Synthesis of ( s)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1 h-pyrrolo[2,3-b]pyridin-3-YL)pyridin-2(1 h)-one

Abstract

The present invention concerns a chiral process for the preparation of (S)-1-(1-(3- chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3- yl)pyridin-2(1H)-one.

Description

[0001] SYNTHESIS OF (S)-1-(1-(3-CHLOROPHENYL)-2-(DIMETHYLAMINO)ETHYL)- 4-(5-MORPHOLINO-1H-PYRROLO[2,3-b]PYRIDIN-3-YL)PYRIDIN-2(1H)-ONE FIELD OF THE INVENTIONThe present invention relates to a novel chiral preparation process of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3- yl)pyridin-2(1H)-one which is an inhibitor of ERK kinases (ERK1 and ERK2). ERK protein belongs to the RAS / RAF / MEK / ERK pathway which plays a major role in cellcycle, proliferation, growth, and survival. RAS / RAF / MEK / ERK pathway is activated bygrowth factors through their receptor tyrosine kinase that allows activation of GTPases RAS. In its turn, RAS activates RAF proteins. Then, RAF activates MEK, which activates ERK. Finally, this enables phosphorylation of many substrates that have key roles in metabolism, protein synthesis, cell proliferation and survival. RAF mutations lead specifically to an over-activation of this RAS / RAF / MEK / ERK pathway and are responsible for 7% of all human cancers (Davies et al., Nature.2002; Garnett et al., Cancer Cell.2004).Indeed, RAF mutations are frequently observed in melanomas (27-70%), thyroid cancers(36-53%), colorectal cancers (5-22%) and ovarian cancers (30%). Likewise, RAS mutations occur in almost 30% of cancers and are present in pancreatic (90%), lung (35%), colorectal (45%) and liver (30%) cancers (Downward, Nat. Rev. Cancer.2003). Thus, proteins of RAS / RAF / MEK / ERK pathway represent targets of interest for cancerstreatment. Indeed, pharmaceutical companies are focusing on upstream kinases (RAF,MEK). However, resistances ultimately appear after current treatment with RAF and MEK inhibitors (Lito et al., Nat. Med.2013; Caunt et al., Nat. Rev. Cancer, 2015). Moreover, most resistances to MEK or RAF inhibitors induce ERK reactivation, through different mechanisms such as MEK mutation, B-RAF amplification, C-RAF mutation... (Little et al., Oncogene.2013). Furthermore, RAF or MEK inhibition suppresses ERK negative feedback that restores upward signaling and finally ERK activity (Lito et al., Nat. Med., 2013). Considering the resistance phenomena that emerged after current treatment with RAF and MEK inhibitors, it is essential to develop new therapeutic options. Except for its key role in hyperproliferative diseases, ERK signaling has also been described as implied in neurodegenerative disorders such as in Parkinson’s, Alzheimer’s and Huntington’s diseases (Cheung et al., Sci. STKE.2004; Bodai et al., Bioessays., 2012) and in inflammation such as in the pathogenesis of Rheumatoid Arthritis (Thalhamer et al., Rheumatology.2008). The compound (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one of formula (I), depicted below, has beendeveloped, and is an efficient inhibitor of ERK kinases (ERK1 and ERK2). It may be usedin particular as anticancer agent. A racemic synthesis of this compound has already been described in WO2023135233.An important disadvantage of known synthesis is thus that it leads to a racemic mixture.Thus, such synthesis requires a final chiral separation. Therefore, half of the materialsprepared along the steps goes to waste. Consequently, the yield of the known process is not high enough. Further, while feasible on small scale for the initial in vitro and animal research phase, theknown process poses the problems of scalability in terms of time, cost and generalapplicability to clinical development phase for industrial preparation of a pharmaceuticallyactive ingredient. There is therefore a need to provide new means for improving the preparation of (S)-1-(1- (3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one, and to develop a chiral process for the preparation of this compound. The present invention is precisely directed to a novel chiral process of preparing (S)-1-(1- (3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3- yl)pyridin-2(1H)-one.Thus, a first subject of the invention concerns a process for the preparation of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one comprising performing a Sharpless asymmetric dihydroxylation on acompound of formula (2): to selectively form a chiral compound of formula (3):and then converting said compound of formula (3) into the corresponding chiral epoxide offormula (4): .Another subject of the invention concerns a process for the preparation of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one comprising a Suzuki coupling reaction of a compound of formula (7)and a compound of formula (11): The present invention also relates to a process for the preparation of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3- yl)pyridin-2(1H)-one, characterized in that: A) a compound of formula (1): is subjected to a direct olefination to obtain a compound of formula (2): B) the compound of formula (2) is subjected to a Sharpless asymmetric dihydroxylation to form the chiral compound of formula (3): C) the compound of formula (3) is converted to the corresponding chiral epoxide offormula (4): D) the compound of formula (4) is then put in the presence of dimethylamine, to forma chiral compound of formula (5): E) the compound of formula (5) is converted to the chiral compound of formula (6):

[0002] F) the compound of formula (6) is subjected to a reaction of N-alkylation with 4-bromo-1H-pyridin-2-one to give the chiral compound of formula (7): is subjected to a Buchwald-Hartwig coupling reaction with morpholine to obtain a compound of formula (9): H) the compound of formula (9) is subjected to a protection reaction of the pyrrolylmoiety of the 7-azindole core to obtain a compound of formula (10):

