Process for preparing venetoclax, and method for preparing an amorphous form of venetoclax

Abstract

A process for preparing Venetoclax, the compound of Formula I, or a salt or a solvate thereof (Formula I). The process allows to decrease the DMSO amount using a solvent mixture in compliance with the safety process requirements. Moreover, in step a) a certain percentage of DMSO in the reaction solvent mixture is necessary to obtain the desired degree of conversion and purity. The process of the present invention thus allows to combine process productivity with process safety, leading to compound VI with a very high overall yield and purity.

Description

[0001] PROCESS FOR PREPARING VENETOCLAX, AND METHOD FOR PREPARING AN AMORPHOUS FORM OF VENETOCLAX

[0002] Field of Invention

[0003] The present invention relates to an improved process for preparing the Active Pharmaceutical Ingredient (API ) Venetoclax on a large scale . The present invention also relates to a process intermediate characteri zed by high purity . Background of the invention

[0004] Venetoclax is an Active Pharmaceutical Ingredient (API ) commerciali zed under the name of Venclexta™ ( FDA approval on April 11th, 2016 ) or Venclyxto® (EMA approval on December 4th, 2016 ) . It is the first orally bio-available and highly selective inhibitor of BCL2 protein authori zed for chronic lymphocytic leukaemia ( LCC ) , small lymphocytic leukaemia ( SLL ) and acute myeloid leukaemia . Venetoclax, binding selectively to BCL2 proteins , restores apoptosis in tumour cells causing the tumour cells death . Moreover, its selectivity avoids causing thrombocytopenia, the main drawbacks of non-selective inhibitors of the same class .

[0005] Considering the therapeutic potential on Venetoclax, having a productive , sustainable and green process would be mandatory .

[0006] The most critical advanced intermediates of the process are shown below (herein after referred to as compounds o f Formula Vl-VIa ) .

[0007] The synthesis of these intermediates is known in the art. For example, US8546399B2 discloses the synthesis of compound of Formula Via involving two different synthetic steps (Scheme 1 below) . The first step is a nucleophilic aromatic substitution between compound of Formula II (electrophile) and compound of Formula III (nucleophile) to give compound of Formula IV. This first step is carried out at high temperatures in DMSO in the presence of K2HPO4, the reported synthesis is performed at 135°C in 13 volumes of DMSO (referred to compound of formula II) . Subsequently, the reaction of compound of Formula IV with NaOH in 1,4-dioxane gives the corresponding compound of Formula Via.

[0008] Scheme 1

[0009] However, the process of US8546399B2, with particular reference to the preparation of compound IV, has many drawbacks, including safety, toxicity issues and yield issues. As for safety issues, these are mainly related to the DMSO employed as solvent for the first reaction. Indeed, its high decomposition energy is known since 1950s. Pure DMSO thermal autocatalytic decomposition starts at its boiling point of 189°C. Moreover, the presence of certain classes of compounds, such as bases, can lower the onset temperature of the decomposition .

[0010] As for toxicity issues, these are mainly related to solvent toxicity, particularly 1,4-dioxane employed as solvent for the hydrolysis step. According to ICH guideline Q3C(R8) , 1,4-dioxane is a class 2 solvent, the use of which should be limited. Lastly, this process is characterized by a low overall yield and a difficult industrial scale-up.

[0011] In WO2014165044A1, the coupling step to obtain compound of Formula IV employs a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent. The starting raw material is a brominated analogue of compound of Formula II (shown below) .

[0012] The synthetic process to produce compound of Formula IV is different from that of US8546399B2, but it is also characterized by several drawbacks: inter alia, the use of air and moisture sensitive materials, the formation of undesired by-products, and a difficult scale-up. Moreover, the cost per gram of the bromo derivative of compound II is several hundred dollars greater than the corresponding aryl fluoride.

[0013] In view of the above, the use of solvent, in particular DMSO and specifically at high temperatures and in presence of a base, is to be considered a critical aspect. These conditions could lead to a thermal autocatalytic degradation of the solvent and, accordingly, a potential runaway scenario (see e.g. Yang, Q. , et al., Potential Explosion Hazards Associated with the Autocatalytic Thermal Decomposition of Dimethyl Sulfoxide and Its Mixtures. Org. Process Res. Dev. 2020, 24 (6) , 916-939; Deguchi, Y., et al., Study on Autocatalytic Decomposition of Dimethyl Sulfoxide (DMSO) III: Investigations Regarding the Main Decomposition. Org. Process Res. Dev. 2021, 25 (12) , 2669-2678) .

[0014] Indian patent IN396841B discloses a process in which a solution of Venetoclax in one or more solvents is provided, an anti-solvent is added, and finally the amorphous form is isolated. This process has several disadvantages, in particular compound of formula I crystallizes incorporating solvent which makes filtration slow, and the quantity of solvent that remains in the product is over the limit of the ICH guideline. Furthermore, the yield of the process to obtain the amorphous form is about 90%, therefore the process costs are high.

[0015] For all the reasons above, there is a strong need to develop an industrially feasible and easier process for producing Venetoclax in amorphous form.

[0016] Summary of the invention

[0017] The Applicant has now found a process for the preparation of the API Venetoclax, as defined in claim 1, which overcomes the problems of the prior art, and which represents a process that can be easily and efficiently implemented on an industrial scale.

[0018] Therefore, according to a first aspect, the present invention concerns a process for preparing Venetoclax, the compound of Formula I, or a salt or a solvate thereof

[0019] Formula I the process comprising the following steps: a) reacting a compound of Formula II Formula II with a compound of Formula III or a salt thereof Formula III in the presence of an organic base and in a mixture of solvents, wherein said mixture of solvents comprises acetonitrile (ACN) and dimethylsulfoxide (DMSO) , under heating, to obtain compound of Formula IV Formula IV wherein said compound of Formula IV is obtained in a solution with at least one organic solvent; b) reacting the compound of Formula IV in the solution obtained in step a) , with an alkali metal or alkaline earth metal hydroxide and at least one alcohol , to obtain a compound of Formula V Formula V wherein : Mn+is a cation of an alkali metal or alkaline earth metal , n is 1 or 2 , and n=n' ; c ) isolating the compound of Formula V; d) preparing a solution of the compound of Formula V in a biphasic mixture of solvents , wherein said mixture comprises water and at least one organic solvent immiscible with water, and adding an organic inorganic acid until reaching a pH value of from 5 . 5 to 7 . 5 , to obtain, after separation of the aqueous phase , an organic solution of the compound of Formula

[0020] Via ormula Via in the solution obtained in step d) with an organic inorganic acid, to obtain the compound of Formula VI Formula VI wherein X is selected from the group comprising an anion of an organic acid selected from: acetic acid, citric acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid, and an anion of an inorganic acid selected from: HC1, HBr, HF, H2SO4 and H3PO4; and f) reacting the compound of Formula VI obtained in step e) with the compound of Formula VII Formula VII in the presence of an activating agent, a catalyst and a base, in an organic solvent, to obtain the compound of Formula I, or a salt or a solvate thereof.

