Method of preparation of zavegepant, synthesis intermediates of zavegepant and methods of preparation thereof

Abstract

The present invention relates to a method of preparation of zavegepant and to reaction intermediates useful in the preparation of zavegepant, to a method of preparation of said intermediates, and to the use of said intermediates in the preparation of zavegepant.

Description

[0001] DESCRIPTION

[0002] METHOD OF PREPARATION OF ZAVEGEPANT, SYNTHESIS INTERMEDIATES OF ZAVEGEPANT AND METHODS OF PREPARATION THEREOF

[0003] FIELD OF THE INVENTION

[0004]

[0001] The present invention relates to a method of preparation of zavegepant and to reaction intermediates useful in the preparation of zavegepant, to a method of preparation of said intermediates, and to the use of said intermediates in the preparation of zavegepant.

[0005] BACKGROUND OF THE INVENTION

[0006]

[0002] Zavegepant is an active pharmaceutical ingredient used in the treatment of migraine with and without aura in adults, which is authorized for commercialization as a medicinal product in the United States by the Food & Drug Administration (FDA) in its hydrochloride salt form. Zavegepant belongs to a class of medicinal products called calcitonin gene-related peptide (CGRP) receptor antagonists. CGRP is released by sensory nerves and acts as a potent vasodilator and, because of these properties, is involved in pain pathways. The molecular formula (XII) of zavegepant is as follows

[0007]

[0003] Zavegepant is known in the prior art and has been described, for example, in international patent application WO 2011 / 123232 A1.

[0008]

[0004] International patent application WO 2011 / 123232 A1 also describes a synthesis pathway for the preparation of zavegepant as shown in scheme 1 Scheme 1

[0009]

[0005] This document also describes a method of synthesis which allows obtaining the compound of formula (VII) as shown in scheme 2.

[0010] Scheme 2

[0006] Variations of this same synthetic pathway have been described in Cann, R. O., et al. Organic Process Research and Development 2012, Vol. 16, pages 1953-1966 or in Chaturvedula, P. V. etal. Bioorganic & Medicinal Chemistry Letters 2013, Vol. 23, pages 3157- 3161.

[0011]

[0007] The method of scheme 2 for the preparation of the intermediate of formula (VII) has drawbacks. Firstly, the use of chlorine iodide in step a) of forming compound 2) produces a reddish product. Secondly, the formation of mixtures of E and Z stereoisomers of product (5) by reaction of compound (2) with compound (4) requires purification of the Z stereoisomer by precipitation of the salt formed with methanesulfonic acid and subsequent formation of the free base or by hot filtration. Thirdly, the use of the chiral reagent of formula (3) represents another drawback of this method. In reaction step (b), this high-priced reagent is transformed into product (4), which has lost chirality, and said chirality is not recovered until step (d) by means of the use of a specific rhodium catalyst which, besides its high price, requires subsequent purification of the reaction mixture to remove the rhodium. For that reason, there is a need in the prior art for improved methods for obtaining zavegepant, and particularly the intermediate of formula (VII) used in its preparation.

[0012] SUMMARY OF THE INVENTION

[0013]

[0008] The inventors have discovered a new method of synthesis of zavegepant using the synthetic pathway of scheme 1 in which the intermediate of formula (VII) has been obtained by a new method. The method developed is shown schematically in scheme 3

[0014] Scheme 3

[0015] wherein R1is selected from the group consisting of tert-butyl group and benzyl group, and X represents a bromine or iodine atom.

[0009] In particular, this synthesis pathway allows obtaining the intermediate of formula (VII), preventing the drawbacks described above with good yields and using simple reaction steps.

[0016]

[0010] To that end, a first aspect of the invention relates to the intermediate of formula (I) useful for the preparation of zavegepant (XII) wherein R1is selected from the group consisting of tert-butyl group and benzyl group, X is selected from the group consisting of bromine and iodine, or a salt or solvate thereof.

[0011] A second aspect of the invention relates to a method of obtaining the compound of formula (I) as defined in the first aspect of the invention or a salt or solvate thereof, comprising the step of reacting a compound of formula (II), wherein X is selected from the group consisting of bromine and iodine or a salt thereof with an acylating agent of formula G-CO-OR1, wherein R1is selected from the group consisting of tert-butyl group and benzyl group, and G is selected from an OR1group and a halogen atom, in the presence of a base. The compound of formula (II) is designated as (Ila) when X is a bromine and as (lib) when it is an iodine.

[0017]

[0012] Likewise, a third aspect of the invention relates to a method of obtaining an intermediate of formula (V) which comprises reacting the compound of formula (I) or a salt thereof with methylboronic acid or an anhydride of methylboronic acid in the presence of a catalyst, which is a palladium complex, and of a base to obtain a compound of formula (V).

[0013] Likewise, a fourth aspect of the invention relates to a method of obtaining an intermediate of formula (VII) or a salt or solvate thereof, comprising the steps of a) reacting the compound of formula (I) or a salt thereof with methylboronic acid or an anhydride of methylboronic acid in the presence of a catalyst, which is a palladium complex, and in the presence of a base to obtain a compound of formula (V) b) reacting the compound of formula (V) with isopentyl nitrite at a pH comprised between 3 and 6 to obtain a compound of formula (VI) c) reacting the compound of formula (VI) with hydrogen (H2) in the presence of a palladium catalyst, with HBr in the presence of glacial acetic acid, or with HCI to obtain methyl (R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate of formula (VII)

[0018]

[0014] Likewise, a fifth aspect of the invention relates to a compound of formula (Va) or a solvate or salt thereof.

[0019]

[0015] In a preferred embodiment of the fifth aspect of the invention, the compound of formula (Va) is in crystalline solid form.

[0020]

[0016] In a preferred embodiment of the fifth aspect of the invention, the compound of formula (Va) is characterized in that its X-ray powder diffraction spectrum measured with CuKa radiation has diffraction peaks at the 20 values of 10.5 ± 0.2° 20; 16.7± 0.2° 20; 1 .7± 0.2° 20; 21.3 ± 0.2° 20; 22.1 ± 0.2° 20; and 22.8 ± 0.2° 20.

[0021]

[0017] In a preferred embodiment of the fifth aspect of the invention, the compound of formula (Va) is characterized in that its X-ray powder diffraction spectrum measured with CuKa radiation has diffraction peaks at the 20 values of 7.2 ± 0.2° 20; 9.6 ± 0.2° 20; 10.5 ± 0.2° 20;

[0022] 16.7 ± 0.2° 20; 17.7 ± 0.2° 20; 18.3 ± 0.2° 20; 19.3 ± 0.2° 20; 21.3 ± 0.2° 20; 22.1 ± 0.2° 20;

[0023] 22.8 ± 0.2° 20; 23.8 ± 0.2° 20; 24.3 ± 0.2° 20; and 29.2 ± 0.2° 20.

[0024]

[0018] In a preferred embodiment of the fifth aspect of the invention, the compound of formula (Va) is characterized in that its X-ray powder diffraction spectrum measured with CuKa radiation is essentially as depicted in Figure 8.

[0019] Likewise, a sixth aspect of the invention relates to a method of obtaining zavegepant (XII) or a pharmaceutically acceptable solvate or salt thereof comprising the steps of: a) reacting the compound of formula (I) as defined in the first aspect of the invention with methylboronic acid or an anhydride of methylboronic acid in the presence of a catalyst, which is a palladium complex, and in the presence of a base to obtain a compound of formula (V) b) reacting the compound of formula (V) with isopentyl nitrite at a pH comprised between 3 and 6 to obtain a compound of formula (VI) c) reacting the compound of formula (VI) with hydrogen (H2) in the presence of a palladium catalyst or with HBr in the presence of glacial acetic acid or with HCI to obtain methyl (R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate of formula (VII) or a salt or solvate thereof d) reacting the compound of formula (VII) with 3-(piperidin-4-yl)quinolin-2(1 H)-one of formula (VIII) in the presence of a coupling agent and an organic base to obtain the compound of formula (IX) e) reacting the compound of formula (IX) with a base to obtain the compound of formula

[0025] (X) f) reacting the compound of formula (X) with 1-(1-methylpiperidin-4-yl)piperazine of formula (XI) in the presence of a coupling agent.

[0020] A seventh aspect of the invention relates to the use of the compound of formula (I) according to the first aspect of the invention or a salt or solvate thereof in the preparation of a compound of formula (VII) or a salt or solvate thereof.

[0026]

[0021] An eighth aspect of the invention relates to the use of the compound of formula (I) according to the first aspect of the invention or a salt or solvate thereof in the preparation of zavegepant (XII) or a salt or solvate thereof.

[0027]

[0022] A ninth aspect of the invention relates to the use of the compound of formula (Va) according to the fifth aspect of the invention or a salt or solvate thereof in the preparation of a compound of formula (VII) or a salt or solvate thereof.

[0028]

[0023] A tenth aspect of the invention relates to the use of the compound of formula (Va) according to the fourth aspect of the invention or a salt or solvate thereof in the preparation of a compound of formula (XII) or a salt or solvate thereof.

[0029]

[0024] An eleventh aspect of the invention relates to the use of the compound of formula (VII) obtained by the method of the fourth aspect of the invention or a salt or solvate thereof in the preparation of zavegepant (XII) or a solvate or salt thereof.

[0030] DESCRIPTION OF THE FIGURES

[0031]

[0025] Figure 1 shows the X-ray powder diffraction spectrum measured with CuKa radiation of the compound of formula (lab).

[0032]

[0026] Figure 2 shows the X-ray powder diffraction spectrum measured with CuKa radiation of the compound of formula (Vb).

[0033]

[0027] Figure 3 shows the X-ray powder diffraction spectrum measured with CuKa radiation of the compound of formula (lib).

[0034]

[0028] Figure 4 shows the X-ray powder diffraction spectrum measured with CuKa radiation of the compound of formula (Ibb).

[0035]

[0029] Figure 5 shows the X-ray powder diffraction spectrum measured with CuKa radiation of the compound of formula (Via).

[0036]

[0030] Figure 6 shows the X-ray powder diffraction spectrum measured with CuKa radiation of the compound of formula (VII -2HCI).

[0037]

[0031] Figure 7 shows the X-ray powder diffraction spectrum measured with CuKa radiation of the compound of formula (XII HCI).

[0032] Figure 8 shows the X-ray powder diffraction spectrum measured with CuKa radiation of the compound of formula (Va).

[0038] DETAILED DESCRIPTION OF THE INVENTION

[0039]

[0033] In the context of the invention, the term “salt” should be understood to mean an ionic compound formed by a cation and an anion. In the case of acidic products, the product will form the anion together with a cationic counterion, and in the case of basic products the product will form the cation together with an anionic counterion. Examples of anionic counterions are acid anions, whether inorganic (such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, inter alia) or organic (such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate, inter alia). Examples of cationic counterions are cations of bases such as alkali metals, preferably sodium or potassium, alkali- earth metals, preferably calcium and magnesium and cations of organic nitrogenous bases such as primary, secondary, or tertiary amines.

