Process and intermediates for the preparation of a phosphoglicerate dehydrogenase inhibitor

Abstract

The present invention relates to a process for the preparation of a PHGDH inhibitor, i.e. a stereoisomer of 2-(4-(1-(4-chloro-1,6-dimethyl-1H-indole-2-carboxamido)-2- hydroxyethyl)phenyl) propanoic acid, or a pharmaceutically acceptable salt thereof. The present invention also relates to intermediate compounds which are useful in such process and their preparation thereof. The synthesized PHGDH inhibitor is suitable for use in pharmaceutical applications, for instance in the treatment of fibrosis.

Description

[0001] PROCESS AND INTERMEDIATES FOR THE PREPARATION OF A PHOSPHOGLICERATE DEHYDROGENASE INHIBITOR

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a process for the preparation of a PHGDH inhibitor, i.e. a stereoisomer of 2-(4-(l-(4-chl oro-1, 6-dimethyl-lH-indole-2-carboxamido)-2-hydroxyethyl) phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof. The present invention also relates to intermediate compounds which are useful in such process and their preparation thereof. The synthesized PHGDH inhibitor is suitable for use in pharmaceutical applications, for instance in the treatment of fibrosis.

[0004] BACKGROUND OF THE INVENTION

[0005] 3 -phosphoglycerate dehydrogenase (PHGDH) is the enzyme that catalyzes the first ratelimiting step in the de novo biosynthesis of L-serine starting from glucose, which is the conversion of 3 -phosphoglycerate into 3-phosphohydroxypyruvate with a reduction of nicotinamide adenine dinucleotide (NAD+) to NADH, and it is considered as a major enzyme in the diversion of glycolysis towards serine synthesis.

[0006] PHGDH is required to promote collagen protein synthesis. Indeed, glycine accounts for one- third of all amino acids within the collagen molecule, and the high content of glycine is critical for the stabilization of collagen helix.

[0007] Collagen is the main structural protein in the extracellular space, and it is produced in excess in idiopathic pulmonary fibrosis (IPF) patients during fibroblasts into myofibroblasts differentiation that accumulates within the fibrotic tissue and leads to loss of organ architecture and function.

[0008] Moreover, PHGDH and the serine / glycine synthesis pathway is part of a wider network which links glycolysis with one-carbon metabolism and nucleotide synthesis contributing to cell proliferation in pathologies such as inflammation and fibrosis.

[0009] Therefore, the PHGDH inhibition has the potential to reduce the aberrant production and release of collagen such as inhibit cell proliferation (see Selvarajah et al., Science Signaling, 2019;12(582):eaav 3048)

[0010] Various compounds have been described in the literature as potent PHGDH inhibitors.

[0011] Raze Therapeutics disclosed in various patent applications (for example WO2017156179) compounds which are effective as orthosteric PHGDH inhibitors, and their use in the treatment of many PHGDH-mediated disorders, in particular melanoma, breast, or lung cancer.

[0012] Examples of PHGDH inhibitors useful for treating proliferative diseases, benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases are disclosed in WO2016115463 (Whitehead Institute For Biomedical Research; Dana-Farber Cancer Institute, Inc).

[0013] 2-(4-(l-(4-chloro-l,6-dimethyl-lH-indole-2-carboxamido)-2-hydroxyethyl) phenyl) propanoic acid is a potent PHGDH inhibitor which has the following structural formula compound (1)

[0014] As stereoisomers of 2-(4-(l-(4-chloro-l,6-dimethyl-lH-indole-2-carboxamido)-2- hydroxy ethyl) phenyl)propanoic acid (compound 1) have been considered for drug development, there was a need to develop an efficient, simple and industrially viable synthetic route, which could overcome or at least lessen the drawbacks of the prior art method. It was of particular importance to devise an improved process that could achieve an increase in the overall yield, good optical purity, a reduced consumption of starting materials and solvent and that was suitable for scale-up. Such a process has been surprisingly developed and it is herein described. At the same time novel process intermediate compounds which are useful in the preparation of 2-(4-(l-(4-chloro-l,6- dimethyl-lH-indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoic acid (compound 1) and preparations thereof are described.

[0015] SUMMARY OF THE INVENTION

[0016] In a first aspect, the present invention relates to a process for the preparation of compound

[0017] 1, or a pharmaceutically acceptable salt thereof : compound 1 comprising the steps of: a) reacting Intermediate compound of formula (III) with CH3R2 in the presence of an inorganic base,

[0018] Intermediate III to obtain Intermediate compound of formula (IV)

[0019] Intermediate IV wherein

[0020] Ri is selected from the group consisting of H and -(Ci-C3)alkyl, or the two Ri are fused together in a -(C5-Cs)cycloalkyl;

[0021] Rz is selected from the group consisting of halogen and sulfonate; b) amidic coupling of Intermediate compound 6, which is tert-butyl 2-(4-(l-amino-2- hydroxyethyl)phenyl)propanoate

[0022] Intermediate 6 with 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid to obtain Intermediate compound 7, which is tert-butyl 2-(4-(l-(4-chl oro-1, 6-dimethyl- IH-indole- 2-carboxamido)-2-hydroxyethyl)phenyl)propanoate

[0023] Intermediate 7 thus after ester hydrolysis obtaining compound 1.

[0024] In a second aspect, the invention provides Intermediate compound of formula (III)

[0025] Intermediate III wherein Ri is selected from the group consisting of H and -(Ci-C3)alkyl, or the two Ri are fused together in a -(C5-Cs)cycloalkyl; as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof.

[0026] In a third aspect, the invention provides Intermediate compound of formula (IV)

[0027] Intermediate IV as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof.

[0028] In another aspect, the present invention relates to the use of intermediate compound of formula (III) and / or intermediate compound of formula (IV) for the preparation of compound 1.

[0029] DETAILED DESCRIPTION OF THE INVENTION

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by the skilled person in the art.

[0031] ABBREVIATIONS

[0032] 'H-NMR: Proton nuclear magnetic resonance; 2-MeTHF: 2-methyltetrahydrofuran; CDI: l,l'-carbonyl diimidazole; COMU: (l-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino- morpholino-carbenium hexafluorophosphate; DABCO: l,4-diazabicyclo[2.2.2]octane; DBU: 1,8- diazabicyclo[5.4.0]undec-7-ene; DIBAL-H: diisobutylaluminum hydride; DIPEA: NJV- diisopropylethylamine; DMA: / V,,V-dimethylacetamide; DMF: A, / V-dimethylformamide; DMSO: dimethylsulfoxide; A-(3-dimethylaminopropyl)-A"-ethylcarbodiimide; eq.: equivalents; ESI: electrospray ionisation; FCC: flash column chromatography; h: hour / hours; HATU: 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-Z>]pyridinium 3 -oxide hexafluorophosphate); HBTU : (9-fbenzotri azol- 1 -yl )-;V,AA"A"-t etram ethyl uroni um hexafluorophosphate; HPLC: high pressure liquid chromatography; HPLC-MS / MS: high pressure liquid chromatography-mass spectrometry / mass spectrometry; IPF: idiopathic pulmonary fibrosis; LC: liquid chromatography; LCMS: liquid chromatography-mass spectrometry; LDA: lithium diisopropylamide; LiHMDS: lithium bis(trimethylsilyl)amide; min: minutes; MPLC: mediumpressure liquid chromatography; MS: mass spectrometry; MS ESI+: mass spectrometry-positive electrospray ionization; NAD+ / NADH: nicotinamide adenine dinucleotide; NaHMDS: sodium bis(trimethylsilyl)amide; NMP: A-methyl-2-pyrrolidone; NMR: nuclear magnetic resonance; PHGDH: phosphoglycerate dehydrogenase; PyAOP: (3-hydroxy-3Z / -l,2,3-triazolo[4,5- Z)]pyridinato-(9)tri-l-pyrrolidinyl-phosphorus hexafluorophosphate; PyBOP: benzotriazole- 1-yl- oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; r.t., retention time; RT: Room temperature; SFC: supercritical fluid chromatography; SPhos: 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl; T3P®: 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; TBTU: A,A,A',A'-tetramethyl-O-(benzotriazol-l-yl)uronium tetrafluoroborate; TEA: triethylamine; THF: tetrahydrofuran; TLC: thin layer chromatography; TMSC1: trimethyl silyl chloride; XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; UPLC®: Ultra Performance Liquid Chromatography; UV: ultraviolet.

[0033] The term “compound 1” refers to any stereoisomer of 2-(4-(l-(4-chloro-l,6-dimethyl-lH- indole-2-carboxamido)-2 -hydroxyethyl) phenyl)propanoic acid. The term compound l refers to the single diastereoisomer (R)-2-(4-((S)-l-(4-chloro-l,6-dimethyl-lH-indole-2- carboxamido)-2-hydroxyethyl) phenyl)propanoic acid. It is to be understood that besides the compound 1 showing a preferred configuration, the racemic form and all the single stereoisomers are encompassed within the scope of the present invention.

[0034] The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0035] The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.

[0036] The term "diastereomer " refers to stereoisomers that are not mirror images. The term "racemate" or "racemic mixture" or “racemic form” refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.

[0037] When one of the compounds of this invention is defined as a specific enantiomer or diastereoisomer, the number reported in the name of this specific enantiomer or diastereoisomer is intended to define the order of elution of the compound during any process of chiral separation. For example, a compound defined as “Diastereoisomer 1” is intended to be the first eluted compound in the above described chiral separation process.

[0038] The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom(s) and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

[0039] The term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchanged by migration of an atom or group within the molecule.

[0040] The term "(Cx-Cy)alkyl" wherein x and y are integers, refers to a straight or branched chain alkyl group having from x to y carbon atoms. Thus, when x is 1 and y is 3, for example, the term includes methyl, ethyl, n-propyl, isopropyl.

[0041] The term “halogen” or “halogen atoms” or “halo” as used herein includes fluorine, chlorine, bromine and iodine atom.

[0042] The term “about” is to be construed as modifying a term or value such that it is not an absolute. Such term will be defined by the circumstances. This includes, at the very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

[0043] The term “room temperature”, abbreviated to RT, means a temperature in the range of about 15°C to about 25°C, with an average of about 23°C.

[0044] The term “pharmaceutically acceptable salts”, as used herein, refers to compound 1 compound la or derivatives of compound 1 or compound la (such as for example Intermediate 3, Intermediate 4, Intermediate 5, Intermediate 6, Intermediate 7) wherein such compound is suitably modified by converting the free basic or acid group into the corresponding addition salt with any acid or base conventionally intended as being pharmaceutically acceptable. Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups. The salts obtained by reacting the compound, functioning as a base, with an inorganic or organic acid to form a salt comprise, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.

[0045] Likewise, in the presence of acidic groups, such as for instance COOH groups, corresponding pharmaceutically acceptable cations of inorganic bases may be present, for instance including alkaline or alkaline earth metal ions, including lithium, sodium, potassium, magnesium, calcium and the like, or cations of organic bases, such for example Diethanolamine, Triethylamine, Ethanolamine, Ethylenediamine, Arginine, Benzathine, Lysine, Meglumine, Choline, Procaine, Histidine.

[0046] The term “treating”, or “treatment” of a disease state includes: (i) inhibiting the disease state, i.e. arresting the development of the disease state or its clinical symptoms, or (ii) relieving the disease state, i.e. causing temporary or permanent regression of the disease state or its clinical symptoms.

[0047] The term “preventing”, or “prevention” of a disease state includes causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state but does not yet experience or display symptoms of the disease state. For example, treating or preventing a respiratory disease or disorder includes treating or preventing the symptoms of the disorder such as cough and / or urge to cough associated with a respiratory disease.

[0048] The term “therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to affect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route, and form of administration.

[0049] The terms "fibrosis" or "fibrotic disorder," as used herein, refers to conditions that are associated with the abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.

