Process for preparing 3-piperidin-4-il-1h- quinolin-2-one or a salt thereof and its use as an intermediate for the preparation of pharmaceutical active ingredients antagonists of the CGRP peptide receptor

Abstract

The present invention relates to a process for preparing the compound of Formula I in the form of a base or a salt thereof, and its use as an intermediate for the preparation of calcitonin gene- related peptide (CGRP) receptor antagonist active pharmaceutical ingredients, in particular zavegepant, where the compound of Formula I is the following: (I)

Description

[0001] PROCESS FOR PREPARING 3-PIPERIDIN-4-IL-1H-QUINOLIN-2- ONE OR A SALT THEREOF AND ITS USE AS AN INTERMEDIATE FOR THE PREPARATION OF PHARMACEUTICAL ACTIVE INGREDIENTS ANTAGONISTS OF THE CGRP PEPTIDE RECEPTOR

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a process for preparing the compound of Formula I in the form of a base or a salt thereof: Formula I and its use as an intermediate for the preparation of calcitonin gene-related peptide (CGRP) receptor antagonist active pharmaceutical ingredients, in particular zavegepant (compound of Formula XX): Formula XX

[0004] The present invention further relates to intermediates of said process. BACKGROUND

[0005] In March 2023, in the United States, the Food and Drug Administration (FDA) approved zavegepant, an active ingredient belonging to the class of drugs known as gepants, i.e., antagonists of the calcitonin gene- related peptide (CGRP) receptor which is used for the acute treatment of migraine with or without aura in adults. Migraine is characterized by debilitating attacks lasting from 4 to 72 hours, with multiple symptoms, including pulsating headaches of moderate to severe intensity, often associated with nausea or vomiting, and / or sensitivity to sound (phonophobia) and light (photophobia). Zavegepant is the first drug belonging to the gepant class to be formulated as a nasal spray, a formulation that allows for faster pain relief compared to other routes of administration and represents a valid alternative for patients who cannot take oral medications due to nausea or vomiting.

[0006] Patent application WO2011123232 discloses a synthetic route for preparing zavegepant according to synthetic scheme 1

[0007]

[0008] Zavegepant

[0009] Scheme 1. Zavegepant according to WO2011123232 wherein zavegepant is prepared starting from compounds A, B, and C.

[0010] Compound A, reported in the prior art document WO2011123232 (and corresponding to the compound of Formula I of the present invention), is prepared according to synthetic scheme 2, reported below:

[0011] Scheme 2.

[0012] Such synthetic route for preparing compound A has several disadvantages, including the use of reagents such as lithium diisopropylamide (LDA), which requires cryogenic temperature conditions (-78°C), and the exothermic nature of this reaction, which makes the process difficult to apply at an industrial scale.

[0013] Temperature is a critical parameter for the formation of impurities that are particularly difficult to remove, both by crystallization and by chromatographic column.

[0014] Patent application W02023060255A1 describes the process for preparing the compound of Formula L, which is a positional isomer of the compound of Formula I, comprising the steps of:

[0015] • reacting the compound of Formula M with the compound of Formula V to obtain the compound of Formula N;

[0016] • reducing the compound of Formula C with hydrogen in the presence of Pd / C to obtain the compound of Formula 0;

[0017] • deprotecting the compound of Formula 0 to obtain the compound of Formula L.

[0018] The process described in W02023060255A1 is reported in the following Scheme 3:

[0019]

[0020] Scheme 3.

[0021] This synthetic route has several disadvantages, including the need for a very high quantity of Pd / C catalyst for the reduction reaction and the use of a reverse-phase chromatographic column for purifying the compound of Formula L.

[0022] The Applicant has therefore addressed the problem of finding a process for producing the compound of Formula I at industrial scale that overcomes the problems of the prior art, particularly with regard to yield and the purity of the final product. SUMMARY OF THE INVENTION

[0023] The Applicant has overcome the problems of the prior art through a simplified process as defined in claim 1, which allows to obtain the compound of Formula I with high purity, high process yields, and reduced preparation times, making it adapted to be made at industrial scale.

[0024] The present invention therefore relates to a process for preparing the compound of Formula I Formula I in the form of a base or a salt thereof, said process comprising the following steps: a) reacting the compound of Formula IV Formula IV with the compound of Formula V / Boc Formula V in an aprotic polar organic solvent, in the presence of a base, a catalyst comprising palladium, and a phosphine ligand, to obtain a solution of the compound of Formula

[0025] VI Boc Formula VI; b) reacting the compound of Formula VI in solution obtained in step a) with an acid to obtain the compound of Formula VII or a salt thereof Formula VII; c) reacting the compound of Formula VII obtained in step b) with a reducing agent, in the presence of a catalyst, in a polar solvent, to obtain the compound of Formula I in the form of a base or a salt thereof; d) isolating the compound of Formula I in the form of a base or a salt thereof.

[0026] Advantageously, the process described by the Applicant involves few synthetic steps, characterized by the use of inexpensive and easy-to-handle reagents. Advantageously, the reaction conditions applied are mild throughout all steps, without the need to use very low temperatures such as those employed in the cryogenic reactions of the prior art.

[0027] Advantageously, the compound of Formula I obtained according to the present invention can be isolated by filtration, a technique easily usable in the industrial practice, and has a high purity that does not require further purification steps. Therefore, column chromatographic purifications are not required.

[0028] In addition, the overall molar yield of the process according to the present invention is significantly improved compared to prior art processes.

[0029] Advantageously, the process of the present invention represents a strategic simplification in terms of economics (time and cost) and in the complexity of the process itself.

[0030] In accordance with a further aspect, the present invention relates to a process for preparing the compound of Formula IV Formula IV as defined in the attached claims.

[0031] Such process comprises the following steps: f) reacting a compound of Formula II Formula II with an oxidizing agent, in an aprotic polar solvent, to obtain a solution of the compound of Formula III Formula III g) reacting the compound of Formula III in solution obtained at the end of step f) with a sulfonyl halide to obtain the compound of Formula IV. In accordance with a further aspect, the present invention relates to the intermediate of Formula VI: Formula VI

[0032] In accordance with a further aspect, the present invention relates to the compound of Formula I-A, that is, a salt of the compound of Formula I:

[0033] Formula I-A

[0034] The present invention further relates to a process for preparing CGRP peptide receptor antagonist active pharmaceutical ingredients, which comprises: i) preparing the compound of Formula I according to the process of the invention; ii) using the compound of Formula I thus obtained to prepare a CGRP peptide receptor antagonist active ingredient.

[0035] In accordance with a further aspect, the present invention relates to a process for preparing zavegepant (compound of Formula XX), or a salt or solvate thereof, according to the attached claims. Further aspects, features, and advantages of the invention will become more apparent from the following detailed description.

[0036] BRIEF DESCRIPTION OF THE FIGURES

[0037] Figure 1.1H-NMR of the compound of Formula VI.

[0038] Figure 2.13C-NMR of the compound of Formula VI.

[0039] Figure 3. LC-MS of the compound of Formula VI.

[0040] Figure 4.1H-NMR of the compound of Formula I-A (formate salt).

[0041] Figure 5.13C-NMR of the compound of Formula I-A (formate salt).

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043] For the purposes of the present invention, in the following description and claims, the definitions of numerical ranges comprise the individual values within the range itself, as well as the corresponding endpoints, unless otherwise specified.

