is stirred at room temperature.
Then, 600 mg. of sodium borohydride is added and9 after stirring for 90 minutes9 4 m~. of acetone is added.
rrhe mixture is further stirred for 30 minutes, after which the sol~ent is distilled off under reduced pressure.
To the residue are added water and dilute hydrochloric acid, followed by extrac-tion with ether. The extract is washed with water and a saturated aqueous solution of sodium chloride and~ then, dried. Finally the solvent is distilled off under reduced pressure, whereupon methyl l-hydroxyindan-4-carboxylate is obtained. Recrystal]ization from ether-petroleum ether gives crystals melting at 65-67C.

Exam~les_2-(2~ -_2-~3) In lO0 me. of water is dissolved 4~4 g. of sodium hydroxide, followed by the addition of 17.6 g. of l-oxoindan-4-carboxylic acid~
l~hile the mixture is cooled in an ice-water bath9 1.89 g.

_ ,zg ~4~
of sodium borohydride is added. The bath is removed and the mixture is stirred for 3 hours, after which 5 mQ. of acetone is added. After 1 hour, the reaction mixture is added to a solution of 70 g. of ice and 30 mQ. of concentrated hydro-chloric acid and the resultant crystals are collected by filtration and recrystallized from acetone. The procedure gives l-hydroxyindan-4-carboxylic acid melting at 174 - 176C
(decomp.).
By a similar manner to the above, l-hydroxy-1,2,3,4-tetrahydro-5-naphthoic acid is obtained from 19 g. of 1,2,3,4-tetrahydro-l-oxo-naphthoic acid and 1.89 g. of sodium boro-hydride. me]ting point: 160.5 - 162.5QC ~acetone).
Example 2-~4) To 200 mQ. of ethanol is added 10.9 g. of ethyl 1,2,3,4-tetrahydro-1-oxo-5-naphthoate and while the solution is stirred at room temperature, 950 mg. of sodium borohydride is added. The mixture is stirred for 4 hours, after which 2 mQ.
of acetone is added. The mixture is further stirred for 30 minutes and, then, the solvent is distilled off under reduced pressure. Following the addition of 30 mQ. of 2N hydrochloric acid, the residue is extracted with ethyl ether. The organic layer is washed with water and dried over anhydrous ma~nesium sulfate. The solvent is then distilled off under reduced pressure and the oily residue is purified by column chromatog-raphy on silica gel ~100 g. silica gel; eluted with chloroform).
The described procedure gives ethyl l-hydroxy-1,2,3,4-tetra-hydro-5-naphthoate as an oily product.
Infrared absorption spectrum ~neat) 1715 cm 1 ~carbonyl of ester) 4~
Nuclear magnetic resonance spectrum (CDC~ , 100 MHz) o~ 0 1.36(3H, -t, -CH~, 4.31(2H, q9 0-CH2-) 4.74(1H9 t, Cl-H).

Example 3- ~
To 30 m~. o~ benzene is added 5.35 g. o~ l-hydroxyindan-4-carboxylic acid. Following the addition of 15 me. of thionyl chloride 9 the mixture is stirred for 3 hours. Then, the reaction mixture is concentrated to dryness under reduced pressure and the resultant crystals are recrystallized from benzene. The described procedure gives l-chloroindan-4-carboxylic acid melting at 135.5-137.5C.

ExamE~ 3-(2) In 6 m~. of chloroform is dissolved 5.7 g. of methyl 1-hydroxyindan-4-carboxylate and9 under cooling with ice, the solution is stirred. Then, 3 m~ of thionyl chloride is added drop~.Tise and9 after the dropwiss addition has been completed, the mixture is further stirred under cooling ~rith ice for one hour. Then~ the solvent and the excess thionyl chloride are distilled off under redu.ced pressure. The residue obtained is purified by column chromatography on silica gel (500 g. silica gel9 eluantO chloroform). The procedure gives methyl l-chloroindan-4-carbo~ylate as an oily product.
Infrared a-bsorption spectrum (nea-t) 1720 cm 1 (carbonyl of ester) Nuclear magnetic resonance spectru.~ (CDC~39 60 MHz) 6 . 3.9 (3H, s9 CH~)9 5.41(1H9 t9 ~l~H) .. _ ~ _ - ~o ~

E ~E~ 3) 3y a similar manner to Example 3-(2), ethyl l-chloro-1929394-tetrahydro-5-naphthoate is produced from ethyl 1-hydroxy-1929394-tetrahydronaphthoate and thionyl chloride.
Infrared absorption spectrum (neat) 1720 cm 1 (carbonyl of ester) Nuclear magnetic resonance spectrum (CDC~39 lC0 MHz~
1.36(3H, t-CH3)9 4.31(2H9 q9 0-CH2-)9 5.29(1H, t, C, -H) ~xample 4-(1) In 15 m~. of dimethylformamide is dissolved 1.97 g. of l-chloroindan-4-carboxylic acid 9 followed by the addition of 1.47 gO of sodium cyanide. The mixture is stirred for 5 hours9 after which 150 m~. of water and 10 me. of concentrated hydrochloric acid are added. The resultant crystals are collected by filtration and recrystallized from benzene.
The described procedure gives l-cyanoindan-4-carboxylic acid, melting point 206-208C.

Example 4- ~
In 80 m~. of dimethylsulfoxide is dissolved 15 g. of methyl l-chloroindan-4-carboxylate and the solution is stirred.
Then9 5.3 g. of sodium cyanide is added9 followed by stirring for 8 hours. ~ollowing the addi-tion of 750 m~. of water9 the reaction mixture is extracted w~th ether The extract is washed with a saturated aqueous solution of sodium chloride and9 then9 dried, The solvent is distilled off under reduced pressure and the residue is purified by column chromatography ~014~09L~
on silica gel (500 g. silica gel9 eluant chloroform). The described procedure gives methyl l-cyanoindan-4 carboxylate as crystals melting at 76.5-77~5C.

Example 4-(3) In a mixture of 50 m~. of methanol and 50 me. of water is dissolved 2.0 g. of sodium hydroxide, and 6.0 g. of meth~yl l-cyanoindan-4-carboxylate is added to the resultant solution.
The mixture is heated in a water bath maintained at about 50C for about 20 minutes, after which time it is cooled, followed by the addition of 60 m~. of lN hydrochloric acid.
The resultant precipitate is extracted with chloroform and the extract is washed with water and dried. Then, the solvent is distilled off under reduced pressure9 whereupon l-cyanoindan-4-carboxylic acid is obtained as crystals melting at 206-208C.

Example 4-(4~
In 44 m~. of dimethylsulfoxide is dissolved 4.4 g. of ethyl l-chloro-1,2,3,4-tetrahydro-5-naphthoate 9 followed by the addition of 2 g. of sodium cyanide. The mixture is stirred at 50C for 3 hours and following the addition of 450 m~. of 0.2N hydrochloric acid, the mixture is extracted with ethyl ether. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resultant oily residue is purified by col~n chromatography on silica gel (100 g, silica gel9 eluted with benzene). The procedure gi~es ethyl l-cyano-192,394-tetrahydro 5-naphthoate as an _ 4,~ _ - 3 ~

4~
oily product.

Infrared absorption spectrum (neat) 1720 cm (ester carbonyl) 2240 cm~l (nitrile) ~uclear magnetic resonance spectrum (in C'DC~3, 100 MHz) 1.36(3H9 t9 -CH3)9 4.00(1H, t9 Cl-H)9 4-33(2H, q, O-CH2- ) Example 4-(5) In 90 m~. of ethanol is dissolved 9.6 g. of ethyl 1-cyano-19293,4-tetrahydro-5-naphthoate and a solution of 2.5 g.
of sodium hydroxide in 90 m~ of water is added. The mixture is stirred under heating at 50C for 3 hours, after which the ethanol is distilled off. ~hen9 following the addition of 2N hydrochloric acid9 the residue is extracted with chloroform. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the crystalline residue is recrystallized from ~enzene. The described procedure gives l-cyano-1,2,3 9 4-tetrahydro-5-naphthoic acid9 melting pointO
177-179C.

To 40 m~. of pyridine is added 19.2 g. of methyl 1-hydroxyindan-4-carboxylate and 9 while the mixture is stirred at a temperature of not more than 10C, 21 g. of p-toluene-sulfonyl chloride is added in small installments. After the addition has been completed, the reaction mixture is allowed to stand at a temperature not exceeding 10C for 6 hours. Then, following the addition of ice 9 the reaction _ 33 -4~L
mixture is extracted with ether. The extract is washed with water and dried. The solvent is then distilled off under reduced pressure and the resultant 4-carbomethoxy-1-indanyl p-toluenesulfonate is dissolved in 100 m~. of dimethylsulfo-xide7 followed by stirring. Then, 5.5 g. of sodium cyanide is added and the mixture is stirred at room temperature for 11 hours, ~ollowing the addition of 850 m~. of ~Tater, the reaction mixture is extracted with etherO The extract is washed with a saturated aqueous solution of sodium chloride and9 then9 dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (600 g. silica gel 9 eluant. chloroform). The described procedure gives methyl l-cyanoindan-4-carboxylate as crystals melting at 76-77C.

Example 5-(2) To 100 m~. of benzene is added 19.2 g. of l-hydroxy-1,29394-tetrahydro-5-naphthoic acid, and following the addition of 50 m~. of-thionyl chloride, the solution is stirred for 8 hours. ~he solvent and the excess thionyl chloride are distilled off under reduced pressure and~ then9 150 m~. of dimethylsulfoxide and 19.6 g. of sodium cyanide are added9 followed by stirring at 50~ for 6 hours~ Then9 i-t is added to 1.5 ~. of lN hydrochloric acid and extracted with ethyl ether. The organic layer is extracted with 800 m~.
of 5 ~ aqueous sodium hydroxide solution and af-ter the addi-tion of 100 m~0 of concentrated hydrochloric acid, the solu-tion is extracted with chloroform. The chloroform layer is washed with water and dried over anhydrous magnesium 3~9~
sulfate. The solvent is distilled of~ under reduced pressure and the crystalline residue is recrystallized from benzene~
The procedure gives l~cyano-1,293-4-tetrahydro-5-naphthoic acid9 melting point: 177-179C.

Examp e 6-(1) To dilute sulfuric acid, prepared from 54 m~, of water and 45 m~. of concentrated sulfuric acidp there is added 3 g.
of 4-benzoylindan-1-carbonitrile. The mixture is refluxed in a current of nitrogen gas for three hours and a half.
After cooling9 the reaction mixture is diluted with water and extracted with ether. The ethereal layer is further extracted with a 5 ~ aqueous solution of potassium carbonate and the extract is washed with ether and rendered acidic with hydrochloric acid. The precipitate is extracted with chloroform and the extract is washed with water and dried.
The solvent is distilled off under reduced pressure, where-upon 4-benzoylindan-1-carboxylic acid is obtainedO
Recrystallization from benzene-cyclohexane (7 20) gives crystals melting at 100-102C.

