MXPA01006131A - Method for producing 3-alkanoylindoles and 3-alkylindoles - Google Patents

Abstract

The invention relates to a method for producing compounds of formula (I), wherein R, R1, R2 and n have the meanings given in Claim 1 and X stands for O or H,H. The invention also relates to the acid addition salts of said compounds. Said method is characterised in that a) when X stands for O and R, R1, R2 and n have the given meanings, a compound of formula (II) wherein R1 and R2 have the meanings given in Claim 1 is converted with a compound of formula (III):R-(CH2)n-CO-L wherein R, L and n have the meanings given in Claim 1 in a Friedel-Crafts acylation and using the catalysis of Lewis acid metal halogenides of the type R'-Al(Cl)2 wherein R'has the meaning given in Claim 1 or b) when X stands for H,H and R, R1, R2 and n have the given meanings, a compound of formula (I), wherein X stands for O and R, R1, R2 and n have the given meanings, is reduced with complex hydrides using activation by means of Lewis acid metal halogenides of the type R'-Al(Cl)2 wherein R'has the meaning given in Claim 1 and/or in that an obtained base of formula (I) is converted into one of the acid addition salts of said base by treating said base with an acid.

Description

PROCEDURE TO PREPARE 3 -ALCANOILINDÓLES AND 3-ALQUI INDÓLES DESCRIPTION OF THE INVENTION The invention relates to a process for preparing compounds of formula I wherein R represents Hal or methyl, R1, R2 independently represent H, A ', aryl, NK2 / NHA' ', iA' ';, COOA' '', CN or Ilal, X represents O or H, H, A ', A ", A" "independently represent alkyl of 1 to 6 C atoms, Hal represents F, Cl, Br or I and n is -1, 2, 3, 4, 5 or 6, and the salts of these compounds formed by addition of acid, process characterized in that a) when X represents O and R, R1, R2 and n have the meanings indicated, a compound of formula II is reacted Ref: 128863 wherein R-, R2 independently represent H, A ', aryl, NH2"NHA", N (A ") 2, COOA' '', CN or Hal, A ', A' ', A' '' independently represent alkyl of 1 to 6 C atoms and Hal represents F, Cl, Br or I, with a compound of formula III R- (CH2) n-CO-L III, wherein R represents Hal or methyl, L represents Cl, Br, I, OH or an OH group functionally transformed into a reactive group, Hal represents F, Cl, Br or I and n is 2, 3, 4, 5 or 6 , in the form of a Friedel-Crafts acylation catalyzed by metal halides of the R'-A1 (C1) 2 type which are Lewis acids and in which R 'represents A or aryl', A represents alkyl of 1 to 6 atoms of C, aryio 'represents phenyl unsubstituted or mono or disubstituted with A', OA 'or Hal, Hal represents F or Cl, or b) when X represents H, H and R, R1, R2 and n have the meanings indicated, a compound of formula I is reduced, where X represents O and R, R1, R2 and n have the meanings indicated, cor. complex hydrides and with the activation of metal halogen-type R'-Al (Cl) 2 which are Lewis acids and er. wherein R 'represents A or aryl', A represents alkyl of 1 to 6 carbon atoms, aryl represents phenyl unsubstituted or mono or disubstituted with A ', OA' or Hal, Hal represents F or Cl, and / or by converting a base of formula I, thus obtained, into one of its salts by the addition of an acid.

The processes for preparing acylated Índols are known and among them is, for example, the one described by M.Tam et al. in Chem. Pharm. Bull. 38 C.2), p. 3261 to 3267 (1990), whereby the indole indigo is replaced at position 2 with an ethoxycarbonyl group. Bottcher et al. describe in Liebigs Ann. Chem. 1988, pgs. 749 to 752, a process for preparing methyl 3- (4-chloro-l-oxobut l) -5-mdol carboxylate catalyzed by A1C13. C. Gueremy describes in J. Med. Chem. 1980, 23, p. 1306-131C, an acylation of indole with R-CO-X passing first through the formation of MgX salts as intermediates.

