Process for the synthesis of substituted tetrahydrofuran modulators of sodium channels

Abstract

In this application, compound I Processes for making TIFF2024522290000122.tif4263(I) and pharma- ceutically acceptable salts thereof are provided, which are useful as inhibitors of sodium channels. Processes for making various intermediate products and suitable salts thereof are also provided. In one embodiment, one skilled in the art can prepare any of the compounds of formula I, or intermediate compounds of formula II-V and VII-XX, starting from any of the compounds of formula II-V and VII-XX according to the reactions shown in Schemes 1 and 2.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 196,868, filed June 4, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] BACKGROUND OF THEINVENTION Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to damaged tissue. Nevertheless, there are many conditions in which pain persists beyond its usefulness or in which patients would benefit from the suppression of pain. Neuropathic pain is a form of chronic pain caused by damage to sensory nerves (Dieleman, JP, et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3): p. 681-8). Neuropathic pain can be divided into two categories: pain caused by systemic metabolic damage to the nerve and pain caused by discrete nerve damage. Metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for discrete nerve damage include nerve entrapment injuries such as post-amputation pain, post-operative nerve injury pain, and neuropathic back pain.

[0003] Voltage-gated sodium channels (Na V ) is involved in pain signaling. VSodium channel receptors (SCHs) are biological mediators of electrical signaling and mediate the rapid upstroke of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac myocytes). Evidence for a role of these channels in normal physiology, pathological conditions resulting from mutations in sodium channel genes, preclinical studies in animal models, and clinical pharmacology of known sodium channel modulators all support the role of Na channel receptors in pain sensation. V (Rush, A. M. and T. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Na V 1.8 Sodium Channels. Mol. Interv.,2007. 7(4): p. 192-5), England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17(12), p. 1849-64(2008), Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), p. 50-56(2008)). Na V Ion channels mediate the rapid upstroke of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac myocytes) and are therefore involved in the initiation of signal transduction in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Na is important in the initiation and propagation of neuronal signals. V Because of the role played by Na V Antagonists that reduce the current can prevent or reduce nerve signaling, and NaV It has been suggested that the channels may potentially reduce pain in conditions where hyperexcitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7(2), p. 144-58(2008)). Several clinically useful painkillers are V Local anesthetics such as lidocaine have been identified as inhibitors of the Na channel. V Other compounds such as carbamazepine, lamotrigine, and tricyclic antidepressants, which have been shown to block pain by inhibiting the channel and are effective in reducing pain, have also been suggested to act by blocking sodium channels (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9 (2002); Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na + currents by antidepressant sertraline and paroxetine. J. Membr. Biol. 222(2), p. 79-90(2008)).

[0004] Na V form a subfamily of voltage-gated ion channels that mediate the regulation of Na V 1.1~Na V It contains nine isoforms, designated 1.1 and 1.9. The tissue localization of the nine isoforms varies. V 1.4 is the primary sodium channel in skeletal muscle and is V 1.5 is the primary sodium channel in cardiac myocytes. Na V 1.7, 1.8, and 1.9 are primarily localized in the peripheral nervous system and V1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behavior of the nine isoforms is similar, but distinct in the details of their voltage-dependence and kinetic behavior (Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57(4),p. 397(2005)).

[0005] At the time of their discovery, Na V The NaV1.8 channel was identified as a likely target for analgesia (Akopian,AN,L. Sivilotti,and JN Wood,A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature,1996. 379(6562): p. 257-62). NaV1.8 was subsequently shown to be the carrier of the sodium current that sustains action potential firing in small dorsal root ganglion (DRG) neurons (Blair,NT and BP Bean,Roles of tetrodotoxin(TTX)-sensitive Na+ current,TTX-resistant Na + current,and Ca 2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci.,2002. 22(23): p. 10277-90). Na V 1.8 is involved in spontaneous firing in injured neurons, such as those that cause neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na +channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol.,2003. 550(Pt 3): p. 921-6、Jarvis,M.F.,et al.,A-803467,a potent and selective Na V 1.8 sodium channel blocker,attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A,2007. 104(20): p. 8520-5、Joshi,S.K.,et al.,Involvement of the TTX-resistant sodium channel Na V 1.8 in inflammatory and neuropathic,but not post-operative,pain states. Pain,2006. 123(1-2): pp. 75-82、Lai,J.,et al.,Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel,Na V 1.8. Pain,2002. 95(1-2): p. 143-52、Dong,X.W.,et al.,Small interfering RNA-mediated selective knockdown of Na V1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience,2007. 146(2): p. 812-21、Huang,H.L.,et al.,Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. Mol. Pain,2008. 4: p. 33、Black,J.A.,et al.,Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol.,2008. 64(6): p. 644-53、Coward,K.,et al.,Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states. Pain,2000. 85(1-2): p. 41-50、Yiangou,Y.,et al.,SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett.,2000. 467(2-3): p. 249-52、Ruangsri,S.,et al.,Relationship of axonal voltage-gated sodium channel 1.8(Na V 1.8)mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem. 286(46): p. 39836-47)。Na VThe small DRG neurons in which Na1.8 is expressed contain nociceptors involved in pain signaling. V 1.8 mediates large amplitude action potentials in small neurons of the dorsal root ganglion (Blair, NT and BP Bean, Roles of tetrodotoxin (TTX)-induced Na + Current, TTX-resistant Na + current,and Ca 2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci.,2002. 22(23): p. 10277-90). Na V 1.8 is required for rapid repetitive action potentials in nociceptors and for spontaneous activity of injured neurons. (Choi, JS and SG Waxman, Physiological interactions between Na V 1.7 and Na V 1.8 sodium channels: a computer simulation study. J. Neurophysiol. 106(6): p. 3173-84, Renganathan, M., TR Cummins, and SG Waxman, Contribution of Na( V )1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol.,2001. 86(2): p. 629-40, Roza,C.,et al.,The tetrodotoxin-resistant Na + Channel Na V1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol.,2003. 550(Pt 3): p. 921-6). V 1.8 is thought to be a driver of hyperexcitability (Rush, AM, et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006. 103(21): p. 8245-50). In some animal pain models, Na V 1.8 mRNA expression levels have been shown to increase in DRG (Sun,W.,et al.,Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain,135(Pt 2): p. 359-75,Strickland,IT,et al.,Changes in the expression of Na V 1.7,Na V 1.8 and Na V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur. J. Pain,2008. 12(5): p. 564-72, Qiu,F.,et al.,Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 and Na V1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett.,512(2): p. 61-6). Some known Na V The main drawback of the inhibitors is their poor therapeutic window, which is likely a result of lack of isoform selectivity. V 1.8 is naturally restricted to pain-sensing neurons, and thus is a selective Na V 1.8 Blockers are non-selective Na V It is unlikely to induce the adverse events common to blockers. Therefore, additional Na V There remains a need to develop channel modulators, preferably those that are highly potent and selective for NaV1.8. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Dieleman,JP,et al.,Incidence rates and treatment of neuropathic pain conditions in the general population. Pain,2008. 137(3): p. 681-8 [Non-Patent Document 2] Rush, AM and TR Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels. Mol. Interv., 2007. 7(4): p. 192-5) [Non-Patent Document 3] England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17(12), p. 1849-64(2008) [Non-Patent Document 4] Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), p. 50-56(2008) [Non-Patent Document 5] Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001) [Non-Patent Document 6] Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7(2), p. 144-58(2008) [Non-Patent Document 7] Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9(2002) [Non-Patent Document 8] Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na+ currents by antidepressant sertraline and paroxetine. J. Membr. Biol. 222(2), p. 79-90(2008) [Non-Patent Document 9] Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57(4), p. 397(2005) [Non-Patent Document 10] Akopian, AN, L. Sivilotti, and JN Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62 [Non-Patent Document 11] Blair, NT and BP Bean, Roles of tetrodotoxin(TTX)-sensitive Na+ current,TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90 [Non-Patent Document 12] Roza, C., et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6 [Non-Patent Document 13] Jarvis, M.F., et al., A-803467, a potent and selective NaV1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A, 2007. 104(20): p. 8520-5

Non-Patent Document 14

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Non-Patent Document 17

[0007] In one aspect, the present invention provides a compound of formula I [ka] and methods for preparing pharma- ceutically acceptable salts thereof.