[0040]

[0034] In the context of the present invention, the terms “approximate” and “about” in relation to a value refer to any value that is comprised in the interval defined by the value ±5% of said value including the value itself.

[0041]

[0035] In the context of the present invention, the term “acid” refers to a substance capable of donating a proton (to a base). Said substance can be inorganic, as in the case of hydrochloric, nitric, sulfuric, phosphoric, hydrobromic, and boric acids, or organic, as in the case of formic, acetic, trifluoroacetic, propionic, oxalic, malic, maleic, fumaric, succinic, citric, tartaric, mandelic, methanesulfonic, p-toluenesulfonic, and benzoic acids.

[0042]

[0036] In the context of the present invention, the term “base” refers to a substance capable of accepting a proton (from an acid). Said substance can be inorganic, as in the case of hydroxide salts of alkali metals and carbonate salts of alkali and alkali-earth metals, or organic, as in the case of pyridine, imidazole, and primary amines of formula NH2Ra, secondary amines of formula NHRaRb, or tertiary amines of formula NRaRbRc, wherein each of Ra, Rb, or Rcis a (Ci-Ce)alkyl group.

[0043]

[0037] In the context of the present invention, the term “solvate”, when used in the context of a solvate of a compound, refers to the presence of a stoichiometric or non-stoichiometric amount of one or more molecules of one or more solvents in the crystal structure of said compound. In particular, the “hydrate” form of a compound refers to the presence of a stoichiometric or non-stoichiometric amount of water in the crystal structure of the compound. A solvate of a compound in its free form or in a salt thereof can be formed.

[0044]

[0038] The inventors have discovered a new method in the preparation of zavegepant, and particularly of the compound of formula (VII), which compound is useful in the preparation of zavegepant. The compound of formula (VII) is obtained using a new intermediate in which the amino group of the amino-ester moiety of the molecule is functionalized by means of an amine protecting group. Amines can be protected by means of forming an amide group, such as acetamide, an arylamine group such as 3,4-dimethoxyphenylamine or para-methoxyphenylamine, an arylalkylamine group such as benzylamine or para-methoxybenzylamine, a sulfonamide group such as methylsulfonamide, para-toluenesulfonamide, p-nitrophenylsulfonamide, or a carbamate group such as benzyloxycarbonylamino, tert-butoxycarbonylamino, or fluorenylmethyloxycarbonylamino. Particularly preferred is the use of a carbamate group as an amine protecting group, and more particularly, a benzyloxycarbonylamino or tert-butoxycarbonylamino group.

[0045]

[0039] In this manner and as defined above, a first aspect of the invention relates to the intermediate of formula (I) which is useful for the preparation of zavegepant (XII). wherein R1is selected from the group consisting of tert-butyl group and benzyl group, and X is selected from the group consisting of iodine and bromine or a salt or solvate thereof. The compound of formula (II) is designated as (laa) when X is a bromine and R1is tert-butyl, it is designated as (lab) when X is a bromine and R1is benzyl, it is designated as (Iba) when X is an iodine and R1is tert-butyl, and it is designated as (Ibb) when X is an iodine and R1is benzyl.

[0040] In one embodiment of the first aspect of the invention, the compound is methyl (2R)-3-(4-amino-3,5-dibromophenyl)-2-(benzyloxycarbonylamino)propanoate or a salt or solvate thereof.

[0046]

[0041] In another embodiment of the first aspect of the invention, the compound is methyl (2R)-3-(4-amino-3,5-dibromophenyl)-2-(tert-butoxycarbonylamino)propanoate or a salt or solvate thereof.

[0047]

[0042] A second aspect of the invention relates to a method of obtaining the compound of formula (I) as defined in the first aspect of the invention or a salt or solvate thereof, comprising the step of reacting a compound of formula (II), wherein X is selected from the group consisting of iodine and bromine or a salt thereof with an acylating agent of formula G-CO-OR1, wherein R1is selected from the group consisting of tert-butyl group and benzyl group and G is selected from an OR1group and a halogen atom, preferably a chlorine atom, in the presence of a base.

[0048]

[0043] In one embodiment of the second aspect of the invention, the base is an amine base such as a primary amine of formula NH2Ra, a secondary amine of formula NHRaRb, or a tertiary amine of formula NRaRbRc, wherein each of Ra, Rb, and Rcis a (Ci-C6)alkyl group.

[0049]

[0044] In one embodiment of the second aspect of the invention, the reaction is carried out in a solvent, preferably methylene chloride or tetra hydrofuran.

[0050]

[0045] In another embodiment of the second aspect of the invention, the amine base is a tertiary amine, preferably N,N-diisopropylethylamine or triethylamine.

[0051]

[0046] In another embodiment of the second aspect of the invention, the compound of formula (II) has been previously obtained by reaction of a compound of formula (III), wherein X is selected from the group consisting of iodine and bromine or a salt or solvate thereof such as a hydrate thereof with an agent for the formation of esters from an acid. The compound of formula (III) is designated as (Illa) when X is a bromine and as (I lib) when it is an iodine.

[0052]

[0047] In one embodiment, the esterification agent is selected from the group consisting of an alcohol, a C1-3 dialkyl carbonate, and diazomethane, preferably an alcohol or C1-3 dialkyl carbonate, more preferably methanol or dimethyl carbonate, even more preferably, methanol.

[0053]

[0048] In another embodiment of the second aspect of the invention, the compound of formula (III) has been previously obtained by reaction of a compound of formula (IV) or a salt or hydrate thereof with a brominating agent or an iodinating agent.

[0054]

[0049] In one embodiment, the brominating agent is selected from the group consisting of bromine in an acetic acid and hydrobromic acid or N-bromosuccinimide (NBS) mixture, more preferably, bromine in an acetic acid and hydrobromic acid mixture.

[0055]

[0050] In one embodiment, the iodinating agent is selected from the group consisting of iodine monochloride (ICI) or N-iodosuccinimide (NIS), more preferably iodine monochloride (ICI).

[0056]

[0051] Likewise, a third aspect of the invention relates to a method of obtaining an intermediate of formula (V) which comprises reacting the compound of formula (I) or a salt thereof with methylboronic acid or an anhydride of methylboronic acid in the presence of a catalyst, which is a palladium complex, and of a base to obtain a compound of formula (V).

[0057]

[0052] Likewise, a fourth aspect of the invention relates to a method of obtaining an intermediate of formula (VII) or a salt or solvate thereof, comprising the steps of: a) reacting the compound of formula (I) with methylboronic acid or an anhydride of methylboronic acid in the presence of a catalyst, which is a palladium complex, and in the presence of a base to obtain a compound of formula (V) b) reacting the compound of formula (V) with isopentyl nitrite at a pH comprised between 3 and 6 to obtain a compound of formula (VI) c) reacting the compound of formula (VI) with hydrogen (H2) in the presence of a palladium catalyst, with HBr in the presence of glacial acetic acid or with HCI to obtain methyl (R)-2-amino-3-(7-methyl-1 H-indazol-5-yl)propanoate of formula (VII) or a salt or solvate thereof.

[0058]

[0053] In one embodiment of the fourth aspect of the invention, the base used in step a) is selected from tetraalkylammonium halides and inorganic bases exhibiting a pKb less than 4, preferably carbonates and hydrogen phosphates, more preferably alkaline carbonates and more preferably K2CO3.

[0059]

[0054] In one embodiment of the fourth aspect of the invention, steps (b) and (c) are carried out in the same reaction medium, such that step (c) is carried out without isolating the product of step (b). This embodiment has the advantage of saving a step of purification in the process.

[0055] Likewise, a fifth aspect of the invention relates to a compound of formula (Va) or a solvate or salt thereof.

[0060]

[0056] In a preferred embodiment of the fifth aspect of the invention, the compound of formula (Va) is in crystalline solid form.

[0061]

[0057] In a preferred embodiment of the fifth aspect of the invention, the compound of formula (Va) is characterized in that its X-ray powder diffraction spectrum measured with CuKa radiation has diffraction peaks at the 20 values of 10.5 ± 0.2° 20; 16.7± 0.2° 20; 1 .7± 0.2° 20; 21.3 ± 0.2° 20; 22.1 ± 0.2° 20; and 22.8 ± 0.2° 20.

[0062]

[0058] In a preferred embodiment of the fifth aspect of the invention, the compound of formula (Va) is characterized in that its X-ray powder diffraction spectrum measured with CuKa radiation has diffraction peaks at the 20 values of 7.2 ± 0.2° 20; 9.6 ± 0.2° 20; 10.5 ± 0.2° 20;

[0063] 16.7 ± 0.2° 20; 17.7 ± 0.2° 20; 18.3 ± 0.2° 20; 19.3 ± 0.2° 20; 21.3 ± 0.2° 20; 22.1 ± 0.2° 20;

[0064] 22.8 ± 0.2° 20; 23.8 ± 0.2° 20; 24.3 ± 0.2° 20; and 29.2 ± 0.2° 20.

[0065]

[0059] In a preferred embodiment of the fifth aspect of the invention, the compound of formula (Va) is characterized in that its X-ray powder diffraction spectrum measured with CuKa radiation is essentially as depicted in Figure 8.

[0066]

[0060] A sixth aspect of the invention relates to a method of obtaining zavegepant (XII) or a pharmaceutically acceptable solvate or salt thereof comprising the steps of: a) reacting the compound of formula (I) as defined in any one of claims 1 to 4 with methylboronic acid or an anhydride of methylboronic acid in the presence of a catalyst, which is a palladium complex, and in the presence of a base to obtain a compound of formula (V) b) reacting the compound of formula (V) with isopentyl nitrite at a pH comprised between 3 and 6 to obtain a compound of formula (VI) c) reacting the compound of formula (VI) with hydrogen (H2) in the presence of a palladium catalyst or with HBr in the presence of glacial acetic acid or with HCI to obtain methyl (R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate of formula (VII) or a salt or solvate thereof d) reacting the compound of formula (VII) with 3-(piperidin-4-yl)quinolin-2(1 H)-one of formula (VIII) in the presence of a coupling agent and an organic base to obtain the compound of formula (IX) e) reacting the compound of formula (IX) with a base to obtain the compound of formula (X) f) reacting the compound of formula (X) with 1-(1-methylpiperidin-4-yl)piperazine of formula (XI) in the presence of a coupling agent.

[0067]

[0061] The base used in step a) of the method of the sixth aspect of the invention is as defined in step a) of the method of the fourth aspect of the invention.

