WO2008037783A1 - Processus de préparation de 2-oxo-2,5-dihydro-1h-pyrido[3,2-b]indole-3-carbonitriles - Google Patents

Processus de préparation de 2-oxo-2,5-dihydro-1h-pyrido[3,2-b]indole-3-carbonitriles Download PDF

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Publication number
WO2008037783A1
WO2008037783A1 PCT/EP2007/060288 EP2007060288W WO2008037783A1 WO 2008037783 A1 WO2008037783 A1 WO 2008037783A1 EP 2007060288 W EP2007060288 W EP 2007060288W WO 2008037783 A1 WO2008037783 A1 WO 2008037783A1
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Prior art keywords
formula
compound
substituted
alkyl
indole
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PCT/EP2007/060288
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English (en)
Inventor
Wim Bert Griet Schepens
Bart Rudolf Romanie Kesteleyn
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Tibotec Pharmaceuticals Ltd.
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Publication of WO2008037783A1 publication Critical patent/WO2008037783A1/fr

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    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • This invention relates to a process for preparing 2-oxo-2,5-dihydro-lH-pyrido[3,2-b]- indole-3-carbonitriles starting from 1 -substituted indole-2-carboxaldehydes with an aromatic amine and reacting the thus obtained intermediates with a cyanoacetic acid ester.
  • HIV human immunodeficiency virus
  • HIV inhibitors which comprises the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs).
  • NRTIs nucleoside reverse transcriptase inhibitors
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • NRTIs nucleoside reverse transcriptase inhibitors
  • NcRTIs nucleotide competitive RT inhibitors
  • NcRTI compounds involve multi-step procedures of four or more steps.
  • WO 2005/111047 at p. 73 describes a procedure for preparing 2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indole-3- carbonitriles starting from N-acetyl-3 -hydroxy- indole wherein the 3 -hydroxy group is substituted by an arylamino group, then the acetyl group is removed and the resulting indole derivative is formylated in a Vilsmeier-Haack procedure using POCI3 and DMF to a 2-formyl-3-arylamino-indole.
  • the latter is cyclized with ethyl cyanoacetate to a 2-0X0-2, 5-dihydro-lH-pyrido[3,2-b]indole-3-carbonitrile, which is alkylated in its 5-position with an alkyl iodide.
  • This alkylation has to be postponed until after the formylation reaction because when using 1 -alkyl- indoles as starting materials, the formylation reaction gives rise to side reactions resulting in lower yields and complex purification procedures.
  • the Vilsmeier-Haack formylation reaction in the procedure of WO 2005/111047 runs in low yield (25% in the example that is referred to) so that the described procedure is inappropriate for scaling up due to its low overall yield.
  • the present invention is aimed at providing new synthesis processes for preparing
  • NcRTI compounds that comprise less steps, that can be scaled up for the production of multi-kilogram or larger quantities, that are reproducible, economical and through which the end product is obtained in high yield and with a high degree of purity.
  • the present invention concerns a process for preparing a compound of formula:
  • R 1 is Ci_ 6 alkyl optionally substituted with diCi_ 6 alkylamino, pyrrolidinyl, piperidinyl, morpholinyl;
  • R 2 is hydrogen or Ci_6alkyloxy
  • Ar is phenyl or pyridyl, both optionally substituted with one, two or three substituents selected from Chalky!, halo, nitro, cyano and Ci_6alkoxy; wherein the process comprises condensing a 1 -substituted indole-2-carboxaldehyde of formula (II) with an aromatic amine Ar-NH 2 (III), thus obtaining a (2-iminomethyl-lH-indol-3-yl)- amine (IV-a), which is optionally converted to an aldehyde (IV-b), and reacting the (2-imino methyl- lH-indo 1-3 -yl)-amine (IV-a) or the aldehyde (IV-b), or a mixture thereof, with a cyanoacetic acid ester (V) as represented in the following reaction scheme, wherein R 1 , R 2 and Ar are as specified above, Lg is a leaving group and R is Ci_ 4 alky