[0021] The process of the present invention allows to decrease the DMSO amount using a solvent mixture in compliance with the safety process requirements. Indeed, step a) is performed under heating, preferably at a temperature of from 60°C to 105°C, more preferably at the reflux temperature of the reaction solvent mixture, i.e. 80°-105°C, which is lower than that of the above mentioned prior art (US8546399B2 ) . The TD24 (temperature at which the time to maximum rate is 24 hours) for the employed solvent mixture resulted to be 125°C, therefore at the reflux temperature as indicated above the process is safe: no industrial malfunction can lead to temperatures higher than the reflux temperature, which is well under the TD24 value.

[0022] Moreover, the inventors have found that in step a) a certain percentage of DMSO in the reaction solvent mixture is necessary to obtain the desired degree of conversion and purity : the process of the present invention thus allows to combine process productivity with process safety, leading to compound VI with a very high overall yield and purity . The compound of Formula VI is a crucial intermediate of the multistep synthesis according to the present invention : a higher isolated yield means a greener and more ef ficient process , resulting also in a huge economical advantage .

[0023] In step a ) of the process according to the present invention, the compound of Formula IV is obtained in solution, without the need of isolating it . This also allows a remarkable increase in the overall yield of the process , at the same time rendering it more ef ficient .

[0024] The presence of both an acid and a basic functional group in the structure of compound VI ( shown below) potentially allows to isolate three di f ferent forms : acid salt ( compound of Formula VI ) , basic salt ( compound of Formula V) , and zwitterionic species ( compound of Formula Vi a ) .

[0025] The process according to the present invention allows to isolate the compound of Formula VI , and in particular the compound of Formula VIb (hydrochloride salt ) , with high yield and purity through an innovative approach passing through the zwitterionic form Via . This approach leads to a higher purity compared with that of the prior art and compared to that obtainable via a simple precipitation from the reaction mixture as hydrochloride salt .

[0026] In accordance with a further aspect , the present invention relates to the intermediate VI with high purity as defined in the appended claims .

[0027] In accordance with a further aspect , the present invention relates to a process for preparing a compound of Formula I in amorphous form, said process comprising : i ) dissolving the compound of Formula I , or a solvate thereof , in a solvent mixture comprising an organic acid and an organic base , under heating; ii ) adding the solution obtained in step i ) to water, under heating, and stirring until formation of a solid precipitate ; and iii ) isolating the compound of Formula I in amorphous form .

[0028] Further aspects , features and advantages of the invention will become apparent from the following detailed description .

[0029] Brief description of the figures

[0030] Figure 1 shows a HPLC chromatogram of the compound of Formula VIb prepared according to the present invention .

[0031] Figure 2 shows a XRPD spectrum of the compound of Formula I in amorphous form prepared according to the present invention .

[0032] Detailed description In the following description and claims, definitions of numerical ranges comprise the single values within the range itself and the corresponding endpoints, unless otherwise specified.

[0033] In the following description and claims, the term "comprising" also includes the terms "consisting of" or "consisting essentially of".

[0034] In a preferred embodiment of the process according to the present invention, in step a) the organic base is selected from DBU and DBN, preferably said organic base is DBU.

[0035] Preferably, the molar ratio between the organic base and the compound of Formula II is of from 3.5 to 4.5, more preferably of from 3.7 to 4.0. The use of an organic base is necessary to obtain a complete dissolution of the base in the DMSO / ACN mixture.

[0036] In a preferred embodiment of the process according to the present invention, in step a) said mixture of solvents essentially consists of ACN and DMSO, even more preferably said mixture of solvents consists of ACN and DMSO.

[0037] According to a preferred embodiment of the process of the present invention, in step a) the ratio between ACN and DMSO, calculated in volume / volume (v / v) , is of from 9:1 to 6:4 v / v, preferably of from 8:2 to 7:3 v / v. Indeed, the Inventors have found that the higher the DMSO percentage the higher was the conversion, leading however to a lower HPLC purity. The preferred ratios above proved to be those able to provide the best balance between conversion and purity.

[0038] According to a preferred embodiment the ratio between the solvent mixture and the compound of Formula II, calculated in volume / weight (v / w) is of from 5 to 7 v / w, preferably 6 (v / w) .

[0039] Indeed, the inventors have found that the concentration heavily affects the reaction of step a) : using less than 5 volumes of solvent, with respect to the compound of Formula II, negatively affects miscibility of the reaction mass. On the other hand, a higher amount has a detrimental impact on the reaction kinetics.

[0040] According to a preferred embodiment, in step a) the molar ratio between the compound of Formula III and the compound of Formula II is between 1.10 and 1.55, preferably the molar ratio between the compound of Formula III and the compound of Formula II is between 1.20-1.45, more preferably is between 1.25-1.40.

[0041] Advantageously, in the step a) of the process of the present invention the reaction is carried out under heating, preferably at a temperature of from 60°C to 105°C, more preferably 80-105°C (such latter range herein also referred to as reflux temperature) . According to a preferred embodiment, the reaction is carried out at the reflux temperature of the solvent mixture. It is to be noted that the reflux temperature of the mixture is directly linked to the amount of DMSO used and the ratio between ACN and DMSO. For a mixture comprising AON and DMSO in a ratio of from 9:1 to 6:4 v / v, the reflux temperature is between 80°-105°C, therefore in step a) the reaction is preferably carried out at a temperature of 80°- 105°C.

[0042] In a preferred embodiment of the process according to the present invention, in step a) the compound of Formula III is in the form of a salt.

[0043] In a particular preferred embodiment of the process according to the present invention, in step a) the compound of Formula III is a hydrogen halide salt. Preferably, the hydrogen halide salt is a hydrochloride or a hydrobromide salt, even more preferably a hydrochloride salt. In a particularly preferred embodiment, said compound of Formula III is a bishydrochloride salt. In a preferred embodiment , in step a ) the reaction mixture is kept under stirring and heating until substantial conversion of compound of Formula I I to compound of Formula IV, e . g . for a time between 15 and 30 hours , more preferably between 18 and 24 hours , even more preferably between 20 and 22 hours .

[0044] Preferably, according to the present invention, in step a ) the at least one organic solvent forming the solution of the compound of Formula IV is an ether, preferably selected from CPME , THF and Me-THF . Preferably, said solution is obtained by : a ' ) adding water and at least one polar solvent not miscible with water to the reaction mixture containing the compound of Formula IV, to obtain a biphasic mixture ; a ' ' ) separating the two phases of the biphasic mixture to obtain the compound of Formula IV in the organic phase .

