WO2008037783A1

WO2008037783A1 - Process for preparing 2-oxo-2,5-dihydro-1h-pyrido[3,2-b]indole-3-carbonitriles

Info

Publication number: WO2008037783A1
Application number: PCT/EP2007/060288
Authority: WO
Inventors: Wim Bert Griet Schepens; Bart Rudolf Romanie Kesteleyn
Original assignee: Tibotec Pharmaceuticals Ltd.
Priority date: 2006-09-29
Filing date: 2007-09-28
Publication date: 2008-04-03

Abstract

A process for preparing 2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitriles starting from 1-substituted indole-2-carboxaldehyde with an aromatic amine and reacting the thus obtained intermediate with a cyanoacetic acid ester.

Description

Process for Preparing 2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indole-3-carbonitriles

Field of the Invention

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.

Background of the Invention

The virus causing the acquired immunodeficiency syndrome (AIDS) is generally known as the human immunodeficiency virus (HIV). The spread of HIV has caused and continues to cause serious health problems throughout the world. A number of HIV inhibitory drugs have been developed that currently are used to combat the virus. These drugs have proven out to be effective in suppressing the virus, in particular when used in combination therapy. However no therapy is capable of completely eliminating the virus from the body.

Several classes of HIV inhibitors at present are available and new ones are being explored. One such class is that of the reverse transcriptase inhibitors, which comprises the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs). Recently a further class of reverse transcriptase inhibitors has been identified which interact with the nucleotide binding site and not with the NNRTI binding site which are nucleotide competitive RT inhibitors (hereafter referred to as "NcRTIs"). Compounds of this class have been described in WO 2004/046163, WO 2005/111034, WO 2005/111035, WO 2005/111047 and WO 2005/111044. Combinations of the compounds of WO 2004/046163 with certain HIV inhibitors have been described in WO 2005/110411. Compounds of this class are promising for use in HIV therapy for use against NRTI and NNRTI mutant strains. Synthetic approaches for the preparation of these compounds have been described in these references.

Compounds of this new class are being considered for further development, including clinical studies. Consequently there is a need for producing larger quantities of these active ingredients based on processes that provide the products in high yield and with a high degree of purity.

The synthetic approaches that have been described to prepare NcRTI compounds involve multi-step procedures of four or more steps. In particular 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. Moreover, 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.

Description of the Invention

The present invention concerns a process for preparing a compound of formula:

or a pharmaceutically acceptable salt thereof, wherein

R¹ is Ci_₆alkyl optionally substituted with diCi_₆alkylamino, pyrrolidinyl, piperidinyl, morpholinyl;

R² 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-NH₂ (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 R¹, R² and Ar are as specified above, Lg is a leaving group and R is Ci_₄alkyl:

In a further aspect, 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-NH₂ (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 R¹, R² and Ar are as specified above, Lg is a leaving group:

In still a further aspect, 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-NH₂ (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 R¹, R², Ar, Lg and R are as specified above:

In this process variant, the conversion product from (II) with (III), i.e. intermediate (IV-a) is not isolated.

As used herein, the term Ci_₄alkyl 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_₄alkyl (i.e. n.Ci_₄alkyl, i.e. methyl, ethyl, n.propyl or n.butyl). Ci_₆alkyl 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 R¹ is Ci_₄alkyl, in particular methyl; or wherein R¹ is linear Ci_₄alkyl, in particular n.propyl or n.butyl, substituted in with diCi_₆alkylamino, pyrrolidinyl, piperidinyl, morpholinyl.

Particular subgroups of the compounds of formula (I) or of the intermediates used in the processes described herein are those wherein R² is hydrogen.

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. In a further embodiment 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.

In one embodiment 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. In one embodiment 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)PdCl₂ (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. palladium (II) acetate (Pd(OAc)₂) or (palladium)2(dibenzylideneacetone)3 (Pd₂(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. Na₂CO₃ or K₂CO₃, an alkoxide base, in particular an alkali metal Ci_₆alkoxide 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.