[0008] In a second embodiment, the method comprises converting any of the compounds of formulae II-V and VII-XXI to a compound of formula I according to the reaction steps described herein. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 shows the X-ray diffraction pattern of Form A of Compound III AMB salt. [Diagram 2] FIG. 2 shows the X-ray diffraction pattern of Form A of the quinine salt of formula IV. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In one embodiment, one skilled in the art can prepare a compound of formula I, or any of the intermediate compounds of formulae II-V and VII-XX, starting from any compound of formulae II-V and VII-XX by following the reactions shown in Schemes 1 and 2. [ka] [ka]

[0011] The process steps described herein may refer to converting starting compounds of formulas II-V and VII-XXI to compounds of formula I. Those skilled in the art will appreciate that such processes can also be used to prepare any intermediate between any starting compound and a compound of formula I. For example, the conversion of a compound of formula III to a compound of formula I goes through intermediate compounds II, IV, V. As such, those skilled in the art will appreciate that the processes described for converting a compound of formula III to a compound of formula I can be used to prepare any of intermediate compounds II, IV, and V from a compound of formula III. Similarly, the conversion of a compound of formula IX to a compound of formula I goes through the preparation of intermediate compounds II-V, VII, and VIII. Thus, those skilled in the art will appreciate that the processes described for converting a compound of formula IX to a compound of formula I can be used to prepare any of intermediate compounds II-V, VII, and VIII starting from a compound of formula IX, or that any intermediate compound can be converted to a desired intermediate compound using the processes described herein. Thus, the present application contemplates the preparation of intermediate compounds II-V and VII-XXI starting from any intermediate or starting material preceding the intermediate to be prepared. For example, intermediate compound II may be prepared starting from any of compounds III-V and VII-XXI. Similarly, compound VII may be prepared starting from any of compounds VIII-XXI.

[0012] In one embodiment, the present application relates to a compound of formula III: [ka] or a salt thereof to a compound of formula I.

[0013] In some embodiments, the method of converting a compound of formula III to a compound of formula I includes preparing a compound of formula IV: [ka]

[0014] The compound of formula IV may be prepared directly from the compound of formula III by reacting the compound of formula III with quinine in a solvent comprising a polar solvent. In some embodiments, the compound of formula IV may be prepared by dissolving or suspending the compound of formula III and quinine in a solvent comprising a polar solvent. In some embodiments, the solvent comprises DCM and heptane; toluene, EtOAc and heptane; MTBE, acetonitrile and heptane; 2-MeTHF and heptane, or MEK and heptane. In other embodiments, the solvent comprises DCM, heptane, toluene, EtOAc, MTBE, acetonitrile, 2-MeTHF, or MEK.

[0015] In some embodiments, the compound of formula IV is prepared by first converting the compound of formula III into a salt (e.g., a salt of the compound of formula III with 1-phenylethylamine) and then converting such salt into a quinine salt using any method known to one of skill in the art. Additionally, a salt of compound III (e.g., a 1-phenylethylamine salt of the compound of formula III) may be first converted into the free base and then the latter converted into the quinine salt of compound III (i.e., the compound of formula IV). [ka]

[0016] Compound III may be converted to compound I via an esterification reaction between compounds III and VI. The esterification reaction may be carried out via an intermediate compound of formula V. Alternatively, the esterification of compounds VI and III to give compound II may be carried out via a coupling agent without the use of a chlorinating agent.

[0017] In some embodiments, the method of converting a compound of formula III to a compound of formula I includes reacting a compound of formula III or a salt thereof (such as a compound of formula IV or an (R)-1-phenylethylamine salt of a compound of formula III) with a chlorinating agent to obtain a compound of formula V. [ka] In the compound of formula V, brackets around the compound indicate that the compound of formula V may not be isolated.

[0018] A mixture of compounds of formula III and IV may also be converted to a compound of formula II via a coupling reaction that may or may not involve a compound of formula V. In some embodiments, the mixture is first converted to a compound of formula V, followed by the reaction between a compound of formula V and a compound of formula VI as described elsewhere in this application. In other embodiments, a mixture of compounds of formula III and IV may be converted to a compound of formula II via a coupling reaction that includes a step in which a compound of formula IV in the mixture is first converted to the free acid of formula III, and then coupling the acid with a compound of formula VI.

[0019] Any chlorinating agent suitable for chlorinating compound III or its salt may be used. In some embodiments, the chlorinating agent is thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosgene, oxalyl chloride, isobutyl chloroformate (IBCF), pivaloyl chloride (PivCl), or diphenylphosphinic chloride (DPPCl). In some embodiments, the chlorinating agent is phosgene.

[0020] The reaction between compound III and the chlorinating agent may be carried out in the presence of a non-nucleophilic base. Any suitable non-nucleophilic base may be used to scavenge the HCl generated by the chlorination reaction.

[0021] Suitable non-nucleophilic bases are typically tertiary or aromatic amines in which the nitrogen of the amine base does not carry an H atom. The non-nucleophilic base may be a bulky base that is non-nucleophilic due to steric hindrance. Examples of suitable bases include Hunig's base, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, butylamine, or 1,5-diazabicyclo(4.3.0)non-5-ene, or mixtures thereof. In some embodiments, the reaction between compound III and the chlorinating agent is carried out at a temperature of about 90° C. or less. In some embodiments, the esterification reaction between compound III or a salt thereof and the compound of formula VI may be carried out at a temperature of about 60° C., about 70° C., or about 80° C. or less. In other embodiments, the esterification reaction between compound III or a salt thereof and the compound of formula VI may be carried out at a temperature of about 70° C. or less.

[0022] In a further embodiment, the method of converting a compound of formula III to a compound of formula I comprises halogenating a compound of formula III or IV to obtain a compound of formula V, followed by esterifying the compound of formula V with a compound of formula VI, [ka] to obtain a compound of formula II. [ka]

[0023] The esterification reaction was carried out using DCM, toluene, MeCN, EtOAc, 2-methyl-THF, CH 2 Cl 2The esterification reaction may be carried out in a solvent containing 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl), or propylphosphonic anhydride (T3P). In some embodiments, the esterification reaction may be carried out in the presence of a base selected from the group consisting of trimethylamine, N-methylimidazole, pyridine, 4-methylmorpholine, Hunig's base, DABCO, and NaOH, and the like. In further embodiments, the base may be any C1-C4 alkyl tertiary amine, such as triethylamine, ethyldimethylamine, ethyldipropylamine, and various alkyl combinations thereof.

[0024] After completion of the esterification reaction (either via the acid chloride of formula V or directly between compounds III and VI using a coupling agent), the compound of formula II may be purified by recrystallizing it from a solvent containing, for example, methanol or water, or a mixture thereof. Other suitable combinations of two solvents include ethanol / water, toluene / heptane, IPA / water, etc. In any of these combinations, the compound of formula II is dissolved in one solvent at or near boiling temperature, and then the second solvent is added until the solution becomes cloudy. The cloudy suspension is cooled to room temperature (or cooled in an ice bath), and then the solid is filtered.

[0025] In some embodiments, the method of converting a compound of formula III to a compound of formula I further comprises an amidation reaction comprising reacting a compound of formula II with ammonia to obtain a compound of formula I. In some embodiments, the amidation reaction may be carried out in a solvent. In some embodiments, the solvent is methanol, ethanol, IPA, MeCN, THF, 2-MeTHF, water, or a mixture thereof. The amidation of a compound of formula II to obtain a compound of formula I may be carried out in the presence of a weak non-nucleophilic base. An example of a base suitable as an additive for the amidation reaction is Mg(OMe) 2 , CaCl 2 , DIPEA, and K. 2CO 3 Examples include:

[0026] The amidation reaction may be carried out using a solution of ammonia in the reaction solvent, ammonia in gaseous form (i.e., by bubbling ammonia gas through the reaction solution), or in the form of ammonium hydroxide or an ammonium salt (such as the chloride) where ammonia is generated in situ (e.g., by neutralizing ammonium hydroxide with an acid).

[0027] The compound of formula I may be recrystallized from a solvent system comprising acetone to obtain the compound of formula I as a solid. In some embodiments, the recrystallization solvent system comprises acetone and water. In other embodiments, the recrystallization solvent may comprise IPA or the following solvent pairs: ethyl acetate / heptane, IPA / water, ethanol / water, isopropyl acetate / heptane.