Example 6-~2) To dilu-te sulfuric acid, prepared from 27 m~. of water and 23 m~. of concentrated sulfuric acid, there is added 3 g.
of 4-(p-toluoyl)indan~l-carbonitrile. The mixture is refluxed in a current of nitrogen gas for 3.5 hours. Af-ter cooling9 the reaction mixture is diluted with water and extracted with ether. The ethereal layer is extracted with a 5 %
aqueous solution of potassium carbonate and the extract is washed with water and rendered acidic with hydrochloric acidO The precipitate is extracted with chlorof'orm and the extract is washed with a saturated aqueous solution of sodium chloride and dried. The solvent is then distilled off under reduced pressure and the residue is crystallized from benæene-cyclohexane (7020). The described procedure gives 4-p-toluoylindan-1-carboxylic acid as crystals melting at 128~131C, Exa_E~e, 6,(3) In 500 m~. of methanol is dissolved 15 g. of 4-benzoyl-indan-l-carbonitrile, followed by the addition of 150 r~.
of a 5 ~0 aqueous solution of sodium hydroxide and 50 r~e. of a 30 ~0 aqueous solution of hydrogen peroxide.
The mixture is heated ~t 60C for 2 hours and cooled.
The reaction mixture is rendered acidic by the addition of dilu-te hydrochloric acid and the resultan-t precipitate is extracted with ethyl acetateO
~ he extract is washed with water and dried. The solvent is distilled off u~der reduced pressure and the residue is purified by column chromatography on silica gel (500 g. silica gel9 eluted with chloroform-acetone (7 3)).
The described procedure gives 4-benzoylindan-1-carboxamide as crystals melting at 16405-166C.

Examples 6-(4) - 6-( 11 ~ y a similar manner to Example 6-(1)9 following compounds are produced~

_ ~ _ , - ~G--4~
. __ __~__ ~xample Produced-compound Starting compound 4-(p-chlorobenzoyl)- 4-(p-chlorobenzoyl)-indan-l-carboxylic indan-l-carbonitrile 6-(4) acid melting point~
. 138.5-139 5C
(benzene-cyclohexane (3~10)) ... _ ._ 4-(p-bromobenzoyl)- 4-(p-bromobenzoyl)-indan-l-carboxylic indan-l-oarbonitrile 6-(5) acid melting poin-to 147.0-149.0C
(benzene-cyclohexane . ___ (]. ol)) _ . 4-(p-chloro m-methyl- 4-(p-chloro-m-methyl-benzoyl)indan-l- benzoyl)indan-l-6-(6) carboxylic acid carbonitrile melting poin-to 116-117C(benzene-cyclohexane(3020)) 4-(p--t-butylbenzoyl)- 4-(p-t-butylbenzoyl)-indan-l-carboxylic indan-l-carbonitrile 6-(7) acid melting pointo 139-142C (benzene-. petroleum ether) 4-(p-fluorobenzoyl)- 4--(p-fluorobenzoyl)-indan-l-carboxylic indan-l-carbonitrile 6-(~) acid melting point~
109-110~ (benzene-cyclohexane (3~20))

5-benzoyl-1,293,4- 5-benzoyl-1,2,394-tetrahydro-l- tetrahydro-l-

6 (9) naphthoic acid naphthonitrile _ melting point.
~6~~165C
[benzene~
_ 5-(p-toluoyl)-1,2939 5-(p--toluoyl)-192,3, 4-tetrahydro-1- 4-tetrahydro-1-6-(10) naphthoic acid naphthonitrile melting pointo (cyclohexane) _ 5-(p-chlorobenzoyl)- 5-(p-chlorobenzoyl)-192,3,4-tetrahydro-l- 19 2 9 394-tetrahydro-6 (11~ naphthoic acid l-naphthoni-trile _. , melting point:
152.5-153C
__ (benzene-hexane) -3~-~6~4~
~xamples ~ 121 - 6-(15~
By a similar manner to ~xample 6-(3), following compounds are produced.

Example Produced-compound Starting compound 5-benzoyl-17 2,3,4- 5-benzoyl-19 2,3,4-tetrahydro-l- tetrahydro-l-6 (12) naphthamide naphthonitrile _ melting pointo 145.5-147.5C
(cyclohexane) 5~(p-toluoyl)-1 9 2 9 5-(p-toluoyl)-1 9 2, 3 9 4-tetrahydro-1- 3 9 4-tetrahydro-1-6 ~13) naphthamide naphthonitrile _~ melting point:
178-178.5C
[ethanoI~ _ 5-(p-chlorobenzoyl)- 5-(p-chlorobenzoyl)-19293,4-tetrahydro- 1,2,~94-tetrahydro-l-6-(14) l-naphthamide naphthonitrile melting point:
150~5-152.5C
(benzene) 4-(2,4,6-trimethyl- 4-(29496-trimethyl-benzoyl)indan-l- benzoyl)indan-l-r , ~ carboxamide carbonitrile ~-~15) melting pointo ~ethanol) _ -E mple 6-(16) To 100 g. of polyphosphoric acid is added 2 g. of 4-(p-chlorobenzoyl~indan-1-carbonitrile and the mixture is heated at 150-170C for 2 hours~
The mixture is allowed to stand at room temperature overnight and following the addition of water, it is extracted with ethyl acetate~ The extract is washed with 5 ~0 aqueous sodium bicarbonate and water in that order and, _ ~, _ 31~4~
then9 dried over sodium sulfateO
The solvent is distilled off under reduced pressure and the solid residue is recrystallized from 80 Tne. 0~
benzene. The procedure gives 4-(p-chlorobenzoyl)indan-l-carboxamide as colorless crystals melting at 159-161C.
The crystal includes 1/6 mole equivalent of benzene.

Example 6-(~
To 2.3 g, of 4-(p-toluoyl)indan~l-carbonitrile is added 75 g. of polyphosphoric acid and the mixture is worked into a homogeneous solution by heating on a water bath at 90C for 30 minutes and9 then, on an oil bath at 120-130C
for 30 minutes, ~ollowing the addition of water to decompose the polyphosphoric acid, the reaction mixture is extracted with ethyl acetate~ The extract lS washed wlth water9 5 ~o aqueous sodium hydrogen carbonate and ~ater in the order mentioned and, then9 dried. It is, then, treated with activated carbon and concentrated under reduced pressure.
~he resultant crystalline residue is recrystallized from a mixture of ethanol and ethyl acetate. The described procedure gives 4-(p-toluoyl)indan-1-carboxamide as crystals melting at 188-191Co Examp ~
To 3.0 g. of 4-(p-methoxybenzoyl)indan-1-carbonitrile is added 150 g. of polyphosphoric acid and the mixture is homogenized l~y heating in an oil bath at about 120C.
After 40 mimltes of heating, the mixture is allowed to stand at room temperature overnight. The polyphosphoric acid is _ ~9_ ~ e)4~
decomposed with 200 m~. o~ water, followed by extraction with ethyl acetate. The extract is washed with wat~r and dried, The solvent is then dis~illed o-ff under reduced pressure and the residue is recrystallized from benzene.
The described procedure gives 4-(p-methoxybenzoyl)indan-1-carboxamide as crystals melting at 164-166C.

EJxample 6-(19) In 1 ~. of a 10 % aqueous solution of hydrogen peroxide is dissolved ~ g. of sodium hydroxide and, then, 20.1 g. of l-cyano 1,2 9 ~ ~ 4-tetrahydro-5-naphthoic acid is added.
The mixture is stirred at 50C for 20 hours9 after which time 250 m~. of 1~ hydrochloric acid is added. The resultant crystals are collected by filtration, washed with water and recrystallized from ethanol. The procedure gives l-carbamoyl-192,3 9 4-tetrahydro-5-naphthoic acid 9 melting point. 247-249C.

Exam~e 6-( ? ) To 500 g. of polyphosphoric acid is added 22.4 g. of ethyl l-cyano-192,3,4-te-trahydro-5-naphthoate and the mixture is stirred at 90-100C for 2 hours. Then, 1 ~. of water is added, followed by cooling. The resultan-t crystals are collected by filtration, washed with water and recrystallized from ethanol. The procedure gives ethyl l-carbamoyl-1~293, 4-tetrahydro-5-naphthoate9 melting pointO 159.5-161.5C.

Example 6-(21~
To 60 m~. of 60 ~/0 sul~uric acid is added 3.0 g. of 4-(p-chlorobenzyl)indan-l-carbonitrile and the mixture is _~ _ ~v -refluxed in a current of nitrogen gas for 2 hours. hfter cooling9 water is added and the mixture is extracted with ether. The ethereal solution is washed ~ith water and extracted with a 5 Gjo aqueous solution of potassium carbonate.
The extract is rendered acidic with hydrochloric acid and the resultant precipitate is extracted with chloroform.
The chloroform layer is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is crystallized from cyclohexane. The described procedure gi~es 4-(p-chlorobenzyl)indan l-carboxylic acid as crystals melting at l27-l2goc.

Example 6-(2?) - 6-(24) By a similar manner to Example 6-(21)9 the following compounds are produced.

Example Produced-compound Starting compound 4-benzylindan-1- 4-benzylindan-1-carboxylic acid ca~bonitril-6-(22) melting pointo 119.5-121C
(cyclohexane) _ _ ...... ___ 4-(p-methylbenzyl)- 4-(p-methylbenzyl)-indan-l-carboxylic indan-1-carbonitrile 6 (2~) acid melting point.
124.5-126.5C
(cyclohexane) 4-(p-methoxybenzyl)- 4-(p-methoxybenzyl)-indan-l-carboxylic indan~l-carbonitrile 6-(24) melting point~
109.5-111.5C
~cyclohexane) _ ~ .

~xamE_e 7 ~ ~
In 100 m~. of' dry tetrahydrofuran is dissolved 3.6 g.
of 193-dithian and while the solution is chilled to -30~
in nitrogen gas streams and stirred9 10 m~. of a 20 ~o solution of n-butyl lithium in hexane is added dropwise over a period of about 15 minutes. After the dropwise addition has been completed9 the ,solution is stirred at that temperature for 2 hours and, then, at -5C for 30 minutes.
The solution is chilled again to -20C and9 under stirring9 a solution of 7.1 g. of 4-benzoylindan-1-one in 75 m~. of dry tetrahydrofuran is added dropwise. After the dropwise addition has been completed, the mixture is stirred at that temperature for 1 hour9 a-fter which it is allowed to stand at 0C overnight. Then9 the solvent is distilled off under reduced pressure. To the residue is added 15 m~. of dilute hydrochloric acid, followed ~y extraction with ether.
The extract is washed with water and aqueous sodium chloride and9 then9 dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (500 gO silica gel, eluted with a 20.1 mixture of benzene and ethyl acetate). The described procedure gives 2-(4-benzoyl-1-hydroxy-1-indanyl )-1 9 3-dithian as an oily product. The infrared absorption spectrum (neat) of this product is in good agreement with the assumed structure 9 absorbing at 1660 cm (ketone) and 3450 cm l(hydroxyl).

