Process for the preparation of 1-(N-(quinolin-2-yl)-(phenylamino)-1-deoxy-beta-D-glucopyranuronic acid derivatives

Abstract

The present invention relates to a method for purifying a crude compound of formula (I): [Formula 1] JPEG2024545967000044.jpg48170, wherein the method comprises isolating the crude compound of formula (I), the isolating step comprising (i) solubilizing the crude compound of formula (I) in methanol, and precipitating with water, and (ii) drying at a temperature below 30° C. A manufacturing method for preparing the compound of formula (I) is further provided in the present application.

Description

[Technical field]

[0001] Provided herein is a novel process for purifying 1-(N-(quinolin-2-yl)-(phenylamino)-1-deoxy-β-D-glucopyranuronic acid derivatives (herein named "quinolinyl-2-yl-phenylalamin glucuronide derivatives"), in particular a novel process for purifying 1-(N-(8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenylamino)-1-deoxy-β-D-glucopyranuronic acid. The provided process is more particularly suitable for industrial scale. Also provided herein is an improved process for the preparation of quinolinyl-2-yl-phenylalamin glucuronide derivatives, in particular 1-(N-(8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenylamino)-1-deoxy-β-D-glucopyranuronic acid, a process more suitable for industrial implementation. [Background technology]

[0002] WO2016 / 135052 describes the preparation and use of quinolin-2-yl-phenylamine glucuronide derivatives, which are N-glucuronide metabolites of chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (also named ABX464). The compounds are disclosed as being useful in the treatment or prevention of viral or retroviral infections and viral-related conditions, in particular AIDS or AIDS-related conditions or Human Immunodeficiency Virus (HIV). In WO2020 / 127843, they are further disclosed as being useful in the treatment of various inflammatory diseases.

[0003] ABX464 is a drug candidate in clinical trials for the treatment of moderate to severe ulcerative colitis (UC).

[0004] The synthesis route of the glucuronide derivative is disclosed in International Publication No. WO2016 / 135052 and follows the synthesis route shown below. [ka] Here, the above compound (4) is also disclosed as a novel intermediate compound.

[0005] The reaction of compound (2) with compound (3) can be carried out according to the Koenigs-Knorr synthesis, after which compound (4) can be deprotected to give compound (1).

[0006] However, the purification process as disclosed in WO2016 / 135052, i.e., extraction of crude compound (1) with ethyl acetate and then concentration to dryness to obtain a solid extract, is not suitable for industrial scale. In fact, performing concentration to dryness after said extraction is not desirable, and it is even not feasible to handle solid extracts on an industrial scale. In other words, the inventors state that scale-up has caused purification problems. Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, there is a need to provide a purification method for the quinolinyl-2-yl-phenylalamine glucuronide derivatives of formula (I) as defined herein after it is adapted for industrial scale production.There is a further need to provide a quinolinyl-2-yl-phenylalamine glucuronide derivatives of formula (I) that exhibit improved purity and respect the requirements of ICH levels, especially with regard to the amount of residual solvents.There is another further need to provide a manufacturing method for preparing the quinolinyl-2-yl-phenylalamine glucuronide derivatives of formula (I) as defined herein after it is adapted for industrial implementation with an acceptable yield.

[0008] Other advantages of WO2016 / 135052 related to industrial scale constraints are detailed later in this specification. [Means for solving the problem]

[0009] The inventors have surprisingly found specific conditions for purifying the crude quinolinyl-2-yl-phenylalanine glucuronide derivative of formula (I) as defined hereinafter, obtained in particular after a deprotection step of compound (IV) as defined hereinafter. The inventors have in particular developed a procedure for purifying said derivative of formula (I) starting from the solution phase and not from a solid extract.

[0010] The present invention is additionally intended to provide a method for preparing quinolinyl-2-yl-phenylalanine glucuronide derivatives of formula (I) as defined hereinafter, which is improved in terms of industrial-scale mass production.The inventors have in particular simplified various aspects, as will become more apparent in the following description, so that the claimed method is fully adapted to industrial scale worldwide.