[0003] I) the compound of formula (10) is subjected to a selective borylation of the azaindole core in position 3 to obtain a compound of formula (11): J) the compound of formula (7) and the compound of formula (11) are subjected to aSuzuki coupling reaction to give the chiral compound of formula (12): and K) the compound of formula (12) is subjected to a deprotecting reaction to give (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3- b]pyridin-3-yl)pyridin-2(1H)-one. The process of the present invention presents the advantages of selectively preparing (S)-1- (1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one, without requiring a final chiral separation.In addition, the process provides high yielding synthesis of (S)-1-(1-(3-chlorophenyl)-2- (dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one,as well as robust and scalable conditions, which fulfills the current clinical and industrialrequirements. ABBREVIATIONS AND DEFINITIONS In the context of the present invention, the following abbreviations and empirical formulae are used: CaCl2Calcium Chloride CDCl3 Deuterated chloroform CH3CN AcetonitrileCs2CO3Caesium carbonate DCM Dichloromethane(DHQ)2PHAL Hydroquinine 1,4-phthalazinediyl dietherDMA DimethylamineDMF DimethylformamideDMSO Dimethylsulfoxide°C Degree CelsiusEq EquivalentEt2O Diethyl etherEt3N TriethylamineEtOAc Ethyl acetateEtOH Ethanolg gram(s)h hour(s)H2CO2Formic acid HPLC High performance liquid chromatographyIR Infrared SpectroscopyK2CO3Potassium carbonate Kg KilogramL LiterLC / MS Liquid chromatography / mass spectrometryLiHMDS Lithium bis(trimethylsilyl)amideM Mole(s) per literMeCN AcetonitrileMeOH MethanolMeONa Sodium methoxidemg Milligram(s)MH+ Pseudo-molecular ion (positive ion mode in mass spectrometry)MS Mass Spectrometryµl Microliter(s)ml Milliliter(s)mmol Millimole(s)mol Mole(s)MsCl Mesyl chlorideNa2CO3 Sodium carbonateNaH Sodium hydrideNaHCO3Sodium hydrogen carbonate Na2CO3 Sodium carbonate Na2SO4 Sodium sulfateNH4Cl Ammonium chlorideNMR Nuclear Magnetic ResonancePor PorosityRH Relative HumidityRuPhos 2-Dicyclohexylphosphino-2’,6’-diisopropoxybiphenylRuPhos Pd G2 Chloro(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-bi-phenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II)RuPhos Pd G3 (2-Dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonateRuPhos Pd G4 [Dicyclohexyl(2’,6’-diisopropoxy-2-biphenylyl)phosphine-κP](methanesulfonatato-κO)[2’-(methylamino-κN)-2- biphenylyl-κC2]palladiumTBAF Tetrabutylammonium fluoridetBuOH tert-Butyl alcoholtBuOK Potassium tert-butoxideTEBAC Benzyltriethylammonium chlorideTEOA Triethyl orthoacetateTHF TetrahydrofuranTLC Thin Layer ChromatographyTMSCl Trimethylsilyl chlorideTs TosylUV UltravioletAs used herein, the term “ambient temperature” or “room temperature” refers to a temperature ranging from 15°C to 30°C, more particularly from 18°C to 25°C. Other features, properties and advantages of the invention will emerge more clearly from the description and examples that follow. DETAILED DESCRIPTION Olefination The compound of formula (2) is obtained by direct olefination of commercially availablealdehyde of formula (1). The reaction is generally performed with methyltriphenylphosphonium bromide in presenceof a base, such as NaH or K2CO3, preferably K2CO3, and in an anhydrous solvent, such as1,4-dioxane, Et2O, DCM or THF, preferably 1,4-dioxane. In particular, the reaction is performed at a temperature varying from 90°C to 110°C, preferably at 100°C.In particular, the reaction is performed for 1 to 3 hours, in particular for 1 to 2 hours,preferably for 1.5 hours.In particular, the reaction is performed under argon atmosphere. asymmetric dihydroxylation The compound of formula (3) is obtained by performing a Sharpless asymmetricdihydroxylation of the compound of formula (2). A Sharpless asymmetric dihydroxylation, also named a Sharpless bishydroxylation, is a chemical reaction of an alkene with osmium tetroxide in the presence of a chiral quinine ligand to form a vicinal diol. In particular, the reaction of Sharpless asymmetric dihydroxylation is performed in presenceof K3Fe(CN)6, K2CO3, K2Os(OH)4 and (DHQ)2PHAL. This dihydroxylation can also beperformed directly with AD-mix-α ασ ρεαχταντ.The reaction is generally performed in presence of a solvent, in particular in tBuOH or in amixture tBuOH / H2O, and preferably the solvent is tBuOH. In particular, the reaction is performed at room temperature.In particular, the reaction is performed for 15 to 20 hours, preferably for 16 hours. The compound of formula (4) is obtained by performing an epoxidation of the compound offormula (3). In particular, the reaction is performed in two steps. In particular, the first step is performed with the compound of formula (3), triethylorthoacetate (TEOA) and trimethylsilyl chloride (TMSCl), in presence of a solvent, inparticular DCM. In particular, the first step is performed at 0°C.In particular, the first step is performed for 2 to 4 hours, preferably for 3 hours.In particular, the first step is performed under argon atmosphere.In particular, the second step is performed with K2CO3, in presence of a solvent, in particularmethanol. In particular, the second step is performed at 0°C.In particular, the second step performed for 0.1 to 2 hours, preferably for 1 hour.In particular, the second step is performed under argon atmosphere. In particular, the first step is performed in the presence of triethyl orthoacetate (TEOA) and trimethylsilyl chloride (TMSCl) and a solvent, and the second step is performed in thepresence of K2CO3, and a solvent.More particularly, the first step is performed in the presence of triethyl orthoacetate (TEOA)and trimethylsilyl chloride (TMSCl) and DCM as a solvent, and the second step is performedin the presence of K2CO3, and methanol as a solvent. Selective epoxide opening of the compound of formula (4) is carrying out with commercially available dimethylamine.The reaction is generally performed with a solvent, in particular in