Process for preparing n-(6-((1h-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol- 3-yl)-2-methoxybenzenesulfonamide

Abstract

The present invention relates to a process for preparing N-(6-((1H-pyrazol-1- yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide.

Description

[0001] Process for preparing / V-(6-((1 H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol- 3-yl)-2-methoxybenzenesulfonamide

[0002] Field of the Invention

[0003] The present invention is directed to a process for preparing / V-(6-((1 H-pyrazol-1 - yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide or a salt thereof and intermediates useful in the preparation of this compound.

[0004] Background of the Invention

[0005] A / -(6-((1 H-pyrazol-1 -yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2- methoxybenzenesulfonamide (also referred herein as “Compound 1”) is a compound which act as a Lysine Acetyl Transferase (KAT) inhibitor of the MYST family and may thus have utility in the treatment of abnormal cell growth, such as cancer, in patients. It may also be identified under the chemical name 2-methoxy- / V-{4-methoxy-6-[(1 H- pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide and is of formula:

[0006] Compound 1 and its synthesis according to two alternative routes have been described in example 45 of the PCT international patent application published as WO 2020 / 254946, the content of which is incorporated herein by reference in its entirety. The preparation of the anhydrous free acid Form 1 of Compound 1 is also described therein as example 45b. These synthetic routes to Compound 1 are however not adapted for large scale preparation. There is thus a need to propose a manufacturing process enabling the preparation of large quantities of Compound 1 in a safe and cost- effective way. While batch production has been the standard for pharmaceutical manufacturing for decades, continuous flow manufacturing presents advantages such as reduction in facility size and energy consumption, decreased cost, improved quality, and increased flexibility and productivity that far outweigh the advantages of the batch manufacturing approach. Accordingly, the development of a synthetic route enabling the continuous flow production of Compound 1 at large scale is particularly desirable.

[0007] Summary of the Invention

[0008] The present invention provides intermediates and synthetic steps for preparing

[0009] Compound 1 using the route which is depicted below in Scheme 1 :

[0010] Scheme 1

[0011] Step 2

[0012] Int-1 lnt-2 lnt-3 wherein the hydroxide salts used in step 2 and 3 may be the same or different and are preferably selected from a hydroxide salt of an alkali metal ( / TOFT) or a hydroxide salt of a tetraalkyl or benzyltrialkyl ammonium or phosphonium (NR4+OH_or PR4+OH’). The process of the present invention contains several differences compared to previously disclosed processes for preparing Compound 1 , which are described in detail below. Also, the process of the present invention is particularly advantageous because it enables continuous flow manufacturing in addition to batch production.

[0013] Detailed Description of the Invention

[0014] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.

[0015] The following embodiments, E1 to E28 are representative embodiments of the present invention.

[0016] According to a first embodiment E1 , the present invention relates to a process for preparing the compound of Formula lnt-4: comprising the step of reacting the compound of formula lnt-3: with hydroxylamine or a salt thereof in the presence of a hydroxide salt. E2 The process of embodiment E1 wherein the hydroxide salt is a tetraalkylammonium hydroxide, a benzyltrialkylammonium hydroxide, a tetraalkylphosphonium hydroxide or an alkali metal hydroxide.

[0017] E3 The process of embodiment E2 wherein the hydroxide salt is selected from the group consisting of sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, tetrahexylammonium hydroxide, benzyltrimethylammonium hydroxide and tetrabutylphosphonium hydroxide.

[0018] E4 The process of embodiment E3 wherein the hydroxide salt is tetrabutylphosphonium hydroxide, tetraethylammonium hydroxide, benzyltrimethylammonium hydroxide or tetrapropylammonium hydroxide.

[0019] E5 The process of embodiment E4 wherein the hydroxide salt is tetrapropylammonium hydroxide.

[0020] E6 The process of any one of embodiments E1 to E5 wherein the hydroxylamine or salt thereof is selected from the group consisting of hydroxylamine, hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine phosphate, hydroxylammonium oxalate and hydroxylamine 4-methylbenzenesulfonate.

[0021] E7 The process of embodiment E6 wherein the hydroxylamine or salt thereof is hydroxylamine sulfate.

[0022] E8 The process of any one of embodiments E1 to E7 wherein the step of reacting the compound of formula lnt-3 is performed in a solvent which is selected from the group consisting of acetonitrile, tetrahydrofuran and a mixture thereof.

[0023] E9 The process of any one of embodiments E1 to E8 wherein the compound of formula lnt-3 is prepared by: a) reacting a compound of formula lnt-1 : with methanesulfonyl chloride (MsCI) or methanesulfonic anhydride (MS2O) in the presence of a base in anhydrous conditions to form the compound of formula lnt-2: and b) immediately reacting the compound of formula lnt-2 with pyrazole, optionally in the presence of a hydroxide salt, to afford the compound of formula lnt-3.