[0028] Although one of ordinary skill in the art may devise methods for making the compounds of formula III that are used to prepare compounds of formula I, the inventors of the present application contemplate using the following process to prepare compounds of formula III.

[0029] In one embodiment, the compound of formula III is obtained by hydrolysis of a cyano compound of formula VII, [ka] A compound of formula III can be obtained. Any base or acid suitable for hydrolyzing the CN group without affecting other functional groups in the compound of formula VII may be used. In one embodiment, a strong base (NaOH, KOH, etc.) or a strong acid (HCl, sulfuric acid, etc.) may be used. In one embodiment, the CN group in the compound of formula VII is enzymatically hydrolyzed using a nitrilase. The CN hydrolysis of the compound of formula VII may be carried out in a solvent or solvent mixture. For example, ethanol, methanol, 1-propanol, 2-propanol, dioxane, water, THF, or a mixture thereof may be used. The hydrolysis reaction may be carried out at about 25-75°C, about 30-70°C, about 35-65°C, about 40-60°C, about 45-60°C, about 50-60°C, or about 55°C. As used in this paragraph, the term "about" before a temperature range applies to both ends of the range. It also means ±2.5°C.

[0030] A compound of formula VII may be obtained by reacting a compound of formula VIII [ka] where OR is a leaving group; A cyanating agent (e.g., trimethylsilyl cyanide, diethylaluminum cyanide, KCN, NaCN, TBACN, HCN, etc.) provides a compound of formula VII. In one embodiment, the reaction between a cyanating agent (e.g., trimethylsilyl cyanide) and a compound of formula VIII may be carried out in the presence of a Lewis acid. In some embodiments, the Lewis acid is boron trifluoride ethyl etherate (BF 3 OEt 2 ), TiCl 4 , InCl 3 , AgSbF 6 , Iodine, ZnBr 2 , Al(OiPr) 3 , MgCl 2 , Mn(acac) 2 , MnCl 2 , TMSOTf, SnCl 4 , ZnBr 2 , Al(OiPr)3 , ZnCl 2 , FeCl 2 , Cu(NO 3 ) 26 H 2 O, Fe(OAc) 2 , ScCl 3 In a further embodiment, the Lewis acid is BF 3 OEt 2 The cyanation reaction may be carried out in an organic solvent such as toluene, dichloromethane, 2-methylTHF, acetonitrile, methanol, 1,2-dichloroethane, nitromethane, CPME, MTBE, DMAc, t-BuOAc, and the like.

[0031] In the compound of formula VIII, OR is a leaving group. In some embodiments, the leaving group OR on compound VIII is of the formula OC(=O)-Z, OC(=O)OZ, OC(=O)CH=CH-Z, or OP(=O)Z. 2 where Z is an unsubstituted aryl, or CN, halo, NO 2 or a short chain alkyl, alkoxy, haloalkyl, or haloalkoxy group, where the short chain contains 1, 2, 3, or 4 carbon atoms. Alternatively, Z is a short chain (i.e., having 1 to 4 carbon atoms) alkyl or haloalkyl group. Examples of aryl groups include phenyl and naphthyl.

[0032] The compound of formula IX may be converted to a compound of formula VII by introducing an R group into the compound of formula IX, [ka] The resulting compound (compound VIII) contains a leaving group OR. One skilled in the art will appreciate that the hydroxyl group of the compound of formula IX can be converted to any of the OR leaving groups prior to replacing the OR group with CN.

[0033] In some embodiments, the compound of formula VIII may be obtained by reacting an alcohol of formula IX with an acid anhydride or acid chloride to obtain a compound of formula VIII. The compound of formula IX can be reacted with a non-nucleophilic base (such as TEA, pyridine, Hunig's base, K) in a polar solvent (such as toluene, cyclopentyl methyl ether (CPME), dichloromethane, dichloroethane, pyridine, chloroform, acetonitrile, THF, 2-MeTHF, EtOAc, IPAC, or a combination thereof). 2 CO 3 , Na 2 CO3, NaHCO 3 The compound VIII may be converted to compound VIII by reaction with a suitable acid chloride in the presence of an appropriate amine (such as 2,6-lutidine, NMM, DABCO, etc.). Examples of esters (including carbonates) of the compound of formula VIII include: [ka]

[0034] The compound of formula IX can be prepared by reacting a compound of formula X with [ka] Suitable reducing agents (e.g., diisobutylaluminum hydride, Red-Al, NaBH 4 / BF 3 , titanocene with polymethylhydrosiloxane or phenylsilane, superhydride, L-selectride, Li(tBuO) 3 The reduction reaction may be carried out in an organic solvent or mixture of solvents. Suitable solvents include toluene, dichloromethane, 2-methyl THF, THF, TFT, MTBE, CPME, heptane, or mixtures thereof. The reaction may be carried out below room temperature, for example, at about -78°C to 0°C, about -60°C to 0°C, about -50°C to -10°C, about -40°C to -10°C, about -30°C to -10°C, about -30°C to -15°C, about -25°C to -15°C, or about -20°C. ... such as CuCl, CuI, CuTol, CuBr, CuF, Cu(II)Cl 2, DMAP, 2,6-lutidine, LiI, or pyridine.

[0035] The compound of formula X is obtained via asymmetric hydrogenation of the compound of formula XI, [ka] Compounds of formula X can be obtained. The asymmetric hydrogenation reaction may be catalyzed by any hydrogenation catalyst. Examples of hydrogenation catalysts include Pd / C, Pd / Al, using any suitable hydrogen source. 2 O 3 , Pt / C, Pt / Si, Ni(Raney), Co(Raney), Rh / C, Ir / C, Ru / C, Pd(OH) 2 , homogeneous chiral Ru and Rh. Examples of suitable hydrogen sources include H 2 NiCl in gas, methanol 2 / NaBH 4 , Et 3 Examples of suitable pressures include SiH. In some embodiments, hydrogen gas and Pd / C (catalyst) are used. The asymmetric hydrogenation reaction may be carried out in an organic solvent at about 20-40 bar. Lower pressures may be used at higher temperatures and vice versa. For example, about 5 bar may be suitable at about 40° C. Conversely, about 15-20 bar may be suitable at about 30° C. One skilled in the art can match the pressure, temperature, and reaction time to obtain the desired results. The asymmetric hydrogenation reaction may be carried out in an organic solvent or mixture of solvents. In one embodiment, the organic solvent is IPA, EtOAc, MeOH, nBuOH, THF, MTBE, CPME, IPAc, nBuAc, toluene, ethanol, or a mixture thereof. The asymmetric hydrogenation reaction may be carried out in an organic solvent such as citric acid, benzoic acid, TFA, AcOH, H 2 SO 4 , H 3 PO 4 , MSA, Cs 2 CO 3 , CuCl, MgF 2 , LiBr, CsF, ZnI, LiOTf, Imidazole, KF, Bu 4 NOAc, or NH 4 BF4 The reaction may be carried out in the presence of

[0036] In another embodiment, the compound of formula X is obtained via hydrogenation reaction of the compound of formula XI, [ka] A compound of formula X can be obtained. The hydrogenation reaction may be catalyzed by any hydrogenation catalyst. Examples of hydrogenation catalysts include Pd / C, Pd / Al, using any suitable hydrogen source. 2 O 3 , Pt / C, Pt / Si, Ni(Raney), Co(Raney), Rh / C, Ir / C, Ru / C, Pd(OH) 2 Examples of suitable hydrogen sources include H 2 NiCl in gas, methanol 2 / NaBH 4 , Et 3 Examples of suitable pressures include SiH. In some embodiments, hydrogen gas and Pd / C (catalyst) are used. The hydrogenation reaction may be carried out in an organic solvent at about 20-40 bar. Lower pressures may be used at higher temperatures and vice versa. For example, about 5 bar may be suitable at about 40° C. Conversely, about 15-20 bar may be suitable at about 30° C. One skilled in the art can match the pressure, temperature, and reaction time to obtain the desired results. The hydrogenation reaction may be carried out in an organic solvent or mixture of solvents. In one embodiment, the organic solvent is IPA, EtOAc, MeOH, nBuOH, THF, MTBE, CPME, IPAc, nBuAc, toluene, ethanol, or mixtures thereof. The hydrogenation reaction may be carried out in an organic solvent such as citric acid, benzoic acid, TFA, AcOH, H 2 SO 4 , H 3 PO 4 , MSA, Cs 2 CO 3 , CuCl, MgF 2 , LiBr, CsF, ZnI, LiOTf, Imidazole, KF, Bu 4 NOAc, or NH 4 BF 4 The reaction may be carried out in the presence of