[0050] The term “PHGDH” or “phosphoglycerate dehydrogenase”, is alternatively referred to as 3- PGDH, 3PGDHm HEL-S-113, NLS, PDG, PGAD, PGD, PGDH, PHGDHD, or SERA. The term “PHGDH” encompasses mutants, variants, homologs, fragments, and synthetically modified phosphoglycerate dehydrogenases.

[0051] A straightforward, efficient and large scale synthesis of 2-(4-(l-(4-chloro-l,6-dimethyl- lH-indole-2-carboxamido)-2-hydroxyethyl) phenyl (propanoic acid (compound 1) has been devised and reported above in Scheme 1, wherein methylation of Intermediate (III) to obtain Intermediate (IV) and amidic coupling of Intermediate compound 6 with 4-chl oro-1, 6-dimethyl- lH-indole-2-carboxylic acid to obtain Intermediate compound 7, thus after ester hydrolysis obtaining compound 1, were done. The synthesis of compound 1 has been devised and reported in Scheme 1. Such synthesis is clean and leads to compound 1 in very good yield and with a high purity, as it may be appreciated in the experimental part of the present application.

[0052] Scheme 1

[0053] The process of this invention can be used for obtaining all the stereoisomers of compound 1, in particular for obtaining (7?)-2-(4-((5)-l-(4-chl oro-1, 6-dimethyl- 17 / -indole-2-carboxamido)-

[0054] 2-hydroxyethyl)phenyl)propanoic acid (compound la). Compound la was previously obtained with the analogue method to what reported in WO2017156179, when Ri is methyl, according to Scheme 2, starting from Intermediate compound 8, tert-butyl (5)-(l-(4-bromophenyl)-2- hydroxy ethylcarbamate. Scheme 2

[0055] The a-methylation reaction of esters bearing a protected amino alcohol was poorly selective, because involves the formation also of dimethylated compounds as side product, and dimethylated impurity was hardly removed from the final product by chromatography, as many fractions needed to be discarded as not pure enough and consequently the yield of isolated a-methylated esters was generally low

[0056] The process of the present invention leads to obtain Intermediate compound of formula (IV) from Intermediate compound of formula (III) in a very selective way, with high yield in the methylation step, in comparison with the method reported in Scheme 2.

[0057] As an example, as reported below in Example 3 in the Experimental part, the yield for the alkylation step was 88%, higher than the yield obtained with the method reported below in Example 12 in the Experimental part, where the yield was 50% . Advantagously, in the final process step of the present invention the t-butyl ester could be removed by hydrolysis using acidic conditions, avoiding the epimerization of the final product.

[0058] According to the method reported in Scheme 2, the total yield for obtaining (A)-2-(4-((5)-l- (4-chloro-l,6-dimethyl-l / / -indole-2-carboxamido)-2-hydroxy ethyl) phenyl)propanoic acid (compound la) from tert-butyl (5)-(l-(4-bromophenyl)-2-hydroxyethyl)carbamate (Intermediate 8) (Examples 10-16 in the Experimental part) was 10%, while according to this invention the total yield for obtaining (A)-2-(4-((S)-l-(4-chloro-l,6-dimethyl-l / / -indole-2-carboxamido)-2- hydroxy ethyl) phenyl)propanoic acid (compound la) from benzyl (5)-4-(4-bromophenyl)-2,2- dimethyloxazolidine-3-carboxylate (Intermediate 2a) (Examples 1-7 in the Experimental part) was higher, 30%.

[0059] As a further advantage, while in the standard procedures known in the art for the syntheses of a compound suitable for drug development require the separation of the mixture of stereoisomers at the final step in order to obtain a single optically pure final compound, in the process described above the separation of stereoisomers was moved earlier in the synthesis. In this way the moles of intermediates to be converted to the following steps to compound (1) were less than 50% in respect to a final chiral separation, reducing the consumption of reagents and solvents in the following steps. The consumption of starting material 4-chl oro-1, 6-dimethyl- l / / -indole-2- carboxylic acid was significantly reduced, and it is a very relevant advantage in view of a scale- up synthesis.

[0060] According to the process reported in Scheme 2, the yield for obtaining (7?)-2-(4-((5)-l-(4- chloro- l,6-dimethyl- 17 / -indole-2-carboxamido)-2-hydroxy ethyl) phenyl)propanoic acid

[0061] (compound la) from 4-chloro-l,6-dimethyl-177-indole-2-carboxylic acid (Examples 14-16 in the Experimental part) was 30%, while according to this invention the yield for obtaining (7?)-2-(4- ((5)-l-(4-chloro-l,6-dimethyl-1 / -indole-2-carboxamido)-2-hydroxyethyl) phenyl)propanoic acid (compound la) from 4-chloro-l,6-dimethyl-l / f-indole-2-carboxylic acid (Examples 6-7 in the Experimental part) was 90%.

[0062] Even more advantageously, in the process of the present invention there is the possibility to recover the undesired stereoisomers of Intermediate V isolated from the chiral separation step.

[0063] In the process of the present invention the a-ester chiral center of Intermediate V can be fully epimerized, converting the undesired diastereoisomer to the initial Intermediate IV that can be recycled in a new chiral separation, according to Scheme 3 (see Example 8 in the Experimental part). Scheme 3

[0064] According to this invention, the desired compound was obtained even with higher optical purity, as with the method reported in Scheme 2 compound la was obtained with a diastereoisomeric excess of 98.8% (Example 16 in the Experimental part), while according to this invention compound la was obtained with a diastereoisomeric excess of 99.6 % (Example 7 in the Experimental part).

[0065] In a first aspect, the present invention relates to a process for the preparation of compound 1, or a pharmaceutically acceptable salt thereof : compound 1 comprising the steps of: a) reacting Intermediate compound of formula (III) with CH3R2 in the presence of an inorganic base,

[0066] Intermediate III to obtain Intermediate compound of formula (IV)

[0067] Intermediate IV wherein

[0068] Ri is selected from the group consisting of H and -(Ci-C3)alkyl, or the two Ri are fused together in a -(C5-Ce)cycloalkyl;

[0069] R2 is selected from the group consisting of halogen and sulfonate; b) amidic coupling of Intermediate compound 6, which is tert-butyl 2-(4-(l-amino-2- hydroxyethyl)phenyl)propanoate Intermediate 6 with 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid to obtain Intermediate compound 7, which is tert-butyl 2-(4-(l-(4-chloro-l,6-dimethyl-lH- indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoate

[0070] Intermediate 7 thus after ester hydrolysis obtaining compound 1.

[0071] In another embodiment, the present invention relates to a process for the preparation of compound 1, or a pharmaceutically acceptable salt thereof: compound 1 comprising the steps of: i) chiral resolution of Intermediate compound of formula (IV) to obtain the 2 diastereoisomers of Intermediate compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein

[0072] Ri is selected from the group consisting of H and -(Ci-C3)alkyl, or the two Ri are fused together in a -(C5-Ce)cycloalkyl; b) amidic coupling of intermediate compound 6, which is tert-butyl 2-(4-(l-amino-2- hydroxyethyl)phenyl)propanoate

[0073] Intermediate 6 with 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid to obtain Intermediate compound 7, which is tert-butyl 2-(4-(l-(4-chloro-l,6-dimethyl-lH- indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoate: or a pharmaceutically acceptable salt thereof, thus after ester hydrolysis obtaining compound 1.

[0074] In a preferred embodiment, the present invention relates to a process for the preparation of compound 1, or a pharmaceutically acceptable salt thereof, compound 1 comprising the steps of: a) reacting Intermediate compound of formula (III) with CH3R2 in the presence of an inorganic base,

[0075] Intermediate III to obtain Intermediate compound of formula (IV) or a pharmaceutically acceptable salt thereof, in the presence of an inorganic base wherein R1 is selected from the group consisting of H and -(Cl-C3)alkyl, or the two R1 are fused together in a -(C5-C6)cycloalkyl;

[0076] R2 is selected from the group consisting of halogen and sulfonate; i) chiral resolution of Intermediate compound of formula (IV) to obtain the 2 diastereoisomers of Intermediate compound of formula (V) or a pharmaceutically acceptable salt thereof; b) amidic coupling of Intermediate compound 6, which is tert-butyl 2-(4-(l-amino-2- hydroxyethyl)phenyl)propanoate

[0077] Intermediate 6 with 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid to obtain Intermediate compound 7, which is tert-butyl 2-(4-(l-(4-chloro-l,6-dimethyl-lH- indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoate:

[0078] Intermediate 7 or a pharmaceutically acceptable salt thereof, thus after ester hydrolysis obtaining compound 1.

[0079] In a preferred embodiment such a process has been developed wherein Ri is methyl, and it is herein described in Scheme 4.

[0080] Scheme 4 Thus, in a preferred embodiment, the present invention relates to a process for the preparation of compound 1, or a pharmaceutically acceptable salt thereof : compound 1 comprising the steps of: a) reacting benzyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)phenyl)-2,2-dimethyloxazolidine- 3 -carboxyl ate, which is Intermediate 3 with CH3R2 in the presence of an inorganic base, to obtain benzyl 4-(4-(l-(tert-butoxy)-l-oxopropan-2-yl)phenyl)-2,2-dimethyloxazolidine- 3-carboxylate, which is Intermediate 4 or a pharmaceutically acceptable salt thereof, in the presence of an inorganic base wherein

[0081] R2 is selected from the group consisting of halogen and sulfonate; b) amidic coupling of Intermediate compound 6, which is tert-butyl 2-(4-(l-amino-2- hydroxyethyl)phenyl)propanoate with 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid to obtain Intermediate compound 7, which is tert-butyl 2-(4-(l-(4-chloro-l,6-dimethyl-lH- indole-2-carboxamido)-2 -hydroxy ethyl)phenyl)propanoate: or a pharmaceutically acceptable salt thereof, thus after ester hydrolysis obtaining compound 1.

[0082] In another preferred embodiment, the present invention relates to a process for the preparation of compound 1, or a pharmaceutically acceptable salt thereof, comprising the steps of i) chiral resolution of Intermediate 4 to obtain benzyl 4-(4-(-l-(tert-butoxy)-l- oxopropan-2-yl)phenyl)-2,2-dimethyloxazolidine-3 -carboxylate, Intermediate 5

[0083] Intermediate 5 or a pharmaceutically acceptable salt thereof; b) amidic coupling of Intermediate compound 6, which is tert-butyl 2-(4-(l-amino-2- hydroxyethyl)phenyl)propanoate

[0084] Intermediate 6 with 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid to obtain Intermediate compound 7, which is tert-butyl 2-(4-(l-(4-chloro-l,6-dimethyl-lH- indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoate: or a pharmaceutically acceptable salt thereof, thus after ester hydrolysis obtaining compound

[0085] 1.

[0086] In a more preferred embodiment, the present invention relates to a process for the preparation of compound 1, or a pharmaceutically acceptable salt thereof, comprising the steps of a) reacting Intermediate 3 with CH3R2 in the presence of an inorganic base, to obtain benzyl 4-(4-(l-(tert-butoxy)-l-oxopropan-2-yl)phenyl)-2,2-dimethyloxazolidine- 3-carboxylate, which is Intermediate 4

[0087] Intermediate 4 or a pharmaceutically acceptable salt thereof wherein

[0088] R2 is selected from the group consisting of halogen and sulfonate; i) chiral resolution of Intermediate 4 to obtain benzyl 4-(4-(-l-(tert-butoxy)-l- oxopropan-2-yl)phenyl)-2,2-dimethyloxazolidine-3 -carboxylate, Intermediate 5

[0089] Intermediate 5 or a pharmaceutically acceptable salt thereof; b) amidic coupling of Intermediate compound 6, which is tert-butyl 2-(4-(l-amino-2- hydroxyethyl)phenyl)propanoate

[0090] Intermediate 6 with 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid to obtain Intermediate compound 7, which is tert-butyl 2-(4-(l-(4-chloro-l,6-dimethyl-lH- indole-2-carboxamido)-2 -hydroxy ethyl)phenyl)propanoate:

[0091] Intermediate 7 or a pharmaceutically acceptable salt thereof, thus after ester hydrolysis obtaining compound 1.