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. In some circumstances, 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-NH₂ (III). This washing step may cause the hydrolysis of the enamine (IV-a) to the aldehyde (IV-b). Depending on the substituents this hydrolysis may be relatively slow, leading to a mixture of (IV-a) and (IV-b) or relatively quick, leading to (IV-b). It has been found that if the intermediate (IV-a) is insoluble in the reaction medium, this will result in a precipitation of (IV-a) and no or little hydrolysis to (IV-b) will occur, while where intermediate (IV-a) is soluble in the reaction medium, hydrolysis has been found to occur. The solubility of (IV-a) in the reaction medium depends upon the medium selected and on the nature of the substituents.

Where a mixture of (IV-a) and (IV-b) is obtained, said mixture can be reacted with (V) to the desired end product (I). The condensation of (IV) with cyanoacetic acid ester (V) to the end product (I) may be conducted in a reaction-inert solvent, e.g. 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, in the presence of 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 R¹ -Lg, wherein R¹ 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.

In one embodiment, 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

Ar_N NH

\ R¹ (IV) are novel compounds.

Therefore, in a further aspect, the invention provides a compound of formula (IV) having the chemical structure as specified above, wherein the radicals Ar, R¹, and R² and X are as defined above, and =X represents =0 or =N-Ar. Particular intermediates of formula (IV) are those wherein the radicals Ar, R¹, and R² 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.

All references cited in this specification are incorporated herein in their entirety.

The following examples are meant to illustrate the present invention and not to limit it thereto. Examples Example 1

N-Bromosuccinimide (NBS) (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

(1200 ml). The reaction mixture was stirred at room temperature for 2 h. Ethyl acetate was added, the organic phase was washed with a 2 M aqueous NaOH solution and brine, dried with MgSO₄, and concentrated in vacuo. The crude reaction product was recrystallized from heptane to give 2 (52.0 g, yield = 79%). 1H NMR (δ, CDCl₃): 4.08 (3H, s), 7.23 - 7.27 (IH, m), 7.38 (IH, d, J = 8.4 Hz), 7.45 - 7.49 (IH, m), 7.69 (IH, d, J = 8.2 Hz), 10.13 (IH, s) ppm

An oven-dried reaction flask was charged with rac-2,2'-bis(diphenylphosphino)-l,l'- binaphthyl ((rac)-BINAP) (0.09 equiv., 3.9 mmol, 2.4 g), Pd2(dibenzylideneacetone)3 (Pd₂(dba)₃) (0.03 equiv., 1.3 mmol, 1.2 g), grinded Cs₂CO₃ (1.4 equiv., 58.6 mmol, 19.2 g) and dry toluene (140 ml), and then flushed with Ar. The reaction mixture was heated at 80⁰C for 30 min. After cooling to room temperature, compound 2 (1.0 equiv., 42.0 mmol, 10.0 g) and 4-nitroaniline (2.1 equiv., 88.2 mmol, 12.2 g) were added. The mixture was stirred at 110⁰C under Ar atmosphere until no starting material was left. The reaction was monitored by LCMS. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and a 3 M aqueous HCl solution was added. The resulting precipitate was filtered off, washed with a 1 M aqueous NaOH solution, water and dioxane, and dried in a vacuum to give 3 (8.3 g, yield = 48%).

A mixture of compound 3 (1.0 equiv., 1.20 mmol, 0.500 g), ethyl cyanoacetate (3.0 equiv., 3.61 mmol, 0.408 5 g) and piperidine (3.0 equiv., 3.61 mmol, 0.307 g) in glycol (10 ml) was stirred at 120 ⁰C for 2 h. After cooling to room temperature, the precipitate was filtered off and several times washed with methanol to give compound 4 (0.414 g, yield = 48%, purity (LC) = 100%).

¹H NMR (δ, DMSO-D6): 3.93 (3H, s), 6.12 (IH, d, J ~ 8 Hz), 6.89 (IH, t, J ~ 8 Hz), 7.45 (IH, t, J ~ 8 Hz), 7.64 (IH, d, J ~ 8 Hz), 7.89 (2H, d, J = 8.5 Hz), 8.54 (2H, d, J = 8.5 Hz), 8.99 (IH, s) ppm

Example 2

6 R² = H 7 R² = H 10 R² = MeO 11 R² = MeO

Preparation of Compound 7.