[0044] For the purposes of the present invention, in the following description and claims, the term "comprising" further includes the terms "consisting of" or "consisting essentially of".

[0045] According to a preferred aspect of the invention, the synthetic route of the compound of Formula I is reported in Scheme 4:

[0046]

[0047] Scheme 4.

[0048] With reference to step a) of the process according to the invention, such step refers to the reaction between the compound of Formula IV and the compound of Formula V in an aprotic polar organic solvent, in the presence of a base, a catalyst, and a ligand to obtain a solution of the compound of Formula VI.

[0049] According to a preferred aspect, in step a) the weight ratio between the compound of Formula V and the compound of Formula IV, calculated as weight on weight, is between 1.20 and 1.70 w / w, more preferably between 1.30 and 1.60 w / w.

[0050] Preferably, in step a), the aprotic polar organic solvent is selected from ethers, more preferably tetrahydrofuran and 2-methyltetrahydrofuran, 1,4- dioxane, amides, more preferably dimethylformamide, sulfoxides, more preferably dimethyl sulfoxide, water, or mixtures thereof.

[0051] In step a), the ratio between the solvent and the compound of Formula IV, calculated as volume on weight (v / w), is preferably between 7.0 and 15.0, more preferably between 9.0 and 13.0.

[0052] Preferably, in step a), the base is selected from alkali metal carbonates, alkali earth metal carbonates, alkali metal bicarbonates, alkali earth metal bicarbonates, alkali metal phosphates, or mixtures thereof.

[0053] Preferably, in step a), the weight ratio between the base and the compound of Formula IV, calculated as weight on weight, is between 1.05 and 1.43, more preferably between 1.12 and 1.36.

[0054] In step a), the base is preferably dissolved in water; preferably the ratio between the quantity of water and the compound of Formula IV, calculated as volume on weight (v / w), is between 2.0 and 6.0, preferably between 3.0 and 5.0. According to a preferred aspect of the invention, in step a), the catalyst comprising palladium is selected from organometallic compounds comprising Pd(II), preferably Pd(OAc)2 (palladium (II) acetate) or

[0055] Pd (dppf)CI2 (bis(diphenylphosphino)ferrocene) palladium (II) dichloride). Preferably, in step a), the ratio between the catalyst containing palladium and the compound of Formula IV, calculated as weight on weight, is between 0.005 and 0.015 w / w, more preferably between 0.008 and 0.012 w / w.

[0056] Preferably, in step a), the phosphine ligand is selected from monodentate and bidentate phosphine ligands, preferably triphenylphosphine.

[0057] In step a), the ratio between the phosphine ligand and the compound of Formula IV, calculated as weight on weight, is preferably between 0.018 and 0.028 w / w, more preferably between 0.020 and 0.026 w / w.

[0058] Preferably, in step a), the temperature is between 10°C and the reflux temperature.

[0059] Preferably, in step a), the reaction time is at least 1 hour, and stirring is however maintained until the end of the reaction.

[0060] According to a preferred aspect, in step a), at the end of the reaction, the solution of the compound of Formula VI is obtained through a process comprising the following steps: a1) adding a palladium scavenger; a11) filtering the suspension on a bed of inert filtering material; a111) adding a water-immiscible organic solvent, obtaining a clear biphasic mixture; aIV) separating the organic phase containing the compound of Formula VI from the biphasic mixture obtained in step a111); av) concentrating the organic phase; aVI) washing the organic phase obtained in step av) with water; aVI1) anhydrifying the organic phase to obtain a solution of the compound of Formula VI.

[0061] Preferably, in step a1), the palladium scavenger is selected from acetylacetone, acetylcysteine, functionalized resins, and functionalized silicas, more preferably the scavenger is acetylcysteine.

[0062] Preferably, in step a1), the ratio between the palladium scavenger and the compound of Formula IV, calculated as weight on weight, is between 0.035 and 0.053 w / w, more preferably between 0.040 and 0.048 w / w.

[0063] In step a1), the palladium scavenger is preferably dissolved in water; preferably, the ratio between the water and the compound of Formula IV, calculated as volume on weight (v / w), is between 0.28 and 0.42, more preferably between 0.31 and 0.39.

[0064] Preferably, in step a1), after adding the palladium scavenger, stirring is maintained for at least one hour.

[0065] According to a preferred aspect of the invention, in step a11), the suspension is cooled to a temperature of 60°C and filtered on an inert filtering material, preferably selected from diatomaceous earth, fossil flour, celite, dicalite, and cellulose, more preferably the inert filtering material is celite.

[0066] Preferably, in step a111), the water-immiscible organic solvent is selected from ethers, preferably 2- methyltetrahydrofuran . Preferably, in step a111), the ratio between the water-immiscible organic solvent and the compound of Formula IV, calculated as volume on weight (v / w), is between 1.0 and 15.0.

[0067] Preferably, in step a111), the water-immiscible organic solvent is used to wash the celite bed, obtaining a clear biphasic mixture. Preferably, in step a111), the temperature of the biphasic mixture is between 50-60°C to obtain the optimal separation of the two phases.

[0068] According to a preferred aspect, in step aIV), the organic phase containing the compound of Formula VI is separated from the biphasic mixture.

[0069] Preferably, in step av), the organic phase is concentrated, preferably the concentration occurs under atmospheric pressure.

[0070] In step av), the organic phase is preferably concentrated until reaching a final volume between 3 v / w and 7 v / w, more preferably between 4 v / w and 6 v / w.

[0071] Preferably, in step av), the operations of adding the water-immiscible organic solvent and concentrating the organic phase are repeated a second time.

[0072] These operations of concentrating the organic phase are intended to remove the aprotic polar organic solvent used in step a) and replace it with the water-immiscible organic solvent used in step a111).

[0073] Preferably, in step av), the organic phase is diluted with the water-immiscible organic solvent; preferably, the ratio between the water-immiscible organic solvent and the compound of Formula IV, calculated as volume on weight (v / w), is between 8.0 and 16.0, more preferably between 10.0 and 14.0. Preferably, in step av), the temperature is between 50°C and the reflux temperature. According to a preferred aspect of the invention, in step aVI), the organic phase obtained in step av) is washed with water to remove traces of the aprotic polar organic solvent used in step a). Preferably, in step aVI), the ratio between the water and the compound of Formula IV, calculated as volume on weight (v / w), is between 1.0 and 2.0.

[0074] According to a further preferred aspect of the invention, in step aVI1), the organic phase obtained in step aVI) is contacted with a 30% sodium chloride aqueous solution. Preferably, the ratio between the 30% sodium chloride aqueous solution and the compound of Formula IV, calculated as volume on weight (v / w), is between 1.0 and 2.0.

[0075] Preferably, in order to remove residual traces of water, in step aVI1), the organic phase containing the compound of Formula VI is heated to reflux, separating the water being de-mixed into the distilled solvent.

[0076] With reference to step b) of the process according to the invention, said step refers to the reaction between the compound of Formula VI in solution obtained in step a) and an acid, to obtain the compound of Formula VII or a salt thereof.

[0077] According to a preferred aspect, in step b), the acid is selected from hydrohalic acids, trifluoroacetic acid, sulfonic acids, preferably methanesulfonic acid, trifluoromethanesulfonic acid, or para-toluenesulfonic acid.