[0037] Alternatively, the compound of formula X may be prepared by coupling the compound of formula XXIV with 1-bromo-3,4-difluoro-2-methoxybenzene in the presence of a strong non-nucleophilic base (such as LiHMDS) and a Pd catalyst (such as bis(dibenzylideneacetone)palladium(0)) in the presence of QPhos to give the compound of formula XXIII, where R1 is =OMe, R2 and R3 are F. See Scheme 3. Isomerization of the compound of formula XXIII gives the compound of formula III. [ka]

[0038] The compound of formula XI can be prepared by reacting a compound of formula XIII with [ka] is obtained by coupling with a compound of formula XII, [ka] The compound of formula XI can be obtained. The coupling reaction between the compound of formula XII and the compound of XIII is carried out in the presence of a coupling agent or a chlorinating agent. Examples of coupling agents suitable for the reaction between the compound of formula XII and the compound of XIII include CDI, T3P, etc. The coupling reaction between the compound of formula XII and the compound of XIII may be carried out in the presence of a weak base or a non-nucleophilic base. Examples of weak bases or non-nucleophilic bases suitable for the coupling reaction between the compound of formula XII and the compound of XIII include imidazole, DIPEA, TEA, NMM, TBD, Na 2 CO 3 , K 3 PO 4, DBU, DABCO, and MTBD. In some embodiments, the weak base or non-nucleophilic base is imidazole, DIPEA, TEA, NMM, or TBD. The coupling reaction between the compound of formula XII and the compound of formula XIII may be carried out in a polar aprotic solvent. Examples of polar aprotic solvents that may be suitable for the claims of the present application include solvents including MTBE, toluene, EtOAc, MeCN, THF, DMC, MeOAc, NMP, DMF, DMSO, THF, 2-MeTHF, and combinations thereof. The coupling reaction between the compound of formula XII and the compound of formula XIII may be carried out at about 20°C to about 60°C, about 25°C to about 55°C, about 30°C to about 50°C, about 30°C to about 45°C, about 30°C to about 40°C, or about 35°C. As used in this paragraph, the term "about" means ±2.5°C.

[0039] When using a chlorinating agent, the acid chloride of the compound of formula XIII is first prepared, and then the acid chloride is reacted with the compound of formula XII. In this regard, it is not necessary to isolate the acid chloride of the compound of formula XIII before coupling with the compound of formula XII. Examples of chlorinating agents suitable for coupling the compound of formula XII with the compound of formula XIII include oxalyl chloride, thionyl chloride, phosgene, etc.

[0040] Alternatively, a compound of formula III may be prepared by oxidizing a compound of formula XIV: [ka] A compound of formula III is obtained.

[0041] Compounds of formula XIV may be obtained by ring closure of compounds of formula XVI, [ka] To obtain a compound of formula XV [ka] The compound of formula XV is then deprotected to give a compound of formula XIV. In one embodiment, the ring-closing reaction comprises reacting compound XVI with methanesulfonyl chloride or a similar chlorinating agent in the presence of a non-nucleophilic base. In one embodiment, the non-nucleophilic base is a tertiary amine. The ring-closing reaction may be carried out at about -5°C to about 5°C. In some embodiments, the reaction is carried out at about -5°C to about 5°C. Deprotection of compound XV can be carried out by reacting compound of formula XV with methanesulfonyl chloride or a similar chlorinating agent in the presence of a hydrogenation catalyst (e.g., Pd / C catalyst or a similar catalyst). 2 to obtain a compound of formula XIV.

[0042] In one embodiment, the present application is directed to a process for preparing a compound of formula I, or a salt thereof, comprising converting a compound of formula IX using a process described herein for converting a compound of formula IX to a compound of formula I.

[0043] Another embodiment of the present application is directed to a method for preparing a compound of formula I, or a salt thereof, comprising converting a compound of formula X using a method described herein for converting a compound of formula X to a compound of formula I. Another embodiment of the present application is directed to a method for preparing a compound of formula I, or a salt thereof, comprising converting a compound of formula X using a method described herein for converting a compound of formula X to a compound of formula I.

[0044] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula XXI using a method described herein for converting a compound of formula XXI to a compound of formula I.

[0045] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula XX using a method described herein for converting a compound of formula XX to a compound of formula I.

[0046] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula XIX using a method described herein for converting a compound of formula XIX to a compound of formula I.

[0047] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula XVIII using a method described herein for converting a compound of formula XVIII to a compound of formula I.

[0048] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula XVII using a method described herein for converting a compound of formula XVII to a compound of formula I.

[0049] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula XVI using a method described herein for converting a compound of formula XVI to a compound of formula I.

[0050] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula XV using a method described herein for converting a compound of formula XV to a compound of formula I.

[0051] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula XIV using a method described herein for converting a compound of formula XIV to a compound of formula I.

[0052] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula XIII using a method described herein for converting a compound of formula XIII to a compound of formula I.

[0053] Another embodiment of the present application is directed to a method for preparing a compound of formula I, or a salt thereof, comprising converting a compound of formula XII using a method described herein for converting a compound of formula XII to a compound of formula I.

[0054] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula XI using a method described herein for converting a compound of formula XI to a compound of formula I.

[0055] Another embodiment of the present application is directed to a method for preparing a compound of formula I, or a salt thereof, comprising converting a compound of formula X using a method described herein for converting a compound of formula X to a compound of formula I.

[0056] Another embodiment of the present application is directed to a method for preparing a compound of formula I, or a salt thereof, comprising converting a compound of formula IX using a method described herein for converting a compound of formula IX to a compound of formula I.

[0057] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula VIII using a method described herein for converting a compound of formula VIII to a compound of formula I.

[0058] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula VII using a method described herein for converting a compound of formula VII to a compound of formula I.

[0059] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula V using a method described herein for converting a compound of formula V to a compound of formula I.

[0060] Another embodiment of the present application is directed to a method for preparing a compound of formula I, or a salt thereof, comprising converting a compound of formula IV using a method described herein for converting a compound of formula IV to a compound of formula I.

[0061] Another embodiment of the present application is directed to a method for preparing a compound of formula I or a salt thereof, comprising converting a compound of formula III using a method described herein for converting a compound of formula III to a compound of formula I.

[0062] Another embodiment of the present application is directed to a method for preparing a compound of formula I, or a salt thereof, comprising converting a compound of formula II using a method described herein for converting a compound of formula II to a compound of formula I.

[0063] In another embodiment, the present application is directed to methods for preparing intermediate compounds of formulas II-V and VII-XXI using the methods described herein.

[0064] In one embodiment, the present application is directed to a process for preparing a compound of formula II or a salt thereof, comprising converting any of the compounds of formulas III-V and VII-XXI to a compound of formula II using a method described herein.

[0065] In another embodiment, the present application is directed to a process for preparing a compound of formula III or a salt thereof, comprising converting any of the compounds of formulas IV-V and VII-XXI to a compound of formula III using a method described herein.

[0066] In another embodiment, the present application is directed to a method for preparing a compound of formula IV or a salt thereof, comprising converting any of the compounds of formulas V and VII-XXI to a compound of formula IV using the methods described herein.

[0067] In another embodiment, the present application is directed to a method for preparing a compound of formula V or a salt thereof, comprising converting any of compounds VII-XXI to a compound of formula V using a method described herein.

[0068] In another embodiment, the present application is directed to a process for preparing a compound of formula VII or a salt thereof, comprising converting any of compounds VIII-XXI to a compound of formula VII using a method described herein.

[0069] In another embodiment, the present application is directed to a method for preparing a compound of formula VIII or a salt thereof, comprising converting any of compounds IX-XXI to a compound of formula VIII using the methods described herein.

[0070] In another embodiment, the present application is directed to a method for preparing a compound of formula IX or a salt thereof, comprising converting any of compounds X-XXI to a compound of formula IX using the methods described herein.

[0071] In another embodiment, the present application is directed to a method for preparing a compound of formula X or a salt thereof, comprising converting any of compounds XI-XXI to a compound of formula X using a method described herein.