EtOH or in an EtOH / watermixture, preferably in EtOH, more preferably in EtOH 96%.In particular, the reaction is performed at 0°C for 0.5 to 2 hours, preferably for 1 hour, andthen at room temperature for 20 to 24 hours, preferably for 21 hours. Conversion of the alcohol into the corresponding chloroderivative The benzylalcohol derivative of formula (5) is converted to the correspondingbenzylchloride derivative of formula (6) using MsCl and Et3N. The reaction is generally performed in presence of an anhydrous solvent, preferably DCM. In particular, the reaction is performed at 0°C. In particular, the reaction is performed under argon atmosphere. N-alkylation The compound of formula (7) is obtained by a substitution of the chlorine atom, usingcommercially available 4-bromo-1H-pyridin-2-one in the presence of a base such as K2CO3or Na2CO3, preferably K2CO3, and in DMF or DMA, preferably in DMF.The reaction could also be done in another solvent such as THF, Et2O, DCM or acetone and with other bases like NaOH or tBuOK. In particular, the reaction is performed at room temperature.In particular, the reaction is performed for 10 to 20 hours, preferably for 14 hours.Buchwald-Hartwig coupling reaction The 5-morpholino-7-azaindole compound of formula (9) is obtained from commerciallyavailable compound of formula (8), by carrying out a Buchwald-Hartwig coupling reactionin the presence of morpholine, with a base such as LiHMDS, a catalyst like RuPhos and aRuPhos ligand such as RuPhos Pd G2. Other RuPhos ligands such as RuPhos Pd G3 orRuPhos Pd G4 could also be used to obtain compound of formula (9). Preferably, the reactionis performed with LiHMDS as a base, RuPhos as catalyst and RuPhos Pd G2 as ligand.This reaction is generally performed in an anhydrous solvent, preferably THF.In particular, the reaction is performed at a temperature varying from 60°C to 70°C, preferably at 66°C.In particular, the reaction is performed for 1 to 3 hours, in particular for 1 to 2 hours,preferably for 1.5 hours.In particular, the reaction is performed under argon atmosphere. Protection of the pyrrolyl moiety of the 7-azindole core The compound of formula (10) is obtained by performing a protection of the pyrrolyl moietyof the 7-azaindole core with Ts as a protecting group, and using TEBAC, a base, such asNaOH or K2CO3, preferably NaOH, in an anhydrous solvent, such as DMF, DCM or THF,preferably DCM. This reaction is generally performed at 0°C to room temperature.In particular, the reaction is performed for 3 to 5 hours, preferably for 4 hours.Selective borylation The compound of formula (11) is obtained by a selective borylation of the azaindole core inposition 3, using (1,5-cyclooctadiene)(methoxy)iridium(I), in presence of a ligand, such as4,4’-di-tert-butylbipyridine, and a source of boron, such as bis(pinacolato)diboron.In particular, the reaction is performed in methyltetrahydrofuran.In particular, the reaction is performed at reflux, preferably at 80°C, for 30 min to severalhours, preferably for 1 hour. In particular, the reaction is performed under argon atmosphere. Suzuki coupling reaction The compound of formula (12) is prepared by coupling synthetic intermediates of formula(7) and (11).In particular, the Suzuki coupling reaction is performed in the presence of a base, like K2CO3or Na2CO3 (in powder or in aqueous solution), preferably Na2CO3, and a palladium IIcatalyst, preferably bis(triphenylphosphine)palladium dichloride, in MeCN, in particular ata temperature comprised between 60°C and 110°C.Other conditions can be used for this step, for example other solvents, such as 1,4-dioxane,DMSO, 1,2-dimethoxyethane, EtOH or DMF, other catalysts, such as palladium chloride ortris(dibenzylideneacetone)dipalladium, or other bases, such as NaOH or Cs2CO3.In particular, the reaction is performed at a temperature varying from 60°C to 110°C,preferably at 70°C. Deprotection of the protecting group The compound of formula (12) is then deprotected to give (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one by using NaOH in DMSO at room temperature or Na2CO3solution at 110°C. This step could also be performed with other conditions like TBAF in THF at 66°C, or MeONa in MeOH at room temperature. Preferably, this step is performed by using NaOH in DMSO at room temperature.In particular, the reaction is performed for 2 to 4 hours, preferably for 3 hours.According to a particular embodiment, the process of the present invention may beaccomplished according to the Schemes 1 to 3 below.In particular, the synthetic intermediate of formula (7) may be prepared according to Scheme1 below. Scheme 1 The compound of formula (2) is obtained by direct olefination of commercially availablealdehyde of formula (1). The reaction is generally performed withmethyltriphenylphosphonium bromide in presence of a base, such as K2CO3, and in a solventsuch as 1,4-dioxane. The reaction may be performed at 100°C for 1 to 2 hours, in particularfor 1.5 hours.Alkene of formula (2) is converted to the chiral compound of formula (3), using a solventsuch as tBuOH / H2O, and using K3Fe(CN)6, K2CO3, K2Os(OH)4 and (DHQ)2PHAL. Thereaction may be performed at room temperature, for example for 16 hours.Then, the compound of formula (3) is converted to the corresponding chiral epoxide offormula (4) using in a first step triethyl orthoacetate (TEOA) and trimethylsilyl chloride(TMSCl), and DCM as solvent, at 0°C, for 3 hours, and in a second step K2CO3 andmethanol, at 0°C for 1 hour.The chiral epoxide of formula (4) is then put in the presence of dimethylamine. The reactionis preferably performed in EtOH at 0°C for 1 hour, and then at room temperature for 21hours.The chiral benzylalcohol derivative of formula (5) is then converted to the correspondingchiral compound of formula (6) using MsCl and Et3N at 0°C in DCM as an anhydroussolvent.The compound of formula (7) is finally obtained from the compound of formula (6) usingcommercially available 4-bromo-1H-pyridin-2-one in the presence of K2CO3 