[0092] The process of this invention can be used for obtaining all the stereoisomers of compound 1, in particular for obtaining (R)-2-(4-((S)-l-(4-chloro-l,6-dimethyl-lH-indole-2-carboxamido)- 2-hydroxyethyl)phenyl)propanoic acid (compound la). Such a process has been developed and it is herein described in Scheme 5. Scheme 5

[0093] Thus, in a more preferred embodiment, the present invention relates to a process for the preparation of (R)-2-(4-((S)-l-(4-chloro-l,6-dimethyl-lH-indole-2-carboxamido)-2- hydroxy ethyl) phenyl)propanoic acid, compound la, or a pharmaceutically acceptable salt thereof :

[0094] Compound la comprising the steps of: a) reacting Intermediate compound 3a, which is benzyl (S)-4-(4-(2-(tert-butoxy)-2- oxoethyl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate, with CH3R2 in the presence of an inorganic base,

[0095] Intermediate 3 a to obtain Intermediate 4a, which is benzyl (4S)-4-(4-(l-(tert-butoxy)-l-oxopropan-2- yl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate or a pharmaceutically acceptable salt thereof, wherein

[0096] R2 is selected from the group consisting of halogen and sulfonate; b) amidic coupling of Intermediate compound 6a, which is tert-butyl (R)-2-(4-((S)-l- amino-2-hydroxyethyl)phenyl)propanoate

[0097] Intermediate 6a with 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid to obtain Intermediate compound 7a, which is tert-butyl (R)-2-(4-((S)-l-(4-chloro-l,6- dimethyl-lH-indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoate or a pharmaceutically acceptable salt thereof, thus after ester hydrolysis obtaining compound la.

[0098] In another more preferred embodiment, the present invention relates to a process for the preparation of (R)-2-(4-((S)-l-(4-chl oro-1, 6-dimethyl- lH-indole-2-carboxami do)-2- hydroxy ethyl) phenyl)propanoic acid, compound la, or a pharmaceutically acceptable salt thereof , comprising the steps of: i) chiral resolution of Intermediate 4a to obtain benzyl (S)-4-(4-((R)-l-(tert-butoxy)- l-oxopropan-2-yl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate, Intermediate 5a or a pharmaceutically acceptable salt thereof; b) amidic coupling of Intermediate compound 6a, which is tert-butyl (R)-2-(4-((S)-l- amino-2-hydroxyethyl)phenyl)propanoate with 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid to obtain Intermediate compound 7a, which is tert-butyl (R)-2-(4-((S)-l-(4-chloro-l,6- dimethyl-lH-indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoate or a pharmaceutically acceptable salt thereof, thus after ester hydrolysis obtaining compound la.

[0099] In a more preferred embodiment, the present invention relates to a process for the preparation of (R)-2-(4-((S)-l -(4-chl oro-1, 6-dimethyl-lH-indole-2-carboxamido)-2-hydroxyethyl) phenyl )propanoic acid, compound la, or a pharmaceutically acceptable salt thereof, comprising the steps of: a) reacting Intermediate compound 3a with CH3R2 in the presence of an inorganic to obtain Intermediate 4a or a pharmaceutically acceptable salt thereof, wherein

[0100] R2 is selected from the group consisting of halogen and sulfonate; i) chiral resolution of Intermediate 4a to obtain Intermediate 5a or a pharmaceutically acceptable salt thereof; b) amidic coupling of Intermediate compound 6a, which is tert-butyl (R)-2-(4-((S)-l- amino-2-hydroxyethyl)phenyl)propanoate with 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid to obtain Intermediate compound 7a, which is tert-butyl (R)-2-(4-((S)-l-(4-chloro-l,6- dimethyl-lH-indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoate

[0101] Intermediate 7a or a pharmaceutically acceptable salt thereof, thus after ester hydrolysis obtaining compound la.

[0102] As to step a), the methylation was done in the presence of a suitable solvent, an inorganic base and CH3R2, wherein R2 is selected from the group consisting of halogen and sulfonate.

[0103] The solvent may be selected from the group consisting of DMF, DMA, NMP, DMSO, THF, 2-MeTHF, toluene and 1,4-dioxane, or mixtures thereof. Preferably, the solvent is THF. In step a), CH3R2 was used for the methylation, wherein R2 is selected from the group consisting of halogen and sulfonate. In one embodiment, CH3R2 was used for the methylation, wherein R2 is a sulfonate selected form the group consisting of mesylate, besylate, tosylate and methylsulfate. In another embodiment, CH3R2 was used for the methylation, wherein R2 is halogen. In a preferred embodiment, CH3R2 was used for the methylation, wherein R2 is halogen, selected from Iodide, Chloride, Bromide. More preferably, methylation was done with iodomethane.

[0104] The base may be selected from the group consisting of metal hydrides, like NaH or others, and metal amides, such as for example LDA, Lithium bis(trimethylsilyl)amide (LiHMDS), Sodium bis(trimethylsilyl)amide, Potassium bis(trimethylsilyl)amide, or metal alcolates, such as for example potassium t-butoxide or others, or mixtures thereof. Preferably, the inorganic base is LiHMDS.

[0105] As to step i), a chiral resolution of Intermediate of formula (IV) or Intermediate 4 or intermediate 4a was done to obtain a single enantiomer. It is possible to perform chiral resolution through all the method known from the skilled person of the art, such as for example the use of preparative chiral chromatography, enzymatic optical resolution, crystallization from solvent or solvent mixtures. Preferably, the chiral resolution of Intermediate (IV) was done with preparative chiral chromatography. Preferably, the chiral resolution of Intermediate 4 was done with preparative liquid chiral chromatography. More preferably, the chiral resolution of Intermediate 4 was done with a chiral Supercritical Fluid Chromatography (SFC).

[0106] Advantageously, the process of this invention with chiral resolution of Intermediate of formula (IV) or Intermediate 4 or Intermediate 4a with a chiral Supercritical Fluid Chromatography (SFC) leads to high loading capacity in the chiral separation, with less time and minor solvent consumption.

[0107] The invention also provides a process for the preparation of Intermediate (III) comprising the step of coupling of Intermediate (II) with a suitable organometallic reagent in the presence of a suitable Pd catalyst.

[0108] Intermediate of formula (III) was prepared by coupling Intermediate of formula (II)

[0109] Intermediate II wherein Ri is selected from the group consisting of H and -(Ci-C3)alkyl, or the two Ri are fused together in a -(C5-Ce)cycloalkyl, with a suitable organometallic reagent in the presence of a Pd catalyst and a suitable ligand if needed, in a suitable solvent.

[0110] The reaction may be carried out in a solvent selected from the group consisting of dialkylethers (such as for example diethyl ether, methyl tert-butyl ether, etc.), cyclic ethers (such as THF, 2-Me-THF, 1,4-di oxane), DMF, DMA, NMP, toluene, or others, or mixtures thereof. Preferably, the solvent is 2-methyl tetrahydrofuran.

[0111] The preferred Pd catalyst is tris(dibenzylideneacetone)dipalladium with a suitable ligand, such as for example XPhos or others, or other Pd catalysts known in the art may be used, for instance XPhos Pd crotyl Cl, [(Pd-pBr)[P(tBu)3]]2, [tBuXPhos Pd(allyl)]OTf, P(Cy)3 Pd(crotyl)Cl, SPhosPdG2, XPhos Pd G2, or others.

[0112] Preferably, the organometallic reagent is (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide, obtained by suspending Zinc granular in anhydrous solvent, adding an activating agent, such as for example DIBAL-H, or 1,2-dibromoethane and TMSC1, or others, then dropping in the reactor a solution of t-butyl 2-bromoacetate.

[0113] Intermediate 3 was prepared by coupling Intermediate 2, which is benzyl-4-(4- bromophenyl)-2,2-dimethyloxazolidine-3 -carboxylate, with a suitable organometallic reagent in the presence of a Pd catalyst and a suitable ligand if needed, in a suitable solvent.

[0114] Intermediate 2

[0115] The reaction may be carried out in a solvent selected from the group consisting of dialkylethers (such as for example diethyl ether, methyl tert-butyl ether, etc.), cyclic ethers (such as THF, 2-Me-THF, 1,4-di oxane), DMF, DMA, NMP, toluene, or others, or mixtures thereof. Preferably, the solvent is 2-methyl tetrahydrofuran.

[0116] The preferred Pd catalyst is tris(dibenzylideneacetone)dipalladium with a suitable ligand, such as for example XPhos or others, or other Pd catalysts known in the art may be used, for instance XPhos Pd crotyl Cl, [(Pd-pBr)[P(tBu)3]]2, [tBuXPhos Pd(allyl)]OTf, P(Cy)3 Pd(crotyl)Cl, SPhos Pd G2, XPhos Pd G2, or others.

[0117] Preferably, the organometallic reagent is (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide, obtained by suspending Zinc granular in anhydrous solvent, adding an activating agent, such as for example DIBAL-H, or 1,2-dibromoethane and TMSC1, or others, then dropping in the reactor a solution of t-butyl 2-bromoacetate. Intermediate 3a was prepared by coupling Intermediate 2a, which is benzyl (S)-4-(4- bromophenyl)-2,2-dimethyloxazolidine-3-carboxylate

[0118] Intermediate 2a with a suitable organometallic reagent in the presence of a Pd catalyst in a suitable solvent, for instance as described in Example 2.

[0119] Preferably, the solvent is 2-methyltetrahydrofuran. The preferred Pd catalyst is tris(dibenzylideneacetone)dipalladium. Preferably, the organometallic reagent is (2-(tert-butoxy)- 2-oxoethyl)zinc(II) bromide, obtained by suspending Zinc granular in anhydrous solvent, dropping in the reactor a solution of t-butyl 2-bromoacetate and adding Diisobutylaluminium hydride.

[0120] The Intermediate 2a, which is benzyl (S)-4-(4-bromophenyl)-2,2-dimethyloxazolidine-3- carboxylate, may be prepared as described in Example 1.

[0121] In a preferred embodiment, the present invention relates to a process for the preparation of compound 1, or a pharmaceutically acceptable salt thereof, further comprising the step of deprotecting the 2 diastereoisomers of Intermediate of formula (V) or Intermediate 5 to obtain Intermediate 6, which is tert-butyl 2-(4-(l-amino-2-hydroxyethyl)phenyl)propanoate

[0122] Intermediate 6 or a pharmaceutically acceptable salt thereof, in presence of Palladium.

[0123] The reaction can be performed in a suitable solvent, in presence of palladium and hydrogen gas or a suitable source of hydrogen, such as for example formic acid, or ammonium formate, or others. Preferably, the reaction was performed in methanol and water. Preferably, the reaction was performed in presence of Palladium on charcoal and formic acid. More preferably, the reaction was performed in presence of Palladium 10% on charcoal and formic acid. In a more preferred embodiment, the reaction was performed in presence of Palladium 5% on charcoal and formic acid.

[0124] In another preferred embodiment, the present invention relates to a process for the preparation of compound la, or a pharmaceutically acceptable salt thereof , further comprising the step of deprotecting Intermediate 5a to obtain Intermediate 6a, which is tert-butyl (R)-2-(4-((S)-l- amino-2-hydroxyethyl)phenyl)propanoate

[0125] Intermediate 6a or a pharmaceutically acceptable salt thereof, in presence of palladium. The Intermediate 6a may be prepared as described in Example 5. The reaction can be performed in a suitable solvent, in presence of palladium and hydrogen gas or a suitable source of hydrogen, such as for example formic acid, or ammonium formate, or others. Preferably, the reaction was performed in methanol and water. Preferably, the reaction was performed in presence of Palladium on charcoal and formic acid. More preferably, the reaction was performed in presence of Palladium 10% on charcoal and formic acid. In a more preferred embodiment, the reaction was performed in presence of Palladium 5% on charcoal and formic acid.

