WO2021224280A1 - Synthesis of a sickle cell disease agent and intermediates thereof - Google Patents

Abstract

New processes for preparing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)benzaldehyde, an agent developed for the treatment of sickle cell disease, and intermediates thereof, are provided herein.

Description

SYNTHESIS OF A SICKLE CELL DISEASE AGENT AND INTERMEDIATES

THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of Italian Application No. 102020000009970 filed May 05, 2020. This application also claims priority to and the benefit of Italian Application No. 102020000025135 filed October 23, 2020. The contents of both applications are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

New processes for preparing 2-hydroxy-6-((2-( 1 -isopropyl- 1 H-pyrazol-5- yl)pyri din-3 -yl)methoxy)benzaldehyde, an agent developed for the treatment of sickle cell disease, and intermediates thereof, are provided herein. BACKGROUND

2-Hydroxy-6-((2-( 1 -Nopropyl- 1 H-pyrazol-5 -yl)pyridin-3 - yl)methoxy)benzaldehyde, also known as voxelotor, with the following formula (I)

is a hemoglobin oxygen-affinity modulator, which showed in clinical trials to have the ability to increase hemoglobin levels and to decrease hemolysis indicators in sickle cell patients. Sickle cell disease is caused by a single amino acid substitution in the b chain of hemoglobin (Hb), wherein the hydrophobic amino acid βVal6 substitutes the hydrophilic βGlu6. The so formed sickle hemoglobin polymerizes when deoxygenated, and the resulting red-cell sickling and membrane damage lead to hemolysis, chronic anemia, inflammation, and vaso-occlusion. Voxelotor has been identified as a sickle hemoglobin polymerization inhibitor, which reversibly binds to hemoglobin and stabilizes the oxygenated hemoglobin state. Clinical studies demonstrated that voxelotor was able to significantly reduce anemia and hemolysis. Based on these results, on November 25, 2019, voxelotor gained its first global approval in the USA for the treatment of sickle cell disease in adults and paediatric patients aged 12 years or older.

Voxelotor is known from US 9,018,210, which claims the compound as such and pharmaceutically acceptable salts thereof.

The need of voxelotor at a purity suitable to meet the regulatory requirements has stimulated the search for alternative methods for its preparation, which at the same time have to be efficient, cost-effective and amendable to industrial scale manufacturing and purification.

The inventors of the present application have found a new and safe alternative method for the preparation of voxelotor and intermediates thereof, which thanks to the high yields and a minor presence of side products is particularly suitable for an industrial production. This new process, thanks to the particular reaction conditions, provides a highly pure product, which is suitable to meet regulatory requirements required for APIs (Active Pharmaceutical Ingredients).

SUMMARY OF THE INVENTION

One embodiment of the invention is directed to a process for preparing a compound of formula (II), or a salt thereof,

wherein R is hydrogen or an alcohol protecting group, comprising reacting a compound of formula (III), or a salt thereof,

wherein R is as defined above, with a compound of formula (IV), or a salt thereof,

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention is directed to a process for preparing a compound of formula (II), or a salt thereof,

wherein R is hydrogen or an alcohol protecting group, comprising reacting a compound of formula (III), or a salt thereof,

wherein R is as defined above, with a compound of formula (IV), or a salt thereof,

According to the present invention, by "comprising" is herein meant that additional steps may be taken in the process, which do not substantially change the product produced by the reaction. The term comprising encompasses the terms "consisting of' and "consisting essentially of.

An alcohol protecting group R can be a protective group known to the person skilled in the art, for example among those described by T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Synthesis" Third Edition Wiley, New York 1999. For instance, R may be selected from an ether, for example an allyl ether, an optionally substituted phenyl ether or an optionally substituted alkylphenyl ether, such as benzyl, p- halobenzyl, e.g. p-bromobenzyl, 2,6-dichlorobenzyl; or p-methoxybenzyl; an acetal, such as methoxymethyl (MOM), tetrahydropyranyl (THP), 2-methoxyethoxymethyl (MEM); or a silyl group.

The silyl protective group can be a C₁-C₆ alkyl silyl, an aryl silyl or an aralkyl silyl group, for example a tri-( C₁-C₆)-alkyl silyl or a tri-aryl-silyl, in particular trimethyl silyl, triethylsilyl, triispropylsilyl, di methyliopropylsilyl, tert-butyldimethylsilyl, diphenylmethylsilyl, triphenylsilyl and tribenzylsilyl. Preferably, the silyl group is trimethylsilyl, triethylsilyl or tert-butyldimethylsilyl, more preferably tert- butyldimethylsilyl.

The term " C₁-C₆ alkyl" refers to a straight, branched or cyclic hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms. In a preferred embodiment, the "C₁-C₆ alkyl" group is a linear or branched C₁-C₄ alkyl group. Examples include methyl, ethyl, n-propyl, /isopropyl, n-butyl, sec-butyl or tert- butyl.

The term "aryl" refers to a mono or bicyclic aromatic ring system of, respectively, 6, 9 or 10 atoms, such as benzene, indene and naphthalene and includes also indan and tetrahydronaphthal ene .

The term "aralkyl" refers to a straight, branched or cyclic hydrocarbon chain radical substituted by a mono or bicyclic aromatic ring system of, respectively, 6, 9 or 10 atoms. Examples include benzyl or 2-phenylethyl.

The term “salt” or “salts” of a compound of formula (II), (III), or (IV) refers to, for example, acid addition salts with inorganic acids, e.g., nitric, hydrochloric, hydrobromic, sulfuric and phosphoric acids and the like, or organic acids, e.g., acetic, propionic, glycolic, lactic, oxalic, malonic, malic, tartaric, citric, succinic, benzoic, cinnamic, mandelic, methanesulfonic, p-toluenesulfonic and salicylic acids, and the like.

The invention also includes various isomers and mixtures thereof.

The term "isomer" refers to compounds that have the same composition (molecular formula) and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers).

The term "geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration.

A compound of formula (II) may be converted into another compound of formula (II) according to known methods. For example, a compound of formula (II), wherein R is hydrogen, can be converted into another compound of formula (II), wherein R is an alcohol protecting group, according to methods well known in the art. Vice versa, a compound of formula (II), wherein R is an alcohol protecting group, can be deprotected into a compound of formula (II), wherein R is hydrogen, according to well-known methods for the deprotection of the hydroxylic functions.

For example, the hydroxyl group can be protected as ether by reaction with dihydropyran, unsubstituted or substituted benzyl halides or a silyl halide, wherein the halide can be chloride or bromide.

For instance, the silylation reaction of a compound of formula (II), wherein R is hydrogen, into a compound of formula (II), wherein R is an silyl group, can be carried out in the presence of a solvent, for example in a dipolar aprotic solvent, typically dimethylformamide, dimethylacetamide, acetonitrile, or dimethyl sulfoxide; in an ethereal solvent, typically tetrahydrofuran or dioxane; in an apolar aprotic solvent, such as hexane or toluene; or in a mixture of two or more, for example two or three, of the solvents listed above. A preferred solvent is toluene or a dipolar aprotic solvent, typically dimethylformamide, dimethylacetamide, acetonitrile, or dimethylsulfoxide.

The silylation reaction can be carried out at a temperature between about -10 °C and the reflux temperature of the solvent, preferably between about 0 °C to about 80 °C, for instance at about 0 °C, at about 15 °C, at about 25 °C, at about 35 °C, at about 45 °C, at about 55 °C, at about 60 °C or at about 70 °C.

The cleavage of the tetrahydropyran or the silyl ether can be performed for example by treatment with an acid, and the cleavage of the benzyl protecting group by hydrogenation.

The cleavage of the silyl ether can be performed for example by treatment with a mineral acid or organic acid.

A mineral acid can be for example selected from the group comprising sulfuric acid, phosphoric acid and a hydrohalic acid, for example hydrochloric acid.