[0045] Preferably, said polar solvent not miscible with water is selected from : ethers not miscible with water, preferably Me-THF; chlorinated solvents , preferably dichloromethane ; esters not miscible with water, preferably ethyl acetate . Me- THF is particularly preferred . In case the polar solvent not miscible with water is an ether, such as Me-THF, the organic phase containing the compound of Formula IV may be the solution suitable for carrying out step b ) . Otherwise , when the polar solvent not miscible with water is not an ether, e . g . a chlorinated solvent or an ester not miscible with water, after separation of the two phases the organic phase is distilled and the obtained residue containing the compound of Formula IV is then dissolved in an ether, preferably CPME , THF or Me-THF .

[0046] Preferably, in step a ) the compound of formula IV is obtained in a solution without isolating it .

[0047] According to a preferred embodiment of the process of the present invention, in step b ) the alcohol is selected from MeOH, EtOH, and IPA. Preferably the alcohol is MeOH .

[0048] According to particularly preferred embodiments of the process of the present invention, step b ) is carried out by reacting the compound of Formula IV in an ether solution, wherein the ether is preferably selected from Me-THF, CPME and THE, with an alkali metal or alkaline earth metal hydroxide and an alcohol selected from MeOH, EtOH, IPA, preferably MeOH .

[0049] Therefore , in said embodiments , the solvent mixture o f step b ) is preferably MeOH / Me-THF or MeOH / THF which is an excellent replacement of 1 , 4-dioxane used in the prior art , which should be avoided due to its toxicity, allowing the reali zation of a telescoping procedure in which compound of Formula IV is no longer isolated . The telescoping procedure from compound of Formula I I to compound of Formula V has the remarkable ef fect to overcome the prior art issue concerning the residual DMSO content in the isolated compound of Formula IV, which af fects the subsequent hydrolysis reaction .

[0050] Preferably, in step b ) the alkal i metal or alkaline earth metal hydroxide is in an aqueous solution .

[0051] When an alkaline earth metal hydroxide is used, compound of Formula V' is obtained : wherein the cation M2+is preferably selected from beryllium (Be2+) , magnesium (Mg2+) , and calcium ( Ca2+) . When an alkali metal hydroxide is used, compound of Formula

[0052] V' ' is obtained: wherein the cation M+ is preferably selected from lithium (Li+) , sodium (Na+) , potassium (K+) , and caesium (Cs+) .

[0053] In a particularly preferred embodiment, in step b) NaOH is used and the compound obtained is the compound of Formula Formula Va. According to a preferred embodiment of the process of the present invention, in step b) the reaction is carried out at a temperature of from 50°C to 80°C, preferably of from 60°C to 70°C, for example at about 65°C. Preferably, the reaction mixture is kept under stirring until substantial conversion of compound of Formula IV to compound of Formula V, e.g. for about 3 hours .

[0054] The isolation of compound of Formula V in step c) can be carried out according to techniques known to those skilled in the art. In a preferred embodiment, in step c) the compound of Formula V is crystallized from the reaction mixture after replacing, by distillation, the solvent mixture of step b) with ACN, which is a suitable solvent to precipitate compound of Formula V and completely purge the residual starting material, i.e. compound of Formula III.

[0055] According to a preferred embodiment of the process of the present invention, in step d) the at least one organic solvent immiscible with water is Me-THF. Thus, preferably, said compound of Formula Via is obtained in a Me-THF solution.

[0056] According to a preferred embodiment of the process of the present invention, in the step d) if an organic acid is used, it is selected from acetic acid, citric acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid, and if an inorganic acid is used, it is selected from HC1, HBr, HF, H2SO4 and H3PO4. Preferably, in step d) the compound of Formula V is reacted with an inorganic acid, preferably HC1.

[0057] Preferably, in step d) said organic or inorganic acid is added until reaching a pH value of from 5.5 to 7.5, preferably about 6.5.

[0058] Preferably, in step d) the compound of Formula V is solubilized in water and Me-THF is added to obtain a biphasic system. In a particularly preferred embodiment, compound of Formula V is converted to its zwitterionic form (Via) by adjusting the pH of the reaction mixture to a value of from 5.5 to 7.5, preferably 6.5, by adding the acid, preferably HC1. This procedure allows to transfer the zwitterionic specie in the organic phase while the salt remains in water.

[0059] Preferably, in step d) the reaction is carried out at a temperature of from 15°C to 35°C, more preferably at a temperature of from 18°C to 25°C, for example at about 18°C. According to a preferred embodiment of the process of the present invention, in step e) the acid is an inorganic acid. Advantageously, said inorganic acid is preferably selected from HCI, HBr, HF, H2SO4and H3PO4.

[0060] According to a preferred embodiment, in step e) the acid is HC1 and the compound obtained is the compound of Formula VIb. Formula VIb.

[0061] In a particularly preferred embodiment of the process of the present invention, in step e) the reaction is carried out at a temperature between 50°-60°C, for example at about 55°C. Typically, the reaction mixture is kept under stirring until substantial conversion of compound of Formula Via to compound of Formula VI, e.g. for about 60 minutes.

[0062] Compound VI can then be isolated from the reaction mixture via techniques known to those skilled in the art, e.g. via filtration of the solid and subsequent drying under vacuum.

[0063] At the end of step e) of the process of the invention, it is possible to obtain compound of Formula VI with a very low amount of impurities. Two of the impurities found in the compound of Formula VI are shown below:

[0064]

[0065] VIII IX

[0066] LC-MS analysis confirmed that compounds of Formulae IX, and VIII are related to the hydrolysis of by-products formed from DBU and compound of Formula II, i.e. compounds of Formulae X and XI, shown below:

[0067] X XI

[0068] Indeed, during the hydrolysis of step b) , the compound

[0069] X is converted into compound VIII while compound XI is converted into compound IX. To the best of Applicant's knowledge, the compounds of

[0070] Formulae IX, X and XI have never been reported in the art. Moreover, the amount of these compounds of Formulae IX-XI was shown to increase as the DBU equivalents increased.

[0071] The amount of compound of Formula IX has to be carefully limited because it is subject to react in step f) to give an impurity which can affect the quality of the compound of

[0072] Formula I (see Scheme 2 below) .

[0073] IX XII

[0074] Scheme 2

[0075] According to a preferred embodiment, the process of the present invention further comprises, after step e) and before step f ) , an additional step e' ) wherein the compound of Formula VI is further purified. Said purification can be preferably performed adding the compound of Formula VI obtained in step e) to a solvent mixture comprising acid acetic and an organic solvent, water, or a mixture thereof, then stirring the mixture, optionally heating, and then filtering off the purified compound of Formula VI. Preferably, the purified compound of Formula VI is dried under vacuum.