[0072] In another embodiment, the present application is directed to a process for preparing a compound of formula XI or a salt thereof, comprising converting a compound of XII-XXI to a compound of formula XI using a method described herein.

[0073] In another embodiment, the present application is directed to a method for preparing a compound of formula XII or a salt thereof, comprising converting any of compounds XIII-XXI to a compound of formula XII using a method described herein.

[0074] In another embodiment, the present application is directed to a method for preparing a compound of formula XIII or a salt thereof, comprising converting any of compounds XIV-XXI to a compound of formula XIII using the methods described herein.

[0075] In another embodiment, the present application is directed to a method for preparing a compound of formula XIV or a salt thereof, comprising converting any of compounds XV-XXI to a compound of formula XIV using a method described herein.

[0076] In another embodiment, the present application is directed to a method for preparing a compound of formula XV or a salt thereof, comprising converting any of compounds XVI-XXI to a compound of formula XV using a method described herein.

[0077] In another embodiment, the present application is directed to a method for preparing a compound of formula XVI or a salt thereof, comprising converting any of compounds of XVII-XXI to a compound of formula XVI using a method described herein.

[0078] In another embodiment, the present application is directed to a process for preparing a compound of formula XVII or a salt thereof, comprising converting any of compounds of XVIII-XXI to a compound of formula XVII using a method described herein.

[0079] In another embodiment, the present application is directed to a method for preparing a compound of formula XVIII or a salt thereof, comprising converting any of compounds of XIX-XXI to a compound of formula XVIII using a method described herein.

[0080] In another embodiment, the present application is directed to a method for preparing a compound of formula XIX or a salt thereof, comprising converting any of compounds XX-XXI to a compound of formula XIX using a method described herein.

[0081] In another embodiment, the present application is directed to a method for preparing a compound of formula XX or a salt thereof, comprising converting any of the compounds of XXI to a compound of formula XX using the methods described herein.

[0082] For purposes of this invention, chemical elements are identified according to the Periodic Table, CRC Handbook of Chemistry and Physics, 75th Edition, CAS Edition. In addition, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0083] Another embodiment of the present invention is directed to compounds of the formula: [ka]

[0084] Another embodiment of the present invention is directed to compounds of the formula: [ka]

[0085] Another embodiment of the present invention is directed to compounds of the formula: [ka]

[0086] Another embodiment of the present invention is directed to compounds of the formula: [ka]

[0087] Another embodiment of the present invention is directed to compounds of the formula: [ka]

[0088] Another embodiment of the present invention is directed to compounds of the formula: [ka]

[0089] Another embodiment of the present invention is directed to compounds of the formula: [ka]

[0090] Another embodiment of the present invention is directed to a compound salt of the following formula: [ka]

[0091] As used herein, in any chemical structure or formula, a bold or dashed straight bond (respectively) attached to a chiral center of the compound is represented as: [ka] or [ka] )teeth, [ka] A bold or dashed linear bond indicates the relative stereochemistry of a chiral center with respect to the other chiral center to which it is attached.

[0092] As used herein, in any chemical structure or formula, a bold or dashed wedge-shaped bond (respectively) attached to a chiral center of the compound is represented as follows: [ka] or [ka] )teeth, [ka] The absolute stereochemistry of a chiral center relative to other chiral centers to which a bold or dashed wedge-shaped bond is attached is shown, as well as the relative stereochemistry of the chiral center.

[0093] As used herein, the prefix "rac-" when used in reference to a chiral compound refers to a racemic mixture of the compound. In compounds bearing the "rac-" prefix, the (R)- and (S)-designators in the chemical name reflect the relative stereochemistry of the compounds.

[0094] As used herein, the prefix "rel-", when used in reference to a chiral compound, refers to a single enantiomer of unknown absolute configuration. In compounds having the "rel-" prefix, the (R) and (S)-designators in the chemical name reflect the relative stereochemistry of the compound, but do not necessarily reflect the absolute stereochemistry of the compound.

[0095] The term "compound" as used herein, when referring to a compound described in this application, refers to a collection of molecules having the same chemical structure, except that there may be isotopic variations between the constituent atoms of the molecule. The term "compound" includes a collection of molecules, regardless of the purity of a given sample containing the collection of molecules. Thus, the term "compound" includes such a collection of molecules in pure form, in a mixture with one or more other substances (e.g., a solution, suspension, colloid, or pharmaceutical composition or dosage form), or in the form of a hydrate, solvate, or co-crystal.

[0096] In this specification and claims, unless otherwise specified, any atom not specifically designated as a specific isotope of any compound of the present invention is intended to represent any stable isotope of the specified element. In the examples, if an atom is not specifically designated as a specific isotope of any compound of the present invention, no effort was made to enrich that atom in a specific isotope, and therefore, those skilled in the art will understand that such atom is likely to have existed in approximately the natural abundance isotopic composition of the specified element.

[0097] As used herein in the specification and claims, "H" refers to hydrogen and includes any stable isotope of hydrogen, i.e. 1 Includes H and D. In the examples, when an atom is designated as "H," no attempt was made to enrich that atom in a particular isotope of hydrogen, and thus, one of skill in the art will understand that such hydrogen atom was likely present in a concentration about the natural abundance of hydrogen.

[0098] As used herein, " 1 "H" refers to protium. When an atom in a compound of the invention or a pharma- ceutically acceptable salt thereof is designated as protium, protium is present at the designated position at least at the natural abundance concentration of protium.

[0099] As used herein, "D," "d," and " 2 "H" refers to deuterium.

[0100] In some embodiments, the compounds described in this application contain each constituent atom in about the natural abundance isotopic composition of the specified element.

[0101] In some embodiments, the compounds described herein, and pharma- ceutically acceptable salts thereof, contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope of the designated element ("isotopically labeled" compounds and salts). Examples of stable isotopes that are commercially available and suitable for the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, e.g., 2 H, 13 C. 15 N, 18 O. 17 O, and 31 These include, but are not limited to, P. The term "compound of formula" followed by a number (typically a Roman numeral) and the term "compound" followed by the same number (Roman numeral or otherwise) may be used interchangeably. For example, "compound of formula V" and "compound V" refer to the same compound.

[0102] When referring to a chemical reaction, the term "reacting" means the addition or mixing of two or more reagents under appropriate conditions to produce a designated and / or desired product. Of course, the reaction that produces the designated and / or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e., there may be one or more intermediates produced in the mixture that ultimately lead to the formation of the designated and / or desired product.

[0103] When referring to a reaction, the term "carried out in a solvent" means that the substrates and reagents are dissolved or suspended in the specified solvent or in a mixture of solvents that includes the specified solvent.

[0104] The term "chromatographic purification" refers to any method of purification that relies on differential retention by a stationary phase. Methods of chromatographic purification include flash chromatography, medium pressure liquid chromatography, preparative thin layer chromatography, and high performance liquid chromatography.

[0105] The term "converting," as used herein to refer to the step of converting a first compound or salt into a second compound or salt, refers to the process of changing the first compound or salt into the second compound or salt in one or more chemical steps.

[0106] The term "acid" refers to a chemical species having a pKa (in water) of less than 7. The term includes inorganic (mineral) acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, and the like. The term also includes organic acids, such as acetic acid, propionic acid, n-butyric acid, i-butyric acid, n-valeric acid, i-valeric acid, n-hexanoic acid, succinic acid, glutaric acid, adipic acid, aspartic acid, formic acid, citric acid, o-chlorobenzoic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, nicotinic acid, lactic acid, oxalic acid, picric acid, picolinic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, phthalic acid, isophthalic acid, terephthalic acid, maleic acid, malonic acid, and the like.

[0107] The term "base" refers to a chemical species whose conjugate acid has a pKa (in water) greater than 7. The term includes "inorganic bases" such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (monobasic, dibasic, or tribasic), sodium hydride, and potassium hydride. The term also includes "anionic organic bases" such as methyllithium, butyllithium, lithium diisopropylamide, and sodium acetate. The term also includes "anionic organic bases" such as trimethylamine, dimethylethylamine, diethylmethylamine, triethylamine, di-n-propylmethylamine, dimethylcyclohexylamine, diisopropylethylamine, tri-n-propylamine, diisopropylisobutylamine, dimethyl-n-nonylamine, tri-n-butylamine, di-n-hexylmethylamine, dimethyl-n-dodecylamine, tri-n-pentylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), dimethicone, ... "Neutral organic bases" such as ethylaminopyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, and 3,5,6-collidine.