[0126] In another preferred embodiment, the present invention relates to a process for the preparation of compound 1, or a pharmaceutically acceptable salt thereof, further comprising the step b) of amidic coupling of intermediate 6 with 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid to obtain Intermediate 7 or a pharmaceutically acceptable salt thereof, thus obtaining compound 1.

[0127] The reaction of step b) of amidic coupling may be carried out in a suitable solvent, such as di chloromethane, ethers (such as for example THF, 2-Me-THF, 1,4-di oxane), DMF, DMA, NMP, toluene or mixtures thereof, in presence of an organic base (such as for example TEA, DIPEA or others) and a peptide coupling agents (such as for example HBTU, TBTU, HATU, PyBOP, PyAOP, COMU, CDI, EDC, T3P®, or others). Preferably, the reaction can be performed in N,N- dimethylformamide, in presence of triethylamine and HATU.

[0128] In another preferred embodiment, the present invention relates to a process for the preparation of (R)-2-(4-((S)-l-(4-chl oro-1, 6-dimethyl- lH-indole-2-carboxamido)-2- hydroxy ethyl) phenyl)propanoic acid, compound la, or a pharmaceutically acceptable salt thereof, further comprising the step of ami die coupling of Intermediate 6a with 4-chloro-l, 6-dimethyl- 1H- indole-2-carboxylic acid, to obtain Intermediate 7a, which is tert-butyl (R)-2-(4-((S)-l-(4-chloro- l,6-dimethyl-lH-indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoate

[0129] Intermediate 7a or a pharmaceutically acceptable salt thereof, thus obtaining compound la.

[0130] The Intermediate 7a may be prepared as described in Example 6. The reaction of amidic coupling may be carried out in a suitable solvent, such as di chloromethane, ethers (such as for example THF, 2-Me-THF, 1,4-di oxane), DMF, DMA, NMP, toluene or mixtures thereof, in presence of an organic base (such as for example TEA, DIPEA or others) and a peptide coupling agents (such as for example HBTU, TBTU, HATU, PyBOP, PyAOP, COMU, CDI, EDC, T3P®, or others). Preferably, the reaction can be performed in N,N-dimethylformamide, in presence of triethylamine and HATU.

[0131] In another preferred embodiment, the present invention relates to a process for the preparation of compound 1, or a pharmaceutically acceptable salt thereof, further comprising the step of deprotecting intermediate 7 by hydrolysis to obtain compound 1. The reaction of deprotection may be carried out in a suitable solvent, such for example a mixture of tetrahydrofuran and water, using acidic conditions. In a preferred embodiment the hydrolysis was carried out in a mixture of tetrahydrofuran and water 1 : 1 , in presence of hydrochloric acid.

[0132] In a more preferred embodiment, the present invention relates to a process for the preparation of compound la, or a pharmaceutically acceptable salt thereof, further comprising the step of deprotecting intermediate 7a by hydrolysis to obtain compound la. The compound la may be prepared as described in Example 7. The reaction of deprotection may be carried out in a suitable solvent, such for example a mixture of tetrahydrofuran and water, using acidic conditions. In a preferred embodiment the hydrolysis was carried out in a mixture of tetrahydrofuran and water 1:1, in presence of hydrochloric acid.

[0133] In another preferred embodiment, the present invention relates to a process for the preparation of compound 1, or a pharmaceutically acceptable salt thereof, further comprising the step of recovering the unwanted diastereoisomer of benzyl 4-(4-(l-(tert-butoxy)-l-oxopropan-2- yl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 4) isolated from the Supercritical Fluid Chromatography (SFC) that can be recycled in a new chiral separation.

[0134] In more preferred embodiment, the present invention relates to a process for the preparation of compound la, or a pharmaceutically acceptable salt thereof , further comprising the step of recovering the benzyl (S)-4-(4-((S)-l-(tert-butoxy)-l-oxopropan-2-yl)phenyl)-2,2- dimethyloxazolidine-3-carboxylate (intermediate 5b) isolated from the Supercritical Fluid Chromatography (SFC) for obtaining intermediate 4b that can be recycled in a new chiral separation.

[0135] Intermediate 5b

[0136] The reaction was performed in presence of a suitable solvent, such as for example THF, t- BuOH, heptane, and with catalytic and stoichiometric equivalents of an inorganic base. In a preferred embodiment, the reaction was performed inlBuOH as solvent.

[0137] The rection was performed in presence of a suitable inorganic base, such as for example DABCO, DBU, KOt-Bu, NaCF-Bu, LiOt-Bu, LiHMDS, NaHMDS, potassium 3,7-dimethyl-3- octanolate.

[0138] In a preferred embodiment, the reaction was performed in presence of 0.2 eq. of an inorganic base. In a more preferred embodiment, the reaction was performed in presence of 0.2 eq. of NaCF- Bu. In another preferred embodiment, the reaction was performed at 25°C: in these preferred conditions it was shown that after two hours epimerization was complete to a 50 / 50 mixture of diasteroisomers with limited (less that 2%) degradation.

[0139] In another aspect, the present invention provides an Intermediate compound of formula (III) as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof.

[0140] In another aspect, the present invention provides an Intermediate compound of formula (IV) as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof. In another embodiment, the present invention relates to the use of Intermediate compound of formula (III) and / or Intermediate compound of formula (IV) for the preparation of compound 1. In a preferred embodiment, the present invention relates to the use of Intermediate 3 and / or Intermediate 4 and / or for the preparation of compound 1. In a more preferred embodiment, the present invention relates to the use of Intermediate 3a and / or Intermediate 4a for the preparation of compound la.

[0141] In another embodiment, the present invention provides an Intermediate compound of formula (II). In another embodiment, the present invention relates to the use of Intermediate compound of formula (II) for the preparation of compound 1.

[0142] In a preferred embodiment, the invention provides benzyl 4-(4-bromophenyl)-2,2- dimethyloxazolidine-3-carboxylate (Intermediate 2) or a pharmaceutically acceptable salt thereof. In another embodiment, the invention provides the use of Intermediate 2 for the preparation of compound 1, or a pharmaceutically acceptable salt thereof.

[0143] In a preferred embodiment, the invention provides benzyl (S)-4-(4-bromophenyl)-2,2- dimethyloxazolidine-3-carboxylate (Intermediate 2a) or a pharmaceutically acceptable salt thereof. In another embodiment, the invention provides the use of Intermediate 2a for the preparation of compound la, or a pharmaceutically acceptable salt thereof.

[0144] In another embodiment, the invention provides Intermediate 3 as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof. In a preferred embodiment, the invention provides benzyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate

[0145] (Intermediate 3) or a pharmaceutically acceptable salt thereof. The invention further provides the use of Intermediate 3 for the preparation of compound 1, or a pharmaceutically acceptable salt thereof.

[0146] In a preferred embodiment, the invention provides benzyl (S)-4-(4-(2-(tert-butoxy)-2- oxoethyl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 3a) or a pharmaceutically acceptable salt thereof. The invention also provides a process for the preparation of Intermediate 3a comprising the step of coupling of Intermediate 2a in the presence of a suitable Pd catalyst. Intermediate 3a may be prepared as described in Example 2.

[0147] The invention further provides the use of Intermediate 3a for the preparation of compound l , or a pharmaceutically acceptable salt thereof.

[0148] The invention also provides benzyl 4-(4-(l-(tert-butoxy)-l-oxopropan-2-yl)phenyl)-2,2- dimethyloxazolidine-3-carboxylate (Intermediate 4) as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof. The invention also provides a process for the preparation of Intermediate 4 comprising the step of reacting Intermediate 3 in the presence of a suitable solvent, a base and CH3R2, wherein R2 is selected from the group consisting of halogen and sulfonate.

[0149] The invention further provides the use of Intermediate 4 for the preparation of compound 1, or a pharmaceutically acceptable salt thereof.

[0150] The invention also provides benzyl (4S)-4-(4-(l-(tert-butoxy)-l-oxopropan-2-yl)phenyl)- 2, 2-dimethyloxazolidine-3 -carboxylate (Intermediate 4a) or a pharmaceutically acceptable salt thereof.

[0151] The invention also provides a process for the preparation of Intermediate 4a comprising the step of reacting Intermediate 3a in the presence of a suitable solvent, an inorganic base and CH3R2, wherein R2 is selected from the group consisting of halogen and sulfonate.

[0152] The invention further provides the use of Intermediate 4a for the preparation of compound la, or a pharmaceutically acceptable salt thereof.

[0153] In another embodiment, the invention provides Intermediate 5 as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof. The invention further provides the use of Intermediate 5 for the preparation of compound 1, or a pharmaceutically acceptable salt thereof.

[0154] In another embodiment, the invention provides Intermediate 5a or a pharmaceutically acceptable salt thereof. The invention further provides the use of Intermediate 5a for the preparation of compound la, or a pharmaceutically acceptable salt thereof.

[0155] In another embodiment, the present invention provides Intermediate 6 or Intermediate 7 or a pharmaceutically acceptable salt thereof. In a preferred aspect, the invention provides Intermediate 6a or Intermediate 7a or a pharmaceutically acceptable salt thereof.

[0156] In another embodiment, the invention refers to the use of Intermediate 6 and / or Intermediate 7 for the preparation of compound 1, or a pharmaceutically acceptable salt thereof.

[0157] In a preferred embodiment, the present invention relates to the use of Intermediate 6a and / or Intermediate 7a for the preparation of compound la.

[0158] Accordingly, the invention provides Intermediate 6 as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof. The invention further provides the use of Intermediate 6 for the preparation of compound 1, or a pharmaceutically acceptable salt thereof.

[0159] In a preferred embodiment, the invention provides Intermediate 6a or a pharmaceutically acceptable salt thereof. The invention further provides the use of Intermediate 6a for the preparation of compound l , or a pharmaceutically acceptable salt thereof. In another embodiment, the invention provides Intermediate 7 as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof. The invention further provides the use of Intermediate 7 for the preparation of compound 1, or a pharmaceutically acceptable salt thereof.

[0160] In a preferred embodiment, the invention provides Intermediate 7a as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof. The invention further provides the use of Intermediate 7a for the preparation of compound la, or a pharmaceutically acceptable salt thereof.

[0161] Compound 1 and compound la as prepared by the process according to the invention may be used in pharmaceutical compositions for medical use, for the treatment of disorders associated with 3 -phosphoglycerate dehydrogenase (PHGDH) receptors mechanism. In a preferred embodiment, compound 1 as prepared by the process according to the invention may be used in pharmaceutical compositions for the prevention and / or treatment of fibrosis and / or diseases, disorders, or conditions that involve fibrosis.

[0162] PREPARATIONS OF INTERMEDIATES AND EXAMPLES

[0163] Chemical Names of the compounds were generated with Structure To Name Place IUPAC Name by PerkinElmer ChemDraw® Professional 21.0.0.28 or are common chemical names. All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

[0164] In the procedures that follow, some of the starting materials are identified through an “Intermediate” or “Example” number with indications on step number. This is provided merely for assistance to the skilled chemist.

[0165] When reference is made to the use of a “similar” or “analogous” procedure, as it will be appreciated by those skilled in the art, such a procedure may involve minor variations, for example reaction temperature, reagent / solvent amount, reaction time, work-up conditions or chromatographic purification conditions, that will be appreciated by those skilled in the art.