In a preferred embodiment, the mineral acid is an aqueous solution of hydrochloric acid, for example at approximately 2 molar, 6 molar or 12 molar concentration.

An organic acid can be for example selected from the group comprising a sulfonic acid, typically camphorsulfonic acid, para-toluene sulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid; a carboxylic acid, typically benzoic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, 2,3-dibenzoil tartaric acid, mandelic acid, 3- chloromandelic acid, or abietic acid; and a C₁-C₄ alkyl-carboxylic acid, wherein the C₁-C₄ alkyl group may be linear or branched, optionally substituted by one or more halogen atoms, for example one to three chlorine or fluorine atoms, typically acetic acid or trifluoroacetic acid.

Alternatively, the silyl group may be cleaved using hydrogen fluoride (HF) or tetra- //-butylammonium fluoride (TBAF).

According to one embodiment, the reaction of the compound of formula (III) with the compound of formula (IV) can be carried out without any further solvent (neat).

According to another embodiment, if the case, the reaction of the compound of formula (III) with the compound of formula (IV) can be carried out in the presence of a solvent, which can be for example a polar aprotic solvent, such as dimethylformamide, dimethylacetamide, A -m ethyl pyrrol i done, acetonitrile or dimethylsulfoxide; or an acyclic or cyclic ether, for example methyl /c/7- butyl ether, tetrahydrofuran or dioxane; a chlorinated solvent, for example, dichloromethane, dichloroethane, chloroform or chlorobenzene; an apolar aprotic solvent, typically toluene; a polar protic solvent, typically a linear or branched C₁-C₆ alcohol, for example a C₁-C₄ alcohol, typically methanol, ethanol, n-propanol, is opropanol or n-butanol; or a mixture of two or more, for example two or three, of said solvents.

In a preferred embodiment, the reaction of the compound of formula (III) with the compound of formula (IV) can be carried out in ethanol.

In one embodiment, the reaction of the compound of formula (III) with the compound of formula (IV) can be carried out at a temperature raging from about 0 °C and the reflux temperature of the solvent.

In a preferred embodiment, the reaction of the compound of formula (III) with the compound of formula (IV) can be carried out at room temperature. The reaction time is typically about 0.5 hour to 48 hours, for instance about 1 hour, about 2.5 hours, about 4 hours, about 6 hours, about 9 hours, about 12 hours, about 18 hours, about 24 hours or about 36 hours.

In case R is hydrogen, the compound of formula (III) may form a compound of formula (Ilia), or a salt thereof,

which is equally suitable for preparing a compound of formula (II) at the same conditions as outlined above.

The salt of a compound of formula (Ilia) can be, for example, an acid addition salt with inorganic acids, e.g., nitric, hydrochloric, hydrobromic, sulfuric and phosphoric acids and the like, or organic acids, e.g., acetic, propionic, glycolic, lactic, oxalic, malonic, malic, tartaric, citric, succinic, benzoic, cinnamic, mandelic, methanesulfonic, p-toluenesulfonic and salicylic acids, and the like.

The herein claimed process for preparing an intermediate of formula (II) from the compound of formula (III) is particularly advantageous compared to the process described in US 9,018,210, page 73, because it allows obtaining exclusively the compound of formula (II) and not the corresponding pyrazol-3-yl isomer. Indeed, the process of US 9,018210, page 73, starting from the 3-(dimethylamino)-prop-2-en-l-one compound furnishes a mixture of pyrazol-3-yl and 5-yl isomers at a yield after purification on silica gel using EtOAc as eluent of 71% and 25%, respectively [US 9,018210, page 73, lines 46-60],

The herein claimed process for preparing an intermediate of formula (II) from the compound of formula (III), is of particular advantage, because the compound of formula (II) can be obtained without employing chromatography, for instance ion-exchange chromatography, normal or reverse column chromatography, such as silica gel chromatography.

A compound of formula (III) may be converted into another compound of formula (III) according to known methods. For example, a compound of formula (III), wherein R is hydrogen, can be converted into another compound of formula (III), wherein R is an alcohol protecting group, according to methods well known in the art, for instance by methods as described above. Vice versa, a compound of formula (III), wherein R is an alcohol protecting group, can be deprotected into a compound of formula (III), wherein R is hydrogen, according to well-known methods for the deprotection of the hydroxylic functions, for instance by methods described above.

The compound of formula (III), or a salt thereof,

wherein R is as defined above is a new compound and is a further embodiment of the invention.

The compound of formula (Ilia), or a salt thereof,

is a new compound and is a further embodiment of the invention.

The compounds of formula (III) or of formula (Ilia) may be individual isomers, for instance single geometric isomers, or an isomeric mixture.

The compound of formula (IV), or a salt thereof, is a known compound and is commercially available. For instance, the hydrochloride salt is commercialized by Sigma Aldrich (catalogue number: CDS002842).

The compound of formula (III) or of formula (Ilia) can be for instance be prepared by a process comprising reacting a compound of formula (V), or a salt thereof,

wherein R is as defined above, first with a compound of formula (VI)

wherein X is a halide, and then with morpholine.

The salt of a compound of formula (V) can be, for example, an acid addition salt with inorganic acids, e.g., nitric, hydrochloric, hydrobromic, sulfuric and phosphoric acids and the like, or organic acids, e.g., acetic, propionic, glycolic, lactic, oxalic, malonic, malic, tartaric, citric, succinic, benzoic, cinnamic, mandelic, methanesulfonic, p-toluenesulfonic and salicylic acids, and the like.

The halide can be chloride, bromide or iodide.

In one embodiment, the Grignard reaction of the compound of formula (V) with the compound of formula (VI) can be carried out in an ether-based solvent such as tetrahydrofuran (THF), diethyl ether, di-isopropyl ether, dimethoxyethane and the like.

In a preferred embodiment, the Grignard reaction of the compound of formula (V) with the compound of formula (VI) can be carried out in tetrahydrofuran (THF).

The reaction may be advantageously carried out using about 4.0 to about 0.6 moles of the ethynylmagnesium compound of formula (VI) per mole of compound of formula (V).

In a preferred embodiment, the reaction may be carried out using from about 3.0 to about 1.1 moles of the ethynylmagnesium compound of formula (VI) per mole of compound of formula (V), more preferably from about 2.5 to about 1.5 moles, for instance 2.0 moles.

The Grignard reaction may be performed at a temperature below room temperature, preferably below 10 °C, for instance at 4 °C or below or at about 0 °C.

An alternative to the ethynylmagnesium compound of formula (VI), triphenyl silyl acetylene or an organolithium reagent, such as methyllithium, n-butyllithium, sec-butyl lithium, /c/V-butyllithium, hexyllithium or phenyllithium, may be used.

The morpholine formed in the reaction of a compound of formula (V) with the ethynylmagnesium compound of formula (VI) subsequently adds to the triple bond forming the compound of formula (III) or (Ilia).

In one embodiment, no further morpholine is added to the reaction mixture.

In one embodiment, subsequently to the Grignard reaction additional morpholine can be added.

In a further embodiment, before adding morpholine, the obtained reaction mixture can be quenched, for instance by adding water or an ammonium chloride solution in water.

The term “quenching” or “quenched” means decomposing a reactive species in order to stop a reaction and to convert intermediate products to stable materials which can be isolated or removed without danger.

The quenching step and the addition of morpholine can be carried out keeping the temperature of the reaction mixture below 30° C, for instance at room temperature.

The procedure of the compound of formula (V) with the ethynylmagnesium compound of formula (VI) and morpholine can be carried out in the same vessel or reactor.

The herein claimed process for preparing an intermediate of formula (III) or of (Ilia) from the compound of formula (V), is of particular advantage, because the intermediate of formula (III) or of (Ilia) can be obtained without employing chromatography, for instance ion-exchange chromatography, normal or reverse column chromatography, such as silica gel chromatography.

The compound of formula (V), or a salt thereof,

wherein R is as defined above, is a new compound and is a further embodiment of the invention.