[0108] The term "alcohol protecting group" refers to a chemical moiety suitable for protecting an alcohol group from undesired side reactions during a synthetic procedure. Common alcohol protecting groups include methyl, ethyl, isopropyl, benzyl, 2-tetrahydropyranyl, acetyl, trifluoroacetyl, trialkylsilyl, aryldialkylsilyl, alkyldiarylsilyl, or triarylsilyl. Other alcohol protecting groups are also well known in the art. See, for example, PGM Wuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0109] The term "deprotection" refers to the step of reacting a compound or salt containing a protecting group, such as an alcohol protecting group, under conditions suitable to remove the protecting group to reveal the protected moiety. For example, if the compound or salt contains an alcohol protecting group, the term "deprotection" refers to reacting the compound or salt under conditions suitable to remove the alcohol protecting group to reveal the alcohol. Conditions for removing various protecting groups are well known in the art. See, for example, PGM Wuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0110] The term "hydrogenation catalyst" refers to any homogeneous or heterogeneous catalyst that catalyzes the hydrogenolysis of benzylic carbon-oxygen single bonds. Suitable hydrogenation catalysts are well known in the art and include palladium on activated carbon, platinum oxide, and Raney nickel.

[0111] The term "coupling", when referring to a reaction between a carboxylic acid or acid halide and an amine, refers to the final conversion of combining the carboxylic acid or acid halide with an amine to form an amide. The term includes the direct reaction between a carboxylic acid and an amine, as well as the reaction between an activated derivative of a carboxylic acid (such as the derivative formed by reaction between a carboxylic acid and a coupling reagent) and an amine.

[0112] The term "coupling reagent" refers to a reagent suitable for reacting with a carboxylic acid to activate the carboxylic acid for coupling with an amine to form an amide bond. Coupling reagents are well known in the art. Coupling reagents include, but are not limited to, thionyl chloride, oxalyl chloride, 1,1'-carbonylbis-(4,5-dicyanoimidazole) (CBDCI), 1,1'-carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), and 1-hydroxybenzotriazole (HOBt).

[0113] The term "monovalent cation" refers to the alkali metal cation, NH 4 + It refers to any cation that has a +1 charge, such as ammonium, ammonium alkoxide, and tetraalkylammonium.

[0114] The term "alkali metal cation" refers to lithium (Li + ), sodium (Na+), potassium (K + ), Rubidium (Rb + ), and cesium (Cs + "Cations" refers to cations derived from Group I metal atoms, including, but not limited to,

[0115] The term "substituted benzyl" refers to C1-C3 alkyl, C 1 ~C 3 It refers to a benzyl group substituted with 1 to 3 substituents selected from the group consisting of alkoxy, halogen, and cyano.

[0116] The term "ketone solvent" refers to a compound of formula C n H 2n+1 C(O)C m H2m+1 In the formula, n and m each independently represent an integer of 1 to 6. n H 2n+1 and C m H 2m+1 The and groups may be linear or branched and each may be substituted with up to three halogens. Ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, 3-pentanone, and methyl tert-butyl ketone.

[0117] The term "ethereal solvent" refers to an organic solvent having at least one ether moiety. Ethereal solvents include, but are not limited to, tetrahydrofuran, dimethoxyethane, dioxane, and dialkyl ethers such as diethyl ether and methyl isobutyl ether.

[0118] The term "ester solvent" refers to a compound of formula C n H 2n+1 O.C.(O)C m H 2m+1 In the formula, n and m each independently represent an integer of 1 to 6. n H 2n+1 and C m H 2m+1 The and groups may be linear or branched and each may be substituted with up to three halogens. Ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, butyl acetate, and ethyl propionate.

[0119] The term "halogenated solvent" refers to C substituted with up to six halogens. 1 ~C 6 Alkane or C 2 ~C 6 Refers to alkenes. Halogenated solvents include, but are not limited to, dichloromethane, dichloroethane, chloroform, tetrachloroethylene, and carbon tetrachloride.

[0120] The term "aromatic solvent" refers to 6~10Refers to aromatic hydrocarbons. Aromatic hydrocarbons may be substituted with up to six halogens. Aromatic solvents include, but are not limited to, benzene, trifluoromethylbenzene, xylene, and toluene.

[0121] The term "about" means that the stated number may vary ±10% from that value. When a term defines a temperature, the stated temperature may vary ±10%. For example, about 80°C means 72°C to 88°C. When a term defines a pressure, the term "about" means that the pressure may vary ±10%. Thus, about 100 bar means 90 to 110 bar. When a term defines a quantity (such as equivalents or weight), the term means that the quantity may vary ±10%. For example, about 1 equivalent means 0.9 to 1.1 equivalents. When a term defines a time, the term means that the stated time may vary ±10%. For example, about 1 hour means 0.9 to 1.1 hours.

[0122] The term "leaving group" refers to a chemical group that is easily displaced by a desired incoming chemical moiety. Thus, the selection of a particular suitable leaving group is determined based on its ability to be easily displaced by an incoming chemical moiety, such as a CN group. Suitable leaving groups are well known in the art, see, for example, "Advanced Organic Chemistry," Jerry March, 5th Ed., pp. 351-357, John Wiley and Sons, NY. For purposes of converting compound IX to compound VII, the leaving group on compound VIII can be of the formula OC(=O)-Z, OC(=O)OZ, OC(=O)CH=CH-Z, or OP(=O)Z. 2 where Z is unsubstituted aryl or CN, halo, NO 2or aryl substituted with a short chain alkyl, alkoxy, haloalkyl, or haloalkoxy group, where the short chain contains 1, 2, 3, or 4 carbon atoms. Alternatively, Z is a short chain (i.e., having 1 to 4 carbon atoms) alkyl or haloalkyl group. Examples of aryl groups include phenyl and naphthyl.

[0123] As used herein, the term "cyanating agent" (e.g., trimethylsilyl cyanide, diethylaluminum cyanide, KCN, NaCN, TBACN, HCN, etc.) is used to obtain a compound of formula VIII. In one embodiment, the reaction between a cyanating agent (e.g., trimethylsilyl cyanide) and a compound of formula VIII may be carried out in the presence of a Lewis acid. In some embodiments, the Lewis acid is boron trifluoride ethyl etherate (BF 3 OEt 2 ), TiCl 4 , InCl 3 , AgSbF 6 , Iodine, ZnBr 2 , Al(OiPr) 3 , MgCl 2 , Mn(acac) 2 , MnCl 2 , TMSOTf, SnCl 4 In a further embodiment, the Lewis acid is BF 3 OEt 2 The cyanation reaction may be carried out in an organic solvent such as toluene, dichloromethane, 2-methyl THF, acetonitrile, methanol, 1,2-dichloroethane, nitromethane, and the like.

[0124] Uses of the Compounds and Pharmaceutically Acceptable Salts and Compositions In another aspect, the invention features a method of inhibiting voltage-gated sodium channels in a subject, the method including administering to the subject a compound of formula I, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0125] In one aspect, the disclosure relates to a method of treating or reducing the severity of pain in a subject, the method comprising administering to the subject a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0126] In another aspect, the disclosure relates to the use of a compound of formula I, or a pharma- ceutically acceptable salt thereof, in a method of treating or reducing the severity of pain in a subject, the method comprising administering to the subject a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0127] In another aspect, the disclosure relates to a composition comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, for use in a method of treating or reducing the severity of pain in a subject, wherein the composition is prepared for administration to a subject of the compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0128] Synthesis of Compounds of the Invention The compounds of the present invention can be prepared from known materials by the methods described in the examples, other similar methods, and other methods known to those skilled in the art. As will be understood by those skilled in the art, the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Protecting groups may be added or removed according to standard techniques well known to those skilled in the art. The use of protecting groups is described in detail in TGM Wuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0129] Radiolabeled Analogs of the Compounds of the Invention In another aspect, the present invention relates to radiolabeled analogs of the compounds of the present invention. As used herein, the term "radiolabeled analogs of the compounds of the present invention" refers to compounds that are identical to the compounds of the present invention as described herein, including all embodiments herein, except that one or more atoms are replaced with a radioisotope of an atom present in the compounds of the present invention.