[0011] Accordingly, provided herein is a method for purifying a crude compound of formula (I): [ka] Where: each R independently represents a hydrogen atom, a halogen atom, -CN, hydroxyl, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy, (C3-C6)cycloalkyl, -NO2, -NR1R2, (C1-C4)alkoxy, phenoxy, -NR1-SO2-NR1R2, -NR1-SO2-R1, -NR1-C(=O)-R1, -NR1-C(=O)-NR1R2, -SO2-NR1R2, -SO3H, -O-SO2-OR3, -OP(=O)-(OR3)(OR4), -O-CH2-COOR3 or (C1-C3)alkyl, wherein the alkyl may be mono- or di-substituted by a hydroxyl group, a group of formula (IIa) or a group of formula (IIIa): [ka] [ka] Each of R1 and R2 is independently a hydrogen atom or a (C1-C3) alkyl; Each of R3 and R4 is independently a hydrogen atom, Li+, Na+, K+, N+(Ra)4, or benzyl; each R' is independently a hydrogen atom, a (C1-C3) alkyl, a hydroxyl, a halogen atom, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, a (C1-C3) fluoroalkyl, a (C1-C4) alkoxy, -OP(=O)-(OR3)(OR4), -CN, a group of formula (IIa) below, or a group of formula (IIIa) below, [ka] [ka] A is a covalent bond, an oxygen atom or NH; B is a covalent bond or NH; m is 1, 2, 3, 4 or 5; p is 1, 2 or 3; Each of Ra and Rb is independently a hydrogen atom, a (C1-C5) alkyl, or a (C3-C6) cycloalkyl; or Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle, which may be substituted by one or more Ra, provided that, when R' is a (IIa) or (IIIa) group, n' may be 2 or 3 only if the other R' group is different from said (IIa) or (IIIa) group; and n is 1, 2 or 3; n' is 1, 2 or 3; wherein the process comprises a step of isolating the crude compound of formula (I), the step of isolating comprising (i) solubilizing the crude compound of formula (I) in methanol and precipitating with water; and (ii) Drying at a temperature of 30°C or less Includes.

[0012] More particularly, provided herein is a method for purifying a compound of formula (1): [ka]

[0013] A process for preparing a compound of formula (I) as defined above, comprising the steps of: In step 1, a compound of formula (II) is reacted with a compound of formula (III) in a solvent selected from aromatic solvents, such as toluene or xylene, in particular in toluene, in the presence of CdCO3, with fractional introduction of the compound of formula (III) into the solution, to obtain a compound of formula (IV) [ka] [ka] [ka] where R, R', n and n' are as defined in any one of claims 1 to 4, and each R" represents a (C1-C4) alkyl group. continuation, In step 2, the compound of formula (IV) is deprotected using lithium hydroxide, potassium hydroxide or sodium hydroxide, particularly lithium hydroxide, in the absence of hydrogen peroxide and in the presence of a solvent selected from an aromatic hydrocarbon, such as toluene or xylene; an ether, such as tetrahydrofuran or methyl tert-butyl ether (MTBE), particularly tetrahydrofuran, at room temperature to obtain a compound of formula (I): Further provided herein is the above method, comprising:

[0014] As used herein, the terms "ambient temperature" or "room temperature" refer to temperatures in the range of from 15°C to 30°C, more particularly from 18°C ​​to 25°C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] As described in more detail later in this specification, isolation of the desired product is achieved through precipitation, which may be preceded by a purification step on a silica gel chromatography column, optionally preceded by a silica gel pretreatment step itself.

[0016] According to one embodiment, R, n, R' and n' have the following meanings: each R independently represents a hydrogen atom, a halogen atom, or a group selected from -CN, hydroxyl, -COOR1, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy, -NO2, -NR1R2, (C1-C4)alkoxy, phenoxy and (C1-C3)alkyl, wherein the alkyl is optionally monosubstituted by a hydroxyl group; R1 and R2 are independently a hydrogen atom or a (C1-C3) alkyl group; n is 1, 2 or 3; n' is 1 or 2, and Each R' independently represents a hydrogen atom or a group selected from a (C1-C3) alkyl group, a halogen atom, a hydroxyl group, a -COOR1 group, a -NO2 group, a -NR1R2 group, a morpholinyl group or a morpholino group, an N-methylpiperazinyl group, a (C1-C3) fluoroalkyl group, a (C1-C4) alkoxy group, and a -CN group.

[0017] According to another embodiment, R, n, R' and n' have the following meanings: each R independently represents a hydrogen atom, a halogen atom, or a group selected from a (C1-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group, a -NR1R2 group, a (C1-C4)alkoxy group, a phenoxy group, and a (C1-C3)alkyl group, wherein the alkyl group is optionally monosubstituted by a hydroxyl group; R1 and R2 are independently a (C1-C3) alkyl group; n is 1, 2 or 3, preferably 1 or 2, even more preferably 1; n' is 1 or 2, preferably 1; and Each R' independently represents a hydrogen atom or a group selected from a (C1-C3) alkyl group, a halogen atom, a -NR1R2 group, a (C1-C3) fluoroalkyl group, and a (C1-C4) alkoxy group.

[0018] According to another embodiment, the compound of formula (I) is a compound of formula (1) [ka]

[0019] In the context of the present invention, the terms have the following meanings:

[0020] "Halogen atom" is understood to mean a chlorine, fluorine, bromine or iodine atom, and in particular denotes a chlorine, fluorine or bromine atom.

[0021] As used herein, "(C1-C x)Alkyl" are C1 to C x "alkyl" refers to primary, secondary, or tertiary saturated hydrocarbons of the formula: 1. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, butyl, and pentyl.