J. Bergman et al also describe in Tetrahedron Letters 28 (32), p. 3741-3744 (1987) the acylation of an indole through MgX salts that are formed as intermediates. Agarwal et al describe in Synthetic Communications 23 (8), p. 1101-1110 (1993) another acetylation of 5-cyano? Ndol with acetyl chloride using SnCl4 as a catalyst. The reduction of 4-? Ndol-3-yl-4-oxobutyric acid with L1AIH4 is described by J. S. L. Ibaceta-Lizana in J. Chem. Soc. Perkm Trans. II 1987, pgs. 1221-1226. B? Ttcher et al. describe in Liebigs Ann. Chem. 1988, pgs. 749-752, the reduction of a residue of 3 -alkanoylindole with NaBH4 / BF3-ether. Agarwal et al describe in Synthetic Communications 23 (8), p. 1101-1110 (1993) another reduction of a phthalimide derivative of 3-acetyl-5-cyanoindole with NaBH using isopropanol as a catalyst. The tests carried out in the context of the synthesis of drugs that are described, for example, in German Patent No. 43 33 254 (European Patent No. 0 648 767), surprisingly revealed that the compounds of Formula I can be obtained in yields superior or at least comparable to those of the state of the art, but with the fundamental advantage of a simple reaction and capable of being carried out in homogeneous phase, which in turn provides the benefit of a simple isolation of the product. In short, this also implies a lower consumption of solvent and energy. This allows that during the acylation of stage a) of the preparation of compounds of formula I, wherein X represents O, it is possible to employ as catalyst, for example, liquid isobutylaluminum dichloride (i-Bu-A1C12) by pump and undiluted The formation of poorly soluble and difficult-to-agitate solid parts, which occurs frequently during catalysis with A1C13 and whose existence is well known in the state of the art, is avoided. Another advantage is that fewer side products are formed, since, for example, the aforementioned i-Bu-AlCl2 behaves as weaker Lewis acid than AlCl 3, which strongly represses the activation of a chloroalkyl function in the side chain and in turn prevents Friedel-Crafts alkylation from occurring as a secondary reaction. Among the advantages offered by the reduction of step b) of the invention, in which the compounds of formula I, in which X represents 0, are reduced to the compounds of formula I, in which X represents H, H, also it is possible to mention the obtaining of yields superior or at least comparable to those of the state of the art, the greater facility to carry out the reaction and a much simpler isolation of the product. Another advantage that this reaction also offers is that fewer by-products are formed, in particular when at positions 4 to 7 of the indole there are substituents capable of being reduced such as the CN group or the ester groups. The 3- (4-chlorobutanoyl) -indol-5-carbonitrile is a particular example of a compound prepared according to the process of the invention, which is then transformed into the 1- [4- (5-c? Ano-indol-3- il) -butyl] -4- (2-carbamoyl-benzofuran-5? I) -piperazine published in German Patent No. 43 33 254.

Accordingly, the invention particularly relates to a process for preparing compounds of formula I wherein R represents Hal, R1 represents H, R 'represents CN, X represents 0 or H, H, Hal represents F, Cl, Br or I and n is 2, 3 or 4, and the salts of these compounds formed by acid addition, process characterized in that a) when X represents O and R, R ', R7 and n have the meanings indicated, a compound of formula II is reacted wherein R "represents H, R2 represents CN, with a compound of formula III R-> CH2) r.-CO-L III, in aonae R represents Hal, L represents Cl, Br, I, OH or a group of OH transformed functionally in a reactive group, Hal represents F, Cl, Br or I and n is 2, 3 or 4, in the form of a Friedel-Craf acylation catalyzed by metal nalogenides of the type R'-Al (Cl); Lewis acids and in which R 'represents A, A represents alkyl of 1 to β C atoms, or b) when X represents H, H and R, R 1, R 2 and n have the meanings indicated, a compound of formula I is reduced wherein X represents O and R, R1, R2 and n have the indicated meanings, with complex hydrides and with the activation of metal halides of the type R'-Al (Cl) _ which are Lewis acids and in which R 'represents A, A represents alkyl of 1 to 6 C atoms, and / or by transforming a base of formula I, thus obtained, into one of its salts by the addition of an acid.

The compounds of formula I, in which X represents 0 and which are reduced in step b), can also be prepared in accordance with conventional methods of catalyzed acylation, for example by AlCl 3. However, it is preferred to prepare these compounds according to step a) of the reaction and then reduce them according to step b). Therefore, the object of the invention is preferably a process according to both processes mentioned above, which makes it possible to prepare compounds which correspond to formula I, in which X represents H, H and R, R1, R2 and n have the meanings indicated, process characterized in that compounds of formula I are prepared, in which X represents O and R, R1, R2 and n have the meanings indicated, according to step a) and then reduced according to step b). A ', A' 'and A' '' represent alkyl of 1, 2, 3, 4, 5 or 6 C atoms, preferably of 1, 2, 3 or 4 C atoms, with particular preference being given, for example, to methyl or ethyl, then propyl, isopropyl, then also butyl, isobutyl, sec-butyl or tert-butyl. In the compounds of formula I and III, R preferably represents Cl or methyl.