[0166] General Experimental details

[0167] Purifications

[0168] Purification by “chromatography”, “flash chromatography” or “flash column chromatography (FCC)” refers to purification using a Biotage, or Interchim puriFlash purification system, or equivalent MPLC system using a pre-packed polypropylene column containing stationary phase (cartridge). Fractions containing the required product (identified by TLC and / or LCMS analysis) were pooled and concentrated in vacuo. NMR Methods

[0169] 'H NMR spectra were recorded on a Varian MR-400 spectrometer operating at 400MHZ (proton frequency), equipped with a self-shielded Z-gradient coil 5 mm IH / nX broadband probe head for reverse detection, deuterium digital lock channel unit, quadrature digital detection unit with transmitter offset frequency shift. DMSO-de, MeOD-d4 or CDCh were used as solvents. All experiments were recorded at 298 K, unless stated differently. Chemical shifts are reported as 8 values in ppm relative to tetramethylsilane as an internal standard. Coupling constants (J values) are given in hertz (Hz) and multiplicities are reported using the following abbreviation: s=singlet, d=doublet, t=triplet, q=quartet, dd= doublet of doublets, dt=doublet of triplets, m=multiplet, b abroad, nd=not determined.

[0170] LC / UV / MS Analytical Methods

[0171] Method 1: Acquity CSH C18 column 50mm*2.1mm 1.7pm, maintained at 40°C; Mobile phase: Eluent B (acetonitrile + 0.05% formic acid) in Eluent A (water + 0.05% formic acid) from 5% to 95% within 3.5 min. Flow rate: 1 ml / min. Wavelength: 210-400 nm DAD. UPLC + Waters™ PDA + Waters™ QDA.

[0172] Method 4: Acquity CSH C18 column 50mm*2.1mm 1.7pm, maintained at 40°C; Mobile phase: Eluent B (acetonitrile + 0.05% formic acid) in Eluent A (water + 0.05% formic acid) from 5% to 95% within 1.9 min. Flow rate: 1 ml / min. Wavelength: 210-400 nm DAD. UPLC + Waters™ PDA + Waters™ QDA.

[0173] Chiral SFC Analytical Methods

[0174] Method 2: Lux-5pm Cellulose 3 column 250*4.6mm, maintained at 30 °C; run time: 12min; eluent CO2 / methanol ( + 0.1% ammonia) 90 / 10, Flow rate 1.5ml / min; back pressure: lOObar

[0175] Method 3: Lux-5pm Cellulose 3 column 250*4.6mm, maintained at 40 °C; runtime: 12min; eluent CO2 / methanol ( + 0.1% ammonia) 80 / 20. Flow rate 3 ml / min; back pressure: lOObar.

[0176] Method 5: Lux-5pm Cellulose 3 column 250*4.6mm, maintained at 40 °C; run time: 12 min; eluent CO2 / methanol ( + 0.1% ammonia) 80 / 20. Flow rate: 3 mL / min; back pressure: 125 Bar.

[0177] Method 6: Lux-5pm Cellulose 3 column 250*4.6mm maintained at 40 °C; run time: 25 min; eluent CO2 / methanol ( + 0.1% ammonia) 80 / 20. Flow rate: 3 mL / min; back pressure: 125 Bar;

[0178] Synthetic procedures

[0179] Example 1: benzyl (S)-4-(4-bromophenyl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 2a)

[0180] Benzyl (S)-(l-(4-bromophenyl)-2-hydroxyethyl)carbamate (276 g, 0.79 mol) was dissolved in acetone (2760 ml) and 2,2-dimethoxypropane (820.8 g, 7.9 mol). Para-toluenesulfonic acid (14.99 g, 0.079 mol) was added and reaction mixture was stirred for 18 hours at room temperature. Solvent was evaporated under vacuum and the residue was dissolved in ethyl acetate (1500 ml); the solution was extracted with aqueous 5% potassium hydrogencarbonate (400 ml) and then with brine (300 ml). The solution was concentrated under vacuum and Intermediate 2a (307 g, 0.79 mol, 100% yield) was obtained as a pale yellow oil that turned to waxy solid upon standing. It was used as is in the following step.

[0181] LC-MS Method 1: r.t. 2.33 min ( 225 nm), MS ESI(+) m / z = 389.9,391.7 [M+H]+.

[0182] 1H NMR (300MHz, DMSO-d6) 5 ppm 1.53 (br s, 3H), 1.66 (br s, 3H), 3.80 (dd, J=9.2, 2.5 Hz, 1H), 4.31 (dd. J=9.2, 6.6 Hz, 1H), 4.97 ( h, J=12.5 Hz, 3H), 6.84-7.00 (m, 1H), 7.12-7.46 ( m, 6H), 7.52 (d, J=8.2 Hz, 2H).

[0183] Example 2: benzyl (S)-4-(4-(2-(tert-butoxy)-2-oxoethyl)phenyl)-2,2- dimethyloxazolidine-3-carboxylate (Intermediate 3a)

[0184] Zinc granular (47.95 g, 733 mmol) was suspended in anhydrous 2-methyltetrahydrofuran (500 ml) under nitrogen atmosphere, the mixture was stirred at 40°C. t-butyl 2-bromoacetate (130g, 666 mmol) was dissolved in anhydrous 2-methyltetrahydrofuran (150ml) and about 5% of the solution was dropped in reactor. Diisobutylaluminium hydride IM in toluene (2.6 ml, 2.6 mmol) was added: the mixture turned cloudy and temperature rose to about 45°C, which indicated the start of formation of (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide. The rest of t-butyl 2- bromoacetate solution was dropped in 1 hour, keeping temperature at about 40°C. The mixture was stirred at 40°C for additional 30 min, then it was cooled to room temperature: a suspension of (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide was obtained. Intermediate 2a (103 g, 263 mmol), tris(dibenzylideneacetone)dipalladium(0) (12.0 g, 13.2 mmol) and dicyclohexyl[2',4',6'-tris(propan-2-yl)[l,l'-biphenyl]-2-yl]phosphane (12.3 g, 26.4 mmol) were dissolved in anhydrous 2-methyltetrahydrofuran (500 ml) and the mixture was heated at 55°C in nitrogen atmosphere. The suspension of (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide was added portion wise during 50 minutes at 60°C, then the mixture was stirred at 60°C for additional 30 minutes. After cooling to room temperature and addition of a saturated solution of ammonium chloride (500 ml), the mixture was filtered through a pad of celite, washing with ethyl acetate (1000 ml). All the filtrates were mixed and stirred, the aqueous phase was separated and extracted with ethyl acetate (500 ml) and the blended organic phase was washed with brine (500 ml), dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The dark oily residue was purified by column chromatography (silica gel, dichloromethane-ethyl acetate, 0-5%). Intermediate 3a (95.2g, 224 mmol, 85% yield) was obtained as a brown oil.

[0185] LC-MS Method 1: r.t. 2.66 min (X 225 nm), MS ESI(+) m / z = 326.2 [M+H-100]+, 370.1 [M+H-56]+

[0186] ‘HNMR (400MHz, DMSO-d6) 5 ppm 1.33-1.45 (m, 9H), 1.47-1.57 (m, 3H), 1.59-1.78 (m, 3H), 3.44-3.62 (br s, 2H), 3.70-3.88 (m, 1H), 4.19-4.39 ( m, 1H), 4.81-5.17 (m, 3H), 6.83-7.00 (m, 2H), 7.11-7.28 (m, 5H), 7.29-7.46 (m, 2H).

[0187] Example 3: benzyl (4S)-4-(4-(l-(tert-butoxy)-l-oxopropan-2-yl)phenyl)-2,2- dimethyloxazolidine-3-carboxylate (Intermediate 4a)

[0188] Intermediate 3a (85.4g, 196 mmol) was dissolved in anhydrous tetrahydrofuran and cooled to -20°C under nitrogen atmosphere. Lithium bis(trimethylsilyl)amide IM in tetrahydrofuran (215ml, 215mmol) was dropped in keeping T<-10°C and the mixture was stirred for 1 hour, then a solution of iodomethane (22.5 g, 215 mmol) was added and the mixture was stirred for 2 hours at -20°C, then it was quenched with aqueous saturated ammonium chloride. The mixture was extracted twice with ethyl acetate (500 ml) at room temperature, the organic solution was washed with brine (500 ml) and evaporated under vacuum. The oily residue was purified by column chromatography (silica gel, dichloromethane-ethyl acetate, 0-5% ). Intermediate 4a (74.3 g, 173 mmol, 88 % yield) was obtained as a brown oil that turned solid upon standing.

[0189] LC-MS Method 1 : r.t.2.78 min (X 225 nm), MS ESI(+) m / z = 340.2 [M+H-100]+, 384.2 [M+H-56]+. 1HNMR (400MHz, DMSO-d6) 5 ppm 1.25-1.45 (m, 12H), 1.53 (br s, 3H), 1.68 (br s, 3H), 3.65 (br d, J=6.80 Hz, 1H), 3.80 (dd, J=9.21, 1.97Hz, 1H), 4.30 (br t, J=7.78 Hz, 1H), 4.82-5.17 (m, 2H), 6.89 (br s, 2H), 7.13-7.28 (m, 5H), 7.38 (br s, 2H).

[0190] Example 4: benzyl (S)-4-(4-((R)-l-(tert-butoxy)-l-oxopropan-2-yl)phenyl)-2,2- dimethyloxazolidine -3-carboxylate and benzyl (S)-4-(4-((S)-l-(tert-butoxy)-l-oxopropan-2- yl)phenyl)-2,2-dimethyloxazolidine -3-carboxylate (Intermediate 5a and Intermediate 5b)

[0191] Intermediate 4a (mixture of two diastereoisomers S,R and S,S, 100 g, 228 mmol) was dissolved in ethanol (1660 ml) and the so obtained mixture (concentration 60.2 mg / ml) was separated through chiral supercritical fluid chromatography according to the following conditions:

[0192] Column: Chiralcel OK® (50mm*250mm, 20pm)

[0193] Column temperature: 30°C

[0194] Flow rate: 375ml / min

[0195] Eluent: CO2 / ethanol 95:5

[0196] Backpressure: 130 BarG

[0197] Detector wavelength: 235 nm

[0198] Injection volume: 8ml (corresponding to 482mg mixture)

[0199] Retention time: 4.23min (first eluting peak)

[0200] 7.23min (second eluting peak)

[0201] Collected fractions containing the first eluting peak were combined and solvent was evaporated under vacuum. The same procedure was applied to collected fractions containing the second eluting peak.

[0202] Product obtained from the first eluting peak corresponded to Intermediate 5a, benzyl (S)-4- (4-((R)- 1 -(tert-butoxy)- 1 -oxopropan-2-yl)phenyl)-2,2-dimethyloxazolidine-3 -carboxylate (45.8 g, 104 mmol, 46% yield, 99.6% diastereoisomeric excess) was obtained as a white solid.

[0203] Intermediate 5b, benzyl (S)-4-(4-((S)-l -(tert-butoxy)- l-oxopropan-2-yl )phenyl)-2, 2- dimethyloxazolidine-3-carboxylate was recovered as a white solid from the second eluting peak (46.8 g, 107 mmol, 47% yield, 99.8% diastereoisomeric excess).

[0204] LC-MS Method 1: r.t 2 78 min ( 225 nm), MS ESI(+) m / z = 340.2 [M+H-100]+, 384.2

[0205] [M+H-56]+.

[0206] Chiral SFC Method 2: r.t. benzyl (S)-4-(4-((R)- 1 -(tert-butoxy)- 1 -oxopropan-2-yl)phenyl)-2,2-dimethyloxazolidine -3-carboxylate = 3.52min r.t. benzyl (S)-4-(4-((S)- 1 -(tert-butoxy)- 1 -oxopropan-2-yl)phenyl)-2,2-dimethyloxazolidine -3-carboxylate = 4.41min

[0207] 1HNMR (400MHz, DMSO-d6) 5 ppm 1.25-1.45 (m, 12H), 1.53 (br s, 3H), 1.68 (br s, 3H), 3.65 (br d, J=6.80 Hz, 1H), 3.80 (dd, J=9.21, 1.97Hz, 1H), 4.30 (br t, J=7.78 Hz, 1H), 4.82-5.17 (m, 2H), 6.89 (br s, 2H), 7.13-7.28 (m, 5H), 7.38 (br s, 2H).