[0024] E10 The process of any one of embodiments E1 to E8 wherein the compound of formula lnt-3 is prepared by: a) reacting a compound of formula lnt-1 : with methanesulfonic anhydride (MS2O) in the presence of a base in anhydrous conditions to form the compound of formula lnt-2: and b) reacting the compound of formula lnt-2 with pyrazole, optionally in the presence of a hydroxide salt, to afford the compound of formula lnt-3. E11 The process of embodiment E9 wherein the base used in step a) is selected from the group consisting of / V, / V-diisopropylethylamine (DIPEA), lithium te / Y-butoxide, diisopropylaniline, / V-methylmorpholine, / V-methylimidazole, triethylamine and pyridine.

[0025] E12 The process of embodiment E10 wherein the base used in step a) is diisopropylethylamine (DIPEA).

[0026] E13 The process of any one of embodiments E9 to E11 wherein step b) of the reaction is performed in the presence of a hydroxide salt.

[0027] E14 The process of embodiment E12 wherein the hydroxide salt is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, tetrahexylammonium hydroxide, benzyltrimethylammonium hydroxide and tetrabutylphosphonium hydroxide.

[0028] E15 The process of embodiment E13 wherein the hydroxide salt is benzyltrimethylammonium hydroxide or tetrapropylammonium hydroxide.

[0029] E16 The process of any one of embodiments E9 to E14 wherein step b) of the reaction is performed in the presence of a hydroxide salt which is identical to the hydroxide salt used in any one of embodiments E1 to E8.

[0030] E17 The process of any one of embodiment E9 to E15 wherein step b) of the reaction is performed in the presence of an excess of hydroxide salt and pyrazole compared to the amount of compound of formula lnt-2.

[0031] E18 The process of any one of embodiments E9 to E16 wherein the steps a) and b) of reacting the compounds of formula lnt-1 and lnt-2 are performed in a solvent which is selected from the group consisting of acetonitrile, tetrahydrofuran, water and a mixture thereof. E19 The process of any one of embodiments E9 to E16 wherein the steps a) and b) of reacting the compounds of formula lnt-1 and lnt-2 are performed in a solvent which is selected from the group consisting of acetonitrile, tetrahydrofuran and a mixture thereof.

[0032] E20 The process of any one of embodiments E1 to E17 wherein the compound of formula lnt-4 is further reacted with the compound of formula lnt-5: in the presence of a branched alkoxide salt to afford Compound 1 of formula:

[0033] E21 The process of embodiment E18 wherein the branched alkoxide salt is added after the addition of the compounds of formula lnt-4 and lnt-5 is complete.

[0034] E22 The process of any one of embodiments E18 to E19 wherein the branched alkoxide salt is a branched sodium alkoxide or a branched potassium alkoxide.

[0035] E23 The process of embodiment E20 wherein the branched alkoxide salt is sodium te / t-butoxide or sodium te / t-pentoxide.

[0036] E24 The process of any one of embodiments E18 to E21 wherein the step of reacting the compound of formula lnt-4 is performed in a solvent which is tetrahydrofuran or acetonitrile.

[0037] E25 The process of embodiment E22 wherein the solvent is tetrahydrofuran.

[0038] E26 A process for preparing Compound 1 of formula: comprising the steps of:

[0039] 1 ) reacting a compound of formula lnt-1 : lnt'1 with methanesulfonyl chloride (MsCI) in the presence of anhydrous diisopropylethylamine (DIPEA) in a mixture of acetonitrile and tetrahydrofuran to afford the compound of formula lnt-2: lnt-2

[0040] 2) adding pyrazole and aqueous tetrapropylammonium hydroxide to the mixture of step 1 to afford the compound of formula lnt-3:

[0041] 3) adding hydroxylamine sulfate dissolved in water and aqueous tetrapropylammonium hydroxide to the mixture of step 2 to afford the compound of formula lnt-4: lnt-4

[0042] OCH3

[0043] 4) and reacting the compound of formula lnt-4 with 2-methoxybenzenesulfonyl chloride of formula lnt-5: in the presence of sodium te / Y-butoxide or sodium te / Y-pentoxide in tetrahydrofuran to afford Compound 1 .

[0044] E27 A process for preparing Compound 1 of formula: comprising the steps of:

[0045] 1 ) reacting a compound of formula lnt-1 : with methanesulfonic anhydride (MS2O) in the presence of anhydrous / \ / , / \ / ~ diisopropylethylamine (DIPEA) in a mixture of acetonitrile and tetrahydrofuran to afford the compound of formula lnt-2: lnt-2

[0046] 2) adding pyrazole and aqueous tetrapropylammonium hydroxide to the mixture of step 1 to afford the compound of formula lnt-3: 3) adding hydroxylamine sulfate dissolved in water and aqueous tetrapropylammonium hydroxide to the mixture of step 2 to afford the compound of formula lnt-4: lnt-4 OCH3

[0047] 4) and reacting the compound of formula lnt-4 with 2-methoxybenzenesulfonyl chloride of formula lnt-5: in the presence of sodium te / Y-butoxide in tetrahydrofuran to afford Compound 1.

[0048] E28 The process of any one of embodiments E1 to E25 wherein Compound 1 is further recrystallized in a suitable solvent. E29 The process of embodiment E26 wherein the suitable solvent is selected from the group consisting of acetonitrile, a mixture of acetonitrile and toluene, a mixture of acetonitrile and tetrahydrofuran, and a mixture of acetonitrile and ethanol.