The ethynylmagnesium compound of formula (VI), for instance ethynylmagnesium chloride or bromide, is a known compound and is commercially available. For instance, ethynylmagnesium chloride or bromide solutions are commercialized by Sigma Aldrich (catalogue numbers for chloride: 346160, bromide: 346152).

The compound of formula (V), or a salt thereof,

wherein R is as defined above, may be prepared from pyridine-2, 3-dicarboxylic acid of formula (VII), or a salt thereof,

The herein disclosed process for preparing an intermediate of formula (III) or of (Ilia) from the compound of formula (V), is of particular advantage, because the intermediate of formula (III) or of (Ilia) can be obtained without employing chromatography, for instance ion-exchange chromatography, normal or reverse column chromatography, such as silica gel chromatography.

Pyridine-2, 3-dicarboxylic acid of formula (VII) is a known compound and is commercially available. For instance, it is commercialized by Sigma Aldrich (catalogue number: P63204).

For instance, the compound of formula (V), or a salt thereof,

wherein R is as defined above, can be prepared by a process comprising reacting the compound of formula (VIII), or a salt thereof,

with morpholine, and if the case, the conversion of a compound of formula (V) into another compound of formula (V).

A compound of formula (V) may be converted into another compound of formula (V) according to known methods. For example, a compound of formula (V), wherein R is hydrogen, can be converted into another compound of formula (V), wherein R is an alcohol protecting group, according to methods well known in the art, for instance by methods as described above. Vice versa, a compound of formula (V), wherein R is an alcohol protecting group, can be deprotected into a compound of formula (V), wherein R is hydrogen, according to well-known methods for the deprotection of the hydroxylic functions, for instance by methods as described above.

The compound of formula (VIII), or a salt thereof,

is a known compound and can be prepared according to known methods, for instance as described by Nandhikonda et al. in Org. Letters 2010, 12, 4796-4799 or by He et al. in Angewandte Chemie Int. Ed. 2011, 50, 5192-5196.

For instance, the compound of formula (VIII), or a salt thereof, can be prepared from pyridine-2, 3-dicarboxylic acid of formula (VII)

Pyridine-2, 3-dicarboxylic acid of formula (VII) can be first reacted with acetic anhydride forming pyridine-2, 3-dicarboxylic anhydride and then with an alcohol forming the compound of formula (IX)

wherein R¹ is C₁-C₆ alkyl, and C₁-C₆ alkyl is as defined above.

The compound of formula (IX), wherein R¹ is methyl, can be then converted into the compound of formula (VIII) for instance by activating the carboxylic acid of the compound of formula (IX), for instance with thionyl chloride or oxalyl chloride, and then treating the activated acid with a reducing agent, for instance with sodium borohydride (NaBH₄).

Alternatively to the use of thionyl chloride, the acid can be activated according to well-known methods, for instance by treatment with carbonyldiimidazole, isobutyl chloroformate or bis-trichloromethylcarbonate. According to a further embodiment of the invention, the compound of formula (IX), wherein R¹ is C₁-C₆ alkyl, can be converted in a compound of formula (V), or a salt thereof,

wherein R is as defined above, by a process comprising activating the carboxylic acid of the compound of formula (IX), or a salt thereof, for instance with thionyl chloride or oxalyl chloride, and then treating the activated acid with a reducing agent, for instance with sodium borohydride (NaBTB), and then with morpholine. Alternatively to the use of thionyl chloride or oxalyl chloride, the acid can be activated according to well-known methods, for instance by treatment with carbonyldiimidazole, isobutyl chloroformate or bis-trichloromethylcarbonate.

According to a further embodiment of the invention, the compound of formula (IX), wherein R¹ is C₁-C₆ alkyl, can be converted into a compound of formula (V), or a salt thereof,

wherein R is as defined above, by a process comprising reacting first with thionyl chloride, then with a reducing agent, for instance with sodium borohydride (NaBH₄), and finally with morpholine, and if the case protecting the hydroxyl group according to procedures as defined above.

The term “salt” or “salts” of a compound of formula (VII), (VIII), or (IX) refers to, for example, acid addition salts with inorganic acids, e.g., nitric, hydrochloric, hydrobromic, sulfuric and phosphoric acids, and the like, or organic acids, e.g., acetic, propionic, glycolic, lactic, oxalic, malonic, malic, tartaric, citric, succinic, benzoic, cinnamic, mandelic, methanesulfonic, p-toluenesulfonic and salicylic acids, and the like. Alternatively, salts of a compound of formula (VII), (VIII), or (IX) may be derived from an appropriate base, such as salts of an alkali metal (such as sodium or potassium), an alkaline earth metal (such as calcium or magnesium), ammonium and NR'₄ ⁺, wherein each of R', which can be the same or different, is a C₁-C₆ alkyl.

Alternatively, the compound of formula (II), or a salt thereof,

wherein R is hydrogen, can be prepared by reacting a compound of formula (X)

wherein R² and R³ are, independently, hydrogen; C₁-C₆ alkyl; or taken together with the boron atom to which they are bound form a ring, with a compound of formula (XI)

wherein Z is halogen, in the presence of a palladium catalyst and a base.

A compound of formula (X) is a known compound and is commercially available. For instance, (l-isopropyl-lH-pyrazol-5-yl)boronic acid is commercialized by Sigma Aldrich (catalogue number: CDS023420).

A compound of formula (XI) is a known compound and is commercially available. For instance, (2-bromopyridin-3-yl)methanol is commercialized by Sigma Aldrich (catalogue number: AMBH93E4C447). The palladium catalyst includes for instance palladium acetate (Pd(OAc)₂), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄), bis(triphenylphosphine)palladium(II) di chloride (PdCl₂(PPh₃)₂) or [1, 1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride, or tris(dibenzylideneacetone)dipalladium.

In a preferred embodiment, the palladium catalyst is bis(triphenylphosphine)palladium(II) dichloride or tris(dibenzylideneacetone)dipalladium.

In one embodiment, the base for the Suzuki type reaction includes for instance lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate or calcium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium hydrogen carbonate or calcium hydrogen carbonate, sodium phosphate, potassium phosphate, magnesium phosphate or calcium phosphate.

In a preferred embodiment, the base for the Suzuki type reaction is sodium hydrogen carbonate or potassium phosphate. A further embodiment of the invention further comprises a process for preparing a compound of formula (I)

from a compound of formula (II), or a salt thereof,

wherein R is hydrogen or an alcohol protecting group.

According to an embodiment, if the case, the compound of formula (II), wherein R is an alcohol protecting group, may be first converted into a compound of formula (II), wherein R is hydrogen, according to conditions described above.

According to a further embodiment, the compound of formula (II), wherein R is hydrogen, can be then converted into a compound of compound of formula (XII), or a salt thereof,

wherein Y is a leaving group by conventional methods, for instance by treatment with SOC1₂ to provide the corresponding compound of formula (XII), wherein Y is chloride, or with toluenesulfonyl chloride or methanesulfonyl chloride to obtain the compound of formula (XII), wherein Y is tosylate or mesylate.

According to a preferred embodiment, the leaving groups Y in a compound of formula (XII) include halogen, mesylate, tosylate, benzenesulfonate, trifluoromethanesulfonate, and the like.

The halogen substituent Y in a compound of formula (XII) may be a chloride, bromide or iodide atom.

According to a preferred embodiment, the substituent Y in a compound of formula (XII) is chloride.

Salts of a compound of formula (XII) include, for example, acid addition salts with inorganic acids, e.g., nitric, hydrochloric, hydrobromic, sulfuric and phosphoric acids, and the like, or organic acids, e.g., acetic, propionic, glycolic, lactic, oxalic, malonic, malic, tartaric, citric, succinic, benzoic, cinnamic, mandelic, methanesulfonic, p-toluenesulfonic and salicylic acids, and the like.

Alternatively, the compound of formula (XII) may be prepared according to known methods, for instance as described in ACS Med Chem. Lett. 2017, 8, 321-326 or in US 9,018,210.

