BE615395A - - Google Patents

Description

       

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  * METHODS AND COMPOUNDS OF THE INDOL SERIES "

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The present invention relates to new chemical compounds. It relates more particularly to a new class of compounds of the indol series. More particularly still, the invention relates to novel lower α- (3-indolyl) -aliphatic acids containing an aromatic carboxylic acyl group (eg an aroyl or heteroaroyl group) containing less than three fused rings attached to the. nitrogen atom of the indol ring. The invention also relates to salts, esters, and amide derivatives of these compounds. Finally, the invention relates to the synthesis of these compounds.



   The novel aroyl and hetero-aroyl indolyl aliphatic acids according to the present invention correspond to the following structural formula:
 EMI2.1
 in which A is an aroyl or hetero-aroyl radical, B is hydrogen, a lower alkyl or lower alkenyl radical and M is an -OH, -NH2 or OZ radical, Z being a hydrocarbon radical or a cation.In the preferred compounds, D in the formula given above denotes hydrogen or a hydrocarbon radical containing less than 9 carbon atoms. These compounds can be considered as functionally substituted indols. They can also be described as being lower α- (3-indolyl) -aliphatic acids having an aroyl or hetero-aroyl radical in the 1 position (that is to say the nitrogen atom) of the ring. indol.



   In a more limited embodiment, the invention encompasses the indolyl aliphatic acids corresponding to the following formulas:

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 EMI3.1
 in which R3 is hydrogen, lower alkyl or lower alkenyl, Rest is hydrogen or a hydrocarbon radical containing less than 9 carbon atoms and M is -OH, 0NH2 or OZ, Z being a cation or a hydrocarbon radical, Ar is an aryl or substituted aryl radical and Het is an aromatic heterocyclic ring.



   In the preferred compounds according to the invention, R- denotes hydrogen or a lower alkyl, lower alkoxy, nitro, amino or substituted amino radical. As examples of alkyl and alkoxy radicals, mention may be made of methyl, ethyl, propyl, t-butyl, methoxy, ethoxy, i-propoxy, etc. radicals. R5 is not limited to this class of substituents and can, if desired, denote other substituents, such as hydrogen or aryl, aryloxy, hydroxy, mercapto, halo, pseudohalo, especially CF3. CHF2 haloalkyl, nitro, amino, alkylamino, acylamino haloalkyl cyano, sulfamyl, sulfoxide, amino-methyl, substituted amino methyl, carboxy and carbalkoxy.



   An important feature of the new compounds described in this specification resides in the presence of an aryl or heteroaroyl radical attached to the nitrogen atom occupying position 1 of the indole ring. These acyl groups can be further substituted in the aromatic nucleus by hydrocarbon residues or radicals or by functional substituents.



  Thus, suitable aroyl substituents are the benzoyl and naphthoyl radicals. The aromatic rings of these groups may contain, and in fact do contain, preferred compounds; at least one functional substituent. This substituent can be an optionally etherified hydroxyl radical (hydrocarbonoxy), such as

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 a lower alkoxy radical, for example methoxy, ethoxy, isopropoxy, allyloxy, propoxy, an aryloxy or aralkoxy radical, for example phenoxy, benzyloxy, halobenzyloxy, lower alkoxy, benzyloxy, etc. It can also be a nitro radical, a halogen such as chlorine, bromine, iodine or fluorine, an amino radical or a substituted amino radical.

   As examples of substituted amino radicals, mention may be made of acylamino, amine oxide, ketimines, urethanes, lower alkylamino, di-lower alkyllamino amidine, acylated amidine, hydrazine or substituted hydrazine, alkoxyamine or sulfonated amine. In addition, the substituent in question may be a mercapto or substituted mercapto radical, in particular an alkylthio radical, such as the methylthio radical:., Ethylthio or propylthio, or else an arylthio or aralkylthio radical, such as the benzylthio or phenylthio radical. .

   The aroyl radical occupying the N-1 position can, if desired, be haloalkyl, for example using a trifluoromethyl, trifluoroethyl, perfluoroethyl, ss-chloroethyl or the like, acylated, for example with an acetyl radical, propionyl, benzoyl, phenylacetyl, trifluoroacetyl and the like acyl groups, or it may contain a haloalkoxy or haloalkylthio radical. The invention also encompasses compounds, wherein the alkyl radical contains a sulfamyl, benzylthiomethyl, cyano, sulfonamido or dialkylsulfonamido radical.

   In addition, it may contain a carboxy substituent or a derivative of such a substituent, such as an alkali metal salt or a lower alkyl ester of the carLoxy radical, an aldehyde, an azide, an amide, a hydrazide, etc. or an aldehyde derivative of the type represented by acetals or thioacetals. In preferred compounds, the N-1 aroyl radical is a benzoyl radical and the functional substituent is in the para position of the six member ring.



   The N-1 group can also be a heteroacyl substituent and, more precisely, a heteroaroyl substituent of the formula:

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 EMI5.1
 in which Het denotes a heteroaromatic radical with 5 or 6 elements having, preferably, less than 3 fused rings. As examples of such radicals, mention may be made of furyl, thienyl, pyrryl, thiazolyl, thiadiazolyl, pyrazinyl, pyridyl, alkylpyridyl, pyrazolyl, imidazolyl, oxazolyl, pyrimidinyl and isoxazolyl radicals.



   The α- (3-indolyl) -aliphatic acids described herein are preferably lower aliphatic acids, such as α- (3-indolyl) derivatives of acetic, propionic, butyric, valerian, ss-. halopropionic, acrylic, 4-pentenoic and the like.



   The esters, salts and amides of these aliphatic acids also fall within the scope of the present invention. Esters are important intermediates in the synthesis of free acids and in themselves, in many cases, are important end products. Among the preferred esters, mention may be made of lower alkyl esters, such as methyl, ethyl, propyl or t-butyl esters, p-halobenzyl benzyl esters, as well as analogous esters containing less than 9 carbon atoms.



   The salts of these new lower α- (1-aroyl or hetero-aroyl-3-indolyl) -aliphatic acids can be obtained by treating the free acid with a base under moderate conditions. In this way, alkali metal salts, such as sodium and potassium, as well as gold aluminum salts can be obtained. magnesium or alkaline earth metal salts such as barium and calcium. Salts of organic amines, such as dimethylamine, morpholine, methyl cyclohexylamine or glucosamine can be obtained by reacting the acid with the appropriate organic base.

   The amides which may be represented by the formulas I and II given above are advantageously prepared, by first preparing the amide

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 EMI6.1
 of an α- (3-indolyl) -aliph'atiqne lower unsubstituted in position 1, and then acylating this compound by the method described later. These amides are advantageously obtained by reacting the free acid with urea or by treating the appropriate acid chloride with ammonia or with an alkyllamide (so as to form an N-alkyllamide). .



   Position 2 of the indole ring (R in formulas I and II) may be occupied by hydrogen, although it is preferred that in this position of the molecule be present a hydrocarbon radical containing less than 9. carbon atoms. Lower alkyl radicals, such as methyl, ethyl, propyl or butyl radicals, are the most satisfactory, but indols substituted in position 2 by phenyl or benzyl radicals fall within the scope of the present invention, as well as the indols. indols comprising, in position 2, an unsaturated aliphatic radical, such as an allyl or vinyl radical or a cycloaliphatic residue of the cyclohexyl type.



   As examples of compounds which fall within the scope of the present invention and which can be prepared by the process described below, there may be mentioned the following compounds:
 EMI6.2
 iethyl-a- (1-p-chlorobenzoyl-2-methy? - $ - methoxy-3-indolyl) - methyl acetate, a- (lp-chlorobenzoyl) -2,5- <2imethyl-3-indō lyl) -methyl acetate, a- (lp-methyl-thiobenzoyl-2-methyl-5-methoxy-3-indolyl} -methyl acetate, a- (lp-chlorobenzoyl- 2-methyl-5-methoxy-3-indolyl acid ) -propionic, .cY- (1-p-chlorobenzoyl- 2-methyl-5-methoxy-3-indolyl) -acetamide, oc- (1-benzoyl-2-methy2- $ -methoxy-3-indolyl) -acetamide , a-1- (2,4-dichlorobenzoTl) -2-methyl-5¯raethoxy-3-i.ndolyl.'7-propionate, ethyl a-l1- (2'-thénoyl) -2-methyl- Methyl S-methoxy-3-indoly17-acetate, rl- (4I-thiazolyl) -2-ethyl-5-methyl-3-indolyJ. / R-propionate, a-1- (2'-furoyl.- 2,

  Benzyl 5-dimethyl-3-indolyl7-propionate, tx rl- (ni.cot: i.noyl) -2-methyl - $ - propyl-methoxy-3-indolyl7-acetate, a tl- {naphthoy3j-2-methyl -µ-methoxy --- indoly-acetate

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 EMI7.1
 benzyl, ts-I- (4t-thà.azolyl) -2-methyl - $ - methoxy-3-indolypropionamide, etc.



   The lower a- (1-aroyl or hetero-aroyl-3-indolyl) -aliphatic acids and the derivatives of these acids described in this specification are synthesized by acylation of the acid.
 EMI7.2
 α- (3-Indolyl) -aliphatic lower or an ester or amide of this acid having the desired substituents in the 2 and 5 positions of the ring. It is preferred to carry out the acylation on an ester or on an amide of lower aliphatic acid. If it is desired to obtain the free acid, the ester can be converted to the free acid under suitable reaction conditions. It has been found that the 1-proyl or netero-aroyl substituent hydrolyzes readily, under the conditions normally employed for the saponification of an ester to free acid.



  For this reason, care must be taken to convert the lower aliphatic cc- (1-aroyl or heteroar-yl-3-indolyl) acid esters into the corresponding free acids. It has been found that a suitable method of achieving this transformation is to acylate the benzyl ester and then proceed with hydrogenolytic removal of the benzyl ester. Or, other esters, such as tert.-butyl esters, which are subject to selective removal by other treatments, in particular by heating to a temperature above 210 ° C. or by heating to a temperature of 25 to 110. C, in the presence of a catalytic amount of an aryl sulfonic acid or other acids, can be used.

   When preparing amides of these acids, instead of an ester, the free acids are formed by reacting the amides with a stoichiometric amount of nitrous acid in an inert solvent.



   The acylation reaction is preferably carried out by
 EMI7.3
 treating the starting <x- (3-indolyl) -aliphatic acid with an alkali metal hydride, such as sodium hydride, so as to form, for example, a sodium salt, which is then placed intimately in contact with a halide

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 EMI8.1
 ¯daciciearoyl flu hrtéro arovlique, in an anhydrous solvent.



    It is preferred to use solvents such as dimethylformamide, mixtures of benzene and dimethylformamide, benzene, toluene and xylene. It is preferred to carry out the acylation at room temperature, although lower temperatures can be employed, if the particular reagents used are likely to undergo decomposition.