[0068]

[0062] In one embodiment of the sixth aspect of the invention, steps (b) and (c) are carried out in the same reaction medium, such that step (c) is carried out without isolating the product of step (b). This embodiment has the advantage of saving a step of purification in the process.

[0063] In one embodiment of the sixth aspect of the invention, the coupling agent used in step d) is preferably selected from the group of the urea-forming agents such as the N,N’- disuccinimidyl carbonate or 1 ,1’-carbonyldiimidazole.

[0069]

[0064] In one embodiment of the sixth aspect of the invention, the organic base used in step d) is preferably selected from primary amines of formula NH2Ra, secondary amines of formula NHRaRb, and tertiary amines of formula NRaRbRc, wherein each of Ra, Rbor Rcis a (Ci-Ce)alkyl group, preferably triethylamine or diisopropylethylamine.

[0070]

[0065] The base used in step e) is preferably selected from inorganic bases exhibiting a pKb less than 3, preferably alkaline hydroxides, more preferably LiOH.

[0071]

[0066] The coupling agent used in step f) is preferably selected from the group consisting of ethyl cyano(hydroxyimino)acetate, 1 -hydroxybenzotriazole, 7-aza-1 -hydroxybenzotriazole, N,N’-dicyclohexylcarbodiimide, 1-[3-(dimethylamine)-propyl]-3-ethylcarbodiimide or mixtures thereof, preferably a mixture of 1 -hydroxybenzotriazole and 1-[3-(dimethylamine)-propyl]-3- ethylcarbodiimide.

[0072]

[0067] The organic base used in step f) is preferably selected from primary amines of formula NH2Ra, secondary amines of formula NHRaRb, and tertiary amines of formula NRaRbRc, wherein each of Ra, Rb, or Rcis a (Ci-Ce)alkyl group, preferably diisopropylethylamine.

[0073] EXAMPLES

[0074] Ultra-high performance liquid chromatography

[0075]

[0068] The purity of the obtained products was analyzed by means of the ultra-high performance liquid chromatography technique in a Waters Acquity model apparatus provided with a photodiode detector, a mass detector, and a thermostatted oven for the column. A BEH C18 column (100 x 2.1 mm; 1.8 pm) and mobile phases A (50 mM ammonium formate, pH 4.8), B (acetonitrile), and C (water) were used with the following analysis conditions:

[0076] Flow rate: 0.5 mL / min

[0077] Column temperature: 40°C

[0078] Wavelength: 225 nm

[0079] Injection volume: 1 pL Diluent: Acetonitrile / Water (1 :1)

[0080] Gradient:

[0081] Differential scanning calorimetry (DSC)

[0082]

[0069] DSC analysis was performed in a Mettler Toledo 822e apparatus with STARe SW15 software using the following parameters: heating interval of 30 to 300°C with a ramp of 10°C / min and N2 flow of 50 ml / min. Measurement is taken with a closed perforated capsule.

[0083] Nuclear magnetic resonance

[0084]

[0070] Proton nuclear magnetic resonance (1H-NMR) and13C-NMR analyses were performed in a 400 MHz Brucker Avance III spectrometer. Chemical shifts were in reference to the CDCI3 signal (7.25 ppm for proton and 77 ppm for carbon) or DMSO-de signal (2.49 ppm for proton and 39.5 ppm for carbon) as indicated in the analysis of the corresponding product.

[0085] X-ray crystallography (XRPD)

[0086]

[0071] XRPD analysis was performed using a BRLIKER D2 PHASER X-ray powder diffractometer equipped with a copper anode. The radiation used is CuKa with a wavelength of 1.54 A. The following scan parameters were used: 3-50 degrees 20, continuous scan, ratio: 5.6 degrees / minute.

[0072] Example 1. Synthesis of 4-nitro-L-phenylalanine monohydrate

[0087]

[0073] 100 g (0.546 mol) of L-phenylalanine monohydrate were dissolved in 275 ml of 90% v / v H2SO4, maintaining the temperature between 5 and 10°C. The resulting solution was slowly added to a previously prepared mixture containing 68 ml of concentrated HNO3 (about 70% v / v) and 60 ml of concentrated H2SO4 (about 98% v / v), maintaining the temperature of the reaction mixture between 5 and 10°C. The resulting solution was kept under stirring and at the temperature of about 20°C for 3 hours.

[0088]

[0074] Thereafter, the pH of the reaction mixture was adjusted to a value between 2.5 and 2.6 by means of slowly adding a 40% aqueous NaOH solution, observing the presence of a white solid in the reaction mixture. The resulting solid was filtered and recrystallized in 1150 ml of water. The resulting solid in the recrystallization reaction mixture was filtered and washed successively with two fractions of 60 mL of water each. Finally, it was dried in a vacuum oven at the temperature of 50°C to obtain 115.2 g of a white solid corresponding to 4-nitro-L- phenylalanine monohydrate (92.5% yield, 99.89% purity by means of LIHPLC).

[0089]

[0075] Example 2. Synthesis of 4-amino-L-phenylalanine monohydrate (IV)

[0090]

[0076] 70 g (0.307 mol) of 4-nitro-L-phenylalanine monohydrate were mixed with 7 g of 5% Pd / C and 1000 ml of water at the temperature of about 20°C in a hydrogenation flask. Two successive sequences of inertization were performed with vacuum and N2 and finally the inner pressure of the flask was adjusted to about 5 bars with H2 atmosphere. The resulting mixture was heated to the temperature of about 30°C and kept under stirring for 20 hours at said temperature and about 5 bars of H2 pressure.

[0091]

[0077] Thereafter, the reaction mixture was depressurized and inertized with N2 and heated to about 40°C. It was kept under stirring at said temperature for 15 minutes and filtered through a diatomaceous earth filter that was subsequently washed with two fractions of 22 mL of water each. The solvent was removed by means of vacuum distillation to obtain a solid residue wet with water. 100 ml of methanol were added and the solvent was again removed by means of vacuum distillation to obtain a solid residue to which 280 ml of acetone were added. The mixture obtained was kept under stirring at the temperature of between 25 and 30°C for 30 minutes. The resulting solid was filtered and washed successively with three fractions of 40 mL of acetone each. Finally, it was dried in a vacuum oven at the temperature of 40°C to obtain 56.36 g of a beige solid corresponding to 4-amino-L-phenylalanine monohydrate (92.7% yield, 99.9% purity by means of LIHPLC).

[0092]

[0078] Example 3. Synthesis of 4-amino-3,5-dibromo-L-phenylalanine (Illa)

[0093]

[0079] 30 g (0.15 mol) of 4-amino-L-phenylalanine monohydrate were mixed with 504 ml of glacial acetic acid, 72 ml of water, and 0.5 ml of 48% HBr at the temperature of about 20°C. The mixture was kept under stirring at said temperature for 10 minutes to obtain a perfect solution. A solution prepared previously from 15.5 ml (0.30 mol) of Br2 and 24 ml of glacial acetic acid was slowly added to this solution, maintaining the temperature of the reaction mixture between 20 and 25°C. The reaction mixture obtained was kept under stirring at the temperature of about 20°C for 2 hours (the appearance of a whitish solid was observed).

[0094]

[0080] Thereafter, 500 ml of water were added, obtaining an orange-colored solution. The solution was cooled at the temperature of about 10°C and, by maintaining this temperature, a 40% aqueous NaOH solution was slowly added until reaching a mixture pH of about 5. The resulting solid was filtered and washed successively with two fractions of 80 mL of a 1 : 1 mixture of water / methanol each and 80 ml of acetone. Finally, it was dried in a vacuum oven at the temperature of 40°C to obtain 49.68 g of a beige solid corresponding to 4-amino-3,5-dibromo- L-phenylalanine (94.5% yield, 99.4% purity by means of LIHPLC). The isolated solid has a Karl-Fischer of about 2.3%, which would correspond to a hemihydrate form of the compound obtained.

[0095]

[0081] Example 4. Synthesis of the hydrochloride salt of 4-amino-3,5-dibromo-L- phenylalanine methyl ester (Ila)

[0096]

[0082] 20 g (0.058 mol) of the hemihydrate of 4-amino-3,5-dibromo-L-phenylalanine were mixed with 120 ml of methanol. About 60 ml of solvent were removed by means of vacuum distillation and an additional 60 ml of methanol were added. About 60 ml of solvent were removed by means of vacuum distillation and an additional 60 ml of methanol were added. The reaction mixture was cooled at the temperature of about 2°C and 6.5 ml (0.090 mol) of thionyl chloride were slowly added, maintaining the temperature of the reaction below about 10°C. After the addition, the reaction mixture was heated at the temperature of about 50°C and kept under stirring at the temperature of between 50 and 55°C for 4 hours.

[0083] Thereafter, the solvent was removed by means of vacuum distillation and 80 ml of methanol were added to the obtained residue and the obtained mixture was heated at the reflux temperature to obtain a solution. The solution was cooled at the temperature of about 50°C, observing the appearance of a precipitate. 240 ml of methyl-tert-butyl ether were slowly added to the mixture, maintaining the temperature of about 50°C. The mixture thus obtained was slowly cooled at the temperature of about 20°C and kept under stirring at said temperature for 1 hour. The resulting solid was filtered and washed successively with two fractions of 20 mL of methyl-tert-butyl ether each. Finally, it was dried in a vacuum oven at the temperature of 40°C to obtain 18.38 g of a white solid corresponding to the hydrochloride salt of 4-amino- 3,5-dibromo-L-phenylalanine methyl ester (82.1% yield, 99.56% purity by means of LIHPLC).

[0097]

[0084] Example 5. Synthesis of methyl (2R)-3-(4-amino-3,5-dibromophenyl)-2- (benzyloxycarbonylamino)propanoate (lab)

[0098]

[0085] 39 g (0.100 mol) of the hydrochloride salt of 4-amino-3,5-dibromo-L- phenylalanine methyl ester were mixed with 390 ml of dichloromethane and 43.8 ml (0.251 mol) of N,N-diisopropylethylamine were subsequently added, maintaining the temperature of the mixture at about 20°C. The solution thus obtained was cooled at the temperature of between 0 and 2°C and 15.8 ml (0.111 mol) of benzyloxycarbonyl chloride were slowly added, maintaining the temperature of the mixture between 0 and 5°C during the addition. The resulting solution was kept under stirring at the temperature of between 2 and 5°C for 2 hours.

