AN IMPROVED PROCESS FOR THE PREPARATION OF 7-AZAINDOLYL-3-CARBOXYLIC ACID

Abstract: A process for the preparation of 7-azaindolyl-3-carboxylic acid is described starting from succinonitrile (VIII) which is condensed with ethyl formate and the so formed salt of 2-hydroxymethylenebutyrronitrile (VII) is reacted with tert.butylamine to give N-tert.butylaminomethylene-succinonitrile (VI) which is reacted in a warm ambience in the presence of a base to give 1-tert.butyl-2-amino-4-cyanopyrrole (V) which is reacted with a malondialdehyde acetal to give 1-tert.butyl-3-cyano-7-azaindole (IV) which in a suitable solvent is heated under reflux with a Lewis acid and the corresponding dichloroderivative (III), treated with a suitable proton donor, gives 3-cyano-7-azaindole (II) which is hydrolyzed at the temperature of 70 DEG C at pH 2.5 to provide 7-azaindolyl-3-carboxylic acid (I).

Description: Description An improved process for the preparation of 7- azaindolyl-3-carboxylic acid The object of the present invention relates to an improved process for the preparation of 7-azaindolyl- 3-carboxylic acid, starting compound for the synthesis of compounds having relevant pharmacological interest. More particularly 7-azaindolyl-3-carboxylic acid or lH-pyrrole[2,3-b]pyridin-3-carboxylic acid of structure formula: represents the starting compound of a class of compounds having non-narcotic antitussive activity which is described and claimed in United States Patent n°5,750,536, among which 7-azaindolyl- carboxytropylamide proved to be of particular therapeutical interest. Background of the invention Up to the present time 7-azaindolyl-3-carboxylic acid has been prepared from 7-azaindole by means of a method consisting in a Friedel-Cra ts acylation with trichloroacetyl chloride and a molar excess of A1C1 3 followed by a treatment of the so obtained 7- azaindolyl-3-trichloroacetyl with a suitable base to remove chloroform and provide the desired 7- azaindolyl-3-carboxylic acid (I) . The starting compound of such a process, 7-azaindole, is a compound hard to find on the market and, when available, it is very expensive: consequently the market price of the 7-azaindolyl-3-carboxylic acid, due both to the difficulty in finding the starting compound and to the complexity of the synthesis in obtaining it, is so high that a possible production of the active principles described in USP n°5,750,536 would be too expensive . Description of the invention The process of the present invention for the preparation of 7-azaindolyl-3-carboxylic acid shows, when compared to what is already known in the art, considerable advantages which make it undoubtedly competitive and, consequently, make economically less expensive the production of those active principles which uses the mentioned compound as a starting compound. As far as the first steps are concerned, the process of the present invention is essentially based on the method described in both Helv.Chimica Acta 33,273,1950 and J.Chem.Soc. Perk 1,1910,1975; then removal of the tert.butyl radical from the new intermediate 1- tert .butyl-3-cyano-7-azaindole (IV) is performed with an alternative technology which is certainly advantageous in respect to the one followed to the present time. More particularly, succinonitrile (VIII) and a suitable alkyl formate are condensed in the presence of a base to form a salt of 2- hydroxymethylenebutyrronitrile (VII) which is not separated from the reaction mixture but made to react with an excess of ter .butyla ine, giving the corresponding enaminonitrile. (VI) from which, by internal condensation, in. the presence of a base, the corresponding l-tert.butyl-2-amino-4-cyanopyrrole (V) is obtained. l-tert.Butyl-2-amino-4-cyanopyrrole (V) 5 is then reacted with a alondialdehyde acetal in the presence of a suitable catalyst, such as p.toluensulphonic acid, to provide l-tert.butyl-3- cyano-7-azaindole (IV) which is then treated in a warm ambience with at least three molar equivalents of a Lewis acid to remove the tert. utyl radical, and the so obtained derivative (III) suitably protonated to give 3-cyano-7-azaindole (II) which is hydrolysed with an aqueous solution of a mineral acid to give the dssirsd 7-assir.doiyi-3-cϊ.rbc-.yiic acid (I). 