  • this invention concerns a process for preparing a compound of formula (IV-a) or (IV-b), or a mixture thereof, wherein the compound of formula (IV-a) or (IV-b) is as specified above, wherein said process comprises condensing a 1 -substituted indole-2-carboxaldehyde of formula (II) with an aromatic amine Ar-NH 2 (III), thus obtaining a (2-iminomethyl-lH-indol-3-yl)-amine (IV-a), which is optionally converted to an aldehyde (IV-b) as represented in the following reaction scheme, wherein R 1 , R 2 and Ar are as specified above, Lg is a leaving group:
  • the invention concerns a process for preparing a compound of formula (I), as specified above, wherein the compound of formula (I) is prepared by condensing a 1 -substituted indole-2-carboxaldehyde of formula (II) with an aromatic amine Ar-NH 2 (III), and with a cyanoacetic acid ester (V), without isolation of the condensation product of the reaction between (II) and (III), to obtain the desired end product of formula (I), as outlined in the following reaction scheme wherein R 1 , R 2 , Ar, Lg and R are as specified above:
  • Ci_ 4 alkyl defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methyl-l -propyl, 2-methyl-2-propyl.
  • Ci_4alkyl may be a linear Ci_ 4 alkyl (i.e. n.Ci_ 4 alkyl, i.e. methyl, ethyl, n.propyl or n.butyl).
  • Ci_ 6 alkyl encompasses Ci_4alkyl and the homologues having 5 or 6 carbon atoms such as, e.g., pentyl, 2-methylbutyl, 3-methylbutyl, 2-ethylpropyl, hexyl, 2-methylpentyl, 3-methyl- pentyl, 2-ethylbutyl, and the like.
  • Particular subgroups of the compounds of formula (I) or of the intermediates used in the processes described herein are those wherein R 1 is Ci_ 4 alkyl, in particular methyl; or wherein R 1 is linear Ci_ 4 alkyl, in particular n.propyl or n.butyl, substituted in with diCi_ 6 alkylamino, pyrrolidinyl, piperidinyl, morpholinyl.
  • Particular subgroups of the compounds of formula (I) or of the intermediates used in the processes described herein are those wherein Ar is phenyl substituted with nitro or halo, in particular Ar is phenyl substituted with nitro, more in particular Ar is 4-nitrophenyl.
  • Ar is pyridyl substituted with halo, in particular with chloro, more in particular Ar is a group which can be designated as 2-chloro-pyridin-5-yl or 6-chloro-3-pyridinyl.
  • Lg is halo, in particular chloro, bromo, iodo, or Lg is a triflate (or trifluoromethanesulfonate) group.
  • the conversion from (II) with (III) to (IV-a) is an aryl animation reaction in which an aromatic halide or pseudohalide (such as a triflate) is reacted with an amine.
  • this aryl amination reaction is a Buchwald-Hartwig type of reaction, which comprises reacting an aromatic halide or pseudohalide with the amine in the presence of a catalyst, in particular a palladium catalyst.
  • Suitable palladium catalysts are palladium phosphine complexes, such as the palladium Xantphos complexes, in particular Pd(Xantphos)2 (Xantphos being 9,9'-dimethyl-4,5-bis(diphenylphosphino)- xanthene), the DPPF complexes of palladium such as (DPPF)PdCl 2 (DPPF being l,l '-bis(diphenylphosphino)ferrocene), the palladium complexes of l,l'-binaphthalene- 2,2'-diylbis(diphenylphosphine) (BINAP), which can be used as such or can be prepared in situ such as by reaction of a palladium salt or palladium complex such as e.g.
  • BINAP palladium (II) acetate (Pd(OAc) 2 ) or (palladium)2(dibenzylideneacetone)3 (Pd 2 (dba) 3 ), with BINAP.
  • the BINAP ligand may be used in its racemic form.
  • This reaction may be conducted in a suitable solvent such as an aromatic hydrocarbon, e.g. toluene, or an ether, e.g. tetrahydrofuran (THF), methylTHF, dioxane and the like, in the presence of a base such as an alkali metal carbonate or phosphate, e.g.
  • an alkoxide base in particular an alkali metal Ci_ 6 alkoxide such as sodium or potassium t.butoxide (NaOtBu or KOtBu), or an organic bases such as l,8-diazabicyclo(5.4.0)undec-7-ene (DBU) or a tertiary amine (e.g. triethylamine), and in particular in the presence of cesium carbonate.
  • Ci_ 6 alkoxide such as sodium or potassium t.butoxide (NaOtBu or KOtBu)
  • organic bases such as l,8-diazabicyclo(5.4.0)undec-7-ene (DBU) or a tertiary amine (e.g. triethylamine), and in particular in the presence of cesium carbonate.
  • DBU l,8-diazabicyclo(5.4.0)undec-7-ene
  • a tertiary amine e.g. triethyl
  • the intermediates of formula (IV-a) may be converted to the corresponding aldehydes of formula (IV-b) by treatment of the former with aqueous acid, e.g. aqueous HCl or HBr.
  • aqueous acid e.g. aqueous HCl or HBr.