   Another method of acylating the 1-position is to use a phenolic ester of the acylating acid, for example p-nitrophenolic ester. The latter ester is prepared by mixing the acid with p-nitrophenol in tetranitrofuran and slowly adding the dicyclohexylcarbodiimide in tetrahydrofuran. The dicyclohexylurea which forms is separated by filtration and the nitrophenolic ester is recovered from the filtrate.



  It is also possible to use the anhydride, the azide or the thiophenolic ester of the acylating acid. Whichever method is used, the acylation of the starting a- (3-indolyl) -aliphatic acid is effected by forming a sodium salt of this material with sodium hydride in an anhydrous solvent and adding - both the nitrophenyl ester.
 EMI8.2
 



  The compounds of the tX- (1-aroyl or hetero-aroyl-3-indolyl) -aliphatic acid type lower corresponding to the formulas I and II given above have high anti-inflammatory activity, while they are effective in preventing and inhibit the formation of granuloma / tissue. Some of these compounds possess this activity to a high degree and are valuable for the treatment of arthritic and skin conditions, as well as similar conditions which are susceptible to treatment with anti-inflammatory agents. In addition, the compounds according to the present invention possess high anti-pyretic activity.

   In these various applications, these compounds are normally administered by the buccal route, in tablets or capsules, the optimum dose obviously depending on the particular compound.

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 used, as well as the type and severity of the condition to be treated. Although the optimum amounts of the compounds according to the invention to be used in this manner will depend on the compound used, as well as the particular type of condition being treated, the doses of the preferred compounds according to the invention, by the oral route, are between 1.0 and 2000 mg per day, in the fight against arthritic conditions, the particular dose depending on the activity of the specific compound used, as well as the sensitivity to this compound of the patient.



   Indolyl aliphatic acids used as starting material in the reaction described above and which respond to
 EMI9.1
 the following formula: 3 R5-CHCOY.-wNR2 H in which R2 ′ R3 and R5 have the meanings indicated above and Y denotes a hydrocarbonoxy radical containing less than 9 carbon atoms or an -NH2 ′ radical can be synthesized from various ways.

   When R2 denotes hydrogen, a methyl radical, an aryl radical or an aralkyl radical, it is preferred to form these compounds, by reacting an appropriately substituted phenylhydrazine III) and a compound of formula IV, so as to form an intermediate phenylhydrazone, which undergoes cyclization under the reaction conditions,
 EMI9.2
 so as to form the indolyqe compound: p II R, 3 R- -NHNH2 + R2CCH2CHCOY ###### III R3 IV R5- '-CHCOY oNR 2 H V

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 in which R3 'R 1 and Y have the meanings indicated above, while R2 denotes hydrogen or a methyl, aryl or aralkyl radical.

   The reaction normally takes place in a lower alkanol, such as methanol, ethanol, isopropanol and butanol containing an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or l. 'acetic acid, or in an aqueous mineral acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid or concentrated acetic acid or other Lewis acids, such as ZnC12' BF .-, SnC14 and the like. The acid acts as a catalyst in the condensation and cyclization reactions leading to the formation of the indole compound V. When the compound
IV is an ester, the nature of the ester is not critical, although it is preferred to use a lower alkyl ester, such as methyl, ethyl, propyl, isobutyl or isopropyl ester.

   To avoid the possibility of transesterification, the alcohol used as a solvent is preferably the same as that from which the ester is derived. When R 2 deigns hydrogen, the aldehyde should be used in the form of an acetal, for example in the form of methyl Y, Y-dimethoxy butyrate. An acid addition salt of the phenyl hydrazine reactant, such as the hydrochloride, is normally preferred over the free base, for practical reasons, although these salts and the base are equivalent for the reaction itself.



   The formation of α- (3-indolyl) -aliphatic acid or an ester thereof takes place at elevated temperatures. Good results are obtained by heating the reaction mixture under reflux for at least about 15 minutes. Longer reaction times are not detrimental and can be applied, if desired. The desired compound is recovered from the reaction mixture and purified by techniques such as solvent extraction, chromatography and / or distillation. Since the esters of formula V are solids at low point

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 They are conveniently purified by distillation under reduced pressure. These esters are saponified by treatment with an alkali metal hydroxide.



   The substituted phenylhydrazines employed as starting materials in this synthesis are prepared by known methods; A suitable process is that of diazotizing the substituted aniline in an appropriate manner, to obtain the diazo compound, which is treated with stannous chloride, so as to form a tin complex, the latter being decomposed into phenylhydrazine. by reaction with sodium hydroxide.



   The 1-acyl group contained in α- (1-acyl-3-indolyl) -aliphatic acids and their esters according to the present invention is, as already pointed out, readily hydrolyzed under the conditions normally used for saponification. an ester. For this reason, the benzyl ester of intermediate α- (1-Unsubstituted-3-indolyl) aliphatic acids is a suitable starting material.

   These latter compounds are obtained by forming free α- (1-unsubstituted-3-indolyl) aliphatic acid and by esterifying this compound with benzyl alcohol in an inert solvent, in the presence of an acid catalyst, such as as sulfuric acid, arylsulfonic acid, etc. The intermediate benzyl ester can also be synthesized directly, using the appropriate levulinic acid benzyl ester in the original synthesis of the indole ring, this ester can also be obtained by ester exchange catalyzed by means of. a base, from other esters.

   After acylation of the indole nitrogen atom of these intermediate benzyl esters, the benzyl radical can be easily removed by hydrogenolysis, this process leaving the 1-acyl radical intact.



   It is also possible to first obtain an indol of the formula:
 EMI11.1
 

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   @ in which R2 and R5 have the meaning indicated above, then to introduce the rest of the carboxylic acid in the position
3. This is done by treating the indol of formula VI under the conditions of the Mannich reaction with a mixture of formaldehyde and dialkylamine, so as to obtain a substituted gramine, the latter compound then being reacted with a. alkali metal cyanide within a lower alkanol, hydrolysis being finally carried out using a strong base, such as sodium or potassium hydroxide.



   Although this process of introducing the residue of aliphatic acid into position 3, after elaboration of the indol nucleus, is obviously applicable, in general, to compounds having the structure shown above, it is particularly suitable. to prepare the compounds according to the present invention, in which R2 denotes an alkyl radical other than a methyl radical, in particular a 2-ethyl, 2-propyl, 2-allyl radical or the like. The compounds of formula V1 are readily prepared by applying the methods described in the literature.



   The compounds in which R5 denotes an acyloxy radical, a halogen, a cyano group or a carboxy, c @ balcoxy, alkyl, aryl, aralkyl, nitro or hydrocarbonoxy radical are prepared by synthesis starting from a 2-nitrotoluene or d ' a substituted 2-nitrobenzaldehyde.



   The synthesis of the various compounds according to the present invention which have, on the indol ring, a substituent in position 5, of which a nitrogen atom is attached to the homocyclic ring of indol is generally based. on the use, as a starting compound, of the nitro compound in position 5, the nitro group being transformed into the desired substituent. This transformation can be done before or after acylation of position 1, depending on the extent to which the desired substituent at position 5 is likely to hinder acylation. If such hindrance or interference is possible, the 1-acylation should occur on 5-nitroindol and the nitro group should be

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 subsequently transformed to the desired substituent.

   This transformation can take place in a number of ways.



  Reduction of the 5-nitro group gives a 5-amino group. By reaction of the amino group with alkyl halides ,. mono- and di-alkylamino radicals are obtained. If the alkyl halide is a dihaloalkane, for example 1,4-dibromobutane, a heterocyclic ring, for example a pyrrolidino ring, is formed. Likewise, bis (ss-chloroethyl) ether will give an N-morpholinic compound. The alkylation can also be carried out simultaneously with a reduction, for example using formaldehyde, as well as Raney nickel and hydrogen. Acylation can also be carried out on 5-amino compounds or on 5-nitro compounds (with simultaneous reduction), to give 5-acvlamino compounds.

   The 5-amino group can be reacted with isocyanates to form 5-ureido compounds.



   The following examples are given by way of illustration and not by way of limitation.



   EXAMPLE 1 A. Ethyl a- (2-methyl-5-methoxy-3-indolyl) -propionate.



   A solution of 25 g of p-methoxyphenylhydrazine hydrochloride and 20 g of ethyl a-methyl ethyl levulinate in 250 ml of 2 N ethanolic HCl is heated in a steam bath. for a few minutes. An exothermic reaction occurs with separation of ammonium chloride. The reaction vessel is removed from the steam buri and the mixture is allowed to reflux gently until the initial reaction ceases. The mixture is again heated on a steam bath under reflux for 30 minutes, after which it is concentrated in vacuo to a volume of about 80 ml. The concentrate is diluted with about 400 ml of water and extracted with ether.

   The ethereal extract obtained is washed with saturated sodium bicarbonate solution and with water, then it is dried over anhydrous sodium sulfate.

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  The dried solution is filtered and evaporated to a dark brown syrup which is purified by chromatography on one pound of acid washed alumina in a 2.25 inch diameter column, using , mixtures of ether and petroleum ether (v / v 1: 9 to 1: 1) as eluent. The light yellow syrup thus obtained is distilled in a short path distillation apparatus and the product collected boils at 150-
 EMI14.1
 153 C (0.25 mm). The distillate of a- (2-methyl - $ - nrethoxy-3-indolyl) - ethyl propionate crystallizes by trituration with petroleum ether, PF53-55.5 C. By recrystallization from a mixture of ether and petroleum ether, the melting point does not change.



  Calculated for C15H19O3N: C = 68.94%; H = 7.33%; N, 5.36%.
 EMI14.2
 



  Found: C = 69.23%; Ii = 7.31 /; N = 5.6O #.



   When the methyl, propyl, isopropyl or benzyl ester of α-methyl levulinic acid is employed in the above-described reaction, instead of the ethyl ester, one obtains
 EMI14.3
 Methyl α (2-methyl = 5-methocy-3-indolyl) -propionate, propyl α-92-methyl-5-methoxy-3-indolyl) -propionate, α- ( Isopropyl or isopropyl 2-methyl-5-methoxy-3-indolyl) -propionate
 EMI14.4
 Benzyl oc- (2-niethyl-5-methoxy-3-indolyl) -propionate respectively. When an ester of levulinic acid is used as a starting material in the process described above, o-n
 EMI14.5
 obtains the corresponding ester of (-(2-methyl-5-methoxy-3-indolyl) -acetic acid.



  B. ethyl ot- (2,5-dimethyl-3-indolyl) -propionate.



   20 g of p-methylphenylhydrazine hydrochloride and 20 g of ethyl α-methyl levulinate are added to 250 ml of 2N ethanol HCl and the mixture is heated until the reaction is initiated. When the initial exothermic reaction ceases, the mixture is heated under reflux for about 30 minutes, after which it is concentrated in vacuo to about one-third of its volume. 400 ml of water are then added and the

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 aqueous solution with ether. The ethereal extracts are washed successively with sodium bicarbonate solution and with water, after which they are dried over sodium sulfate.