Then, the compound of formula (I) can be prepared by a process comprising reacting the compound of formula (XII) with 2,6-dihydroxybenzaldehyde of formula

(XIII)

in presence of a base.

2,6-Dihydroxybenzaldehyde of formula (XIII) is a known compound and is commercially available. For instance, 2,6-dihydroxybenzaldehyde is commercialized by Sigma Aldrich (catalogue number: AMBH2D6F5229).

The base may be a non-nucleophilic organic base or an inorganic base.

The non-nucleophilic organic base is typically triethylamine, di/.vopropy 1 ethyl am i ne, A-G-G, alkyl pyrrolidines, A-G-G, alkyl morpholine, diazabicycloundecene, pyridine, C₁-C₆ alkyl pyridines, C₁-C₆ alkyl piperazines, di-C₁-C₆ alkyl piperazines, wherein "C₁-C₆ alkyl" is as defined above.

The inorganic base is typically a hydroxide, a carbonate, a hydrogen carbonate, or a phosphate of an alkali metal or of an alkaline earth metal. Examples of inorganic bases are sodium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate or calcium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium hydrogen carbonate or calcium hydrogen carbonate, sodium phosphate, potassium phosphate, magnesium phosphate or calcium phosphate.

According to a preferred embodiment, the inorganic base is potassium carbonate. Said base may be typically used in an at least stoichiometric quantity in respect to the compound of formula (XII). In case, the reaction is carried out with a salt of a compound of formula (XII), a further stoichiometric quantity of the base in respect to the compound of formula (XII) may be used.

The reaction of a compound of formula (XII) with a compound of formula (XIII) can be carried out in presence of an iodide salt.

According to one embodiment, the iodide salts include lithium iodide, sodium iodide, potassium iodide, or tetra-n-butylammonium iodide. The iodide salt can be added in equimolar amounts or in defect with respect to the amount of the compound of formula (XII). For instance, the iodide salt can be added in catalytic quantities, such as at about 0.01, 0.05, 0.10 or 0.15 moles of the iodide salt with respect to one mole of the compound of formula (XII).

The reaction may be advantageously carried out using about 1.6 to about 0.7 moles of 2,6-dihydroxybenzaldehyde of formula (XIII) per mole of compound of formula (XII), preferably from about 1.4 to about 0.8 moles, more preferably from about 1.1 to about 0.9 moles, for instance in equimolar amounts.

In one embodiment, the reaction of a compound of formula (XII) with a compound of formula (XIII) can be carried out in presence of acetonitrile.

The present reaction conditions of a compound of formula (XII) with a compound of formula (XIII) with acetonitrile are particularly advantageous, even at equimolar amounts of a compound of formula (XIII) and of a compound of formula (XII), since they allow obtaining the desired compound of formula (I) at high purity and with a low content of the impurity of formula (XIV)

The impurity of formula (XIV) is formed by alkylation of both hydroxyl groups. The present reaction conditions advantageously suppress the formation of the impurity of formula (XIV). Consequently, there is no need of using a twofold excess of 2,6- dihydroxybenzaldehyde of formula (XIII) as disclosed in Examples 17 and 18 of US 9,018,210. Thus, the process of the present disclosure is particularly advantageously even at equimolar amounts of a compound of formula (XIII) and of a compound of formula (XII), because it allows avoiding any procedure for recovering the excessive amounts of dihydroxybenzaldehyde of formula (XIII) or the formation of excessive waste.

The reaction of a compound of formula (XII) with a compound of formula (XIII) may be performed at temperatures from about room temperature to the reflux temperature of the reaction mixture. The reaction may be carried out, for example, at a temperature of at about 30°C or above, or at about 40°C or above, for instance at about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, or about 75°C.

According to a preferred embodiment, the reaction can be carried out at a temperature of at about 30°C or above, or at about 40°C or above, for instance at about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, or about 75°C, more preferably at about 65°C.

The reaction time of a compound of formula (XII) with a compound of formula (XIII) is typically about 0.5 hour to 48 hours, for instance about 1 hour, about 2.5 hours, about 4 hours, about 6 hours, about 9 hours, about 12 hours, about 18 hours, about 24 hours or about 36 hours.

The reaction of a compound of formula (XII) with a compound of formula (XIII) in acetonitrile can be carried out in acetonitrile as sole solvent or in a mixture of acetonitrile and further solvents. These further solvents can be chosen from a dipolar aprotic solvent, typically dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-pyrrolidone (NMP) or dimethylsulfoxide (DMSO); an ether, typically tetrahydrofuran or dioxane; Ci- C₆ alkyl esters of a carboxylic acid, wherein the C₁-C₆ alkyl group can be linear or branched, for example methyl acetate, ethyl acetate (EtOAc), propyl acetate, isopropyl acetate or butyl acetate; or a mixture of two or more, for example two or three, of the above mentioned solvents.

In one embodiment, the reaction of a compound of formula (XII) with a compound of formula (XIII) is carried out in acetonitrile and in absence of any further solvent.

The term “solvent” herein is meant as a substance capable of dissolving the compounds of the reaction mixture to a sufficient extent to form a homogeneous mixture.

Thus, thanks to the particular reaction conditions and reagents, a compound of formula (I) obtained by this process and prior to further purification steps has already a chemical purity determined by HPLC at 254 nm greater than 95% (Area %), typically around 96 to 98%, and wherein the content of impurity of formula (XIV) is lower than 1%, typically around 0.6 to 0.9% or lower.

A further embodiment of the invention is directed to a process for preparing 2- hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde of formula (I) as defined above comprising reacting a compound of formula (XII), or a salt thereof, as defined above, with 2,6-dihydroxybenzaldehyde of formula (XIII), wherein the reaction is carried out in presence of a base and acetonitrile, and wherein the process is carried out without any purification step by chromatography. Said process may be advantageously carried out using about 1.6 to about 0.7 moles of 2,6- dihydroxybenzaldehyde of formula (XIII) per mole of compound of formula (XII), preferably from about 1.4 to about 0.8 moles, more preferably from about 1.1 to about 0.9 moles, for instance in equimolar amounts.

The compound of formula (XII) can be prepared according to the procedures disclosed herein as described above or according to known methods, for instance as described in ACS Med Chem. Lett. 2017, 8, 321-326 or in US 9,018,210.

In a preferred embodiment, the process for preparing 2-hydroxy-6-((2-(l-isopropyl- lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde of formula (I) comprising reacting a compound of formula (XII), or a salt thereof, with 2,6-dihydroxybenzaldehyde of formula (XIII), is carried out using about one mole of 2,6-dihydroxybenzaldehyde of formula (III) per mole of compound of formula (II).

In one embodiment, the reaction of a compound of formula (XII) with a compound of formula (XIII) can be carried out using one mole of 2,6-dihydroxybenzaldehyde of formula (III) per mole of compound of formula (II), and wherein the reaction is carried out in presence of a base and acetonitrile, preferably at 65°C. The compound of formula (I) with a purity suitable to meet regulatory requirements required for APIs can be obtained without employing chromatography, for instance silica gel chromatography. Optionally, the reaction of a compound of formula (XII) with a compound of formula (XIII) can be carried out in presence of an iodide salt, which can be added in catalytic quantities, preferably as at about 0.01, 0.05, 0.10 or 0.15 moles of the iodide salt with respect to one mole of the compound of formula (XII). The compound of formula (XII) can be prepared according to the procedures disclosed herein as described above or according to known methods, for instance as described in ACS Med Chem. Lett. 2017, 8, 321-326 or in US 9,018,210.

The reaction mixture containing the compound of formula (I) may be purified by known methods. For example, the reaction mixture may be concentrated, optionally under reduced pressure.

At this point, the obtained compound of formula (I) can be further purified by chromatography, for instance by ion-exchange chromatography, normal or reverse column chromatography, such as silica gel chromatography.