[0049] E30 The process of embodiment E27 wherein the suitable solvent is a mixture of acetonitrile and toluene, preferably a mixture of acetonitrile to toluene in a 70:30 ratio.

[0050] In the process described above and as depicted in Scheme 1 , the reaction of step 1 may be performed at a temperature comprised between about 5°C and about 75°C, the reaction of step 2 may be performed at a temperature comprised between about 25°C and about 70°C, preferably about 25°C and about 85°C, the reaction of step 3 may be performed at a temperature comprised between about 25°C and about 90°C, preferably between about 50°C and about 70°C, more preferably between about 65°C and about 80°C and the reaction of step 4 may be performed at room temperature.

[0051] The synthetic steps described in Scheme 1 present several advantages compared to previously known synthetic routes for preparing Compound 1. In particular, the specific conditions of steps 1 and 2, specifically the MsCI or MS2O activation and the introduction of a hydroxide base in step 2, allow faster kinetics and provide a better impurity profile than the reaction described in WO 2020 / 254946 (preparation of compound A-1 in example 01 , Scheme A). The introduction of the hydroxide base in step 2 also substantially reduces the reaction time compared to a process with no additional base. When appropriately selected, the conditions of steps 1 and 2 are also homogeneous thus enabling continuous flow manufacturing. In addition, the use of hydroxylamine or a salt thereof for formation of the isoxazole in step 3 is quite unique. In WO 2020 / 254946, the formation of the isoxazole is indeed performed by reacting Int- 3 with acetohydroxamic acid (preparation of compound A-2 in example 01 , Scheme A). However, this reactant has a poor safety profile which makes it unsuitable for large scale manufacturing. The use of hydroxylamine or a salt thereof to form a benzoisoxazole has already been described in the literature for different compounds (Bioorganic & Medicinal Chemistry Letters, Volume 21 , Issue 21 , 1 November 2011 , Pages 6253-6257 and J. Med. Chem., 2008, 51 , 6280-6292). However these articles describe a multi-step process with different reaction conditions passing through an aldehyde and are referring to small-scale experiments. A multi-step process is more costly, and less environmentally friendly than the single-step process proposed herein. Additionally, the literature syntheses pose safety concerns due to the potential to generate the highly toxic and corrosive hydrofluoric acid (HF), which requires the introduction of additional controls to ensure the safety of the operators and the public when performed on a large scale. This is because the literature conditions involve an acid-promoted cyclization following the nucleophilic aromatic substitution (SuAr) on an aryl fluoride, which is completely avoided by the basic conditions employed in step 3 of the process of the present invention. In WO 2006 / 090224, the use of a salt of hydroxylamine has also been described. Specifically, hydroxylamine sulfate is used in combination with potassium carbonate and sodium sulfite to form 4-(2,2,2- trifluoroethoxy)-1 ,2-benzisoxazol-3-ol starting from methyl 2-hydroxy-6-(2,2,2- trifluoroethoxy)benzoate (example 1 ) and hydroxylamine hydrochloride is used in combination with potassium hydroxide in methanol to form 4-isobutoxy-1 ,2- benzisoxazol-3-ol starting from methyl 2-hydroxy-6-isobutoxybenzoate (example 8). Besides the fact that different compound structures are involved in both examples, the reactions described seem extremely inefficient as they involve 30 hours and 2.5 days stirring respectively, which is not amenable to large scale production and continuous flow processing. On the contrary, step 3 of the present process has been shown to be very efficient with formation of lnt-4 with a good yield and limited amounts of impurities in less than 1 hour. The conditions used in step 3 are also homogenous and compatible with the conditions of steps 1 and 2, hence allowing steps 1 , 2 and 3 to be performed in a telescoped fashion and continuous mode. Finally, the introduction of a sodium salt as the base for the coupling of step 4 has been observed to prevent side reactions hence resulting in improved impurity profile.

[0052] Alternatively, the steps depicted in Scheme 1 may be reordered as depicted in

[0053] Scheme 2 below: Scheme 2 lnt-4

[0054] The difference resides in the formation of the benzoisoxazole in the first step followed by the installation of the pyrazole moiety rather than the other way round. The reaction conditions nevertheless remain essentially the same as those described for Scheme 1 above in embodiments E1 to E28. Similar advantages as detailed above for Scheme 1 are also observed for the corresponding reaction steps of Scheme 2. 2-Fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile (lnt-1 ) may be prepared as described in WO 2020 / 254946 Scheme 1 . Alternatively, lnt-1 may be synthetized in three steps starting from commercial 4-bromo-2,6-difluorobenzonitrile as shown below:

[0055] The first step is a SNAC on 4-bromo-2,6-difluorobenzonitrile with sodium methoxide in methanol. This step is followed by halogen-metal exchange with a Grignard reagent (cyclohexylmagnesium chloride) to form a nucleophilic species which reacts with DMF to afford 2-fluoro-4-formyl-6-methoxybenzonitrile. The aldehyde is converted into its bisulfite adduct to aid purification, prior to isolation. Finally, reduction of the aldehyde to the alcohol with LiBF delivers the desired compound lnt-1 .