  The ethereal solution is concentrated to a small volume in vacuo and chromatographed on acid washed alumina (one alumina live in a 2.25 inch inside diameter cone). The material eluted with mixtures of ether and ether
 EMI15.1
 of petroleum (volume / volume): 1: at 1: 1 is distilled in a short path distillation apparatus. Lra - 2,5-dimethyl-3-indolyl) - ethyl propionate distills at 150-170 (bath temperature) 1 mm and crystallizes by trituration with petroleum ether, m.p. 88-88.5 C.



   When lower alkyl or benzyl levulinate is used instead of ethyl α-methyl levulinate, one obtains
 EMI15.2
 lower alkyl or benzyl- (2,5-dimethyl-3-indolyl) -acetate.



     EXAMPLE- 2
 EMI15.3
 ethyl a- (1-p-methylthiobenzoyl-2-methyl-5-methoxy-3-indolyl) - propionate.



   A suspension of 2.3 g (0.046%) of a 50% solution of sodium hydride in mineral oil in 250 ml of dimethylformamide is stirred for 20 minutes under nitrogen while cooling with ice. 8.64 g (0.035 mol) of ethyl α- (2-methyl-5-methoxy-3-indolyl) -propionate are then added and the mixture is stirred for 20 minutes. 8.6 g (0.046
 EMI15.4
 mole) of p-methylthiobenzoyl chloride in 50 ml of dimethylformamide are added dropwise over 30 minutes. The mixture is stirred in an ice bath for 5 hours under nitrogen. It is then poured into a mixture of 500 ml of ether, 5 ml of acetic acid and one liter of ice water. The organic products are extracted with 3 x 300 ml of ether.

   The ether solutions are combined and washed with plenty of water, then dried over sodium sulfate. The solution is filtered, then evaporated almost to dryness, after which the residue is
 EMI15.5
 loaded onto a column of 300 g of alumina. A (1-p-methylthio-

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 EMI16.1
 ethyl benzo3rl-2-ra'ethyl-5¯Héthbxy-3- "iîtdoiyi} -prèpionate is eluted with a 10% solution of ether in petiole ether. This ester is obtained in the form of d 'a yellow oil, by concentrating the eluates to dryness.



   The starting p-methylthiobenzoyl chloride is obtained by heating a mixture of 27 g (0.15 mole) of p-methyl-thiobenzoic acid and 21.4 g (0.18 mole) of thionyl chloride in a steam bath for 1 hour. We then add enviror
20 ml of benzene and heat to boiling. The remaining solution is centrifuged and diluted with petroleum ether.



   --On cooling the acid chloride separates, R.F. 40-44 C.
 EMI16.2
 



  When methyl 2-methyl - $ - methoxy-3-indolyl) -aceatate is used as the starting material in the above process, (lp-methylthiobenzo ± 1) -2-methyl -5 - is obtained. methyl 3-methoxy-indolyl) -acetate.



   EXAMPLE 3
 EMI16.3
 methyl ec- (1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl) -acetate.



   To 3.9 g (0.078 mol) of a 51% solution of sodium hydride in mineral oil suspended in 150 ml of distilled dimethylformamide, in a 1 liter bottle with 3 nozzles, is added while stirring, at 0 C, 9.5 g (0.040 mol) of (2-methyl-5-methoxy-3-indolyl) -ethyl acetate in 150 ml of dimethylformamide.Dn stir the mixture for 1 hour, after which is added dropwise over 30 minutes, 9.1 g (0.052 mol) of p-chlorobenzoyl chloride in 50 ml of dimethylformamide. The reaction mixture is stirred for a further 30 minutes at 0 C, then left to stand for 12 hours in the cold.



   The reaction mixture is then filtered and the solids are washed with ether. Ether is added to the filtrate which is washed with water and dried over sodium sulfate.



  After removing the sodium sulfate by filtration, about 75 g of acid washed alumina is added to the ethereal solution and the mixture is concentrated to dryness. Coated alumina

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 EMI17.1
 of indol is placed at the top of a column of 400 g of alumina. This column is eluted with petroleum ether containing increasing amounts of ethyl ether.
 EMI17.2
 Methyl a- (1-p-Chlorobenzoyl-2-methyl-5-methoxy-3-indolyl) -acetate is eluted with a 15% solution of ether in petroleum ether. These latter eluates are combined and concentrated to dryness.

   By recrystallization of the residue from a mixture of benzene and petroleum ether, substantially pure cc- (lp-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl) -acetate is obtained. , PF 99-100 C.



   The execution of the method described above with a-
 EMI17.3
 Ethyl (2-methyl-5-methoxy-3-indolyl) -propionate or benzyl cc- (2,5-dirnethyl-3-indolyl) -propionate, respectively gives α- ( ethyl lp-chlorobenzoyl-2-methyl-5-rqethoxY-3-indolyl) -propionate and <x- (lp-chlorobenzoyl-2,5-dimethyl-3-indolyli; -prop2Lonate of benzyl.



  EXAMPLE 4 cC-L 1- (0- methyl-p-methylthiobenzoyl) -2-mPthyl - $ - methoYy- 3-indoly -pripionate
A mixture of 100 ml of. dimethylformamide, 5.2 g
 EMI17.4
 (0.02 m) ethyl a- (2-methyl-5-methoxY-3-indolyl) -propionte and 1.2 (0.025 m) sodium hydride in mineral oil (dispersion 50%) is stirred in an ice bath, under nitrogen for 1 hour. A solution of 4.0 g (0.02 mole) of 2-methyl-4-dmethylthiobenzoyl chloride (prepared from acid, m.p.



    159-162 C and thionyl chloride) and 25 ml of dimethylformamide) is then added over 30 minutes, after which stirring is continued for 16 hours at room temperature.



  The mixture is poured into 300 ml of water, extracted with ether, after which the ethereal solution is washed with water, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. . The residual oil is dissolved in petroleum ether (60-70 C) and chromatographed on 250 g of alumina washed with acid.

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 EMI18.1
 



  Ethyl oc r1- (o-methyl-p-methylthiobenzorl) -2-methyl-5-methoxy-3-indolyl¯7-propionate is eluted using a 15% solution of ether in petroleum ether and isolated as an oil. I. R. # CHC135.75 (CO), 5.94 (CO), 6.2l, 6.73.



   EXAMPLE 5
 EMI18.2
 x- (1-Benzoyl-2-methyl - $ - methoxy-3-indolyl) -ethylpropionate To a solution of 5.22 g of a- (2-methyl-5-methoxy-3-indolyl) - ethyl propionate in 20 ml of dimethylformamide, a suspension of 1.2 g of a 51% solution of hydride is added.
 EMI18.3
 sodium in mineral oil in 40 ml of ethylformamide.



  After stirring for 1 hour at room temperature, a solution of 2.88 ml of benzoyl chloride in 10 ml of dimethylformamide is added, so as to initiate a moderate exothermic reaction with precipitation of sodium chloride. The reaction mixture is stirred for 6 hours, after which it is left to stand overnight. The mixture is poured into approximately 200 g of ice and extracted three times with ether. The ethereal solution is washed with water and sodium bicarbonate, after which it is dried over potassium bicarbonate. After filtration, the solution is evaporated until a si- rop is obtained and chromatographed on a column of 100 g of acid-washed alumina, using mixtures of benzene and petroleum ether (2 : 1 to 3: 1 v / v.) As elaunt.

   We obtain in total
 EMI18.4
 1.06 g of ethyl α- (1-Benzoyl-2-methyl-5-methoxy-3-indolyl) -propionate, as a thick yellow oil. The infra-red spectrum does not reveal NH absorption near the 2.8-3 region but reveals strong absorptions of C = 0 to 5.8 and 5.95 #, these absorptions characterizing the ester and amide functions which are respectively present in the compound.



   EXAMPLE 6
 EMI18.5
 ethyl a- (1-p-chlorobenzoyl-2-methyl - $ - methoxy-3-W dolyl) -pripiona-te te¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯
13 g of (2-methyl-5-methoxy-3-indolyl) -propionate e-

 <Desc / Clms Page number 19>

 thyl are added to a mixture of 2.5 g of a 51% solution of sodium hydride in mineral oil in 240 ml of dimethylformamide. The resulting mixture is stirred at room temperature for 30 minutes, after which a solution of 8.75 g of p-chlorobenzoyl chloride in 50 ml of dimethylformamide is added slowly over 40 minutes. The mixture then stirred in an ice bath for 4 hours under nitrogen. It is then poured into a mixture of ether, acetic acid and water, as described in Example 2.

   By then operating in the above-described manner and using a column of 200 g of alumina for chromatography, the elution taking place with a 1: 1 mixture of benzene and petroleum ether, a- (lp-chloro-
 EMI19.1
 Ethyl benzoyl-2-raethyl-5-metihoxy # 3 # indolyl) -propionate.



  EXAMPLE 7 (1-Benzoyl-2-methyl-5-methoxy-3-indolyl) -acetic acid A. A solution of 15 g of (2-r.iethyl - $ - methoxy-3-indolyl) - methyl acetate and 0.2 g of sodium in 60 ml of benzyl alcohol is slowly fractionated over 4.5 hours in a Vigreux column to remove methanol. The excess benzyl alcohol is then distilled off at 60 ° C. (2.5 mm), which gives a residue of 18.6 g of (2-methyl-5-me-
 EMI19.2
 Benzyl thoxy-3-indolyl) -acetate.



   B. 10 g of the benzyl ester obtained above are added to 3.3 g of an emulsion containing 51% sodium hydride in mineral oil in 260 ml of dimethylformamide according to the procedure. - ratory of Example 2. This mixture is treated as described in this example in 7.7 ml of p-chlorobenzoyl chloride and the reaction mixture is treated as described above, using a chromatographic column. 340 g of alumina eluting with 20-30% solutions of ether in petroleum ether.

   From these eluates, benzyl (1-benzoyl-2-methyl-5-methoxy-3-indolyl) -acetate is obtained m.p. 91-92 ° C.

 <Desc / Clms Page number 20>

 C. they g of the ester obtained in B is added to 20 ml of acetate. of ethyl containing a drop of acetic acid and the mixture is
 EMI20.1
 Catalytically reduced at room temperature in the presence of palladium on charcoal. When the reduction is complete, the catalyst is separated by filtration and the filtrate is evaporated until a crystalline residue is obtained.

   This residue is crystallized from aqueous ethanol so that acid is obtained.
 EMI20.2
 1-Benzoyl- (2-methyl-5-methoxy-3-indolyl) -aceticue, PF 172-173 C. The residue obtained by removing the reaction solvent can also be purified by dissolving in chloroform and precipitation by adding ether. of petroleum to chloroform solution.