Alternatively, the obtained compound of formula (I) may be recrystallized to further increase the degree of purity, for instance according to the methods described in US 9,447,071.

In a preferred embodiment, the compound of formula (I) with a purity suitable to meet regulatory requirements required for APIs can be obtained without employing chromatography, for instance ion-exchange chromatography, normal or reverse column chromatography, such as silica gel chromatography.

The inventors of the present application have surprisingly found that the compound of formula (I) prepared according to the present process has a chemical purity, evaluated by HPLC at 254 nm, equal to or greater than 99.8% (Area %), preferably equal to or greater than 99.9%, more preferably equal to or greater than 99.97%, and wherein each impurity is typically present in a percentage equal to or less than 0.1%, for instance in a percentage equal to or less than 0.05%, preferably equal to or less than 0.03%, more preferably equal to or less than 0.01%. The compound of formula (XIV) as impurity is typically present in a percentage equal to or less than 0.1%, preferably less than 0.05%, for example at about 0.03%, about 0.01%, about 0.005%, about 0.001%, or about 0.0005%. Said pure product can be even obtained without using a chromatography, for instance ion-exchange chromatography, normal or reverse column chromatography, such as silica gel chromatography.

A further embodiment of the invention comprises the use of the compound of formula (III), or a salt thereof,

wherein R is as defined above; or of the compound of formula (Ilia), or a salt thereof,

or of pyridine-2, 3-dicarboxylic acid of formula (VII)

in a process for the preparation of the compound of formula (I)

The following examples further illustrate, but do not limit, the invention. Example 1 - Synthesis of 2,3-Pyridinedicarboxylic Anhydride

A suspension of pyridine-2, 3-dicarboxylic acid (40.0 g, 239 mmol) of formula (VII) and acetic anhydride (45.7 mL, 49.5 g, 484 mmol) was warmed in an oil bath to 147 °C (bath temp) over 25 minutes before becoming homogeneous. The reaction was allowed to cool to room temperature over 2.5 h. The solids which formed were filtered off, washed twice with diethyl ether and air dried to give 26.2 g (73%) of 2,3-pyridinedicarboxylic anhydride as a white solid. Concentrating the filtrate and recrystallizing the residue from acetic anhydride yielded an additional 3.56 g (10%) of 2,3-pyridinedicarboxylic anhydride as a white solid. ¹H NMR (400 MHz, DMSO-d₆) ∂ ppm 7.95 (dd, J= 7.82, 4.89 Hz, 1 H) 8.54 (dd, J=7.82, 1.34 Hz, 1 H) 9.15 (dd, J=4.83, 1.41 Hz, 1 H). Example 2 - Synthesis of 2-(Methoxycarbonyl)nicotinic acid of Formula (IX)

A suspension of 2,3-pyridinedicarboxylic anhydride (Example 1, 20.0 g, 134 mmol) and methanol (100 mL, 2469 mmol) was warmed to reflux. The reaction became homogeneous upon heating. After refluxing for 25 min, the reaction mixture was concentrated in vacuo and the resulting crude oil was dissolved in hot ethyl acetate (EtOAc) (100 mL). The solution was then cooled to room temperature. The crystals which formed were filtered off and dried with a nitrogen press to give 14.4 g (59%) of 2- (methoxycarbonyl)nicotinic acid of formula (IX) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) ∂ ppm 3.84 (s, 3 H) 7.67 (dd, J=7.95, 4.77 Hz, 1 H) 8.29 (dd, J=7.95, 1.59 Hz, 1 H) 8.76 (dd, 7=4.83, 1.53 Hz, 1 H) 13.76 (br. s., 1 H).

Example 3 - Synthesis of Furo[3,4-b]pyridin-7(5H)-one of Formula (VIII)

A white suspension of2-(methoxycarbonyl)nicotinic acid of formula (IX) (Example 2, 21.6 g, 119 mmol) and thionyl chloride (86.9 mL, 142 g, 1.19 mol) was warmed to reflux. The reaction mixture became homogeneous with heating. After warming for 1 h, the mixture was concentrated in vacuo. The crude yellow oil was stirred with dry THF and concentrated in vacuo. In this fashion the thionyl chloride was chased from the reaction three more times with dry THF. The crude residue was dissolved in dry THF (100 mL) and the reaction mixture was cooled in an ice water bath to 5 °C. To the cold reaction mixture was added sodium borohydride (4.51 g, 119 mmol). After 50 min, HPLC and TLC (ethyl acetate, EtOAc) of an aliquot of the reaction quenched in methanol indicated that the reaction was 63% complete. Additional sodium borohydride (1.44 g, 38.1 mmol) was added. After an additional 3 hours the reaction was removed from the ice bath and allowed to stir for another hour before carefully pouring onto crushed ice (500 mL). The quenched reaction was stirred overnight. The aqueous reaction mixture was extracted with dichloromethane (6 x 100 mL). The combined di chi orom ethane layers were dried with magnesium sulfate and concentrated in vacuo to give 9.50 g (59%) of furo[3,4-b]pyridin- 7(5H)-one of formula (VIII) as a tan solid that was 100% pure by HPLC and used without further purification. ¹H NMR (400 MHz, CDC1₃) ∂ ppm 5.40 (s, 2 H) 7.59 (dd, 7=7.82, 4.65 Hz, 1 H) 7.94 (d, J=7.82 Hz, 1 H) 8.91 (d, 7=4.65 Hz, 1 H). Example 4 - Synthesis of 4-{[3-({[terf-Butyl(dimethyl)silyl]oxy}methyl)pyridin- 2-yl]carbonyl}morpholine of Formula (V)

Into a solution of furo[3,4-b]pyridin-7(5H)-one of formula (VIII) (Example 3, 9.48 g, 70.2 mmol) and acetonitrile (480 mL) was added morpholine (6.73 mL, 6.72 g, 77.2 mmol) followed by lH-imidazole (5.73 g, 84.2 mmol) and then tert-butyldimethylsilyl chloride (12.7 g, 84.2 mmol). The reaction mixture was warmed to 60 °C. After 19 h, HPLC showed that the reaction was 30% complete. Additional morpholine (6.12 mL, 6.11 g, 70.2 mmol) was added and the reaction was held at 60 °C. After 43 h, HPLC showed the reaction was 87% complete. Additional morpholine (6.12 mL, 6.11 g, 70.2 mmol) was added and the temperature was maintained. After 46.5 h, HPLC showed the reaction was 92% complete. lH-Imidazole (1.05 g, 15.4 mmol) and tert-butyl dimethyl silyl chloride (2.33 g, 15.4 mmol) were added to the warm reaction. After warming for 67 hours at 60 °C, HPLC showed that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with dichloromethane (625 mL) and washed with water (300 mL). The organic layer was washed with brine (1 x 300 mL, 1 x 150 mL), dried with magnesium sulfate and concentrated in vacuo. The crude product was dissolved in methyl tert -butyl ether (MTBE, 350 mL) and washed with brine (2 x 100 mL), dried with sodium sulfate and concentrated in vacuo to give 23.6 g (100%) of 4-{ [3-( { tert - butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]carbonyl}morpholine of formula (V) as a tan waxy solid that was 99% pure by HPLC and which was used without further purification. ¹H NMR (400 MHz, CDC1₃) d ppm 0.13 (s, 6 H) 0.95 (s, 9 H) 3.24 - 3.39 (m, 2 H) 3.59 - 3.72 (m, 2 H) 3.75 - 3.92 (m, 4 H) 4.81 (s, 2 H) 7.35 (dd, J= 7.95, 4.77 Hz, 1 H) 7.94 (dt, J=7.86, 0.72 Hz, 1 H) 8.48 (dd, J=4.77, 1.47 Hz, 1 H). LCMS (ESI) m/z: [M+H] calcd for C₁₇H₂₈N₂O₃Si: 336.19; found: 337.2. Example 5 - Synthesis of l-[3-({[terf-Butyl(dimethyl)silyl]oxy}methyl)pyridin-