[0022] As used herein, "(C3-C6)cycloalkyl" refers to each cyclic saturated hydrocarbon. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0023] As used herein, "(C1-C4)alkoxy" refers to an O-(C1-C4)alkyl moiety, respectively, where alkyl is as defined above. Examples include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, and butoxy.

[0024] "Fluoroalkyl group" and "fluoroalkoxy group" refer respectively to alkyl and alkoxy groups as defined above, where the groups are substituted with at least one fluorine atom. Examples are perfluoroalkyl groups, such as trifluoromethyl or perfluoropropyl.

[0025] As used herein, "saturated 5- or 6-membered heterocycle" refers to a saturated ring containing at least one heteroatom, respectively. Examples include, but are not limited to, morpholine, piperazine, thiomorpholine, piperidine, and pyrrolidine.

[0026] Purification method / process

[0027] The purification steps disclosed in WO2016 / 135052 consist of extracting the crude compound (1) with ethyl acetate after quenching the reaction mixture, then acidifying it, followed by extraction with ethyl acetate, drying over sodium sulfate, and finally purifying the solid extract obtained after removing the solvent on a silica column.

[0028] The inventors state that this procedure was not suitable for industrial scale because of the great difficulties involved in carrying out a solid dry extract, especially on an industrial scale.

[0029] The inventors have therefore developed an isolation process which allows working with solutions or suspensions instead of solid concentrates and respecting the acceptable purity requirements of said compound (1) as well as the acceptable levels of residual solvents according to the general standards of the pharmaceutical industry, i.e. the ICH residual solvent requirements of the European Medicines Agency. The inventors have therefore found a specific solvent precipitation system at a specific temperature, which may be preceded by a purification step using a silica gel column, optionally preceded by a silica gel pretreatment, in order to be able to meet these expectations.

[0030] According to a particular embodiment, the drying step may be carried out at a temperature ranging from 20 to 30°C.

[0031] Thus, the reaction mixture obtained after the deprotection step of the crude compound of formula (I), in particular crude compound (1), in particular compound (IV) as defined hereinafter, can be diluted with methanol and after addition of cold water a brown solid precipitate can be obtained.

[0032] As will be seen in Example 2 herein below, by using the particular solvent system for precipitation and drying at temperatures below 30° C., significant improvements in residual solvent tolerance were obtained.

[0033] As further evident in Example 2 herein below, the residual amounts of toluene, methylene chloride, methanol and tetrahydrofuran can be obtained in compliance with the ICH level requirement. That is, the ICH level requirement for methanol is less than 3000 ppm relative to the total amount of desired compounds. Similarly, the ICH level requirement for tetrahydrofuran is 720 ppm relative to the total amount of desired compounds. Similarly, the ICH level requirement for toluene is 890 ppm relative to the total amount of desired compounds. Similarly, the ICH level requirement for methylene chloride is 600 ppm relative to the total amount of desired compounds.

[0034] According to one aspect, there is provided herein a process for purifying the crude compound of formula (I) as defined above, wherein said purifying step is preceded by a purification step using a silica gel column, optionally preceded by a silica gel pretreatment.

[0035] Thus, there is provided herein a purification method as disclosed above, wherein the purification method is preceded by purification on a silica gel chromatography column, in particular purification on a silica gel chromatography column eluted with methylene chloride, methanol or mixtures thereof, optionally preceded by a pretreatment of the silica gel prior to purification on the silica gel chromatography column.

[0036] During the optional pretreatment with silica gel, the compound of formula (I) as defined above is adsorbed on the silica gel. This optional pretreatment of purification makes it possible to avoid many runs of the silica gel column to obtain the compound of formula (I). This pretreatment of silica gel also presents the advantage of making it possible to collect the unreacted compound of formula (II), in particular of formula (2), so that it can be reused for further production batches to prepare derivatives of formula (I), in particular of formula (1).

[0037] The silica gel may be washed a first time with a solvent selected from methylene chloride, tetrahydrofuran or a combination thereof. The number of these first series of washes may vary from 1 to 3. The product may then be desorbed in a second series of washes using only THF or only methanol. The number of washes in these second series of washes may vary from 1 to 3.

[0038] As regards the silica gel chromatography step, the silica gel column may in particular be chosen from normal phase, in particular silica gel "Chromatorex GS60-20 / 45". Elution may be carried out with a methylene chloride / methanol mixture.

[0039] By carrying out the further method of purification according to the present invention, the overall yield of compound (1) could reach 10%-20%, in particular 11%-17%.

[0040] Overall, the purification steps described above make it possible to obtain a compound of formula (I) exhibiting good quality characteristics, i.e. high purity, and also exhibiting an acceptable level of residual solvents.

[0041] Among the impurities that the inventors have detected in the final compounds of formula (I), and in particular in the final compounds of formula (1), there may be mentioned the starting compounds of formula (II), as well as the methyl esters having formula (V) below: [ka] Here, in the case of compound (1), it is compound (5) shown below. [ka]

[0042] The compound of formula (I), in particular compound (1), obtained according to the present invention typically exhibits a purity in the range of 90-97%, in particular 92-96%, even more particularly 93-96%, with an amount of compound of formula (II), in particular compound (2), in the range of 0.3-2.1%, and an amount of impurity of formula (V), in particular impurity (5), in the range of 1.9-2.3%.