[0076] Preferably, said solvent mixture comprises AcOH and an organic solvent selected from ethers and alcohols, among the ethers, Me-THF is preferred. In said preferred embodiment the ratio between AcOH and Me-THF, calculated in volume / volume (v / v) , is of from 1:1 to 8:2 v / v, preferably of from 6.5:3.5 to 7.5: 2.5 v / v, and the ratio between the solvent mixture and the compound of Formula VI, calculated in volume / weight (v / w) is of from 4 to 8 v / w, preferably is from 5 to 7 (v / w) .

[0077] Preferably, said step e' ) is carried out by heating the mixture at a temperature of from 50°C to 60°C, e.g. about 55°C, for a time of e.g. about 60 minutes.

[0078] In a preferred embodiment, in said step e' ) the purified compound of formula VI is filtered off at a temperature of from 40°C to 60°C.

[0079] In a particularly preferred embodiment, the process further comprises, after step e' ) , a step e' ' ) of providing a slurry of compound of Formula VI in an organic solvent selected from ethers, ketones, alcohols, DCM, and ACN. Preferably said organic solvent is Me-THF. Indeed, to completely remove the residual acetic acid a very long drying process is needed, thus providing a slurry in an organic solvent, e.g. in 5 volumes of said organic solvent, allows to drastically reduce the drying time. Preferably, said organic solvent is Me-THF.

[0080] According to a preferred embodiment of the process of the present invention, step f) is carried out following known prior art techniques. For example, the compound of Formula VI can be reacted with the compound of Formula VII in the presence of l-ethyl-3- ( 3-dimethylaminopropyl ) carbodiimide hydrochloride as activating agent, 4-dimethylaminopyridine as catalyst, and triethylamine as base, in DCM. Those of ordinary skill in the art will be able to select other suitable activating agents, catalysts, bases and solvents to implement this step according to the common general knowledge and the known prior art.

[0081] Advantageously, step f) can be carried out at room temperature, stirring until substantial conversion of the compound of Formula VI into compound of Formula I.

[0082] Advantageously, the compound of Formula I can be isolated using techniques known in the art, such as for example by recrystallization with suitable solvents. According to a preferred embodiment, the compound of Formula I is isolated as a THF-solvate.

[0083] A preferred embodiment of the process according to the present invention is reported in the following Schemes 3 and 4.

[0084]

[0085] Scheme 4

[0086] As regards the further aspect of the present invention relating to a process for preparing Venetoclax in amorphous form, the following are preferred features.

[0087] Preferably, in step i) said organic acid is selected from: acetic acid, formic acid, propionic acid, and trifluoroacetic acid. Preferably, in step i) said organic base is selected from: TEA, DIPEA, N-Methylmorpholine, ethanolamine, di-ethanolamine, and triethanolamine.

[0088] In a preferred embodiment, in step i) the organic base and the organic acid are in equimolar ratio.

[0089] In a preferred embodiment, in step i) the ratio between the solvent mixture and the compound of Formula I, calculated in volume / weight (v / w) , is of from 3 to 7 v / w, preferably the ratio is of from 4 to 6 (v / w) .

[0090] In a preferred embodiment, in step i) the temperature of heating is between 20°C and 70°C.

[0091] According to a preferred embodiment, in step ii) the ratio between the water and solvent mixture used in step i) , calculated in volume / volume (v / v) , is of from 1 to 4 v / v.

[0092] Preferably, in step ii) the temperature of heating is between 20°C and 50°C.

[0093] Preferably, in step iii) the isolation is carried out by filtration. Such filtration is simple and fast and the compound of Formula I does not retain solvents, in this way a very efficient purge of impurities is obtained and the purity of the compound of formula I is particularly high.

[0094] More preferably, after the step iii) the compound of Formula I is dried under vacuum.

[0095] In preferred embodiments, after the step iii) the compound of Formula I is dried at a temperature between 20°C and 80°C, preferably 40°C and 70°C.

[0096] The compound of Formula I is obtained with a quantitative yield (98-99%) , therefore the process of the present invention is very efficient and particularly suitable for use on an industrial scale. The compound of Formula I , obtained in amorphous form as described in the present invention, has chemical-physical properties such as solubility, dissolution rate and purity, resulting particularly suitable for pharmaceutical formulations .

[0097] In accordance with a further aspect , the present invention relates to a compound of Formula VIb Formula VIb comprising an amount of a compound of Formula IX equal to or lower than 0 . 9% in HPLC area % measured at 220 nm, and an amount of a compound of Formula VI I I equal to or lower than 0 . 15% in HPLC area % measured at 220 nm, wherein the Formulas VI I I and IX are the following :

[0098] Formula VIII Formula IX Said determination can be conveniently carried out using the analytical method described in detail in example 10 .

[0099] In a further preferred embodiment said compound of Formula VIb comprises an amount of the compound of Formula IX equal to or lower than 0 . 4 % in HPLC area % measured at 220 nm, and an amount of the compound of Formula VIII equal to or lower than 0.10% in HPLC area % measured at 220 nm.

[0100] EXAMPLES

[0101] Abbreviation list

[0102] ACN acetonitrile

[0103] AcOH acetic acid

[0104] API Active Pharmaceutical Ingredient

[0105] ARC Accelerating Rate Calorimetry

[0106] CPME cyclopentyl methyl ether

[0107] DBN l,5-diazabicyclo[4.3.0] non-5-ene

[0108] DBU l,8-diazabicyclo[5.4.0] undec-7-ene

[0109] DCM dichloromethane

[0110] DMSO dimethyl sulfoxide

[0111] EtOH ethanol

[0112] FDA Food & Drug Administration

[0113] HPLC High Performance Liquid Chromatography

[0114] HCL Hydrochloric acid

[0115] HBr Hydrobromic acid

[0116] HF Hydrofluoric acid

[0117] H2SO4 Sulfuric acid

[0118] H3PO4 Phosphoric acid

[0119] IPA isopropyl alcohol

[0120] MeOH methanol

[0121] EtOH Ethanol

[0122] Me-THF 2-methyl tetrahydrofuran

[0123] MTBE methyl tertbutyl ether

[0124] TD24 Temperature at which the time to maximum rate is 24 hours

[0125] ARC Accelerating Rate Calorimetry

[0126] THE tetrahydrofuran

[0127] USD Unite States Dollar

[0128] DIPEA N, N-Diisopropylethylamine

[0129] TEA triethylamine EDC*HC1 l-ethyl-3- ( 3-dimethylaminopropyl ) carbodiimide hydrochloride

[0130] DMAP 4-dimethylaminopyridine

[0131] RT retention time

[0132] RRT relative retention time

[0133] NaOH Sodium hydroxide

[0134] KOH Potassium hydroxide

[0135] Example la. Preparation of compound of Formula Va according to the present invention.