[0078] Preferably, in step b), the weight ratio between the acid and the compound of Formula IV, calculated as weight on weight, is between 1.03 and 2.06 w / w, more preferably between 1.16 and 1.89 w / w. Preferably, in step b), the temperature is between 30°C and 60°C. In step b), stirring is preferably maintained for at least 1 hour, during this time, precipitation of the compound of Formula VII is observed.

[0079] Preferably, in step b), at the end of the reaction, the temperature is brought to the range between 0°C and 25°C.

[0080] According to a preferred aspect, in step b), the compound of Formula VII is isolated, preferably by filtration .

[0081] Preferably, in step b), the compound of Formula VII is dried under vacuum.

[0082] In step b), the compound of Formula VII is preferably dried to a temperature of 30°C-60°C.

[0083] Preferably, in step b), the compound of Formula VII is dried for at least 6 hours.

[0084] According to a preferred aspect of the invention, in step b), the compound of Formula VII is dried under vacuum, at a temperature of 30°C-60°C, for at least 6 hours.

[0085] According to an aspect of the invention, the salt of the compound of Formula VII is selected from methanesulfonate, para-toluene sulfonate, trifluoromethanesulfonate, hydrochloride, hydrobromide, and trifluoroacetate.

[0086] At the end of step b) of the process according to the invention, it is possible to obtain a compound of Formula VII with a very low quantity of impurities. The impurities found in the compound of Formula VII obtained according to the process of the invention are listed in Table 4. With reference to step c) of the process according to the invention, such step refers to the reaction between the compound of Formula VII obtained in step b) and a reducing agent, in the presence of a catalyst, in a polar solvent, to obtain the compound of Formula I in the form of a base or a salt thereof.

[0087] According to a preferred aspect, in step c), the reducing agent is selected from formic acid, hydrogen, and ammonium formate, preferably the reducing agent is formic acid.

[0088] Preferably, in step c), the ratio between the reducing agent and the compound of Formula VII, calculated as weight on weight, is between 0.46 and 0.69 w / w, more preferably between 0.51 and 0.63 w / w.

[0089] In step c), the polar solvent is preferably selected from alcohols, ethers, water, or combinations thereof.

[0090] Preferably, in step c), the ratio between the polar solvent and the compound of Formula VII, calculated as volume on weight (v / w), is between 3.0 and 7.0, more preferably between 4.0 and 6.0.

[0091] According to a preferred aspect, in step c), the catalyst is selected from compounds comprising palladium and platinum, more preferably the catalyst is a compound comprising palladium.

[0092] Preferably, in step c), the ratio between the catalyst and the compound of Formula VII, calculated as weight on weight, is between 0.03 and 0.10 w / w, more preferably between 0.04 and 0.08 w / w.

[0093] Preferably, in step c), the temperature is between 10°C and the reflux temperature. According to a preferred aspect, step d) of isolating the compound of Formula I or a salt thereof comprises the following steps: d1) cooling the suspension to a temperature between 10°C and 30°C; d11) filtering the suspended solid on inert filtering material; d111) adjusting the pH with a base; dIV) filtering the compound of Formula I or a salt thereof; dv) drying the compound of Formula I or a salt thereof.

[0094] Preferably, in step d11), the inert filtering material is selected from diatomaceous earth, fossil flour, celite, dicalite, and cellulose, more preferably the inert filtering material is celite.

[0095] Preferably, in step d111), the base is selected from alkali metal hydroxides, alkali earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali earth metal bicarbonates, more preferably the base is sodium hydroxide.

[0096] According to a preferred aspect, in step d111), the pH is adjusted between 1.0 and 11.0 for isolating the compound of Formula I in the form of a salt, whereas the pH is adjusted between 11.0 and 13.5 for isolating the compound of Formula I as a free base.

[0097] In step dIV), the temperature is preferably between 0°C and 25°C, more preferably between 15°C and 25°C. According to a preferred aspect, in step dv), the compound of Formula I or a salt thereof is dried under vacuum. Preferably, in step dv), the drying temperature is between 40°C and 80°C, more preferably between 45°C and 60°C.

[0098] Preferably, in step dv), the compound of Formula I or a salt thereof is dried for at least 6 hours.

[0099] According to a preferred aspect, in step dv), the compound of Formula I is dried under vacuum, at a temperature of 40°C-80°C for at least 6 hours.

[0100] According to a preferred aspect, the salt of the compound of Formula I is selected from formate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, propionate, oxalate, and tartrate, preferably it is formate.

[0101] At the end of step d) of the process according to the invention, it is possible to obtain a compound of Formula I with a very low quantity of impurities. The impurities found in the compound of Formula I obtained according to the process of the invention are listed in Table 5.

[0102] In accordance with another preferred aspect of the invention, the compound of Formula IV is prepared according to the process described in the following Scheme 5:

[0103] With reference to step f) of the process according to the invention, such step refers to the reaction between the compound of Formula II and an oxidizing agent in an aprotic polar solvent to obtain a solution of the compound of Formula III.

[0104] According to a preferred aspect, in step f), the oxidizing agent is selected from peroxyacids, more preferably meta-chloroperbenzoic acid; oxidizing mixtures comprising an anhydride and a peroxide, more preferably a mixture of maleic anhydride and hydrogen peroxide-urea, and trifluoroacetic anhydride and hydrogen peroxide-urea, and oxidizing mixtures comprising a carboxylic acid and a peroxide, more preferably a mixture of acetic acid and hydrogen peroxide-urea .

[0105] Preferably, in step f), when the oxidizing agent comprises an anhydride, the ratio between the anhydride and the compound of Formula II, calculated as weight on weight, is between 0.80 and 1.08 w / w, preferably between 0.85 and 1.03 w / w.

[0106] Preferably, in step f), when the oxidizing agent comprises a peroxide, the ratio between the peroxide and the compound of Formula II, calculated as weight on weight, is between 0.76 and 1.03 w / w, more preferably between 0.81 and 1.00 w / w.

[0107] In step f), the aprotic polar solvent is preferably selected from chlorinated solvents, more preferably methylene chloride, nitriles, more preferably acetonitrile, and esters, more preferably isopropyl acetate.

[0108] Preferably, in step f), the ratio between the aprotic polar solvent and the compound of Formula II, calculated as volume on weight (v / w), is between 3.0 and 9.0 v / w, more preferably between 4.0 and 8.0 v / w. In step f), the temperature is preferably between 10°C and 60°C.

[0109] According to a preferred aspect, step f) comprises, at the end of the reaction, the following steps: f1) adding a reducing agent; f11) adjusting the pH to 7.5-8.5 with a base, obtaining a suspension; f111) filtering the suspension to obtain a clear biphasic mixture, said mixture comprising the compound of Formula III in the organic phase; fIV) separating the organic phase containing the compound of Formula III; fv) concentrating the organic phase; fVI) adding a solvent mixture comprising an organic solvent, to obtain a solution of the compound of Formula III.

[0110] Preferably, in step f1), the reducing agent is selected from sodium thiosulfate (Na2S2O3), potassium thiosulfate, sodium dithionite (Na2S2C>4), sodium sulfite (Na2SO3), manganese dioxide (MnCb), acidic ferrous sulfate solution, sodium iodide, potassium iodide, sodium bisulfite (NaHSO3), sodium metabisulfite (Na2S2O3), more preferably, the reducing agent is sodium thiosulfate .