[0043] The compounds of formula (I) obtained according to the present invention, in particular compound (1), may typically exhibit residual contents of less than 750 ppm of methanol, less than 420 ppm of methylene chloride, less than 360 ppm of tetrahydrofuran and less than 445 ppm of toluene.

[0044] Process for the preparation of compounds of formula (I)

[0045] According to one embodiment, the inventive step of purification may be carried out after the deprotection step of the compound of formula (IV). [ka] where R, R', n, n' and R" are as defined above and are described in detail in step 2 herein below.

[0046] The compound of formula (IV) may be prepared by reacting a compound of formula (II) below with a compound of formula (III) below according to the Koenigs-Knorr synthesis, as described in detail in step 1 herein below. [ka] [ka] where R″ is as defined above.

[0047] There is further provided an improved process for preparing a compound of formula (I) as defined above, wherein steps 1 and 2 as defined hereinafter are carried out prior to purification of the crude compound of formula (I) as provided herein.

[0048] The preparation process disclosed in WO 2016 / 135052 for obtaining chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine glucuronide in amounts of less than 5 g cannot be applied as far as scale-up is envisaged.

[0049] Process 1

[0050] As detailed later in this specification, step 1 differs from the coupling step disclosed in WO2016 / 135052 primarily by the introduction of the compound of formula (III) in solution and by split introduction.

[0051] Further improvements may be implemented. For example, the 12 hour reflux step before introducing compound (III) may be omitted. Furthermore, the purification step by silica gel chromatography may be avoided. In addition, the obtained crude product (IV), especially compound (4), may be kept in solution in a solvent, such as THF, rather than being worked-up as a viscous dry extract. Finally, the amount of solvent may be reduced to increase productivity.

[0052] The conversion rate of the compound of formula (II) defined above to the compound of formula (IV) is rather low. For example, retesting of International Publication No. WO2016 / 135052 could give about 50% of the compound (2) remaining even after 5 days of reaction. Moreover, it is stated that compound (3) may decompose, which strongly affects the overall yield of the reaction.

[0053] According to the present invention, step 1 may be carried out by reacting a compound of formula (II) with a compound of formula (III) as defined above in the presence of CdCO3 in a solvent selected from aromatic solvents, such as toluene or xylene, more particularly in toluene.

[0054] There is now provided herein an improved process for preparing a compound of formula (IV), wherein a compound of formula (III) is reacted in the presence of toluene in a molar ratio ranging from 1.2 to 3, particularly from 1.4 to 2.5, even more particularly from 1.5 to 1.7, to a compound of formula (II) and in a volume ratio ranging from 10 to 30, particularly from 10 to 20, more particularly from 10 to 15, to a compound of formula (II).

[0055] The reaction may be carried out at reflux temperature, ie, 111°C.

[0056] By reducing the amount of solvent, the conversion could be increased.

[0057] Moreover, the inventors state that they were able to improve the reaction conversion by introducing the compound of formula (III) into the solution in portions.

[0058] Thus, according to a particular embodiment, step 1 can be carried out by split introduction, particularly split introduction in two portions, of the compound of formula (III), in particular compound (3), in solution. Further according to the above particular embodiment, the first introduction can be carried out with a molar ratio of the compound of formula (III) to the compound of formula (II), in particular compound (3) to compound (2), in the range of 0.6 to 1, in particular in the range of 0.7 to 0.9, and the second introduction can be carried out with a molar ratio of the compound of formula (III) to the compound of formula (II), in particular compound (3) to compound (2), in the range of 0.6 to 1, in particular in the range of 0.7 to 0.9, where the total molar ratio to the compound of formula (II) is 1.2 to 2, in particular in the range of 1.4 to 1.8.

[0059] Step 1 may be carried out for 10 to 120 hours, particularly 20 to 80 hours, and even more particularly 30 to 50 hours.

[0060] The yield at this stage of the process is quantitative.

[0061] Example 1.1 illustrates step 1 above in more detail.

[0062] Process 2

[0063] As explained in more detail herein below, step 2 differs from the deprotection step disclosed in WO2016 / 135052 primarily by the removal of hydrogen peroxide, which provides advantages in terms of the safety of the process.

[0064] Further improvements may be made further. For example, step 2 of the present invention no longer requires the use of sodium thiosulfate. Finally, the amount of solvent, e.g., THF and water, may be reduced. The improvement of the isolation step and work-up using isolation by precipitation with a mixture of methanol and water has already been described above, as well as the implementation of an optional pretreatment step on silica gel.