5 The process of the invention is described in the following depicted scheme: VI SlIBSTπUTΕ SHEET (RULE 26) The condensation reaction (a) is preferably performed in an inert organic solvent and the base is represented by a metal alkaline salt of an aliphatic alcohol, more preferably a sodium or potassium salt of an aliphatic alcohol, such as, for example, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert.butoxide, sodium tert.butoxide; sodium methoxide and potassium tert.butoxide being the preferred ones. Suitable solvents are, for example, aliphatic alcohols such as ethanol, ethanol, 2- propanol, sec.butanol and tert.butanol as well as aromatic solvents such as benzene and toluene. SUPSTIΠΠESHEET(RULE 26) The cyclization reaction (c) is preferably carried out in a warm ambience, in the presence of sodium or potassium hydroxide in a solvent consisting of aliphatic alcohol, preferably ethanol. The reaction (d) for obtaining the azaindolyl ring is carried out under reflux in an aromatic solvent such as toluene. The reaction (e) for removing the tert.butyl radical is performed reacting 1-tert .butyl-3-cyano-7-azaindole (IV) in a high boiling organic solvent with at least three molar equivalents of a Lewis acid selected in the group consisting of aluminium chloride, boron chloride and boron bromide, preferably aluminium chloride. preferred high boiling organic solvent is represented by an aromatic hydrocarbon, which is ecologically compatible, such as, for example, toluene, xylenes and chlorobenzene . After removal of the ter .butylchloride, the dichloroaluminate intermediate (III) is suitably protonated (f) to give the cyano derivative (II) then hydrolyzed (g) at 70°C with an aqueous solution of a mineral acid to provide, with very high yields, the desired 7-azaindolyl-3-carboxylic acid (I) . The proton donor may be represented by an aliphatic alcohol containing 1-4 carbon atoms selected in the group consisting of methanol, ethanol, isopropanol and tert .butanol: methanol being the preferred one. Should chlorobenzene as a high boiling organic solvent, be used, water, optionally in the form of ice, may be satisfactorily utilized as proton donor. Similar results are obtained even if the 3-cyano-7- azaindole intermediate (II) is not isolated as a crystalline product provided that, after separation of the organic phase, the normality of the aqueous phase is corrected by addition of concentrated hydrochloric acid and the temperature is strictly maintained at about 70°C. In the last step the hydrochloric acid concentration as well as the reaction temperature are binding items in order to avoid a possible simultaneous decarboxylation of the 7-azaindolyl-3-carboxylic acid to 7-azaindole (IX) . The compounds 2-amino-l-tert .butyl-4-cyanopyrrole (V) and 1-tert .butyl-3-cyano-7-azaindole (IV) are new compounds, never having been mentioned before in literature: they are prepared, as previously described, from aliphatic compounds widely used and easily available on the market by applying already known procedures thereby avoiding the use of costly and almost unavailable heteroaromatic precursors. These considerations, together with the high yields obtained in the conversion from 1-tert .butyl-3-cyano- 7-azaindole (IV) into 7-azaindolyl-3-carboxylic acid (I), make the process of the invention highly advantageous and competitive. In the present process, when the saponification of 3- cyano-7-azaindole (II) is performed at the reflux temperature, only the 7-azaindole (IX) is formed rather than the 7-azaindolyl-3-carboxylic acid (I) . The following examples are given for a better illustration of the invention without limiting it. Example 1 N-tert . Butylaminomethylenesuccinonitrile (VI) In a nitrogen atmosphere and under stirring, to a suspension of 4Kg sodium methoxide in 60L anhydrous toluene, a solution consisting of 60L anhydrous toluene, 6.17Kg ethyl formate and 5.6Kg succinonitrile is added dropwise, cooled to about 5°C and the dripping time is controlled so that the inner temperature of the reaction mixture does not exceed 20°C. When the addition is completed, the mixture is kept under stirring for two and a half hours at room temperature, still in a nitrogen atmosphere. Kilograms 