[0111] Preferably, in step f1), the ratio between the reducing agent and the compound of Formula II, calculated as weight on weight, is between 0.72 and 0.98 w / w. Preferably, in step f1), the reducing agent is dissolved in water. In step f1), the temperature is preferably between 18°C and 22°C, and stirring is preferably maintained for 30 minutes. Preferably, in step f11), the base is selected from alkali metal hydroxides and alkali earth metal hydroxides, preferably the base is sodium hydroxide.

[0112] According to a preferred aspect, in step f11), the pH is between 7.5 and 8.5.

[0113] Preferably, in step f111), the suspension is filtered on an inert filtering material selected from diatomaceous earth, fossil flour, celite, dicalite, and cellulose, more preferably the inert filtering material is celite.

[0114] Preferably, in step fIV), from the biphasic mixture obtained in step f111), the organic phase containing the compound of Formula III is separated.

[0115] Preferably, in step fIV), the organic phase containing the compound of Formula III is washed with water.

[0116] According to a preferred aspect, in step fv), the organic phase containing the compound of Formula III is concentrated at atmospheric pressure to a final volume, calculated as volume on weight (v / w) with respect to the compound of Formula II, between 1.5 and 3.0. Preferably, in step fVI), the organic solvent is selected from apolar solvents, preferably toluene, aprotic polar solvents, preferably ethers, more preferably tetrahydrofuran, 2- methyltetrahydrofuran, nitriles, more preferably acetonitrile, amides, esters, water, or mixtures thereof.

[0117] Preferably, step fv) of concentrating the organic phase is repeated by distilling the solvent under vacuum to a final volume, calculated as volume on weight (v / w) with respect to the compound of Formula II, between 3.0 and 7.0, more preferably between 4.0 and 6.0. Preferably, in step fv), at the end of the concentration, water is added, preferably, the volume of added water, calculated as volume on weight (v / w) of the compound of Formula II, is between 1.0 and 2.0 v / w.

[0118] According to a preferred aspect, in step fVI), the compound of Formula III is dissolved in a mixture of tetrahydrofuran and water. The mixture of water- tetrahydrofuran has proven to be the best solvent for minimizing the formation of impurity 8 (see Table 2) in the subsequent step g) of the reaction between the compound of Formula III and a sulfonyl halide.

[0119] Preferably, in step fVI), the volume of tetrahydrofuran, calculated as volume on weight (v / w) of the compound of Formula II, is between 3.0 and 6.0; preferably, the volume of water, calculated as volume on weight of the compound of Formula II, is between 1.0 and 2.0 v / w.

[0120] With reference to step g) of the process according to the invention, such step refers to the reaction between the compound of Formula III in solution obtained in step f) and a sulfonyl halide, to obtain the compound of Formula IV.

[0121] According to a preferred aspect, in step g), the sulfonyl halide is selected from methanesulfonyl chloride and 4-toluenesulfonyl chloride.

[0122] Preferably, in step g), the ratio between the sulfonyl halide and the compound of Formula II, calculated as weight on weight, is between 0.93 and 1.27, more preferably between 1.00 and 1.21.

[0123] In step g), the temperature is preferably between

[0124] 30°C and 60°C. According to a preferred aspect, step g) comprises, at the end of the reaction, the following steps: g1) lowering the temperature; g11) adjusting the pH in the range of 6-7 with a base to obtain a suspension of the compound of Formula IV; g111) cooling the suspension; gIV) filtering the compound of Formula IV; gv) drying the compound of Formula IV.

[0125] Preferably, in step g1), the temperature is lowered to a temperature between 15°C and 25°C.

[0126] In step g11), the base is preferably selected from alkali metal hydroxides and alkali earth metal hydroxides, more preferably the base is sodium hydroxide.

[0127] Preferably, in step g11), the pH is between 6 and 7.

[0128] In step g111), the temperature is preferably between 0°C and 15°C.

[0129] Preferably, in step gv), the compound of Formula IV is dried under vacuum.

[0130] Preferably, in step gv), the drying temperature is between 25°C and 60°C, preferably between 30°C and 50°C.

[0131] Preferably, in step gv), the compound of Formula IV is dried for at least 6 hours.

[0132] According to a preferred aspect, in step gv), the compound of Formula IV is dried under vacuum, at a temperature of 25°C-60°C for at least 6 hours.

[0133] At the end of step g) of the process of the invention, it is possible to obtain a compound of Formula IV with a very low quantity of impurities. The impurities found in the compound of Formula IV obtained according to the process of the invention are listed in Table 2. According to a further aspect, the present invention relates to a process for preparing CGRP peptide receptor antagonist active pharmaceutical ingredients according to a process comprising: i) preparing the compound of Formula I according to the process of the invention; ii) using the compound of Formula I thus obtained to prepare a CGRP peptide receptor antagonist active ingredient. Step ii) can be performed according to what is known in the field for obtaining CGRP peptide receptor antagonist active ingredients. For example, reference can be made to what is described in W02005000807.

[0134] According to a preferred aspect of the invention, the compound of Formula I is used for preparing the compound of Formula XX according to the synthetic scheme 6 reported below:

[0135]

[0136] Scheme 6 According to a further aspect, the present invention relates to a process for preparing zavegepant (compound of Formula XX) or a salt or solvate thereof, which comprises: i) preparing the compound of Formula I by the process described above; ii) reacting the compound of Formula I with the compound of Formula X: Formula X in an aprotic polar solvent, in the presence of a base and a coupling agent, to prepare the compound of Formula

[0137] XI: Formula XI; iii) reacting the compound of Formula XI with an alkali metal hydroxide to obtain the compound of Formula XII-

[0138] Formula XII-A wherein M+is an alkali metal cation; iv) reacting the compound of Formula XII-A with an acid to obtain the compound of Formula XII: Formula XII; v) reacting the compound of Formula XII with the compound of Formula XIII: Formula XIII to obtain zavegepant (compound of Formula XX) or a salt or solvate thereof:

[0139] Formula XX

[0140] In order to prepare zavegepant starting from the compounds of Formula I and Formula X, reference can be made, for example, to what is described in WO2011123232. In accordance with a further aspect, the present invention relates to the intermediate of Formula VI: Formula VI

[0141] In accordance with a further aspect, the present invention relates to the compound of Formula I-A:

[0142] As illustrated above, the process being the subject of the present invention differs from the process reported in patent application W02023060255A1 (described on a positional isomer of the compound of Formula I) in the order in which the steps are carried out. The two procedures are schematized in the following Table 1:

[0143] Table 1.

[0144] By applying the procedure indicated in patent application W02023060255A1, the compound of Formula VI is reduced to obtain the compound of Formula VII-B, which is then deprotected to obtain the compound of Formula I.

[0145] From comparative experiments, several disadvantages have been detected in the use of the procedure according to W02023060255A1, including the low solubility of the compound of Formula VI, which required the identification of a suitable solvent for hydrogenation (2-methyltetrahydrofuran instead of methanol), and the use of a high solvent quantity (25 v / w instead of 5 v / w). The reaction was also significantly slower than the reduction according to the method of the invention (8.5 hours instead of 4), and less practical, since all steps had to be carried out at high temperature to prevent product precipitation. The compound of Formula I obtained according to the process of the present invention is further easily isolable by filtration, a technique widely used in industrial practice, and has a high purity that does not require further purifications, in particular it does not require chromatographic column purifications .