2-yl]-3-morpholin-4-ylprop-2-en-l-one of Formula (III)

A solution of 4-{[3-({[ tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2- yljcarbonyl (morpholine of formula (V) (Example 4, 23.6 g, 70.2 mmol) and dry THF (200 mL) was cooled in an ice water bath to 3 °C. A solution of 0.5 M ethynylmagnesium chloride of formula (VI) in THF (281 mL, 140 mmol) was added over 25 min keeping the temperature <4 °C. The ice bath was allowed to warm to room temperature. After 5 hours the temperature had reached 17 °C. The reaction was quenched with saturated aqueous ammonium chloride (350 mL). The temperature of the reaction rose to 27 °C. Morpholine (4.90 mL, 4.89 g, 56.2 mmol) was added to the reaction mixture. After 30 min of stirring at room temperature, the reaction mixture was diluted with water (500 mL) and extracted with MTBE (3 x 110 mL). The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give 25.8 g (>100%) of 1 -[3-(i \tert- butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]-3-morpholin-4-ylprop-2-en-l-one of formula (III) as a viscous dark oil that was 87% pure as two geometric isomers (11.4:1), which was used in the next step without further purification. 'H NMR (400 MHz, CDC1₃) d ppm 0.12 (s, 6 H) 0.96 (s, 9 H) 3.36 - 3.50 (m, 4 H) 3.68 - 3.82 (m, 4 H) 5.16 (s, 2 H) 6.35 (d, J= 12.72 Hz, 1 H) 7.39 (dd, J=7.95, 4.65 Hz, 1 H) 7.67 (d, J=13.08 Hz, 1 H) 8.12 - 8.21 (m, 1 H) 8.45 - 8.56 (m, 1 H). LCMS (ESI) m/z: [M+H] calcd for C₁₈H₃₀N₂O₃Si: 362.20; found: 363.3.

Example 6 - Synthesis of 3-({[terf-Butyl(dimethyl)silyl]oxy}methyl)-2-(l- isopropyl-lH-pyrazol-5-yl)pyridine of Formula (II)

Isopropyl hydrazine hydrochloride of formula (IV) (12.6 g, 114 mmol) was added to a solution of 1 -[3-( { [ tert-butyl(dimethyl)silyl]oxy }methyl)pyridin-2-yl]-3-morpholin-4- ylprop-2-en-l-one of formula (III) (Example 5, 25.5 g, 70.2 mmol) and ethanol (300 mL). After stirring 14 hours at room temperature the reaction was concentrated in vacuo. The residue was partitioned between MTBE (400 mL) and a saturated aqueous solution of sodium bicarbonate (200 mL). The aqueous layer was washed with MTBE (3 x 100 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (100 mL) and then with brine (150 mL), dried with sodium sulfate and concentrated in vacuo to give 22.6 g (97%) of 3-({[ tert-butyl(dimethyl)silyl]oxy}methyl)- 2-( 1 -/^'.vopropyl- 1 H-pyrazol-5-yl)pyridine of formula (II) as a dark oil that was 93% pure by HPLC, which was used in the next step without further purification. ¹H NMR (400 MHz, CDC1₃) d ppm 0.06 (s, 6 H) 0.92 (s, 9 H) 1.45 (d, J= 6.72 Hz, 6 H) 4.53 (spt, J= 6.62 Hz, 1 H) 4.62 (s, 2 H) 6.30 (d, J=1.83 Hz, 1 H) 7.37 (dd, J= 7.82, 4.77 Hz, 1 H) 7.60 (d, J=1.71 Hz, 1 H) 8.00 (dd, J=7.95, 0.73 Hz, 1 H) 8.62 (dd, J=4.77, 1.47 Hz, 1 H). LCMS (ESI) m/z: [M+H] calcd for C₁₈H₂₉N₃OSi: 331.21; found: 332.2.

Example 7 - Synthesis of [2-(1-Isopropyl-lH-pyrazol-5-yl)pyridin-3- yljmethanol of Formula (II)

6 M HC1 (aq) (25 mL, 150 mmol) was added to a solution of 3 -{{[tert- butyl(dimethyl)silyl]oxy [methyl )-2-( 1 -Is opropyl- 1 H-pyrazol-5-yl)pyridine of formula (II) (Example 6, 21.7 g, 65.6 mmol) and ethanol (100 mL). After 2 hours the reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc (600 mL) and a saturated aqueous solution of sodium bicarbonate (300 mL). The aqueous layer was diluted with additional saturated sodium bicarbonate (100 mL) and with brine (100 mL) and extracted with EtOAc (3 x 200 mL). The combined EtOAc layers were washed with brine, dried with sodium sulfate and concentrated in vacuo to give 15.7 g (90%) of [2-(l- isopropyl-lH-pyrazol-5-yl)pyridin-3-yl]methanol of formula (II) as a dark oil that contained 15 wt% residual tert-bMutRyl (dim ethyl )silanol (TBDMSOH) but was 100% pure by HPLC. This material was used in the next step without further purification. ¹H NMR (400 MHz, CDC1₃) d ppm 1.44 (d, J=6.72 Hz, 6 H) 2.38 (br. s., 1 H) 4.52 (spt, J= 6.62 Hz, 1 H) 4.63 (s, 2 H) 6.34 (d, J=1.83 Hz, 1 H) 7.38 (dd, J=7.82, 4.77 Hz, 1 H) 7.57 (d, J=1.71 Hz, 1 H) 7.97 (dd, J=7.82, 1.47 Hz, 1 H) 8.64 (dd, J=4.77, 1.59 Hz, 1 H). LCMS (ESI) m/z: [M+H] calcd for C_I2H_I5N₃0: 217.12; found: 218.1.

Example 8 - Synthesis of 3-(Chloromethyl)-2-(l-isopropyl-lH-pyrazol-5- yl)pyridine hydrochloride of Formula (XII)

Thionyl chloride (70.0 mL, 960 mmol) was added to a solution of [2-(l-Aopropyl- lH-pyrazol-5-yl)pyridin-3-yl]methanol of formula (II) (Example 7, 15.7 g, 59.1 mmol) and dichloromethane (200 mL). After 5 hours the reaction mixture was concentrated to dryness in vacuo. The residual thionyl chloride was chased from the residue by stirring with toluene and concentrating in vacuo. This step was repeated three more times. The residue was dried in vacuo to give 17.8 g (>100%) of 3-(chloromethyl)-2-( 1-isopropyl-1H-pyrazol-5- yl)pyridine hydrochloride of formula (XII) as a brown solid that was 98% pure by HPLC and clean enough to be used in the next step. ¹H NMR (400 MHz, CD₃OD) d ppm 1.49 (d, J= 6.60 Hz, 6 H) 4.32 (spt, =6.54 Hz, 1 H) 4.69 (s, 2 H) 6.83 (d, =2.08 Hz, 1 H) 7.87 (d, .J=1.96 Hz, 1 H) 8.22 (dd, .7=8.19, 5.62 Hz, 1 H) 8.87 (dd, .7=8.13, 1.41 Hz, 1 H) 8.99 (dd, J= 5.62, 1.47 Hz, 1 H). LCMS (ESI) m/z: [M+H] calcd for C₁₂H₁₄CIN₃: 235.09; found: 236.1.