[0099]

[0086] Thereafter, 20 ml of an 8% aqueous NaHCCh solution were added and the resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were separated and 100 ml of a 8% aqueous NaHCCh solution were added to the resulting organic phase. The resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were separated and 200 ml of water were added to the resulting organic phase. The phases were again separated and the resulting organic phase was treated with 1.25 g of 4S carbon. It was kept under stirring at the temperature of about 20°C for 15 minutes and filtered through a diatomaceous earth filter that was subsequently washed with two fractions of 25 mL of dichloromethane each. The solvent was removed by means of vacuum distillation to obtain a residue to which 100 ml of isopropyl alcohol were added. The mixture was heated at the temperature of about 80°C and kept under stirring at said temperature for 10 minutes, observing a perfect solution. The solution was slowly cooled, observing the formation of a precipitated solid at the temperature of about 45°C. The mixture was maintained at the temperature of 40-45°C for 15 minutes and then slowly cooled to the temperature of about 20°C and kept under stirring at said temperature for 1 hour. The resulting solid was filtered and washed successively with three fractions of 12 mL of isopropyl alcohol each. Finally, it was dried at the temperature of 50°C to obtain 42.5 g of a slightly grayish solid corresponding to methyl (R)-3-(4-amino-3,5-dibromophenyl)-2-(benzyloxycarbonylamino) propanoate (86.6% yield, 99.42% purity by means of LIHPLC).

[0100]

[0087] XRPD: 4.9° 20, 8.8° 20, 16.6° 20, 17.4° 20, 18.2° 20, 20.8° 20, 21.7° 20, 22.4° 20, 22.8° 20, 24.9° 20, and 32.8° 20, all of them with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound is shown in Figure 1.

[0101]

[0088] The differential scanning calorimetry (DSC) spectrum of the compound of formula (lab) comprises an endothermic peak having a threshold temperature of about 88.7°C.

[0102]

[0089] 1H-NMR (CDCI3, 400 MHz) 6 (ppm): 7.34-7.27 (m, 5H), 7.09 (s, 2H), 5.30 (d, 1 H), 5.11- 5.03 (dd, 2H), 4.52 (dd, 1 H), 4.44 (brs, 2H), 3.69 (s, 3H), 2.97-2.85 (ddd, 2H).

[0103]

[0090] 13C-NMR (CDCh, 400 MHz) 5 (ppm): 171.7, 155.6, 141.1 , 136.2, 134.4, 128.6, 128.2, 128.0, 127.1 , 108.7, 67.1 , 54.9, 52.4, 36.8.

[0104]

[0091] Example 6. Synthesis of methyl (2R)-3-(4-amino-3,5-dibromophenyl)-2-(tert- butoxycarbonylamino)propanoate (laa)

[0105]

[0092] 2 g (5.14 mmol) of the hydrochloride salt of 4-amino-3,5-dibromo-L-phenylalanine methyl ester were mixed with 20 ml of tetra hydrofuran and 2.2 ml (15.8 mmol) of triethylamine were subsequently added, maintaining the temperature of the mixture at about 20°C. The solution thus obtained was cooled at the temperature of between 0 and 5°C and a solution prepared previously with 1.46 g (6.69 mmol) of di-tert-butyl dicarbonate and 2 ml of tetra hydrofuran was added, maintaining the temperature of the mixture between 0 and 5°C during the addition. The resulting solution was kept under stirring at the temperature of between 5 and 10°C for 3 hours.

[0106]

[0093] Thereafter, the solvent was removed by means of vacuum distillation and 50 ml of isopropyl acetate and 50 ml of an 8% aqueous NaHCCh solution were added and the resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were separated and the organic phase was washed successively with two fractions of 50 ml of water each. The solvent of the resulting organic phase was removed to obtain 2.27 g (97.4% yield, 98.58% purity by means of LIHPLC) of a slight grayish solid corresponding to methyl (2R)-3-(4-amino-3,5-dibromophenyl)-2-(tert-butoxycarbonylamino)propanoate.

[0107]

[0094] ^-NMR (DMSO-d6, 400 MHz) 6 (ppm): 7.20 (d, 2H), 4.08-4.02 (m, 1 H), 3.96 (brs, 1 H), 3.56 (s, 3H), 2.84-2.79 (dd, 1 H), 2.67-2.59 (dd, 1 H), 1.27 (s, 9H).

[0108]

[0095] 13C-NMR (DMSO-d6, 400 MHz) 5 (ppm): 172.8, 155.8, 141.7, 132.9, 128.5, 107.8, 78.8, 55.4, 52.3, 35.1 , 28.6.

[0109]

[0096] Example 7. Synthesis of methyl (2R)-3-(4-amino-3,5-dimethylphenyl)-2- (benzyloxycarbonylamino)propanoate (Vb)

[0110]

[0097] 5 g (0.010 mol) of methyl (R)-3-(4-amino-3,5-dibromophenyl)-2- (benzyloxycarbonylamino)-propanoate, 3.69 g (0.061 mol) of methylboronic acid, and 67 mg (1.0 mmol) of [1 ,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) (PdCh(dtbpf)) were mixed with 20 ml of dioxane and the reaction mixture was homogenized by means of stirring at the temperature of about 30°C. 8.52 g (0.061 mol) of K2CO3 were subsequently added and the reaction mixture was heated at the temperature of about 70°C and kept under stirring at said temperature for 2 hours.

[0111]

[0098] Thereafter, the reaction mixture was cooled at the temperature of about 20°C and 50 ml of acetone were added and it was kept under stirring at said temperature for 30 minutes. The reaction mixture was filtered through a diatomaceous earth filter that was subsequently washed with two fractions of 25 mL of acetone each. The solvent was removed by means of vacuum distillation to obtain a residue to which 50 ml of isopropyl acetate and 50 ml of an 8% aqueous NaHCCh solution were added and the resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were separated and 100 ml of an 8% aqueous NaHCCh solution were added to the resulting organic phase. The resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were separated and 50 ml of water were added to the resulting organic phase. The phases were again separated and 50 ml of water were added to the resulting organic phase. The phases were again separated and the solvent of the organic phase was removed by means of vacuum distillation to obtain a solid residue (3.6 g with a 96.2% purity by means of HPLC). 30 ml of methyl-tert-butyl ether were added and the mixture was heated at the reflux temperature to obtain a solution which was kept under stirring at said temperature for 10 minutes. The solution was slowly cooled, observing the formation of a precipitated solid at the temperature of about 40°C. The mixture was maintained at the temperature of 40-42°C for 10 minutes and then slowly cooled to the temperature of about 20°C and kept under stirring at said temperature for 2 hours. The resulting solid was filtered and washed with two fractions of 15 mL of methyl-tert- butyl ether each. Finally, it was dried at the temperature of 50°C to obtain 3.01 g of a slightly grayish solid corresponding to methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2- (benzyloxycarbonylamino)-propanoate (82.1 % yield, 98.46% purity by means of LIHPLC).

[0112]

[0099] XRPD: 9.2° 20, 9.3° 20, 14.0° 20, 18.0° 20, 18.3° 20, 19.1 ° 20, 20.1 ° 20, 21.4° 20, 22.6° 20, and 25.3° 20, all of them with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound is shown in Figure 2.

[0113]

[0100] Example 8. Synthesis of methyl (2R)-3-(4-amino-3,5-dimethylphenyl)-2-(tert- butoxycarbonylamino)propanoate (Va)

[0114]

[0101] 5.0 g (0.011 mol) of methyl (2R)-3-(4-amino-3,5-dibromophenyl)-2-(tert- butoxycarbonylamino)propanoate, 3.97 g (0.066 mmol) of methylboronic acid, 72 mg (0.110 mmol) of [1 ,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) (PdCh(dtbpf)), and 9.15 g (0.066 mol) of K2CO3 were mixed with 20 ml of dioxane and the reaction mixture was heated at the temperature of about 70°C and kept under stirring at said temperature for 2 hours.

[0115]

[0102] Thereafter, 50 ml of isopropyl acetate and 50 ml of water were added at the temperature of about 20°C. The resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were separated and 50 ml of water were added to the resulting organic phase. The phases were again separated and 50 ml of water were added to the resulting organic phase. The phases were again separated and the organic phase was filtered through a diatomaceous earth filter that was subsequently washed with a fraction of 25 mL of isopropyl acetate. The solvent of the organic phase was removed by means of vacuum distillation to obtain 3.57 g of a light brown color oil corresponding to methyl (2R)-3-(4-amino- 3,5-dimethylphenyl)-2-(tert-butoxycarbonylamino)propanoate (99.4% yield, 96.53% purity by means of LIHPLC).

[0116]

[0103] ^-NMR (DMSO-d6, 400 MHz) 5 (ppm): 7.12 (d, 2H), 4.09-4.02 (m, 1 H), 3.95 (brs, 1 H), 3.60 (s, 3H), 2.80-2.75 (dd, 1 H), 2.68-2.62 (dd, 1 H), 2.05 (s, 6H), 1.27 (s, 9H).

[0104] 13C-NMR (DMSO-d6, 400 MHz) 5 (ppm): 173.4, 155.8, 143.1 , 128.8, 124.7, 120.9, 78.6, 56.3, 52.1 , 36.3, 28.6, 18.3.

[0117] Example 9. Methyl (2R)-3-(4-amino-3,5-dimethylphenyl)-2-(tert- butoxycarbonylamino)propanoate (Va)

[0118]

[0105] 300.0 g (0.664 mol) of methyl (2R)-3-(4-amino-3,5-dibromophenyl)-2-(tert- butoxycarbonylamino)propanoate, 218.4 g (3.649 mmol) of methylboronic acid, 4.33 mg (6.643 mmol) of [1 ,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) (PdCh(dtbpf)), and 458.5 g (3.318 mol) of K2CO3 were mixed with 1200 ml of dioxane and the reaction mixture was heated at the temperature of about 90°C and kept under stirring at said temperature for 2 hours.

[0119]

[0106] Thereafter, 1200 ml of water and 1200 ml of isopropyl acetate were added at the temperature of about 25°C. The resulting mixture was kept under stirring for 30 minutes at the temperature of about 20°C. The phases were separated and the organic phase was filtered through a diatomaceous earth filter that was subsequently washed with three fractions of 50 mL of isopropyl acetate. 600 ml of a 5% aqueous NaCI solution were added to the resulting organic phase. The phases were again separated and 600 ml of a 5% aqueous NaCI solution were added to the resulting organic phase. The phases were again separated and the organic phase was filtered through a diatomaceous earth filter that was subsequently washed with 1 fraction of 50 mL of isopropyl acetate. The solvent of the organic phase thus obtained was finally removed by means of vacuum distillation to obtain 209.7 g of a light brown solid corresponding to methyl (2R)-3-(4-amino-3,5-dimethylphenyl)-2-(tert-butoxycarbonyl- amino)propanoate (98.1% yield, 96.97% purity by means of LIHPLC).

[0120]

[0107] The1H-NMR (DMSO-d6, 400 MHz) and13C-NMR (DMSO-d6, 400 MHz) spectra coincide with those recorded for the product obtained following the methodology described in Example 8.