[0146] Furthermore, following the method reported in patent application W02023060255A1, the overall molar yield from the compound of Formula VI to the compound of Formula I is 55%, whereas when following the process of the present invention, the overall molar yield from the compound of Formula VI to the compound of Formula I is 86%.

[0147] EXAMPLES

[0148] Further details of the process according to the invention are reported below. In particular, the following exemplary embodiments are provided solely for the purpose of illustrating the present invention and should not be construed as limiting the scope of protection defined by the appended claims.

[0149] LIST OF ABBREVIATIONS

[0150] Vol: volumes w / w: ratio between the weights of two compounds v / w: ratio between the volume of a compound or a solvent and the weight of another compound THF: tetrahydrofuran

[0151] NMR: nuclear magnetic resonance spectroscopy

[0152] 13C-NMR: carbon nuclear magnetic resonance spectroscopy

[0153] 1H-NMR: hydrogen nuclear magnetic resonance spectroscopy s: singlet d: doublet m: multiplet

[0154] Example 1. Preparation of the compound of Formula IV.

[0155] The weight quantities of the reagents reported in Example 1 were parametrized with respect to the compound of Formula II, according to the following general formula:

[0156] Relative weight ratio of compound A = (weight of compound A / weight of compound of Formula II)

[0157] As an example, therefore, the calculation for compound A is reported:

[0158] Weight of loaded compound A: 10.5 kg.

[0159] Weight of loaded compound of Formula II: 10.0 kg .

[0160] Relative weight ratio of compound A = (10.5 / 10.0) = 1.05 w / w.

[0161] The volume quantities of the solvents reported in Example 1 were parametrized with respect to the compound of Formula II, according to the following general formula :

[0162] Relative volume-on-weight ratio of solvent B =

[0163] (volume of solvent B / weight of compound of Formula ID

[0164] As an example, therefore, the calculation for a generic solvent B is reported: Volume of loaded solvent B: 3.5 L

[0165] Weight of loaded compound of Formula II: 2.0 kg

[0166] Relative volume-on-weight ratio of solvent B = (3.5 / 2.0) = 1.75 v / w.

[0167] The end-of-distillation volume reported in Example 1 was parametrized with respect to the compound of Formula II, according to the following formula:

[0168] End-of-distillation volume = (volume of the solution in the reactor / weight of compound of Formula II)

[0169] A calculation example is reported:

[0170] Volume of solution contained in the reactor: 5.0 L

[0171] Weight of loaded compound of Formula II: 2.0 kg

[0172] End-of-distillation volume = (5.0 / 2.0) = 2.5 v / w.

[0173] In a reactor maintained under inert atmosphere with a nitrogen flow (reactor A), the compound of Formula II (1.00 w / w) and methylene chloride (6 v / w) were loaded, and stirring was maintained at a temperature of 20°C until dissolution. Maleic anhydride (0.94 w / w) was then loaded, and stirring was maintained until complete dissolution. Hydrogen peroxide-urea (0.90 w / w) was added to the solution, obtaining an orange suspension. The reaction mass was heated to a temperature of 40-50°C for at least 4 hours. An end-of-reaction control was performed, the compound of Formula II should preferably have been < 1.0%. If the result was negative, stirring was maintained at 40°C for 2 more hours. If the result was positive, the mass was cooled to 20°C. In reactor B, a solution of anhydrous Na2S20s (0.85 w / w) dissolved in 2.0 v / w of water was prepared. The solution prepared in reactor B was slowly loaded into the reactor A while maintaining the temperature of 20°C; at the end of the addition, stirring was maintained for 30 minutes at 20°C. A peroxide quantity control was performed; the value should preferably have been < 5 mg / L. If the result was negative, 0.5 v / w of a 30% Na2S20s aqueous solution (calculated in w / w) was loaded. If the result was positive, while maintaining the temperature at 20°C, a 30% NaOH solution (approximately 1.7 w / w) was slowly dripped until reaching a pH in the range of 7.5-8.5 and maintained in stirring for at least 30 minutes, obtaining a suspension. The suspended solid was filtered on celite at a temperature of 20°C, and the bed was washed with methylene chloride (1 v / w). The filtered solution, formed by two phases, was loaded into the reactor C. The lower organic phase, containing the product, was separated and sent to the reactor D, while the aqueous phase was sent to disposal. In reactor D, containing the organic phase, water (1 v / w) was loaded at the temperature of 20°C and stirring was maintained for at least 30 minutes. The lower organic phase, containing the compound of Formula III, was separated and sent to the reactor E, while the aqueous phase was sent to disposal. The organic phase was concentrated at atmospheric pressure, at reflux temperature of methylene chloride, until reaching a final volume of 2 v / w. THE (10 v / w) was loaded into the reactor, and the solution was concentrated under vacuum maintaining an internal temperature of 35-40°C until a final volume of 5 v / w. At the end of the distillation, water (1.5 v / w) was loaded. The solution was heated to a temperature of 35°C and methanesulfonyl chloride (1.10 w / w) was slowly added, allowing the temperature to rise to 40°-50°C. At the end of the addition, stirring was maintained for at least 1.5 hours at a temperature of 40°-50°C, obtaining a white suspension. An end-of-reaction control was performed: the compound of Formula ITT should preferably have been < 0.5%. If the result was negative, stirring was continued at 40-50°C for 1 more hour. If the result was positive, the reaction was cooled to 20°C and a 30% NaOH solution (approximately 1.9 w / w) was added until reaching a pH in the range of 6-7, and stirring was maintained for at least 30 minutes at a temperature of 20°-25°C. A suspension was obtained. The suspension was cooled to 10°C and stirring was maintained for at least 1 hour. The solid was filtered and the bed was washed three times with 2 v / w of a mixture of water:THF 1:1 pre-cooled to 10°C. The wet solid was dried under vacuum at a temperature of 35-40°C for 12 hours, obtaining the compound of Formula IV with a molar yield of 76% and a weight yield of 82%.

[0174] Table 2 shows the detected impurities.

[0175] Table 2. Main impurities related to the compound of

[0176] Formula IV.

[0177] Impurity 8.1H-NMR (300 MHz, DMSO-d6): 7.66-7.98 (m, 4H), 8.87 (s, 1H). Example 1-B. Effect of the solvent in the preparation of the compound of Formula IV.

[0178] During the reaction between the compound of Formula III and methanesulfonyl chloride, the formation of impurity 8 was noted in a significant quantity. Therefore, the effect of the reaction solvent was studied in order to minimize its formation. The study was carried out by evaluating the end-of-reaction controls. The results are summarized in Table 3.

[0179] Table 3.

[0180] As can be seen from Table 3, the mixture of water- tetrahydrofuran proves to be the best solvent for minimizing the formation of impurity 8.

[0181] Example 2. Preparation of the compound of Formula VII methanesulfonate salt.

[0182] The weight quantities of the reagents reported in Example

[0183] 2 were parametrized with respect to the compound of Formula IV, according to the following general formula:

[0184] Relative weight ratio of compound A = (weight of compound A / weight of compound of Formula IV)

[0185] As an example, therefore, the calculation for compound A is reported:

[0186] Weight of loaded compound A: 10.5 kg.

[0187] Weight of loaded compound of Formula IV: 10.0 kg .

[0188] Relative weight ratio of compound A = (10.5 / 10.0) = 1.05 w / w.