as a base, inDMF. The reaction may be performed at room temperature for 14 hours.The present invention also concerns a process for preparing the compound of formula (7), wherein the following steps are carried out in that order, starting from the commercially available compound of formula (1): 1) an olefination of the aldehyde to give the corresponding alkene of formula (2),2) a conversion of the alkene to a vicinal diol to obtain the chiral compound of formula(3), by performing a Sharpless asymmetric dihydroxylation, 3) an epoxidation to obtain the chiral compound of formula (4),4) a regioselective ring opening to conduct to the chiral benzylalcohol of formula (5),5) a conversion of the chiral alcohol into the corresponding chiral chloroderivative to givethe compound of formula (6), directly followed by, 6) a N-alkylation of commercially available 4-bromo-1H-pyridin-2-one by the compoundof formula (6) to finally give the compound of formula (7).The synthetic intermediate of formula (11) may be prepared according to Scheme 2 asdefined below. Scheme 2 The 5-morpholino-7-azaindole compound of formula (9), as shown in Scheme 2, is obtainedfrom the commercially available compound of formula (8), by carrying out a Buchwald-Hartwig coupling reaction in the presence of morpholine, with LiHMDS as base, RuPhos ascatalyst and RuPhos Pd G2 as ligand. This reaction is generally performed in THF as anhydrous solvent and at a temperature of 60-70°C, for 1.5 hours.Then, the compound of formula (10) is obtained by performing a protection of the pyrrolylmoiety of the 7-azaindole core with Ts as protecting group, and using NaOH as base, andTEBAC, in DCM as anhydrous solvent. This reaction is generally performed at 0°C to roomtemperature, for 4 hours.Finally, the compound of formula (11) is obtained by a selective borylation of the azaindolecore in position 3, using (1,5-cyclooctadiene)(methoxy)iridium(I), in presence of 4,4’-di-tert-butylbipyridine as ligand, and bis(pinacolato)diboron as a source of boron. This reactionis generally performed in methyltetrahydrofuran at 80°C for 1 hour.Thus, the present invention also describes a process for preparing the compound of formula(11), wherein the following steps are carried out in that order, starting from the compoundof formula (8): a) a Buchwald-Hartwig coupling reaction to obtain the 5-morpholino-7-azaindole offormula (9), b) a protection of the pyrrolyl moiety of the 7-azindole core to obtain the compound offormula (10), andc) a selective borylation of the azaindole core in position 3 to finally obtain the compoundof formula (11). Finally, (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo [2,3-b]pyridin-3-yl)pyridin-2(1H)-one may be prepared according to Scheme 3, as defined below. Scheme 3 The compound of formula (12) is prepared by coupling synthetic intermediates of formula(7) and (11) previously described in Schemes 1 and 2.The Suzuki coupling reaction is typically performed in the presence of a base like Na2CO3(in powder or in aqueous solution), a palladium II catalyst such as bis(triphenylphosphine)palladium dichloride in MeCN, at a temperature comprised between 60°C and 110°C, preferably at 70°C. The compound of formula (12) can be then deprotected to give (S)-1-(1-(3-chlorophenyl)-2- (dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one by using NaOH in DMSO at room temperature, for 3 hours. According to an embodiment, (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5- morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one may be prepared by a process wherein the following steps are carried out in that order, starting from syntheticintermediates of formula (7) and (11):i. a Suzuki coupling reaction performed at a temperature comprised between 60°Cand 110°C, to give the compound of formula (12), andii. a deprotection of the protecting groups to give (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3- yl)pyridin-2(1H)-one. The present invention will be better understood by referring to the following examples which are provided for illustrative purpose only and should not be interpreted as limiting in any manner the instant invention. EXAMPLES Equipment and analytical methods used for the syntheses of examples Flash chromatography: Apparatus: Biotage SP with auto‐collector and UV detection (2 wavelengths). Normal phase columns: 120 g or 300 g Biotage external dry load cartridge kit, packed with Sigma-Aldrich 40-63 μm silica gel. Liquid Chromatography: Apparatus: Waters alliance 2695 HPLC system with autosampler and Waters 2996 diode array detector. Column: Macherey-Nagel Nucleoshell RP18 plus (5 μm, 4 mm x 100 mm). Column temperature: 40°C. Solvents: A (H2O 99.9%, H2CO20.1%); B (CH3CN 99.9%, H2CO20.1%). Flow rate: 1 mL / min. Gradient (A / B v / v): 90 / 10 (t = 0 min), 90 / 10 (t = 1 min), 0 / 100 (t = 7 min), 0 / 100 (t = 10 min). Detection: 210-400 nm range. Chiral Chromatography: Chiral column: Daicel ChiralPak IG (Amylose-based) 20 μm, 4.6 mm x 100 mm. Chiral column: Daicel ChiralPak IG (Amylose-based) 5 μm, 4.6 mm x 250 mm. Column temperature: 25°C. Analysis of compound 3 (Isocratic conditions): Solvents Heptane 95% / EtOH containing 0.1% Et3N 5%, flow rate: 1mL / min. Analysis of compound 7 (Isocratic conditions): Solvents Heptane 90% / EtOH containing 0.1% Et3N 10%, flow rate: 1mL / min. Analysis of compound 12 (Isocratic conditions): Solvents Heptane 41.5% / EtOH containing 0.1% Et3N 32.5% and DCM 25%, flow rate: 1mL / min. Analysis of final compound (S)-1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one (Isocratic conditions):Solvents Heptane 50% / EtOH containing 0.1% Et3N 40% and DCM 10%, flow rate: 1mL / min. Mass Spectrometer: Apparatus: Waters Micromass ZQ (simple quad). Mass detection method: Electrospray positive mode (ESI+), mass range: 50‐800 uma. NMR Spectrometer: Apparatus: Bruker 400 MHz. Methods:1H NMR spectra performed in DMSO-d6 using DMSO-d5 as internal reference, chemical shifts expressed in parts per million (ppm), signals