[0121]

[0108] XRPD: 7.2° 20, 9.6° 20, 10.5° 20, 16.7° 20, 17.7° 20, 18.3° 20, 19.3° 20, 21 .3° 20, 22.1 ° 20, 22.8 ± 0.2° 20; 23.8° 20, 24.3° 20, and 29.2° 20, all of them with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound is shown in Figure 8.

[0122]

[0109] Example 10. Synthesis of 4-amino-3,5-diiodo-L-phenylalanine (lllb)

[0110] 2.0 g (10.1 mmol) of 4-amino-L-phenylalanine monohydrate were mixed with 40 ml of glacial acetic acid at the temperature of about 20°C. The mixture was kept under stirring for 10 minutes to obtain a perfect solution to which 1.1 ml (21.9 mmol) of iodine monochloride (ICI) were added at the temperature of about 20°C. The reaction mixture was kept under stirring at said temperature for 3 hours.

[0123]

[0111] Thereafter, 40 ml of water were slowly added and the pH of the resulting mixture was adjusted to a value of about 4.2 by means of adding a 30% aqueous NaOH solution at the temperature of about 20°C. The resulting solid was filtered and washed with a fraction of 10 ml of a 1 :1 mixture of water / acetone and a fraction of 10 ml of acetone. Finally, it was dried at the temperature of 50°C to obtain 2.68 g of a slightly brown solid corresponding to 4-amino- 3,5-diiodo-L-phenylalanine (61.5% yield, 98.78% purity by means of LIHPLC).

[0124]

[0112] ^-NMR (DMSO-d6, 400 MHz) 6 (ppm): 7.53 (s, 2H), 4.91 (s, 2H), 4.00-3.60 (brs, 1 H), 3.20 (m, 1 H), 2.86 (dd, 1 H), 2.56 (dd, 1 H).

[0125]

[0113] 13C-NMR (DMSO-d6, 400 MHz) 5 (ppm): 174.0, 145.0, 139.7, 131.3, 81.6, 56.1 , 35.1.

[0126]

[0114] Example 11. Synthesis of the hydrochloride salt of 4-amino-3,5-diiodo-L-phenylalanine methyl ester (lib)

[0127]

[0115] 2.3 g (5.32 mmol) of 4-amino-3,5-diiodo-L-phenylalanine were mixed with 16.5 ml of methanol. About 10 ml of solvent were removed by means of vacuum distillation and additional 10 ml of methanol were added. The reaction mixture was cooled at the temperature of about 2°C and 0.8 ml (11.0 mol) of thionyl chloride were slowly added, maintaining the temperature of the reaction below about 5°C. After the addition, the reaction mixture was heated at the temperature of about 50°C and kept under stirring at the temperature of between 50 and 55°C for 6 hours.

[0128]

[0116] Thereafter, 150 ml of methanol were added to the reaction mixture and the solvent was removed by means of vacuum distillation. 40 ml of methanol were added to the obtained residue and the obtained mixture was heated at the reflux temperature to obtain a solution. The solution was cooled at the temperature of about 55°C and 120 ml of methyl-tert-butyl ether were slowly added to the mixture, maintaining the temperature of about 55°C. The mixture thus obtained was slowly cooled at the temperature of about 20°C and kept under stirring at said temperature for 2 hours. The resulting solid was filtered and washed successively with 5 fractions of 2.5 ml of methyl-tert-butyl ether each. Finally, it was dried in a vacuum oven at the temperature of 40°C to obtain 1.96 g of a yellowish solid corresponding to the hydrochloride salt of 4-amino-3,5-diiodo-L-phenylalanine methyl ester (76.3% yield, 98.59% purity by means of UHPLC).

[0129]

[0117] XRPD: 5.7° 20, 21.2° 20, 29.8° 20, and 31 .9° 20, all of them with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound is shown in Figure 3.

[0130]

[0118] The differential scanning calorimetry (DSC) spectrum of the compound of formula (lib) comprises an endothermic peak having a threshold temperature of about 219.3°C and an exothermic peak corresponding to the decomposition of the hydrochloride salt having a threshold temperature of about 229.0°C.

[0131]

[0119] 1H-NMR (DMSO-d6, 400 MHz) 5 (ppm): 8.76 (brs, 1 H), 7.53 (s, 2H), 5.3-4.9 (brs, 1 H), 4.16 (s, 1 H), 3.70 (s, 3H), 2.50 (m, 1 H).

[0132]

[0120] 13C-NMR (DMSO-d6, 400 MHz) 5 (ppm): 169.1 , 146.0, 139.8, 126.5, 81.7, 53.0, 52.4, 33.2.

[0133]

[0121] Example 11. Synthesis of methyl (R)-3-(4-amino-3,5-diiodophenyl)-2- (benzyloxycarbonylamino)-propanoate (Ibb)

[0134]

[0122] 1.4 g (2.90 mmol) of the hydrochloride salt of 4-amino-3,5-dibromo-L-phenylalanine methyl ester were mixed with 14 ml of dichloromethane and 1.3 ml (7.45 mmol) of N,N- diisopropylethylamine were subsequently added, maintaining the temperature of the mixture at about 20°C. The solution thus obtained was cooled at the temperature of between 0 and 2°C and 0.5 ml (3.50 mol) of benzyloxycarbonyl chloride were slowly added, maintaining the temperature of the mixture between 0 and 5°C during the addition. The resulting solution was kept under stirring at the temperature of between 2 and 5°C for 1 hour. Thereafter, 20 ml of an 8% aqueous NaHCCh solution were added and the resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were separated and 20 ml of an 8% aqueous NaHCCh solution were added to the resulting organic phase. The resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were separated and the organic phase was dried with the addition of MgSC The MgSC>4 was filtered and washed with 5 ml of dichloromethane. The solvent was removed by means of vacuum distillation to obtain a residue to which 9.0 ml of isopropyl alcohol and 3 ml of methanol were added. The mixture was heated at the reflux temperature and kept under stirring at said temperature for 10 minutes, observing a perfect solution. The solution was slowly cooled, observing the formation of a precipitated solid at the temperature of about 50°C. The mixture was maintained at the temperature of between 45 and 50°C for 10 minutes and then slowly cooled to the temperature of about 20°C and kept under stirring at said temperature for 1 hour. The resulting solid was filtered and washed successively with three fractions of 12 mL of isopropyl alcohol each. Finally, it was dried at the temperature of 50°C to obtain 1.27 g of a slightly brown solid corresponding to methyl (R)-3-(4-amino-3,5-diiodophenyl)-2- (benzyloxycarbonyl-amino)propanoate (75.8% yield, 98.67% purity by means of LIHPLC).

[0135]

[0123] XRPD: 7.0° 20, 13.8° 20, 20.6° 20, 21.5° 20, 23.6° 20, and 24.9° 20, all of them with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound is shown in Figure 4.

[0136]

[0124] The differential scanning calorimetry (DSC) spectrum of the compound of formula (Ibb) comprises an endothermic peak having a threshold temperature of about 122.4°C.

[0137]

[0125] ^-NMR (DMSO-d6, 400 MHz) 5 (ppm): 7.79 (d, 1 H), 7.55 (s, 2H), 7.38-7.24 (m, 5H), 5.00 (brs, 4H), 4.18-4.13 (m, 1 H), 3.62 (s, 3H), 2.89-2.84 (dd, 1 H), 2.67-2.61 (dd, 1 H).

[0138]

[0126] 13C-NMR (DMSO-d6, 400 MHz) 5 (ppm): 172.0, 155.8, 145.5, 139.6, 136.8, 129.5, 128.3, 127.6, 127.3, 81.4, 65.3, 55.4, 51.8, 34.0.

[0139]

[0127] Example 13. Synthesis of methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2- (benzyloxycarbonylamino)-propanoate (Vb)

[0140]

[0128] 2.1 g (3.62 mmol) of methyl (R)-3-(4-amino-3,5-diiodophenyl)-2- (benzyloxycarbonylamino)-propanoate, 1.29 g (21 .6 mmol) of methylboronic acid, and 23.6 mg (0.036 mmol) of [1 ,T-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) (PdCh(dtbpf)) were mixed with 8.5 ml of dioxane and the reaction mixture was homogenized by means of stirring at the temperature of about 20°C. 3 g (21.7 mol) of K2CO3 were subsequently added and the reaction mixture was heated at the temperature of about 75°C and kept under stirring at said temperature for 10 hours.

[0141]

[0129] Thereafter, the reaction mixture was cooled at the temperature of about 20°C and 21 ml of acetone were added and it was kept under stirring at said temperature for 15 minutes. The reaction mixture was filtered through a diatomaceous earth filter that was subsequently washed with two fractions of 10 mL of acetone each. The solvent was removed by means of vacuum distillation to obtain a residue to which 20 ml of isopropyl acetate and 25 ml of an 8% aqueous NaHCCh solution were added and the resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were separated and 50 ml of an 8% aqueous NaHCCh solution were added to the resulting organic phase. The resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The two phases were separated and the solvent of the organic phase was removed by means of vacuum distillation to obtain a solid residue. 14 ml of methyl-tert-butyl ether were added and the mixture was heated at the reflux temperature to obtain a solution which was kept under stirring at said temperature for 15 minutes. The solution was slowly cooled, observing the formation of a precipitated solid at the temperature of about 45°C. The mixture was maintained at the temperature of about 45°C for 5 minutes and then slowly cooled to the temperature of about 20°C and kept under stirring at said temperature for 2 hours. The resulting solid was filtered and washed with three fractions of 8 mL of methyl-tert-butyl ether each. Finally, it was dried at the temperature of 50°C to obtain 0.80 g of a grayish solid corresponding to methyl (R)-3-(4- amino-3,5-dimethylphenyl)-2-(benzyloxycarbonylamino)-propanoate (62.0% yield, 98.19% purity by means of LIHPLC). The XRPD analysis of the compound obtained according to the present example is consistent with the XRPD analysis of the compound obtained following the methodology described according to Example 7

[0142]

[0130] Example 14. Synthesis of methyl (2R)-2-(benzyloxycarbonylamino)-3-(7-methyl-1 H- indazol-5-yl)propanoate (Vlb)

[0143]

[0131] 2.02 g (5.67 mmol) of methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2- (benzyloxycarbonylamino)propanoate, 0.70 g (7.13 mmol) of potassium acetate, 0.5 ml of acetic acid, and 25 ml of ethyl acetate were mixed. The reaction mixture was homogenized by means of stirring for 10 minutes at the temperature of about 20°C and 0.85 ml (6.31 mmol) of isopentyl nitrite were subsequently added. The resulting reaction mixture was heated at the temperature of between 65 and 70°C and kept under stirring at said temperature for 4 hours.