[0208] Example 5: tert-butyl (R)-2-(4-((S)-l-amino-2-hydroxyethyI)phenyI)propanoate (Intermediate 6a)

[0209] Intermediate 5a (20g, 45.5 mmol) was dissolved in methanol (300ml) and water (10ml) and the solution was cooled to 15°C. Palladium 10% on charcoal ( 4g, 50% wet) was added followed by dropping of formic acid (11g, 230mmol); the mixture was stirred for 30min and then filtered through a pad of celite. The solvent was evaporated under vacuum, the residue was dissolved in water (200ml) and added with potassium carbonate raising pH from initial 3 5 to 8. The mixture was extracted with methyltetrahydrofuran (4*70ml) at 40-50°C and the organic solution was washed with aqueous saturated sodium hydrogencarbonate (100ml), brine (100ml) and dried (anhydrous sodium sulfate). The solution was filtered and the solvent was evaporated under vacuum. Intermediate 6a (11 ,7g, 44.1 mmol, 97% yield ) was obtained as a waxy solid. It was used as it is in the following step.

[0210] LC-MS Method 1: r.t. 0.78 min (X 225 nm), MS ESI(+) m / z = 266.3 [M+H]+

[0211] 'HNMR (400MHz, DMSO-d6) 8 ppm 1.31 (d, J=7.02 Hz, 3H), 1.35 (s, 9H), 2.08 (br s, 2H), 3.22-3.30 (m, 1H), 3.43 (br dd, J=10.19, 4.49 Hz, 1H), 3.60 (q, J=7.02Hz, 1H), 3.84 (dd, J=7.89, 4.60 Hz, 1H), 4.77 (br s, 1H), 7.18 (d, J=7.89Hz, 2H), 7.30 (d, J=7.89 Hz, 2H).

[0212] Example 6: tert-butyl (R)-2-(4-((S)-l-(4-chIoro-l,6-dimethyI-lH-indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoate (Intermediate 7a)

[0213] Intermediate 6a (10.9g, 41.1 mmol) and 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid (9.2g, 41.1 mmol) were dissolved inN,N-dimethylformamide (90 ml), triethylamine ( 6.24 g, 61.7 mmol) was added and the mixture was cooled to 0-5°C. HATU (16.4 g, 61.8 mmol ) was added portionwise in 30 minutes, then the mixture was stirred for 60 minutes. Sodium hydrogencarbonate 5% aq. (300ml) was added and the mixture was extracted twice with ethyl acetate (2*300ml). The organic solution was washed with brine (300ml), dried (anhydrous sodium sulfate), then solvent was evaporated under vacuum. The waxy residue was purified by column chromatography (silica gel, dichloromethane-ethyl acetate, 0-20% ). Intermediate 7a (18.4g, 39.1 mmol, 95% yield) was obtained as a waxy solid.

[0214] LC-MS Method 1 : r.t. 2.6 min (X 225 nm), MS ESI(+) m / z = 415.2 [M+H-56]+, 471.3[M+H]+

[0215] Chiral SFC Method 3: r.t. tert-butyl (R)-2-(4-((S)-l-(4-chloro-l,6-dimethyl-lH-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoate 3.89min r.t. tert-butyl (S)-2-(4-((S)-l-(4-chloro-l,6-dimethyl-lH-indole-2-carboxamido)-2- hy droxy ethyl)phenyl)propanoate 5.58min

[0216] 'HNMR (400MHz, DMSO-d6) 5 ppm 1.31 (d, J=7.23, Hz, 3H), 1 36 ( s, 9H), 243 (s, 3H), 3.57-3.77 (m, 3H), 3.93 (s, 3H), 4.96 (t, J=5.70 Hz, 1H), 4.99-5.11 (m, 1H), 7.05 (s, 1H), 7.23 (d, J=7.89Hz, 2H), 7.32 (d, J=3.73 Hz, 2H), 7.36 (d, J=7.89 Hz, 2H), 8.84 (d, J=8.33 Hz, 1H).

[0217] Example 7: (R)-2-(4-((S)-l-(4-chIoro-l,6-dimethyI-lH-indole-2-carboxamido)-2- hydroxyethyl) phenyl)propanoic acid (compound la) Intermediate 7a (19.2 g, 40.6 mmol) was dissolved in di chloromethane (150 ml) and trifluoroacetic acid (46.3 g, 406 mmol) was added: the mixture was stirred at room temperature for 3 hours. The solution was concentrated under vacuum and the residue was diluted with tetrahydrofuran (100ml) and water (100ml), then aqueous ammonia was dropped in raising pH to 10-11. The mixture was stirred for 30 min, then added with hydrochloric acid to lower pH to 2, added with brine and extracted with 2-methyltetrahydrofuran (4* 100ml). The organic solution was washed with brine (200 ml), dried (anhydrous sodium sulfate), filtered and evaporated under vacuum: the residue was triturated in warm dichloromethane for 2 hours, cooled to 5°C and filtered. The solid was dried under vacuum at 40°C overnight. Desired compound la (16.1g, 38.7 mmol, 95% yield) was obtained as a whitish powder.

[0218] The total yield for obtaining (R)-2-(4-((S)-l-(4-chl oro-1, 6-dimethyl- lH-indole-2- carboxamido)-2-hydroxyethyl) phenyl)propanoic acid (compound la) from benzyl (S)-4-(4- bromophenyl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 2a) (Examples 1-7) was 30%.

[0219] The yield for obtaining (R)-2-(4-((S)-l-(4-chloro-l,6-dimethyl-lH-indole-2-carboxamido)- 2 -hydroxy ethyl) phenyl )propanoic acid (compound la) from 4-chl oro-1, 6-dimethyl- lH-indole-2- carboxylic acid (Examples 6-7) was 90%.

[0220] LC-MS Method 1: r.t. 1.92min (X 225 nm), MS ESI(+) m / z = 415.2 [M+H]+

[0221] Chiral SFC method 3: r.t.(R)-2-(4-((S)-l-(4-chl oro-1, 6-dimethyl-lH-indole-2-carboxamido)-2- hydroxyethyl)phenyl) propanoic acid 12.05min r t. (S)-2-(4-((S)-l-(4-chl oro-1, 6-dimethyl- lH-indole-2-carboxami do)-2- hydroxyethyl)phenyl) propanoic acid 13.79min

[0222] 1HNMR (400MHz, DMSO-d6) 5 ppm 1.34 (d, J=7.02 Hz, 3H), 2.43 (s, 3H), 3.54-3.78 (m, 3H), 3.93 (s, 3H), 4.96 (br s, 1H), 4.99-5.107 (m, 1H), 7.05 (s, 1H), 724 (d, 1=8.11 Hz, 2H), 7.32 (d, J=5.92 Hz, 2H), 7.36 (d, J=8.11 Hz, 2H), 8.84 (d, J=8.11 Hz, 1H).

[0223] Example 8: Recovery of benzyl (4S)-4-(4-(l-(tert-butoxy)-l-oxopropan-2-yl)phenyl)-

[0224] 2,2-dimethyloxazolidine-3-carboxylate (Intermediate 4a) from Intermediate 5b Intermediate 5b benzyl (S)-4-(4-((S)-l -(tert-butoxy)- l-oxopropan-2-yl )phenyl)-2, 2- dimethyloxazolidine-3-carboxylate isolated from the preparative chiral chromatography (see Example 4) could be epimerized at the a-ester chiral center according to the following procedure.

[0225] Benzyl (S)-4-(4-((S)-l -(tert-butoxy)- l-oxopropan-2-yl)phenyl)-2,2-dimethyloxazolidine-3- carboxylate ( 2.2g, 5mmol) was dissolved in t-butanol (22ml) at 25°C and the sodium ‘-butoxide 2M in THF ( 0.5ml, Immol) was added. The solution was stirred for 2 hours at 25°C, then heptane (100ml) and 10% aqueous sodium hydrogen carbonate were added and the mixture was heated at 40°C. The organic phase was separated, washed with brine and concentrated under vacuum. Benzyl (4S)-4-(4-(l-(tert-butoxy)-l-oxopropan-2-yl)phenyl)-2,2-dimethyloxazolidine-3- carboxylate (intermediate 4a, 2.13g, 4.85 mmol, mixture of S,R and S,S diastereoisomers, yield 97%) was recovered as a colourless oil that turned solid upon standing.

[0226] LC-MS Method 1: r.t. 2.78 min ( 225 nm), MS ESI(+) m / z = 340.2 [M+H-100]+, 384.2 [M+H-56]+.

[0227] Chiral SFC method 2: r.t. benzyl (S)-4-(4-((R)- 1 -(tert-butoxy)- 1 -oxopropan-2-yl)phenyl)-2,2-dimethyloxazolidine -3-carboxylate = 3.52min r.t. benzyl (S)-4-(4-((S)- 1 -(tert-butoxy)- 1 -oxopropan-2-yl)phenyl)-2,2-dimethyloxazolidine -3-carboxylate = 4.41min

[0228] 1HNMR (400MHz, DMSO-d6) 5 ppm 1.28-1.44 (m, 12H), 1.54 (br s, 3H), 1.70 (br s, 3H), 3.65 (br d, J=6.80 Hz, 1H), 3.74-3.87 (m, 1H), 4.30 (br t, J=7.78 Hz, 1H), 4.84-5.21 (m, 2H), 6.90 (br s, 2H), 7.13-7.30 (m, 5H) 7.38 (br s, 2H).

[0229] Example 9: tert-butyl (A)-(l-(4-bromophenyl)-2-hydroxyethyl)carbamate

[0230] (Intermediate 8)

[0231] (S)-2-amino-2-(4-bromophenyl)ethan-l-ol (5 g, 23.1 mmol) was suspended in a mixture of dichloromethane (50 m ) and ethanol (2.5 mL). Triethylamine (2.58 g, 26 mmol) was added and the mixture was cooled at 5-10 °C. A solution of BOC anhydride (5.56 g, 26 mmol) in dichloromethane (10 mL) was dropped and then the mixture was stirred for 2 hrs at RT. The mixture was heated and dichloromethane was distilled while slowly dropping n-heptane (50 mL). The suspension was cooled to 5-10 °C for 2 h and filtered, the solid was dried under vacuum at 35 °C. Title compound (6.81 g, 21.5 mmol, 93% yield) was obtained as a white solid. LC-MS Method 4: r.t. 0.99 min (X 225 nm), MS ESI(+) m / z = 262.1 [M+H-56]+.

[0232] 1HNMR (400 MHz, CDCh) 5 ppm 1.40 (br s, 9H) 2.06 (br s, 1H) 3.67-3.88 (m, 2H), 4.69 ( br s, 1H) 5.28 (br s, 1H) 7.16 (d, J=7.58, 2H) 7.46 (d, J=7.58, 2H).

[0233] Example 10 : tert-butyl (5)-4-(4-bromophenyl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 9)

[0234] Intermediate 8 (6.81 g, 21.5 mmol) was dissolved in acetone (70 mL), / ?-toluenesulfonic acid monohydrate (0.44 g, 2.3 mmol) and 2,2-dimethoxypropane (24.1 g, 230 mmol) were added and the mixture was stirred at RT overnight. The mixture was concentrated under vacuum and the residue was suspended in heptane (25 m ) at 50 °C. The suspension was cooled to 5-10 °C and filtered, the solid was dried under vacuum at 35 °C. Title compound (6.82 g, 19.1 mmol, 89% yield) was obtained as a white solid.