5.22 tert.butylamine and 5. OKg glacial acetic acid, the latter in a controlled manner in order not to exceed 40°C, are added to the reaction mixture. It is heated under reflux (T=83°C) for two and a half hours, then cooled to room temperature and a solution of 3Kg sodium chloride in 17L water added thereto and the phases separated. The aqueous phase is extracted twice with toluene (7-5L) and organic extracts, collected together, are evaporated under reduced pressure to give 10.26Kg N-tert .butylaminomethylenesuccinonitrile as a brown solid. Example 2 N-tert . Butylamino ethylenesuccinonitrile (VI) In a nitrogen atmosphere and under stirring, to a suspension of llOg potassium tert.butoxide (1.05 moles) in IL toluene, a solution consisting of 250mL tert.butanol, 96mL ethyl formate (1.19 moles) and 80g succinonitrile (1 mole) is added dropwise, then cooled to about 5°C, the dripping time being controlled so that the inner temperature of the reaction mixture does not exceed 20°C. At first the reaction mixture thickens then it turns to a fluid and a yellow-ochre solid separates . When the addition is completed, the mixture is kept under stirring for two hours at room temperature, keeping it in a nitrogen ambience. Milliliters 107 (1.02 moles) tert .butylamine and, by dripping, 72mL (1.26 moles) glacial acetic acid are added to the reaction mixture: the temperature spontaneously rises to 45 °C and the reaction mass considerably thickens. It is heated under reflux, reaching a temperature of 83°C, for two hours, then cooled to room temperature. The reaction mixture is diluted with 250mL water, transferred into a separating funnel and after shaking, the phases are separated. The aqueous phase, at pH 6.98, is extracted with lOOmL toluene and the organic phases, collected together, made anhydrous on Na^SO^, filtered and evaporated under reduced pressure give 17Og N- tert .butylaminomethylene-succinonitrile as a brown solid. A sample, crystallized from acetone/diethyl ether, melts at 118-119°C. [TLC Si0 2 : (CHCl 3 /MeOH/cyclohexane/NH 4 OH 60/14/24/2) two spots corresponding to the two cis and trans iso ers having Rf=0.7 and 0.8]. Example 3 2-Amino-l-tert .butyl-4-cyanopyrrole (V) Grams 182 (2 moles) 85-'έ potassium hydroxide are dissolved in IL ethanol, the opalescent solution is filtered and, under stirring, a solution of 170g N- tert .butyl-aminomethylenesuccinonitrile in 300mL ethanol at the temperature of 50°C is added thereto. It is kept under stirring for 4 hours at room temperature, then the solution is concentrated under reduced pressure till a precipitate forms and the reaction mass is taken up with IL water, kept one night under stirring, the solid is filtered, washed with 250mL water and dried . to give 114.5g (0.7 moles) 2-amino-l-tert.butyl-4-cyanopyrrole (V), as a brown solid. The total yield calculated on starting succinonitrile is 72%. A sample crystallized from isopropyl ether melts at 112-113°C. [TLC(CHCl 3 /MeOH/cyclohexane/NH 4 OH 60/14/24/2) Rf=0.35]. Example 4 1-tert ,Butyl-3-cyano-7-azaindole (IV) To a solution of 30g (0.184 moles) 2-amino-l- tert .butyl-4-cyanopyrrole (V) in 300mL toluene, 33mL (0.2 moles) 1, 1, 3, 3-tetramethoxypropane and then 3.5g (0.0184 moles) p. toluensulphonic acid onohydrate are added. The reaction mixture is heated to reflux temperature, then the azeotrope between methanol, which is liberated during the reaction, and toluene is distilled off. After about two hours, the reaction mixture is cooled to room temperature and filtered off from the cake. The solid masses are taken up with lOOmL boiling cyclohexane and then discharged. The organic phases are collected together, evaporated under reduced pressure to give 29.3g (0.15 moles) 1- tert.butyl-3-cyano-7-azaindole (IV) . Yield 80 ! έ. A sample crystallized from cyclohexane melts at 91- 92°C. [TLC SiO;, (isopropylether) Rf=0.8]. Example 5 3-Cyano-7-azaindole (II) To a suspension of 10.22Kg anhydrous aluminium chloride in 50L chlorobenzene, 5.11Kg 1-tert .butyl-3- cyano-7-azaindole are added portionwise under stirring. The reaction mixture is heated under reflux for 8 hours then cooled to room temperature and, under stirring, 125Kg crushed ice are added thereto. Stirring is maintained