[0144]

[0132] Thereafter, the reaction mass was cooled at the temperature of about 20°C and a previously prepared solution of 1.7 g of K2CO3 in 12 ml of water was added. The resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were subsequently separated and the organic phase was washed with 25 ml of a 10% aqueous NaCI solution. The solvent of the organic phase obtained was removed by means of vacuum distillation to obtain a solid residue that was mixed with 50 ml of toluene. The solvent of this mixture was again removed by means of vacuum distillation to obtain a solid residue (2.27 g with a 96.2% purity by means of HPLC). 12 ml of toluene were added and the mixture was heated at the temperature of about 100°C to obtain a solution which was kept under stirring at said temperature for 10 minutes. The solution was slowly cooled, observing the formation of a precipitated solid at the temperature of about 55°C. The mixture was maintained at the temperature of 50-55°C for 10 minutes, 4.2 ml of toluene were added, and the reaction mixture was then slowly cooled to the temperature of about 20°C and kept under stirring at said temperature for 2 hours. The resulting solid was filtered, washed with two fractions of 10 ml of a 1 :1 mixture of toluene and n-heptane each, and finally was dried at the temperature of 50°C to obtain 1.76 g of a slightly grayish solid corresponding to methyl (2R)-2- benzyloxycarbonylamino-3-(7-methyl-1 H-indazol-5-yl)propanoate (84.6% yield, 99.16% purity by means of LIHPLC).

[0145]

[0133] Example 15. Synthesis of methyl (2R)-2-(tert-butoxycarbonylamino)-3-(7-methyl-1 H- indazol-5-yl)propanoate (Via).

[0146]

[0134] 3.80 g (11.8 mmol) of methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2-(tert- butoxycarbonylamino)propanoate and 1.45 g (14.8 mmol) of potassium acetate were mixed with 50 ml of ethyl acetate at the temperature of about 20°C. 1 ml (17.5 mmol) of acetic acid was added to the reaction mixture at the temperature of about 20°C and 1.75 ml (13.0 mmol) of isopentyl nitrite were added to a resulting solution. The resulting reaction mixture was heated at the temperature of between 65 and 70°C and kept under stirring at said temperature for 6 hours.

[0147]

[0135] Thereafter, the reaction mass was cooled at the temperature of about 20°C and a previously prepared solution of 3.54 g of K2CO3 in 27 ml of water was added. The resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were subsequently separated and the organic phase was washed with 27 ml of a 10% aqueous NaCI solution. The solvent of the organic phase obtained was removed by means of vacuum distillation to obtain a solid residue that was mixed with 37 ml of toluene. The mixture was heated at the temperature of about 70°C to obtain a solution which was kept under stirring at said temperature for 10 minutes. The solution was slowly cooled to the temperature of about 20°C and 87 ml of n-heptane were slowly added, observing the appearance of a precipitated solid. It was kept under stirring at said temperature for 2 hours and the reaction mixture was subsequently cooled at the temperature of about 5°C. The resulting solid was filtered, washed with a fraction of 27 ml of a 1 :2.3 mixture of toluene and n-heptane, and finally vacuum-dried at the temperature of 50°C to obtain 2.76 g of a slightly brown solid corresponding to methyl (2R)-2-(tert-butoxycarbonylamino)-3-(7-methyl-1 H-indazol-5-yl)propanoate (70.2% yield, 99.26% purity by means of LIHPLC).

[0148]

[0136] XRPD: 3.5° 20, 5.5° 20, 5.7° 20, 7.0° 20, 7.5° 20, 8.8° 20, 9.2° 20, 9.6° 20, 12.1 ° 20, 14.0° 20, 17.1 ° 20, 18.4° 20, 20.9° 20, 23.3° 20, and 23.6° 20, all of them with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound is shown in Figure 5.

[0149]

[0137] ^-NMR (DMSO-d6, 400 MHz) 6 (ppm): 13.05 (s, 1 H), 7.99 (s, 1 H), 7.39 (s, 1 H), 7.00 (s, 1 H), 4.22-4.16 (m, 1 H), 4.08 (brs, 1 H), 3.61 (s, 3H), 3.07-3.02 (dd, 1 H), 2.94-2.88 (dd, 1 H), 2.49 (s, 3H), 1.31 (s, 9H).

[0150]

[0138] 13C-NMR (DMSO-d6, 400 MHz) 6 (ppm): 173.2, 155.8, 139.7, 133.9, 130.0, 127.7, 123.2, 120.0, 118.1 , 78.7, 56.2, 52.2, 37.0, 28.6, 17.3.

[0151]

[0139] Example 16. Synthesis of methyl (R)-2-amino-3-(7-methyl-1 H-indazol-5-yl)propanoate dihydrochloride (VII -2HCI)

[0152]

[0140] 1 g (2.72 mmol) of methyl (2R)-2-benzyloxycarbonylamino-3-(7-methyl-1 H-indazol-5- yl)propanoate was mixed with 308 mg of 5% Pd / C, 5 ml of methanol, and 2.7 ml of ethyl acetate at the temperature of about 20°C in a hydrogenation flask. Three successive sequences of inertization were performed with vacuum and N2 and finally the inner pressure of the flask was adjusted to about 4 bars with H2 atmosphere. The resulting mixture was kept under stirring for 20 hours at the temperature of about 25°C and an H2 pressure of about 4 bars.

[0153]

[0141] Thereafter, the reaction mixture was depressurized and filtered through a 0.22 pm PP filter which was washed with 3 ml of ethyl acetate. 5 ml of ethyl acetate were added to the resulting solution and N2 was bubbled through same for 5 minutes. 4.5 ml of ethyl acetate were added to the resulting solution and 1 .27 g of a 17 wt% solution of HCI in isopropyl alcohol (6.01 mmol of HCI) were subsequently added at the temperature of about 20°C, immediately observing the presence of a precipitated solid. The reaction mixture was kept under stirring at the temperature of about 20°C for 15 minutes, the resulting solid was filtered and washed with two fractions of 1.5 ml of ethyl acetate each. Finally, it was vacuum-dried at the temperature of 35°C to obtain 0.72 g of a slightly grayish solid corresponding to the dihydrochloride salt of methyl (R)-2-amino-3-(7-methyl-1 H-indazol-5-yl)propanoate (86.7% yield, 98.96% purity by means of LIHPLC).

[0154]

[0142] XRPD: 10.2° 20, 11.2° 20, 14.5° 20, 19.3° 20, 20.6° 20, 22.8° 20, and 24.9° 20, all of them with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound is shown in Figure 6.

[0155]

[0143] The differential scanning calorimetry (DSC) spectrum of the compound (VII-2HCI) comprises two endothermic peaks having corresponding threshold temperatures of about 180.2°C and 250.6°C.

[0156]

[0144] Example 17. Synthesis of methyl (R)-2-amino-3-(7-methyl-1 H-indazol-5-yl)propanoate dihydrobromide (VII-2HBr)

[0157]

[0145] 1.1 g (2.99 mmol) of methyl (2R)-2-benzyloxycarbonylamino-3-(7-methyl-1 H-indazol-5- yl)propanoate were mixed with 4.0 ml of glacial acetic acid at the temperature of about 20°C. The mixture was kept under stirring for 10 minutes until a perfect solution of the solid was observed and 4.5 ml of a 33% solution of HBr in acetic acid were then slowly added, maintaining the temperature at about 20°C. The solution obtained was kept under stirring for 1 hour at the temperature of about 20°C.

[0158]

[0146] Thereafter, 20 ml of acetonitrile were added to the resulting solution, observing the appearance of a white solid. The mixture obtained was kept under stirring for 1 hour at the temperature of 20°C. The resulting solid was filtered and washed with two fractions of 5 ml of acetonitrile each. The filtered solid was recrystallized in 25 ml of isopropyl alcohol by heating the mixture at the reflux temperature and subsequently cooling same to the temperature of about 20°C. The resulting solid was filtered and washed with two fractions of 5 ml of acetonitrile and acetone successively. Finally, it was dried at the temperature of 50°C to obtain 0.97 g of a white solid corresponding to the dihydrobromide salt of methyl (R)-2-amino-3-(7-methyl-1 H- indazol-5-yl)propanoate (82.5% yield, 98.77% purity by means of LIHPLC).

[0159]

[0147] Example. 18. Synthesis of methyl (R)-2-amino-3-(7-methyl-1 H-indazol-5- yl)propanoate dihydrochloride (VII 2HCI)

[0160]

[0148] 1.50 g (4.50 mmol) of methyl (2R)-2-(tert-butoxycarbonylamino)-3-(7-methyl-1 H- indazol-5-yl)propanoate were dissolved in 7.5 ml of isopropyl alcohol at the temperature of about 20°C. 10.8 ml of a 1.25 M solution of HCI in isopropyl alcohol were added to this solution, observing the appearance of a precipitate. The reaction mass was heated at the temperature of about 50°C and kept under stirring at said temperature for 6 hours.

[0161]

[0149] Thereafter, 7.5 ml of isopropyl alcohol were added and the reaction mass was cooled at the temperature of about 10°C. The resulting solid was filtered and washed with two fractions of 3 ml of isopropyl alcohol each. Finally, it was vacuum-dried at the temperature of 40°C to obtain 1.06 g of a slightly grayish solid corresponding to the dihydrochloride salt of methyl (R)- 2-amino-3-(7-methyl-1 H-indazol-5-yl)propanoate (76.8% yield, 98.95% purity by means of LIHPLC). The XRPD analysis of the compound obtained according to the present example is consistent with the XRPD analysis of the compound obtained following the methodology described according to Example 16.

[0162]

[0150] Example 19 Synthesis of methyl (R)-2-amino-3-(7-methyl-1 H-indazol-5- yl)propanoate dihydrochloride (VII 2HCI)

[0163]

[0151] 198.7 g (616.3 mmol) of methyl (R)-3-(4-amino-3,5-dimethylphenyl)-2-(tert- butoxycarbonylamino)propanoate Va (obtained by means of the methodology described in Example 9) and 30.3 g (308.3 mmol) of potassium acetate were mixed with 2000 ml of ethyl acetate at the temperature of about 20°C. 53 ml (924.4 mmol) of acetic acid were added to the reaction mixture at the temperature of about 20°C. The resulting solution was cooled at the temperature of about 5°C and 91 ml (677.3 mmol) of isopentyl nitrite were added. The resulting reaction mixture was heated at the temperature between 65 and 70°C and kept under stirring at said temperature for 7 hours.