~,xample ~
In 300 m~. of benzene is dissol~ed 1.4 g. of 2-(4-benzoyl-l-hydroxy-l-indanyl)-193-dithian9 followed by the , - ~?-~)4~0~
addition of 600 mg. of p-tolue~esulfonic acid. The mixture is re-fluxed for 3 hours with remo~ing the ~Jater azeotropically.
After cooling9 the solution is washed with water, aqueous sodium bicarbonate and water in the order mentioned and dried. The solvent is distilled off under reduced pressure, whereupon 2-(4-benzoyl-i-indanylidene-1,3-dithian is obtained as an oily product. This product is used in the following reaction without purification.

Example 9~
To ~,8 g. of 2-(4-benzoyl-1-indanylidene~ dithian are added 150 m~. of glacial acetic acid and 50 m~. of con-centrated hydrochloric acid and the mixture is refluxed for 3 hours, after which the solvent is distilled off under reduced pressure. The residue is extracted with ether.
The ethereal layer is washed wi-th water and extracted with 5 ~ aqueous sodium carbonate. The extract is washed with ether and rendered,acidic with hydrochloric acid. The oily precipitate is extracted with ether. The extract is washed with water and aqueous solution of sodium chloride 9 and dried. The solvent is distilled off under reduced pressure and the residue is crystallized from benzene-cyclohexane. The described procedure gives'4-benzoylindan~
l-carboxylic acid as crystals melting at 100-102C.

Fxam~le 9-(2~
In 200 m~. of ethanol is dissolved 2.0 g. of the 2-(4-benzoyl-1-indanylidene)-1,3-dithian obtained by the procedure of ~xam~le ~,and the solution is cooled with ice.

_ ~ _ ~ ~3 Hydrogen chloride gas is bubbled through the solution for 15 minutes9 after which it is allowed to stand under cooling with ice for 2 hours andg then9 at room tempera-ture over-night. The excess hydrogen chloride and solvent are distilled off under reduced pressure and, following the addition of water J the residue is extracted with ether. The extract is washed with water and dried. The solvent is distilled off under reduced pressure and t~e residue is purified by column chromatography on silica gel (200 g. silica gel 9 eluted with a 2.5 5~o solution of ethyl acetate in benzene). The described procedure gives ethyl 4-benzoylindan~l~carboxylate as an oil.
Infrared absorption spectrum (neat) 1720 cm (ester carbonyl) 1650 cm 1 (ketone carbonyl) Example 10-(1) .
In 100 m~. of dry tetrahydrofuran is dissolved 3.6 g.
of 193-dithian and9 under cooling at ~30C and stirring in a current of nitrogen gas9 10 m~. of a 20 /o solution of n~
butyl lithium in hexane is added dropwise over a period of about 20 minutes. ~fter the dropwise addition has been completed9 the mixture is stirred at the temperature mentioned for 2 hours andg then, at ~5C for 30 minutes. The solution is chilled again to -20C and, under stirring9 a solution of 8.1 g. of 4-(p-chlorobenzoyl)indan-1-one in 75 m~. of dry tetrahydrofuran is added dropwise. After the drop-by-drop addition has been completed, the mixture is stirred at the temperature mentioned for 1 hour and9 then, allowed to stand at 0C overnight. ~hen, the solvent is removed by 1~415~
distillation under reduced pressure. Dilute hydrochlorla acid is added to the residue and the mixture is extracted with ether. The extract is washed with water and aqueous solution of sodium chloride and7 then, dried. The solvent is distilled off under reduced p~essure and the residue is subjected9without being purified9 to the dehydration reaction~
Thusg the residue is dissolved in 350 m~. of benzene, and 600 mg. of p-toluenesulfonic acid is added. The solution is refluxed for 3 hours with removing the water azeotropically.
After cooling9 the solution is washed with water9 aqueous sodium bicarbonate and water in the order mentioned. The solvent is distilled off under reduced pressure and the residue is hydrolyzed9 without a purification procedure.
Thus 9 to the residue are added 150 m~. of glacial acetic acid and 50 m~. of concentrated hydrochloric acid and the mixture is refluxed for 3 hours9 after which the solvent is distilled off under reduced pressure. The residue is diluted with water and extracted with ether. The ethereal layer is washed with water and extracted with a 5 % aqueous solution of sodium carbonate. The extract is washed with ether and rendered acidic with h~-drochloric acid. The resultant precipitate is extracted with chloroform and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is crystallized from benzene-cyclohexane (3,10). The foregoing procedure gives 4-(p-chlorobenzoyl)indan-1-carboxylic acid as crystals melting at 137-139~.

_~ _ _ ~5 ~

8~4~L
~xamples _ ~ 2)_- 10 (7) By a similar manner to ~xample 10-(1), ~ollowing compounds is produced.
.
Example Produced-compound Starting compound .. . . _ _ ..
4-(p-methylbenzoyl)- 1,3-dithian n-butyl indan--l-carboxylic lithium 4-(p-methyl-10 (2) acid benzoyl)indan-l-one _ melting pointo 129.5-131~0C
(benzene-cyclohexane (8.25)) . ... _ __ _ __ 4-(p-chloro-m-methyl- 193-dithian n-~utyl benzoyl)indan-l- lithium 4-(p-chloro-carboxylic acid m-methylbenzoyl)-10-(3) me]t'ng pointo indan-l-one 115.0-116.5C
(benzene-cyclohexane _ _ (3:20)) 5-benzoyl-1,293,4- 193-dithian n-butyl tetrahydro 1- lithium 5-benzoyl-1-10-(4) naphthoic acid tetralone melting point:
164-165C(benzene) .... . .. ... _ 5-(p-methylbenzoyl)- 193-dithian n-butyl 192,3,4-tetrahydro- lithium 5-(p-methyl~
10 (5) l-naphthoic acid benzoyl)-l-tetralone _ melting point.

(cyclohexane) __ 5-(p-chlorobenzoyl)- 1,3-dithian n-butyl 192,3,4-tetrahydro-l- lithium 5-(p-chloro-naphthoic acid benzoyl)-l-tetralone 10-(6) melting pointo 152.5-153,5C
(benzene-hex~ne) indan-194-dicarboy- 193~dithian n-butyl ic acid lithium methyl 1-10-(7) melting pointo oxoindan-4-carboxylate 2~5.5-248C
_ (acetone) . ~ _ _~6 -Examp~
To 100 m~. of dry benzene are added 17.6 g. OI' l-oxo-indan-4-carboxylic acid and 22.9 g~ o-f phosphorus penta-chloride and9 after stirring for 1.5 hoursg 40 g. of aluminum chloride is added. The mixture is stirred for 5 hours, after which the product is poured into dilute hydrochloric acid and extracted with ether. The organiic layer is dried and distilled free of the solvent under reduced pressure.
The crystalline residue is recrystallized from cyclohexane.
The described procedure gives 4-benzoylindan-1-one which melts at 87-89C~

Exam~ -(2) To 100 m~. of dry toluene are added 17.6 g. of 1-oxoindan-4-carboxylic acid and 22.9 g. of phosphorus penta-chloride. The mixture is stirred at room temperature for 1.5 hours, after which time 40 g. of aluminum chloride is added. The mixture is stirred overnight and, then~ poured into 400 m~. of 3N hydrochloric acid9 ~ollowed by extraction with benzene. The organic layer is washed with water, aqueous sodium hydroxide and water in the order mentioned and dried with anhydrous rnagnesium sulfate. Tke solvent is distilled off under reduced pressure and the resultant crystalline residue is purified by column chromatography on silica gel (200 g. silica gel9 eluted wi-th chloroform).
Finally,the el~ate is recrystalliæea from acetone to give 4-(p-toluoyl)indan-1-oney melting point: 105-108C.

o~
~xam ~ 3 ~ 11-(5) By a similar manner to Example 11-(2), the following compounds are produced.

~xample Produced-compound ¦Starting compound .__ . .
4-(2,4,6-trimethyl- 1-oxoindan-4-carboxylic benzoyl)indan-l-one acid mesitylene 11-(3)1m5e9ting6pointo (benzene-hexane (1 ol)) .
5~benzoyl-3 9 4- 1~2 9 3 9 4-tetrahydro-dihydro-1(2H)- l-oxo-5-naphthoic 11-t4) naphthalenone acid benzene ' melting pointO
72.5-73.5C
~cyclohexane) ... . . _ ~
5-(p-chlorobenzoyl)- 1,2,3,4-tetrahydro-3 9 4-dihydro-1(2~I)- l~oxo-5-naphthoic 11 (5) naphthalenone acid p-chlorobenzene _ melting pointO
96-98~
(cyolohexane) . . _ Exam~le ~
To 200 m~. of chlorobenzene are added 17.6 g. of 1-oxoindan-4-carboxylic acid and 23 g. of phosphorous penta-chloride~ The mixture is stirred at room temperature for 3 hours, after which time 40 g. of aluminum chloride is added. ~he mixture is stirred at about 65C for 3 hours.
After cooling~ the mixture is poured into ice and hydrochloric acid, followed by extraction with chloroform. The extract is washed with water,a saturated a~ueous solution of sodium bicarbonate and water in the order mentioned. ~fter drying, the sol~ent is distilled off under reduced pressure and the ~L~141~04;~
residue is purified by column chromatography on silica gel (200 g. silica gel; eluted with chloroform). Finally, recrystallization from a 2005 mixture of benzene and hexane gi~es 4-(p-chlorobenzoyl)indan-1-one as crystals melting at 144~5-146Co Examples 11-~7) - 11-~10~
By a similar manner to Example 11-(6), the following compounds are produced.