   EXAMPLE 8
 EMI20.3
 ethyl dr (1-n-fluorobenzoyl-2-methyl-5-methoxy-3-indolyl) -propionate.



  10.5 g of - (2-methyl-5-methoxy-3-indolyl) -prionate ethyl are added to a suspension of 2.2 g of a 51% emulsion of sodium hydride in mineral oil in 240 ml of dimethylformamide. After stirring for 25 minutes 7.5 g of p-fluorobenzoyl chloride are added slowly over 40 minutes, after which the resulting mixture is stirred for 40 minutes at 10-15 C. The mixture is stirred for 40 minutes. reaction mixture is then poured into 400 ml of water and the product is isolated as described in Example 4, so that a- (lp- -propionate
 EMI20.4
 Substantially pure kfluorobenzoyl-2-methyl-5-methoxy-3-indolyl) ft'ethyl.



   When the process described above is put into service in
 EMI20.5
 reacting the sodium salt of methyl a- (2-ntethyl-5-methoxy-3-indolyl) -propionate with p-trifluoromethylbenzoyl chloride to give c1- (1-p- methyl trzfluoromethylbenzoyl-2-methyl-5-methoxy-3-indolyl) -propionate.



   EXAMPLE 9
The N-1 aroyl hetero-aroyl derivatives correspond to
 EMI20.6
 --- dantS-ae'1'a- (2-methyl-S-methoxY-3-indo1y1) -benzylpropionate

 <Desc / Clms Page number 21>

 
 EMI21.1
 and benzyl (2-methyl-5-inethoxy-3-indolyl) -acetate are obtained by reacting together, in equimolar amounts and according to the procedure of Example 3, the sodium salts of these esters and one of the following compounds:

   3,4,5-trimethoxy-benzoyl, p-phenoxy benzoyl chloride, chloride
 EMI21.2
 p-trifluoroacetyl benzoyl, p-'r¯Id-dimethylsulf a-myl benzoyl chloride, 3-furoyl chloride, 1-methylimidazol-5-carboxylic acid chloride, 1,3-dimethyl acid chloride -
 EMI21.3
 2,3-Dihydro-2-oxoimidazol- ° -earbaxylic, 2-carboxy.- 1-methyl-benzimidazol chloride, 5-fluoro-2-thenoyl chloride, 3-thenoyl chloride, $ -ni chloride. tro-2-furoyl 3-carboxy, ¯ 1-mPthylindazo7.e chloride oo:

  3-arboxy, .. 1-methyl-6-nitro-indazole chloride 4 -carboxy d, oxazolj 2-carboxychloride .- benzoxazolj4-carboxychloride - thiazoly2-earboxy-thiazol chloride, 4-carboxychloride 2-phenylthiazol, 4-carboxy-2-benzylmercaptothiazol chloride, p-acetylbenzoyl chloride, N, N-dimethyl-p-carboxamidobenzoyl chloride, p-
 EMI21.4
 cyanobenzyl, p-carbomethoxyben zo chloride, ie, p-formylbenzoyl chloride, p-trifluoromethyithiobenzoy7.e chloride, N, N-dimethyl-p-sulfonmidobenzoyl chloride, p-ne-thylsulfinylbenzoyl chloride methylsulfonylbenzoyl, p-benzyl-thiobenzoyl chloride, p-mercaptobenzoyl chloride, p-nitrobenzoyl chloride, p-dimethylaminobenzoyl chloride, p-acetaminobenzoyl chloride,

     lo-fluoco- chloride
 EMI21.5
 p # chlorobenzoyl, o-methoxy-p-chlorobenzoyl chloride, ô-hydroxy-p-ch7.orobenzoyl chloride 2, .5-trichlorobenzoyl chloride.



   The 1-substituted indolyl esters obtained are converted into the corresponding free acids by the process of Example 7C.



   EXAMPLE 10
 EMI21.6
 1-p-Chlorobenzoyl-2-methyl-5-methoxy-3-indolyl-acetic acid (A) 2-Methyl-5-methoxy-3-indolylacetic anhydride.



   Dicyclohexylcarbodiimide (10 g, 0.049 mol) is dissolved in a solution of 2-methyl-5-methoxy-3-indolyl- acid.

 <Desc / Clms Page number 22>

 acetic acid (22 g, 0.10 mol) in 200 ml of THF and the solution is left to stand at room temperature for 2 hours. The precipitated urea is separated by filtration and the filtrate is evaporated in vacuo until a residue is obtained which is / washed with Skellysolve B. The residual oily anhydride is used without further purification in the next step.



  (B) tert.-Butyl 2-methyl-5-methoxy-3-indolylacetate
Tert-butyl alcohol (25 ml) and molten ZnC12 (0.3 g) are added to the anhydride obtained in A. The solution is heated under reflux for 16 hours, then the excess alcohol is removed in vacuo. . The residue is dissolved in ether, washed several times with saturated bicarbonate, with water and with saturated salt solution. After drying over magnesium sulfate, the solution is treated with charcoal, evaporated and repeatedly rinsed with Skellysolve B to completely remove the alcohol. The residual oily ester
 EMI22.1
 (18 g, 93%) and v7tisê "without purification.



  , (C) 1-p "tert -butyl-ehlorobenzoyl-2-methyl-5-inethoxy-3-indolylacetate.



   A stirred solution of ester (18 g, 0.065 mole) in anhydrous DMF (450 ml) is cooled to 4 C in an ice bath, after which sodium hydride (4.9 g, 0.098 mole, susp. 50%) is added in fractions. After 15 minutes p-chlorobenzoyl chloride (15 g, 0.085 mol) is added dropwise over 10 minutes, then the mixture is stirred for 9 hours, without renewing the ice bath. The mixture is then poured into 1 liter of 5% acetic acid, extracted with a mixture of ether and benzene, washed vigorously with water, with bicarbonate and with a saturated solution of salt, dried over sulfate. magnesium, treated with charcoal
 EMI22.2
 and evaporated until a residue is obtained which partially crystallizes.

   This residue is stirred with ether, then filtered. The filtrate is evaporated until a residue (17 9) is obtained which solidifies after cooling overnight.

 <Desc / Clms Page number 23>

 crude X The product obtained is boiled with 300 ml of Skellysolve B and then cooled to room temperature, the gummy material present is separated, the product is treated with charcoal, concentrated to 100 ml and let crystallize.



  The product thus obtained (10 g) is recrystallized from 50 ml of methanol and gives 4.5 g of analytically pure material.



    103-4.
 EMI23.1
 



  (D) 1-p-Chlorobenzoyl-2-methyl-5-methoxy-3-indolylacetic acid
A mixture of 1 g of ester and 0.1 g of powdered porous metal is heated in an oil bath at 210 ° C., with magnetic stirring, under a nitrogen atmosphere, for about 2 hours.



  No intensification of the pale yellow color is evident during this period. After cooling under nitrogen, the product is dissolved in benzene and ether, filtered and extracted with bicarbonate. The aqueous solution is filtered under vacuum to remove the ether, neutralized with acetic acid, then weakly acidified with dilute hydrochloric acid. The crude product (0.4 g, 47%) is recrystallized from aqueous ethanol and dried under vacuum at 65 C; P.F. 151.



   EXAMPLE 11
 EMI23.2
 1-p-Methylthiobenzoyl-2-methyl-5-methoxy-3-indolyl-apropionic acid.



  (A) 2-Methyl-5-methoxy-3-indolyl-a-propionic anhydride Dicyclohexylcarbodiimide (9 g 0.044 mole) is dissolved in a solution of 2-methyl -5 -methoxy-3 -indolyl a-propionic acid. -nique (21 g, 0.09 mol) and 200 ml of THF and the solution is left to stand at room temperature for 2 hours.



  The precipitated urea is separated by filtration and the filtrate is evaporated under vacuum until a residue is obtained which is washed with Skellysolve B. The residual oily anhydride: .. is used without purification.
 EMI23.3
 



  (B) tert.-Butyl 2-m, <'thyl-5-methoxy-3-indolyl-α-propionate
Tbutyl alcohol (25ml) and molten ZnCl2 (0.3g) are added to the above anhydride. The solution is heated at reflux for 16 hours and the excess alcohol is removed in vacuo.

 <Desc / Clms Page number 24>

 



  The residue is dissolved in ether, washed several times with saturated bicarbonate solution, with water and with saturated salt solution. After drying over magnesium sulfate, the solution is treated with charcoal, evaporated and washed several times with Skellysolve B, to completely remove the alcohol. The residual oily ester (14 g) is used without purification.
 EMI24.1
 toc) tert.-Butyl 1-p-methylthiobenzoyl-2-nethyl-5-methoxy-3-indolyl-x-propionate.



   A stirred solution of the ester obtained in B (20 g, 0.69 mol) in 450 ml of anhydrous dimethylformamide is cooled to 4 C in an ice bath after which sodium hydride (5.2 g, 0 , 10 mol, susp. 50%) is added in fractions. After stirring the mixture for 10 minutes, chloride is added
 EMI24.2
 p-methylthiobenzoyl (m.p. 51; 17z; t, 091 mole) in portions over 10 minutes, the mixture then being stirred for hours at room temperature, without replacing the ice bath. The mixture is then poured into a liter of a 5% solution of acetic acid, then extracted with ether, washed well with water, with bicarbonate and with a saturated solution of salt, dried over sulfate of magnesium, treated with charcoal and evaporated in vacuo until a residue is obtained (33 g).



  This is dissolved in ether and the solution obtained is mixed with 100 g of alumina washed with acid and evaporated in vacuo to dryness. The residue obtained is placed on a column of 300 g of acid washed alumina in Skellysolve B. After washing with Skellysolve B, the product is eluted with a 5% solution of ether in Skellysolve. B. A yellow oil is obtained (11g, 36%).
 EMI24.3
 



  (D) 1-p-Methylthiobenzoyl-2-methyl - $ - methoxy-3-indolyl-a-propionic acid.



   The pyrolysis is carried out in the same manner as with t.-butyl 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl acetate (Example 10D). The product is recrystallized from aqueous methanol or from a mixture of benzene and Skellysolve B; P.F.



  175-6.

 <Desc / Clms Page number 25>

 



  EXAMPLE 12
 EMI25.1
 Lp-Chlorobgnzoyl-2-methyl-5-inethoxy-3-indolyl-α-propionic acid (A) To a solution of 20.0 g (0.07 mole) of α- (2-methyl-5-me- tert.-Butyl thoxy-3-indolyl) -propionate in 270 ml of dimethylformamide, 7.0 g (0.14 mol) of a 51% suspension of Na hydride are added in small portions in mineral oil under nitrogen with stirring and cooling with ice. After 15 minutes, 17.5 g (0.10 mol) of p-chlorofenzoyl chloride are added dropwise. The white precipitate separated almost immediately. The mixture is stirred at 0 ° C. for 2 hours and left to stand in cold alcohol until the following day. The next morning the mixture is filtered and diluted; c. Ether.