[0164]

[0152] Thereafter, the reaction mass was cooled at the temperature of about 20°C and a previously prepared solution of 170.3 g of K2CO3 in 1300 ml of water was added. The resulting mixture was kept under stirring for 15 minutes at the temperature of about 20°C. The phases were subsequently separated and the organic phase was washed with 1300 ml of a 5 wt% aqueous NaCI solution. The solvent of the organic phase obtained was removed by means of vacuum distillation to obtain a solid residue that was mixed with 250 ml of methyl-tert-butyl ether. The solvent was removed by means of vacuum distillation to obtain a solid residue comprising the compound methyl (2R)-2-(tert-butoxycarbonylamino)-3-(7-methyl-1 H-indazol- 5-yl)propanoate.

[0153] The solid obtained was dissolved under stirring in 1225 ml of methanol at the temperature of about 20°C. 615 ml (2460 mmol) of a 4 M solution of HCI in 1 ,4-dioxane were added to this solution. The reaction mass was heated at the temperature of about 45°C and kept under stirring at said temperature for 7 hours.

[0165]

[0154] Thereafter, 2050 ml of 1 ,4-dioxane were added and the reaction mass was cooled at the temperature of about 10°C, keeping under stirring for 2 hours at the indicated temperature. The resulting solid was filtered and washed with three fractions of 510 mL of 1 ,4-dioxane each. Finally, it was vacuum-dried at the temperature of 40°C to obtain 135.8 g of a slightly grayish solid corresponding to the dihydrochloride salt of methyl (R)-2-amino-3-(7-methyl-1 H-indazol- 5-yl)propanoate (72.0% yield, 98.40% purity by means of LIHPLC). The XRPD analysis of the compound obtained according to the present example is consistent with the XRPD analysis of the compound obtained following the methodology described according to Example 16.

[0166]

[0155] Example 20. Synthesis of (2R)-3-(7-methyl-1 H-indazol-5-yl)-2-(4-(2-oxo-1 ,2- dihydroquinolin-3-yl)piperidine-1-carboxamido)-5-propanoic acid (X)

[0167]

[0156] 3.0 g (9.80 mmol) of methyl (2R)-2-amino-3-(7-methyl-1 H-indazol-5-yl)propanoate dihydrochloride (obtained by means of the methodology described in Example 16) and 13 ml of dimethylformamide were mixed at the temperature of about 20°C. 3.6 ml (20.6 mmol) of diisopropylethylamine were subsequently added to obtain a solution that was kept under stirring for 30 minutes at the temperature of about 20°C. The solution was cooled at the temperature of about -20°C and a previously prepared mixture of 1.9 g of N,N’- carbonyldiimidazole in 8.6 ml of dimethylformamide was slowly added, maintaining the reaction mixture at the temperature between -20 and -10°C. The reaction mixture was kept under stirring at said temperature for 1 hour.

[0168]

[0157] Thereafter, a mixture prepared previously from 1 ml of water and 2 ml of dimethylformamide was added, maintaining the temperature of about -10°C, and the solution was kept under stirring at said temperature for 20 minutes. 2.65 g (10 mmol) of 3-(piperidin-4- yl)quinolin-2(1 H)-one hydrochloride (VIII), 1.9 ml (10.9 mmol) of diisopropylethylamine, and 6.5 ml of dichloromethane were then sequentially added. The reaction mixture was heated at the temperature of about 40°C and kept under stirring at said temperature for 18 hours.

[0169]

[0158] Thereafter, the reaction mixture was cooled at the temperature of about 20°C and 14 ml of a 2N aqueous HCI solution were slowly added. 17 ml of dichloromethane were subsequently added, the organic phase (comprising the reaction product methyl (2R)-3-(7- methyl-1 H-indazol-5-yl)-2-(4-(2-oxo-1 ,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propa- noate (IX)) was separated and washed with 30 ml of water. A solution prepared previously by mixing 0.63 g (15.0 mmol) of LiOH monohydrate and 8.6 ml of water at the temperature of about 20°C was added to the resulting organic phase. The reaction mixture was kept under stirring at said temperature for 1 hour.

[0170]

[0159] Thereafter, the resulting phases were separated and 17.2 ml of water were added to the aqueous phase. The resulting aqueous solution was slowly added to a 1 N aqueous HCI solution previously cooled at the temperature between 0 and 2°C, observing the appearance of a whitish precipitate. The reaction mixture was maintained at the temperature of about 10°C for 2 hours and the resulting solid was filtered and washed successively with four fractions of 30 mL of water each and one fraction of 30 ml of methyl-tert-butyl ether. Finally, it was vacuum- dried at the temperature of 35°C to obtain 4.0 g of a white solid corresponding to (2R)-3-(7- methyl-1 H-indazol-5-yl)-2-(4-(2-oxo-1 ,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)-5- propanoic acid (86.2% yield, 98.68% purity by means of LIHPLC).

[0171]

[0160] Example 21 Synthesis of zavegepant hydrochloride (XII)

[0172]

[0161] 3.9 g (8.24 mmol) of (2R)-3-(7-methyl-1 H-indazol-5-yl)-2-(4-(2-oxo-1 ,2- dihydroquinolin-3-yl)piperidine-1-carboxamido)-5-propanoic acid, 1.26 g (8.23 mmol) of 1- hydroxybenzotriazole monohydrate, and 8.1 ml (46.4 mmol) of diisopropylethylamine were mixed with 6.5 ml of dimethylacetamide at the temperature of about 20°C. 2.92 g (9.98 mmol) of 1-(1-methyl-4-piperidyl)piperazine trihydrochloride (XI) were added to the resulting reaction mass. The resulting reaction mixture was heated at the temperature of about 45°C and kept under stirring at said temperature for 15 minutes. 2.16 g (11.3 mmol) of 1-[3-(dimethylamine)- propyl]-3-ethylcarbodiimide hydrochloride were added in portions to the reaction mixture and it was cooled at the temperature of about 20°C and kept under stirring at said temperature for 20 hours.

[0173]

[0162] Thereafter, the reaction mixture was filtered through a diatomaceous earth filter which was washed with 5 ml of absolute ethanol. After filtering the reaction mixture, the resulting solution was heated at the temperature of about 40°C and 24 ml of acetone were added. 0.01 g of zavegepant hydrochloride mixed with 4.5 ml of acetone were added to the obtained solution and the suspension obtained was kept under slow stirring for 1 hour at the temperature of about 40°C. 93 ml of acetone were slowly added, maintaining said temperature, and the suspension obtained was again kept under slow stirring for 1 hour at the temperature of about 40°C. It was then slowly cooled at the temperature of about 20°C, kept under stirring for 3 hours at said temperature, the resulting solid was filtered and washed with a fraction of 15 ml of acetone. Finally, it was vacuum-dried at the temperature of 45°C to obtain 4.77 g of an almost white solid corresponding to zavegepant hydrochloride (85.8% yield, 99.08% purity by means of LIHPLC).

[0174]

[0163] XRPD: 10.0° 20, 12.8° 20, 13.8° 20, 14.2° 20, 15.0° 20, 16.3° 20, 17.7° 20, 19.2° 20, 19.9° 20, 21.0° 20, and 21.9° 20, all of them with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound is shown in Figure 7.

[0175]

[0164] The differential scanning calorimetry (DSC) spectrum of the compound of formula XII comprises an endothermic peak having a threshold temperature of about 277.0°C.

[0176]

[0165] Example 22. Synthesis of (2R)-3-(7-methyl-1 H-indazol-5-yl)-2-(4-(2-oxo-1 ,2- dihydroquinolin-3-yl)piperidine-1-carboxamido)-5-propanoic acid

[0177]

[0166] 110.0 g (359.3 mmol) of methyl (2R)-2-amino-3-(7-methyl-1 H-indazol-5-yl)propanoate dihydrochloride (obtained by means of the methodology described in Example 19) and 586 ml of dimethylformamide were mixed at the temperature of about 20°C. 131 ml (752.0 mmol) of diisopropylethylamine were subsequently added to obtain a solution which was kept under stirring for 30 minutes at the temperature of about 20°C. The solution was cooled at the temperature of about -10°C and a previously prepared mixture of 69.7 g (429.8 mmol) of N,N’-carbonyldiimidazole in 315 ml of dimethylformamide was slowly added, maintaining the reaction mixture at the temperature of between -10 and 0°C. The reaction mixture was kept under stirring at said temperature for 1 hour.

[0178]

[0167] Thereafter, a mixture prepared previously from 31 ml of water and 76 ml of dimethylformamide was added, maintaining the temperature of about -10°C, and the solution was kept under stirring at said temperature for 30 minutes. 173.5 g (366.4 mmol) of 3- (piperidin-4-yl)quinolin-2(1 H)-one hydrochloride, 69 ml (396.1 mmol) of diisopropylethylamine, and 236 ml of dichloromethane were then sequentially added. The reaction mixture was heated at the temperature of about 40°C and kept under stirring at said temperature for 20 hours.

[0179]

[0168] Thereafter, the reaction mixture was cooled at the temperature of about 20°C and 500 ml of a 2 N aqueous HCI solution were slowly added. 630 ml of dichloromethane were subsequently added, the organic phase (comprising the reaction product methyl (2R)-3-(7- methyl-1 H-indazol-5-yl)-2-(4-(2-oxo-1 ,2-dihydroquinolin-3-yl)piperidine-1- carboxamido)propanoate) was separated and washed with 1100 ml of water. A solution prepared previously by mixing 23.22 g (553.3 mmol) of LiOH monohydrate and 315 ml of water at the temperature of about 20°C was added to the resulting organic phase. The reaction mixture was kept under vigorous stirring at said temperature for 1 hour.

[0180]

[0169] Thereafter, the resulting phases were separated and 210 ml of dimethylformamide and 625 ml of water were added to the aqueous phase. The resulting aqueous solution was slowly added to 790 ml of a 1 N aqueous HCI solution previously cooled at the temperature of between 5 and 10°C, observing the appearance of a whitish solid. The reaction mixture was maintained at the temperature of about 15°C for 3 hours and the resulting solid was filtered and washed successively with four fractions of 200 mL of water each and one fraction of 200 ml of methyl- tert-butyl ether. Finally, it was vacuum-dried at the temperature of 40°C to obtain 142.6 g of a white solid corresponding to (2R)-3-(7-methyl-1 H-indazol-5-yl)-2-(4-(2-oxo-1 ,2- dihydroquinolin-3-yl)piperidine-1-carboxamido)-5-propanoic acid (83.8% yield, 98.45% purity by means of LIHPLC).