In metal halides of type R'-Al (Cl). which are Lewis acids, R 'preferably represents methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, isobutyl, pentyl, neopentyl, isopentyl, phenyl, o-, m- or o-tolyl, o-, m- or p- methoxyphenyl, o-, m- or p-fluoro-, o-, m- or p-chlorophenyl. Particularly preferred meanings for R 'are isopropyl and isobutyl. The preferred compound of isobutii-Al (Cl) 2 is also known, for example, from the chemistry of polymers. In the compounds of formula I and II, aryl represents phenyl not unsubstituted or mono or disubstituted with A, OA or Kai.

Preferred meanings independently of R1 and R2 in the compounds of formula I and II are H, methyl, ethyl, propyl, phenyl, amino, methylamino, ethyl-ammo, dimethylamino, diethylamino, methoxycarbonyl, ethoxycarbonyl, cyano, fluorine or chlorine, then also carboxy. The particularly preferred meaning of R1 is H and R2 of R2 is cyano. The preferred value of n in the compounds of formula I and II is 2, 3 or 4, in particular 2 or 3. The majority of the compounds of formula II and III is known. In the compounds of formula III, L preferably represents Cl or Br; however, it may also represent I, OH or an OH group functionally transformed in a reactive group such as a group of alkylsulfonyloxy of 1 to 6 C atoms (preferably a group of ethylsulphonyloxy) or a group of arylsulfonyloxy of 6 to 10 C atoms (preferably a phenylsulfonyloxy group), p-tolyl-sulfonyloxy, 1- or 2-naphidenesulfonyloxy). L can also represent a suitable anhydride. In general, the compounds of formula II and III are prepared according to known methods, as described in the literature (for example, in certain standard works such as those of Houben-Weyl, "Methoden der organischen Chemie" (Methods of Organic Chemistry), Georg-Thieme-Veriag, Stuttgart) and under reaction conditions that are known and suitable for the reactions mentioned. You can also make use of known variants of these methods that are not detailed in this text.

The reaction of compounds II and III is carried out in a suitable solvent. Suitable solvents include, for example, hydrocarbons such as benzene, toluene or xylene; chlorinated hydrocarbons such as, for example, dichloromethane; ketones such as acetone, butanone; ethers such as tetrahydrofuran (THF) or dioxane; amides such as N-methylpyrrolidone or dimethylformamide (DMF); nitriles such as acetonitrile, and also optionally mixtures of the aforementioned solvents.

The reaction times are comprised, depending on the conditions employed, between a few minutes and 14 days, and the reaction temperatures range from about 0 ° to 150 °, usually between 0 ° and 60 °. The reduction of the compounds of formula I, in which X represents O, is carried out with complex hydrides and with activation of Lewis acids in a suitable solvent. Among the suitable solvents there may be mentioned, for example, hydrocarbons such as benzene, toluene or xylene; chlorinated hydrocarbons, such as, for example, the chloroform; ketones such as acetone, buta-none; ethers such as tetrahydrofuran (THF) or dioxane; amides such as N-methylpyrrclidone or di me il ormamide (DMF); nitriles such as acetonitrile, and also optionally mixtures of the aforementioned solvents. As the complex hydrides, those of the M3H4 type are preferred, with M =, for example, Na, Li or 0.5 Ca. The reaction times are comprised, according to the conditions employed, between a few minutes and 14 days, and the Reaction temperatures range from about 0 ° to 150 °, usually between 0 ° and 60 °. A base of formula I can be converted into its salt by the addition of an acid, for example, by reaction of equivalent amounts of the base and the acid in an inert solvent such as ethanol, and by subsequent evaporation. For this reaction, acids which form acceptable salts from a physiological point of view are particularly suitable. Therefore, inorganic acids such as, for example, sulfuric acid, nitric acid, hydrocides such as hydrochloric or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulphamic acid, then also organic acids can be used. , in particular the aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic, sulfonic or sulfuric monobasic or polybasic acids such as, for example, formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fu aric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonic, methanesulfonic or ethanesulfonic, ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naph alenomonosulphon, naphthalenedisulfonic and lauryl sulfuric. Salts of physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify the compounds of formula I. All temperatures indicated in this text are given in ° C. In the examples that follow, the expression "one works (or treats) in a usual manner" means the following: if necessary, water is added, if necessary it is adjusted, according to the constitution of the final product, to pH values comprised between 2 and 10, it is extracted with ethyl acetate or dichloroethane, the phases are separated and the organic phase is dried over sodium sulphate, concentrated by evaporation and purified by chromatography on silica gel and / or by recrystallisation.