[0065] As revealed in WO2016 / 135052, compound (4) was reacted in a second step in the presence of hydrogen peroxide in a suspension of lithium hydroxide monohydrate, and the inventors state that the presence of hydrogen peroxide is not in fact essential for this deprotection step.

[0066] Provided herein is an improved process for the preparation of a compound of formula (I) as defined above from a compound of formula (IV) as defined above, wherein the compound of formula (IV) is reacted with lithium hydroxide, potassium hydroxide or sodium hydroxide, particularly lithium hydroxide, in the presence of a solvent selected from an aromatic hydrocarbon, such as toluene or xylene; an ether, such as tetrahydrofuran or methyl tert-butyl ether (MTBE), particularly tetrahydrofuran, at room temperature.

[0067] The solvent is preferably from 5 to 30, more preferably from 5 to 15, and even more preferably from 5 to 7, based on the compound of formula (IV). The volume ratio may range from 0.1 to 1.

[0068] The yield at this stage of the preparation process, i.e. after the purification steps including the above-mentioned pretreatment with silica gel, purification on a silica gel column and a precipitation step, is 10%-20%, in particular 12%-17%.

[0069] Example 1.2 illustrates step 2 above in more detail.

[0070] Thus, there is further provided herein a purification step according to the invention, wherein said purification step is preceded by a step of deprotecting the compound of formula (IV) below using lithium hydroxide, potassium hydroxide or sodium hydroxide, in particular lithium hydroxide, in the presence of a solvent selected from aromatic hydrocarbons, such as toluene or xylene; ethers, such as tetrahydrofuran or methyl tert-butyl ether (MTBE), in particular tetrahydrofuran, at room temperature to obtain a compound of formula (I). [ka] where R, R', n and n' are as defined in any one of claims 1 to 4, and each R" represents a (C1 to C4) alkyl group.

[0071] According to one variant, R″ is a methyl group.

[0072] According to another variant, the purification method according to the above claim, wherein the compound of formula (IV) is compound (4) below: [ka]

[0073] A purification method according to the present invention is further provided herein, in which, prior to said deprotection step, a step is carried out in which a compound of formula (II) below is reacted with a compound of formula (III) below in a solvent selected from aromatic solvents, such as toluene or xylene, in particular in toluene, in the presence of CdCO3, with the compound of formula (III) being introduced in portions into the solution, to obtain a compound of formula (IV) below. [ka] [ka] [ka] where R, R', n and n' are as defined in any one of claims 1 to 4, and each R" represents a (C1-C4) alkyl group, in particular a methyl group.

[0074] According to one variant, the compound of formula (II) is compound (2) below and the compound of formula (III) is compound (3) below: [ka] [ka]

[0075] Also provided herein is a novel process for preparing compound (1), which comprises carrying out steps 1 and 2 as described above, more particularly a process for preparing the compound of formula (I) above, comprising: In step 1, a compound of formula (II) is reacted with a compound of formula (III) in a solvent selected from aromatic solvents, such as toluene or xylene, in particular in toluene, in the presence of CdCO3, with the compound of formula (III) being introduced in portions into the solution, to obtain a compound of formula (IV): [ka] [ka] [ka] where R, R', n and n' are as defined in any one of claims 1 to 4, and each R" represents a (C1-C4) alkyl group. continuation, In step 2, the compound of formula (IV) is deprotected using lithium hydroxide, potassium hydroxide or sodium hydroxide, particularly lithium hydroxide, in the absence of hydrogen peroxide and in the presence of a solvent selected from an aromatic hydrocarbon, such as toluene or xylene; an ether, such as tetrahydrofuran or methyl tert-butyl ether (MTBE), particularly tetrahydrofuran, at room temperature to obtain a compound of formula (I): Also provided herein is a method of manufacture comprising:

[0076] Further provided herein is a process for preparing a compound of formula (I) as defined above, in particular compound (1) as defined above, which further comprises the step of preparing a pharmaceutical composition comprising such a compound of formula (I), in particular compound (1), together with a pharma- ceutically acceptable excipient.

[0077] Throughout this specification, including the claims, the word "comprising" should be understood as being synonymous with "comprising at least one," unless otherwise specified.

[0078] The expressions "to" and "in the range of" should be understood to mean that the limits are included, unless otherwise specified.

[0079] Hereinafter, the present invention will be described in more detail with reference to the following examples, which are provided to illustrate the present invention and should not be construed as limiting the scope and spirit of the present invention.

[0080] Working Example

[0081] List of abbreviations Methylene chloride: DCM, Tetrahydrofuran: THF

[0082] Example 1: Manufacturing method for preparing crude compound (1)

[0083] 1.1 Process 1

[0084] 1.1.1 By separate introduction of the solid compound (3) (Comparative Example)

[0085] Compound (2) (20.0 g) as defined above was mixed with cadmium carbonate (6.0 g, 0.6 eq) and toluene (580 mL, 29 vol). The resulting mixture was azeotropically dried for 1 h, then compound (3) (38.0 g, 1.6 eq) as defined above was added to the refluxing mixture in 4 portions over 28 h. The mixture was heated at reflux for an additional 46 h, then cooled to room temperature, filtered, and washed with methylene chloride. The filtrates were combined and concentrated to dryness, then diluted with DCM, washed three times with water, dried over sodium sulfate, concentrated to dryness, and diluted with THF, then subjected to step 2.