[0181]

[0170] Example 23. Synthesis of zavegepant hydrochloride (XII)

[0182]

[0171] 10 g (21.1 mmol) of (2R)-3-(7-methyl-1 H-indazol-5-yl)-2-(4-(2-oxo-1 ,2-dihydroquinolin- 3-yl)piperidine-1-carboxamido)-5-propanoic acid (obtained by means of the methodology described in Example 22) and 6.8 g (23.2 mmol) of 1-(1-methyl-4-piperidyl)piperazine trihydrochloride were mixed with 50 ml of dimethylformamide at the temperature of about 20°C and the mixture was kept under stirring for 10 minutes at the mentioned temperature. 20.2 ml (116 mmol) of diisopropylethylamine were added to the mixture and the mixture was kept under stirring for 10 minutes at the mentioned temperature. The mixture was cooled at the temperature of about 0°C and 20 ml (33.8 mmol) of a 50% solution of 2,4,6-tripropyl-2,4,6- trioxo-1 ,3,5,2,4,6-trioxatriphosphorinane in ethyl acetate were slowly added. The resulting reaction mixture was kept under stirring at the temperature of between 0 and 5°C for 2 hours.

[0183]

[0172] Thereafter, the reaction mixture was heated at the temperature of about 40°C and 100 ml of acetone were slowly added to obtain a solution with a slight turbidity. The mixture obtained was kept under slow stirring for 1 hour at the temperature of about 40°C and 150 ml of acetone were slowly added, maintaining said temperature. The suspension obtained was again kept under slow stirring for 1 hour at the temperature of about 40°C. It was then slowly cooled at the temperature of about 20°C, kept under stirring for 4 hours at said temperature, the resulting solid was filtered and washed with 4 fractions of 15 ml of acetone each. Finally, it was vacuum-dried at the temperature of 45°C to obtain 12.0 g of an almost white solid corresponding to zavegepant hydrochloride (84.3% yield, 99.14% purity by means of LIHPLC).

[0184]

[0173] The X-ray powder diffractogram (XRPD) and the differential scanning calorimetry (DSC) spectrum of the compound of formula XII obtained by means of the methodology of the experiment are consistent with those obtained by means of the methodology of the experiment described in Example 21.

Claims

CLAIMSA compound of formula (I)wherein R1is selected from the group consisting of tert-butyl group and benzyl group, and X is selected from bromine and iodine or a solvate or salt thereof.

2. The compound according to claim 1, wherein X is bromine and R1is selected from the group consisting of tert-butyl group and benzyl group.

3. The compound according to any one of claims 1 and 2, which is methyl (R)-3-(4-amino-3.5-dibromophenyl)-2-(((benzyloxy)carbonyl)amino)propanoate or a solvate or salt thereof.

4. The compound according to any one of claims 1 and 2, which is methyl (R)-3-(4-amino-3.5-dibromophenyl)-2-((tert-butoxycarbonyl)amino)propanoate or a solvate or salt thereof.

5. A method of preparation of a compound of formula (I)wherein R1is selected from the group consisting of tert-butyl group and benzyl group, and X is selected from bromine and iodine, comprising the step of reacting a compound of formula (II), wherein X is selected from bromine and iodine or a salt thereofwith an acylating agent of formula G-CO-OR1, wherein R1is selected from the group consisting of tert-butyl group and benzyl group and G is selected from an -OR1group and a halogen atom, preferably a chlorine atom, in the presence of a base.

6. The method according to claim 5, characterized in that the reaction is carried out in a solvent, preferably methylene chloride or tetra hydrofuran.

7. The method according to any one of claims 5 to 6, characterized in that the base is an amine base, such as a primary amine of formula NH2Ra, a secondary amine of formula NHRaRb, or a tertiary amine of formula NRaRbRc, wherein each of Ra, Rb, and Rcis a (Ci- Ce)alkyl group.

8. The method according to claim 7, characterized in that the amine base is a tertiary amine, preferably N,N-diisopropylethylamine or triethylamine.

9. The method of preparation of a compound of formula (I) according to any one of claims 5 to 8, wherein the compound of formula (II) has been obtained by reaction of a compound of formula (III), wherein X is selected from bromine and iodine or a salt or hydrate thereofwith an agent for the formation of esters from an acid.

10. The method according to claim 9, wherein the agent for the formation of esters from an acid is selected from the group consisting of an alcohol, C1-6 dialkyl carbonate and diazomethane, preferably an alcohol or a C1-6 dialkyl carbonate, more preferably methanol or dimethyl carbonate, even more preferably, methanol.

11. The method according to any one of claims 9 and 10, wherein the compound of formula (III) has been obtained by reaction of a compound of formula (IV) or a salt thereofwith a brominating agent or an iodinating agent.

12. The method according to claim 11, wherein the brominating agent is selected from the group consisting of bromine in an acetic acid and hydrobromic acid or N-bromosuccinimide mixture, and the iodinating agent is selected from the group consisting of iodine monochloride or N-iodosuccinimide.

13. A method of obtaining an intermediate of formula (V)which comprises reacting the compound of formula (I) as defined in any one of claims 1 to 4(I) or a salt thereof with methylboronic acid or an anhydride of methylboronic acid in the presence of a catalyst, which is a palladium complex, and in the presence of a base to obtain a compound of formula (V).

14. The method according to claim 13, characterized in that the base used is a tetraalkylammonium halide or an inorganic base selected from carbonates and hydrogen phosphates.

15. The method according to claim 14, characterized in that the base is a carbonate, preferably an alkaline carbonate and more preferably K2CO3.

16. A method of obtaining methyl (R)-2-amino-3-(7-methyl-1 H-indazol-5-yl)propanoate of formula (VII) starting from a compound of formula (I), comprising the steps of: a) reacting the compound of formula (I) as defined in any one of claims 1 to 4 with methylboronic acid or an anhydride of methylboronic acid in the presence of a catalyst, which is a palladium complex, and in the presence of a base to obtain a compound of formula (V)b) reacting the compound of formula (V) with isopentyl nitrite at a pH comprised between 3 and 6 to obtain a compound of formula (VI)c) reacting the compound of formula (VI) with hydrogen (H2) in the presence of a palladium catalyst or with HBr in the presence of glacial acetic acid or with HCI to obtain methyl (R)-2-amino-3-(7-methyl-1 H-indazol-5-yl)propanoate of formula (VII)or a salt or solvate thereof.

17. The method according to claim 16, characterized in that the base used in step a) is a tetraalkylammonium halide or an inorganic base selected from carbonates and hydrogen phosphates.

18. The method according to claim 17, characterized in that the base is a carbonate, preferably an alkaline carbonate and more preferably K2CO3.

19. A compound of formula (Va)or a solvate or salt thereof.

20. The compound according to claim 19, which is in crystalline solid form.

21. The compound according to claim 20, characterized in that its X-ray powder diffraction spectrum measured with CuKa radiation has diffraction peaks at the 20 values of 10.5 ± 0.2° 20; 16.7± 0.2° 20; 17.7± 0.2° 20; 21.3 ± 0.2° 20; 22.1 ± 0.2° 20; and 22.8 ± 0.2° 20; preferably its X-ray powder diffraction spectrum measured with CuKa radiation has diffractionpeaks at the 20 values of 7.2 ± 0.2° 20; 9.6 ± 0.2° 20; 10.5 ± 0.2° 20; 16.7 ± 0.2° 20; 17.7 ± 0.2° 20; 18.3 ± 0.2° 20; 19.3 ± 0.2° 20; 21.3 ± 0.2° 20; 22.1 ± 0.2° 20; 22.8 ± 0.2° 20; 23.8 ± 0.2° 20; 24.3 ± 0.2° 20; and 29.2 ± 0.2° 20; more preferably its X-ray powder diffraction spectrum measured with CuKa radiation is essentially as depicted in Figure 8.

22. A method of obtaining (R)-N-(3-(7-methyl-1 H-indazol-5-yl)-1-(4-(1-methylpiperidin-4- yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1 ,2-dihydroquinolin-3-yl)piperidin-1 -carboxamide of formula (XII)comprising the steps of: a) reacting the compound of formula (I) as defined in any one of claims 1 to 4 with methylboronic acid or an anhydride of methylboronic acid in the presence of a catalyst, which is a palladium complex, and in the presence of a base to obtain a compound of formula (V)b) reacting the compound of formula (V) with isopentyl nitrite at a pH comprised between 3 and 6 to obtain a compound of formula (VI)(VI) c) reacting the compound of formula (VI) with hydrogen (H2) in the presence of a palladium catalyst or with HBr in the presence of glacial acetic acid or with HCI to obtain methyl (R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate of formula (VII)or a salt or solvate thereof d) reacting the compound of formula (VII) with 3-(piperidin-4-yl)quinolin-2(1 H)-one of formula (VIII)in the presence of a coupling agent and an organic base to obtain the compound of formula (IX)e) reacting the compound of formula (IX) with a base to obtain the compound of formula (X)f) reacting the compound of formula (X) with 1-(1-methylpiperidin-4-yl)piperazine of formula (XI)in the presence of a coupling agent.

23. The method according to claim 22, characterized in that the base used in step a) is a tetraalkylammonium halide or an inorganic base selected from carbonates and hydrogen phosphates.

24. The method according to claim 22, characterized in that the base of step a) is a carbonate, preferably an alkaline carbonate and more preferably K2CO3.

25. The method according to any one of claims 22 to 24, characterized in that the coupling agent used in step d) is preferably selected from the group of urea-forming agents such as N,N’-disuccinimidyl carbonate or 1 ,1’-carbonyldiimidazole.

26. The method according to any one of claims 22 to 25, characterized in that the organic base used in step d) is preferably selected from primary amines of formula NH2Ra, secondary amines of formula NHRaRb, and tertiary amines of formula NRaRbRc, wherein each of Ra, Rb, or Rcis a (Ci-Ce)alkyl group, preferably triethylamine or diisopropylethylamine.

27. The method according to any one of claims 22 to 26, characterized in that the base used in step e) is preferably selected from the inorganic bases exhibiting a pKb of less than 3.

28. The method according to claim 27, characterized in that the base used in step e) is selected from alkaline hydroxides, preferably LiOH.

29. The method according to any one of claims 22 to 28, characterized in that the coupling agent used in step f) is preferably selected from the group consisting of 1 -hydroxybenzotriazole, 1-[3-(dimethylamine)-propyl]-3-ethylcarbodiimide, and an organic base, preferably diisopropylethylamine.

30. Use of a compound of formula (I)wherein R1is selected from the group consisting of tert-butyl group and benzyl group, and X is selected from bromine and iodine or a solvate or a salt thereof for the preparation of the compound of formula (VII) or a solvate or a salt thereof.

31. Use of a compound of formula (I)wherein R1is selected from the group consisting of tert-butyl group and benzyl group, X is selected from bromine and iodine or a solvate or a salt thereof for the preparation of the compound of formula (XII) or a solvate or a salt thereof.

32. Use of a compound of formula (Va)or of a solvate or a salt thereof for the preparation of the compound of formula (VII) or a solvate or a salt thereof.

33. Use of a compound of formula (Va)or of a solvate or a salt thereof for the preparation of the compound of formula (XII) or a solvate or a salt thereof.

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