   Half of the solution is washed with water, then with sodium bicarbonate and again with water, after which it is dried over magnesium sulfate. The dried solution is concentrated until a syrup is obtained which is chromatographed on 400 g of acid washed alumina. After elution of mineral oil and trace impurities with petroleum ether and a 5% solution of ether in petroleum ether, the desired product is obtained by elution with a 10% solution of ether in petroleum ether, as a yellow oil.

   The other half of the solution is freighted in the same way ..,
The aforementioned ester and a few pieces of porous metal are placed in a flask soaked in an oil bath. A constant stream of nitrogen is introduced into the test tube through the opening thereof, while the temperature of the oil bath is slowly raised to 215 C. After 30 minutes of residence at 215 C. , the mixture is dissolved in ether, filtered and washed with sodium bicarbonate. The bicarbonate extract is acidified with dilute hydrochloric acid and the precipitate is taken up in ether, washed with water, dried over sodium sulfate and evaporated to dryness.

   The solid residue is recrystallized from a mixture of benzene and petroleum ether, so

 <Desc / Clms Page number 26>

 to obtain the desired acid, m.p. 87-88 *.



   EXAMPLE 13
 EMI26.1
 -1-isonicotinyl-2-methyl-5-methoxy-3-indolyl) methyl acetate (A) In a 500 ml round-bottom flask (flame-dried), 13.9 g of p-nitrophenol and 12 , 3 g of isonitotini- acid
 EMI26.2
 than in 250 ml of dry / 6etrahydrofuran. 20.6 g of dicyclohexylcarbodimide in 100 ml of dry tetrahydrofuran are added over the course of 30 minutes through a funnel. The reaction is allowed to proceed overnight with stirring. The dicyclohexylurea which forms during the reaction is filtered. The filter cake is washed with dry tetrahydrofuran. The solution is evaporated to dryness. The solid material is taken up in benzene, washed with sodium bicarbonate solution, then with water and dried over anhydrous sodium sulfate.

   The solid p-nitrophenylisonicotinate is then recrystallized from benzene, m.p. 126-127.



  (B) In a round-bottom flask with a capacity of 250 ml (flimme-dried) is placed at 0 C, under nitrogen, 100 ml of dim-
 EMI26.3
 thylformamide and 10, - g of a- (2-methyl-5-methoxv-3-indblyl) acetate. 2.5 g of a 50% sodium hydride in mineral oil emulsion are added. After stirring the mixture for 30 minutes, a solution of 11 g of p-nitrophenylisonicotinate in 50 ml of anhydrous dimethylformamide is added over the course of 15 minutes. The reaction mixture is stirred for 4 hours at 0 ° C. under nitrogen, after which it is further stirred under nitrogen overnight at room temperature.

   The reaction mixture is then poured into a solution of ether and ice water containing a few ml of acetic acid and the layers are separated.



  The aqueous phase is washed with ether and the ethereal extracts are combined. Zux ethereal layers, a saturated solution of chlorinated hydrogen gas in anhydrous ether is added. The ether is separated by decantation, so that a heavy oil is obtained. This oil is washed with ether, after which an aqueous solution of sodium bicarbonate is added thereto. The product is then

 <Desc / Clms Page number 27>

 extracted with ether. The ethereal layer is dried over anhydrous sodium sulfate and concentrated to dryness. The product is crystallized from anhydrous ether, m.p. 114-115 C.
 EMI27.1
 Microanalysis: calculated for C = 67.45%; H = 5.37 #; H = 8.28 ±.



  Found: C, 67.67%; H = 5.50%; N, 8.14%.



   EXAMPLE 14
 EMI27.2
 Methyl (2-methyl-5-nitro-3-indolyl) acetate
A solution of 40 g of levulinic acid in 300 ml of hot water is added to a solution of 65 g of p-riitrophenylhydrazine hydrochloride in 700 ml of hot water, while stirring. After about half an hour, the hydrazone derivative is collected on a filter, washed with water and dried at 110 ° C. under vacuum. 84 g of product melting at 175-179 ° C. are thus obtained.



   42 g of the aforementioned hydrazone are added to a solution of 120 g of molten zinc chloride in 100 ml of absolute ethanol and the mixture is heated under reflux for 18 hours. The cooled solution is poured into dilute hydrochloric acid with stirring, and the insoluble, gum-like material which separates is extracted with hot ethanol. The ethanolic extract is evaporated under vacuum until a syrup is obtained which is redissolved in ether. The ethereal solution is extracted several times with a 10% sodium carbonate solution. By acidification of the aqueous solution, a crude product is obtained which is recrystallized from chloroform. We
 EMI27.3
 thus obtains (2-methyl-5-nitro-3-indolyl) acetic acid M.P. 238.



   The aforementioned acid is treated with a mixture of 3 g of sulfuric acid and 40 ml of methanol at reflux temperature for 6 hours. The methyl ester is obtained in the form of yellow crystals melting at 132-41 after recrystallization from benzene.
 EMI27.4
 



  Likewise, methyl lfa (2-methyl-5-nitro-3-indolyl) -propionate is prepared using an equivalent amount.

 <Desc / Clms Page number 28>

 # -methyl levulinic acid as a starting material.



     EXAMPLE 15 Methyl (2-methyl-5-amino-3-indolyl) acetate.



   3 g of methyl (2-methyl-5-nitro-3-indolyl) acetate are dissolved in 300 ml of anhydrous methanol and reduced with hydrogen, in an autoclave, in the presence of Raney nickel as catalyst. when the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off. The catalyst and the reaction vessel are washed with methanol.



  The methane solution is evaporated to dryness. The product is crystallized from benzene, m.p. 144-145. Microrassay: Calculated: C = 66.03%; H-6.47%; N, 12.84%; Found: C, 65.96%; H = 6.29%; N, 12.56%.



   EXAMPLE 16
 EMI28.1
 Methyl 2-methyl-5- (11-pyrrolidino) -3-indolyl7acetate 80 ml of ethanol are placed in a 125 ml flask. 1.0 g of (2-methyl-5-amino-3-in (methyl iolyl) acetate, 0.99 g of 1,4-dibromobutane and 0.975 g of anhydrous CO 3 Na 2 are added. This mixture is stirred at temperature. reflux in a nitrogen atmosphere for 6 hours The reaction mixture is then filtered and the filtrate is concentrated in vacuo to a small volume and diluted with ether The solution is then washed twice with of water, poached over anhydrous sodium sulfate and concentrated in vacuo to dryness The product is absorbed on 6 g of silica gel.

   The product is then chromatographed on 30 g of silica gel, using petroleum ether containing ether in a volumetric ratio of 3: 1 as eluent; then mixtures containing less and less ether and finally pure ether.



   The eluted material is crystallized from a mixture of benzene and Skellysolve B, m.p. 117-118.



  Microanalysis. Calculated: C = 70.56%; H = 7.40%; N, 10.29%; Found =
 EMI28.2
 # C = 70 ', 77 ± 1 H = 32; N, 10.00%.

 <Desc / Clms Page number 29>

 



    When using ethylene dibromide instead of
 EMI29.1
 dibromobutane, the product obtained is the compound 5- (1- <zcvr7.opropylsindole.



  EXAMPLE 17 (1-p-chlorobenzoyl-2-methyl-5- (11-pyrrolidono) -3-indolyl methyl acetate
In a dry 125 ml flask, 1.2 g of methyl (2-methyl-5- (l'-pyrrolidino) -3-indolyl) acetate are placed in 60 ml of anhydrous dimethylformamide. To this solution, cooled to 0 ° C., 0.23 g of a 50% suspension of sodium hydride in mineral oil is added. This mixture is stirred for 30 minutes.



  Then a solution of 0.8 g of p-chlorobenzoyl chloride diluted with 5 ml of anhydrous dimethylformamide is added.



  This reaction mixture is stirred for 4 hours at 0 C under a nitrogen atmosphere. The reaction mixture is then stirred overnight at room temperature, under a nitrogen atmosphere. The reaction mixture is added to a mixture of ice water and ether containing a few ml of acetic acid.



   The ethereal layer is separated and the aqueous layer is washed with ether. The combined ether layers are washed once with sodium carbonate solution and twice with water, after which they are dried over anhydrous sodium sulfate and evaporated in vacuo, until an oil is obtained. . The product is absorbed on 10 g of silica gel and chromatographed on 60 g of silica gel. The product is collected using mixtures of 1: 3 to 1: 1 volume of ether and petroleum ether.
 EMI29.2
 



  The collected material is crystallized from ether, m.p. 6264.



  EXAMPLE 18- (1-p-Chlorebenzoyl-2-methyl-5-nitro-3-indolyl) methyl acetate
In a dried 250 ml flask, 3.9 g of methyl (2-methyl-5-nitro-3-indolyl) acetate is placed in 125 ml of dimethylformamide. To this solution cooled to 0 ° C., 0.8 g of a 50% suspension of sodium hydride in mineral oil is added.

 <Desc / Clms Page number 30>

 



  The mixture is stirred under nitrogen for 30 minutes, after docking
 EMI30.1
 2.75 g of p-chlorobenzoyl chloride in 15 ml of dry dimethylformamide are added dropwise thereto over 5 minutes.



  The reaction mixture is stirred for 4 hours at 0 C under nitrogen, after which it is stirred overnight at room temperature under nitrogen. It is then poured into a solution of benzene and ice water containing a few mml of acetic acid.



  The benzene layer is separated and the aqueous layer is washed with benzene. The combined benzene layers are washed with sodium bicarbonate solution, then with water, after which they are dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The product is crystallized from a mixture of benzene and Skellysolve B, m.p. 170-171.
 EMI30.2
 Microanalysis. Hold. C = 59, OON; H = 3.91, N = 7.24%. Found: C, 59.24%; H = 4.00%; N, 7.39.



   The corresponding propionate is formed when a quantity
 EMI30.3
 The equivalent amount of the corresponding methyl α- (2-methyl-5-nitro-3-indolyl) propionate prepared in Example 13 was used as the starting material.



   EXAMPLE 19
 EMI30.4
 Methyl (1-p-chlorobenzoyl-2-methyl-5-dimethylamino-3-indolyl) acetate To a solution of 0.387 g of methyl dia- (lp-chlorobenzoyl-2-methyl-5-nitro-3-indolyi) acetate 1.5 ml of glacial acetic acid and 0.5 ml of a 37% aqueous formaldehde solution are added to 20 ml of distilled dimethoxyethane. Ce: mixture is reduced with Raney nickel at a pressure of 2.8 kg per cm2 and at room temperature. When the theoretical amount of hydrogen has been absorbed, the reaction mixture is filtered, concentrated in vacuo to a small volume and diluted with ether.