[0136] In a reactor equipped with bubble cooler and mechanical stirrer, 23.0 g of compound of Formula II, 42.3 g of compound of Formula III, 96.6 ml of ACN, 41.4 ml of DMSO and 47.09 g of DBU were charged. The mechanical stirring was activated, and the reaction mixture was heated to reflux for 21.5 hours to obtain compound of Formula IV.

[0137] The temperature was cooled down to 40°C, 230 ml of Me- THF and 115 ml of H2O were added, then the mixture was stirred at a temperature of 40°C for 15 minutes and the two phases were separated.

[0138] The organic phase was re-charged in the reactor and, maintaining the temperature of 40°C, 115 ml of H2O were added; the stirring was continued for 15 minutes. The two phases were then separated.

[0139] The organic phase, containing compound of Formula IV in Me-THF, was concentrated under vacuum maintaining the temperature below 40°C to a final volume of 184 ml.

[0140] Maintaining the temperature of 40°C, 46.0 ml of MeOH and 26.8 g of NaOH 30% were added to the reaction mixture. The temperature was increased to 65°C and the stirring was maintained for 3 hours to obtain compound of Formula Va.

[0141] Maintaining the temperature below 40°C, the reaction mixture was concentrated under vacuum to a final volume of 184 ml, then 138 ml of ACN were added and the reaction mixture was concentrated again under vacuum to a final volume of 184 ml. The cycle of addition of ACN and concentration of the reaction mixture was repeated 2 more times. The stirring was maintained for at least 1.5 hour at the temperature of 40°C; during that time the compound of Formula Va precipitated from the reaction mixture .

[0142] The product was filtered under vacuum and the panel was washed with ACN. The product was dried for 12 hours under vacuum at the temperature of 45°C. 51.0 g of the compound of Formula Va were obtained (molar yield 75-80%) .

[0143] Example lb. Preparation of compound of Formula Va according to the present invention.

[0144] In a reactor equipped with bubble cooler and mechanical stirrer, 23.0 g of compound of Formula II, 42.3 g of compound of Formula III, 96.6 ml of ACN, 41.4 ml of DMSO and 47.09 g of DBU were charged. The mechanical stirring was activated, and the reaction mixture was heated to reflux for 21.5 hours to obtain compound of Formula IV.

[0145] The temperature was cooled down to 30°C, 230 ml of DCM and 115 ml of H2O were added, then the mixture was stirred at 30 °C for 15 minutes. The two phases were separated.

[0146] The organic phase was re-charged in the reactor and, maintaining the temperature of 30°C, 115 ml of H2O were added; the stirring was continued for 15 minutes. The two phases were then separated.

[0147] The organic phase, containing compound of Formula IV in DCM, was concentrated under vacuum, maintaining the temperature below 35°C, to a final volume of 115 ml. Maintaining the temperature of 35°C, 184 ml of THF were charged and the mixture was concentrated under vacuum to a final volume of 184 ml. The cycle of addition of THF and concentration of the reaction mixture was repeated 2 more times to obtain a final solution of compound of Formula IV in THF. Maintaining the temperature of 40°C, 46.0 ml of MeOH and 26.8 g of NaOH 30% were added to the reaction mixture. The temperature was increased to 65°C and the stirring was maintained for 3 hours to obtain compound of Formula Va.

[0148] Maintaining the temperature below 40°C, the reaction mixture was concentrated under vacuum to a final volume of 184 ml, then 138 ml of ACN were added and the reaction mixture was concentrated again under vacuum to a final volume of 184 ml. The cycle of addition of ACN and concentration of the reaction mixture was repeated two more times. The stirring was maintained for at least 1.5 hour at the temperature of 40°C. During that time the compound of Formula Va precipitated from the reaction mixture.

[0149] The product was filtered under vacuum and the panel was washed with ACN. The product was dried for 12 hours under vacuum at the temperature of 45°C. 49.0 g of the compound of Formula Va were obtained (molar yield 75-80%) .

[0150] Example 1c. Preparation of the compound of Formula TV, comparative experiment

[0151] As a comparative experiment, the procedure disclosed in US8546399B2 has been tested. In order to better compare the yield and purity of the product obtained with the US8546399B2 procedure and that of the present invention (Examples la-lb above) , the purification step disclosed in the prior art, i.e. column chromatography, has been replaced by a crystallization. The procedure was also tested with reduced volumes, i.e. 10 vol and 6.5 vol, however no increase in yield nor purity was observed. Finally, although it has been demonstrated that a small percentage of residual DMSO can be tolerated during the subsequent hydrolysis step, the amount of DMSO retained by the solid after the precipitation was so high to prove detrimental, thus a further consecutive slurring of isolated compound of Formula IV was introduced to reduce the DMSO content. In a reactor equipped with bubble cooler and mechanical stirrer, 476 g of compound of Formula II, 831.4 g of compound of Formula III, 1135.8 g of K2HPO4 and 6071 ml of DMSO were charged. The mechanical stirring was activated and the reaction mixture was heated at a temperature of 110°C for 16 h. During that time, the inorganic salts precipitated from the reaction mixture. The temperature was cooled down to 30°C, the suspension was filtered and the panel was washed with DMSO. The solid (inorganic salts) was sent for disposal.

[0152] In a reactor equipped with mechanical stirrer, 14944 ml of H2O was charged and the temperature was cooled to 3°C. The previously filtered solution was added slowly under stirring onto the cooled water over a period of between 40 and 90 minutes maintaining the temperature below 5°C. The mixture was maintained under stirring at a temperature of 3°C for 1 hour. The suspension was filtered and then the panel was washed with H2O obtaining crude compound of Formula IV.

[0153] The wet solid was loaded in a reactor equipped with mechanical stirrer and 18680 ml of H2O was added. The mixture was heated at a temperature of 50°C and maintained under stirring at these conditions for 60 minutes. The temperature was cooled down to 30°C, the suspension was filtered and then the panel was washed with H2O. The product was dried under vacuum at the temperature of 55°C. 871.0 g of the compound of Formula IV were obtained.

[0154] Example 2. Preparation of compound of Formula VIb according to the present invention

[0155] In a reactor equipped with bubble cooler and mechanical stirrer 50 g of compound of Formula Va, as obtained in Example la or lb, 500 ml of Me-THF and 200 ml of H2O were charged. The mixture was stirred at a temperature of 18°C for 20 minutes, then about 10.5 g of HC1 37% (concentration in water, calculated in weight / weight, w / w) were added dropwise under stirring until reaching a pH value between 5.5 and 7.5, to obtain compound of Formula Via. The two phases were separated.