[0130] As used herein, the term "radioisotope" refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include: 3 H, 14 C. 32 P, 35 S, 18 F, 36 Cl, as well as isotopes whose decay modes are identified in VS Shirley & CM Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0131] Radiolabeled analogs can be used in many beneficial ways, including various types of assays such as substrate tissue distribution assays. For example, tritium ( 3 H) labeling and / or carbon-14 ( 14 C) Labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability.

[0132] In another aspect, the invention relates to a pharma- ceutically acceptable salt of a radiolabeled analogue according to any of the embodiments described herein in relation to the compounds of the invention.

[0133] In another aspect, the invention relates to a pharmaceutical composition comprising a radiolabeled analogue, or a pharma- ceutically acceptable salt thereof, according to any of the embodiments described herein in relation to the compounds of the invention, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0134] In another aspect, the invention relates to methods of inhibiting voltage-gated sodium channels, as well as methods of treating or lessening the severity of various diseases and disorders, including pain, in a subject comprising administering an effective amount of a radiolabeled analogue, pharma- ceutically acceptable salt thereof, and pharmaceutical compositions thereof, according to any of the embodiments described herein in connection with the compounds of the invention.

[0135] In another aspect, the invention relates to radiolabeled analogues, pharma- ceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use according to any of the embodiments described herein in connection with the compounds of the invention.

[0136] In another aspect, the invention relates to the use of a radiolabeled analogue, or a pharma- ceutically acceptable salt thereof, and pharmaceutical compositions thereof, according to any of the embodiments described herein in relation to the compounds of the invention, for the manufacture of a medicament.

[0137] In another aspect, the radiolabeled analogs, their pharma- ceutically acceptable salts, and pharmaceutical compositions thereof, may be used in combination therapy according to any of the embodiments described herein in connection with the compounds of the invention. EXAMPLES

[0138] Common method. 1 H NMR (400 MHz) spectra were obtained using dimethylsulfoxide-d 6 (DMSO-d 6 ) in a suitable deuterated solvent.

[0139] Analytical supercritical fluid chromatography (SFC) separation of various isomeric mixtures was achieved using a Waters UPC2-SFC instrument, including a convergence manager, sample manager, binary solvent manager, column manager-30S, PDA detector, isocratic solvent manager, and QDa detector. Columns used included those manufactured by Regis Technologies (e.g., R'R Whelk 0-1, particle size 3.5 μm, size 5.0 cm × 3.0 mm), and the mobile phase solvent A: liquid CO 2(58-60 bar / 40 °C) Solvent B: HPLC grade methanol with 20 mM NH3 was used at a flow rate of 2 mL / min, injection volume was 2 μl. Gradient: 0 min (95:5) A:B, 3.5 min (50:50) A:B, 3.55 min (40:60) A:B, 3.95 min (40:60) A:B, and 4.0 min (95:5) A:B. Samples for analytical SFC were dissolved in methanol at a concentration of approximately 0.5 mg / mL.

[0140] Preparative SFC used the same stationary and mobile phases as described herein for analytical SFC, but samples were purified using different equipment and gradient methods as follows: Preparative SFC separations of various isomeric mixtures were performed using a backpressure regulator, 2767 sample manager, 2545 quaternary gradient module, column oven, 2998 PDA detector, isocratic solvent manager, P-200 CO 2 This was accomplished using a Waters Prep-100 SFC instrument including a pump, SFC flow splitter-100, 3 heat exchangers, a Series III LC pump, and a QDa detector. Columns used included those manufactured by Regis Technologies (e.g., R'R Whelk 0-1, particle size 5.0.5 μm, size 25.0 cm × 21.1 mm), and mobile phase solvent A: liquid CO 2(58-60 bar / 40 °C) Solvent B: HPLC grade methanol with 20 mM NH3 was used at a flow rate of 100 mL / min, with an injection volume of 500 μl (50 mg crude load). A 2:1 ratio of methanol-dichloroethane was used for solubilization of the crude compounds and for SFC injections. For injections of 500 μl / 50 mg load, the following method was used: Isocratic: 0 min to 7.6 min (80:20) A:B, gradient: 8.1 min (75:25) A:B, isocratic 8.2 to 10.6 min (75:25) (A:B), gradient: 10.7 min (80:20) A:B, and isocratic: 11 min (80:20) (A:B). For injections of 1500 μl / 150 mg load, the following method was used: Isocratic: 0 min to 7.6 min (80:20) A:B, gradient: 8.1 min (75:25) A:B, isocratic: 8.2 min to 10.6 min (75:25) (A:B), gradient: 10.7 min (80:20) A:B, and isocratic: 11 min (80:20) (A:B). For injections of 1500 μl / 150 mg load, the following method was used: Isocratic: 0 min to 7.5 min (80:20) A:B, Gradient: 7.6 min (75:25) A:B, Gradient: 8.1 min (60:40) A:B, Isocratic: 8.7 min to 10.6 min (60:40) A:B, Gradient: 10.7 min (80:20) A:B, Isocratic: 12 min (80:20) A:B.

[0141] LC / MS method: LC / MS analysis was performed using a Waters Acquity UPLC BEH C 8 The run was performed using a column (50 x 2.1 mm, 1.7 μm particle size) (product number: 186002877) with a (2.1 x 5 mm, 1.7 μm particle size) guard column (product number: 186003978), and a dual gradient run of 2 to 98% mobile phase B over 4.45 min. Mobile phase A = H 2 O (10 mM ammonium formate containing 0.05% ammonium hydroxide). Mobile phase B = acetonitrile. Flow rate = 0.6 mL / min, injection volume = 2 μL, column temperature = 45 °C.

[0142] Solid-state NMR analysis was performed on a Bruker-Biospin 400 MHz wide-bore spectrometer equipped with a Bruker-Biospin 4 mm HFX probe. Samples were prepared using 4 mm ZrO 2 The rotor was loaded and spun under magic angle spinning (MAS) conditions, with the spinning speed typically set at 12.5 kHz. Proton relaxation times were 13To set the probe recycle delay for a C cross-polarization (CP) MAS experiment, 1 H M A S T 1 The fluorine relaxation times were measured using saturation recovery relaxation experiments. 19 To set the probe recycle delay for the F MAS experiment, 19 F M A S T 1 Measurements were made using a saturation recovery relaxation experiment. The CP contact time for the carbon CPMAS experiment was set to 2 ms. A CP proton pulse with a linear ramp (50%-100%) was used. The carbon Hartmann-Hahn match was optimized with an external reference sample (glycine). Both carbon and fluorine spectra were recorded with proton decoupling using a TPPM15 decoupling sequence with a field strength of approximately 100 kHz.

[0143] Thermogravimetric analysis (TGA) data were collected on a TA Discovery thermogravimetric analyzer or equivalent instrument. Samples weighing approximately 1-5 mg were scanned from 25°C to 350°C at a heating rate of 10°C / min. Data were collected with Thermal Advantage Q SeriesTM software and analyzed with Trios and / or Universal Analysis software (TA Instruments, New Castle, DE).

[0144] Differential scanning calorimetry (DSC) data were obtained using a TA Instruments Q2000 or equivalent instrument. Samples weighing 1-10 mg were weighed into aluminum pans. The pans were placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and the cell was filled with N 2 Gas was passed through. The heating program was set to heat the sample at a heating rate of 10° C. / min to a temperature of 300° C. Once the run was completed, the data was analyzed with Trios and / or Universal Analysis software (TA Instruments, New Castle, Del.).

[0145] Infrared (IR) spectra were collected using a Thermo Scientific Nicolet iS50 spectrometer equipped with a diamond ATR sampling accessory.