Example 9 - Synthesis of 2-Hydroxy-6-{[2-(1-isopropyl-1H -pyrazol-5- yl)pyridin-3-yl]methoxy}benzaldehyde of Formula (I)

Acetonitrile (175 mL) was added to a mixture of 3-(chloromethyl)-2-( 1iso propyl- lH-pyrazol-5-yl)pyridine hydrochloride of formula (XII) (Example 8, 17.5 g, 64.3 mmol), 2,6-dihydroxybenzaldehyde (9.84 g, 67.7 mmol), tetra-//-butylammonium iodide (940 mg, 2.6 mmol), and potassium carbonate (18.7 g, 136 mmol). The reaction was warmed in oil bath to 60 °C. After 5 h, the reaction was concentrated in vacuo. The residue was partitioned between EtOAc (400 mL) and aqueous saturated ammonium chloride (400 mL). The aqueous layer was extracted with EtOAc (200 mL), diluted with water (200 mL) and extracted with EtOAc (200 mL). The combined organic phases were diluted with EtOAc (200 mL) and washed with saturated ammonium chloride (2 x 100 mL), brine (1 x 200 mL) and aqueous Na₂S₂O₃ (100 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo to give a thick orange residue. The residue was dissolved in EtOAc and loaded onto a plug of Magnesol XL (350 g) (https://magnesol.com/, MAGNESOL® is a product of The Dallas Group of America) that had been equilibrated with EtOAc. Four 450 mL fractions that contained 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3- yl]methoxy}benzaldehyde of formula (I) contaminated with traces of 2,6- dihydroxybenzaldehyde were collected. These fractions of impure product were combined and concentrated in vacuo. The residue (19.2 g) was recrystallized from approximately 80 mL of isopropanol (IP A) : water (1:1) to give 15.0 g (69%) of 2-hydroxy-6-{[2-(l- /.vopropyl- 1 H-pyrazol-5-yl)pyridin-3-yl]methoxy [benzaldehyde of formula (I) as a tan solid that was 98% pure by HPLC. ¹H NMR (400 MHz, CDCh) d ppm 1.48 (d, J= 6.60 Hz, 6 H) 4.66 (spt, J= 6.62 Hz, 1 H) 5.09 (s, 2 H) 6.27 (d, J=8.19 Hz, 1 H) 6.36 (d, J=1.83 Hz, 1 H) 6.58 (d, J=8.44 Hz, 1 H) 7.33 - 7.49 (m, 2 H) 7.61 (d, J=1.83 Hz, 1 H) 7.98 (dd, J=7.95, 1.47 Hz, 1 H) 8.76 (dd, J=4.77, 1.59 Hz, 1 H) 10.38 (s, 1 H) 11.94 (s, 1 H). MS (ESI) m/z: [M+H] calcd for C19H19N3O3: 337.14; found: 338.2.

Example 10 - Synthesis of [2-(l-Isopropyl-1H-pyrazol-5-yl)pyridine-2- yl]methanol of Formula (II)

In a 500 mL round bottom flask fitted with magnetic stir bar, (2-bromopyridin-3- yl)methanol of formula (XI) (10.01 g, 53.24 mmol), 1,4-dioxane (166.2 mL), water (40 mL), potassium phosphate (33.70 g, 158.8 mmol) and (l-isopropyl-lH-pyrazol-5- yl)boronic acid of formula (X) (14.13 g, 89.02 mmol) were degassed and placed under a nitrogen atmosphere. Dicyclohexyl(2^,,4^,,6’-triisopropylbiphenyl-2-yl)phosphine (XPhos ligand) (1.00 g, 2.10 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.975 g, 1.065 mmol) were added and the reaction vessel again degassed under nitrogen. Then a long needle was inserted into the solvent and the reaction was slowly sparged with nitrogen for 10 minutes. The reaction was then placed into a 90°C oil bath and stirring begun. The reaction was heated for 2.5 hours and allowed to cool. The reaction was then poured into EtOAc (250 mL), placed into a separatory funnel and washed with water (50 mL) twice. The organic phase was washed with brine (50 mL) and dried over magnesium sulfate. The combined aqueous phase was back extracted with EtOAc (100 mL). The organic phase was washed with brine (50 mL). The combined organic extracts were treated with Darco (2 g, activated charcoal) by stirring for 30 minutes then filtered to remove Darco and drying agent. The solvent was removed from the filtrate by rotary evaporation to provide the crude product as a pale-yellow oil (16.03 g). The product was purified by silica gel chromatography (300 g), eluting with a gradient (35-90%) EtOAc in hexane to provide 2- (l-isopropyl-lH-pyrazol-5-yl)pyridine-2-yl]methanol of formula (II) (7.9 g, 68%) as a pale yellow oil. ¹H NMR (400 MHz, CDCI3) d 8.67 (ddj = 4.8, 1.6 Hz, 1H), 7.98 (dd,j = 7.9, 1.7 Hz, 1H7.61 (d J = 1.7 Hz, 1H), 7.39 (ddj = 7.9, 4.8 Hz, 1H), 6.37 (d J = 1.8 Hz, 1H), 4.66 (d J = 5.5 Hz, 2H), 4.55 (sptj = 6.6 Hz, 1H), 1.47 (d J = 6.6 Hz, 6H). MS m/z calcd for C12H15N3O: 217.12, calc’ d for [M + H]⁺: 218.1, found: 218.2.

Example 11 - Synthesis of 3-(Chloromethyl)-2-(l-isopropyl-1H-pyrazol-5- yl)pyridine hydrochloride of Formula (XII)

In a 250 mL round bottom flask fitted with a magnetic stir bar, under a nitrogen atmosphere and cooled in an ice water bath, a solution of [2-(l-isopropyl-lH-pyrazol-5- yl)pyridine-3-yl] methanol of formula (II) (Example 10, 8.18 g, 37.6 mmol) in dichloromethane (70 mL) was stirred. Thionyl chloride (5.49 mL, 75.3 mmol) was added over 5 minutes. After the addition was complete, the ice bath was removed, and the reaction allowed to warm to room temperature. Hexane (300 mL) was added and a white solid formed immediately. The reaction was cooled in a refrigerator for 4 hours and filtered. The white solid was air dried overnight to give 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5- yl)pyridine hydrochloride of formula (XII) (9.15 g, 89%) as a white powder. 'H NMR (400 MHz, CD3OD) d 8.93 (dd,j = 5.4, 1.5 Hz, 1H), 8.71 (ddj = 8.2, 1.5 Hz, 1H), 8.08 (ddj = 8.1, 5.4 Hz, 1H), 7.84 (d, j = 2 Hz, 1H), 6.78 (d J = 2.1 Hz, 1H), 4.69 (s, 2H), 4.35 (sptj = 6.6 Hz, 1H), 1.49 (d J = 6.6 Hz, 6H). MS m/z calcd for C12H14CIN3: 235.1, calc’d for [M + H]⁺: 235.1, found: 236

Example 12 - Synthesis of 2-Hydroxy-6-{[2-(l-isopropyl-1H-pyrazol-5- yl)pyridin-3-yl]methoxy}benzaldehyde of Formula (I)

Tetra-n-butylammonium iodide (1.44 g, 3.89 mmol) was added to a magnetically stirred mixture of 2,6-dihydroxybenzaldehyde (5.66 g, 38.9 mmol) of formula (XIII), 3- (chloromethyl)-2-(isopropyl- 1H-pyrazol-5-yl (pyridine hydrochloride of formula (XII) (Example 11, 10.6 g, 38.9 mmol), and potassium carbonate (10.8 g, 77.9 mmol) in acetonitrile (690 mL). The reaction mixture was then warmed to 50°C and stirring was continued for 9 hours, after which the reaction was allowed to cool to room temperature with continued stirring overnight. The reaction was filtered through a silica gel plug (60 g). The funnel was rinsed twice with acetonitrile (100 mL each) and the filtrate concentrated by evaporation under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate (EtOAc)/hexanes gradient = 1:1 to 2:1) to afford the 2- hydroxy-6-{[2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl]methoxy}benzaldehyde of formula (I) (13.7 g) as a pale-yellow oil that slowly crystallized. The product was further purified by recrystallizing from EtOAc and hexane (1 : 10, v:v) to provide white crystals that were filtered and rinsed with cold hexane (11.7 g, 89%). ¹H NMR (400 MHz, CDC1₃) d 11.95 (s, 1H), 10.39 (s, 1H), 8.77 (dd,j = 4.8, 1.6 Hz, 1H), 8.00 (dd,j = 7.9, 1.5 Hz, 1H), 7.63 (d J = 1.8 Hz, 1H), 7.45 (dd,j = 7.8, 4.8 Hz, 1H), 7.39 (t J = 8.4 Hz, 1H), 6.59 (d J = 8.4 Hz, 1H), 6.37 (d J = 1.8 Hz, 1H), 6.29 (d J = 8.2 Hz, 1H), 5.10 (s, 2H), 4.68 (m, 1H), 1.50 (d J = 6.6 Hz, 6H). MS m/z [M + H]⁺ calcd for C19H19N3O3: 337.1, calc’d for [M + H]⁺: 338.1, found: 338.1.