expressed as follows: singlet = s, d = doublet, t = triplet, q = quadruplet, sept = septuplet, dd = double doublet, dt = double triplet, m = multiplet or large singlet, br = broad, H = proton.31P NMR spectra performed in DMSO-d6, chemical shifts expressed in parts per million (ppm), signals expressed as follows: s = singlet. Example 1: Synthesis of -1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5- morpholino-1H-pyrrolo[2,3- 3-yl)pyridin-2(1H)-one Step 1: 3-Chlorostyrene 150 g of aldehyde 1 (1.07 mol) are added to a solution that contained the triphenylphosphonium ylide reactive (457.4 g, 1.28 mol) dissolved in 900 ml of anhydrous 1,4-dioxane under Argon atmosphere. The white suspension is then heated at reflux for 2 hours.The reaction is then cooled to room temperature and evaporated under reduced pressure. Theresidue is diluted with 1,2 L of Et2O and stirred for 45 min. The crude is then filtrated in afunnel (por 3) charged with celite (20 cm x 4 cm), previously washed with Et2O. The solidis rinsed 3 times with 0.2 L of Et2O. The filtrate is evaporated and the residue is redissolvedin 200 mL of pentane. The pentane solution is filtrated over two silica pad (200 g SiO2) andthen eluted with 800 ml of pentane, followed by 0.2 L of pentane / Et2O 95 / 5 to give 96.7 gof the compound 2 as a yellow oil.Yield: Quantitative. TLC: Rf = 0.2 (solvent 3% Et2O / Heptane). LC purity: 90%. MH+: non ionizable. Step 2: 1-(3-Chlorophenyl)ethane-1,2-diol In three different flasks of 5 L placed at 0°C in an ice bath, 4.3 L of water are added (thirdvolume on each flask). K3Fe(CN)6(351 g, 1.07 mol), K2CO3(148 g, 1.07 mol), K2Os(OH)4(65 mg, 178 μmol), (DHQ)2PHAL (2.77 g, 3.57 mmol) are added in each flask, followed by49.3 g of 3-chlorostyrene 2 (described in the previous step) (0.36 mol) dissolved in 1.43 Lof tBuOH (temperature maintained below 15°C during the addition). The different mixturesare stirred at 0°C for 1 h, then allowed to slowly warm up to reach room temperature andstirred for 16 hours. 1.2 L of EtOAc are then added into each reaction and stirred for 15 minat room temperature. Each flask precipitate is filtered on celite and rinsed with EtOAc (2 x800 ml). Filtrates are combined, decanted and aqueous layer separated. Organic layer iswashed with water / brine (3 / 1) (for each 1 L of organic phase, 200 ml of water / brine areused). All organic layers are washed by 2 x 300 ml of brine. Organic layers are combinedand dried over Na2SO4, filtered and evaporated to dryness to give a residue of more of 217.3g as a black oil. Purification is performed by filtration on silica pads divided in two batches(200 g, limited by funnel size) and dissolving the crude with 5% EtOAc / Hexane. The oil is dragged with the eluent for each step of elution. Product elution with 1.5 L of 5% EtOAc / Hexane per batch and then 50% EtOAc / Hexane until no more product was theneluted ~ 2 L (control TLC) to obtain 174.2 g of diol 3 as a brown oil.Yield: 95%. TLC: Rf = 0.35 (solvent 50% EtOAc in Hexane). LC purity: 78%. Chiral purity: 98%. MH+: 155.2 (M-OH)+.1H NMR (DMSO-d6, 600 MHz): δ 7.39-7.26 (m, 4H); 5.37 (d, J=4.5Hz, 1H); 4.75 (t, J=6.1Hz, 1H); 4.58-4.53 (m, 1H); 3.50-3.41 (m, 2H). Step 3: (S)-2-(3-Chlorophenyl)oxirane 78.6 g of diol 3 (455 mmol) are dissolved in 0.85 L of dry DCM and the solution is cooleddown to 0°C under argon atmosphere. 104.3 ml of triethyl orthoacetate (TEOA, 570 mmol)diluted in 100 ml of DCM are then slowly added into the solution (temperature of reactionmixture at approx.8°C, time of addition 45 min).72.2 ml of trimethylsilyl chloride (TMSCl, 570 mmol) dissolved in 50 ml of DCM and cooled in an ice bath under argon atmosphere,are then slowly added with a dropping funnel and checking the temperature that was keptbetween 6 and 8°C (time of addition 45 min). The reaction is then stirred under argonatmosphere at 0°C for 30 min. 0.25 eq. of TEOA and 0.25 eq. of TMSCl are added and the reaction is kept stirring at 0°C for 1 hour more. The reaction is then evaporated (bath temperature 25°C) to give a pale yellow oil. The crude product is dissolved in dry methanol(470 ml) cooled at 0°C and 141.6 g of K2CO3 (1.02 mol) are slowly added keeping thetemperature between 8 and 12°C (time of addition 15 min) under argon atmosphere. Thereaction is stirred at 0°C for 3 hours. Reaction is warmed to 15°C for 1 hour. The reaction isfiltrated on celite and concentrated under vacuum (bath temp 25°C). The cake is rinsed by 3x 300 ml of Et2O. The concentrated filtrate is dissolved in 600 ml of water and extractedwith the Et2O used to rinse the cake and with 2 x 300 ml of Et2O more. Combined organiclayers are washed with brine (600 ml), dried over Na2SO4, filtered and evaporated to dryness(bath temp 25°C) to give a pale yellow oil. Crude product (117.5 g) is diluted with 200 mlof pentane and filtered over a pad of silica (200 g, limited by funnel size) and rinsed with 1.5 L of pentane, 1.5 L of 10% Et2O / pentane to obtain a pale yellow oil of 82.2 g of compound 4. Yield: Quantitative. TLC: Rf = 0.3 (solvent 3% of Et2O in pentane). LC purity: 93.2%. MH+: non-ionizable.1H NMR (DMSO-d6, 600 MHz): δ 7.41-7.32 (m, 3H); 7.28-7.25 (m, 1H); 3.97-3.95 (m, 1H); 3.14-3.10 (m, 1H); 2.88-2.85 (m, 1H). Step 4: (S)-1-(3-Chlorophenyl)-2-(dimethylamino)ethan-1-ol In a flask placed at 0°C in an ice bath, a solution of oxirane 4 (82.2 g, 531 mmol) in 1.3 L ofethanol 96% (v / v) is added followed by cold 532 ml of dimethylamine (2M solution in THF),checking temperature between 4 and 9°C. The solution is stirred for 1 hour at 0°C and then21 hours at room temperature, and then it is stirred at 50°C for 2.5 hours. The crude is evaporated under vacuum and diluted in a mixture of 700 ml of EtOAc, 1 L of water and300 ml of brine. The mixture is decanted and aqueous layer is extracted with EtOAc (300ml x 2). Combined organic layers are dried over Na2SO4, filtered and evaporated to drynessto give 104.3 g of an orange-red liquid. The crude residue is diluted with 1.24 L of Et2O andstirred at room temperature for 30 min. This solution is then filtrated on celite, rinsed by 2 x150 ml of Et2O and evaporated to dryness to give 99 g of desired compound 5 as a yellowoil. Yield: 93%. TLC: Rf = 0.28 (solvent 10% MeOH in DCM). LC purity: 96.4%. MH+: 200.3; 202.4 (M; M+2).1H NMR (DMSO-d6, 600 MHz): δ 7.40-7.25 (m, 4H); 5.16 (br s, 1H); 4.68-4.62 (m, 1H); 2.44-2.38 (m, 1H); 2.36-2.30 (m, 1H); 2.19 (s, 6H). Step 5: (R)-2-Chloro-2-(3-chlorophenyl)-N,N-dimethylethan-1-amine A solution of 5 (170 g, 851 mmol) in 1.7 L of dry DCM is cooled to 0°C in argon atmosphereand 356 ml of triethylamine (2.55 mol) are added. 