Methods and Compounds Useful for the Synthesis of AAK1 Inhibitors

Abstract

Methods for synthesizing (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine and salts thereof, as well as compounds useful in the methods, are disclosed.

Description

[Technical field]

[0001] 1 Field of the Invention The present application relates to a process for the preparation of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine and its salt forms, as well as synthetic intermediates useful therein. [Background technology]

[0002] 2. Background of the Invention Adaptor-associated kinase 1 (AAK1) is a member of the Ark1 / Prk1 family of serine / threonine kinases. AAK1 mRNA exists in two splice forms, termed short and long. The long form predominates and is highly expressed in brain and heart (Henderson and Conner, Mol. Biol. Cell. 2007, 18, 2698-2706). AAK1 is enriched in synaptosomal preparations and colocalizes with endocytic structures in cultured cells. AAK1 regulates clathrin-coated endocytosis, a process important for synaptic vesicle recycling and receptor-mediated endocytosis. AAK1 associates with the AP2 complex, which binds receptor cargo to the clathrin coat. Binding of clathrin to AAK1 stimulates the kinase activity of AAK1 (Conner et al., Traffic 2003, 4, 885-890; Jackson et al., J. Cell. Biol. 2003, 163, 231-236). AAK1 phosphorylates the mu-2 subunit of AP-2, which promotes binding of mu-2 to tyrosine containing sorting motifs on cargo receptors (Ricotta et al., J. Cell Bio. 2002, 156, 791-795; Conner and Schmid, J. Cell Bio. 2002, 156, 921-929). Phosphorylation of Mu2 is not required for receptor internalization, but phosphorylation increases the efficiency of internalization (Motely et al., Mol. Biol. Cell. 2006, 17, 5298-5308).

[0003] AAK1 has been identified as an inhibitor of neuregulin-1 / ErbB4 signaling in PC12 cells. Loss of AAK1 expression by RNA interference-mediated gene silencing or treatment with the kinase inhibitor K252a (which inhibits AAK1 kinase activity) enhances neurite outgrowth induced by neuregulin-1. These treatments increase ErbB4 expression and lead to its accumulation in or near the plasma membrane (Kuai et al.,Chemistry and Biology 2011,18,891-906). NRG1 and ErbB4 are putative schizophrenia susceptibility genes (Buonanno,Brain Res. Bull.2010,83,122-131). SNPs in both genes are associated with multiple schizophrenia endophenotypes (Greenwood et al.,Am.J.Psychiatry 2011,168,930-946). Neuregulin 1 and ErbB4 KO mouse models showed morphological changes and behavioral phenotypes associated with schizophrenia (Jaaro-Peled et al., Schizophrenia Bulletin 2010, 36, 301-313; Wen et al., Proc. Natl. Acad. Sci. USA. 2010, 107, 1211-1216). In addition, a single nucleotide polymorphism in an intron of the AAK1 gene has been associated with age of onset of Parkinson's disease (Latourelle et al., BMC Med. Genet. 2009, 10, 98). These results suggest that inhibition of AAK1 activity may be useful for the treatment of schizophrenia, cognitive impairment in schizophrenia, Parkinson's disease, neuropathic pain, bipolar disorder, and Alzheimer's disease.

[0004] In addition, studies with Huh-7.5 cells have shown that AAK1 kinase inhibitors may be useful for treating hepatitis C (HCV) infection. Reduction of AAK1 protein by RNA interference-mediated gene silencing, treatment with the kinase inhibitor sunitinib (a potent AAK1 inhibitor), and overexpression of a Mu2 phosphorylation site mutant (a substrate of AAK1) all reduce HCV virion assembly. Furthermore, the same treatments were shown to inhibit HCV entry, suggesting that AAK1 inhibitors can disrupt two host-dependent stages of the viral life cycle (Neveu et al. PLoS Pathog. 2012, 8, 1-16; Neveu et al., J. Virol. 2015, published online February 4). AAK1 inhibitors may also be useful against HIV and HBV (see, e.g., Boge et al., J. Biol. Chem. 1998, 273, 15773-15778).

[0005] Many AAK1 inhibitors have been disclosed in the literature, and some have been suggested to be useful in treating neuropathic pain. See, for example, Hartz, RA et al., J. Med. Chem., 2021 Aug 12; 64(15): 11090-11128. However, human clinical trials are necessary to evaluate the full potential of any pharmaceutical agent.

[0006] The specific AAK1 inhibitor (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine has been prepared on a small laboratory scale. See, for example, U.S. Pat. No. 9,902,722. Unfortunately, synthetic techniques useful in a laboratory setting are rarely suitable for large-scale production of pharma- ceutically acceptable substances. For example, the production of potentially harmful reaction by-products must be minimized, and the use of toxic solvents and reagents is desirably avoided. Furthermore, reaction conditions that may work well on a gram scale are often inefficient or dangerous on a larger scale. Thus, there is a need for synthetic methods that can be used to prepare pharma- ceutically acceptable (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine in commercially useful quantities. Summary of the Invention

[0007] 3. Overview of the Invention The present application relates to the compound (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): [ka] Compound J is an inhibitor of adaptor associated kinase 1 (AAK1) and is believed to be useful in the treatment of diseases and disorders, including pain.

[0008] In one embodiment, the present invention provides (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): [ka] A method for preparing compound H: [ka] Compound D: [ka] or a salt thereof in the presence of a base under conditions sufficient to form compound J.

[0009] In one embodiment, compound H is a compound Q: [ka] with a fluorinating agent under conditions sufficient to form compound H. (The present invention encompasses crystalline forms of compound Q. A particular crystalline form has a melting point of about 150° C.)

[0010] In one embodiment, compound Q is a compound P: [ka] is prepared by contacting with an acid under conditions sufficient to form compound Q.

[0011] In one embodiment, compound P is selected from the group consisting of compound L: [ka] to compound N: [ka] under conditions sufficient to form compound P.

[0012] In one embodiment, compound Q is compound L4: [ka] is prepared by contacting with an acid under conditions sufficient to form compound Q.

[0013] In one embodiment, compound L4 is selected from compound L3: [ka] Compound L1: [ka] in the presence of a catalyst and a base under conditions sufficient to form compound L4.

[0014] The present invention relates to compound K: [ka] A method for preparing a compound S: [ka] with phosphoric acid in a solvent under conditions sufficient to form compound K.

[0015] In one embodiment, compound S is a compound J: [ka] is prepared by contacting with hydrochloric acid in a solvent under conditions sufficient to form compound S.

[0016] The present invention relates to the synthetic intermediate 6-bromo-2-(dimethoxymethyl)-3-fluoropyridine (compound L1): [ka] Also includes.

[0017] The present invention also relates to 2-(dimethoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (compound L3): [ka] Also includes.

[0018] The present invention also relates to 2',6-bis(dimethoxymethyl)-5-fluoro-2,4'-bipyridine (compound L4): [ka] and salts thereof.

[0019] The present invention also relates to the compound 5-fluoro-[2,4'-bipyridine]-2',6-dicarbaldehyde (Compound Q): [ka] Also includes.