[0189] The weight quantities of the solvents reported in Example 2 were parametrized with respect to the compound of Formula IV, according to the following general formula : Relative weight ratio of solvent B =

[0190] (weight of solvent B / weight of compound of Formula IV)

[0191] As an example, therefore, the calculation for a generic solvent B is reported:

[0192] Weight of loaded solvent B: 3.5 kg

[0193] Weight of loaded compound of Formula IV: 2.0 kg

[0194] Relative weight ratio of solvent B = (3.5 / 2.0) = 1.75 w / w. The end-of-distillation volume reported in Example 2 was parametrized with respect to the weight of the loaded compound of Formula IV, according to the following general formula:

[0195] End-of-distillation volume = (volume of the solution in the reactor / weight of compound of Formula IV)

[0196] A calculation example is reported:

[0197] Volume of solution contained in the reactor: 5.0 L

[0198] Weight of loaded compound of Formula IV: 2.0 kg

[0199] End-of-distillation volume = (5.0 / 2.0) = 2.5 v / w.

[0200] In reactor A, maintained under inert atmosphere with a nitrogen flow (reactor A), the compound of Formula IV (1.00 w / w) and THF (5.75 v / w) were loaded at a temperature of 20°C, obtaining a suspension. A previously prepared solution of K2CO3 (1.24 w / w) dissolved in 4 v / w of water at a temperature of 20°C was loaded into the reactor A. Palladium acetate (0.010 w / w) and triphenylphosphine (0.023 w / w) were then loaded, obtaining a suspension. The reaction mass was heated to reflux. In reactor B, the compound of Formula V (1.45 w / w) and THF (5.75 v / w) were loaded and the temperature was increased to 30°C to obtain a complete solution. Over approximately 1.5 hours, the solution contained in the reactor B was loaded into reactor A while maintaining the reflux temperature. The reaction was maintained under stirring at reflux temperature (about 65°C) for at least 2 hours. At the end of the reaction, while maintaining the reflux temperature, a previously prepared solution of acetylcysteine (0.044 w / w) dissolved in 0.35 v / w of water was loaded into reactor A, and stirring was maintained for at least 1 hour. The suspension thus obtained was cooled to the temperature of 60°C and filtered on a celite bed, washing the bed twice with 2-methyltetrahydrofuran (1.0 v / w) preheated to a temperature of 60°C. The filtered biphasic solution was loaded into reactor C, the temperature was stabilized at 55°C, and the two phases were separated. The lower aqueous phase was sent to disposal, while the organic phase, containing the product, was concentrated at atmospheric pressure at an internal temperature of approximately 70°C to a final volume of 5 v / w. During distillation, partial product precipitation was observed. 2-methyltetrahydrofuran (10 v / w) was loaded into the reactor C, and the solution was concentrated at atmospheric pressure with an internal temperature of 70- 80°C until a final volume of 5 v / w. 2- methyltetrahydrofuran (12 v / w) was loaded into the reactor C, and the temperature was increased to reflux, about 80°C, obtaining an orange solution. The solution was cooled to a temperature of 65-70°C, water (1.5 v / w) was loaded into the reactor, and the biphasic solution was stirred for at least 30 minutes. It was noted that at a temperature <60°C the solution became turbid. The lower aqueous phase was separated and sent to disposal. In the reactor containing the organic phase, at a temperature of 65-70°C, a 30% sodium chloride aqueous solution (1.5 v / w) was loaded, and the biphasic solution was stirred for at least 30 minutes. It was noted that, at a temperature <60°C, the solution became turbid. The lower aqueous phase was separated and sent to disposal. A Dean-Stark distiller (or equivalent) was applied to the reactor, and the organic phase containing the compound of Formula VI was heated to reflux for at least 1 hour, during which the separation of water (which was sent to disposal) was noted. The control of KF < 2.0% was performed on the solution containing the compound of Formula VI. If the control was negative, distillation was continued. It was observed that, at a temperature below 60°C, the solution became turbid. The reaction was cooled to a temperature of 40-50°C. While maintaining the temperature of 40°-50°C, methanesulfonic acid (1.287 w / w) was loaded into the reactor. During the addition of methanesulfonic acid, exothermic behaviour and gas evolution were observed. At the end of the addition, stirring was maintained for at least 2 hours, obtaining a dense light-yellow suspension. At the end of the reaction, the suspension was cooled to a temperature of 20°C for at least 2 hours. The suspended solid was filtered, the bed was washed with 2- methyltetrahydrofuran (1.5 v / w). The solid was dried under vacuum at a temperature of 40-45°C for 12 hours, obtaining the compound of Formula VII methanesulfonate with a molar yield of 96% and a weight yield of 141%. Table 4 shows the main impurities detected.

[0201] Characterization of the compound of Formula VI:1H-NMR (300 MHz, DMSO): 1.41 (s, 9H), 2.47 (m, 2H), 3.50 (m,

[0202] 2H), 3.98 (s, 2H), 6.66 (s, 1H), 7.13 (m, 1H), 7.26 (d, 1H), 7.43 (d, 1H), 7.62 (d, 1H), 7.80 (s, 1H), 11.79 (s, 1H).13C-NMR (DMSO): 27.4, 28.5, 40.8, 43.9, 79.2, 114.9, 119.6, 122.2, 125.5, 128.3, 130.3, 131.7, 132.5, 135.5, 138.2, 154.3, 161.4. MS=326.16, M+l=327.1 m / z, M

[0203] Dimer=653.3 m / z (Figures 1-3).

[0204] Table 4. Main impurities of the compound of Formula VII.

[0205]

[0206] H

[0207] Example 3. Preparation of the compound of Formula I.

[0208] The weight quantities of the reagents reported in Example 3 were parametrized with respect to the methanesulfonate compound of Formula VII, according to the following general formula:

[0209] Relative weight ratio of compound A = (weight of compound A / weight of the methanesulfonate compound of Formula VII)

[0210] As an example, therefore, the calculation for compound A is reported:

[0211] Weight of loaded compound A: 10.5 kg.

[0212] Weight of loaded methanesulfonate compound of Formula VII: 10.0 kg.

[0213] Relative weight ratio of compound A = (10.5 / 10.0) = 1.05 w / w.

[0214] The volume quantities of the solvents reported in Example 3 were parametrized with respect to the methanesulfonate compound of Formula VII, according to the following general formula:

[0215] Relative weight ratio of solvent B =

[0216] (volume of solvent B / weight of the methanesulfonate compound of Formula VII)

[0217] As an example, therefore, the calculation for a generic solvent B is reported: Volume of loaded solvent B: 3.5 L

[0218] Weight of loaded methanesulfonate compound of Formula VII: 2.0 kg

[0219] Relative volume-on-weight ratio of solvent B = (3.5 / 2.0) = 1.75 v / w.

[0220] The end-of-distillation volume reported in Example 3 was parametrized with respect to the methanesulfonate compound of Formula VII, according to the following general formula:

[0221] End-of-distillation volume = (volume of the solution in the reactor / weight of the methanesulfonate compound of Formula VII)

[0222] An calculation example is reported:

[0223] Volume of solution contained in the reactor: 5.0 L

[0224] Weight of loaded methanesulfonate compound of Formula VII: 2.0 kg

[0225] End-of-distillation volume = (5.0 / 2.0) = 2.5 v / w.