[0235] LC-MS Method 4: r.t. 1.38 min (X 225 nm), MS ESI(+) m / z = 302.1 [M+H-56]+.

[0236] 1HNMR (400 MHz, CDCh) 5 ppm 1.20-1.44 (br, 9H), 1.57-1.74 (br, 6H), 3.81 (br s, 1H), 4.62 (dd, J=8.88, 6.69 Hz, 1H), 4.72 (br s, 1H), 7.09-7.26 (m, 2H), 7.43 (d, J=8.33, 2H).

[0237] Example 11: tert-butyl ( S)-4-(4-(2-ethoxy-2-oxoethyl)phenyl)-2.2- dimethyloxazolidine-3-carboxylate (Intermediate 10)

[0238] Zinc granular (16.55 g, 253 mmol) was suspended in dry THF (75 mL) under nitrogen atmosphere, the mixture was stirred at 45°C. Ethyl 2-bromoacetate (21.1 g, 126 mmol) was dissolved in dry THF (25 mL); about 5% of the solution was added to the mixture. Diisobutyl aluminium hydride 1 M in THF (2.53 mL, 2.53 mmol) was added: reaction temperature rapidly rose to 55 °C and the mixture turned yellow. Ethyl 2-bromoacetate solution was dropped in 30 min while keeping reaction temperature at 50-55 °C, then the mixture was stirred at 50 °C for 30 min and cooled. Stirring was stopped and zinc residue was allowed to settle. The surnatant solution of (2-ethoxy-2-oxoethyl)zinc(II) bromide was transferred in a flask and filtered under nitrogen atmosphere. Intermediate 9 (15 g, 42.1 mmol), Palladium allyl chloride dimeric (0.308 g, 0.84 mmol) and dicyclohexyl[2',4',6'-tris(propan-2-yl)[l,l'-biphenyl]-2-yl]phosphane (0.803 g, 1.68 mmol) were dissolved in dry THF (50 mL) and the mixture was heated at 60-65 °C under nitrogen atmosphere. The solution of (2-ethoxy-2-oxoethyl)zinc(II) bromide in THF (75 mL, 1.8 eq.) was dropped in 60 min, then the mixture was stirred and heated at 60 °C for additional 30 min, then it was cooled. Ammonium chloride 15% aqueous (150 mL) was dropped while cooling and the mixture was stirred vigorously, the aqueous phase was separated and extracted with MeTHF (150 mL); combined organic layers were washed with sodium chloride 10% aqueous (100 mL). The solution was concentrated under vacuum and the residue was purified by column chromatography (silica gel, heptane-ethyl acetate, 0-15%). Title compound (12.7 g, 35 mmol, 83% yield) was obtained as a pale yellow oil.

[0239] LC-MS Method 1 : r.t. 2.34 min (X 225 nm), MS ESI(+) m / z = 308.1 [M+H-56]+.

[0240] 1HNMR (400 MHz, DMSO-d6) 5 ppm 1.06-1.09 (m, 9H), 1.41 (br s, 3H), 1.51 (br s, 3H), 1.65 (br s, 3H), 3.63 (s, 2H), 3.69-3.79 (m, 1H), 4.02-4.12 ( m, 2H), 4.26 (dd, J=8.99, 6.80 Hz, 1H), 4.74-4.95 (m, 1H), 7.22 (s, 4H).

[0241] Example 12: tert-butyl (45)-4-(4-(l-ethoxy-l-oxopropan-2-yl)phenyl)-2,2- dimethyloxazolidine-3-carboxylate (Intermediate 11)

[0242] Intermediate 10 (2.0 g, 5.5 mmol) was dissolved in dry THF (20 mL) under nitrogen atmosphere and the solution was cooled at -50 °C. Lithium bis(trimethylsilyl)amide 1 M in THF (6.05 mL, 6.05 mmol) was dropped in 10 min at -50 °C: the solution was stirred for 30 min. lodomethane (0.78 g, 5.5 mmol) was dissolved in dry THF (8 mL) and dropped in 10 min, then the reaction mixture was stirred at -50 °C for 30 min. The mixture was poured in aqueous 15% ammonium chloride (100 mL) and extracted twice with ethyl acetate (100+50 mL). The organic solutionwas washed with aqueous 10% sodium chloride (50 mL), then concentrated under vacuum and the residue was purified by column chromatography (silica gel, heptane-ethyl acetate, 0-15%). Pure fractions were pooled and concentrated under vacuum, title compound (1.03 g, 2.7 mmol, 50% yield) was recovered as an orange oil.

[0243] LC-MS Method 1: r.t. 2.52 min ( 225 nm), MS ESI(+) m / z = 278.3 [M+H-100]+.

[0244] 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.00-1.21 (m, 9H), 1.34-1.44 (m, 6H), 1.50 (br s, 3H), 1.65 (br s, 3H), 3.69-3.81 (m, 2H), 3.95-4.13 (m, 2H), 4.25 (dd, J=8.99, 6.58 Hz, 1H) 4.72- 4.94 (m, 1H), 7.16-7.30 (m, 4H). Example 13: ethyl 2-(4-((5)-l-amino-2-hydroxyethyl)phenyl)propanoate (Intermediate 12)

[0245] Intermediate 11 (1.9 , 5.4 mmol) was dissolved in ethanol (10 mL) and 3.5 MHC1 in ethanol (9.3 mL, 32.6 mmol) was added. The solution was stirred at RT overnight, then solvent was evaporated under vacuum and the residue was dissolved in a mixture of ethyl acetate (25 mL) and saturated aqueous solution of sodium hydrogencarbonate (25 mL). The aqueous phase was separated and further extracted with ethyl acetate (25+25 mL), combined organic layers were washed with 10% aqueous sodium chloride (20 mL). Solvent was evaporated under vacuum, leaving a pale yellow oil that turned solid upon standing. Title compound (1.2 g, 93% yield) was recovered as a waxy solid.

[0246] LC-MS Method 1: r.t. 0.45 min (X 225 nm), MS ESI(+) m / z = 238.2 [M+H]+.

[0247] 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.10-1.17 (m, 3H) 1.35 (d, 1=7.02 Hz, 3H) 3.22- 3.31 (m, 1H) 3.39-3.47 ( m, 1H) 3.72 (q, J=7.16 Hz, 1H) 3.83 (dd, J=7.89, 4.82 Hz, 1H) 3.96- 4.14 (m, 2H) 7.19 (d, J=8.11 Hz, 2H) 7.30 (d, J=8.11Hz, 2H).

[0248] Example 14 : ethyl 2-(4-((5)-l-(4-chloro-l,6-dimethyl-17T-indole-2-carboxamido)-2- hydroxyethyl) phenyl)propanoate (Intermediate 13)

[0249] Intermediate 12 (0.949 g, 3.80 mmol) and 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acid (0.85 g, 3.80 mmol) were dissolved in A, di methyl form ami de (10 mL), the solution was cooled at 5-10 °C and triethylamine (0.96 g, 9.50 mmol) was dropped in. Then HATU (hexafluorophosphate azabenzotriazole-tetramethyl uronium, 1.52 g, 3.99 mmol) was added portionwise in 30 min. The mixture was stirred at 5-10 °C for 1 h, then ethyl acetate (100 mL) and aqueous 10% sodium hydrogencarbonate (100 mL) were added and stirred. The organic phase was separated and the aqueous phase extracted twice with ethyl acetate (50 mL). The combined organic layers were washed with aqueous 15% citric acid (50 mL) and brine (50 mL). Solvent was evaporated under vacuum and the residue was purified by column chromatography (silica gel, dichloromethane-ethyl acetate, 0-20%). Pure fractions were pooled and concentrated under vacuum. Title compound (1.46 g, 3.30 mmol, 87% yield) was obtained as a waxy solid.

[0250] LC-MS Method 1: r.t. 2.33 min (X 225 nm), MS ESI(+) m / z = 443.2 [M+H]+.

[0251] 1HNMR (400 MHz, DMSO-d6) 5 ppm 1.06-1.15 (m, 3H) 1.36 (d, J=7.02 Hz, 3H) 2.43 (s, 3H) 3.58-3.81 ( m, 3H) 3.93 ( s, 3H) 3.96-4.07 (m, 2H) 4.89-5.11 (m, 2H) 7.04 (s, 1H) 7.24 (d, J=8.33 Hz, 2H) 7.32 (s, 1H) 7.33 (s, 1H) 7.37 (d, J=8.33 Hz, 2H) 8.85 (d, J=8.11 Hz, 1H).

[0252] Example 15 : 2-(4-((5)- l-(4-chloro- 1 ,6-dimethyl-17f-indole-2-carboxamido)-2- hydroxyethyl)phenyl) propanoic acid (Intermediate 14)

[0253] Intermediate 13 (1.46 g, 3.30 mmol) was dissolved in ethanol (10 mL) at 40 °C. 2 M sodium hydroxide in water (6.6 mL, 13.2 mmol) was added and the solution was heated at 40 °C for 1 h. Ethanol was evaporated under vacuum and 2 M HC1 in water (8.24 mL, 16.48 mmol) was dropped in: the so obtained suspension was cooled to RT and stirred for 1 h, then it was filtered and washed with water until neutrality. The solid was dried at 45 °C under vacuum for 48 h: title compound (1.20 g, 2.77 mmol, 84% yield; mixture of diastereoisomers) was obtained as a white solid.

[0254] LC-MS Method 1: RT 1.92 min (X 225 nm), MS ESI(+) m / z = 415.2 [M+H]+.

[0255] 1HNMR (400 MHz, DMSO-d6) 5 ppm 1.34 (d, J=7.23 Hz, 3H) 2.43 (s, 3H) 3.59-3.75 ( m, 3H) 3.93 ( s, 3H) 4.90-5.09 (m, 2H) 7.05 (s, 1H) 7.24 (d, J=8.11 Hz, 2H) 7.31 (s, 1H) 7.33 (s, 1H) 7.36 (d, J=8.11 Hz, 2H) 8.85 (d, J=8 11 Hz, 1H) 12 29 (br s, 1 H).

[0256] Example 16: ( / ?)-2-(4-((.S')-l-(4-chloro-1.6-diinethyl-l / / -indole-2-c;irboxamido)-2- hydroxyethyl)phenyl) propanoic acid (Compound la)

[0257] Intermediate 14 (1.0 g, 2.41 mmol, mixture of diastereoisomers) was dissolved in methanol (166 mL, added with 0.2% ammonia, concentration 6 mg / mL) and the mixture was separated through chiral supercritical fluid chromatography according to the following conditions:

[0258] Column: Chiralcel OJ-H (21 mm*250 mm, 5 pm) Column temperature: 40 °C

[0259] Flow rate: 50 mL / min

[0260] Eluent: CO2 / methanol (+0.2% v / v ammonia) 75:25

[0261] Backpressure: lOO BarG

[0262] Detector wavelength: 224 nm

[0263] Injection volume: 1.2 mL (corresponding to 7 mg mixture)

[0264] Retention time: 5.82 min (first eluting peak)

[0265] 6.85 min (second eluting peak)

[0266] Collected fractions containing the first eluting peak were pooled and solvent was evaporated under vacuum, the residue was dissolved in methanol and evaporated again, finally freeze dried giving a white solid.

[0267] The same procedure was applied to collected fractions containing the second eluting peak.

[0268] Product obtained from the first eluting peak corresponded to the desired compound la: (R)- 2 -(4-(GS’)-l -(4-chl oro-1, 6-di methyl - l / / -indole-2-carboxamido)-2-hydroxyethyl)phenyl) propanoic acid (403 mg, 0.97 mmol, 40 % yield, 98.8% diastereoisomeric excess) was obtained as a white solid.