[0020] The present invention also relates to (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): [ka] Also included are crystalline pharma- ceutically acceptable salts of:

[0021] The present invention also relates to (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): [ka] or a pharma- ceutically acceptable salt thereof, comprising testing the sample for the presence of one or more of the compounds listed in Table 1.

[0022] The present invention also relates to (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): [ka] or a pharma- ceutically acceptable salt thereof, which composition contains less than 0.01% by weight of one or more of the compounds listed in Table 1 below. [Brief description of the drawings]

[0023] 4. Brief Description of the Drawings [Figure 1] 1 provides a representative X-ray powder diffraction (XRPD) pattern of the crystalline solid form I of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentane-2-aminium dihydrogen phosphate (Compound K). The spectrum was obtained using a Bruker X-ray diffractometer equipped with a LYNXEYE detector (copper Kα radiation). [Diagram 2] A representative differential scanning calorimetry (DSC) thermogram of the crystalline solid form of Compound K is provided. The thermogram was obtained using a TA Instruments DSC Q2000 instrument and a sealed gold crucible filled under ambient conditions. Two scans were performed. After melting was complete in the first scan, the sample was quenched to -50°C at approximately -40K per minute and a second scan was recorded. The heating rate was 10K per minute for both scans. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] 5 Detailed explanation The present invention relates to (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): [ka] and pharmaceutically acceptable salts thereof in quantities sufficient (e.g., greater than 1 kg, greater than 5 kg, or greater than 10 kg) for the manufacture of dosage forms suitable for use in human clinical trials and subsequent commercialization. The methods of the invention maximize synthetic yields while minimizing the production of deleterious impurities.

[0025] A particular method of the present invention comprises the steps of: (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-aminium dihydrogen phosphate (Compound K): [ka] and is used to prepare crystalline solid forms thereof. A particular crystalline form of this salt, designated Form I herein, has an XRPD spectrum substantially similar to that shown in Figure 1, with diffraction peaks at one or more of about 4.81, 5.99, 7.44, 7.89, 11.66, 14.85, 15.77, 19.19, 20.86, 21.65, 23.96, 24.48, or 24.73 degrees 2θ. When referring to XPRD peaks herein, the term "about" means ±0.2 degrees 2θ.

[0026] Crystalline Form I of Compound K has a melting point of about 184° C. as determined by differential scanning calorimetry (DSC) (melting endotherm) (see FIG. 2). When referring to temperatures, the terms "substantially" and "about" mean ±2° C.

[0027] Crystalline form I of compound K is the most stable form discovered for this salt. Storage for up to 4 weeks at 40°C and 75% relative humidity did not alter either the form itself, its morphology, or its purity. Furthermore, although the melting point of form I is lower than that of the hydrochloride salt of compound J (where a form with a melting point of approximately 247°C was discovered), the phosphate salt shows no associated degradation. Instead, melting of form I was observed to recrystallize into another metastable form with a melting point of approximately 172.5°C. Large-scale production and purification of form I is further aided by its water solubility, which is 26.8 mg / mL at 25°C. In comparison, the measured water solubility of the hydrochloride salt of compound J was 2.9 mg / mL at 25°C.

[0028] One embodiment of the invention that can be used to prepare Form I is shown below: [ka] wherein compound K is prepared by contacting compound J with phosphoric acid in a solvent under conditions sufficient to form compound K. Exemplary solvents include water, methanol, ethanol, n-butanol, isopropanol, isobutanol, t-butanol, methyl t-butyl ether, ethyl acetate, isopropyl acetate, THF, and 2-methyl THF, and mixtures thereof. A particular solvent is isopropanol.

[0029] In some embodiments, compound J is contacted with phosphoric acid at a temperature of about 0° C. to about 100° C., or about 50° C. to about 60° C. (When referring to reaction conditions, the term "about" when used to refer to temperature may be interpreted as ±10° C., unless otherwise noted). In some embodiments, compound J is contacted with phosphoric acid for about 0.5 hours to about 24 hours, or about 2 hours to about 16 hours. (When referring to reaction conditions, the term "about" when referring to time may be interpreted as ±5% unless otherwise noted. For example, "about 2 hours" is the same as 2 hours ±6 minutes). In some embodiments, about 0.8 to about 1.2 molar equivalents (e.g., about 1 molar equivalent) of phosphoric acid relative to compound J is utilized (Unless otherwise noted, the term "about" when referring to molar equivalents or concentrations may be interpreted as ±5%). In some embodiments, the concentration of compound J in the solvent is about 2% to about 25%.

[0030] In one embodiment of the present invention, compound K is prepared from compound S as shown below: [ka] In this procedure, compound S is neutralized with a base under conditions sufficient to form compound J and contacted with phosphoric acid under conditions sufficient to form compound K. Bases suitable for neutralization include NaOH, KOH, Na2CO3, and K2CO3. A preferred base is sodium hydroxide.

[0031] Neutralization of compound S with a base is typically carried out in a solvent such as water, water / MTBE, water / THF, and water / 2-MeTHF (preferred solvent is water / MTBE), and at a temperature of about 0° C. to about 60° C. (e.g., about 20° C. to about 40° C.). In some embodiments, the neutralization is carried out for about 0.5 hours to about 24 hours (e.g., about 1 hour to about 2 hours). In some embodiments, about 0.8 to about 5 molar equivalents of base relative to compound S are utilized. In some embodiments, the concentration of compound S in the solvent is about 2% to about 25%.

[0032] The exposure of compound J to phosphoric acid in the second step above is typically carried out in a solvent such as water, methanol, ethanol, n-butanol, isopropanol, isobutanol, t-butanol, methyl t-butyl ether, ethyl acetate, isopropyl acetate, THF and 2-methyl THF, or mixtures thereof. A preferred solvent is isopropanol.

[0033] In some embodiments, the exposure of compound J to phosphoric acid is carried out at a temperature of about 0° C. to about 100° C. (e.g., about 50° C. to about 60° C.). In some embodiments, the exposure of compound J to phosphoric acid is carried out for about 0.5 hours to about 24 hours (e.g., about 7 hours to about 14 hours). In some embodiments, about 0.8 to about 1.2 molar equivalents of phosphoric acid relative to compound J are utilized in the second step. In some embodiments, the concentration of compound J in the solvent is about 2% to about 25%.

[0034] Compound S can be prepared as shown below: [ka] In one embodiment, compound S is prepared by exposing compound J to hydrochloric acid in a solvent under conditions sufficient to form compound S. In some embodiments, the solvent is water, IPA, a water / IPA mixture, MeOH, MeOH / water, EtOH, EtOH / water, n-BuOH, or n-BuOH / water. A preferred solvent is isopropanol.

[0035] Exposure of compound J to hydrochloric acid is carried out at a temperature of about 0° C. to about 60° C. (e.g., about 50° C. to about 60° C.) for about 0.5 hours to about 24 hours (e.g., about 4 hours to about 8 hours). About 0.8 to about 1.2 molar equivalents of hydrochloric acid relative to compound J are typically used. In some embodiments, the concentration of compound J in the solvent is about 2% to about 25%.