[0086] Compound (4) was isolated in quantitative yield and with an HPLC purity of 43% (53% remaining compound (2)).

[0087] 1.1.2 Partial introduction of compound (3) in solution and reduction in dilution (present invention)

[0088] The above compound (2) (65.0 kg) was mixed with cadmium carbonate (52.7 kg, 1.6 equiv.) and toluene (325 L, 5 vol.). The resulting mixture was heated to reflux for azeotropic drying and a solution of compound (3) (61.1 kg, 0.8 equiv.) in toluene (318.5 L, 2.5 vol.) was added at this temperature over 8 hours. A partial distillation of toluene (160 L, 2.5 vol.) was performed and reflux was maintained overnight (10 hours). A second portion of a solution of compound (3) (61.1 kg, 0.8 equiv.) in toluene (318.5 L, 2.5 vol.) was added at reflux over 8.5 hours. A partial distillation of toluene (160 L, 2.5 vol.) was performed and reflux was maintained for 24 hours. The reaction mixture was then cooled to room temperature, filtered, and rinsed with methylene chloride. The filtrates were combined and washed with aqueous sodium bicarbonate solution (5.2 kg in 65 L water), followed by water (65 L). The resulting organic layer was concentrated to dryness and the residue was diluted with THF (130 L) before being subjected to step 2.

[0089] Compound (4) was isolated in quantitative yield (126 kg) and with an HPLC purity of 48%.

[0090] Thus, it has been found herein that the resolved introduction of compound (3) can also afford compound (4) in quantitative yield and with slightly improved purity.

[0091] 1.2 Process 2

[0092] The THF solution of compound (4) resulting from step 1 (310 kg of solution, 126 kg of compound (4)) was diluted with tetrahydrofuran (449 kg). A solution of lithium hydroxide monohydrate (80.6 kg) in water (327 L) was added to the compound (4) solution at 20° C. and stirred at 20° C. for 2 hours. The aqueous layer was discarded and the organic layer was concentrated, diluted with water (252 L) and methylene chloride (670 kg) and acidified to pH 1 with hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with DCM (335 kg). The organic layers were combined and washed with water (252 L). Silica gel (90.8 kg) was added to the organic layer and the mixture was stirred at 20° C. for 30 min, filtered and the silica gel pad was washed with methylene chloride (168 kg) and twice with a mixture of DCM (160 kg) and THF (6.2 L). These three washes were performed for further valorization of unreacted compound (2). The silica gel pad was then washed successively with 112 kg and 2×56 kg of THF. The resulting solution was concentrated under vacuum and the residue was diluted with a mixture of DCM (67 kg) and THF (1.3 L). The resulting solution was purified by silica gel chromatography using a DCM / methanol mixture as the eluent. The collected fractions were combined, concentrated under vacuum and diluted with one volume of methanol (15 L) with respect to the estimated amount of compound (1).

[0093] Example 2: Method for purification of crude compound (1)

[0094] 2.1. Methanol / water system and drying at 30°C (present invention)

[0095] Precipitation of crude compound (1) prepared in Example 1 is carried out as follows.

[0096] The crude compound (1) (15 kg) from Example 1 diluted with 1 volume of methanol (15 L) was then added to 20 volumes of demineralized water (300 L) at 0 / 5° C. for 1 hour and washed with 0.5 volumes of methanol. The suspension was filtered and the cake was washed with demineralized water (15 L). The wet product was dried in a tray oven at 30° C. until the moisture content and residual solvent met specifications. The product obtained was a brown solid with a yield of 95% (14.35 kg).

[0097] Compound (1) obtained according to this protocol had an HPLC purity of 95.3% and contained 0.8% of compound (2) and 2.0% of methyl ester impurity (5). The water content was 3.5% and the residual solvents were as follows: methanol <750 ppm, DCM <150 ppm, THF <180 ppm and toluene <223 ppm.

[0098] The purification process carried out according to the present invention was observed to give compound (1) in an amorphous solid form that is fully compliant on an industrial scale and meets the ICH residual solvent requirements of the European Medicines Agency.

[0099] 2.2. Methanol / water system and drying at 50°C (comparative example)

[0100] Portions divided as in Example 2.1 above were dried at 30° C. for 100 hours and at 50° C. for 11 hours.

[0101] The resulting product was a brown solid with an HPLC purity of 93.4% and contained 2.1% of compound (2) and 2.1% of the methyl ester impurity (5).

[0102] The water content was 3.2% and the residual solvents were as follows: methanol 738 ppm, DCM<300 ppm, THF<360 ppm and toluene<445 ppm.