Emollon 1 Indol-5-carbonitrile 3- (4-chlorobutanoyl) -indol-5-carbonitrile Description of the trial The mdoi-5-carbomotherm (4800 g) is dissolved in di-chloroethane (70 1) under a nitrogen atmosphere and stirred at 0-10 ° C, and then mixed with Cl- (CH2) 3C0C1 ( 6640 g). Next, isobutylaluminum dichloride (7300 g) ba or temperature control (0 -10 ° C) is added. Once the acylation (which is followed and controlled by chromatography) is completed, the mixture is poured over water / ice (64 kg) and the crystalline crude product is separated, which is 3- (4-chlorobutane? L) -mdol-5- carbsn? tr? lo. To purify, the cetcna (6940 g / 82%) must be recrystallized.

Indole-5-carbonitrile 3- (3-chloropropanoyl) -indol-5-carbonitrile Description of the trial The indole-5-carbonitrile (57.0 g) is dissolved in dichloromethane (790 g) under a nitrogen atmosphere and stirred at 0-10 ° C, and then mixed with Cl- (CH2) 2COCl (61 g). Next, isobutylaluminum dichloride (124 g) is added under temperature control (0 -10 ° C). Once the acylation (which is followed and controlled by chromatography) is completed, the mixture is poured on water / ice, the crystalline 3- (3-chloropropanoyl) -indol-5-carbonitrile is separated and the latter is dried under vacuum (ca. 83 g, 89%). ? enripio 2 3 - (4-chlorobutanoyl) -indol-5-carbonitrile 3- (4-chlorobbutyl) -indol-5-carbonitrile or N3 / ~ "-" ^ r-0 Test description 3- (4- chlorobutanoyl) -indol-5-carbonitrile (75.5 g) is dissolved in dichloromethane (1980 g) under a nitrogen atmosphere and with stirring at 0-10 ° C, and then mixed with NaBH 4 (46.3 g). Then, isobutylaluminum dichloride (190 g) is added under temperature control (0 -10 ° C). Once the reduction (which is followed and controlled by chromatography) is completed, the mixture is poured onto water / ice and the crystalline 3- (4-chlorobutyl) -indol-5-carbonitrile is separated as a homogeneous material (68 g, 95% ). 3- (3-chloropropanoyl) -indol-5-carbonitrile 3- (3-chloropro-pyl) -indol-5-carbonitrile Description of the trial The 3- (3-cioropropane? L) -indole-5-carbonitrile (4.8 g) is dissolved in dichloromethane (224 g) under a nitrogen atmosphere and with stirring at 0-10 ° C, and then mixed with NaBH 4 (3.1 g). Next, isobutylaluminum dichloride (13 g) is added under temperature control (0 -10 ° C). Once the reduction (which is followed and controlled by chromatography) is completed, the mixture is poured onto water / ice, the crude crystalline 3- (3-chloropropyl) -indole-5-carbonitrile is separated and the latter is dried under vacuum. The purification of the mdol is carried out by recrystallization (3.9 g, 87%). Comparative example 1 3- (4-chlorobutanoyl) -indol-5-carbonitrile 3- (4-chlorobutyl) -indole-5-carbonitrile Description of the trial The 3- (4-chlorobutanoyl) -indole-5-carbonitrile (75.5 g) is dissolved in dichloromethane (1980 g) under a nitrogen atmosphere and stirred at 0-10 ° C, and then mixed with LiAlH (46 g). Once the normal reaction time had elapsed and after working the mixture in the usual manner it was not possible to isolate any product.