till a white precipitate forms, then the precipitate is filtered in vacuo on Buchner, washed with water and dried at 70°C to give 3.35Kg 3- cyano-7-azaindole. Yield 91.3%. Weight Loss on drying: 0.3% Title on anhydrous ambient: 97.3 ; έ Example 6 3-Cyano-7-azaindole (II) To a solution of 24g (0.12 moles) 1-tert.butyl-3- cyano-7-azaindole dissolved in 240mL toluene, 48g (0.36 moles) anhydrous aluminium chloride are added. The reaction mixture is heated to reflux to give a homogeneous solution and it is kept under reflux temperature for 16 hours. Then it is cooled to room temperature and, while keeping the temperature unchanged, 40 ml of methanol are added dropwise over a period of 15 minutes. It is maintained under stirring for one hour till complete dissolution of the solid materials eventually formed and separated, during the reaction. To the reaction solution, under strong stirring and at room temperature, 600mL 2N hydrochloric acid are added dropwise. The phases are separated: the organic phase is discharged and the aqueous phase, separated by filtration from the insoluble residues, is treated with 32% NaOH, adjusted to pH 2.2 to give 15.35g 3-cyano-7-azaindole as a crystalline precipitate. Yield 89%. A sample crystallized from isopropanol melts at 259- 260°C. [TLC unitary (CHCl 3 /MeOH/cyclohexane/NH 4 OH 60/14/24/2) Rf=0.65]. Example 7 7-Azaindolyl-3-carboxylic acid (I) A suspension of 15g 3-cyano-7-azaindole in 150mL 32% hydrochloric acid and 150mL water is heated to 70°C to give a homogeneous solution which is kept at this temperature for 20 hours. The solution is decolorized at 70°C for about 2 hours with 0.4g charcoal, then filtered in a warm ambience on a celite panel. The filtrate is cooled to about 8-10°C and 7-azaindolyl-3- carboxylic acid starts precipitation, which is complete after addition of about 120mL 32% NaOH, an amount sufficient to keep the pH of the mixture at about 2.5. Stirring is maintained at room temperature for 2 hours, the precipitate is filtered and washed with water till disappearance of chloride ions in the filtrate. The precipitate is dried to give 15.45g 7- azaindolyl-3-carboxylic acid as a white solid. A sample crystallized from 2N EtOH/HCl 4:1 melts at 246°C. Yield 91%. [Unitary TLC (CHCl 3 /MeOH 8/2) Rf=0.6]. Example 8 7-Azaindole (IX) A solution of 5.1g (0.026 moles) 1-tert.butyl-3-cyano- 7-azaindole (IV) in 50mL 37% hydrochloric acid is heated under reflux for 24 hours. After cooling the solution to 70°C, a further 50mL 37% of hydrochloric acid are added and reflux is maintained for further 24 hours . The mixture is cooled to room temperature and diluted with lOOmL water. The solution is decolorized by adding O.lg charcoal and the insoluble is filtered on a celite panel. The filtrate is adjusted to pH 2 with a 32% sodium hydroxide solution, then transferred into a separating funnel and washed with 50mL methylene chloride. The aqueous phase containing 7- azaindole is adjusted to pH 7.5 with a 32% sodium hydroxide solution and extracted twice with 50mL methylene chloride each. The organic phases collected together are made anhydrous on sodium sulphate, evaporated under vacuum to give 2.35g 7-azaindole as a white solid melting at 105-106°C. Yield 75%. [TLC (CHCl 3 /MeOH/cyclohexane/NH 4 OH 60/14/24/2) Rf=0.55] . Example 9 7-Azaindole (IX) A solution of lg (0.07 moles) 3-cyano-7-azaindole (II) in lOmL 37% hydrochloric acid is heated under reflux for 24 hours. After cooling the solution to 70°C, a further lOmL 37% of hydrochloric acid are added and reflux is maintained for a further 24 hours. The solution is cooled to room temperature and, after addition of 20mL water, it is adjusted to pH 2.5 with a 32% sodium hydroxide solution. Grams 0.05 charcoal are added thereto and the insoluble is filtered on a celite panel. The filtrate is adjusted to pH 12 with a 32% sodium hydroxide solution, then transferred into a separating funnel and extracted twice with 25mL methylene chloride each. The organic phases are collected together and made anhydrous on sodium sulphate, the solvent is evaporated under vacuum to give 0.6g 7-azaindole as a white solid melting at 105- 106°C. Yield 73%. [TLC (CHCl 3 /MeOH/cyclohexane/NH 4 OH 60/14/24/2) Rf=0.55] .