An oven-dried reaction flask was charged with rac-2,2'-bis(diphenylphosphino)-l,l'- binaphthyl ((rac)-BINAP) (0.09 equiv., 7.6 mmol, 4.8 g), Pd2(dibenzylideneacetone)3

(Pd₂(dba)₃) (0.03 equiv., 2.6 mmol, 2.4 g), grinded Cs₂CO₃ (1.4 equiv., 118.0 mmol,

38.3 g) and dry toluene (450 ml), and then flushed with Ar. The reaction mixture was heated at 80 ⁰C for 30 min. After cooling to room temperature, compound 2

(1.0 equiv., 84.0 mmol, 20.0 g) and 2-amino-5-chloropyridine (2.1 equiv., 176.0 mmol,

22.7 g) were added. The mixture was stirred at 110 ⁰C under Ar atmosphere until no more starting material was left. The reaction was monitored by LCMS. After cooling to room temperature, a 3 M aqueous HCl solution was added, the reaction mixture was extracted with dichloromethane. The combined organic phases were several times washed with a 3 M aqueous HCl solution, dried with MgSO₄ and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient elution: dichloromethane / ethyl acetate 95:5 -> 90:10) affording 6 (12.O g, yield = 50%).

A mixture of compound 6 (1.0 equiv., 38.8 mmol, 11.1 g), ethyl cyanoacetate (1.1 equiv., 42.7 mmol, 4.8 g) and piperidine (1.2 equiv., 42.7 mmol, 3.6 g) in glycol was stirred at room temperature for 2 h. The precipitate was filtered off and several times washed with methanol to give 7 (6.3 g, yield = 49%, purity (LC) = 100%). 1H NMR (δ, DMSO-D6): 3.94 (3H, s), 6.21 (IH, d, J = 8.3 Hz), 6.98 (IH, t, J = 7.7 Hz), 7.48 (IH, t, J = 7.7 Hz), 7.67 (IH, d, J = 8.5 Hz), 7.93 (IH, d, J = 8.4 Hz), 8.20 (IH, dd, J = 8.4, 2.4 Hz), 8.69 (IH, d, J = 2.4 Hz), 9.02 (IH, s) ppm.

Preparation of Compound 11.

Following the same procedures and starting from the methoxy analog 8 (R² is methoxy, -OMe in the above scheme) there was also prepared compound 11.

Example 3

15

HCI, H₂O

N-Bromosuccinimide (NBS) (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. Ethyl acetate was added, the organic phase was washed with a 2 M aqueous NaOH solution and brine, dried with MgSO₄ and concentrated in vacuo. The crude reaction product was recrystallized from heptane to give 3-bromo-2-carboxaldehyde (13) (8.4 g, yield = 65%).

¹H NMR (δ, DMSO-D6): 7.24 (IH, t, J ~ 8 Hz), 7.38 - 7.52 (2H, m), 7.63 (IH, d, J = 8.1 Hz), 9.94 (IH, s), 12.39 (IH, s(br)) ppm Sodium hydride (3.0 equiv., 13.4 mmol, 0.536 g (60%)) was portion wise added to a solution of 3-bromo-2-carboxaldehyde (13) (1.0 equiv., 4.46 mmol, 1.000 g) and tetrabutylammonium iodide (TBAI) (0.2 equiv., 0.89 mmol, 0.893 g) in dry DMF under Ar atmosphere, the reaction mixture was stirred at room temperature for 1 h. l-(2-Chloroethyl)pyrrolidine hydrochloride (1.5 equiv., 6.7 mmol, 1.000 g) was added and the reaction mixture was stirred at 50 ⁰C under Ar atmosphere until no more starting material was left. The mixture was concentrated under reduced pressure and partitioned between dichloromethane and water. The aqueous layer was further extracted with dichloromethane, the combined organic phases were dried with MgSO₄ and evaporated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: dichloromethane / methanol 98:2) to give 14 (1.3 g, yield = 91%). ¹U NMR (δ, CDC13): 1.80 - 2.20 (4H, m), 2.76 - 2.89 (4H, m), 2.94 (2H, dd, J = 7.8, 7.8 Hz) , 4.81 (2H, dd, J = 7.8, 7.8 Hz), 7.27 (2H, t, J ~ 8 Hz), 7.49 (IH, t, J ~ 8 Hz), 7.58 (lH,d, J ~ 8 Hz), 7.70 (IH, d, J ~ 8 Hz), 10.10 (IH, s) ppm