[0036] One embodiment of the present invention encompasses the process for preparing compound J as follows: [ka] Here, compound J is prepared by neutralizing compound D-benzoate with a base under conditions sufficient to form compound D, which is contacted with compound H in the presence of a base under conditions sufficient to form compound J. Compound D need not be isolated.

[0037] Solvents suitable for use in these reactions include THF, 2-methyl THF, 1,4-dioxane, MTBE, DME, diglyme, t-butanol, and t-amyl alcohol. A particular solvent is THF. The base used in both steps can be added at the beginning of the first step. Examples of suitable bases include potassium t-butoxide, sodium t-butoxide, potassium t-amylate, sodium t-amylate, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, n-butyllithium, sec-butyllithium, and t-butyllithium. A particular base is potassium t-butoxide.

[0038] In some embodiments of the present invention, the neutralization of compound D-benzoate is carried out at a temperature of about -50°C to about 50°C (e.g., about 15°C to about 25°C) for about 0.5 hours to about 24 hours (e.g., about 3 hours to about 5 hours). In some embodiments, compound H is contacted with compound D in the presence of a base at a temperature of about -50°C to about 50°C (e.g., about 0°C to about 25°C) for about 2 hours to about 5 hours.

[0039] About 1.8 to about 3 molar equivalents (e.g., about 2.5 to 3 molar equivalents) of base relative to Compound H are used, and about 1 to about 1.5 molar equivalents (e.g., about 1.2 molar equivalents) of Compound D-benzoate relative to Compound H are used.

[0040] The compound D-benzoate can be prepared as follows: [ka] Here, compound B is contacted with a reducing agent under conditions sufficient to form compound D, and compound D is contacted with benzoic acid under conditions sufficient to form compound D-benzoate.

[0041] Examples of reducing agents include NaBH4 / BF3·Et2O, NaBH4 / I2, NaBH4 / TMSCl, NaBH4 / H2SO4, NaBH4 / MsOH, NaBH4 / TsOH, NaBH4 / HCl, NaBH4 / AlCl3, CDI / NaBH4, BH3THF complex, BH3 dimethylsulfide complex, diborane, LiAlH4, and Li / AlCl3 / t-BuOH. In some embodiments of the present invention, the reducing agent is NaBH4 / BF3·Et2O. The amount of reducing agent can be about 0.5 to about 4 molar equivalents (e.g., about 2 molar equivalents) relative to compound B.

[0042] The reduction of compound B is typically carried out in a solvent such as THF, 2-Me-THF, THF, 2-methylTHF, 1,4-dioxane, MTBE, DME, diglyme, or a mixture thereof. A preferred solvent is THF. In some embodiments, the concentration of compound B in the solvent is about 2% to about 25%. The reduction can be carried out at a temperature of about -50°C to about 50°C (e.g., about 0°C to about 25°C) for about 0.5 hours to about 24 hours (e.g., about 5 hours to about 8 hours).

[0043] According to the above-illustrated procedure, compound D is contacted with benzoic acid in a solvent such as MTBE, MTBE / heptane, THF, THF / heptane, EtOAc, EtOAc / heptane, IPAc, IPAc / heptane, EtOH, EtOH / heptane, IPA, IPA / heptane, toluene, acetonitrile, etc. A preferred solvent is MTBE. In some embodiments of the invention, the reaction is carried out at a temperature of about 0° C. to about 60° C. (e.g., about 45° C. to about 50° C.) for about 1 hour to about 2 hours. In some embodiments, about 0.8 to about 1.5 molar equivalents (e.g., about 1.1 molar equivalents) of benzoic acid relative to compound D are utilized. In some embodiments, the concentration of compound D in the solvent is about 2% to about 25%.

[0044] Another intermediate useful in the large scale synthesis of compound J and its pharma- ceutically acceptable salts is compound H, which can be prepared as shown below: [ka] In this approach, compound H is prepared by contacting compound Q with a fluorinating agent under conditions sufficient to form compound H. Examples of fluorinating agents include SF4, PhSF3, R2NSF3 (DAST, Morph-DAST), dialkylamidodifluorosulfinium tetrafluoroborate ([RN=SF2](XtalFluor-E, XtalFluor-M)BF4), Deoxo-Fluor (BAST), SelectFluor, and 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride. A preferred fluorinating agent is DAST. Depending on the particular agent used, about 1 to about 5 molar equivalents (e.g., about 3.5) of the fluorinating agent are used relative to compound Q.

[0045] Compound Q is preferably contacted with a fluorinating agent in a solvent such as methylene chloride, chloroform, CCl4, and toluene. A preferred solvent is methylene chloride. The concentration of compound Q in the solvent may vary from about 2% to about 25%. The reaction is typically carried out at a temperature of about -20°C to about 60°C (e.g., about 0°C to about 25°C) for about 1 hour to about 100 hours (e.g., about 24 hours to about 30 hours).

[0046] Compound Q can be prepared from compound L4 as shown below: [ka] In this approach, compound Q is prepared by contacting compound L4 or a salt thereof (e.g., a phosphate salt, L4-phosphate) with an acid under conditions sufficient to form compound Q. Examples of suitable acids include HCl, HBr, HI, H2SO4, H3PO4, HNO3, MsOH, TsOH, and HBF4. A preferred acid is hydrochloric acid.

[0047] The reaction with the acid is preferably carried out in a solvent such as water or DMSO / water (the preferred solvent is water) at a temperature of about 0° C. to about 100° C. (e.g., about 55° C. to about 60° C.). The reaction is typically carried out for about 1 hour to about 24 hours (e.g., 2 hours). The concentration of compound L4 can be varied to optimize the yield and can be, for example, about 2 to about 25%. In some embodiments of the invention, about 1 to about 10 molar equivalents (e.g., 5 molar equivalents) of acid relative to compound L4 are utilized.

[0048] A particularly useful salt of compound L4 is the L4-phosphate salt, which can be prepared as shown below: [ka] In this approach, compound L4 is contacted with phosphoric acid under conditions sufficient to prepare compound L4-phosphate. The reaction can be carried out in a solvent such as MeOH, EtOH, IPA, EtOAc, IPAc, MTBE, THF, 2-Me-THF, toluene, heptane, or mixtures thereof. A preferred solvent system is toluene / methanol / heptane.

[0049] The reaction is typically carried out at a temperature of about 0° C. to about 60° C. (e.g., about 15° C. to about 45° C.) for about 1 hour to about 24 hours (e.g., about 10 hours to about 12 hours). In some embodiments of the invention, about 1 to about 2 (e.g., about 1.6) molar equivalents of phosphoric acid relative to compound L4 are utilized. The concentration of compound L4 in the solvent can range from about 2% to about 25%.

[0050] Compound L4 can be prepared by the following procedure: [ka] Here, compound L2 is contacted with a palladium catalyst, a base, a ligand, and a boron reagent under conditions sufficient to form compound L3, which is contacted with compound L1 in the presence of a catalyst and a base under conditions sufficient to form compound L4.