  The ethereal solution is washed with sodium bicarbonate, then with water, after which it is dried over anhydrous sodium sulfate and concentrated in vacuo until an oil is obtained. Microanalysis. Wedge: C = 65.50%; H = 5.50%; N, 7.28%.



    C, 65.66%; H = 5.91%; N, 7.46%.

 <Desc / Clms Page number 31>

 



  EXAMPLE 20
 EMI31.1
 (1-p-chlorobenzoyl-2-methyl- $ -acetamino-3-indoly7.) Methyl acetate A 0.388 g of (lp-chlorobenzoyl-2-methyl-5-nitro-3-indolyl) methyl acetate in abs 30 ml of anhydrous ethyl acetate, 0.306 g of acetic anhydride is added. The mixture is reduced with Raney nickel at room temperature under a pressure of 2.8 kg per cm 2 '. When the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off. The solution is concentrated / in vacuo to a small volume and poured into a mixture of water and ether. The ethereal layer is separated and the aqueous layer is washed with ether.

   The combined ethereal extracts are washed successively with an aqueous solution of sodium bicarbonate and with water, then dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The product is crystallized from a mixture of benzene and ether, m.p. 176-177 C. Microanalysis. Calculated = C = 63.25%;
 EMI31.2
 H = q., 80i; N = 7.02. Found: C = 3.40.r; II =, 82; N, 6.89%.



   EXAMPLE 21 Benzyl (2-methyl-5-nitro-3-indolyl) acetate.



   In a 250 ml vial are placed 80 ml of anhydrous benzene and 20 ml of benzyl alcohol. 3.0 g of 2-
 EMI31.3
 methyl-5-nitro-3-indolyl tpetic and 0.2 g of p-toluenesulfonic acid. The suspension obtained, which clarifies on heating is heated in a relu-x under nitrogen. The water which forms during the reaction is collected in a Star: and Dean tube. The reaction is stopped when the distillate is clear (about 2 hours). The excess benzilic alcohol is removed in vacuo. The residue is dissolved in benzene and washed first with sodium bicarbonate solution, then with water, after which it is dried over anhydrous magnesium sulfate and concentrated in vacuo.

   The product is absorbed on 15 g of acid washed alumina and chromatographed on 75 g of acid washed alumina. The product is eluted with 3: 1 to 3: 1 mixtures of ether and benzene.

 <Desc / Clms Page number 32>

   The eluate is evaporated and the total product is crystallized from a mixture of benzene and Skellysolve B, m.p. 147-148. Microana-
 EMI32.1
 lysis. Calculated: C = 66.66%; H = 4.97%; N, 8.64%. Found: C = 'cs, fi3;' -; H = 4.77%; N, 8.62%.



   EXAMPLE 22
 EMI32.2
 (1-p-chlorobenzoyl-2-methyl-5-nitro-3-indolyl) benzyl acetate
In a dry 125 ml flask, 3.0 g of benzyl (2-methyl-5-nitro-5-indolyl) acetate is placed in 60 ml of anhydrous dimethylformamide. To this solution, cooled to 0 ° C. in a nitrogen atmosphere, is added 0.475 g of a 50% emulsion of sodium hydride in mineral oil. The solution obtained is stirred for 30 minutes. 1.65 g of p-chlorobenzoyl chloride in 10 ml of anhydrous dimethylformamide is then added dropwise over 5 minutes. The reaction mixture is stirred at 0 C for 4 hours under a nitrogen atmosphere, after which it is stirred at room temperature overnight, still under nitrogen. The mixture is then poured into a mixture of benzene and ice water.

   The benzene layer is separated and the aqueous layer is washed with benzene. The combined benzene extracts are washed successively with aqueous sodium bicarbonate solution and with water, then dried over anhydrous sodium sulfate and concentrated in vacuo to dryness.



  The product is crystallized from a mixture of benzene and Skellysolve B, m.p. 166-167 C. Microanalysis: Calculated: C = 64.86%;
 EMI32.3
 H = °, 1 ° j,:; N, 6.05%; Found: C = Ô4.78 ±; H = 4.22%; N, 5.91%. EXAMPLE 23 a- (1-p-chlorobenzoyl-2-methyl-5-amino-3-indolyl) p '<methyl tpionate.



  0.025 mole dsoC- (1-p-chlorobenzoyl-2-raethyl - $ - nitro-3-indolyl) propionate of methyl in 100 ml of ethanol is hydrogenated in the presence of 120 mg of 10% palladium on charcoal, under 40 pounds pressure at room temperature. After absorption of 0.075 mol of hydrogen, the hydrogenation is stopped and the solution is filtered, to remove the catalyst. The filtrate

 <Desc / Clms Page number 33>

 
 EMI33.1
 is, concentrated to "", to dryness in vacuo so that methyl α- (I-p-chlorobenzoyl-2-methyl-5-amino-3-inciolyl) propionate is obtained.



   EXAMPLE 24
 EMI33.2
 Methyl chlorobenzoyl-2-methyl-, 5- (N-methyl-acetamido) -3-indolyl) acetate.



  Methyl 1-p-chlorobenzoyl-2-methyl-5- (N-methyl.acce-tamido-3-indolyl-acetate is added to a suspension of sodium hydride in dimethylformamide with stirring and cooling. - Stiff ice cream After 1 hour, methyl iodide is added and the mixture is stirred overnight The reaction mixture is poured into ice-water and extracted with ether.



  By evaporation of the ethereal solution and chromatography of the residual oil on an alumina column, using mixtures of 15-25% by volume of ether in petroleum ether
 EMI33.3
 as eluent, 1-p-chlorobenzoyl-2-raethyl-5- (N-methyl acetamido) -3-indolyl methyl act is obtained.



  EXAMPLE 25 A. -1-p-Ch1orobenzoyl-2-methyl-5-bis (8-hydroxyethyl) amino-3-indolyl / methyl acetate.



  A mixture of 0.02 mole of methyl a- (lp-chlorobenzoyl-2-methyl-5-amino-3-indolyl) propionate, 0.044 mole of ethylene oxide and 0.03 mole of acid acetic in 300 ml of dimethoxyethane is heated at 100 ° C. for 18 hours in an autoclave. The mixture is then diluted with water and filtered, leaving
 EMI33.4
 te which is obtained crude methyl -1-p-chlorobenzoyl-2-methyl-5-bis (p-hydrocyethyl) -amino-3-indolyl7-propionate.



  B .j / fl-p-chlorobenzoyl-2-methyl-5 - (4 '-methyl-1 -pipera zinyl) -3-indolyl) acetate.



   The product obtained in A is stirred at 0 in pyridine with two molar proportions of p-toluenesulfonyl chloride until the reaction is substantially complete. The mixture
 EMI33.5
 is poured into water and the compound 5-bis (p-toluene-sulfonyloxy-ethyl) amino is isolated. This compound is dissolved in benzene and a molar proportion of methylamine is added to the solution.

 <Desc / Clms Page number 34>

 The mixture is left to stand at room temperature for 3 days. The mixture is then poured into ice water containing two equivalents of sodium carbonate and immediately extracted.
 EMI34.1
 tely with ether. By eii1!> Or: 1.tion of ether is obtained '1-p- choro-benzoyl-2-methyl-5- (c'-methyl-l'-niperazinyl) -3-indolyl% methyl acetate .



   Both of the aforementioned compounds give, by working in the manner described in Example 7, the corresponding free acid.



   EXAMPLE 26
 EMI34.2
 L 1-n-chlorobenzoyl-2-methyl-5- (41-morpholinyl} -3-indolv¯h methyl acetate.



   A solution of tosyl chloride (0.1 mole) in 200 ml of benzene is added dropwise, with stirring, at a
 EMI34.3
 solution of methyl drî6-¯¯ "Ip-chlorobenzoyl-2-methyl-'5 -bis (3-hydroxyethyl) amino-3-indolyl7acetate, (u, 1 mole) and of pyridine (0.3 mole) in 300 ml of benzine at room temperature over 1 hour The mixture is then heated under reflux for 3 hours, washed with water, dried over sodium sulfate and evaporated to obtain a syrup By chromatography of the syrup on an alumina column using 30 to 50% by volume of ether in petroleum ether as elaunt, [lp-
 EMI34.4
 chlorobenzoyl-2-methyl-5- (4 '-morpholinyl) -S-indolyl / methyl acetate.



   The above product gives, when the procedure of Example 7 is applied, the corresponding free acid.



   EXAMPLE 27 A. Methyl 2-methyl-5-cyano-3-indolyl acetate
A solution of p-cyano phenylhydrazine (0.1 mole) and levulinic acid (0.1 mole) in 200 ml of concentrated HCl is heated at 90 for 20 minutes and diluted with ice water (400 ml). The crude product which separates is extracted with ether and chromatographed on a column of silica gel, so that
 EMI34.5
 2-methyl-5-cyazo-3-indoly7lacetic acid is obtained, using 20-50% by volume mixtures of ether and petroleum ether as eluent.

 <Desc / Clms Page number 35>

 
 EMI35.1
 The methyl ester is prepared by emitting with diazomethane in ether until the yellow coloration of the diazomethane persists and the mixture is evaporated.
 EMI35.2
 



  B. ct- (lp-chlorobenzoyl-2-methyl-5-cyano-3-indolyl) methyl acetate .¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ Alkylation of ester (prepared in Example 26A)
 EMI35.3
 in dimethylfor-.lamide with sodium hydride and n-chlorobenzoyl chloride, as described in Example 2, gives (1-p-chlorobenzoyl-2-methyl-5-cyano-3 -indolvl) methyl acetate.



  C. Ct- (1-pwchroi e: aoyï-2-methyl - $ - aminomethyl-3-inùoïyl) methyl acetate
The 5-cyano ester prepared in the example. 278 is hydro-. generated in ethanol in the presence of Raney nickel and 3 moles of anhydrous ammonia at a pressure of 2000 pounds per inch
 EMI35.4
 square to; noi2nte temperature, so that we obtain, after
 EMI35.5
 fi1tr4ftion. catalyst and evaporation of the reaction mixture of methyl (3-p-chlorobenzcyl - methvl - $ - mainomethyl-3-ondolyl) acetate which can be recrystallized from aqueous thnnol.



  D. (1-p-ehlorobenzoyl-2-methyl-5-dimethylaminoethyl-3-indolyl) methyl acetate
By treating the aforementioned α-aminomethyl indol with 2 moles of methyl iodide, a 5-dimethylaminocethyl derivative is obtained.



    B. When the products of Examples 27C and 27D are used in the procedure of Example 7, the corresponding free acids are obtained.



   EXAMPLE 28
 EMI35.6
 A- (1-p-methylmer = ptobenzoyl-2-methyl-S-methoxy-3-indolyl) - butyric acid.