[0156] The organic phase, i.e. a solution of compound of Formula Via in Me-THF, was re-charged in the reactor and, maintaining the temperature of 55°C, 10.5 g of HC1 37% were added. The reaction mixture was further stirred for 60 minutes to obtain compound of Formula VIb.

[0157] The product was filtered under vacuum and the panel was washed with Me-THF. The product was dried for 12 hours under vacuum at the temperature of 55°C. 43 g of compound of Formula VIb were obtained.

[0158] Example 3. Purification of compound of Formula VIb according to the present invention

[0159] In a reactor equipped with bubble cooler and mechanical stirrer, 43 g of the crude compound of Formula VIb as obtained in Example 2, 215 ml of acetic acid and 86 ml of Me-THF were charged. The mechanical stirring was activated and the reaction mixture was heated to a temperature of 55°C and stirred for 60 minutes. The product was filtered under vacuum and the panel was washed with a mixture of acetic acid / Me-THF 7:3 (v / v) and then with Me-THF.

[0160] The obtained wet solid was re-charged in the reactor and 215 ml of Me-THF was added. The mixture was maintained under stirring at a temperature of 55 °C for 60 minutes. The product was filtered under vacuum and the panel was washed with Me-THF.

[0161] The product was then dried for 12 hours under vacuum at the temperature of 50°C. 27.0 g of the compound of Formula VI were obtained as white solid (molar yield 80 - 85%) . A HPLC chromatogram of the compound of Formula VIb is shown in Figure 1.

[0162] The overall yield from compound of Formula II, following the procedure according to examples la-lb and 2, to compound of Formula VIb was of 62%.

[0163] Example 2b. Preparation of compound of Formula Via, comparative experiment

[0164] In this comparative example, the procedure according to US8546399B2 was followed, however in order to improve the industrial application and scalability a few changes were made.

[0165] First of all, the reaction was carried out using 10 volumes of solvent, instead of 50, and 2.5 eq of NaOH instead of 17.5 with respect to compound IV.

[0166] In order to avoid the use of a second reactor to dilute NaOH 30% w / w (solution available) the compound of Formula IV was dissolved in dioxane, the amount of water needed to dilute NaOH 30% to NaOH IM was added, and finally NaOH 30% was added right before heating the reaction mixture.

[0167] Finally, the isolation of Va, via a recrystallization in DMSO / ACN with subsequent slurries with the same couple of solvents, was introduced in order to reduce the amount of impurities due to their scarce purge in Via and Venetoclax synthetic steps.

[0168] In a reactor equipped with bubble cooler and mechanical stirrer, 817.0 g of compound of Formula IV, obtained according to example 1c, 7353 ml of 1,4-dioxane and 3151 ml of water was charged. The mechanical stirring was activated and the mixture was kept under stirring to have a solution, then 476.0 g of NaOH 30% were added. The reaction mixture was stirred at a temperature of 65°C for 3 hours. The reaction mixture was concentrated under vacuum to a final volume of 3268 ml and the obtained solution was added dropwise under stirring into another reactor equipped with bubble cooler and mechanical stirrer containing 13072 ml of preheated AON at a temperature of 55°C. The reaction mixture was concentrated under vacuum to a final volume of 12255 ml and 4085 ml of ACN was added. The obtained suspension was concentrated under vacuum to a final volume of 8170 ml .

[0169] The cycle ( addition of ACN and concentration) was repeated two more times .

[0170] The product was filtered under vacuum and the panel was washed twice with ACN . The product was dried for 18 hours under vacuum at the temperature of 60 ° C .

[0171] In a reactor equipped with bubble cooler and mechanical stirrer, 805 g of the dry crude compound of Formula Va and a mixture of 4025 ml of DMSO and 4025 ml of ACN were added . The mechanical stirring was activated and the reaction mixture was stirred for 16 hours at a temperature of 25 ° C . The product was filtered under vacuum and the panel was washed with a mixture of 483 ml of DMSO and 966 ml ACN and then three times with 2415 ml of ACN . The obtained wet solid was re-charged in the reactor and it was suspended in a mixture of 2175 ml of DMSO and 3622 ml of ACN . The obtained suspension was stirred for 4 hours at a temperature of 25 ° C . The product was filtered under vacuum and the panel was washed with a mixture of 483 ml of DMSO and 966 ml ACN and then three times with 2415 ml of ACN .

[0172] The obtained wet solid was charged in a reactor equipped with bubble cooler and mechanical stirrer and a mixture of 6440 ml of water and 1529 ml of MeOH were added . The mechanical stirring was activated and the mixture was stirred to obtain a solution . To the obtained solution mixture of 161 ml of HC1 35% and 3059 ml of water were added up to pH = 6 . The mixture was maintained under stirring for 2 hours at a temperature of 25 ° C, then compound of Formula Vi a was filtered under vacuum and the panel was washed with water .

[0173] The product was dried for 16 hours under vacuum at the temperature of 60 ° C .

[0174] 351 . 0 grams of compound of Formula Via were obtained . The overall yield from compound o f Formula I I , following the procedure of example 1c, to compound of Formula Via was 37 % , way lower than that obtained with the procedure of the present invention (see example 3 above) .

[0175] Example 4. Preparation of compound of Formula I according to the present invention

[0176] In a reactor equipped with bubble cooler and mechanical stirrer 30.0 g of the compound of Formula VIb, 17.2 g of the compound of Formula VII, 6.6 g of DMAP, 13.5 g of EDC*HC1, 300 ml of DCM were charged.

[0177] The mechanical stirring was activated and 13.7 g of TEA were added, the mixture was stirred at a temperature of 25°C for 22 hours, then a mixture of 18 ml of glacial acetic acid and 162 ml of H2O was added. The reaction mixture was stirred at a temperature of 25°C for 15 minutes. The mechanical stirring was stopped and the two phases were separated.

[0178] The organic phase was re-charged in the reactor and a solution of 9.0 g of NaHCCh in 180 ml of H2O were added. The mixture was stirred at a temperature of 25°C for 15 minutes, then the stirring was stopped and the two phases were separated .

[0179] The organic phase was re-charged in the reactor and 180 ml of H2O were added, the mixture was stirred at a temperature of 25°C for 15 minutes then, after stopping the stirring, the phases were separated. The organic phase was concentrated under vacuum to a final volume of 210, then 300 ml of THF was added. The mixture was concentrated under vacuum to a final volume of 210 ml, then 150 ml of THF was added maintaining the temperature above 40°C. The mixture was concentrated under vacuum to a final volume of 210 ml, then the temperature was cooled to 25°C and kept stirred in this condition for 2 hours.

[0180] The suspension was heated to a temperature of 52 °C and maintained under stirring for 1 hour; then it was cooled to 25°C and maintained under stirring for 20 hours and finally it was cooled to 0°C and maintained under stirring in this condition for 1 hour. The product was filtered under vacuum and the panel was washed with pre-cooled THF. The product was dried for 16 hours under vacuum at the temperature of 50 °C. 29.0 g of the compound of Formula I were obtained (molar yield 65-75%) .