[0056] For convenience, many chemical moieties and compounds are represented using well known abbreviations, including: BnNMesOH (benzyltrimethylammonium hydroxide), Bn (benzyl), BTMG (2-tert-Butyl-1 ,1 ,3,3-tetramethylguanidine), CFCh (trichlorofluoromethane), CH3CN (acetonitrile), CH3OH or MeOH (methanol), CyMgCI (cyclohexylmagnesium chloride), DIPEA ( / V, / V-diisopropylethylamine), DMF ( / V, / V- dimethylformamide), HCI (hydrochloric acid), HF (hydrofluoric acid), LiBH4 (Lithium borohydride), LiHMDS (lithium hexamethyldisilazide), Ms (mesylate or methanesulfonate), MsCI (methanesulfonyl chloride), MS2O (methanesulfonic anhydride), MTBD (7-Methyl-1 ,5,7-triazabicyclo[4.4.0]dec-5-ene), NaHSOs (sodium bisulfite), NaOH (sodium hydroxide), NaOMe (sodium methoxide), NaOtBu (sodium te / t-butoxide), NH2OH (hydroxylamine), Pr4NOH (tetrapropylammonium hydroxide), SuAr (nucleophilic aromatic substitution), THF (tetrahydrofuran) and TMS (tetramethylsilane).

[0057] In addition, HPLC-MS refers to high-performance liquid chromatography-mass spectrometry, LCMS refers to liquid chromatography-mass spectrometry, and PFR refers to plug flow reactor.

[0058] Other abbreviations used herein: NMT (not more than), wrt (with reference to), wt (weight), min (minute or minutes), h (hour or hours), s (second or seconds), aq. (aqueous) and equiv. (equivalent or equivalents). The term “alkyl”, as used herein, refers to saturated monovalent hydrocarbon radicals containing, in certain embodiments, from one to six carbon atoms, having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and fe / Y-butyl.

[0059] The term “tetraalkylammonium hydroxide” as used herein refers to a quaternary ammonium salt with molecular formula N(R)4+OH" wherein R is an alkyl as defined herein.

[0060] The term “benzyltrialkylammonium hydroxide” as used herein refers to a quaternary ammonium salt with molecular formula N(benzyl)(R)s+OH" wherein R is an alkyl as defined herein.

[0061] The term “tetraalkylphosphonium hydroxide” as used herein refers to a quaternary phosphonium salt with molecular formula P(R)4+OH" wherein R is an alkyl as defined herein.

[0062] The term “hydroxide salt of an alkali metal” as used herein refers to a base of formula M+OH_wherein M is an alkali metal which may be selected from lithium, sodium, potassium, rubidium, cesium and francium. In the context of the present invention, the alkali metal is preferably selected from lithium, sodium, potassium and cesium.

[0063] The term “branched alkoxide salt” as used herein refers to a salt of formula M+(0R)’ wherein M represents an alkali metal and R represents a branched alkyl comprising at least 3 carbon atoms. Examples of branched alkyl include fe / t-butyl, tert- pentyl and more generally any tertiary alkoxide. In the context of the present invention, M is preferably sodium or potassium, more preferably sodium.

[0064] As used herein, the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter (± 10%). For example, a temperature of about 10 °C means 10 °C ± 10% i.e. , it may vary between 9 °C and 11 °C.

[0065] The term, "solvate," as used herein, refers to a crystal form of a substance which contains solvent. The term "hydrate" refers to a solvate wherein the solvent is water. The compound of formula lnt-4 may be obtained as a hydrate or may convert to an hydrate, depending on storage conditions, specifically temperature and humidity conditions.

[0066] Unless indicated otherwise, all references herein to Compound 1 and intermediates used in its preparation include references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof.

[0067] EXAMPLES

[0068] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein. Although some of the examples below have been provided at the mL and g scale, it has been assessed that they are all scalable.

[0069] General Experimental Details

[0070] Unless otherwise stated the following generalizations apply. All NMR spectra were recorded on a Broker AVANCE Neo (400 MHz).1H and13C NMR spectral data are reported as chemical shifts (5) in parts per million (ppm) indirectly referenced to TMS at 0.00 ppm.19F NMR spectra are referenced relative to CFCh. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, pent = pentet, sept = septet, br = broad, m = multiplet), coupling constants J (Hz) and integration. Exchangeable protons are not always observed. LCMS data was generated using either an Agilent 6100 Series Single Quad, an Agilent 1260 Infinity Series UPLC / MS, an Agilent 1200 (LCMS-A), a Waters 2695 alliance, an Agilent 6120 Single Quad or mass-directed HPLC-MS; The High Resolution Mass Spectroscopy (HRMS) data were recorded using a SCIEX X500R qTOF in electrospray positive ionization mode (ESI+). -1 -vl)methvl)-2-fluoro-6- d 2, batch lnt-1 lnt-3