[0051] The preparation of compound L3 is typically carried out in a solvent such as THF, 2-MeTHF, 1,4-dioxane, DME, MTBE, Et2O, or ACN. In some embodiments, the solvent is 2-MeTHF. Examples of palladium catalysts that can be used to prepare compound L3 include Pd(OAc)2, PdCl2(dppf), Pd(PPh3)4, PdCl2(PPh3)2, and Pd2(dba)3. A preferred catalyst is Pd2(dba)3. Bases useful for the formation of compound L3 include NaOAc, KOAc, NaHCO3, KHCO3, Na2CO3, K2CO3, K2HPO4, and K3PO4. A preferred base is KOAc. Suitable ligands include PCy3, SPhos, and Xphos. A preferred ligand is Xphos. Useful boron reagents for the reaction include tetrahydrodiboron, PinBH and Pin2B2. The preferred boron reagent is Pin2B2.

[0052] In some embodiments of the invention, compound L2 is contacted with a palladium catalyst, a base, a ligand, and a boron reagent at a temperature of about 0° C. to about 100° C. (e.g., about 70° C. to about 80° C.) for about 0.5 hours to about 48 hours (e.g., about 16 hours to about 24 hours). In some embodiments, about 0.8 to about 2 (e.g., 1) molar equivalents of the boron reagent relative to compound L2 are utilized. In some embodiments, the concentration of compound L2 in the solvent is about 2% to about 25%.

[0053] In the next step of the reaction shown above, compound L3 is reacted with compound L1, typically in a solvent such as water, THF, 2-MeTHF, 1,4-dioxane, DME, MTBE, Et2O, and mixtures thereof. A preferred solvent is water / 2-MeTHF. The concentration of compound L1 may range from about 2% to about 25%, although as with all reaction conditions disclosed herein, these values ​​can be varied using means well known to those skilled in the art to maximize product yield and minimize costs.

[0054] Examples of bases that can be used to form compound L4 include Na2CO3, K2CO3, Na3PO4, K3PO4, NaOH, and KOH. A preferred base is sodium carbonate (Na2CO3). Depending on the base, about 1 to 2 molar equivalents (e.g., 2 molar equivalents) of base are used relative to compound L2. This step is carried out at a temperature of about 20°C to about 100°C (e.g., about 70°C to about 80°C) for about 1 hour to about 48 hours (e.g., about 16 hours to about 24 hours). About 1 to about 2 molar equivalents (e.g., 1 equivalent) of compound L1 are used relative to compound L2.

[0055] The synthetic intermediate compound L2 can be prepared as shown below: [ka] In this procedure, compound SM3 is contacted with trimethoxymethane in the presence of an acid under conditions sufficient to form compound L2. Examples of suitable acids include H2SO4, MsOH, TsOH, H3PO4, HNO3, HCl, and HBr. A preferred acid is hydrochloric acid.

[0056] The above reaction is typically carried out in a solvent such as 1,4-dioxane, DME, Et2O, THF, 2-Me-THF, toluene, DCM, MTBE, ACN, or methanol. The preferred solvent is methanol. The temperature at which this reaction is carried out can range from about 0°C to about 80°C (e.g., about 60°C to about 65°C), and the duration can range from about 0.5 hours to about 48 hours (e.g., about 6 hours to about 10 hours).

[0057] In some embodiments of the invention, about 0.01 to about 1 molar equivalent (e.g., about 0.2 molar equivalent) of acid is utilized relative to SM3, and about 1 to about 4 molar equivalents (e.g., about 2 molar equivalents) of trimethoxymethane is utilized relative to SM3. The concentration of SM3 in the solvent can range from about 2% to about 30%.

[0058] Using similar reaction conditions as above (but with more trimethoxymethane), compound L2 can also be prepared as shown below: [ka]

[0059] The synthetic intermediate compound L1 can be prepared as shown below: [ka] In this method, compound L1 is prepared by contacting compound SM2 with trimethoxymethane in the presence of an acid under conditions sufficient to form acetal compound L1. Examples of suitable acids include H2SO4, MsOH, TsOH, H3PO4, HNO3, HCl, and HBr. A preferred acid is hydrochloric acid.

[0060] The reaction is preferably carried out in a solvent such as 1,4-dioxane, DME, Et2O, THF, 2-Me-THF, toluene, DCM, MTBE, ACN, and methanol. The preferred solvent is methanol.

[0061] In some embodiments of the invention, SM2 is contacted with trimethoxymethane in the presence of an acid at a temperature of about 0° C. to about 80° C. (e.g., about 60° C. to about 65° C.) for about 0.5 hours to about 48 hours (e.g., about 3 hours to about 6 hours). Typically, about 0.01 to about 1 molar equivalent (e.g., about 0.05 molar equivalent) of acid is used relative to SM2. Typically, about 1 to about 4 molar equivalents (e.g., about 2 molar equivalents) of trimethoxymethane is used relative to SM2. In some embodiments, the concentration of SM2 in the solvent is about 2% to about 30%.

[0062] In one embodiment of the present invention, compounds J, K and S are prepared as shown in Scheme 1: [ka]

[0063] In this approach, compound J, or a pharma- ceutically acceptable salt thereof, is prepared by a process comprising: a) contacting compound L3 with compound L1 in the presence of a catalyst and a base under conditions sufficient to form compound L4; b) contacting compound L4, or a salt thereof, with an acid under conditions sufficient to form compound Q; c) contacting compound Q with a fluorinating agent under conditions sufficient to form compound H; and d) contacting compound H with compound D in the presence of a base under conditions sufficient to form said compound J.

[0064] Compound S is prepared by a process comprising exposing compound J to hydrochloric acid in a solvent.

[0065] Compound K is prepared by a process comprising: a) neutralizing compound S with a base under conditions sufficient to form compound J; and b) exposing the resulting compound J to phosphoric acid in a solvent under conditions sufficient to form compound K.

[0066] In a specific embodiment of the invention, compound K is prepared by a process comprising: a) contacting compound L3 with compound L1 in the presence of a catalyst and a base under conditions sufficient to form compound L4; b) contacting compound L4 with an acid under conditions sufficient to form compound Q; c) contacting compound Q with a fluorinating agent under conditions sufficient to form compound H; d) contacting compound H with compound D in the presence of a base under conditions sufficient to form compound J; e) contacting compound J with hydrochloric acid in a solvent under conditions sufficient to form compound S; f) neutralizing compound S with a base under conditions sufficient to form compound J; and g) contacting the resulting compound J with phosphoric acid in a solvent under conditions sufficient to form compound K.

[0067] In another embodiment, compound K is prepared by a process comprising: a) contacting compound L3 with compound L1 in the presence of a catalyst and a base under conditions sufficient to form compound L4; b) contacting L4 with an acid under conditions sufficient to form compound Q; c) contacting compound Q with a fluorinating agent under conditions sufficient to form compound H; d) contacting compound H with compound D in the presence of a base under conditions sufficient to form compound J; e) exposing the resulting compound J to phosphoric acid in a solvent under conditions sufficient to form compound K.