[0181] Example 5 Preparation of Venetoclax amorphous according to the present invention

[0182] In a reactor equipped with bubble cooler and mechanical stirrer, 35.4 ml of TEA were added and the mixture was cooled under stirring at a temperature of 3°C. 14.6 ml of AcOH were added dropwise under stirring, then the mixture was heated to a temperature of 50°C and 10.0 g of compound of Formula I were added slowly. The mixture was stirred at a temperature of 50°C until dissolution, then the obtained solution was filtered to remove insolubilized particles.

[0183] The filtered solution obtained was cooled to a temperature of 30°C.

[0184] In a second reactor equipped with bubble cooler and mechanical stirrer 100 ml of H2O were charged and the mixture was heated at a temperature of 30°C. The solution obtained in previous step was added to the water with an addition rate of 5 ml / min and the reaction mixture was stirred at a temperature of 30°C for 16 hours.

[0185] The product was filtered under vacuum and the panel was washed with water. The obtained wet solid was re-charged in the reactor and 100 ml of H2O were added, the mixture was stirred at a temperature of 30°C for 1 hour. The product was filtered under vacuum and the panel was washed with water.

[0186] The product was dried for 16 hours under vacuum at the temperature of 50 °C. 9.90 g of amorphous compound I were obtained (molar yield 98-100 %) . A XRPD spectrum of the compound of Formula I in amorphous form is shown in Figure 2. Example 5b Preparation of Venetoclax amorphous, comparative

[0187] In a reactor equipped with bubble cooler and mechanical stirrer, 298.0 g of compound of Formula I and 1639 ml of DMSO were charged, the mixture was heated under stirring to a temperature of 35°C and kept stirring until completely dissolved; the obtained solution was filtered to remove any black bodies and the panel was washed afterwards with 298 ml of DMSO.

[0188] The mixture was vigorously stirred while 3278 ml of H2O were added in about 30 minutes, the mixture was kept under stirring at 55°C for 2 hours, then the mixture was cooled to a temperature of 25°C and stirred for 30 minutes. The product was filtered under vacuum and the panel was washed with H2O.

[0189] The obtained wet product was left squeezing until it was transferable, then it was charged the to the reactor and 3278 ml of H2O were added. The slurry was repeated two consecutive times. The product was filtered under vacuum and the panel was washed with H2O.

[0190] The product was dried for 16 hours under vacuum at the temperature of 58 °C. 274.0 g of amorphous compound I were obtained (molar yield 92 %) .

[0191] Example 6a. Effect of organic base (DBU) vs inorganic base on the synthesis of compound of Formula IV.

[0192] Table 1 6. PK2HPO4. f'Hp / DMSO . [64% . [11%”

[0193] *the reported conversions are after 4 hours

[0194] The reactions carried out in the presence of K2HPO4 were biphasic systems (solid-liquid) . The mass transfer between the two phases lowers the reaction kinetics. Indeed, if the base is poorly soluble in the solvent, it is then scarcely available for the reaction.

[0195] Example 6b. Reaction comparison in the different DMSO / ACN ratios and volumes. Table 2 below summarizes the results obtained performing the reaction of step a) of the process of the present invention in the different DMSO / ACN ratios and volumes with 4 eq mol of DBU (molar ratio to compound of Formula II) . The reported conversions are after 16 hours. The formation of the compound of formula XI as by-product is also reported.

[0196] Table 2

[0197] ACN / DMSO Formula Formula Formula

[0198] Entry Volumes ratio II (A%) IV (A%) XI (A%)

[0199] Employing the pair ACN / DMSO allowed to obtain high conversions in reasonable time. The conversion increases lowering the volumes of solvent.

[0200] Example 7. Screening for the hydrolysis of compound of Formula IV to compound of Formula Va in pure solvents (comparative example) .

[0201] Table 3 below summarizes the results obtained performing the hydrolysis of compound of Formula IV to compound of Formula Va, in different pure solvents with 2.5 eq of NaOH 30% acq.

[0202] The results show that none of tested solvents can be used alone in replacement of 1,4-dioxane, because conversion and purity are significantly lower.

[0203] Table 3

[0204] HPLC

[0205] Conv.

[0206] Entry Solvent Volumes purity*

[0207] (%)

[0208] (%)

[0209] *HPLC purity calculated excluding compound of Formula III and compound of Formula VIII, whose amount depends on the previous purification

[0210] Example 8. Screening for the hydrolysis of compound of Formula IV to compound of Formula Va in MeOH / ether mixtures (according to the invention) .

[0211] Table 4 below summarizes the results obtained performing the reaction of step b) of the process of the present invention in different ether / alcohol mixtures, with 2.5 eq of NaOH 30% acq. The results show that THF and Me-THF can be considered equivalent as cosolvents, both leading to a complete hydrolysis in 2.5 hours .

[0212] Table 4

[0213] Entry Solvent Ratio Conversion Formula Formula HPLC

[0214] (A%) IV (A%) Va (A%) purity*

[0215] (%) III and compound of Formula VIII, whose amount depends on the previous purification

[0216] Example 9. Main impurities trend from the reaction of step a to pure compound VIb. Table 5

[0217] Formula Formula Formula Formula Formula Formula

[0218] VIb / VIa / V IV VIII IX X XI

[0219] (A%) (A%) (A%) (A%) (A%) (A%)

[0220] RRT RRT RRT RRT RRT RRT

[0221] 1.00 21.63 0.70 0.68 0.78 0.82

[0222] RRT are calculated on compound VI. Compounds of Formulae VIII- IX-X-XI are shown below.

[0223] VIII IX X XI

[0224] Compound of Formula IX is considered critical because it reacts in the final step of the synthetic process (step f) . Example 10. Analytic method for determining the amount of compound IX and compound X in the compounds of Formulae VI-

[0225] Vla-VIb.