__ . .~
:Example Produced-compound Starting compound .
. _ _ . _ _ . .
4-(p-chloro-m-methyl- 1-oxoindan-4-benzoyl)indan-l-one carboxylic acid 11-(7) melting pointO orthochlorotoluene 88-90C ~benzene~
cyclohexane(3:20)) __ __ . ___ . _ ................ . .... _ 4-(p-fluorobenzoyl)- 1-oxoindan-4-indan-l-one carboxylic acid 11-(8) melting point~ fluorobenzene (chloroform) _ . _ . __ .. .. ._ 4-(p-bromobenzoyl)- 1-oxoindan-4-indan-l-one carboxylic acid melting point: bromobenzene 11-(9) 154-155C
('enzene-cyclohexane . _ 5-(p-toluoyl)-3,4_ 1,2j3 9 4-tetrahydro-dihydro-1(2H)- l-oxo-5-naphthoic 11 ' naphthalenone acid phosphorus -~10) melting point. pentachloride 86-87C toluene (cyclohexane) _ Example 11~ ~

~o 5.5 gO of l-cyanoindan-~-carboxylic acid is added 80 m~. of thionyl chloride, and the mixture is allowed to --~R---- ~q ~

:~gLW4~
stand at room temperature for 15 hours. Then, the excess thionyl chloride is removed under reduced pressure. To the resultant l-cyanoindan-4-carbonyl chloride are added. 50 mQ. of dry benzene and 8.0 g. of anhydrous aluminum chloride powder and the mixture is heated at about 60C for 40 minutes. After cooling, the mixture is poured into ice-hydrochloric acid, followed by extrac-tion with ether. The extract is washed with lN hydrochloric acid and a saturated aqueous solution of sodium chloride and, then, dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (400 g. of silica gel; eluted ~ith chloroform).
The described procedure gives 4-benzoylidan-1-carbonitrile as an oily product.
Infrared absorption spectrum (neat) 1660 cm 1 (carbonyl) 2230 cm 1 ~nitrile) Nuclear magnetic resonance spectrum (CDCQ3, 60 MHz) : 4.26 (lH, t, Cl-H) Example 11-~12) To 6.0 g. of 1 cyanoindan-4-carboxylic acid is added 96 mQ. of thionyl chloride and the mixture is allowed to stand at room temperature for 15 hours. The excess thionyl chloride is removed under reduced pressure. To l-cyanoindan-4-carbonyl chloride, which is thus obtained as the residue, are added 50 mQ. of anisole, 50 mQ. of methylene chloride and 6.0 g. of anhydrous alun3inum chloride powder. The mixture is stirred at room temperature for 90 minutes. After cooling, the product is poured into ice-hydrochloric acid and extracted with ether. The extract is washed with lN hydrochloric acid and a saturated aqueous solution of sodium chloride, followed by drying. The solvent is distilled under reduced pressure and the residue obtained is purified by chromatography on a column of silica gel (700 g. silica gel; eluted with chloroform). The procedure gives 4-(p-methoxybenzoyl)indan-1-carbonitrile as crystals melting at 109 - 112C.
Example 11-(13) .

To 6.0 g. of 1-cyanoindan-4-carboxylic acid is added 96 mQ. of -4~
thionyl chloride and the mix~ure is allowed to stand at room temperature for 14 hours. The excess thionyl chloride is removed under reduced pressure. To l-cyanoindan-4-car~onylchloride, which is thus obtained as the residue, are added 50 m~. of toluene and 50 mQ. of me~hylene chloride, followed by the ad-dition of 6.0 g. of anhydrous aluminum chloride. The mix~ure is stirred at room temperature for 1 hour. After cooling, the reaction product is poured into ice-hydrochloric acid and extracted wi~h ether. The extract is washed with lN hydrochloric acid and a saturated aqueous solution of sodium chloride, followed by drying. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel ~500 g. silica gel; eluted with chloroform). The procedure gives 4-(p-toluoyl)indan-1-carbonitrile as an oily product.
Infrared absorption spectrum ~neat) 1655 cm 1 ~carbonyl) 2230 cm 1 ~nitrile) Nuclear magnetic resonance spectrum ~CDCQ3, 6MHz) : 4.2 ~lH, tJ Cl-H), 2.45~3H, s, -CH3) Example 11-~14) To 6.0 g. of 1-cyanoindan-4-carboxylic acid are added 20 mQ. of chloroform and 80 mQ. of thionyl chloride and the mixture is allowed to stand at room ~emperature for 15 hours. The excess thionyl chloride and chloroform are distilled off under reduced pressure. To l-cyanoindan-4-carbonyl chlo-ride, which is thus obtained as the distillation residue, is added 100 mQ.
of chlorobenzene, follo~ed by stirring under cooling with ice. Then, 6.a g.
of anhydrous aluminum chloride powder is added and the temperature is gradual-ly increased to about 80C, at which temperature the reaction mixture is stirred for 2.5 hours. Af~er cooling, ice-hydrochloric acid is added, fol-lowed by extraction with ether. The extract is ~ashed with water and dried.
Then, the solvent is distilled off under reduced pressure and the residue obtained is purified by column chromatography on silica gel (700 g. silica gel; eluant: chloroform). The described procedure gives 4-~p-chlorobenzoyl) indan-l-carbonitrile as an oily product.

Infrared absorption spectrum ~neat) 1660 cm 1 ~carbonyl) 2230 cm~l (nitrile) Nuclear magnetic resonance spectrum ~CDCQ3, 60 M~lz) : 4.17 (lH, t, Cl-H) Examples 11-(15) - 11-(17) By a similar manner to Example 11-~11) the following compounds are produced.
.. _ . .. _ Example Produced-compound Starting compound .. _ . _ ~_ _ I
ll-~lS) 5-benzoyl-1,2,3,4- 1-cyano-1,2,3J4-tetrah~dro-tetrahydro-l- 5-naphthoic acid naphthonitrile thionyl chloride melting point: _ benzene 91.5 - 93,5Ctn-hexane/
11-~16) 5-~p-toluoyl)- 1-cyano-1,2,3,4-1,2,3,4-tetra- tetrahydro-5-hydro-l-naphtho- naphthoic acid nitrile thionyl chloride melting point: _ toluene 72 - 73C/n-hexane/
11-(17~ 5-(p-chlorobenzyl)- 1-cyano-1,2,3,4-1,2,3,4-tetrahydro- tetrahydro-5-l-naphthonitrile naphthoic acid melting point: thionyl chloride 97 - 99C/n-hexane/ chlorobenzene . . . _ --Example 11-(18~
To 4.0 g. of 1-cyanoindan-4-carboxylic acid are added 60 mQ. of choroform and 60 mQ. of thionyl chloride and the mixture is allowed to stand at room temperature for 2 days.
The excess thionyl chloride and the chloroform are distilled off under reduced pressure and 30 g. of t-butylbenzene added to the resultant acid chloride. Then, under cooling with ice and stirring, 10 g. of aluminum chloride is added. The mixture is stirred a~ room temperature for 30 minutes~
at 50C for another 30 minutes and, then, at room temperature for 3 hours.
Ice is added to the reaction mixture, followed by extraction with benzene. The extract is washed with water and dried. Then, the solvent is distilled off under reduced pressure and the residue is purified by column chromatography (600 g. silica gel; eluted with a 100:0.5 mixture of benzene 1~480~a and ethyl acetate). The described procedure gives l-cyano-4-~p-t-butylbenzyol) indan.
Infrared absorption spectrum (neat) 2250 cm~l ~nitrile) 1660 cm 1 (ketone) Example 11-~19) To 130 mQ. of thionyl chloride is added 10.2 g. of l-carbamoylindan-4-carboxylic acid and the mixture is allowed to stand at room temperature for 14 hours.
The excess thionyl chloride is distilled off under reduced pressure.

To the l-carbamoylindan-4-carbonyl chloride obtained as the distillation resi-due are added 50 m~. of ~nzene, 50 m~. of carbon disulfide and 10.0 g. of anhydrous aluminum chloride powder, and the mixture is stirred at about 40C
for 30 minutes. After cooling, ice-hydrochloric acid is added, followed by extraction with ethyl acetate. The extract is washed with lN hydrochloric acid and a sa~urated aqueous solution of sodium chloride, followed by drying.
The solvent is distilled off under reduced pressure and the residue is puri-fied by column chromatography on silica gel /500 g. silica gel; eluted with chloroform-acetone ~7:3)~.
The described procedure gives 4-benzoylindan-1-carboxamide as crystals melting at 163.5 - 165.5C.
Examples 11-(20) -`11-~22) By a similar manner to Examples 11-~19), the following compounds are produced.

4~
. . _ _ Example Produced-compound Starting compound ~ .. ... .. _ ._ . _ 11-(20) 5-benzoyl-1,2,3,~- 1-carbamoyl-1,2,3,4-tetrahydro-l- tetrahydro-5-naphthoic naph-thamide acid melting point: benzene 145.5 - 147.5C
/cyclohexane/
. . . .. _ _ . .
11-~21) 5-~p-toluoyl)-1,2, 1-carbamoyl-1,2,3,4-3,4-tetrahydro-1- tetrahydro-5-naphthamide naphthoic acid melting point: toluene 178 - 178.5C
/ethanol/
~ . .
11-~22) 5-(p-chlorobenzoyl)- 1-carbamoyl-1,2,3,4-1,2,3,4-tetrahydro- tetrahydro-5-l-naphthamide naphthoic acid melting point: chlorobenzene 150.5 -_152.5C
_ ~ /benzene/

Example 12-(1) To 120 mQ. of carbon disulfide is added 54 g. of anhydrous aluminum chloride powder on an ice bath, followed by the dropwise addition of a solu-tion of 11.4 g. of ethyl indan-l-carboxylate in 60 mQ. of carbon disulfide.
Tbe mixture is stirred for 10 minutes, after which a solution of 42~g. of benzoyl chloride in 60 mQ. of carbon disulfide is added dropwise. After the dropwise addition has been completed, the temperature is gradually increased and the solution is stirred on reflux for 3 hours and thirty minutes to com-plete the reaction. Ice and hydrocllloric acid are addQd to the reaction mix-ture followed by extraction with ether. The extract is washed with lN hydro-chloric acid, water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in the order mentioned and, then, dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is column-chromatographed on silica gel (conditions: 2 Kg. of silica gel, eluant solvent-benzene containing 2.5 % of ethyl acetate). The first-emerging fractions rich in ethyl 4-benzoylindan-1-carboxylate are pooled separate from the ensuing fractions rich in ethyl 6-benzoylindan-l-carboxylate. The former fractions are further purified by rechromatography on a column of silica gel, whereby ethyl 4-benzoylindan-1-carboxylate is obtained as an oily product.
- 5~ -~L~)4~ 4~
Infrared absorption spectrum (neat~
1720 cm 1 ~ester carbonyl) 1650 cm 1 ~ketone carbonyl) Examples 12-~2? - 12-~5) By a similar manner to Example 12-~1), the following compounds are produced.
. __ , _ __ _ Example Produced-compound Starting compound . .. _ . --12-~2) 4-~p-toluoyl)indan-1- indan-l-carboxamide carboxamide p-toluoyl chloride melting pgint:
188 - 191 Clethanol-ethyl acetate~
. -I
12-~3) 5-benzoyl-1,2,3~4-tetra- 1,2,3,4-tetrahydro-hydro-l-naphthamide l-naphthamide melting point: benzoyl chloride 145.5 - 147.5 tcyclohexane/
.. __ .___ . ~
12-~4) 5-~p-toluoyl-1,2,3, 1,2,3,4-tetrahydro-4-tetrahydro-1- l-naphthamide naphthamide p-toluoyl chloride melting point:
178 - 178.5C
/ethanol/
_ _ 12-~5) 5-(p-chlorobenæoyl)- 1,2,3,4-tetrahydro-1,2,3,4-tetrahydro- l-naphthamide l-naphthamide p-chlorobenzoyl melting point: chloride 150.5 - 152.5C
/benzene/

Example 13-~1~
In 100 mQ~ of acetic acid is dissolved 11.1 g. o 4-benzyl indan-l-one, followed by the addition of 13.4 g. of chromic acid and 2.5 mQ. of con-centrated sulfuric acid. The mixture is stirred at room temperature for 2 hours, after which it is poured into 4 Q. of water. After 200 g. of anhydrous potassîum carbonate is added, the mixture is extracted with chloroform. The organic la~er is washed with water and dried over anhydrous magnesium sulfate.
The solvent is distilled off under reduced pressure and the oily residue is purified by column chromatography on silica gel with chloroform as the eluent and, then, recrystallized from cyclohexane. The procedure gives 4-benzoylindan-l-one melting at 87 - 89C.