An oven-dried reaction flask was charged with rac-2,2'-bis(diphenylphosphino)-l,l'- binaphthyl ((rac)-BINAP) (0.12 equiv., 0.19 mmol, 0.116 g), Pd₂(dibenzylidene- acetone)₃ (Pd₂(dba)₃) (0.04 equiv., 0.06 mmol, 0.057 g), grinded Cs₂CO₃ (1.4 equiv., 2.18 mmol, 0.710 g) and dry toluene (50 ml), and then flushed with Ar. The reaction mixture was heated at 80 ⁰C for 30 min. After cooling to room temperature, compound 14 (1.0 equiv., 1.56 mmol, 0.500 g) and 4-nitroaniline (2.1 equiv., 3.27 mmol, 0.452 g) were added. The mixture was stirred at 110 ⁰C under Ar atmosphere for 3 h. The reaction mixture was partitioned between dichloromethane and a 3 M aqueous HCl solution. The organic phase was several times extracted with a 3 M aqueous HCl solution. The combined water phases were basifϊed with a saturated aqueous NaHCO₃ solution and extracted with chloroform. The chloroform phase was dried with MgSO₄ and evaporated under reduced pressure. The resulting residue, containing a mixture of compounds 15, 16 and 4-nitroaniline, was dissolved in glycol (8 ml). Ethyl cyanoacetate (1.0 equiv., 1.56 mmol, 0.176 g) and piperidine (1.0 equiv., 1.56 mmol, 0.133 g) were added, the reaction mixture was stirred at room temperature for 2 h. The precipitate was filtered off and washed with isopropanol and isopropylether to give 17 (0.09 g, yield = 14% starting from 14, purity (LC) = 99%).

¹H NMR (δ, DMSO-D6): 1.50 - 1.80 (4H, m), 2.35 - 2.90 (6H, m), 4.40 - 4.70 (2H, m), 6.12 (IH, d, J = 8.1 Hz ), 6.75 - 7.00 (IH, m), 7.30 - 7.50 (IH, m ), 7.67 (IH, d, J = 8.3 Hz), 7.91 (2H, d, J = 8.2 Hz ), 8.55 (IH, d, J = 8.2 Hz), 8.97 (IH, s) ppm.

Claims

1. A process for preparing a compound of formula:

or a salt thereof, wherein R¹ is Ci_₆alkyl optionally substituted with diCi_₆alkylamino, pyrrolidinyl, piperidinyl, morpholinyl;

R² is hydrogen or Ci_4alkyloxy; Ar is phenyl or pyridyl, both optionally substituted with one, two or three substituents selected from C^alkyl, 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-NH₂ (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 R¹, R² and Ar are as specified above, Lg is a leaving group and R is Ci_₄alkyl:

2. 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-NH₂ (III), thus obtaining a (2-imino methyl- lH-indo 1-3 -yl)-amine (IV-a), which is optionally converted to an aldehyde (IV-b) as represented in the following reaction scheme, wherein R¹, R² and Ar are as specified above, Lg is a leaving group:

3. A process according to claim 1 wherein the process is conducted without isolation of intermediate (IV-a) or (IV-b).

4. A process according to any of claims 1-3 wherein R¹ is Ci_₄alkyl, in particular methyl; or wherein R¹ is linear Ci_₄alkyl, in particular n.propyl or n.butyl, substituted in with diCi_₆alkylamino, pyrrolidinyl, piperidinyl, morpholinyl.

5. A process according to any of claims 1-3 wherein R² is hydrogen.

6. A process according to any of claims 1-3 wherein Ar is phenyl substituted with nitro or halo, in particular Ar is phenyl substituted with nitro, more in particular Ar is 4-nitrophenyl; or Ar is pyridyl substituted with halo, in particular with chloro, more in particular Ar is 6-chloro-3-pyridinyl.

7. A process according to any of claims 1-3 wherein Lg is halo, in particular bromo, iodo, or Lg is a triflate group.

8. A process according to any of claims 1-3 wherein R is methyl or ethyl.

9. A compound of formula

wherein R , 1 , r R> 2 , X and Ar are as defined in claim 1.

10. A compound according to claim 9 wherein X is N-Ar and one or more of R¹, R² and Ar are as defined in claims 4, 5 and 6.