[0269] Undesired diastereoisomer (5)-2-(4-((S)-l-(4-chl oro-1, 6-dimethyl-l / / -indole-2- carboxamido)-2-hydroxyethyl)phenyl) propanoic acid was recovered as a white solid from the second eluting peak (371.3 mg, 0.89 mmol, 37% yield, 99.6% diastereoisomeric excess).

[0270] The total yield for obtaining (R)-2-(4-((S)-l-(4-chl oro-1, 6-dimethyl-lH-indole-2- carboxamido)-2-hydroxyethyl) phenyl)propanoic acid (compound la) from tert-butyl (S)-(l-(4- bromophenyl)-2-hydroxyethyl)carbamate (Intermediate 8) (Examples 10-16) was 10%.

[0271] The yield for obtaining (R)-2-(4-((S)-l-(4-chloro-l,6-dimethyl-lH-indole-2-carboxamido)- 2 -hydroxy ethyl) phenyl )propanoic acid (compound la) from 4-chl oro-1, 6-dimethyl-lH-indole-2- carboxylic acid (Examples 14-16) was 30%.

[0272] LC-MS Method 1: r.t. 1.92 min (X 225 nm), MS ESI(+) m / z = 415.2 [M+H]+

[0273] Chiral SFC Method 3: r.t. (7?)-2-(4-((5)-l -(4-chl oro-1, 6-dimethyl-lH-indole-2-carboxamido)-2- hydroxyethyl)phenyl) propanoic acid 12.05 min r.t. (5)-2-(4-((5)-l -(4-chl oro-1, 6-dimethyl-lH-indole-2-carboxamido)-2- hydroxyethyl)phenyl) propanoic acid 13.79 min

[0274] Example 17: Ethyl (R)-2-(4-((5)-l-(4-chloro-l,6-dimethyl-l / / -indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoate (Intermediate 15)

[0275] (7?)-2-(4-((5)- 1 -(4-chl oro-1, 6-dimethyl- l / 7-indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoic acid (207 mg, 0.5 mmol, diastereoisomeric purity 99.5%) was dissolved in a mixture of DCM (3 mL) and THF (3 mL). A,A-carbonyldiimidazole (122 mg, 0.75 mmol) was added and the mixture was stirred at room temperature for 15 min, then ethanol (5 mL) was added and the mixture was heated at 70 °C for 3 hours. The mixture was concentrated under vacuum and the residue was purified by column chromatography (silica gel, gradient elution of 0 to 25% ethyl acetate in dichloromethane). Pure fractions were pooled and concentrated under vacuum. Ethyl ( ?)-2-(4-((S)-l-(4-chloro-l, 6-dimethyl- IT / -indole-2-carboxami do)-2- hydroxyethyl)phenyl)propanoate (20 mg, 0.05 mmol, 10% yield) was obtained as a waxy solid.

[0276] LC-MS Method 1 min: r.t. 2.35 min (A 225 nm), MS ESI(+) m / z = 443.1 [M+H]+.

[0277] 1HNMR (400 MHz, CDC13) 5 1.23 (t, J=7.13 Hz, 3H) 1.49 (d, .7=7.13 Hz, 3H) 2.47 (s, 3H) 3.71 (q, .7=7.13 Hz, 1H) 3.96 (s, 3H) 4.05-4.19 (m, 2H) 5.22 (dt, .7=7.15, 4.81 Hz, 1H) 6.96-7.01 (m, 2H) 7.01-7.06 (m, 2H) 7.30-7.37 (m, 4H).

[0278] Diasteromeric purity (Chiral SFC Method 5): 98.7% r.t. ethyl (7?)-2-(4-((5)-l-(4-chloro-l,6-dimethyl-l / / -indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoate: 5.86 min r.t. ethyl (5)-2-(4-((5)-l-(4-chloro-l,6-dimethyl-17 / -indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoate: 6.92 min

[0279] Example 18: (7?)-2-(4-((5)-l -(4-chl oro-1, 6-dimethyl- 17 / -indole-2-carboxamido)-2- hydroxyethyl)phenyl) propanoic acid (Compound la)

[0280] Ethyl (7?)-2-(4-((S)-l -(4-chl oro-1, 6-dimethyl- IT / -indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoate (20 mg, 0.05 mmol) was dissolved in ethanol (4 mL) and aqueous sodium hydroxide 0.1 M (1 mL, 0.1 mmol) was added. The solution was heated at 40 °C for 2 hours until complete hydrolysis of ethyl ester. Aqueous hydrogen chloride 1 M (0.12 mL, 0.12 mmol) was added and the solution was concentrated under vacuum. (7?)-2-(4-((5)-l-(4- chloro-l,6-dimethyl-lH-indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoate (15 mg, 0.04 mmol, 80% yield, 63.8% diastereomeric purity) was obtained as a white solid.

[0281] LC-MS Method 1 min: RT 1.93 min (X 225 nm), MS ESI(+) m / z = 415.1 [M+H]+.

[0282] Diasteroisomeric purity (Chiral SFC Method 6): 63.8% r.t. (7?)-2-(4-((5)-l-(4-chl oro-1, 6-dimethyl-l / / -indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoate: 12.8 min r.t. (5)-2-(4-((5)-l-(4-chl oro-1, 6-dimethyl- l / / -indole-2-carboxamido)-2- hydroxyethyl)phenyl)propanoate: 14.6 min

[0283] SUMMARY OF RESULTS The yields of all the Examples and diastereoisomeric excess of product, where available, are reported in Table 1 below.

[0284] Table 1

[0285] The process of the present invention leads to obtain Intermediate compound of formula (IV) from Intermediate compound of formula (III) in a very selective way, with higher yield in the alkylation step, in comparison with the method reported in Scheme 2, and specifically in Example 12 .

[0286] As reported in Table 1, the yield for the alkylation step (Example 3) was 88%, while the yield for the alkylation step with the method reported in Example 12 was 50% .

[0287] The total yield for obtaining (7?)-2-(4-((5)-l -(4-chl oro-1, 6-dimethyl- l / / -indole-2- carboxamido)-2-hydroxy ethyl) phenyl)propanoic acid (compound la) from benzyl (S)-4-(4- bromophenyl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 2a) (Examples 1-7) was 30%, while the total yield for obtaining compound la from tert-butyl (5)-(l-(4-bromophenyl)-2- hydroxyethyl)carbamate (Intermediate 8) was 10% (Examples 10-16).

[0288] The yield for obtaining (7?)-2-(4-((5)-l-(4-chloro-l,6-dimethyl-l / / -indole-2-carboxamido)- 2 -hydroxy ethyl) phenyl )propanoic acid (compound la) from 4-chl oro-1, 6-dimethyl- lH-indole-2- carboxylic acid (Examples 6, 7) was 90%, while the yield for obtaining (7?)-2-(4-((S)-l -(4-chl oro-

[0289] 1.6-dimethyl-127-indole-2-carboxamido)-2-hydroxyethyl) phenyl)propanoic acid (compound la) from 4-chloro-l,6-dimethyl-l / 7-indole-2-carboxylic acid (Examples 14-16) was 30%.

[0290] In Example 7 compound la was obtained with a diastereoisomeric excess of 99.6 %, while in Example 16 compound la was obtained with a diastereoisomeric excess of 98.8%.

[0291] Diasteromerically pure ethyl (7?)-2-(4-((S)-l-(4-chloro-l,6-dimethyl-l / / -indole-2- carboxamido)-2-hydroxyethyl)phenyl)propanoate reported in Example 17 (Intermediate 15, d e. 97.3%) undergoes unacceptable epimerization at a-ester chiral center under the basic hydrolysis conditions. In fact, in Example 18 compound la was obtained with a diastereomeric excess of 68.3%, while in Example 16 compound la was obtained with a diastereoisomeric excess of 98.8%

[0292] All the above results demonstrate that in the present invention a straightforward and efficient synthesis of 2-(4-(l -(4-chl oro-1, 6-dimethyl- l / / -indole-2-carboxamido)-2-hydroxy ethyl) phenyl)propanoic acid (compound 1) has been carried out, wherein methylation of Intermediate (III) to obtain Intermediate (IV) and amidic coupling of Intermediate compound 6 with 4-chloro-

[0293] 1.6-di methyl -17 / -indole-2-carboxylic acid were achieved to obtain Intermediate compound 7, thus obtaining compound 1 after ester hydrolysis.

[0294] An improved process for the syntheses of compound 1 has been obtained, which allows to achieve an increase in the overall yield, good optical purity, reduced consumption of starting materials and solvents and which is suitable for scale-up.

Claims

CLAIMS1. A process for the preparation of compound 1, or a pharmaceutically acceptable salt thereofcompound 1 comprising the steps of: a) reacting Intermediate compound of formula (III) with CH3R2 in the presence of an inorganic baseto obtain Intermediate compound of formula (IV)whereinRi is selected from the group consisting of H and -(Ci-C3)alkyl, or the two Ri are fused together in a -(C5-Cs)cycloalkyl;R2 is selected from the group consisting of halogen and sulfonate; b) amidic coupling of Intermediate compound 6, which is tert-butyl 2-(4-(l-amino-2- hydroxyethyl)phenyl)propanoatewith 4-chloro-l,6-dimethyl-lH-indole-2-carboxylic acidto obtain Intermediate compound 7, which is tert-butyl 2-(4-(l-(4-chloro-l,6- dimethyl-lH-indole-2-carboxamido)-2-hydroxyethyl)phenyl)propanoateIntermediate 7 thus after ester hydrolysis obtaining compound 1.

2. The process according to claim 1 for the preparation of compound 1, or a pharmaceutically acceptable salt thereof, comprising the step of: a) reacting benzyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate, which is Intermediate 3, with CH3R2 in the presence of an inorganic baseto obtain benzyl 4-(4-(l-(tert-butoxy)-l-oxopropan-2-yl)phenyl)-2,2- dimethyloxazolidine-3 -carboxylate, which is Intermediate 4wherein R2 is as defined in claim 1.

3. The process according to claim 1 or 2 for the preparation of compound (la)or a pharmaceutically acceptable salt thereof.

4. The process according to claim 1-3, wherein in step a) CH3R2 is iodomethane.

5. The process according to claim 1-4, wherein in step a) the solvent is THF and the base is Lithium bis(trimethylsilyl)amide.

6. An Intermediate compound of formula (III)Intermediate III wherein Ri is as defined in claim 1; as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof.

7. The Intermediate compound 3 according to claim 6Intermediate 3 as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof.

8. The Intermediate compound 3 a, which is benzyl (S)-4-(4-(2-(tert-butoxy)-2- oxoethyl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate, according to claim 6 or 7Intermediate 3 aand pharmaceutically acceptable salt thereof.

9. An Intermediate compound of formula (IV)Intermediate IV wherein Ri is as defined in claim 1; as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof.

10. The Intermediate compound 4 according to claim 9Intermediate 4 as single deuterate, enantiomer, diastereoisomer or mixtures thereof, in any proportion, or pharmaceutically acceptable salts, hydrates and solvates thereof.

11. The Intermediate compound 4a, which is benzyl (4S)-4-(4-(l-(tert-butoxy)-l-oxopropan-2- yl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate, according to claim 9 or 10and pharmaceutically acceptable salt thereof.

12. Use of Intermediate compound 3 according to claim 7 for the preparation of compound 1 or a pharmaceutically acceptable salt thereof.

13. Use of Intermediate compound 4 according to claim 10 for the preparation of compound 1 or a pharmaceutically acceptable salt thereof.

14. Use of Intermediate compound 3a for the preparation according to claim 12 of (R)-2-(4-((S)- l-(4-chloro-l,6-dimethyl-lH-indole-2-carboxamido)-2 -hydroxy ethyl) phenyl)propanoic acid (compound la) or a pharmaceutically acceptable salt thereof.

15. Use of Intermediate compound 4a for the preparation according to claim 13 of compound la or a pharmaceutically acceptable salt thereof.

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