   When operating as in Examples 1 and 2, using ethyl α-ethyl levulinate instead of α-methyl levulinate.
 EMI35.7
 ethyl linate, ethyl cc- (2-methyl-5-methoxy-3-indolyl) -butyrate and lta- (1-p-methylmercap-tobenzoyl-2-methyl-5-) are successively obtained. methoxy-3-indolyl) - ethyl butyrate.

 <Desc / Clms Page number 36>

 
 EMI36.1
 ... f,, l --- '. P .... s ........ 0 when the latter product is used' in the procedure of Example 7, the corresponding derivative of butyric acid.



     The starting ethyl α-ethyl levulinate is prepared by alkylation of the sodium derivative of ethyl acetoacetate in
 EMI36.2
 ethanol with 1 m. ethyl dtoc-bromobutyrate followed by hydrolysis and decarboxylation. The α-ethyl levulinic acid is re-esterified with hydrochloric acid in 2N ethanolic solution at reflux temperature for 18 hours.



   EXAMPLE 29
 EMI36.3
 6.5 g (0.02 mol) of α- (1-Benzoyl-2-methyl 5-methoxy-3-indolyL) -acetic acid are added to 50 ml of water washed with nitrogen. The suspension is stirred under nitrogen and 20 ml of 1.05 N sodium carbonate solution is added while stirring. When a clear solution has formed, a solution of
 EMI36.4
 2.2 g of A12 (α04) 3.181i20 in 8 ml of water is added while stirring vigorously. The mixture is stirred until it is homogeneous and the solid aluminum salt of (1-benzoyl-2-methyl-5-methoxy-3-indolyl) acetic acid is collected by filtration and washed with water. and ethanol.



     Similarly, the sodium and aluminum salt can be prepared, as well as other salts, such as the potassium, iron and magnesium salts of the various (3-indolyl) aliphatic acids described in the examples.



     EXAMPLE 30
 EMI36.5
 0C- (1-Benzoyl-2-iBethyl-5-methoxy-3-iîidoly.) Ethyl acrylate A. 500 ml of dry ether, 36.02 g of triphenylphosphonium bromide and 94.36 ml of n 1.10 N -butyl lithium are stirred for 1 hour at room temperature under nitrogen. 38 g of (2-m-
 EMI36.6
 Ethyl-3-methocy-indolyl) glyoxylate in 260 ml of benzene and 500 ml of anhydrous ether are added and stirring is continued for 1 hour. The reaction mixture is transferred to an autoclave and heated in this closed autoclave to 65-70 C

 <Desc / Clms Page number 37>

 for 5 hours. The liquid is poured out of the autoclave and the gum obtained is triturated with 500 ml of a 33% solution of benzene in ether.

   The solutions obtained are combined and washed with three 500 ml fractions of au, then dried over sodium sulphate, filtered and concentrated under vacuum, until a syrup is obtained. This is suspended in benzene and loaded onto a column of 200 g of activated alumina.
 EMI37.1
 Ethyl α (2-methyl-5-methoxy-3-indolyl) -acrylate is eluted by washing the column with a 30% solution of ether in petroleum ether and removing the solvents d. lution by evaporation.



   The operation is then carried out in the manner described in Example 13B, using p-nitrophenylbenzoate in equivalent amounts instead of p-nitrophenylisonicotinate; ethyl # - (1-benzoyl-2-methyl-5-methoxy-3-indolyl) -acrylate is obtained.



   EXAMPLE 31
 EMI37.2
 ethyl a- (1-benzoy l-2-methyl-5 -methoxy-3 -ind olyl) -gly copr opyl carboxylate 1.8 g of a- (1-benzyl-2-methyl-5-nitro- Ethyl 3-indolyl) -acrylate in 10 ml of dry tetrahydrofuran is added to 4 g of diiodomethane, 1.25 g of zinc-copper couple and 0.2 g of iodine in 20 ml of dry tetrahydrofuran. The mixture is heated under reflux, below an atmosphere of nitrogen, while stirring, for 20 hours. The reaction mixture is then filtered, then the filtrate is added to ice-cold water and the whole is extracted with three fractions of 50 ml of ether. The combined ether extracts are washed with two fractions of 50 ml of water, dried over sodium sulfate, filtered and concentrated.

   The syrup thus obtained is poured onto a column of 60 g of alumina, in the form of a benzene suspension by elution with a 60% solution.
 EMI37.3
 of ether in petroleum ether, ethyl ltoc- (1-benzoyl - 2-methyl-5-methoiy-3-indolyl) -cyclopropylcarbolate is obtained.

 <Desc / Clms Page number 38>

 



    EXAMPLE 3 2
 EMI38.1
 The corresponding aroyl or heteroaroyl Nl derivatives of benzyl a- (2-uethyl-5-methoxy-3-indolyl) propionate, of (2-methyl - $ - methawy-3-indolyl) acetate and - (2-methyl-5-nitro-3-indolyl) butyl acetate are obtained, by
 EMI38.2
 reacting these esters, by the method of Exenpie 1313, with the p-nitrophenyl esters of the following acids, which p-nitrophenyl esters were obtained from the acids by the procedure of Example 13A, using in each case, the equivalent amount of the acid chosen, instead of the isonicotinic acid used in Example 13A and its nitro-phenyl ester used in Example 13B and equivalent amounts of the indole esters:

   l-methylpyrryl-2-carboxylic acid,
 EMI38.3
 $ -methyl-pyrazol-3-c3rboxvlīue acid, 1,5-dimethyl-4-bromopyrazol-3-carboxylic acid, l-phenylpyrazol-4-carboxylic acid, l-phenyl-5-pyrazolone-3-carboxylic acid , 2-phnnyl-5-methoxazol-4-carboxylic acid, isoxazol-3-carboxylic acid, 5-phenylisoxazol-3-carboxylic acid, 1,2-benzoisothiazol-3-carboxylic acid, l, 2,3-thiadiazol acid -4-carboxylic, methyl-
 EMI38.4
 1,2,3-thi <-zol- ° -carboxylic acid, nicotinic acid, picolinic acid {isonicotinic acid -oxide, 3-chloroisonicotinic acid, 6-methoxynicotinic acid, 6-phenylnicotinic acid,
 EMI38.5
 alpha-pyrone-5-carboxylic acid, pyridazine-4-carboxylic acid,

   3-keto-4-methyl-2-phenyl-2,3-dihydropyridazine -ô-carboxylic acid, cinnoline-4-carboxylic acid, 2-m acid, ethyl mercapto 4-chloropurimidin3-5 # carboxylic acid, 4 -'dichloropyrimidine- 5-carboxylic acid, pyrazinoic acid, 5-methoxypyrazino acid, p-difluoromethov y benzoic acid, (prepared by the action of difluorochloromethane on benzyl alcohol p-hydroxybenzoate, then by hydrogenation of the group benzyl). The esters thus obtained are converted into free acids by operating as described in Example 7C.

 <Desc / Clms Page number 39>

 



    EXAMPLE 33
 EMI39.1
 ethyl a- (1-p-chlorobenzoyl-2-methyl - $ - ethoxy-3-indolyl) propionate
The operation is carried out as in Example 1A using a caun-
 EMI39.2
 p-ethoxyphenylhydrazine hydrochloride equivalent instead of methoxyphenylhydrazine. Ethyl oc- (2-methyl-5-ethoxy-3-indolyl) propionate is obtained. When the operation is carried out as in Example 3, ethyl α- (1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl) propionate was obtained. This product, used as described in Example 7, gives the corresponding free -indolyl propionic acid.



   Similarly, when using p-propoxy
 EMI39.3
 or p-butoxy-nhenylhydr.xzW e, in the procedures described above, the correspondingly substituted indolylic acids are obtained.



   When operating as in Example 1A, using instead of p-methoxyphenylhydrazine, equivalent amounts
 EMI39.4
 p-6thyl.phenylhvdrizine, p-bittylpliényllivdr-izine and p- fluorophenylhydrazine - each of these compounds obtainable by diazotization with the corresponding p-substituted aniline and and
 EMI39.5
 Reduction of the diazo compound, "by acylating the indolyl ester obtained, as described in Example 3, then by operating as described in Example 7, the indolyl esters are obtained. and corresponding 5-substituted acids.



   When operating in the manner described in the examples
 EMI39.6
 1A, 3 and 7, starting from phenylhydrazine, the corresponding dolylesters and acids are obtained which are unsubstituted in position 5.



   EXAMPLE 34
 EMI39.7
 1-Benzoyl-2-methyl-5-methoxy-3-indolyl-acetamide To a suspension of 1.0 g of 50% sodium hydride in 80 ml of benzene, 4.4 g of 2-methyl- 5-methoxy-3-indolylacetamide, while stirring. 20 ml of dimethylformamide is then added, after which 2.8 g of benzoyl chloride are added 20 minutes later. The reaction mixture is stirred

 <Desc / Clms Page number 40>

 
 EMI40.1
 ',.' << '- <- ..., mYF', * '' "'at room temperature for 1 hour, after which it is poured into 400 ml of ice and water. The precipitate is collected by filtration, mp 215-218 The crude product is recrystallized from ethyl acetate twice, mp 219-220 ".



  Its ultraviolet absorption spectrum in ethanol reveals @
 EMI40.2
 maxima at 7 max 2675 Ac, E, 1, t 406 and À max 3160 H ', E, 1% 188. Characteristic of an N # benzoyl indol chromophore. Microanalysis: calculated for C 911. 6BZO3: C = 1.2 ° h; H = 5, O3 ±; Found: C = 71.00; H, 5.35%.



   EXAMPLE 35
 EMI40.3
 1-Benzoyl-2-methyl-5-methoxy-3-indolyl-acetamide To a solution of 3.2 g of 1-benzoyl-2-meth.vl-5-methoxy-3-indolylacetamide in 50 ml of dimethoxyethane containing 1 ml of 12N HCl # 0, 0.7 g of sodium nitrite is added while stirring. When the evolution of gas has ceased, the mixture is poured into 200 ml of ice-water and the precipitate is extracted with methylene chloride. The methylene chloride solution is extracted with sodium glbicarbonate solution. By acidifying the aqueous solution with 2N hydrochloric acid, the desired acid precipitates. This acid is purified by recrystallization from benzene and from a mixture of ethyl acetate and Skellysolve B.



   EXAMPLE 36
The acylation is carried out as described in Example 3 or in Example 12A, using various aromatic acyl chlorides in equivalent amounts, instead of p-chlorobenzoyl chloride, and using, if necessary, of
 EMI40.4
 esters of methyl-3-thoxy-indolyl acetic acid, or a - (2-methyl # 5 -methoxy-3 -indolyl) propionic acid. Some of the esters obtained are converted into the corresponding free acid by the process of Example 7 or of Example 12B, as indicated below. When using the method of Example 12B, the 1-acylation is carried out by the method of Example 12A.