  • the intermediates of formula (IV-a) will be transformed to those of formula (IV-b) during the work-up of the reaction of (II) with (III).
  • Washing with aqueous acid, for example with aqueous HCl, of the reaction mixture of the reaction of (II) with (III) may be done to remove basic components such as unreacted Ar-NH 2 (III). This washing step may cause the hydrolysis of the enamine (IV-a) to the aldehyde (IV-b).
  • an alcohol such as methanol, ethanol, n.propanol, isopropanol
  • an ether such as THF
  • a dipolar aprotic solvent such as DMA, DMF, DMSO, NMP
  • a halogenated hydrocarbon such as dichloromethane, chloroform
  • an aromatic hydrocarbon such as toluene
  • a glycol such as ethylene glycol
  • a base e.g. an amine such as piperidine, pyrrolidine, morpholine, triethylamine, diisopropylethylamine (DIPE), and the like.
  • the intermediates of formula (II) wherein Lg is halo may be prepared by halogenating an indole derivative of formula (VI).
  • Suitable halogenating agents are the halogens themselves or halogenating reagents such as the halogenated succinimides, e.g. N-chloro or N-bromosuccinimide.
  • This halogenating reaction may be conducted in a suitable solvent, such as, for example, an aromatic hydrocarbon, e.g. toluene, or an ether, e.g. tetrahydrofuran (THF), methylTHF, dioxane, and the like.
  • Other derivatives of formula (II) can be prepared by exchanging the halo group by other leaving groups.
  • the intermediates of formula (II) may also be prepared by first preparing 3-bromo- indole-2-carboxaldehyde and subsequent N-alkylation of the latter with a reagent R 1 -Lg, wherein R 1 and Lg are as specified above and Lg in particular is a halo group such as chloro or bromo.
  • the N-alkylation may be conducted in a suitable solvent, e.g. a dipolar aprotic solvent such as DMA, DMF, DMSO and the like in the presence of a base such as an alkali metal hydride, e.g. NaH or LiH.
  • a nucleophilic catalyst may be added to the reaction mixture, e.g. tetrabutylammonium iodide (TBAI).
  • the process for preparing the compound of formula (I) of the invention starts from intermediates (II) and (III) to obtain the intermediate (IV) and subsequent condensation of (IV) with (V) to obtain compound (I). In one embodiment, all of the steps of this process may be conducted in the same solvent or solvent mixture.
  • this process is conducted in a one-pot procedure, without isolation of intermediate (IV).
  • the reaction of (II) with (III) is conducted in the solvent described above for this reaction, in particular a hydrocarbon such as toluene, which is removed partially or completely after which the solvent described above for the reaction of (IV) with (V), in particular an alcohol such as glycol, is added.
  • This process variant offers the possibility to synthesize compound (I) in a quick, simple and straightforward manner.
  • An additional feature of the present invention comprises the fact that the intermediates of formula
  • Particular intermediates of formula (IV) are those wherein the radicals Ar, R 1 , and R 2 have the specific meanings defined above.
  • a subclass of the intermediates of formula (IV) is that wherein X is N-Ar, i.e. intermediates (IV-a).
  • Another subclass of the intermediates of formula (IV) is that wherein X is O, i.e. intermediates (IV-b).
  • the process of the present invention runs in relatively high yield making it suitable for scaling up for the production of multi-kilogram and larger quantities.
  • the process is well-suited for preparing end products having Ar groups with various substitutions, whereas the process described in WO 2005/111047 gave poor results, for example for Ar being chloropyridine.
  • the process moreover is reproducible and economical. Further advantages that may be mentioned are the availability of starting materials and reagents that can be purchased or are easy to prepare.
  • N-Bromosuccinimide (1.05 equiv., 290 mmol, 51.7 g) was added to a solution of l-methylindole-2-carboxaldehyde (1) (1.0 equiv., 276 mmol, 44.0 g) in Me-THF
  • N-Bromosuccinimide (1.2 equiv., 69.4 mmol, 12.4 g) was added to a solution of indole-2-carboxaldehyde (12) [Agnusdei, M.; Bandini, M.; Melloni, A., Alfonso; Umani-Ronchi, A. J. Org. Chem. 2003, 68, 7126-7129] (1.0 equiv., 57.9 mmol, 8.4 g) in Me-THF (500 ml). The reaction mixture was stirred at room temperature for 2 h.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