Claims: Claims 1. A process for the preparation of 7-azaindolyl-3- carboxylic acid in which succinonitrile (VIII) is condensed with ethyl formate in the presence of a base and the so formed salt of 2- hydroxymethylenebutyrronitrile (VII) is directly reacted in the reaction mixture with an excess of tert .butylamine, characterized by the fact that the so obtained N-tert.butylaminomethylenesuccinonitrile (VI) is treated in a warm ambience in the presence of a base to give 1-ter .butyl-2-amino-4-cyanopyrrole (V) which is reacted with a malondialdehyde acetal in the presence of a suitable catalyst to give 1-tert.butyl- 3-cyano-7-azaindole (IV) which is dissolved in a suitable high boiling organic solvent and heated under reflux with at least three molar equivalents of a Lewis acid selected in the group consisting of aluminium chloride, boron chloride and boron bromide, and that the correspondingly formed dichloroderivative (III) is suitably protonated directly in the reaction mixture to give 3-cyano-7-azaindole (II) which is hydrolyzed with an aqueous solution of a mineral acid at the temperature of 70°C at pH 2.5 to provide the desired 7-azaindolyl-3-carboxylic acid (I) . 2. A process according to claim 1, characterized by the fact that the Lewis acid is aluminium chloride. 3. A process according to claim 1 or 2, characterized by the fact that the high boiling organic solvent is an ecologically compatible aromatic hydrocarbon, selected in the group consisting of toluene, xylenes and chlorobenzene. 4. A process according to claim 1, characterized by the fact that the malondialdehyde acetal is reacted with 1-tert.butyl-2-amino-4-cyanopyrrole (V) in the presence of p. toluensulphonic acid as catalyst. 5. A process according to claim 1, characterized by the fact that the proton donor is an aliphatic alcohol containing 1-4 carbon atoms selected in the group consisting of methanol, ethanol, isopropanol and tert .butanol. 6. A process according to claim 1, characterized by the fact that the high boiling solvent is chlorobenzene and the proton donor is water. 7. 2-Amino-l-tert .butyl-4-cyanopyrrole. 8. 1-tert . Butyl-3-cyano-7-azaindole . 9. A process for the preparation of 7-azaindole (IX) in which succinonitrile (VIII) is condensed with ethyl formate in the presence of a base and the formed salt of 2-hydroxymethylenebutyrronitrile (VII) is directly reacted in the reaction mixture with an excess of tert .butylamine, characterized by the fact that the so obtained N-tert .butylaminomethylenesuccinonitrile (VI) is treated in a warm ambience in the presence of a base to give 1-tert .butyl-2-amino-4-cyanopyrrole (V) which is reacted with a malondialdehyde acetal in the presence of a suitable catalyst to provide 1- tert .butyl-3-cyano-7-azaindole (IV) which is dissolved in a suitable high boiling organic solvent and heated under reflux with at least three molar equivalents of a Lewis acid in aqueous condition to give 7-azaindole (IX).

Inventors: CESTA MARIA CANDIDA, CURTI ROBERTO, MANTOVANINI MARCO, NICOLINI LUCA, CESTA, MARIA, CANDIDA, CURTI, ROBERTO, MANTOVANINI, MARCO, NICOLINI, LUCA
Applicants: CESTA MARIA CANDIDA, CURTI ROBERTO, DOMPE SPA, MANTOVANINI MARCO, NICOLINI LUCA, CESTA, MARIA, CANDIDA, CURTI, ROBERTO, DOMPE' SPA, MANTOVANINI, MARCO, NICOLINI, LUCA
Application year: 1999
Main classification: C07D471
IPC codes: C07D207, C07D471