~ig3i9L13~4~
Examples 13-~2) - 13-(3) By a similar manner to Example 13-~1), the following compounds are produced.

Example Produced-compound Starting compound 13-(2) 4-(p-chlorobenzoyl~- 4-~p-chlorobenzyl)-indan-l-one indan-l-one melting point: chromic anhydride /benzene-cyclohexane __ 13-(3) 4-(p-toluoyl)indan-1- 4-~p-methylbenzyl)-one _ indan-l-one _ /acetone/ chromic anhydride E mple 13- (4?
To 60 mQ. of dioxane are added 8.0 g. of 4-~p-methoxybenzyl)indan-l-carbonitrile and 2.8 g. of selenium dioxide and the mixture is refluxed for 12 hours. After cooling, ~ater is added, followed by ex~raction with chloro-form. The extract is washed with water and dried. Theng the solvent is dis-tilled off under reduced pressure and the residue is purified by column chroma-tography ~500 g. silica gel; eluted wi~h chloroform). The crude crystals thus obtained are recrystallized from benzene. The procedure gives 4-(p-methoxy-benzoyl)indan-l-carbonitrile as crystals melting at 115.5 - 117.5C.
Example 13-~5) In 100 mQ. of acetic acid is dissolved 6.7 g. of 5-benzyl-1,2,3,4-tetrahydro-l-naphthoic acid and, under cooling with ice, 3.4 g. of chromic anhydride is added. The mixture is stirred well. After stirring overnightJ
the reaction mixture is poured over 500 g. of ice and extracted with chloro-form.
The chloroform layer is washed with water and dried over anydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residual oily liquid is chromatographed on a column of silica gel equi-librated with oxalic acid with chloroform as the eluent and, then, recrystal-lized from benzene. The procedure gives 5-benzoyl-1,2,3,4-tetrahydro-1-napht~oic acid, melting point: 164 - 165&.

i~48~
Example 13-(6~
In 200 mQ. of lN aqueous sodium hydroxide is dissolved 14 g. of 5-(p-methylbenzyl~-1,2,3,4-tetrahydro-1-naphthoic acid, and a solution of 26 g.
of potassium permanganate in 800 m~. of water is added dropwise. After stir-ring overnight, the reaction mixture is rendered acidic by the addition of concentrated sulfuric acid, followed by the addition of sodium bisulfite. The mixture is extracted with chloroform and the chloroform layer is washed with uater and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the oily residue is purified by column chroma-la tography on silica gel equilibra~ed with oxalic acid and, then, recrystallized from cyclohexane. The described procedure gives 5-~p-toluoyl~-1,2,3,4-tetra-hydro-l-naphthoic acid, melting point: 102 - 103C.
Example 13- (7?
To 200 mQ. of ethyl ether is added 15 g. of 5-~p-chlorobenzyl~-1,2, 3,4-tetrahydro-1-naphthoic acid, and a solution of 5 g. of sodium dichromate in 24 mQ. of 6N sulfuric acid is added dropwise. After stirring overnight, 100 mQ. of water is added and the ethereal layer is further washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off un-der reduced pressure and the oily residue is purified by column chromatography on silica gel equilibrated with oxalic acid with chloroform as the eluent and, then~ recrystallized from benæene. The described procedure gives S-(p-chloro-benzoyl)-1,2,3,4-tetrahydro-1-naphthoic acid, melting point: 152.5 - 153.5C.
Example 13-(8) To lQ0 mQ. of acetic acid is added 6.6 g.of 5-benzyl-1,2,3,4-tetra-hydro-l-naphthamide and, under cooling with ice, 3.4 g of chromic anhydride is added. The mixture is stirred well. After stirring overnight, the reaction mixture is poured over 500 g. of ice and the resultant crystals are collected by filtration. This is subjected to column chromatography on silica gel using chloroform as the eluent and the eluate i5 recrystallized from cyclohexane.
The procedure gives 5-benzoyl-1,2,3J`4-tetrahydro-1-naphthamide, melting point:
145.5 - 147.5C.

D4~
Example 13-~9) To 60 m~. of dioxane are added 6.3 g. of 4-benzylindan-1-carboxylic acid and 2.8 g. of selenium dioxide and the mlxture is refluxed for 12 hours.
After cooling~ water and chloroform are added and the insolubles are filtered off. The filtrate is extracted with chloroform and the chloroform layer is extracted with 5% aqueous potassium carbonate. The extract is decolorized with activated carbon and rendered acidic with hydrochloric acid. The pre-cipitate is extracted with chloroform and ~he extract is washed with water and dried. The solvent is distilled off under reduced pressure and the resi-due is crystallized fiom a 20:7 solvent mixture of cyclohexane and benzene.
The described procedure gives 4-benzoylindan-1-carboxylic acid as crystals melting at 100 - 102C.
Examples 13-(10? - 13 ~12) By a similar manner to Example 13-~6), th0 following compounds are produced.
: _ Example Produced compound Starting compound 13-~10) 4-(p-toluoyl)indan-1- 4-~p-methylbenzyl)-carboxylic acid indan-l-carboxylic melting point:_ acid 130 - 131.5C/benzene-cyclohexane(8.25)~
~ --------- I
13-~11) 4-~p-chlorobenzoyl)- 4-~p-chlorobenzyl)-indan-l-carboxylic indan-l-carboxylic acid acid melting point:
137 - 139C/benzene-cyclohexane(3:10)/
. . ... ____ .
13-(12) 4-~p-methoxybenzoyl)- 4-~p-methoxybenzyl)-indan-l-carboxylic indan-l-carboxylic acid acid melting point:
136.5-138C/benzene/ _ _ Example 13-~13) To 150 mQ. of acetone is added 12.5 g. of 6-benzylindan-1-carboxamide, followed by the dropwise addition of a solution of 5 g. of sodium dichromate in 24 mQ. of 6N sulfuric acid. After the addition has been completed, the mixture is stirred overnight. Then, 200 mQ. of water is added and the acetone is distilled off under reduced pressure. The residue is extracted with ethyl ~L~4l5 04~
acetate. The extract is washed with water and dried, followed by removal of the solvent by distillation under reduced pressure. The residue is purified by column chromatography ~500 g. of silica gel; eluted with a 7:3 solvent mix-ture of chloroform and acetone) and the resultant crude crystals are recrys-tallized from benzene. The procedure gives 6-benzoylindan-1-carboxamide as crystals melting at 195 - 197C.
~ E_e 13-(14) In 100 mQ. of acetic acid is dissolved 7.3 g. of ethyl 4-benzylindan-l-carboxylate andJ under cooling with ice, 3.4 g. of chromic anhydride is ad-ded. After the mixture is stirred overnight, the reaction mixture is poured over 500 g. of ice and extracted with chloroform. The extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography ~700 g. silica gel; eluted with a 40:1 mixture of benzene and ethyl acetate). The procedure gives ethyl 4-benzoylindan-l-carboxylate as an oily product.
Infrared absorption spectrum (neat) 1720 cm 1 (ester carbonyl) 1650 cm 1 (ketone carbonyl) Example 14-(1) Sodium ethoxideJ prepared from 1.1 g. of sodium metalJ is dissolved in a mixture of 24 mQ. of dry ethanol and 48 mQ. of dry dimethoxyethane and, under cooling with ice-water and stirring, the resultant solution is added dropwise to a 120 mQ. of dry dimethoxyethane solution dissolving 9.5 g. o 4-benzoylindan-l-one and 9.4 g. of N-(p-toluenesulfonylmethyl) isonitrile over a period of 20 minutes. After the dropwise addition has been completed, the mixture is further stirred at the same temperature for 30 minutes and at room temperature for 3.5 hours. Following the addition of water, the reaction mix-ture is extracted with ether and the extract is washed with water and dried.
The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel Ll Kg. of silica gel; eluant- benzene-ethyl acetate (50:1~T. The described procedure gives 4-benzoylindan-1-car-bonitrile as an oily product.