[0103] It has been observed that purification steps carried out according to methods outside the present invention (ie, at temperatures above 30° C.) result in much less desirable decomposition.

[0104] 2.3. DCM / heptane system (comparison example)

[0105] Precipitation of crude compound (1) prepared in Example 1 was carried out as follows.

[0106] The crude compound (1) is solubilized (1.4 g) with 4 volumes of DCM and 0.6 volumes of THF to obtain a solution. The solution is added to 10 volumes of heptane (containing 0.5 volumes of IPA) at 20-25° C. over 1 hour 45 minutes, and then rinsed with 0.5 volumes of DCM. The mixture is then stirred at room temperature for 2 hours 30 minutes. The liquid suspension is then filtered and washed with 4*0.5 volumes of heptane, giving 0.856 g of wet brown product.

[0107] The product is dried under vacuum at 20° C. for 16.5 hours and at 50° C. for 4 days. The product obtained was a brown solid with a yield of 77%.

[0108] The isolated compound (1) had an HPLC purity of 89.4% (1.8% methyl ester impurity (5) and 4.6% compound (2)) with the following residual solvent amounts: methanol = 782 ppm, THF = 6157 ppm, toluene = 59 ppm and heptane = 64000 ppm.

[0109] It has been observed that purification steps carried out according to methods outside the present invention (i.e. using alternative solvent systems) give compound (1) in lower yields and with lower purity compared to conditions consistent with the present invention, and furthermore, the European Medicines Agency's ICH residual solvent requirements are not met.

Claims

1. A process for purifying a crude compound of formula (I) comprising the steps of: 【Chemistry 1】 Where: Each R is independently a hydrogen atom, a halogen atom, -CN, hydroxyl, (C 1 ~C 3 ) fluoroalkyl, (C 1 ~C 3 ) fluoroalkoxy, (C 3 ~C 6 ) Cycloalkyl, -NO 2 , -NR 1 R 2 , (C 1 ~C 4 ) Alkoxy, phenoxy, -NR 1 -SO 2 -NR 1 R 2 , -NR 1 -SO 2 -R 1 , -NR 1 -C(=O)-R 1 , -NR 1 -C(=O)-NR 1 R 2 , -SO 2 -NR 1 R 2 , -SO 3 H, -O-SO 2 -OR 3 ,-OP(=O)-(OR 3 )(OR 4 ), -O-CH 2 -COOR 3 Or (C 1 ~C 3 ) alkyl, wherein the alkyl may be mono- or disubstituted by a hydroxyl group, a group of formula (IIa) below or a group of formula (IIIa) below: 【Chemistry 2】 【Chemistry 3】 R 1 and R 2 Each of the groups independently represents a hydrogen atom or (C 1 ~C 3 ) alkyl; R 3 and R 4 Each of the is independently a hydrogen atom, Li+, Na+, K+, N+ (Ra) 4 or benzyl; Each R' is independently a hydrogen atom, (C 1 ~C 3 ) Alkyl, hydroxyl, halogen atom, -NO 2 , -NR 1 R 2 , morpholinyl, morpholino, N-methylpiperazinyl, (C 1 ~C 3 ) fluoroalkyl, (C 1 ~C 4 )Alkoxy, -OP(=O)-(OR 3 )(OR 4 ), -CN, a group of formula (IIa) below, or a group of formula (IIIa) below, 【Chemistry 4】 【Chemistry 5】 A is a covalent bond, an oxygen atom or NH; B is a covalent bond or NH; m is 1, 2, 3, 4 or 5; p is 1, 2 or 3; Each of Ra and Rb independently represents a hydrogen atom, (C 1 ~C 5 ) alkyl, or (C 3 ~C 6 ) cycloalkyl; or Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle, which is optionally substituted by one or more Ra, provided that, when R' is a (IIa) or (IIIa) group, n' may be 2 or 3 only if the other R' group is different from said (IIa) or (IIIa) group; and n is 1, 2 or 3; n' is 1, 2 or 3; wherein the process comprises a step of isolating the crude compound of formula (I), the step of isolating comprising (i) solubilizing the crude compound of formula (I) in methanol and precipitating with water; and (ii) Drying at a temperature of 30°C or less Including, The method.

2. Each R is independently a hydrogen atom, a halogen atom, or a -CN group, a hydroxyl group, -COOR 1 Group, (C 1 ~C 3 ) fluoroalkyl group, (C 1 ~C 3 ) Fluoroalkoxy group, -NO 2 group, -NR 1 R 2 Group, (C 1 ~C 4 ) alkoxy groups, phenoxy groups and (C 1 ~C 3 ) alkyl groups, wherein said alkyl is optionally monosubstituted by a hydroxyl group; R 1 and R 2 are independently a hydrogen atom or (C 1 ~C 3 ) alkyl group, n is 1, 2 or 3; n' is 1 or 2, and Each R' is independently a hydrogen atom or (C 1 ~C 3 ) Alkyl group, halogen atom, hydroxyl group, -COOR 1 group, -NO 2 group, -NR 1 R 2 group, a morpholinyl group or a morpholino group, an N-methylpiperazinyl group, (C 1 ~C 3 ) fluoroalkyl group, (C 1 ~C 4 ) an alkoxy group and an -CN group, 2. A process for purifying the crude compound of formula (I) according to claim 1.