[0226] In reactor A, being maintained under inert atmosphere with a nitrogen flow, the methanesulfonate compound of Formula VII (1.00 w / w) and water (5 v / w) were loaded, and stirring was maintained at a temperature of 20°C until complete dissolution. Pd / C 5% (50% wet, 0.05 w / w) was loaded into the reactor and the suspension was heated to reflux. While maintaining the reflux temperature, formic acid (0.572 w / w) was slowly loaded into the reactor. Gas development was observed, consisting of carbon monoxide, carbon dioxide, and hydrogen. At the end of the addition, stirring was maintained at reflux temperature for at least 2 hours. The end-of-reaction control was performed, the compound of Formula VII should preferably have been < 0.10%. If the result was negative, the reaction was stirred at reflux temperature for 1 hour. If the result was positive, the suspension was cooled to a temperature of 20°C, the suspended solid was filtered on a celite bed, and the bed was washed with water (1.0 v / w). 30% NaOH (approximately 1.8 w / w) was added to the filtered clear solution, maintained at a temperature of 20°C, until reaching pH=12.0-13.0. Stirring was maintained for at least 1 hour. The suspended solid was filtered at a temperature of 20°C and the bed was washed with water (1.0 v / w). The wet solid was dried under vacuum at a temperature of 50°-

[0227] 55°C for 12 hours until KF < 1.0%, obtaining the compound of Formula I with a molar yield of 86% and a weight yield of 59%.

[0228] Table 5 shows the main impurities detected.

[0229] Table 5. Main impurities of the compound of Formula I.

[0230] Example 3-B. Preparation of the compound of Formula I-A

[0231] (formate salt). Formula I-A The weight quantities of the reagents reported in Example 3-B were parametrized with respect to the methanesulfonate compound of Formula VII, according to the following general formula:

[0232] Relative weight ratio of compound A = (weight of compound A / weight of methanesulfonate compound of Formula VII)

[0233] As an example, therefore, the calculation for compound A is reported:

[0234] Weight of loaded compound A: 10.5 kg.

[0235] Weight of loaded methanesulfonate compound of Formula VII: 10.0 kg.

[0236] Relative weight ratio of compound A = (10.5 / 10.0) = 1.05 w / w.

[0237] The volume quantities of the solvents reported in Example 3-B were parametrized with respect to the weight of the methanesulfonate compound of Formula VII, according to the following general formula:

[0238] Relative volume-to-weight ratio of solvent B =

[0239] (volume of solvent B / weight of methanesulfonate compound of Formula VII)

[0240] As an example, therefore, the calculation for a generic solvent B is reported:

[0241] Volume of loaded solvent B: 3.5 L

[0242] Weight of loaded methanesulfonate compound of Formula VII: 2.0 kg

[0243] Relative volume-on-weight ratio of solvent B = (3.5 / 2.0) = 1.75 v / w.

[0244] The end-of-distillation volume reported in Example 3-B was parametrized with respect to the weight of the methanesulfonate compound of Formula VII, according to the following general formula: End-of-distillation volume = (volume of solution in the reactor / weight of methanesulfonate compound of Formula VII)

[0245] A calculation example is reported:

[0246] Volume of solution contained in the reactor: 5.0 L

[0247] Weight of loaded methanesulfonate compound of Formula VII: 2.0 kg

[0248] End-of-distillation volume = (5.0 / 2.0) = 2.5 v / w.

[0249] In reactor A, maintained under an inert atmosphere with a nitrogen flow, the methanesulfonate compound of Formula VII (1.00 w / w) and water (5 v / w) were loaded, and stirring was maintained at a temperature of 20°C until complete dissolution. Pd / C 5% (50% wet, 0.05 w / w) was loaded into the reactor, and the suspension was heated to reflux. While maintaining the reflux temperature, formic acid (0.572 w / w) was slowly loaded into the reactor. Gas development was observed, consisting of carbon monoxide, carbon dioxide, and hydrogen. At the end of the addition, stirring was maintained at reflux temperature for at least 2 hours. An end-of-reaction control was performed; the compound of Formula VII should preferably have been < 0.10%. If the result was negative, the reaction was maintained under stirring at reflux temperature for 1 hour. If the result was positive, the suspension was cooled to a temperature of 20°C, the suspended solid was filtered on a celite bed, and the bed was washed with water (1.0 v / w). 30% NaOH (approximately 1.8 w / w) was added to the filtered clear solution, at a temperature of 20°C, until reaching pH=9.5-10.5. The suspension was cooled to a temperature of 0°-5°C and stirring was maintained for at least 1 hour. The suspended solid was filtered, and the bed was washed with water previously cooled to a temperature of 0°-5°C (1.0 v / w). The wet solid was dried under vacuum at a temperature of 45°-50°C for 12 hours until KF < 1.0%, obtaining the compound of Formula I-A (formate salt) with a molar yield of 90% and a weight yield of 67%.

[0250] Characterization of the compound of Formula I-A:1H-NMR (300 MHz, DMSO): 1.70+1.92 (m+d, 4H), 2.87+3.26 (m+d, 4H), 2.97 (m, 1H), 5-7 (broad, 2.5H), 7.13 (m, 1H), 7.27 (d, 1H), 7.42 (m, 1H), 7.64 (d, 1H), 7.66 (s, 1H), 8.45 (s, 1H), 10-13 (broad, 0.5H).13C-NMR (DMSO): 28.7, 39.4, 44.2, 115.1, 119.7, 122.1, 128.0, 130.0, 134.4, 136.7, 138.0, 161.9, 166.6 (Figures 4-5).

[0251] Example 4. Preparation of the compound of Formula VII-B and of the compound of Formula according to the process described in WQ2023060255A1 (comparative example).

[0252] The weight quantities of the reagents reported in Example 4 were parametrized with respect to the compound of Formula VI, according to the following general formula:

[0253] Relative weight ratio of compound A = (weight of compound A / weight of the compound of Formula VI) As an example, therefore, the calculation for compound A is reported:

[0254] Loaded weight of compound A: 10.5 kg.

[0255] Loaded weight of the compound of Formula VI: 10.0 kg.

[0256] Relative weight ratio of compound A = (10.5 / 10.0) = 1.05 w / w. The volume quantities of the solvents reported in Example 4 were parametrized with respect to the weight of the compound of Formula VI, according to the following general formula:

[0257] Relative volume-to-weight ratio of solvent B =

[0258] (volume of solvent B / weight of the compound of Formula VI)

[0259] As an example, therefore, the calculation for a generic solvent B is reported:

[0260] Volume of loaded solvent B: 3.5 L

[0261] Weight of loaded compound of Formula VI: 2.0 kg

[0262] Relative volume-on-weight ratio of solvent B = (3.5 / 2.0) = 1.75 v / w.

[0263] The end-of-distillation volume reported in Example 4 was parametrized with respect to the weight of the compound of Formula VI, according to the following general formula:

[0264] End-of-distillation volume = (volume of the solution in the reactor / weight of the compound of Formula VI)

[0265] A calculation example is reported:

[0266] Volume of solution contained in the reactor:

[0267] 5.0 L

[0268] Weight of loaded compound of Formula VI: 2.0 kg

[0269] End-of-distillation volume = (5.0 / 2.0) = 2.5 v / w.