[0071] To an inerted reactor was added 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile (Int- 1 , 27.6 Kg, 152.3 mol, 1 equiv.) and CHsCN (248 L, 9 L / Kg) followed by diisopropylethylamine (31.9 L, 182.8 mol, 1.2 equiv.). Finally, methanesulfonyl chloride (13 L, 167.6 mol, 1.1 equiv.) was charged at once at room temperature. The reaction was heated to 60°C and stirred at this temperature for 1 h. Following reaction completion pyrazole (51.9 Kg, 761.7 mol, 5 equiv.) was added to the vessel as a solid and the reaction mixture was heated to 95 °C. The reaction was stirred for 24 h, then the mixture was cooled to 40 °C and water (1104 L, 40 L / Kg) was added prior to further cooling to 5 °C. The slurry was filtered, and the cake washed with CHsCN / water (1 :4, 138 L, 5 L / Kg) and dried at 50 °C to afford the title compound as a white solid (32.54 Kg, 92.4% yield).

[0072] 1H NMR (400 MHz, DMSO) 5 7.90 (dd, J = 2.3, 0.7 Hz, 1 H), 7.53 (dd, J = 1 .9, 0.7 Hz, 1 H), 6.99 (t, J = 1 .0 Hz, 1 H), 6.70 (ddt, J = 9.7, 1 .4, 0.7 Hz, 1 H), 6.38 - 6.23 (m, 1 H), 5.44 (s, 2H), 3.92 (s, 3H).13C NMR (101 MHz, DMSO) 5 163.61 (d, J = 241 .7 Hz), 162.32 (d, J = 8.0 Hz), 147.92 (d, J = 10.0 Hz), 140.17, 131.36, 111.97, 107.83 (d, J = 2.9 Hz), 107.15 (d, J = 20.5 Hz), 106.34, 89.53 (d, J = 18.1 Hz), 57.53, 54.48 (d, J = 2.2 Hz). HRMS: CI2HIOFN30+[M+1 ]+calculated: 232.0883; measured: 232.0881.

[0073] -1 -vl)methvl)-2-fluoro-6- d 2, continuous Step 2 lnt-1 lnt-2 lnt-3

[0074] Note: for a continuous flow process the scale of the process is irrelevant, since larger amount of product can be obtained without changing equipment, but simply running the process for a longer time.

[0075] A feed of 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile (lnt-1), DIPEA (2.2 equiv.), and CHsCN / THF (3:2, 20 L / Kg) (Stream A) was combined with a second stream (stream B) of MsCI (1 .5 equiv.) and CH3CN (5 L / Kg wrt lnt-1 ) at a mixing point inside of a plug flow reactor (PFR) where the reaction was initiated. After entering the reactor, but before mixing, these two streams were pre-cooled inside of the first PFR. The reaction proceeded inside of the PFR for a total target residence time of 20 seconds at 0°C. The product stream (Stream C) entered another PFR which was operated at 40°C. A feed (stream D) of pyrazole (5 equiv.) and aqueous benzyltrimethylammonium hydroxide (40% w / w, 5 equiv.) was fed to the second PFR where it mixed with Stream C. The total target residence time in the second PFR was 5 minutes. The reaction was quenched at 40°C as an integrated operation after the PFR by addition of HCI (aq., 12 M) to pH 2-3, and the solution was collected. 2L of the collected solution, containing about 51.8 g of lnt-3 were transferred into a batch reactor. The solution was distilled at atmospheric pressure to half the initial volume and then cooled to 37 °C, seeded with lnt-3 and cooled to 0 °C. Water (110 mL, 16 mL / g with respect to lnt-3) was added at 0 °C and the mixture stirred overnight. Then the solid was filtered, washed with cold water (240 mL, 4 mL / g with respect to lnt-3) and acetonitrile (60 mL, 1 mL / g with respect to lnt-3) and dried to afford the title compound as an off-white solid. (51.7 g)1H NMR (400 MHz, DMSO) 5 7.90 (dd, J = 2.3, 0.7 Hz, 1 H), 7.53 (dd, J = 1 .9, 0.7 Hz, 1 H), 6.99 (t, J = 1 .0 Hz, 1 H), 6.70 (ddt, J = 9.7, 1 .4, 0.7 Hz, 1 H), 6.38 - 6.23 (m, 1 H), 5.44 (s, 2H), 3.92 (s, 3H).13C NMR (101 MHz, DMSO) 5 163.61 (d, J = 241 .7 Hz), 162.32 (d, J = 8.0 Hz), 147.92 (d, J = 10.0 Hz), 140.17, 131.36, 111.97, 107.83 (d, J = 2.9 Hz), 107.15 (d, J = 20.5 Hz), 106.34, 89.53 (d, J = 18.1 Hz), 57.53, 54.48 (d, J = 2.2 Hz). HRMS: CI2HIOFN30+[M+1 ]+calculated: 232.0883; measured: 232.0881.

[0076] Example 3: Formation of 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzord]isoxazol- 3-amine (steps 3, continuous process)

[0077] Step 3 lnt-3 lnt-4

[0078] Note: for a continuous flow process the scale of the process is irrelevant, since larger amount of product can be obtained without changing equipment, but simply running the process for a longer time.