[0068] The present invention encompasses a method for ensuring that the final active pharmaceutical ingredient has a purity suitable for administration to a human patient. To this end, potential impurities, including those shown in Table 1 below, are synthesized and 1 It was characterized by 1 H NMR and mass spectrometry. [Table 1]

[0069] The present invention includes methods for testing the purity of compound J, or a pharma- ceutically acceptable salt thereof, by testing for the presence of one or more of the compounds listed in Table 1. Preferred methods include using mass spectrometry and / or HPLC to test for the presence of one or more compounds. EXAMPLES

[0070] 5.1 Example Various embodiments of the invention can be understood by consideration of the examples provided below, in which all temperatures are given in degrees Celsius and all parts and percentages are by weight unless otherwise noted. Reagents may be purchased from commercial suppliers and used without further purification unless otherwise noted. (Reagents may also be prepared according to standard literature procedures known to those skilled in the art.)

[0071] Unless otherwise specified, reactions were carried out at ambient (or room) temperature. Reactions were typically monitored by HPLC and terminated as judged by the consumption of starting material.

[0072] The structure and purity of the compound were confirmed by proton nuclear magnetic resonance ( 1 H NMR) spectroscopy, 13 The compounds were characterized by one or more of the following techniques: C NMR spectroscopy, mass spectrometry, infrared spectroscopy, melting point, X-ray crystallography, LC-MS and / or HPLC. Chemical shifts are reported in parts per million (ppm, δ) downfield from a standard, such as an internal standard, e.g., TMS. Alternatively, 1 H NMR chemical shifts were referenced to signals from residual protons in deuterated solvents, as known in the art. Peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; br, broadened; and m, multiplet. Coupling constants are given in Hertz (Hz). Mass spectral (MS) data were obtained using a mass spectrometer equipped with APCI or ESI ionization.

[0073] 5.1.1. Synthesis of 6-bromo-2-(dimethoxymethyl)-3-fluoropyridine (compound L1) [ka] A solution of HCl / MeOH (10 mL of a 3.9 M solution, 0.05 eq.) was charged to a mixture of SM2 (158.5 g, 777 mmol, 1 eq.), MeOH (1585 mL, 10 V) and trimethoxymethane (166 g, 15.6 mol, 2.0 eq.). The resulting mixture was aged at 60-65 °C (reflux) until reaction completion (3-6 h) and then cooled to 10-20 °C. After concentrating to 2-3 V below 50 °C and diluting with 2-Me-THF (10 V), the reaction was quenched with 10% K2CO3 (3 V). The organic layer was separated and concentrated to 1-2 V below 50 °C. This was flushed with 2-Me-THF (5V) and further diluted with 2-Me-THF (5V) to give a 2-Me-THF solution of compound L1 (845.2g, 99% purity, 21.7% assay, 94.4% solution yield). LC-MS: m / z 250, 252, 220, 218 (M-OMe). 1 H NMR (400 MHz, chloroform-d) δ 7.38 (dd, J = 3.5, 8.6 Hz, 1H), 7.17-7.30 (m, 1H), 5.37-5.48 (m, 1H), 3.39 (s, 6H).

[0074] 5.1.2. Synthesis of 4-chloro-2-(dimethoxymethyl)pyridine (compound L2) [ka] HCl / MeOH (42.3 mL of a 3.9 M solution, 0.20 eq.) was charged to a mixture of SM3 (117.3 g, 819.5 mmol, 1 eq.), MeOH (1160 mL, 10 V) and trimethoxymethane (174 g, 1.64 mol, 2.0 eq.). The mixture was heated to 60-65 °C (reflux) until reaction completion (6-10 h) and then cooled to 10-20 °C. After concentration to 3-5 V and dilution with 2-Me-THF (10 V), the reaction was quenched with 10% K2CO3 (3 V, pH 8-9). The organic layer was separated, concentrated to 1-2 V, flushed with 2-Me-THF (5 V × 2), and diluted with 2-Me-THF (5 V) to obtain a 2-Me-THF solution of compound L2 (588.5 g, 99.18% purity by HPLC, 22.3% assay, 85.3% solution yield). 1H NMR (400 MHz, chloroform-d) δ 8.42–8.57 (m, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 2.1, 5.3 Hz, 1H), 5.28–5.39 (m, 1H), 3.38 (s, 6H). LC-MS m / z 187, 156 (M-OMe).

[0075] 5.1.3. Synthesis of 2',6-bis(dimethoxymethyl)-5-fluoro-2,4'-bipyridine phosphate (compound L4-phosphate) [ka] Preparation of L3: A mixture of compound L2 (95.5 g, 1.00 eq., 5-6 V), 2-Me-THF (10 V), Pin2B2 (1.05 eq.), KOAc (3.0 eq.) and Xphos (0.02 eq.) in 2-Me-THF was degassed by sparging with N2. Pd2(dba)3 (0.01 eq.) was added and the mixture was again degassed by sparging with N2. The reaction mixture was heated to 70-80 °C and stirred until boronation of L2 was complete (16-24 h) to give L3, which was used directly in the subsequent Suzuki coupling step.

[0076] Preparation of L4 by Suzuki coupling of L3 and L1: After cooling to 15-25 °C, a solution of compound L1 in 2-Me-THF (0.96 eq., 5-6 V), Na2CO3 (2.0 eq. solid), and H2O (5 V) were added sequentially. After degassing by sparging with N2, the reaction mixture was aged at 70-80 °C until the Suzuki coupling was complete (16-24 h). After cooling to 15-25 °C, the reaction mixture was filtered through a pad of diatomaceous earth (0.5X) and the filter cake was washed with 2-Me-THF (1-2 V). The organic layer of the filtrate was separated, concentrated to 1-2 V, diluted with toluene (10 V), and washed twice with L-cysteine / NaOH (pH>10) (5X, ratio of L-cysteine / NaOH / H2O: 1 / 0.5 / 9). The organic layer was then washed with H2O (5x) and concentrated to 5 V to give a toluene solution of compound L4 free base. An analytical sample of L4 free base was obtained by crystallization in heptane / MTBE. 1H NMR (400 MHz, chloroform-d) δ 8.66-8.77 (m, 1H), 8.06 (d, J = 1.22 Hz, 1H), 7.94 (dd, J = 1.77, 5.20 Hz, 1H), 7.86 (dd, J = 3.55, 8.56 Hz, 1H), 7.51-7.60 (m, 1H), 5.63 (s, 1H), 5.44-5.48 (m, 1H), 3.54-3.60 (m, 6H), 3.43-3.49 (m, 6H); melting point 41.8 °C (DSC peak); XRPD 2θ: 6.70, 7.61, 9.67, 13.56, 13.77, 13.99, 15.36, 19.36, 20.71, 21.81, 23.10, 26.96, 27.72, 28.02, 29.36, 31.88, 32.04, 39.09.