Example 13 - Synthesis of 2-hydroxy-6-{[2-(l-isopropyl-lH-pyrazol-5- yl)pyridin-3-yl]methoxy}benzaldehyde of Formula (I) in Acetonitrile (ACN), Dimethylformamide (DMF) and N-Methyl-pyrrolidone (NMP)

Tetra-n-butylammonium iodide (27 mg, 0.072 mmol) was added to a magnetically stirred mixture of 2,6-dihydroxybenzaldehyde (0.10 g, 0.72 mmol) of formula (XIII), 3- (chloromethyl(-2-(isopropyl- 1H-pyrazol-5-yl (pyridine hydrochloride of formula (XII) (0.21 g, 0.72 mmol), and potassium carbonate (0.20 g, 1.4 mmol) in acetonitrile, DMF or NMP (10 mL). The reaction mixture was then warmed to 65°C. After 2.5 hours stirring at 65 °C, a sample was taken from the solution and analysed by HPLC at a wavelength of 254 nm.

The results of the amount of the formed 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol- 5-yl)pyridin-3-yl)methoxy)benzaldehyde of formula (I) as well as of the starting reagent, 3 -(chi oromethyl(-2-(isopropyl-1H-pyrazol-5-yl (pyridine hydrochloride of formula (XII), and the dimeric impurity of formula (XIV)

are summarized in the following Table 1:

Table 1

The results show that after 2.5 hours at 65 °C the conversion of 3-(chloromethyl)- 2-(isopropyi-1H-pyrazol-5-yl (pyridine of formula (XII) with 2,6-dihydroxybenzaldehyde of formula (XIII) into 2-hydroxy-6-{[2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3- yl]methoxy}benzaldehyde of formula (I) is almost complete in all three solvents, with the content of the compound of formula (XII) of about 0.5% or less. At the same time, the content of the dimeric impurity of formula (XIV) is 0.95% in acetonitrile, wherein the amount is about ten times higher or more in DMF and NMP.

DMF was the solvent used in Examples 17 and 18 of US 9,018,210 for the preparation of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3- yl)methoxy)benzaldehyde of formula (I), but in both examples a 2 times excess of 2,6- dihydroxybenzaldehyde of formula (XIII) over 3-(chloromethyl)-2-(isopropyl-1H- pyrazol-5-yl)pyridine of formula (XII) was employed.

NMP was the solvent used in Example 3 of US 10,077,249 for the preparation of 2- hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde of formula (I), wherein the reaction of 2,6-dihydroxybenzaldehyde of formula (XIII) with 3- (chloromethyl(-2-(isopropyl-1H-pyrazol-5-yl (pyridine of formula (XII) were carried out at equimolar conditions or with an excess of up to 5% of 2,6-dihydroxybenzaldehyde of formula (XIII). However, US 10,077,249 did not furnish any yields of the desired 2- hydroxy-6-((2-(l-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde of formula (I).

Claims

1 A process for preparing a compound of formula (II), or a salt thereof,

comprising reacting a compound of formula (III), or a salt thereof,

with a compound of formula (IV), or a salt thereof,

and wherein R is hydrogen or an alcohol protecting group.

2. The process according to claim 1, wherein the process of preparing a compound of formula (III), or a salt thereof, further comprises the steps of reacting a compound of formula (V), or a salt thereof,

wherein R is as defined in claim 1, first with a compound of formula (VI)

wherein X is a halide, or with triphenyl silyl acetylene, and then with morpholine.

3. The process according to claim 2, wherein the compound of formula (V), or a salt thereof, is prepared from pyridine-2, 3-dicarboxylic acid of formula (VII), or a salt thereof,

4. The process according to claim 2, wherein the process of preparing a compound of formula (V), or a salt thereof, further comprises the steps of reacting the compound of formula (VIII), or a salt thereof,

with morpholine, and if the case, converting a compound of formula (V) into another compound of formula (V).

5. The process according to claim 4, wherein the process of preparing a compound of formula (VIII), or a salt thereof, further comprises the steps of: - reacting pyridine-2, 3-dicarboxylic acid of formula (VII) with acetic anhydride forming pyridine-2, 3-dicarboxylic anhydride, and then with an alcohol forming the compound of formula (IX),

wherein R¹ is a methyl;

- activating the carboxylic acid of the compound of formula (IX), for instance with thionyl chloride or oxalyl chloride,

- and treating the activated acid with a reducing agent, for instance with sodium b orohydride (NaBH₄) .

6. The process according to claim 2, wherein the method of preparing of compound of formula (V), or a salt thereof, further comprises the steps of:

- activating the carboxylic acid of the compound of formula (IX), or a salt thereof,

wherein R¹ is C₁-C₆ alkyl, - treating the activated acid with a reducing agent, for instance with sodium borohydride (NaBH₄), and then with morpholine.

7. The process according to claims 1 to 6 further comprising a process for preparing a compound of formula (I),

8. The process according to claim 7, wherein the process of preparing a compound of formula (I) further comprises the steps of:

- if the case, deprotecting the compound of formula (II), wherein R is an alcohol protecting group into a compound of formula (II), wherein R is hydrogen;

- converting the compound of formula (II), wherein R is hydrogen, into a compound of compound of formula (XII), or a salt thereof,

wherein Y is a leaving group; and

- reacting the compound of formula (XII) with 2,6-dihydroxybenzaldehyde of formula (XIII),

in presence of a base.

9. The process according to claim 8, wherein the reaction of the compound of formula (XII) with 2,6-dihydroxybenzaldehyde of formula (XIII) is carried out in presence of acetonitrile.

10. The process according to claims 8 or 9, wherein the leaving group Y in a compound of formula (XII) is chloride, bromide, iodide, mesylate, tosylate, benzenesulfonate, or trifluoromethanesulfonate.

11. The process according to claims 9 or 10, wherein the reaction of the compound of formula (XII) with 2,6-dihydroxybenzaldehyde of formula (XIII) is carried out in presence of an iodide salt.

12. The process according to claims 9 to 11, wherein the base in the reaction of the compound of formula (XII) with 2,6-dihydroxybenzaldehyde of formula (XIII) is a non- nucleophilic organic base or an inorganic base.

13. The process according to claims 9 to 12, wherein the reaction of the compound of formula (XII) with 2,6-dihydroxybenzaldehyde of formula (XIII) is carried out in acetonitrile and in absence of any further solvent.

14. A process for preparing 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3- yl)methoxy)benzaldehyde of formula (I),

comprising reacting a compound of formula (XII), or a salt thereof, as defined in claim 8 with 2,6-dihydroxybenzaldehyde of formula (XIII), wherein the reaction is carried out in presence of a base and acetonitrile, and wherein the process is carried out without any purification step by chromatography.

15 he process according to claim 14, wherein the process is carried out using about one mole of 2,6-dihydroxybenzaldehyde of formula (III) per mole of compound of formula

(II)

16. A compound selected from the group comprising:

- a compound of formula (III), or a salt thereof,

- a compound of formula (Ilia), or a salt thereof,

- a compound of formula (V), or a salt thereof,

and wherein R is as defined in claim 1.

17. Use of a compound selected from:

- a compound of formula (III), or a salt thereof,

- a compound of formula (Ilia), or a salt thereof,

- a compound of formula (V), or a salt thereof,

wherein R is as defined in claim 1; or - a compound of formula (VII),

in a process for the preparation of the compound of formula (I),