[0270] In the reactor, the compound of Formula VI (1.00 w / w), 2-methyltetrahydrofuran (25 v / w), and 5% Pd / C (50% wet, 0.05 w / w) were loaded and the suspension was heated to 66°C. The suspension was subjected to hydrogenation with H2 at a pressure of 1 atm for 8.5 hours. While maintaining the temperature at 66°C, the suspension was filtered on a celite bed. The filtered clear solution containing the compound of Formula VII-B was concentrated to a final volume of 5 v / w. The solution was cooled to room temperature and methanesulfonic acid (1.7 w / w) was slowly added. The reaction was heated to 45°C for 2 hours and then maintained under stirring at room temperature overnight. The suspension was cooled to a temperature of 0°-5°C and the suspended solid was filtered. The bed was washed with 1.5 v / w of 2-methyltetrahydrofuran. The wet product was dried under vacuum at 40°C, obtaining the compound of Formula I with a molar yield of 55%.

Claims

1. CLAIMS1. A process for preparing the compound of Formula IFormula I in the form of a base or a salt thereof, said process comprising the following steps: a) reacting the compound of Formula IVFormula IV with the compound of Formula VFormula V in an aprotic polar organic solvent, in the presence of a base, a catalyst comprising palladium, and a phosphine ligand to obtain a solution of the compound of FormulaBocFormula VI; b) reacting the compound of Formula VI in solution obtained in step a) with an acid to obtain the compound of Formula VII or a salt thereofFormula VII; c) reacting the compound of Formula VII obtained in step b) with a reducing agent, in the presence of a catalyst, in a polar solvent, to obtain the compound of Formula I in the form of a base or a salt thereof; d) isolating the compound of Formula I in the form of a base or a salt thereof.

2. Process according to claim 1, wherein in step a) the weight ratio between the compound of Formula V and the compound of Formula IV, calculated as weight on weight, is between 1.20 and 1.70 w / w, preferably between 1.30 and 1.60 w / w.

3. Process according to any one of the preceding claims, wherein in step a) the catalyst comprising palladium is selected from: organometallic compounds comprising Pd(II), preferably Pd(0Ac)2 (palladium (II)acetate) or Pd(dppf)C12 (bis(diphenylphosphino)ferrocene palladium (II) dichloride).

4. Process according to any one of the preceding claims, wherein in step a) the phosphine ligand is selected from monodentate and bidentate phosphine ligands, preferably it is triphenylphosphine.

5. Process according to any one of the preceding claims, wherein in step a), at the end of the reaction, the solution of the compound of Formula VI is obtained through a process comprising the following steps: a1) adding a palladium scavenger; a11) filtering the suspension on a bed of inert filtering material; a111) adding a water-immiscible organic solvent, obtaining a clear biphasic mixture; aIV) separating the organic phase containing the compound of Formula VI from the biphasic mixture obtained in step a111); av) concentrating the organic phase; aVI) washing the organic phase obtained in step av) with water; aVI1) anhydrifying the organic phase to obtain a solution of the compound of Formula VI.

6. Process according to claim 5, wherein in step a111) the water-immiscible organic solvent is selected from ethers, preferably it is 2-methyltetrahydrofuran.

7. Process according to any one of the preceding claims, wherein in step b) the acid is selected fromhydrohalic acids, trifluoroacetic acid, sulfonic acids, preferably methanesulfonic acid, trifluoromethanesulfonic acid, or para-toluenesulfonic acid.

8. Process according to any one of the preceding claims, wherein in step b) the compound of Formula VII is isolated, preferably by filtration.

9. Process according to any one of the preceding claims, wherein in step c) the reducing agent is selected from formic acid, hydrogen, and ammonium formate, preferably the reducing agent is formic acid.

10. Process according to any one of the preceding claims, wherein in step c) the catalyst is selected from compounds comprising palladium, and platinum, preferably the catalyst is a compound comprising palladium.

11. Process according to any one of the preceding claims, wherein step d) of isolating the compound of Formula I or a salt thereof comprises the following steps: d1) cooling the suspension to a temperature between 10°C and 30°C; d11) filtering the suspended solid on inert filtering material; d111) adjusting the pH with a base; dIV) filtering the compound of Formula I or a salt thereof; dv) drying the compound of Formula I or a salt thereof.

12. Process according to claim 11, wherein in step d111) the pH is adjusted between 1.0 and 11.0 for isolating the compound of Formula I in the form of a salt, while the pH is adjusted between 11.0 and 14.0 for isolating the compound of Formula I as a free base.

13. Process according to any one of the preceding claims, wherein the compound of Formula IVis prepared according to a process comprising the following steps: f) reacting a compound of Formula IIFormula II with an oxidizing agent in an aprotic polar solvent to obtain a solution of the compound of Formula IIIFormula III g) reacting the compound of Formula III in solution obtained in step f) with a sulfonyl halide to obtain the compound of Formula IV.

14. Process according to claim 13, wherein in step f) the oxidizing agent is selected from peroxyacids, preferably meta-chloroperbenzoic acid, oxidizingmixtures comprising an anhydride and a peroxide, preferably a mixture of maleic anhydride and hydrogen peroxide-urea, and trifluoroacetic anhydride and hydrogen peroxide-urea, and oxidizing mixtures comprising a carboxylic acid and a peroxide, preferably a mixture of acetic acid and hydrogen peroxide-urea.

15. Process according to claim 13 or 14, wherein step f) comprises, at the end of the reaction, the following steps: f1) adding a reducing agent; f11) adjusting the pH to 7.5-8.5 with a base obtaining a suspension; f111) filtering the suspension to obtain a clear biphasic mixture, said mixture comprising the compound of Formula III in the organic phase; fIV) separating the organic phase containing the compound of Formula III; fv) concentrating the organic phase; fVI) adding a solvent mixture comprising an organic solvent to obtain a solution of the compound of Formula III.

16. Process according to any one of claims 13-15, wherein in step fIV) the organic phase containing the compound of Formula III is separated from the biphasic mixture obtained in step f111).

17. Process according to any one of claims 13-16, wherein in step fVI) the compound of Formula III is dissolved in a mixture of tetrahydrofuran and water.

18. Process according to any one of claims 13-17, wherein in step g) the sulfonyl halide is selected from methanesulfonyl chloride and 4-toluenesulfonyl chloride.

19. Process according to any one of claims 13-18, wherein step g) comprises, at the end of the reaction, the following steps: g1) lowering the temperature; g11) adjusting the pH in the range of 6-7 with a base to obtain a suspension of the compound of Formula IV; g111) cooling the suspension; gIV) filtering the compound of Formula IV; gv) drying the compound of Formula IV.

20. Process for preparing a calcitonin gene-related peptide (CGRP) receptor antagonist active pharmaceutical ingredient comprising: i) preparing the compound of Formula I according to any one of the preceding claims; ii) using the compound of Formula I obtained in step i) to prepare a CGRP peptide receptor antagonist active ingredient .

21. Process for preparing zavegepant (compound of Formula XX) or a salt or solvate thereof, comprising: i) preparing the compound of Formula I according to any one of claims 1-19; ii) reacting the compound of Formula I with the compound of Formula X:Formula X in an aprotic polar solvent, in the presence of a base and a coupling agent to prepare the compound of FormulaFormula XI; iii) reacting the compound of Formula XI with an alkali metal hydroxide to obtain the compound of Formula XII-A:Formula XII-A wherein M+is an alkali metal cation; iv) reacting the compound of Formula XII-A with an acid to obtain the compound of Formula XII:Formula XII; v) reacting the compound of Formula XII with the compound of Formula XIII:

22. Compound of Formula VI:BocFormula VI23. Compound of Formula I-A:Formula I-A

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