l'invention concerne un processus de préparation de 2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitriles commençant par indole-2-carboxaldehyde substitué en 1 avec une amine aromatique et qui consiste ensuite à faire réagir l'intermédiaire ainsi obtenu avec un ester d'acide cyanoacétique.
PCT/EP2007/060288 2006-09-29 2007-09-28 Processus de préparation de 2-oxo-2,5-dihydro-1h-pyrido[3,2-b]indole-3-carbonitriles WO2008037783A1 (fr)

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EP06121584.4 2006-09-29
EP06121584 2006-09-29

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WO2008037783A1 true WO2008037783A1 (fr) 2008-04-03

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8349839B2 (en) 2009-04-09 2013-01-08 Boehringer Ingelheim International Gmbh Inhibitors of HIV replication
WO2016054491A1 (fr) 2014-10-03 2016-04-07 Infinity Pharmaceuticals, Inc. Composés hétérocycliques et leurs utilisations
WO2017214269A1 (fr) 2016-06-08 2017-12-14 Infinity Pharmaceuticals, Inc. Composés hétérocycliques et leurs utilisations

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002059123A2 (fr) * 2000-12-18 2002-08-01 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Composes benzoylalkylindolepyridinium et compositions pharmaceutiques comprenant ces composes
WO2004046143A1 (fr) * 2002-11-15 2004-06-03 Tibotec Pharmaceuticals Ltd. Indolepyridinium substitue utilise comme composes anti-infection
WO2005110411A1 (fr) * 2004-05-17 2005-11-24 Tibotec Pharmaceuticals Ltd. Combinaison de substitue 1-phenyl-1,5-dihydro-pyrido- [3,2-b] indol-2-ones et autres inhibiteurs du vih
WO2005111044A1 (fr) * 2004-05-17 2005-11-24 Tibotec Pharmaceuticals Ltd. 1,5-dihydropyrido[3,2-b]indol-2-ones substituees en position 4
WO2005111047A1 (fr) * 2004-05-17 2005-11-24 Tibotec Pharmaceuticals Ltd. 1-heterocyclyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones
WO2005111035A1 (fr) * 2004-05-17 2005-11-24 Tibotec Pharmaceuticals Ltd. 6,7,8,9-substitue 1-phenyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones convenant comme agents pharmaceutiques anti-infectieux

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002059123A2 (fr) * 2000-12-18 2002-08-01 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Composes benzoylalkylindolepyridinium et compositions pharmaceutiques comprenant ces composes
WO2004046143A1 (fr) * 2002-11-15 2004-06-03 Tibotec Pharmaceuticals Ltd. Indolepyridinium substitue utilise comme composes anti-infection
WO2005110411A1 (fr) * 2004-05-17 2005-11-24 Tibotec Pharmaceuticals Ltd. Combinaison de substitue 1-phenyl-1,5-dihydro-pyrido- [3,2-b] indol-2-ones et autres inhibiteurs du vih
WO2005111044A1 (fr) * 2004-05-17 2005-11-24 Tibotec Pharmaceuticals Ltd. 1,5-dihydropyrido[3,2-b]indol-2-ones substituees en position 4
WO2005111047A1 (fr) * 2004-05-17 2005-11-24 Tibotec Pharmaceuticals Ltd. 1-heterocyclyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones
WO2005111035A1 (fr) * 2004-05-17 2005-11-24 Tibotec Pharmaceuticals Ltd. 6,7,8,9-substitue 1-phenyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones convenant comme agents pharmaceutiques anti-infectieux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
N.Z.TUGUSHEVA ET AL: "Investigation of the reaction of N-acetylinindoxyl with substituted anilines - synthesis of derivatives of indolo[3,2-b]quinolines", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, vol. 37, no. 7, 2001, pages 885 - 893, XP002421863 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8349839B2 (en) 2009-04-09 2013-01-08 Boehringer Ingelheim International Gmbh Inhibitors of HIV replication
WO2016054491A1 (fr) 2014-10-03 2016-04-07 Infinity Pharmaceuticals, Inc. Composés hétérocycliques et leurs utilisations
WO2017214269A1 (fr) 2016-06-08 2017-12-14 Infinity Pharmaceuticals, Inc. Composés hétérocycliques et leurs utilisations

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