[0079] In a flow reactor (PFR) pressurized to at least 2 barg with a back pressure regulator, three streams were combined:

[0080] • FEED A: 4-((1 H-pyrazol-1-yl)methyl)-2-fluoro-6-methoxybenzonitrile (lnt-3) in THF (8 mL / g)

[0081] • FEED B: Hydroxylamine sulfate (0.71 equiv. with respect to Int 3) in water (16% wt)

[0082] • FEED C: PnNOH aq. (35% wt, 5.72 equiv. with respect to Int 3)

[0083] Preferred mixing order is Feed B + Feed C then Feed A. The pre-mixing of Feed B and Feed C must be short enough to avoid hydroxylamine degradation, or can be combined inside of the reactor before mixing with Feed A. The reaction is carried out for about 10 min residence time at 85 °C and the outlet stream collected. 25 mL of collected solution was transferred into an EasyMax vessel maintained at 50 °C. The mixture was cooled to 25 °C and seeds of lnt-4 (10 mg) were added prior to further cooling to 10 °C. Water (24 mL) was added and the mixture aged overnight. The mixture was filtered and the solid washed with water / CHsCN (4:1 , 2x 1 mL) and dried to afford the title compound as a white solid (0.771 g).1H NMR (400 MHz, DMSO) 6 7.87 (dd, J = 2.3, 0.7 Hz, 1 H), 7.50 (dd, J = 1 .9, 0.7 Hz, 1 H), 6.70 (q, J = 0.8 Hz, 1 H), 6.63 (d, J = 1 .0 Hz, 1 H), 6.41 - 6.21 (m, 1 H), 5.91 (s, 2H), 5.42 (s, 2H), 3.87 (s, 3H).13C NMR (101 MHz, DMSO) 5 164.36, 158.22, 155.22, 142.93, 139.65, 130.92, 106.10, 105.77, 102.92, 101.28, 56.21 , 55.19. HRMS: C12H13N4O2 [M+1 ]+calculated: 245.1034; measured: 245.1034

[0084] Example 4: formation of 6-((1 H-pyrazol-1-yl)methyl)-4-methoxybenzordlisoxazol-

[0085] 3-amine (lnt-4, telescoped steps 1, 2 and 3, continuous process)

[0086] In a flow reactor (PFR) FEED A and FEED B streams were mixed and the reaction was carried out at 0°C for 20 s. The outlet, FEED C, was combined with FEED D in a PFR which was kept at 55°C. The reaction was carried out for a 5 min residence time. FEED F and FEED G were combined first and then immediately combined with the outlet of the previous step, FEED E, inside a PFR. The reaction was carried out at 85°C for 10 min residence time. The reactor was pressurized to at least 2 barg with a back pressure regulator.

[0087] • FEED A: 2-Fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile (lnt-1) + THF (8 mL / g) + CH3CN (23 mL / g) + DIPEA (1 .8 equiv.)

[0088] • FEED B: MsCI (1 .5 equiv.) + CH3CN (5 mL / g with respect to lnt-1)

[0089] • FEED C: Outcome stream of step 1 containing lnt-2

[0090] • FEED D: PnNOH aq. (35%wt; 4.84 equiv. with respect to lnt-1) + pyrazole (3.35 equiv. with respect to lnt-1)

[0091] • FEED E: Outcome stream of step 2 containing lnt-3

[0092] • FEED F: Hydroxylamine sulfate aq. (25.45% wt, 1.4 equiv. with respect to lnt-1)

[0093] • FEED G: PHNOH aq. (35%wt, 5 equiv. with respect to lnt-1) 202 mL of step 3 reaction mixture from the flow run was received and added to a 1 L reactor vessel. The reaction mixture was warmed to 55°C and then water (118 mL, 40 mL / g with respect to lnt-1) was charged, the mixture was cooled to 20°C, seeded with lnt-4 (30 mg) and cooled to 0°C. Finally, water (148 mL, 50 mL / g with respect to lnt-1) was charged. The slurry was filtered and washed with cold water (14.8 mL, 5 mL / g with respect to lnt-1). Off white / light yellow solids were obtained and dried to afford the title compound (2.46 g).

[0094] 1H NMR (400 MHz, DMSO) 5 7.87 (dd, J = 2.3, 0.7 Hz, 1 H), 7.50 (dd, J = 1 .9, 0.7 Hz, 1 H), 6.70 (q, J = 0.8 Hz, 1 H), 6.63 (d, J = 1 .0 Hz, 1 H), 6.41 - 6.21 (m, 1 H), 5.91 (s, 2H), 5.42 (s, 2H), 3.87 (s, 3H).13C NMR (101 MHz, DMSO) 5 164.36, 158.22, 155.22, 142.93, 139.65, 130.92, 106.10, 105.77, 102.92, 101.28, 56.21 , 55.19. HRMS: C12H13N4O2 [M+1]+calculated: 245.1034; measured: 245.1034.