[0226] The compounds of Formulae IX and X were identified and monitored via the following HPLC method: Chromatographic conditions: Column: X-bridge C8 150x4.6 mm 3.5 pm

[0227] Analysis time: 55 min

[0228] Acquisition time: 45 min

[0229] Injection volume: 5 pl

[0230] Flow: 1.0 ml / min

[0231] Column temperature: 30 °C

[0232] Autosampler temperature (if available) : 5°C Wavelength: 220 nm

[0233] Autosampler wash: CH3CN for HPLC Thinner: CH3CN:H2O 70:30 (v / v)

[0234] Water (H2O) ultrapure grade

[0235] - Acetonitrile (CH3CN) for HPLC

[0236] - Methanol (CH3OH) for HPLC - Potassium Dihydrogen Phosphate (KH2PC>4) for HPLC

[0237] - Diluted phosphoric acid (H3PO4) approximately 85%

[0238] OPERATING AND INSTRUMENTAL CONDITIONS

[0239] Mobile phase A: 1.36 g / L of KH2PO4 at pH 3.0 with H3PO4 approximately 85% Mobile phase B: CH3CN / MeOH 1 / 1

[0240] Applying the conditions described above the retention times are as indicated below

[0241] Compound RT RRT

[0242] Compound of Formula (VIb -Va) 19.25 min 1.00 Compound of Formula (IV) 21 .63 min 1.12

[0243] Compound of Formula (VIII) 13 .51 min 0.70

[0244] Compound of Formula (IX) 13 .17 min 0.68

[0245] Compound of Formula (X) 15.04 min 0.78

[0246] Compound of Formula (XI) 15.89 min 0.82

[0247]

[0248] Wherein RRT (relative retention time) is the comparison of the RT (retention time) of one compound to that of compound of Formula VIb.

Claims

CLAIMS1. A process for preparing Venetoclax, the compound ofFormula I, or a salt or a solvate thereofFormula I the process comprising the following steps: a) reacting a compound of Formula IIFormula II with a compound of Formula III or a salt thereofFormula III in the presence of an organic base and in a mixture of solvents , wherein said mixture of solvents comprises acetonitrile (ACN) and dimethylsulfoxide (DMSO) , under heating, to obtain compound of Formula IVFormula IV wherein said compound of Formula IV is obtained in a solutionwith at least one organic solvent; b) reacting the compound of Formula IV in the solution obtained in step a) , with an alkali metal or alkaline earth metal hydroxide and at least one alcohol, to obtain a compound of Formula VFormula V wherein :Mn+is a cation of an alkali metal or alkaline earth metal, n is 1 or 2, and n=n' ; c) isolating the compound of Formula V; d) preparing a solution of the compound of Formula V in a biphasic mixture of solvents, wherein said mixture comprises water and at least one organic solvent immiscible with water, and adding an organic or inorganic acid until reaching a pH value of from 5.5 to 7.5, to obtain, after separation of the aqueous phase, an organic solution of the compound of Formula ViaFormula Via; e) reacting the compound of Formula Via in the solutionobtained in step d) with an organic or inorganic acid, to obtain the compound of Formula VIFormula VI wherein X is selected from the group comprising an anion of an organic acid selected from: acetic acid, citric acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid, and an anion of an inorganic acid selected from: HC1, HBr, HF, H2SO4 and H3PO4; and f) reacting the compound of Formula VI obtained in step e) with the compound of Formula VIIin the presence of an activating agent, a catalyst and a base, in an organic solvent, to obtain the compound of Formula I, or a salt or a solvate thereof.

2. The process according to claim 1, wherein in step a) said organic base is selected from DBU and DBN, preferably said organic base is DBU.

3. The process according claim 1 or 2, wherein in step a) the ratio between ACN and DMSO, calculated in volume / volume (v / v) , is of from 9:1 to 6:4 v / v, preferably of from 8:2 to 7:3 v / v.

4. The process according to any one of the preceding claims, wherein in step a) the ratio between the solvent mixture and the compound of Formula II, calculated in volume / weight (v / w) is of from 5 to 7 v / w.

5. The process according to any one of the precedingclaims, wherein in step a) the reaction is carried out at a temperature of from 60°C to 105°C.

6. The process according to any one of the preceding claims, wherein in step a) said compound of Formula III is a hydrogen halide salt.

7. The process according to any one of the preceding claims, wherein in step a) the at least one organic solvent forming the solution of the compound of Formula IV is an ether, preferably selected from CPME, THF and Me-THF.

8. The process according to claim 7, wherein in step a) said solution of the compound of Formula IV is obtained by: a' ) adding water and at least one polar solvent not miscible with water to the reaction mixture containing the compound of Formula IV, to obtain a biphasic mixture; a' ' ) separating the two phases of the biphasic mixture to obtain the compound of Formula IV in the organic phase.

9. The process according to claim 8, wherein said at least one polar solvent not miscible with water is selected from: ethers not miscible with water, preferably Me-THF; chlorinated solvents, preferably dichloromethane; esters not miscible with water, preferably ethyl acetate.

10. The process according to claim 9, wherein, when the polar solvent not miscible with water is not an ether, after separation of the two phases, the organic phase is distilled and the obtained residue containing the compound of Formula IV is then dissolved in an ether, preferably CPME, THF or Me-THF.

11. The process according to any one of the preceding claims, wherein in step b) said alcohol is selected from MeOH, EtOH and IPA, preferably the alcohol is MeOH.

12. The process according to any one of the preceding claims, wherein in step b) said hydroxide is NaOH and the obtained compound of Formula V is a compound of Formula VaFormula Va.

13. The process according to any one of the preceding claims, wherein in step d) said at least one organic solvent immiscible with water is Me-THF.

14. The process according to any one of the preceding claims, wherein in step d) the acid is HC1.

15. The process according to any one of the preceding claims, wherein in step e) the acid is HC1, and the compound obtained is a compound of formula VIb16. A process for preparing a compound of Formula Iin amorphous form, said process comprising: i) dissolving the compound of Formula I, or a solvate thereof, in a solvent mixture comprising an organic acid andan organic base, under heating; ii) adding the solution obtained in step i) to water, under heating, and stirring until formation of a solid precipitate; and iii) isolating compound of Formula I in amorphous form.

17. The process according to claim 16, wherein in step i) the compound of Formula I is a THF solvate.

18. The process according to claim 16 or 17, wherein in step i) said organic acid is selected from: acetic acid, formic acid, propionic acid, and trifluoroacetic acid; and said organic base is selected from: TEA, DIPEA, N- methylmorpholine, ethanolamine, di-ethanolamine, and triethanolamine .

19. The process according to any one of claims from 16 to 18, wherein in step i) the organic base and the organic acid are in equimolar ratio.

20. The process according to any one of claims from 16 to 19, wherein in step i) the ratio between the solvent mixture and the compound of Formula I, calculated in volume / weight (v / w) , is of from 3 to 7 v / w, preferably from 4 to 6 (v / w) .

21. The process according to according to any one of claims from 16 to 20, wherein in step i) the temperature of heating is between 20°C and 70°C.

22. The process according to any one of claims from 16 to 21, wherein in step ii) the ratio between water and the solvent mixture of step i) , calculated in volume / volume (v / v) , is of from 1 to 4 v / v.

23. The process according to any one of claims from 16 to 22, wherein in step ii) the temperature of heating is between 20°C and 50°C.

24. The process according to any one of claims from 16 to 23, wherein in step iii) the isolation is carried out byfiltration .

Images