[0077] Preparation of L4-phosphate: A solution of 85% H3PO4 (1.6 eq. based on compound L4 free base) in MeOH (1-2 V) was added to the above L4 solution in toluene over 2 h to give a suspension. The suspension was concentrated to 3 V below 45 °C and n-heptane (10 V) was added over 2 h. The mixture was concentrated to 10 V below 45 °C and the batch temperature was adjusted to 15-25 °C. After stirring for 6-8 h, the mixture was filtered and the filter cake was washed with n-heptane (1-2 V). The wet cake was dried under reduced pressure at 40 °C with a slight N2 sweep to give 190.5 g of L4-phosphate (93.2% yield). 1 H NMR (400MHz, DMSO-d6) δ8.63~8.72(m, 1H), 8.24(dd, J=3.6, 8.7Hz, 1H), 8.11(d, J=1.1Hz, 1H), 8.01(d d, J=1.8, 5.2Hz, 1H), 7.92(dd, J=8.7, 9.9Hz, 1H), 5.58(s, 1H), 5.36(s, 1H), 3.43(s, 6H), 3.35(s, 6H). LC-MS:[M+H] +323.2; melting point 124.2°C (DSC peak); XRPD 2θ: 4.87, 7.35, 9.20, 12.76, 14.66, 15.06, 15.92, 16.99, 19.56, 19.81, 20.26, 21.55, 22.12, 23.09, 23.39, 23.73, 25.61, 26.25, 27.48, 27.73, 28.26, 29.55, 30.35, 31.10, 31.82, 34.13, 34.68, 36.04, 39.48.

[0078] 5.1.4. Synthesis of 5-fluoro-[2,4'-bipyridine]-2',6-dicarboxaldehyde (compound Q) [ka] A mixture of compound L4-phosphate (177 g, 111 g L4 free base = 1.0x), 1N hydrochloric acid (1110 mL, 10 V) and toluene (555 mL, 5 V) was stirred at 15-25 °C for 0.5-1.0 h. The organic phase was separated and the aqueous layer was stirred at 55-60 °C for 2 h. The mixture was concentrated slowly (3 h) under reduced pressure (-0.08 to -0.085 Mpa) at 55-60 °C to remove the evolved MeOH, then cooled to 30-40 °C. DCM (777 V) was charged and the pH of the mixture was adjusted to 5-7 with 15% Na2CO3 (3.5-4.5x). The layers were separated and the aqueous layer was extracted with DCM (2 V). The combined organic layers were washed with H2O (5 V) and filtered through a pad of Na2SO4 (1x). The filter pad was washed with DCM (2V) and the combined filtrate was concentrated to 8-10V. The reactor walls were spray washed with 2V of DCM and n-heptane (8-10V) was charged over 2.0-5.0 h. The mixture was concentrated to 10-12V at <60°C (residual DCM in the supernatant ≤40%) under normal atmospheric pressure. The suspension was aged at 30-40°C for 1.0-2.0 h, 5-10°C for 6-8 h, and filtered. The filter cake was washed with 1:4 DCM / n-heptane (1-2V) and dried under vacuum at 40-50°C to give 80.19 g of compound Q (98% yield). LC-MS: [M+H] + 231;[M+H+H2O] + 249; 1H NMR (400 MHz, chloroform-d) δ 10.27 (s, 1H), 10.18 (s, 1H), 8.91-9.00 (m, 1H), 8.51-8.59 (m, 1H), 8.24-8.31 (m, 1H), 8.17 (dd, J = 3.5, 8.7 Hz, 1H), 7.77 (t, J = 9.0 Hz, 1H); melting point 150 °C (DSC peak).

[0079] 5.1.5. Synthesis of 2',6-bis(difluoromethyl)-5-fluoro-2,4'-bipyridine (Compound H) [ka] A solution of compound Q (30.0 g, 1.00×) and Et3N (0.044×) in dry DCM (KF≦0.02%, 20×) was cooled to 0–5°C. DAST (3.50×) was added slowly at 0–10°C, and the mixture was aged at 20–25°C until reaction completion (ca. 24 h). The reaction mixture was quenched in 15% K2CO3 (28×) at 0–20°C for 2 h and aged at 20–25°C for 0.5 h. The organic layer was separated, cooled to 10–20°C, and treated with 1M hydrochloric acid (9.9–11.1×) at 10–25°C for 0.5–1 h. After settling for 0.5 h, the mixture was filtered through a pad of diatomaceous earth (ca. 0.5×) followed by a brief wash with DCM (2.0–3.0×). The filtrate was allowed to settle, the organic layer was separated, washed with HO (10x), and filtered through a pad of silica gel (ca. 1.5x). The silica pad was washed with DCM (5.0x-6.0x, 3 times) until the purity of compound H in the filtrate fractions was reduced to <90%. The combined filtrates were concentrated to ca. 2-3 V at <30 °C and co-distilled with isopropanol at 50 °C until the residual DCM was <5.0% (6-7x IPA was used in total) to a final volume of 3-4 V. The distillation residue was aged at 55-60 °C for 0.5 h, cooled to 35-40 °C, and aged for 0.5 h. Water (9.0-10.0x) was slowly added (1-3 h) at 33-40 °C, and the mixture was stirred for 0.5 h. After aging at 15-20°C, the suspension was filtered and the filter cake was washed successively with IPA / H2O (1:4, w / w, 1x) and H2O (2x). The wet cake was dried under vacuum at 40-45°C until KF<0.3% and residual IPA<0.1% (18-24 h) to give 30.15 g of compound H (82% yield). Melting point (mp) 75°C (DSC peak). LC-MS: [M+H] + 275.2; 1 H NMR (400 MHz, chloroform-d) δ 8.71–8.89 (m, 1H), 8.22 (s, 1H), 7.91–8.12 (m, 2H), 7.71 (t, J = 8.9 Hz, 1H), 7.00 (s, 1H), 6.87 (s, 1H), 6.82–7.05 (m, 1H), 6.59 (s, 1H), 6.73 (s, 1H).