[0095] New Example: Formation of 6-((1H-pyrazol-1-yl)methyl)-4- methoxybenzordlisoxazol-3-amine (lnt-4, telescoped steps 1, 2 and 3, continuous process)

[0096] In a flow reactor (PFR) FEED A and FEED B streams were mixed and the reaction was carried out at 70°C for 5 s. The outlet, FEED C, was combined with FEED D in a PFR which was kept at 70°C. The reaction was carried out for a residence time of 20 s. FEED F and FEED G were combined first and then immediately combined with the outlet of the previous step, FEED E, inside a PFR. The reaction was carried out at 72°C for 4.25 min residence time. The reactor was pressurized to at least 1 barg with a back pressure regulator.

[0097] • FEED A: 2-Fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile (lnt-1) + THF (6.5 mL / g) + CH3CN (8.8 mL / g) + DIPEA (1 .88 equiv.)

[0098] • FEED B: Ms20 (1.23 equiv.) + CH3CN (1.6 mL / g with respect to lnt-1) • FEED C: Outcome stream of step 1 containing lnt-2

[0099] • FEED D: PnNOH aq. (40%wt; 3.90 equiv. with respect to lnt-1) + pyrazole (2.90 equiv. with respect to lnt-1)

[0100] • FEED E: Outcome stream of step 2 containing lnt-3

[0101] • FEED F: Hydroxylamine sulfate aq. (30% wt, 1 .05 equiv. with respect to lnt-1)

[0102] • FEED G: PHNOH aq. (40%wt, 7.65 equiv. with respect to lnt-1)

[0103] 47 g of step 3 reaction mixture from the flow run was received and added to a 100 mL reactor vessel. The reaction mixture was cooled to 5°C and then seeded with lnt-4 (25 mg). Finally, water (88.19 mL, 102 mL / g with respect to lnt-1) was charged. The slurry was filtered and washed with water (12.9 mL, 15 mL / g with respect to lnt-1). White to light yellow solids were obtained and dried to afford the title compound (0.85 g). -1-vl)methvl)-4-

[0104] 1

[0105] In an inerted reactor were added 6-((1 H-pyrazol-1-yl)methyl)-4- methoxybenzo[d]isoxazol-3-amine (lnt-4, 27.5 Kg, 112.6 mol, 1 equiv.), 2- methoxybenzenesulfonyl chloride (lnt-5, 33.9 Kg, 168.9 mol, 1.5 equiv.) and THF (248 L, 9-L / Kg). A solution of sodium te / Y-butoxide in THF (2 M, 197 L, 394.1 mol, 3.5 eq.) was added to the stirred mixture at 20 °C over 4 h. At the end of the addition the line was rinsed with THF (27.5 L, 1 L / Kg) and the mixture stirred for a further 1 h. Following reaction completion water (413 L, 15 L / Kg) was added at once followed by slow addition of aq. HCI (2 M, 197 L, 394.1 mol, 3.5 equiv.). The mixture was left stirring overnight, then the slurry was filtered, washed twice with CH3OH (82.5 L, 3 L / Kg) and dried to afford the title compound as a white solid (42.32 Kg, 90.6% yield).1H NMR (400 MHz, DMSO) 5 10.09 (s, 1 H), 7.87 (dd, J = 2.3, 0.7 Hz, 1 H), 7.81 (dd, J = 7.8, 1.7 Hz, 1 H), 7.63 (ddd, J = 8.4, 7.4, 1.7 Hz, 1 H), 7.50 (dd, J = 1.8, 0.7 Hz, 1 H), 7.10 (td, J = 7.6, 1 .0 Hz, 1 H), 6.84 (d, J = 1 .0 Hz, 1 H), 6.30 (t, J = 2.1 Hz, 1 H), 5.44 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H).13C NMR (101 MHz, DMSO) 5 164.82, 156.92, 154.39, 151.76, 144.13, 139.80, 135.73, 131.03, 130.43, 127.66, 120.52, 113.34, 106.25, 106.17, 104.42, 101.33, 56.51 , 56.42, 55.01. HRMS: Ci9Hi8N4O5S+[M+1 ]+calculated:

[0106] 415.1072; measured: 415.1071.

Claims

Claims1 . A process for preparing the compound of Formula lnt-4:comprising the step of reacting the compound of formula lnt-3:with hydroxylamine or a salt thereof in the presence of a hydroxide salt.

2. The process of claim 1 wherein the hydroxide salt is: a) a tetraalkylammonium hydroxide, a benzyltrialkylammonium hydroxide, a tetraalkylphosphonium hydroxide or an alkali metal hydroxide; b) selected from the group consisting of sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, tetrahexylammonium hydroxide, benzyltrimethylammonium hydroxide and tetrabutylphosphonium hydroxide; c) tetrabutylphosphonium hydroxide, tetraethylammonium hydroxide, benzyltrimethylammonium hydroxide or tetrapropylammonium hydroxide; or d) tetrapropylammonium hydroxide.

3. The process of claim 1 or claim 2 wherein the hydroxylamine or salt thereof is: a) selected from the group consisting of hydroxylamine, hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine phosphate, hydroxylammonium oxalate and hydroxylamme 4-methylbenzenesulfonate; orb) hydroxylamme sulfate.

