Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

• 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:
• 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 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 .
• 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.
• 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.
• a suitable catalyst such as p.toluensulphonic acid
• 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.
• 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.
• 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 .
• 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.
• 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) .
• a sample crystallized from isopropyl ether melts at 112-113°C.
• 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.
• 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 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 9
• 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%.
• 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.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

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• 1998
  • 1998-11-17 IT IT1998MI002480A patent/IT1303759B1/it active
• 1999
  • 1999-11-12 EP EP99952758A patent/EP1149098A1/de not_active Withdrawn
  • 1999-11-12 WO PCT/IB1999/001834 patent/WO2000029411A1/en not_active Application Discontinuation
  • 1999-11-12 AU AU64845/99A patent/AU6484599A/en not_active Abandoned
  • 1999-11-12 HU HU0104278A patent/HUP0104278A3/hu unknown
  • 1999-11-12 JP JP2000582398A patent/JP2002530282A/ja active Pending

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