- 5~ -~lJ4~
Infrared absorption spectrum (neat) 1660 cm~l (car~onyl) 2230 cm 1 ~nitrile) Nuclear magnetic resonance spectrum (CDC~3, 60 MHz) : 4.26 ~lH, t, Cl-H) Examples 14-~2) - 14-(10 By a similar manner to Example 14-~1), the following compounds are obtained.
. ._ _ _ , Example Produced-compound Starting compound _ _ . .
14-(2) 4-~p-toluoyl)indan- 4-~p-toluoyl)indan-1-l-carbonitrile one IR 1665 cm 1 carbonyl, N-~p-toluenesulfonyl-2225 cm l~nitrile) methyl)isoni~rile 14-(3) 4-~p-fluorobenzoyl)- 4-(p-fluorobenzoyl)-indan-l-carbonitrile indan-l-one IR 1655 cm 1 -1 N-~p-toluenesulfonyl-¦
~carbonyl), 2230 cm methyl)isonitrile ~nitrile) ..... _ . _ . .___ 14-~4) 4-~p-chlorobenzoyl)- 4-~p-chlorobenzoyl)-indan-l-carbonitrile indan-;-one melting point: N-~p-toluenesulfonyl-116 - 118C/benzene- methyl)isonitrile cyclohexane~l:10)~
.. _ . ,.... ... . . _ _ ..
14~(5) 4-~p-bromobenzoyl)- 4-~p-bromobenzoyl)-indan-l-carbonitrile indan-l-one melting point: N-~p-toluenesulfonyl-114 - 116C/benzene- methyl)isonitrile hexane-cyclohexane ~3:20:20)/
_ .
14-~6~ 4-~p-chloro-m-methyl- 4-~p-chloro-m-methyl-benzoyl~indan-l- benzoyl)indan-l-one carbonitrile N-~p-toluenesulfonyl-oily product methyl)isonitrile I~ 1660 cm l~carbonyl), 2240 cm l~nitrile) 14-(7) 4-~2,4,6-tri-methyl- 4-~2,4,6-trimethyl-benzoyl)indan-l- benzoyl)indan-l-one carbonitrile N-~p-toluenesulfonyl-melting point:_ methyl)isonitrile 133.5 - 135C~cyclo-hexane-hexan~T
_ . -14-~8~ 5-benzoyl-1,2,3,4- 5-benzoyl-3~4-dihydro-tetrahydro-l- 1~2H)naphthalenone napththonitrile N-~p-toluenesulfonyl-melting point: methyl)isonitrile 91.5 - 93.5C/~exane~
._ .
Cont'd.

- 60 _ 1C14~
.~ _ _ I
Example Produced-compound Starting compound . . . _ _ 14-~9) 5-~p-toluoyl)-1,2,3, 5-(p-toluoyl)-3,4-4-tetrahydro-l- dihydro-1(2H)-naphthonitrile naphthalenone melting point: _ N-(p-toluenesulfonyl-72 - 73C/hexane/ methyl)isonitrile ._ 14-(10) 5-(p-chlorobenzoyl)- 5-~p-chlorobenzoyl)-1,2,3,4-tetrahydro- 3,4-dihydro-1~2H)-l-naphthonitrile naphthalenone melting point: _ N-(p-toluenesulfonyl-97 - 99C/ hexane/ methyl)ixonitrile . . _ _ _ ___ .
Example 14-(11) Sodium ethoxide, prepared from 1.4 g. of sodium metal, is dissolved in a mixture of 30 mQ. of dry ethanol and 60 mQ. of dry dimethoxyethane and, under cooling with ice and stirring, the resultant solution is added dropwise to a 150 mQ. of dry dimethoxyethane solution dissolving 8.2 g. of ethyl 1-oxoindan-4-carboxylate and 12 g. of N-(p-toluenesulfonylmethyl)isonitrile over a period of 35 minutes. After the dropwise addition has been completed, the mixture is stirred at the same temperature for 35 minutes and, then, at room temperature for 5.5 hours. Following ~he addition of water, the reaction mix-ture is extracted with ether and the extract is washed with water and dried.
The solvent is distilled off under reduced pressure and the residue is puri-fied by column chromatography on silica gel (1 Kg. of silica gel; eluant:
benzene-ethyl acetate ~50:1)). Recrystallization from cyclohexane gives ethyl l-cyanoindan-4-carboxylate as crystals melting at 93 - 95.5C.
Example 14-~12) By a similar manner to Example 14-~11), ethyl ester of l-cyano-1,2,3,4-tetrahydro-5-naphthoic acid is produced as an oily substance from ethyl ester of 1,2,3,4-tetrahydro-1-oxo-5-naphthoic acid and N-(p-toluene-sulfonylmethyl)-isonitrile.
Infrared absorption spectrum (neat) 1720 cm 1 ~carbonyl), 2240 cm~l (nitrile) Nuclear magnetic resonance spectrum (CDC~3, 100 MHz) ~ : 1.36(3H, t, -CH3~, 4.00~1H, t, Cl-H), 4.33~2H, q, O-CH2-) (34~L
Example 14-(13) In 80 m~. of dry dimethoxyethane are dissol~ed 5.2 g. of 4-(p-chlorobenzyl)indan-l-one and 6 g. of N-~p-toluenesulfonylmethyl~isonitrile and while the solution is stirred under cooling with ice, a solution of 0.72 g. of sodium metal in a solvent mixture of 20 mQ. of dry ethanol and 40 mQ.
of dry dimethoxyethane is added dropwise over a period of about 30 minutes.
After the drop-by-drop addition has been completed, the mixture is stirred under cooling ~ith ice for 1 hour and~ then, at room temperature for 3 hours.
After the reaction has been completed, 800 mQ. of dilute hydrochloric acid are added, followed by extraction with ether. The extract is washed with aqueous sodium chloride and dried. The solvent is distilled off under reduced pres-sure and the residue is purified by column chromatography (600 g. of silica gel; elution with a 100:1 mixture of benzene and ethyl acetate). The described procedure gives 4-(p-chlorobenzyl)indan-1-carbonitrile as an oily product.
Infrared absorption spectrum ~neat) 2250 cm 1 (nitrile) Nuclear magnetic resonance spectrum (CDC~3 solution, 60 MHz) : 2.0-3.0 (4H, m, -CH2-CH2-) ~ : 3.85 (2H, s, Ar-CH2-Ar) ~ : 4.02 (lHJ t, /CH-CN) : 6.8-7.4 (7H, m,aromatic protons) ExamRles 14-(14) - 14-(16) By a similar manner to Example 14-(13), the following compounds are produced.
~ . .. _ .
Example Produced compound Starting compound ... .__ I
14-(14) 4-benzylindan-1- 4-benylindan-1-one carbonitrile melting point:

_n-hexan_~
_ ._ . . . _ .. _ 14-~15) 4-(p-methylbenzyl)- 4-(p-methylbenzyl)_indan-l-carbinitrile indan-l-one melting point:

/n-hexane/

Cont'd.

1~4~
. .... ... .~
Example Produced compound Starting compound _ _ . ._ 14-(16) 4-p-methoxybenzyl)- 4-(p-methoxybenzyl)-indan-l-carbonitrile indan-l-one NMR(CDC~3, 100 ~UIz) ~:2.2-3.0(4H,m,-C~2-CH2-), 3.63(3~,s, -OCH3), 3.80~2H,s, ~-CH2-Ar), 3.96(1H, t, >CH-CQ) 6.7-7.3 (7H,m, aromatic) _ Example 15-(1) In 50 mQ. of ether is dissolved 2.7 g. of 4-benzoyl-indan-1-carboxy-lic acid and, then, an ethereal solution of diazomethane is added until the yello~ color of the solution has not disappeared. The solution is then allowed to stand for 30 minutes, after which the excess diazomethane and the ethér are distilled off. The methyl 4-benzoylindan-1-carboxylate thus obtained as the distillation residue is dissolved in 50 mQ. of dimethylsulfoxide and under stirring, the solution is added dropwise to 100 mQ. of dimethylsulfoxide con-taining 1.5 g. o~ sodium hydride over a period of 15 minutes.
After the dropwise addition has been completed~ the mixture is further stirred for 2.5 hours and, then, a solution of 15.0 g. of methyl iodide in 30 mQ. of dimethylsulfoxide is added dropwise over a period of 30 minutes. After the dropwise addition has been completed, the mixture is further stirred for 2.0 hours. The mixture is rendered acidic with dilute hydrochloric acid and, then, extracted with ether. The extract is washed with water and dried. Then3 the solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel ~300 g.
silica gel; eluted with a 40:1 mixture of benzene and eth~l.acetate). The described procedure gives methyl 4-benzoyl-1-methylindan-1-carboxylate as an oily product.
Elemental analysis: ClgH1803 Calcd. C, 77.53; H, 6.16 Found C, 77.34; H, 6.10 Example 15-(2) By a similar manner to Example 15-(1), the following compounds are produced.

~(3 4~
.... .. _ _ __ . . ..
Exam~le Produced-compound Starting compound . .._. _ 15-~2) 4-~enzoyl-1-methyl- 4-benzoylindan-1-indan-l-carboxamide carboxamide melting pgint: methyl iodide 109 - 110 C/b~nzene-hexane ~1:1)/

Example 15-(3) In 50 mQ. of ether is dissolved 3.0 g. of 4-(p-chlorobenzoyl)indan-l-carboxylic acid and the esterification is carried out by adding an ethereal solution of diazomethane.
The excess diazomethane and the ether are distilled off under re-duced pressure. The resultant methyl 4-(p-chlorobenzoyl)indan-1-carboxylate is dissolved in 50 mQ. of dimethylsulfoxide and under stirringJ the solution is added dropwise to lOOmQ. of dimethylsulfoxide containing 1.5 g. of sodium 1~ hydride over a period of 15 minutes. After the dropwise addition has been completed, the mixture is stirred for 3.0 hours and, then, a solution of 15.0 g. of methyl iodide in 30 mQ. of dimethylsulfoxide is added dropwise over 25 minutes. After the dropwise addition has been completed, the mixture is further stirred for 2.0 hours.
It is then rendered acidic with dilute hydrochloric acid and extract-ed with ether. The extract is washed ~ith water and dried. The solvent is then distilled off under reduced pressure and the residue is purified b~
column chromatography ~300 g. silica gel; eluted with a 40:1 mixture of ben-7ene and ethyl acetate). The procedure gives methyl 4-(p-chlorobenzoyl)-1-2~ methylindan-l-carboxylate as an oily product. This product is dissolved in a solvent mixture o~ 35 mQ. ethanol and 35 mQ. water and, then, 1.6 g. of potas-sium hydroxide is added. The mixture is refluxed for 2 hours, after which the e~hanol is distilled off. Following the addition of 100 mQ. of water, the residue is washed with ether. The water layer is rendered acidic with hydrochloric acid and the resultant precipitate is extracted with chloroform.

The extract is washed with water and dried. The solvent is then distilled off under reduced pressure and the residue is crystallized from a 7:20 mix-ture of benzene and hexane. The procedure gives 4~(p-chloroben7oyl~
methylindan-l-carboxylic acid as colorless crystals melting at 146.5 - 149.5C.