3. Each R is independently a hydrogen atom, a halogen atom, or (C 1 ~C 3 ) fluoroalkyl group, (C 1 ~C 3 ) fluoroalkoxy group, -NR 1 R 2 Group, (C 1 ~C 4 ) alkoxy groups, phenoxy groups and (C 1 ~C 3 ) alkyl groups, wherein said alkyl is optionally monosubstituted by a hydroxyl group; R 1 and R 2 are independent, (C 1 ~C 3 ) alkyl group, n is 1, 2 or 3, preferably 1 or 2, even more preferably 1; n' is 1 or 2, preferably 1; and Each R' is independently a hydrogen atom or (C 1 ~C 3 ) alkyl group, halogen atom, -NR 1 R 2 Group, (C 1 ~C 3 ) fluoroalkyl group and (C 1 ~C 4 ) an alkoxy group; A process for purifying the crude compound of formula (I) according to claim 1 or 2.

4. The compound of formula (I) is a compound of formula (1): 【Chemistry 6】 A process for purifying the crude compound of formula (I) according to any one of claims 1 to 3.

5. 5. A process for purifying the crude compound of formula (I) according to any one of claims 1 to 4, wherein purification on a silica gel chromatography column, in particular purification on a silica gel chromatography column eluted with methylene chloride, methanol or a mixture thereof, is carried out, optionally prior to said purification a pretreatment of the silica gel is carried out.

6. This is preceded by a step of deprotecting the compound of formula (IV) using lithium, potassium or sodium hydroxide, in particular lithium hydroxide, in the presence of a solvent selected from aromatic hydrocarbons, such as toluene or xylene; ethers, such as tetrahydrofuran or methyl tert-butyl ether (MTBE), in particular tetrahydrofuran, at room temperature to obtain the compound of formula (I), 【Chemistry 7】 where R, R', n and n' are as defined in any one of claims 1 to 4, and each R" is (C 1 ~C 4 ) an alkyl group; The purification method according to any one of claims 1 to 5.

7. The compound of formula (IV) is the following compound (4): 【Chemistry 8】 The purification method according to claim 6.

8. Prior to the deprotection step, the compound of formula (III) is introduced into the solution in portions with CdCO 3 in the presence of an aromatic solvent, for example toluene or xylene, in particular in toluene, a compound of formula (II) below is reacted with a compound of formula (III) below to obtain a compound of formula (IV) below 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 where R, R', n and n' are as defined in any one of claims 1 to 4, and each R" is selected from the group consisting of (C 1 ~C 4 ) an alkyl group, in particular a methyl group, The purification method according to claim 6 or 7.

9. The compound of formula (II) is the following compound (2), and the compound of formula (III) is the following compound (3): 【Chemistry 12】 【Chemistry 13】 The purification method according to claim 8.

10. Introducing the compound of formula (III) in portions into the solution comprises adding the compound of formula (III) in two separate portions into the solution, where the first introduction is carried out at a molar ratio of the compound of formula (III) to the compound of formula (II) in the range of 0.6 to 1, in particular in the range of 0.7 to 0.9, and the second introduction is carried out at a molar ratio of the compound of formula (III) to the compound of formula (II) in the range of 0.6 to 1, in particular in the range of 0.7 to 0.9, where the sum of the molar ratios to the compound of formula (II) is 1.2 to 2, in particular 1.4 to 1.8, The purification method according to claim 9.

11. A process for preparing a compound of formula (I) as defined in any one of claims 1 to 4, comprising the steps of: In step 1, a compound of the following formula (III) is introduced into a solution in portions to form CdCO 3 reacting a compound of formula (II) with a compound of formula (III) in the presence of 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 where R, R', n and n' are as defined in any one of claims 1 to 4, and each R" is (C 1 ~C 4 ) an alkyl group; continuation, In step 2, the compound of formula (IV) is deprotected using lithium hydroxide, potassium hydroxide or sodium hydroxide, particularly lithium hydroxide, in the absence of hydrogen peroxide and in the presence of a solvent selected from an aromatic hydrocarbon, such as toluene or xylene; an ether, such as tetrahydrofuran or methyl tert-butyl ether (MTBE), particularly tetrahydrofuran, at room temperature to obtain a compound of formula (I): The manufacturing method comprising the steps of:

12. A process for preparing a crude compound of formula (I) as defined in any one of claims 1 to 4, said process further comprising the step of preparing a pharmaceutical composition comprising said compound of formula (I) together with a pharma- ceutically acceptable excipient.

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