132 ml of mesyl chloride (1.7 mol) arethen added dropwise with a dropping funnel checking the temperature between 10 and 15°C(time of addition 1h40). The suspension is stirred at 0°C for 3h30 min. 0.2 equivalents ofEt3N and mesyl chloride are added and stirred for 2 hours more. The reaction is quenchedby the addition of 2 L of water and extracted using two funnels. Aqueous layer is thenextracted with DCM (500 ml x 3). Combined organic layers are dried over Na2SO4, filteredand evaporated to dryness (bath at 20°C) to give 173.8 g of an orange sticky oil.Yield: 94%.TLC: Rf = 0.5 (solvent 10% MeOH in DCM). MH+: 218.4; 220.4 (M; M+2).1H NMR (CDCl3, 400 MHz): δ 7.41-7.39 (m, 1H); 7.32-7.27 (m, 3H); 4.92-4.86 m, 1H); 2.90-2.98 (m, 1H); 2.78-2.70 (m, 1H); 2.33 (s, 6H). Step 6: (S)-4-Bromo-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)pyridine-2(1H)- one 137 g of 4-bromo-1H-pyridin-2-one (787 mmol) are dissolved in 1.5 L of dry DMF to forma off-white suspension, then 130.6 g of K2CO3 (940 mmol) are added and the mixture isvigorously stirred for 1 hour at room temperature under argon atmosphere. Starting material6 (171.8 g, 787 mmol) dissolved in 750 ml of dry DMF is then added and stirred for 14 hoursat room temperature. The reaction mixture is then filtrated on celite, rinsed with Et2O (2 x300 ml) and the filtrate is divided into two flaks and concentrated until approx 150 ml. Theresidues are diluted with 700 ml of water into each flask and 300 ml of Et2O and 300 ml ofEtOAc are added. They are then triturated for 15 min and decanted. Aqueous layer isextracted by 2 x 300 ml of EtOAc and combined organic layers are washed with brine (600ml), dried over Na2SO4, filtered and evaporated to dryness to give 203.6 g of a yellow solid. Purification is performed by flash chromatography on deactivated silica with triethylamine(four columns of 300 g) and the crude is loaded into the columns as a solid sample (the crudeis dissolved in DCM and 400 g of deactivated silica are joined and highly dried undervacuum and divided into four for each column). Eluents used are hexane and EtOAc to obtain103.9 g of the compound 7 as a pale yellow solid. A recrystallization is then performed: Theresidue is suspended in 300 ml of EtOAc and heated to reflux until we obtained a clearsolution (final volume of 500 ml of EtOAc). 700 mL of hexane are then added in smallportions. The solution is hot filtrated and the filtrate is cooled down to room temperature andthen stored at 4°C overnight. The crystalline solid obtained is filtrated to yield 60.2 g ofcompound 7.Yield: 36%.TLC: Rf = 0.3 (solvent 70 % EtOAc in DCM). LC purity: 99.5%. Chiral purity: 97.8%. MH+: 355.4; 357.4; 359.5 (M; M+2; M+4).1H NMR (DMSO-d6, 600 MHz): δ 7.80 (d, J=7.5Hz, 1H); 7.44‐7.41 (m, 1H); 7.40-7.35 (m, 2H); 7.31-7.26 (m, 1H); 6.73 (d, J=2.2Hz, 1H); 6.49 (dd, J=7.5 and 2.3Hz, 1H); 6.09-6.02 (m, 1H); 3.30-3.24 (m, 1H); 2.71-2.64 (m, 1H); 2.17 (s, 6H). Step 7: 4-(1H-Pyrrolo[2,3-b]pyridin-5-yl)morpholine RuPhos (1.52 g, 3.25 mmol, 1% mol) and RuPhos PdG2 (2.52 g, 3.25 mmol, 1% mol) aredissolved in 780 ml of LiHMDS (1M in THF, 780 mmol) under argon atmosphere.64 g ofcompound 8 (325 mmol) and 34 ml of morpholine (390 mmol) are then added and thereaction is stirred at reflux (66°C) for 1.5 hours. The solution is allowed to cool to roomtemperature and quenched by dropping into 1.9 L of an aqueous saturated NH4Cl solution and stirred for 15 min. Aqueous layer is extracted with DCM (3 x 400 ml). Combined organiclayers are dried over Na2SO4, filtered and evaporated to dryness to give 71 g of crudecompound 9. The residue is triturated in 300 ml of 30% EtOAc / hexane for 1 hour, thenfiltrated, rinsed with 300 ml of 10% EtOAc / hexane and dried under vacuum overnight togive rise 63 g of the compound 9 as a slightly brown thin powder.Yield: 95%. TLC: Rf = 0.37 (solvent EtOAc). LC purity: 98.4%. MH+: 204.3 (M+1). Step 8: 4-(1-Tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine Pyrrolopyridine 9 (30 g, 147.6 mmol) is dissolved in anhydrous DCM (400 ml) and stirredat 0°C. Benzyltriethylammonium chloride, TEBAC (1 g, 4.43 mmol) and NaOH (17.71 g,442.8 mmol) are then added. Tosyl chloride (33.77 g, 177.1 mmol) is then portion-wiseadded and stirred for 30 min more at 0°C. The reaction is allowed to warm to roomtemperature and stirred for 4 hours. 0.1 eq. of tosyl chloride is then added. The reaction isdropped into 2 L of fresh water and stirred for few minutes in an ice bath. It is then filtratedand washed with water. The solid precipitate is dissolved in DCM (1.5 L) and washed withNaHCO3 (2 x 400 ml), water (2 x 400 ml) and brine (400 ml). Organic layer is thenevaporated and the residue is triturated in 300 ml of 5% EtOAc / hexane for 2 hours. It isfiltrated, rinsed with hexane and dried over P2O5 to give 48.93 g of the compound 10 as apale brown powder. Yield: 93%. TLC: Rf = 0.41 (solvent 70% EtOAc in hexane). LC purity: 99%. MH+: 358.6 (M+1).1H NMR (DMSO-d6, 400 MHz): δ 8.18 (d, J=2.7Hz, 1H); 7.92 (d, J=8.3Hz, 2H); 7.78 (d, J=4.0Hz, 1H); 7.52 (d, J=2.7Hz, 1H); 7.39 (d, J=8.3Hz, 2H); 6.68 (d, J=4.0Hz, 1H); 3.76- 3.71 (m, 4H); 43.12-3.07 (m, 4H); 2.33 (s, 3H).Step 9: 4-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine Pyrrolopyridine 10 (103.2 g, 289 mmol) is dissolved in 2-methyltetrahyrofuran under argonatmosphere and stirred at room temperature. Bis-pinacolato diborane (B2pin2, 80.7 g, 318 mmol), 4,4’-di-tert-butylbipyridine (3.1 g, 11.5 mmol) and (1,5-cyclooctadiene)(methoxy)iridium (I) dimer ([Ir(OMe)(COD)]2, 3.8 g, 5.8 mmol) are then added. The reaction is heatedto reflux for 50 min. Reaction is then cooled down to -10°C on an ice / acetone bath and isquenched by the addition of 600 ml of cold MeOH. First 12 ml are carefully and slowlyadded checking the temperature (during 30 min) and by then the rest of MeOH is addedfaster. Reaction is then stirred at room temperature for 15 min and evaporated to dryness togive a residue black / brown oil. The residue is dissolved in DCM (1.5 L) and washed with water (3 x 500 ml) and brine (500 ml). Organic layer is evaporated to give a 200 g of a blackpaste. 