[0080] 5.1.6. Synthesis of (S)-2-amino-2,4-dimethylpentan-1-ol benzoate (compound D-benzoate) [ka] BF3·Et2O (200 g, 2.0 eq.) was added slowly to a mixture of NaBH4 (53 g, 2.0 eq.) in THF (1.0 L) at 0–10 °C. The reaction mixture was warmed to 15 °C and (S)-(α)-methylleucine (100 g, 1.0 eq.) was added over 1 h at <25 °C. The mixture was aged at 20–25 °C for 5–8 h and then slowly quenched into 10% aqueous NaOH (750 mL) at 25–30 °C. The organic layer was separated, washed with 15% aqueous NaCl (200 mL) and diluted with n-heptane (300 mL). 2 N hydrochloric acid (ca. 300 mL) was added to the mixture until the pH reached 1–2. The organic layer was separated and extracted with 1 N hydrochloric acid (300 mL). The combined aqueous layers were basified with 30% NaOH (~500 mL) until pH > 13 and extracted with MTBE (500 mL × 3). The combined organic extracts were dried over anhydrous Na2SO4 (100–200 g), filtered, concentrated to ~200 mL, and flushed with MTBE (200–500 mL) until the water content of the concentrate was less than 0.5%. Then, a solution of amino alcohol D was added slowly (5 h) at 45–50 °C to a solution of benzoic acid (93 g, 1.1 eq.) in MTBE (500 mL). After stirring for 1 h, the mixture was cooled slowly (5–8 h) to 20–25 °C and aged for 5–8 h to obtain a suspension. The suspension was filtered, and the filter cake was washed with 1 / 1 MTBE / n-heptane (150 mL) and dried under reduced pressure at 40–50 °C to obtain compound D-benzoate in 92% yield. Melting point 125.4°C (DSC peak); 1H NMR (400 MHz, methanol-d4) δ 7.88-7.99 (m, 2H), 7.27-7.46 (m, 3H), 3.45-3.62 (m, 2H), 1.69-1.87 (m, 1H), 1.56-1.66 (m, 1H), 1.44-1.54 (m, 1H), 1.29 (s, 3H), 1.00 (d, J = 6.60 Hz, 6H); XRPD 2θ:6.67, 6.83, 12.84, 13.37, 15.16, 16.95, 17.83, 19.90, 20.32, 21.23, 22.28 , 23.70, 24.09, 24.42, 26.24, 26.91, 27.49, 30.60, 32.64, 33.98, 34.98, 35.13.

[0081] 5.1.7. Synthesis of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine hydrochloride (Compound S) [ka] Solid t-BuOK (2.5-3.0 eq. based on compound H) was charged portionwise to a mixture of compound D-benzoate (1.2 eq. based on compound H) and THF (10.5-11.6x) at 15-20°C. The mixture was warmed to 20-25°C, stirred for 3-5 h, and then cooled to 0-5°C. A solution of compound H (1.00x) in THF (3.6-4.5x) was added slowly (~1 h) while maintaining the batch temperature below 20°C. The reaction mixture was aged at 20-25°C until reaction completion (1-3 h). MTBE (6x) was added and the mixture was cooled to 10-15°C. H2O (9.0-11.0x) was added slowly (1-3 h) while maintaining the batch temperature below 25°C. The layers were separated and the aqueous layer was extracted with MTBE (2.2x). The combined organic layers were concentrated under reduced pressure to 2-3 V below 30° C. Free base compound J: 1H NMR (400MHz, DMSO-d6) δ8.70~8.84 (m, 1H), 8.40 (d, J=8.8Hz, 1H), 8.33 (s, 1H), 8.22 (br d, J=5.0Hz, 1H), 7.81(d, J=8.8Hz, 1H), 7.17~7.41(m, 1H), 6.89~7.13(m, 1H), 3.82~3.95(m, 2H), 1.74~1.88(m, 1H), 1.55(br s, 2H), 1.33~1.46(m, 2H), 1.12(s, 3H), 0.93(t, J=7.1Hz, 6H). After solvent exchange to IPA by co-distillation (6.0–6.5×) to 2–3 V, more IPA (3.8–4.2×) was added and the mixture was heated to 50–60 °C. A solution of 35% hydrochloric acid (0.44–0.47×) in IPA (1.3–1.5×) was added slowly (ca. 1 h) while keeping the batch at 50–60 °C. The resulting suspension was aged at 50–60 °C for 1.0–2.0 h, cooled to 20–30 °C in 2.0–4.0 h, stirred at 20–30 °C for 1.0–2.0 h, and then filtered. The filter cake was washed with MTBE (3.5–4.0×) and dried under reduced pressure at 40–50 °C for 16–24 h to give compound S. LC-MS m / z 386.1; melting point 246.4 °C (DSC peak), 1 H NMR (400MHz, DMSO-d6) δ8.81(d, J=5.3Hz, 1H), 8.51(br s, 2H), 8.45(d, J=8.9Hz, 1H), 8.34(s, 1H), 8.24(d, J=5.1Hz, 1H), 7.91(d, J=8.9Hz, 1H), 7.56~7.87(m, 1H) ), 6.90~7.23(m, 1H), 4.29(s, 2H), 1.72~1.91(m, 2H), 1.54~1.72(m, 1H), 1.42(s, 3H), 0.86~1.00(m, 6H).

[0082] 5.1.8. Synthesis of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine phosphate (Compound K) [ka] A mixture of compound S (9.5 kg, 1.0×), MTBE (76.0 kg, 8.0×), and water (50.0 kg, 5.3×) was treated with 20% aqueous NaOH (0.95 kg NaOH solid in 4.0 kg water) at 35–40 °C until all solids were dissolved (2.0–5.0 h). The reaction mixture was cooled to 20–25 °C and stirred for 1.0–2.0 h. The organic layer was separated, washed with water (46.5 kg, 4.9×), and concentrated under reduced pressure below 30 °C to approximately 25 L (2–3×). The solvent was exchanged to IPA by co-distillation (79.0 kg IPA, 8.3×) under reduced pressure below 50 °C to a final volume of 29–38 L (3–4×), after which the distillation residue was diluted with IPA (60 kg) and heated to 50–60 °C. A solution of H3PO4 (2.8 kg, 0.29x) in IPA (5.0 kg, 0.53x) was added over 2.0-4.0 h. IPA (22.0 kg, 2.3x) was further added and the batch was stirred at 50-60 °C for 2.0-4.0 h. The batch was cooled to 15-20 °C over 2.0-4.0 h and then stirred at 15-20 °C for 1.0-2.0 h. The resulting suspension was filtered and the filter cake was washed sequentially with IPA (27.0 kg, 2.84x) and MTBE (31 kg, 3.3x). The wet cake was dried under reduced pressure at 45-55 °C for 17-24 h to obtain compound K. The salt ratio of compound J to phosphoric acid in compound K was 1:1 (two separate HPLC methods using UV and IC detectors, respectively). The purity of compound K was 98.7-99.9 area % by HPLC. The crystallinity of compound K was confirmed by XRPD and further supported by DSC. 1 H NMR (400MHz, DMSO-d6) δ8.78(d, J=5.1Hz, 1H), 8.41(d, J=8.8Hz, 1H), 8.31(s, 1H), 8.21(d, J=5.1Hz, 1H), 7.88(brd, H), 7.47(t,J H-C-F =54Hz, 1H), 7.04(t, J H-C-F =54Hz,1H), 4.03~4.29(m, 2H), 1.72~1.87(m, 1H), 1.60~1.69(m, 1H), 1.49~1.59(m, 1H), 1.33(s, 3H), 0.92(d, J=6.6, 3H), 0.87(d, J=6.6, 3H); 13C NMR(100MHz,DMSO-d6)δ21.62, 22.74, 24.61, 24.82, 44.69, 54.57, 72.80, 110.53(t, J C-F =237Hz), 113.84(t,J C-F =238Hz), 116.68, 122.19, 125.03, 140.07(t, J C-F =22Hz), 144.13, 145.98, 150.52, 152.80(t, J C-F =25Hz), 153.51. XRPD:4.80, 5.99, 7.43, 7.88, 9.57, 11.58, 14.84, 15.21, 15.75, 17.91, 18.83, 19.17, 20.41, 20.84, 21.67, 23.23, 23.95, 24.41, 24.72, 25.27, 26.37, 30.14.