4. The process of any one of claims 1 to 3 wherein the step of reacting the compound of formula lnt-3 is performed in a solvent which is selected from the group consisting of acetonitrile, tetrahydrofuran and a mixture thereof.

5. The process of any one of claims 1 to 4 wherein the compound of formula lnt-3 is prepared by: a) reacting a compound of formula lnt-1 :with methanesulfonyl chloride (MsCI) or methanesulfonic anhydride (MS2O) in the presence of a base in anhydrous conditions to form the compound of formula lnt-2:and b) reacting the compound of formula lnt-2 with pyrazole, optionally in the presence of a hydroxide salt, to afford the compound of formula lnt-3.

6. The process of claim 5 wherein the base used in step a) is: a) selected from the group consisting of / V, / V-diisopropylethylamine (DIPEA), lithium fe / Y-butoxide, diisopropylaniline, / V-methylmorpholine, / V-methylimidazole, triethylamine and pyridine; or b) / V, / V-diisopropylethylamine (DIPEA).

7. The process of claim 5 or claim 6 wherein step b) of the reaction is performed in the presence of a hydroxide salt.

8. The process of claim 7 wherein the hydroxide salt is: a) selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, tetrahexylammonium hydroxide, benzyltrimethylammonium hydroxide and tetrabutylphosphonium hydroxide; or b) benzyltrimethylammonium hydroxide or tetrapropylammonium hydroxide.

9. The process of any one of claims 5 to 8 wherein step b) of the reaction is performed in the presence of a hydroxide salt which is identical to the hydroxide salt used in any one of claims 1 to 8.

10. The process of any one of claims 5 to 9 wherein step b) of the reaction is performed in the presence of an excess of hydroxide salt and pyrazole compared to the amount of compound of formula lnt-2.

11. The process of any one of claims 5 to 10 wherein the steps a) and b) of reacting the compounds of formula lnt-1 and lnt-2 are performed in a solvent which is selected from the group consisting of acetonitrile, tetrahydrofuran, water and a mixture thereof.

12. The process of any one of claims 1 to 11 wherein the compound of formula lnt-4 is further reacted with the compound of formula lnt-5: lnt-5in the presence of a branched alkoxide salt to afford Compound 1 of formula:

13. The process of claim 12 wherein the branched alkoxide salt is added after the addition of the compounds of formula lnt-4 and lnt-5 is complete.

14. The process of claims 12 or claim 13 wherein the branched alkoxide salt is a branched sodium alkoxide or a branched potassium alkoxide.

15. The process of claim 14 wherein the branched alkoxide salt is sodium te / Y-butoxide or sodium te / Y-pentoxide.

16. The process of any one of claims 12 to 15 wherein the step of reacting the compound of formula lnt-4 is performed in a solvent which is: a) tetrahydrofuran or acetonitrile; or b) tetrahydrofuran.

17. A process for preparing Compound 1 of formula:comprising the steps of:1 ) reacting a compound of formula lnt-1 : lnt-1with methanesulfonyl chloride (MsCI) in the presence of anhydrous / \ / , / \ / ~ diisopropylethylamine (DIPEA) in a mixture of acetonitrile and tetrahydrofuran to afford the compound of formula lnt-2:lnt-22) adding pyrazole and aqueous tetrapropylammonium hydroxide to the mixture of step 1 to afford the compound of formula lnt-3:3) adding hydroxylamine sulfate dissolved in water and aqueous tetrapropylammonium hydroxide to the mixture of step 2 to afford the compound of formula lnt-4:4) and reacting the compound of formula lnt-4 with 2-methoxybenzenesulfonyl chloride of formula lnt-5: lnt-5in the presence of sodium fe / Y-butoxide or sodium fe / Y-pentoxide in tetrahydrofuran to afford Compound 1 .

18. A process for preparing Compound 1 of formula:comprising the steps of:1 ) reacting a compound of formula lnt-1 :with methanesulfonic anhydride (MS2O) in the presence of anhydrousdiisopropylethylamine (DIPEA) in a mixture of acetonitrile and tetrahydrofuran to afford the compound of formula lnt-2:2) adding pyrazole and aqueous tetrapropylammonium hydroxide to the mixture of step 1 to afford the compound of formula lnt-3:3) adding hydroxylamine sulfate dissolved in water and aqueous tetrapropylammonium hydroxide to the mixture of step 2 to afford the compound of formula lnt-4:4) and reacting the compound of formula lnt-4 with 2-methoxybenzenesulfonyl chloride of formula lnt-5: lnt-5in the presence of sodium te / Y-butoxide in tetrahydrofuran to afford Compound 1.

19. The process of any one of claims 1 to 18 wherein Compound 1 is further recrystallized in a suitable solvent.

20. The process of claim 19 wherein the suitable solvent is: a) selected from the group consisting of acetonitrile, a mixture of acetonitrile and toluene, a mixture of acetonitrile and tetrahydrofuran, and a mixture of acetonitrile and ethanol; or b) a mixture of acetonitrile and toluene, preferably a mixture of acetonitrile to toluene in a 70:30 ratio.

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