Comparative Example 2 3 - (4-chlorobutanoyl) -indol-5-carbonitrile 3- (4-chlorobutyl) -indole-5-carbonitrile Description of the test The 3- (4-chlorobutane? L) -indole-5-carbonyl trile (75.5 g) is dissolved in dichloromethane (1980 g) under a nitrogen atmosphere and with stirring at 0-10 ° C, and then it is mixed with NaBH4 / BF3-ether. Once the normal reaction time had elapsed and after working the mixture in the usual manner it was not possible to isolate any product. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (3)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Process for preparing compounds of formula I wherein R represents Hal or methyl, R ", R ~ independently represent H, A ', aryl, NH2, NHA' ', N (A' ') 2, COOA' '', CN or Hal, X represents O or H , H, A ', A' ', A' '' independently represent alkyl of 1 to 6 carbon atoms, Hal represents F, Ci, Br or I and n is 1, 2, 3, 4, 5 or 6, and salts of these compounds formed by addition of acid, characterized in that a) when X represents O and R, R1, R2 and n have the indicated meanings, a compound of formula II R1 is reacted wherein R1, R2 independently represent H, A ', ary, NH2, NHA' ', N (A' ') 2, COOA' '', CN or Hai, A ', A' ', A' '' independently represent alkyl of 1 to 6 carbon atoms and Hai represents F, Cl, Br or I, with a compound of formula III
1. R- (CH2) n-C0-L III, wherein R represents Hal or methyl, L represents Cl, Br, I, OH or an OH group functionally transformed into a reactive group, Hal represents F, Cl, Br or I and n is 1, 2, 3, 4, 5 or ß, er. the form of a Friedei-Crafts acylation catalyzed by metal halides of the R'-Al (Cl) 2 type which are Lewis acids and in which R 'represents A or aplo', A represents alkyl of 1 to 6 carbon atoms , anium 'represents phenyl unsubstituted or mono or disubstituted with A', OA 'or Hal, Hal represents F or Cl, or b) when X represents H, H and R, R1, R2 and n have the indicated meanings, a compound of formula I is reduced, where X represents 0 and R, R1, R2 and n have the meanings indicated, with complex hydrides and with the activation of metal halides of the type R'-A1 (C1) 2 which are Lewis acids and in which R 'represents A or aryl', A represents alkyl of 1 to 6 carbon atoms, aryl 'represents unsubstituted phenyl or mono or disubstituted with A ', OA' or Hal, Hal represents F or Cl, and / or by transforming a base of formula I, thus obtained, into one of its salts by the addition of an acid.
2. 2. - Process, according to claim 1, for preparing the compounds of formula I where R represents Hal, R ~ represents H, R2 represents CN, X represents 0 or H, H, Hal represents F, Cl, Br or I and n is 2, 3 or 4, and the salts of these compounds formed by addition of acid, characterized in that a) when X represents O and R, R1, R2 and n have the indicated meanings, a compound of formula II is reacted wherein R * represents H, R2 represents CN, with a compound of formula III R- (CH2) n-CO-L III, wherein R represents Hal, L represents Cl, Br, I, OH or an OH group functionally transformed into a reactive group, Hal represents F, Cl, Br or I and n is 2, 3 or 4, in the form of an acylation from Friedel-Crafts catalyzed by metal halides of the type R'-A1 (C1) which are Lewis acids and in which R 'represents A, A represents alkylene of 1 to 6 C atoms, or b) when X represents H, H and R, R1, R2 and n have the indicated meanings, a compound of formula I is reduced, where X represents O and R, R1, R2 and n have the meanings indicated, with complex hydrides and with the activation of metal halides of the type R'-A1 (C1) 2 which are Lewis acids and in which R 'represents A, A represents alkyl of 1 to 6 carbon atoms, and / or by transforming a base of formula I, thus obtained, into one of its salts by the addition of an acid.
3. 3. - Process according to claim 1 or 2, for preparing compounds of formula I, in which X represents H, H and R, R ", R2 and n have the meanings indicated, characterized in that the compounds of formula I, in which X represents 0 and R, R1, R2 and n have the indicated meanings, are prepared according to step a) and then reduced according to step b). SUMMARY OF THE INVENTION A process for preparing compounds of formula I in aonae R, R1, R2 and n have the meanings indicated in claim 1, and X represents 0 or H, H, and the salts of these compounds formed by addition of acid, characterized in that a) when X represents 0 and R, R1 , R2 and n have the indicated meanings, a compound of formula II is reacted in aonae * and R, 2 have the meanings indicated in claim 1, with a compound of formula III R- (CH 2) r.-CO-L III, wherein R, L and n have the meanings indicated in claim 1, in the form of a Friedel-Crafts acylation catalyzed by metal halides of the R'-A1 (C1) 2 type which are Lewis acids and in which R ' has the meaning indicated in claim 1, or b) when X represents H, H and R, R1, R2 and n have the indicated meanings, a compound of formula I is reduced, wherein X represents O and R, R1, R2 and n have the indicated meanings, with complex hydrides and with the activation of metal halides of the type R'-Al (Cl) which are Lewis acids and in which R 'has the meaning indicated in claim 1, and / or because a base of formula I, thus obtained, in one of its salts by the addition of an acid.