1.5 L of Et2O are then added and stirred for 15 min at room temperature. The solutionis then filtrated on a SiO2 pad (1 Kg, with sand on the top) and the silica is rinsed with Et2O(1.5 L x 3). Filtrate is evaporated and coevaporated with hexane to finally give a pale yellow solid foam, dried under vacuum over P2O5 to yield 146.5 g of the compound 11.Yield: 96%. TLC: Rf = 0.5 (solvent 70% EtOAc in hexane). LC purity: 90.8%.MH+: 484.6 (M+1).1H NMR (DMSO-d6, 400 MHz): δ 8.21 (d, J=2.5Hz, 1H); 8.01 (d, J=8.3Hz, 2H); 7.94 (s, 1H); 7.50 (d, J=2.4Hz, 1H); 7.41 (d, J=8.0Hz, 2H); 3.78-3.72 (m, 4H); 3.12-3.07 (m, 4H); 2.33 (s, 3H); 1.30 (s, 12H). Step 10: (S)-1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1-tosyl- 1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one Reaction is divided in two 2 L flasks with half volume into each one. The bromopyridinone7 (60.2 g, 169 mmol) and the compound 11 (98.2 g, 203 mmol) are dissolved in 903 ml ofMeCN under argon atmosphere. Sodium carbonate 2M (903 ml) is added to give a biphasicmixture that is bubbled with argon for 15 min. Bis(triphenylphosphine)palladium (II)dichloride (Pd(PPh3)2Cl2, 2.97 g, 4.2 mmol, 2.5 mol %) is then added and the solution isbubbled for another 15 min. The reaction is stirred at 70°C for 2 hours. 0.025 eq. ofPd(PPh3)2Cl2 are then added and stirred for 1 hour. 0.025 eq more of Pd(PPh3)2Cl2 are thenadded. 0.15 eq. of the compound 11 is then added and stirred for 0.5 hour. The reaction isallowed to cool down to reach room temperature. 1.4 L of cold water (700 ml for each one)are added and stirred in an ice bath for 60 min. An off-white solid crashes out between bothlayers which is filtrated through a sintered glass funnel (size 3). Solid is rinsed with colddeionised water (4 x 100 ml) and three times rapidly with Et2O (4 x 150 ml) dried by suctionfiltration for at least 15 min and then dried in a desiccator over P2O5 to obtain 129 g of thecompound 12 as a pale brown solid.Yield: Quantitative. TLC: Rf = 0,5 (solvent 70% EtOAc in hexane). LC purity: 87%. MH+: 633.0; 635.0 (M; M+2).1H NMR (DMSO-d6, MHz): δ 8.36 (s, 1H); 8.26 (d, J=2.5Hz, 1H); 7.99 (d, J=8.4Hz, 2H); 7.87 (d, J=7.3, 1H); 7.64 (d, J=2.6Hz, 1H); 7.49 (m, 1H); 7.44-7.33 (m, 5H); 6.80-6.72 (m, 2H); 6.22-6.14 (m, 1H); 3.77-3.71 (m, 4H); 3.20-3.14 (m, 4H); 2.76-2.67 (m, 1H); 2.33 (s, 3H); 2.20 (s, 6H). Step 11: -1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H- pyrrolo[2,3- 3-yl)pyridin-2(1H)-one Reaction is divided in three equal batches. Compound 12 (107 g, 170 mmol) is suspended in5 L of DMSO and cooled in an ice bath. Sodium hydroxide 2N solution (133 ml) is thenslowly added keeping the temperature between 16 and 18°C. The reactions are then broughtto room temperature and stirred for 1.5 hours. 0.4 eq of NaOH 2M are then added using theice bath during the addition and stirred at room temperature for 1 hour more. The process is repeated adding 0.3 eq of NaOH until the reaction is finished (from 5 to 6.5 hours and 2.3eq to 2.9 eq of NaOH in different batches). The reactions are then quenched by the additionof 0.42 L of NH4Cl saturated solution into each reaction (volume total: 1.26L) slowly addedand placed in an ice bath in order to keep the temperature below 20°C. The solutions arestirred for another 30 min, divided into two equal parts and each one is poured into 3.2 L ofwater (Volume total: 19.2 L). It is stirred for 1 hour in an ice bath and then the precipitate isfiltrated through a sintered glass funnel (size 3). The yellow cake is washed with deionisedwater (4 x 200 ml) then with Et2O (5 x 200 ml) and dried in a desiccator over P2O5 to obtain 86.2 g of (S)-1-(1-(3-Chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H- pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one as a pale yellow / brown solid. The product is triturated in 434 ml of EtOAc stirred at 60°C for 1 hour, cooled down to room temperatureand filtrated. The product is then triturated again in 434 ml of EtOAc at 60°C. The solid isdried under vacuum for 2 hours and then triturated in 340 ml of Et2O at room temperaturefor 2 hours, filtrated and dried over P2O5 overnight to obtain 67.5 g of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3- yl)pyridin-2(1H)-one as a very pale yellow powder. Yield: 83%. TLC: Rf = 0,25 (solvent 10% MeOH in DCM). LC purity: 99.3%. LC chiral: 98.6%. MH+: 478.7; 480.7 (M; M+2).1H NMR (DMSO-d6, 400 MHz): δ 12.05 (br s, 1H); 8.17 (d, J=2.5Hz, 1H); 8.10 (d, J=2.9Hz, 1H); 7.78-7.74 (m, 1H); 7.71 (d, J=2.5Hz, 1H); 7.49-7.46 (m, 1H); 7.45-7.33 (m, 3H); 6.72- 6.67 (m, 2H); 6.23-6.15 (m, 1H); 3.82-3.76 (m, 4H); 3.32-3.26 (m, 1H); 3.18-3.12 (m, 4H); 2.78-2.69 (m, 1H); 2.22 (s, 6H). 7 g of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one are suspended in 1.2 L of solvent MeCN / H2O(70 / 30). The solution is heated at reflux and several additions of solvent are performed untilcomplete solubilization (total volume of 1.5 L). The solution is hot filtrated and the filtrateis then cooled down to room temperature and stored at 4°C overnight to give 4.1 g of pure(S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one as off-white crystals.TLC: Rf = 0.25 (solvent 10% MeOH in DCM) LC purity: 100% LC chiral: 99.5% MH+: 478.7; 480.7 (M; M+2)