- 6~ -4~
Exam~le 15-~4) In 50 mQ. of ether is dissolved 2.8 g. of 4-~p-toluoyl)-indan-1-carboxylic acid and the esterification is carried out by adding an ethereal solution of diazomethane.
The excess diazomethane and the ether are distilled off under re-duced pressure. The resultant methyl 4-(p-toluoyl)indan-1-carboxylate is dissolved in 50 m~. of dimethylsulfoxide and under stirring, the solution is added dropwise to 100 mQ. of dimethylsulfoxide containing 1.0 g. of sodium hydride over a period of 15 minutes. After the dropwise addition has been completed, the mixture is stirred for 2.5 hours and, then, a solution of 15.0 g. methyl iodide in 30 mQ. dimethylsulfoxide is added drop by drop over a period of 25 minutes. After the dropwise addition has been completed, the mixture is further stirred for 2.5 hours. It is then rendered acidic with dilute hydrochloric acid and extracted with ether. The extract is washed with water and dried. Finally the solvent is distilled off under reduced pres-sure and the residue is purified by column chromatography (300 g. silica gel;
eluted with a 40:1 mixture of benzene and ethyl acetate). The procedure gives ; methyl 4-~p-toluoyl)-1-methylindan-1-carboxylate as an oily product. This product is dissolved in a solvent mixture of 35 mQ. ethanol and 35 mQ. water 2~ and, then, 1.5 g. of potassium hydroxide is added. The mixture is refluxed for 2 hours, after which time the ethanol is distilled off under reduced pres-sure. Following the addition of 100 mQ. of water, the residue is uashed with ether. The water layer is rendered acidic with hydrochloric acid and the precipitate is extracted with chloroform. The extract is washed with water and dried.
Finally the solvent is distilled off under reduced pressure and the residue is crystallized from a 1:4 mixture of benzene and hexane. The de-scribed procedure gives 4-~p-toluoyl)-1-methylindan-1-carboxylic acid as crystals melting at 99 - 101C.
Example 16-(1~
In 35 mQ. of ethanol is dissolved 1.5 g. of ethyl 4-benzoylindan-1-carboxylate, followed by the addition of a solution of 800 mg. of potassium - 65 _ hydroxide in 35 mQ. of water. The mixture is heated on reflux for 2 hours, after which it is concentrated under reduced pressure.
The residue is dissolved in 300 mQ. of water and the water layer is washed with ether and made acidic with hydrochloric acid. The precipitate is extracted with chloroform and the organic layer is washed with water and dried over anhydrous sodium sulfate. Then, the solvent is distilled off, which leaves an oil of 4-benzoylindan-1-carboxylic acid. This product is dissolved in a 7:20 solvent mixture of benzene and cyclohexane and the solution is al-lowed to stand, whereupon crystals separate out gradually, melting point:
101.5 - 103C.
Example 16-~2) To 500 mQ. of concentrated hydrochloric acid is added 15.9 g. of 4-benzoylindan-1-carboxamide and the mixture is refluxed for 5 hours. After cooling, the solution is extracted with chloroform and the chloroform layer is washed with water and extracted with a lN aqueous solution of sodium hydroxide.
The extract is decolorized with activated carbon and rendered acidic by the addition of hydrochloric acid, followed by extraction with chloroform. The extract is washed with water and a saturated aqueous solution of sodium chlo-ride and, then, dried.
The solvent is distilled off under reduced pressure and the residue is crystallized from benzene cyclohexane (7:20). The described procedure gives 4-benzoylindan-1-carboxylic acid as crystals melting at 100.5 - 102C.
Example 16-~3) To 13.3 g. of 4-benzoylindan-1-carboxylic acid is added 50 mQ. of thionyl chloride and the mixture is left standing at room temperature over-night. Then, the excess thionyl chloride is distilled off under reduced pres-sure. Ether is added to the residue and, then, ammonia gas is bubbled through the reaction mixture. The resultant precipitate is recovered by filtration, washed with water and dried. Recrystallization from benzene gives 4-benzoylin-dan-l-carboxamide as crystals melting at 164 -166 C.
Example 16-~4) To 250 mQ. of ethanol is added 20 mQ. of concentrated sulfuric acid, 8Q~9~
followed by the addition of 13.3 g. of 4-benzoylindan-1-carboxylic acid. The mixture is refluxed for 5.5 hours. After cooling, the ethanol is distilled off under reduced pressure and water is added to the residue, followed by extraction with ether. The ethereal layer is washed with a 5% aqueous solu-tion of sodium hydroxide and a saturated aqueous solution of sodium chloride and, then, dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel ~eluted with chloro-form). The described procedure gives ethyl 4-benzoylindan-1-carboxylate as an oily product.
Infrared absorption spectrum (neat) 1720 cm 1 (ester carbonyl) 1650 cm 1 (ketone carbonyl) Example 6-~5) To 3 g. of 4-benzoylindan-1-carboxylic acid are added 25 mQ. of chloroform and 25 mQ. of thionyl chloride. The mixture is allowed to stand overnight and, then, the excess thionyl chloride and the solvent are distilled off under reduced pressure. To the acid ~hloride thus obtained is added 50 mQ.
of benzene. Then, 50 mQ. of water, 7.0 g. of hydroxylamine hydrochloride and 4.0 g. of sodium hydroxide are further added. The mixture is stirred at room temperature for 4 hours. Following the addition of water, the reaction mix-ture is extracted with ethyl acetate and the extract is washed with water and dried. The solvent is then distilled off under reduced pressure and the resi-due is recr~stallized from benzene. The procedure gives N-hydroxy-4-benzoylin-dan-l-carboxamide as crystals melting at 159.5 - 160.5C.
Example 16-(6) To 3.0 g. of 4-benzoylindan-1-carboxylic acid are added 25 m~. of chloroform and 25 mQ. of thionyl chloride. The mixture is allowed to stand at room temperature overnight and, then, the excess thionyl chloride and the solvent are distilled off under reduced pressure. To the acid chloride thus obtained are added 50 mQ. of benzene and 10 mQ. of aqueous methylamine solution ~40%). The mixture is stirred at room temperature for 4 hours, after which water is added, followed by extraction with ethyl acetate. The extract is washed with water and dried. Finally the solvent is distilled off under re-duced pressure and the residue is crystallized from a mixture of benzene and ether. The procedure gives N-methyl-4-benzoylindan-1-carboxamide as crystals melting at 145 - 146.5C.
Example 16-~7) To 3.0 g. of 4-benzoylindan-1-carboxylic acid are added 25 mQ. of chloroform and 25 mQ. of thionyl chloride. The mixture is allowed to stand at room temperature overnight and the excess thionyl chloride and the solvent are distilled off under reduced pressure. To the acid chloride thus obtained are added 50 mQ. of benzene and 5 mQ. of morpholine, followed by stirring at room temperature overnight.
Then, water is added and the mixture is extracted with benzene. The extract is washed with lN hydrochloric acid and then, with water and dried.
The solvent is distilled off under reduced pressure and the residue is puri-fied by column chromatography (300 g. silica gel, eluted with a 100:3 mixture of chloroform and acetone). The procedure gives 4-benzoylindan-1-carboxyl morpholide as an oily product.
Infrared absorption spectrum ~neat) 1655 cm 1 (amide and ketone) Example 16-~8) In a solution of 450 mg. of sodium hydroxide in 20 mQ. of water, there is dissolved 3.35 g. of 4-benzoylindan-1-carboxylic acid and the in-solubles are filtered off. To the filtrate is added a solution of 950 mg. of aluminum chloride hexahydrate in 100 mQ. of water and the mixture is stirred for 3 hours. The resultant crystals are collected by filtration, washed with water, dried and washed with ether. The procedure gives aluminum tris(4-benzoylind~n~-car~ox~lateis obtained as crystals melting at 225 - 230C.
Example 16-~9) In 50 mQ. of ether is dissolved 2.66 g. of 4-benzo~lindan-1-carbox~-lic acid. To this is added an ethanolic solution of sodium ethoxide prepared from 230 mg.`of sodium metal and 10 mQ. of ethanol. The mixture is allowed to stand for 20 minutes, after which time the solvent is distilled off under re-~L~41~3~4L~
duced pressure.
The resultant powder is washed with acetone, whereupon sodium 4-benzoylindan-l-carboxylate is obtained as a powder melting at 238 - 240C
~in a sealed tube).
Example 16-(10) To 14.0 g of 4-(p-toluoyl)indan-1-carboxamide is added 500 mQ. of concentrated hydrochloric acid and the mixture is refluxed for 3.5 hours.
After cooling, the mixture is extracted with chloroform and the chloroform layer is washed with water and extracted with a 5~ aqueous solution of potas-sium carbonate. The extract is decolorized with activated carbon and rendered acidic with hydrochloric acid~ The precipitate is extracted with chloroform.
The extract i5 washed with water and dried. The solvent is distilled off under reduced pressure and the residue is crystallized from an 8:25 mixture of benzene and cyclohexane. The described procedure gives 4-~p-toluoyl)indan-l-carboxylic acid as crystals melting at 130 - 131.5C.
Examples 16 ~ - 16-(14) B~ a similar manner to Example 16-~2), the following compounds are produced.
. ._ Example Produced-compound Starting compound . _ .__ I
16-~11) 4-(p-methoxybenzoyl)- 4-(p-methoxybenzo~l)-indan-l-carbox~lic acid indan-l-carboxamide melting point:
137.5 - 138.5C
/benzene~
.__ 16-(12) 5-benzoyl-1,2,3,4- 5-benzoyl-1,2,3,4-tetrahydro-l- tetrahydro-l-naphthoic acid naphtha~ide melting point:

_benzene~/

16-(13) 5-(p-chlorobenzoyl)- 5-(p-chlorobenzoyl)-1,2,3,4-tetrahydro-1- 1,2,3,4-tetrahydro-1-naphthoic acid naphthamide melting point:
152.5 - 153.5C
- /benzene-hexane~
_ .. _ .. _ 16-(141 4-(2,4,6-trimethyl- 4-(2,4,6-trimethyl-benzoyl)indan-l- benzoyl)indan-l-carboxylic acid carboxamide melting point:
191.5 - 193C/benzene-cyclohexane(l.l)~
_ _ 4~
Example 16-~14) To 5aQ mQ. of concentrated hydrochloric acid is added 17.6 g. of 5-~p-toluoyl)-1,2,3,4-tetrah~dro-1-naphthamide and the mixture is r0fluxed for 5 hours. After cooling, it is extracted with chloroform and the chloro-form layer is washed with water and extracted with lN sodium hydroxide. The extract is decolorized with activated carbon, rendered acidic with hydrochloric acid and extracted with chloroform. The chloroform layer is washed with water and dried. The solvent is distllled off under reduced pressure and the crys-talline residue is recrystallized from benzene. The procedure gives 5-~p-1~ toluoyl)-1,2,3,4-tetrahydro-1-naphthoic acid, melting point: 102 - 103C.
Example 17-~1~
To 60 mQ. of acetone are added 3.2 g. of 4-benzoyl-indan-1-carboxylic acid and 1.70 g. of cinchonidine and the mixture is shaken to dissolve. The solution is allowed to stand at room temperature overnight and the resultant crystals are recovered by filtration and recrystallized twice from acetone.
~`he procedure gives Q-4-benzoylindan-1-carboxylic acid cinchonidine salt as colorless crystals melting at 189 - 192C, ~a]D2 - 132.2 (c=l, CHCQ3).
This product is dissolved in chloroform and the solution is shaken twice with portions of dilute hydrochloric acid to remove the cinchonidine.
The chloroform layer is washed with water and dried over magnesium sulfate, The solvent is distilled off under reduced pressure. The procedure gives Q-4-benzoylindan-1-carboxylic acid as a colorless oilJ ~D2 _ 66.4 ~c=l, MeOH).
The mother liquor after harvest`of the first crop of crystals is concentrated undsr reduced pressure and the residue is shaken with 1.7 g. of cinchonidine and 120 m~. of acetonitrile under stirring and heating, after which the mixture is allowed to stand at room temperature overnight. The resultant crystals are collected by filtration and recrystallized three times from acetonitrile. The described procedure gives d-4-benzoylindan-1-carboxylic acidcin~honidln9 salt as colorless crystals melting at 180 - 183C, ~]D2 11.2 ~c=l, CHCQ3)-~04l3(1 4~1l This product is dissolved in chloroform and the solution is shaken twice with portions of hydrochloric acid to remove the cinchonidine. The chloroform layer is washed with water and dried over magnesium sulfate. Finally, the solvent is distilled off under reduced pressure to obtain d-4-benzoylindan-1-carboxylic acid as a colorless oil~3 D2 66.4 (c=l, Me~H).