[0083] 5.1.9. Synthesis of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine phosphate (Compound K) [ka] To a solution of compound J (9.14 g) in IPA (100 mL) was added compound K seeds (0.18 g) at 50-60 °C. A solution of 85% phosphoric acid (2.87 g, 1.05 eq.) in IPA (7 mL) was added over 2-4 h. The suspension was aged for 2-4 h, cooled to 15-20 °C over 2-4 h, and aged for 1-2 h. The suspension was filtered and the filter cake was washed with IPA (20 mL) and then with MTBE (44 mL). The wet cake was dried under reduced pressure at 45-55 °C for 17-24 h to give 11.3 g of compound K (98% yield).

[0084] Seeding of compound K: Compound J (50.08 mg, 0.134 mmol, 1.0 eq.) was added with IPA (1.0 mL) to give a clear solution at ambient temperature, and phosphoric acid (0.156 mL, 1 M in IPA, 0.156 mmol, 1.20 eq.) was added. The mixture was stirred for 6 h to give a suspension and aged at 60 °C for 30 min. After cooling to room temperature, heptane (0.5 mL) was added and the resulting mixture was stirred for 1 h. The resulting suspension was filtered, the filter cake was washed with MTBE (0.5 mL) and dried overnight at 45-48 °C under reduced pressure to give compound K seeds (59.28 mg, 94.4% yield).

[0085] The salt ratio, purity, XRPD, DSC and TGA data are substantially identical to those obtained for compound K in Example 2.

[0086] Each document (eg, patents, patent applications, and publications) cited herein is hereby incorporated by reference in its entirety.

Claims

1. (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): 【Chemistry 1】 A method for preparing compound H: 【Chemistry 2】 Compound D: 【Chemistry 3】 or a salt thereof in the presence of a base under conditions sufficient to form compound J.

2. The method of claim 1 , wherein the base is an alkoxide.

3. The method of claim 2, wherein the alkoxide is potassium tert-butoxide.

4. Compound H is a compound Q: 【Chemistry 4】 with a fluorinating agent under conditions sufficient to form compound H.

5. The method of claim 4 wherein the fluorinating agent is DAST.

6. Compound Q is compound P: 【Chemistry 5】 with an acid under conditions sufficient to form compound Q.

7. The method of claim 6, wherein the acid is hydrochloric acid.

8. Compound P is a compound L: 【Chemistry 6】 Compound N: 【Chemistry 7】 under conditions sufficient to form compound P.

9. Compound Q is compound L4: 【Chemistry 8】 with an acid under conditions sufficient to form compound Q.

10. The method of claim 9, wherein the acid is hydrochloric acid.

11. Compound L4 is compound L3: 【Chemistry 9】 Compound L1: 【Chemistry 10】 11. The method of claim 9 or 10, wherein the compound is prepared by contacting with a compound L4 in the presence of a catalyst, a ligand, and a base under conditions sufficient to form compound L4.

12. 12. The method of claim 11 , wherein the catalyst is Pd2(dba)2.

13. 13. The method of claim 11 or 12, wherein the ligand is Xphos.

14. The method according to any one of claims 11 to 13, wherein the base is sodium carbonate.

15. The method according to any one of claims 1 to 14, wherein the salt of compound D is a benzoate salt.

16. 14. The method of claim 13, wherein the solvent is isopropyl alcohol.

17. Compound K: 【Chemistry 11】 A method for preparing a compound S (e.g., in MTBE): 【Chemistry 12】 with aqueous NaOH to obtain compound J; and contacting compound J with an acid (e.g., phosphoric acid or hydrochloric acid) in a solvent under conditions sufficient to form compound K.

18. Compound S is compound J: 【Chemistry 13】 with hydrochloric acid in a solvent under conditions sufficient to form compound S.

19. 20. The method of claim 18, wherein the solvent is isopropyl alcohol.

20. The method according to claim 18, wherein compound J is prepared according to any of claims 1 to 16.

21. A compound which is 6-bromo-2-(dimethoxymethyl)-3-fluoropyridine (compound L1): 【Chemistry 14】

22. A compound which is 2-(dimethoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (compound L3): 【Chemistry 15】

23. 2',6-Bis(dimethoxymethyl)-5-fluoro-2,4'-bipyridine (compound L4): 【Chemistry 16】 or a salt thereof.

24. 24. The compound of claim 23 which is a hydrochloride, phosphate or maleate salt.

25. The compound of claim 24, which is crystalline 2',6-bis(dimethoxymethyl)-5-fluoro-2,4'-bipyridine phosphate having a melting point of about 125°C.

26. 26. The compound of claim 25, having an XRPD spectrum including peaks at one or more of about 6.70, about 7.61, about 9.67, about 13.56, about 13.77, about 13.99, about 15.36, about 19.36, about 20.71, about 21.81, about 23.10, about 26.96, about 27.72, about 28.02, about 29.36, about 31.88, about 32.04, about 39.09 °2θ.

27. A compound which is 5-fluoro-[2,4'-bipyridine]-2',6-dicarboxaldehyde (Compound Q): 【Chemistry 17】

28. 28. A crystalline form of the compound of claim 27, having a melting point of about 150°C.

29. A compound which is (S)-2-amino-2,4-dimethylpentan-1-ol benzoate (compound D-benzoate): 【Chemistry 18】

30. 30. A crystalline form of the compound of claim 29.

31. A compound which is 2',6-bis(difluoromethyl)-5-fluoro-2,4'-bipyridine (Compound H): 【Chemistry 19】

32. 32. A crystalline form of the compound of claim 31.

33. (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): 【Chemistry 20】 A crystalline pharma- ceutically acceptable salt of

34. 34. The crystalline pharma- ceutically acceptable salt of claim 33, which is a hydrochloride salt.

35. 35. The hydrochloride salt of claim 34, having a melting point of 247°C (decomposition).

36. 35. The hydrochloride salt of claim 34, having an XRPD spectrum including peaks at one or more of about 9.2, about 11.7, about 13.9, about 18.7, about 22.2, about 25.0, or about 26.8 °2θ.

37. 34. The crystalline pharma- ceutically acceptable salt of claim 33 which is a phosphate salt.

38. 38. The phosphate salt of claim 37, having a melting point of about 184°C.

39. 40. The phosphate salt of claim 38, having an XRPD spectrum including peaks at one or more of about 4.81, about 5.99, about 7.44, about 7.89, about 11.66, about 14.85, about 15.77, about 19.19, about 20.86, about 21.65, about 23.96, about 24.48, or about 24.73 °2θ.

40. (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): 【Chemistry 21】 or a pharma- ceutically acceptable salt thereof, comprising testing said sample for the presence of one or more of the compounds listed in Table 1.

41. (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): 【Chemical 22】 or a pharma- ceutically acceptable salt thereof, said composition comprising less than 0.01% by weight of one or more of the compounds listed in Table 1.

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