Claims

CLAIMS 1. A process for the preparation of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-onecomprising performing a Sharpless asymmetric dihydroxylation on a compound of formula(2): to selectively form a chiral compound of formula (3): and then converting said compound of formula (3) into the corresponding chiral epoxide of formula (4):.

2. The process according to claim 1, wherein the reaction of Sharpless asymmetricdihydroxylation is performed in presence of K3Fe(CN)6, K2CO3, K2Os(OH)4 and (DHQ)2PHAL.

3. The process according to any one of the preceding claims, wherein the reaction ofSharpless asymmetric dihydroxylation is performed in presence of a solvent.

4. The process according to the preceding claim, wherein the solvent is tBuOH.

5. The process according to any one of the preceding claims, wherein the reaction ofSharpless asymmetric dihydroxylation is performed at room temperature.

6. The process according to any one of the preceding claims, wherein the reaction ofSharpless asymmetric dihydroxylation is performed for 15 to 20 hours.

7. The process according to the preceding claim, wherein the reaction is performedfor 16 hours.

8. The process according to any one of the preceding claims, wherein the reaction ofepoxidation is performed in two steps.

9. The process according to the preceding claim, wherein the first step is performedin the presence of triethyl orthoacetate (TEOA) and trimethylsilyl chloride (TMSCl) and asolvent, and the second step is performed in the presence of K2CO3, and a solvent.

10. The process according to the preceding claim, wherein the first step is performedin the presence of triethyl orthoacetate (TEOA) and trimethylsilyl chloride (TMSCl) andDCM as a solvent, and the second step is performed in the presence of K2CO3, and methanolas a solvent.

11. A process for the preparation of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-onecomprising a Suzuki coupling reaction of a compound of formula (7) and a compound offormula (11):

12. The process according to the preceding claim, wherein the reaction is performedin the presence of a base, preferably Na2CO3, and a palladium II catalyst, preferablybis(triphenylphosphine)palladium dichloride, in MeCN.

13. The process according to claim 11 or claim 12, wherein the reaction is performedat a temperature varying from 60°C to 110°C, preferably at 70°C.

14. A process for the preparation of (S)-1-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2(1H)-one, characterized in that: A) a compound of formula (1):is subjected to a direct olefination to obtain a compound of formula (2):B) the compound of formula (2) is subjected to a Sharpless asymmetric dihydroxylation to form the chiral compound of formula (3):C) the compound of formula (3) is converted to the corresponding chiral epoxide of formula (4):D) the compound of formula (4) is then put in the presence of dimethylamine, to form achiral compound of formula (5):E) the compound of formula (5) is converted to the chiral compound of formula (6):F) the compound of formula (6) is subjected to a reaction of N-alkylation with 4-bromo-1H-pyridin-2-one to give the chiral compound of formula (7):(8):is subjected to a Buchwald-Hartwig coupling reaction with morpholine to obtain a compound of formula (9):H) the compound of formula (9) is subjected to a protection reaction of the pyrrolyl moiety of the 7-azindole core to obtain a compound of formula (10):I) the compound of formula (10) is subjected to a selective borylation of the azaindole core in position 3 to obtain a compound of formula (11):J) the compound of formula (7) and the compound of formula (11) are subjected to a Suzukicoupling reaction to give the chiral compound of formula (12):and K) the compound of formula (12) is subjected to a deprotecting reaction to give (S)-1-(1-(3- chlorophenyl)-2-(dimethylamino)ethyl)-4-(5-morpholino-1H-pyrrolo[2,3-b]pyridin-3- yl)pyridin-2(1H)-one.

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