Example 17- (?) To 100 mQ. of acetone are added 3.1 g. of 4-~p-chlorobenzoyl)indan-l-carboxylic acid and 1.5 g. of cincho-nine and the mixture is warmed to dissolve. Then, with the addition of a small amount of activated carbon, the solution is filtered. The filtrate is allowed to stand at room tem-perature overnight and, then, at 0-5C for another night.
The crystals formed are recovered b~ filtration and re-cr~stallized from acetonitrile. The described procedure gives Q-4-~p-chlorobenzoyl)indan-1-carboxylic acid cinchonine salt as colorless crystals, melting point: 193 - 1~6C, ~]23 33.6 (c=l, CHCQ3)-The above product is dissolved in chloroform and the solution is shaken twice with portions of dilute hydro-chloric acid to remove the cinchonine. The chloroform layer is washed with water and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and cyclo-hexane is added to the residue. The resultant crystals are collected by filtration and recrystallized from a 1:4 mixture of benzene and cyclohexane. The procedure gives Q-4-(p-chlorobenzoyl)indan-l-carboxylic acid as colorless crystals ~048~4~

melting at 121-122C. ~a)~ -66.9 (c=19 MeOH) _xam~le 17-~3) In 100 me. of acetone are dissolved 3.1 g. of 4-(p-chlorobenzoyl)indan-l-carboxylic acid and 1.5 gO of cincho-nine under heating and, with the addition of a small amount of activated carbon, the solution is filtered. The filtra-te is allowed to stand at room temperature overnight and, then, at 0-5C again overnight. The resultant crystals are filtered off. The filtrate ls concentrated under reduced pressure and the residue is dissolved in 50 m~. of acetonitrile.
The solution is allowed to stand for a week and the crystals formed are filtered off. The filtrate is concentrated under reduced pressure and the residue is dissolved in 150 m~. of chloro*orm. The solution is washed twice with dilute hydro-chloric acid and once with water, and dried by the addition of magnesium sulfate. The solvent is distilled of~ under reduced pressure a~d the residue is dissolved in 80 m~. of acetonitrile~ followed by the addition of 0.6 g. of Q-a-phenethylamine. The mixture is allowed to stand overnight and the resultant crystals are collected by filtration and recrystallized five times from acetonitrile.
The described procedure gives d-4-(p-chlorobenzoyl)-indan-l-carboxylic acid ~-a-phenethylamine salt as colorless crystals melting at 148-150C~ ~a)24 62.2 (c=l, CHC~3).
This product is dissolved in 150 m~. of chloroform and the solution is washed twice with dilute hydrochloric acid and once with water and dried by the addition of magne-sium sulfate. The solvent is distilled off under reduced _ ~9;L. --pre~sure and cyolohexane is added to the residue. ~he resultant crystals are oollected by filtration and recrystal-lized twice from a 1.4 mixture o~ benzene and cyclohexane.
~he procedure gives d-4-(p-chlorobenzoyl)indan-carboxylic acid as colorless crystals melting a-t 121-122C, ~)24 65~0 (c=l~ MeOH).

_ ~ _

Claims (16)

New Claims

1. A method for producing a compound of general formula:

(I) wherein R1 is a phenyl group which may be substituted by a lower alkyl having 1 to 4 carbon atoms, a lower alkoxy having 1 to 4 carbon atoms, a halogen, a mono- or di-alkyl?amino having 1 to 3 carbon atoms, an acylamino having 2 to 3 carbon atoms or an acyloxy having 2 to 3 carbon atoms, n is 1 or 2, and R is hydroxyl, alkoxy having 1 to 6 carbon atoms, phenyloxy, benzyloxy, amino, hydroxylamino, hydrazino, mono- or di-alkylamino having 1 to 3 carbon atoms the alkyl moieties of which may be substituted by hydroxyl, phenylamino the benzene ring of which may be substituted by methyl, a 5- to 6-membered cyclic amino containing one or two nitrogen atoms, benzylamino the benzene ring of which may be substituted by methyl, phenethylamino, mono- or di-methylhydrazino or phenylhydrazino, or when R is hydroxyl and thus forms a carboxyl group in the 1-position, a salt with an alkali metal, an alkaline earth metal, aluminum or ammonium, or said carboxyl group may form a salt with an amine selected from the group consisting of mono- or di-alkylamine having 1 to 3 carbon atoms the alkyl moieties, of which may be substituted by hydroxyl, phenylamine the benzene ring of which may be substituted by-methyl, a 5- to 6-membered cyclic amine containing one or two nitrogen atoms, benzylamine the benzene ring of which may be subsituted by methyl, phenethylamine, mono- or di methyl-hydrazine and phenylhydrazine, which comprises (a) reacting a compound of general formula:

wherein n and R have the same meanings given above with a compound of general formula:

wherein R1 has the same meaning given above or an acid halide, an acid anhydride, or an ester at the carboxyl function, (b) subjecting a compound of general formula:

wherein R1 and n have the same meanings given above to solvolysis, (c) reacting a compound of general formula:

wherein W is hydroxy, halogen, alkoxy or p-nitrophenyloxy and n and R have the same meaning given above, with a compound of general formula:

wherein R1 has the same meaning given above ( d) oxidizing a compound of general formula:

wherein R1, R and n have the same meanings given above, or (e) subjecting a compound of general formula:

wherein R1 and n have the same meaning given above and R3 and R4 are each a substituted mercapto group; R3 and R4 together may form a ring, to solvolysis.

2. A method as claimed in claim 1, wherein n is 1.

3. A method as claimed in claim 1, wherein 4-benzoylindan-1-carbonitrile is subjected to hydrolysis to give 4-benzoylindan-1-carboxylic acid.

4. A method as claimed in claim 1, wherein 4-(4-chlorobenzoyl)indan-1-carbonitrile is subjected to hydrolysis to give 4-(4-chlorobenzoyl)indan-1-carboxylic acid.

5. A method as claimed in claim 1, wherein 4-(4-methylbenzoyl)indan-1-carbonitrile is subjected to hydrolysis to give 4-(4-methylbenzoyl)indan-1-carboxylic acid.

6. A method as claimed in claim 1, wherein 4-(4-methoxybenzoyl)indan-1-carbonitrile is subjected to hydrolysis to give 4-(4-methoxybenzoyl)indan-1-carboxylic acid.

7. A method as claimed in claim 1, wherein 2-(4-benzoyl-1-indanylidene)-1, 3-dithian is subjected to hydrolysis to give 4-benzoylindan-1-carboxylic acid.

8. A method as claimed in claim 1, wherein 2-[4-(4-methylbenzoyl)-1-indanylidene]-1, 3-dithian is subjected to hydrolysis to give 4-(4-methylbenzoyl)indan-1-carboxylic acid.

9. A compound of the general formula:
(I) wherein R1 is a phenyl group which may be substituted by a lower alkyl having 1 to 4 carbon atoms, a lower alkoxy having 1 to 4 carbon atoms, a halogen, a mono- or di-alkylamino having 1 to 3 carbon atoms, an acylamino having 2 to 3 carbon atoms or an acyloxy having 2 to 3 carbon atoms, n is 1 or 2, and R is hydroxyl, alkoxy having 1 to 6 carbon atoms, phenyloxy, benzyloxy, amino, hydroxylamino, hydrazino, mono- or di-alkylamino having 1 to 3 carbon atoms the alkyl moieties of which may be substituted by hydroxyl, phenylamino the benzene ring of which may be substituted by methyl, a 5- to 6-membered cyclic amino containing one or two nitrogen atoms, benzylamino the benzene ring of which may be substituted by methyl, phenethylamino, mono- or di-methylhydrazino or phenylhydrazino, or when R is hydroxyl and thus forms a carboxyl group in the 1-position, a salt with an alkali metal, an alkaline earth metal, aluminum or ammonium, or said carboxyl group may form a salt with an amine selected from the group consisting of mono- or di-alkylamine having 1 to 3 carbon atoms the alkyl moieties, of which may be substituted by hydroxyl, phenylamine the benzene ring of which may be substituted by methyl, a 5- to 6-membered cyclic amine containing one or two nitrogen atoms, benzylamine the benzene ring of which may be substituted by methyl, phenethylamine, mono- or di-methylhydrazine and phenylhydrazine, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.

10. A compound according to claim 9, wherein n is 1, whenever prepared by the process claimed in claim 2, or by an obvious chemical equivalent thereof.

11. 4-Benzoylindan-1-carboxylic acid, whenever prepared by the process claimed in claim 3, or by an obvious chemical equivalent thereof.

12. 4-(4-Chlorobenzoyl)indan-1- carboxylic acid, whenever prepared by the process claimed in claim 4, or by an obvious chemical equivalent thereof.

13. 4-(4-Methylbenzoyl)indan-1-carboxylic acid, whenever prepared by the process claimed in claim 5, or by an obvious chemical equivalent thereof.

14. 4-(4-Methoxybenzoyl)indan-1-carboxylic acid, whenever prepared by the process claimed in claim 6, or by an obvious chemical equivalent thereof.

15. 4-Benzoylindan-1-carboxylic acid, whenever prepared by the process claimed in claim 7, or by an obvious chemical equivalent thereof.

16. 4-(4-Methylbenzoyl)indan-1-carboxylic acid, whenever prepared by the process claimed in claim 8, or by an obvious chemical equivalent thereof.