   The products obtained by these effects are the following:

 <Desc / Clms Page number 41>

 
 EMI41.1
 (l-p-methoxybenzoyl¯2-methyl-5-methoxy-3-indolyl) aceti- acid
 EMI41.2
 that, m.p. 88-89 C (free acid method of example 7), the acid
 EMI41.3
 Ct- (1-p-methoxybenzoyl-2-methyl - $ - methoxy-3-zndolyl) nronioniqtie,
 EMI41.4
 M.p. 65 C (free acid method of Example 7), (1-p-bromo-
 EMI41.5
 benzoyl-2-methyl-5-methexy-3-indolyl) methyl acetate, P.F.



  106-107.5 C (lp-nitro-benzoyl-2-methyl-5-methoxyl-3-indolyl) methyl acetate, mp 130-132 C, (lo-chlorobenzoyl-2-methyl-5-methoxy-3- methyl indolyl) acetate, PF 91-93 C, (1-m-chlorobenzoyl-2-niethyl-5-methoxy-3-indolyl) acetate, PF 51-52 C., (1-p-hênylbenzoyl-2 -methyl - $ - methoxy-3-indolyl) methyl acetate, mp 10l, 5-103 C., (1p-acetoxybenzoyl-2-methyl-j-metlzoxy-3-indolyl) ace. met., yl, PF 9? -lOPC., rl- (4-thiazolylcarboxy) -2-methyl-5-methoxy-3-indolyl) acetate, PF 76-82 ° C, / * l- Ethyl (2-thenoyl) -2-niethyl-5-methoxy-3-indolyl) acetate (oil), a- (lp-bromobenzoyl-2-methvl- $ -methoxy-3-indolyl) tributyl pronionlte, PF 103-105C., (1-x-naphthoyl-2-mcthyl-5-tëthol 3-indolyl) methyl acetate (Oil), (lp-benzyloxybenzoyl-2-methyl-5-methoxy-3-indolyl) methyl acetate , PF

   116-1l * C, methyl (1p-hydroxybenzoyl-2-methyl-5 -methoxy-3 -indolyl) acetate, PF 155-158 C (prepared from p-ben .-. Ylo1-ybenzoyl compound by hydro- catalytic generation on methyl palladium (1-o-benzyloxybenzoyl- 2-methyl-5-methoxy-3-indolyl) acetate (not isolated) -
 EMI41.6
 used to prepare the following compound by catalytic hydrogenation on palladium), (1-o-hydroxybenzoyl-2-methyl-5-metoxy-3-indolyl) methyl acetate (oil), (1-o-fluorobenzoyl-
 EMI41.7
 Methyl 2-methyl-5-methoxy-3-indoly.l) methyl acetate, PF 98-99 C, rl- (2-thenovl) -Z-methyl-5-methoxy-3-indolyl7 acetic acid, PF 62 (method from Example 12), (1-N-naphthoyl-2-methyl-5-methoxy-3-indolTTl) methyl acetate, PF

   120-1240ü., ± -1- (5- chloro-2-thenoyl) -2-niéfchyl-5 -methoxy-3 -indolyl7 acetate
 EMI41.8
 thyl (oil), acid (1-p-trifluoromethylbenzoyl-2-methyl-
 EMI41.9
 5-indolyl) acetic, m.p. 169-17l C (method of example 12),

 <Desc / Clms Page number 42>

 
 EMI42.1
 1- (2,6-dimethoxbertzoyij-Z-mét'hyI - méthoxy-3-inciolvl% methyl acetate, PF 139.5 - 141 C, 11- (o, p-dichlorobcnzoyl- 2-methyl-5-methoxv Methyl -3-indolyl) acetate (oil).



   EXAMPLE 37
The procedure is as in Example 1A, using an equivalent amount of each of the following phenylhydraines
 EMI42.2
 instead of p-methoxyphenyl hydrazine: p-dimethylsulfon,; r: 1ido-phenylhydrazine, p-benzvlmercaptophén.vlhvdrazine p-vinylphenylhydrazine.



   When the indolylic acid obtained is acylated by the process of Example 3, the corresponding 1-chlorobenzoyl indolylic acids are obtained.



     EXAMPLE 38
Nethyl 5-methoxy-3-indolylacetate is reduced at a pressure of 4000 pounds per square inch of hydrogen over a nickel catalyst at room temperature. 5-methoxy-2,4-
 EMI42.3
 nethyl dihydro-3-indolyl acetate obtainede5O: ile p? The process of Example 3 gives methyl (lp-chlorobenzoyl-5-methoxy-2j3 "dihydro-3-indolyl) acetate. When this compound is stirred at room temperature, in 100 times its weight. of a 0.1N solution of sodium hydroxide in 95% ethanol, the corresponding free acid is obtained.



   CLAIMS.

** ATTENTION ** end of DESC field can contain start of CLMS **.


    

Claims (1)

1.- Compound chosen from the group comprising: (a) compounds of formula: EMI42.4 in which 3 ... is an aromatic carboxylic acyl radical containing less than 3 fused rings R2 denotes hydrogen or a lower alkyl radical, R3 denotes hydrogen, a lower alkyl radical or a lower acyl radical, R5 <Desc / Clms Page number 43> denotes hydrogen or a hydroxy or lower alkyl radical. EMI43.1 lower alkoxy, lower alkenyl, fluorine, polyfluoralcoyl, nitro, amino, substituted amino, cyano, aminomethvl, aminomf> t: substituted yl, dialcoylsulfonamido and mercapto and M denotes OH, NH2 'benzyloxy, lower alkoxy and OZ, being a cation and (b) 2,3-dihydro derivatives of compounds of group (A). 2. - Compounds according to claim 1, in which R2 denotes a lower alkyl radical, R3 denotes a radical; EMI43.2 lower coyl,; 5 denotes a lower alkoxy radical, M denotes a hydroxyl radical ,. a double bond being present in 2,3. 3. - Compounds according to claim 1, in which R2 denotes a lower alkyl radical, 'denotes a lower alkyl radical, R5 denotes a lower alkyl radical, M denotes a hydroxyl group, a double bond being present at 2,3. 4. Compounds according to claim 1, in which R2 denotes a lower alkyl radical, R3 denotes a lower alkyl radical, R5 denotes a radical or substituted amino group, M denotes a hydroxyl group, a double bond being present at 2,3. 5.- compounds / according to claim 4, in which R5 denotes a dimethylamino radical. 6. - Compounds according to claim 2, in which R .. EMI43.3 denotes a p-methylthiobenzoyl radical. 7.- Oc- (1-p-Methlthiobenzoyl-2-methyl-5-methoxy-3-indolyl) -propionic acid. 8.- Compounds according to revebdication 2, in which R1 denotes a p-chlorobenzoyl radical. EMI43.4 9.- α- (1-p-Chlorobenzoyl-2-methyl-5-methoxy-3-indolyl) - propionic acid. 10. Compounds according to claim 4, in which R 1 denotes a p-chlorobenzoyl radical. EMI43.5 11.- (1-p-chlorobenzoyl-2-methyl - $ - métitoYy-3-indolyl) - acetic acid. <Desc / Clms Page number 44> EMI44.1 12.- Ti- (1-p-Chlorobenzoyi-2-methyl-5-dimethylantino-3-indolyl) ptopionic acid. 13.- (1-p-Chlorobenzoyl-2-methyl-5-dimethylamino-3indo1y1) acetic acid. 14.- Process for the synthesis of a compound corresponding to the formula EMI44.2 following: R3 R5- i (-ci-coY R2 ± \ .1 in which R .. denotes an aromatic carboxylic acyl radical containing moir.s of three fused rings, R denotes hydrogen or a lower alkyl radical, R3 denotes hydrogen, a lower alkyl radical or a lower alkenyl radical, R5 denotes hydrogen or a lower alkyl, lower alkoxy, fluorine, polyfluoroalkyl, nitro, amino, substituted amino, cyano, aminomethyl, aminomethyl radical substituted, mercapto, dialcoylsulfonamido and benzylmercapto, and Y denotes a lower alkoxy, benzyloxy or amino radical, characterized in that there is placed, in an inert solvent, a reagent con- By stituated / an aromatic acyl halide or an aromatic acyl ester of p-nitrophéol, the aromatic group of which contains less than three fused rings, in intimate contact with the N alkali metal salt, of a compound of formula : EMI44.3 15.- Process for the synthesis of a compound of formula: <Desc / Clms Page number 45> EMI45.1 in which R 1 denotes an aromatic carboxylic acyl radical containing less than three fused rings, R denotes hydrogen or a lower alkyl radical, R3 denotes hydrogen, a lower alkyl radical or a lower nlkenyl radical, R5 denotes hydrogen or a lower alkyl, lower alkoxy, fluorine, polyfluoroalkyl, nitro, amino, substituted amino, cyano, aminomethyl, substituted aminomethyl, mercapto, dialkoylsulfonamido and benzlymercapto radical, characterized in this (a) on puts, in an inert solvent, a reagent consisting of an aromatic carboxy halide, an aromatic carboxylic azide, an aromatic carboxylic ester of a phenol or an aromatic carboxylic ester of a thiophenol, the aromatic armoatic group / contains less than three fused nuclei, in intimate contact with the alkali metal salt in N1 of a compound corresponding to the formula: EMI45.2 andisolating the 1-acyl indolyl ester ottenu and then (b) stirring a solution of said ester in an inert solvent with a catalytic amount of palladium in a hydrogen atmosphere. 16. - Process for the synthesis of a compound of formula: EMI45.3 <Desc / Clms Page number 46> in which R 1 denotes an aromatic carboxylic acyl radical containing less than three fused rings, R2 denotes hydrogen or a lower alkyl radical, R3 denotes hydrogen or a lower alkyl or lower alkenyl radical, and R5 denotes hydrogen or a lower alkyl, lower alkoxy, fluoro, trifluoromethyl, nitro, amino, substituted amino, cynno, aminomethyl, substituted aminomethyl, mercapto, dialkylsulfonamido and benzylmercapto radical, characterized in that: (a) is placed in an inert solvent, a reagent consisting of an aromatic carboxy halide, an aromatic carboxylic azide, an aromatic carboxylic ester of a phenol and an aromatic carboxylic ester of a thiophenol, of which the group aromatic comprises less than three fused rings, in intine contact with the N11 alkali metal salt of a compound of the formula: EMI46.1 and isolating the 1-acyl indolyl ester thus obtained, and (b) heating this ester. 17. A method according to claim 16, characterized in that the ester is heated to 25-110 C, in the presence of at least one catalytic amount of an organic sulfonic acid. 185- A method according to claim 16, characterized in that the ester is heated to a temperature above 210 C. 19.- Process for the synthesis of compound of formula: EMI46.2 <Desc / Clms Page number 47> : "METHODS AND COMPOUNDS OF THE INDOL SERIES"