[0146] Abbreviation Unless otherwise indicated, or unless the context dictates otherwise, the following abbreviations shall be understood to have the following meanings: [Table 3-1] [Table 3-2] Example 1

[0147] Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (I) [ka]

[0148] Step 1: Synthesis of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one (XI) [ka]

[0149] Compound XIII (Alichem, 3.832 kg, 18.955 mol) was previously dried under vacuum and 2 A 140 L reactor was flushed with gas. 18.85 L of anhydrous acetonitrile was added and the solution was cooled to -2°C. Carbonyldiimidazole (Chem Impex, 99.5%, 3.280 kg, 19.92 mol, 1.05 equiv.) was added to a 140 L reactor flushed with gas. 2The mixture was added in portions from 4 x 820 g bottles pre-weighed in a dry box. Each bottle of CDI was added at 1-2 min intervals to avoid sudden outgassing of CO2. The temperature was allowed to reach +2 °C during the addition. The solution was stirred at 0--2 °C for 1.5 h. A solution of XII in THF (containing 4.028 kg of XII, 20.42 mol, 1.077 equiv) was added rapidly with a metering pump. The pump and vessel were rinsed with 2 L of anhydrous acetonitrile, 325 mesh anhydrous potassium carbonate (3.276 kg, 23.70 mol, 1.25 equiv) was added quickly, and the reaction mixture was stirred at 35 °C for 5 h, then cooled to 15 °C overnight. MTBE (24.5 L) was added, followed by 62.4 kg of 0.62NH 2 SO 4 was added, followed by a 5 L rinse with DI water. The aqueous layer (pH 8) was re-extracted with 20 L of MTBE. The total MTBE was concentrated in vacuo to a dry solid and re-concentrated with 10 L of IPA to a dry solid.

[0150] For recrystallization, the solid was dissolved in 25.5 L of IPA and transferred to a 140 L 5 L reactor, rinsed with 5 L of IPA, and the solution was warmed to 35° C. The pump was set to deliver 47.1 kg of DI water, which was added slowly to the IPA solution over 2.5 hours. The crystal slurry was stirred for an additional 2 hours, after which the slurry was allowed to cool to 15° C. over approximately 3 hours and continued to stir for an additional 12 hours. The slurry was filtered, washed with 2×6 L of 1:4 IPA:DI water, and purified with single-pass heated N 2 Gas (N 2 The gas was heated to 75° C. (cake temperature was approximately 50° C.) and dried for 3 days to constant weight. The final weight of the product was 5.205 kg, 85.2%. The product gave a proton NMR spectrum consistent with the structure of XI.

[0151] Step 2: Synthesis of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (X) [ka]

[0152] Step 1: Compound XI (1200 g, 3.72 mol) obtained from the above reaction was added to an 11 L hydrogenation reactor (previously N 2 Flush with gas, slow N 2 The reactor was set to a gas sweep. Catalyst (1200 g, 4.89% Pd, 63.8% water, corresponding to 21.2 g Pd, 0.0536 molar equivalents) was added. Isopropanol (7.0 L) was added. The reactor was sealed and 3×N 2 The flask was purged with gas / vacuum, then purged with 50 psi nitrogen / hydrogen, and finally adjusted to 225 psi hydrogen. The jacket was set to 30-31 °C and stirring was started. Stirring was continued for 30 h and the NMR sample (0.2 mL + 2.0 mL MTBE + 1.0 mL 5% KHCO 3 , 1.5 mL of MTBE was evaporated and NMR) showed 2.8% starting material. The reaction was deemed complete. The slurry was filtered (solka-floc) and washed with 10 L of IPA followed by 3 L of DCM. The filtrate was concentrated to an oil and redissolved in 3 L of toluene. The toluene solution was reconcentrated to an oil (1152 g, 3.553 mol, 95.5% yield). Proton NMR of the product was consistent with compound X.

[0153] Step 2: A reactor rated for hydrogen and pressure service and equipped with a gas dosing unit and pressure controller was charged with compound XI (1 equivalent, limiting reagent), 5% palladium on carbon (0.05 equivalent, corrected for water content and palladium assay), tetrahydrofuran (1.75 volumes), 2-propanol (5.25 volumes), and trifluoroacetic acid (0.05 equivalents). The vessel was pressurized to 3 barg with nitrogen and then vented to ambient pressure. This sequence was performed three times. The reactor contents were adjusted to 30° C. The vessel was then pressurized to 3 barg with hydrogen and vented to ambient pressure. This sequence was performed three times. The reactor was then pressurized to operating pressure (40 barg) with hydrogen and stirring was started at a rate sufficient to achieve gasification of the liquid from the headspace.

[0154] The reaction mixture was stirred under these conditions until the reaction was complete (less than 1% of compound XI and its diastereomer by GC).

[0155] The hydrogen headspace was vented. The reactor was pressurized to 3 barg with nitrogen and the reactor was vented. This sequence was performed three times. Cyclohexene (0.2 vol) was charged to the reactor and the reaction was maintained at 30° C. with stirring under nitrogen for not less than 15 minutes.

[0156] The reaction mixture was filtered through a bed of diatomaceous earth to remove the catalyst. The filter cake was washed with 2-propanol (4 volumes). The filtrate and washes from the primary filtration were combined.

[0157] In a well mixed vessel, the filtrate was concentrated under reduced pressure at <40° C. to a total of 3 volumes. Toluene (7 volumes) was charged and distillation resumed under reduced pressure at <50° C. until a total of 3 volumes was reached. Toluene (7 volumes) was charged and distillation resumed under reduced pressure at <50° C. until a total of 3 volumes was reached. Toluene (5 volumes) was charged and the solution was well mixed. Proton NMR of the product was consistent with compound X.

[0158] 1 H NMR CDCl 3 : δ 6.93-6.80(m,2 H); 4.48(d,1 H,J=9.5 Hz); 4.03(d,3 H,J=3.1 Hz); 2.89(dq,1 H,J=9.5,7.5 Hz); 1.71(d,3 H,J=1.2 Hz); 0.84-0.76(m,3H)ppm.

[0159] Step 3: Synthesis of (2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol (IX) [ka]

[0160] Step 1: The product of the above reaction (compound X, 1052 g, 3.2445 mol) was added to a 50 L jacketed reactor and N 28.82 L of anhydrous toluene was added under gas. The resulting solution was diluted with N 2 Cool to -31°C under N2O overnight. Diisobutylaluminum hydride (1.96 kg of a 25% solution in toluene, 3.445 mol, 1.056 eq) was added to the flask in a 25°C flask under N2O. 2 Slowly transferred to the reaction vessel through the addition funnel under gas. The hydride reagent was added to the reaction solution over 2 hours, the reactor temperature going from -31.6°C to -27.4°C during the addition. The solution was stirred at -26 to -27°C for 90 minutes. A solution of 2.75 kg of potassium / sodium tartrate in 20 L of DI water was added over 2.5 hours. The reaction mixture was allowed to increase in temperature until it reached 0°C and then cooled to +24°C after approximately 2 hours of addition. Toluene (5 L) was added and the mixture was stirred at +20°C overnight.

[0161] The mixture was transferred to a separatory funnel and the aqueous phase was separated from the organic phase. The aqueous phase was re-extracted with 5 L of toluene. The two toluene solutions were combined, treated with magnesium sulfate, and filtered. The solids were washed with toluene and the combined toluene solutions were concentrated in vacuo to give an oil of crude lactol weighing 1055 g, 3.2336 mol, 99.7%. The crude product was used directly in the next step (acetylation is exemplified below). Proton NMR of the crude lactol was consistent with compound IX.

[0162] Step 2: A solution of compound X in toluene (target 8 volumes) was added to the reactor. Agitation was started and the mixture was cooled to -25±5°C. A solution of diisobutylaluminum hydride (25% w / w toluene) was added to the reaction mixture while maintaining the batch temperature at or below -20°C. The temperature was adjusted to -25±5°C and the batch was stirred for not less than 1 hour. Upon reaction completion, a solution of acetone in toluene (0.3 equivalents in 0.5 volumes) was added to the reaction mixture while maintaining the temperature at -25±5°C and stirred for not less than 30 minutes. The reaction mixture was then warmed to 0±5°C. A 12 volume solution of 0.62 M citric acid was transferred to the reactor while maintaining the temperature at 20±5°C and the biphasic mixture was stirred for not less than 4 hours. The phases were allowed to settle and the bottom aqueous phase was drained. A 12 volume solution of 0.62 M citric acid was added to the batch and the biphasic mixture was stirred at 20±5°C for not less than 30 minutes. The phases were allowed to settle and the bottom aqueous layer was drained. 5 volumes of water was charged to the batch and the biphasic mixture was stirred at 20±5° C. for not less than 30 minutes. The phases were allowed to settle and the bottom aqueous layer was drained. The organic layer was distilled to a total of 5 volumes while maintaining an internal temperature below 45° C. 5 volumes of toluene was charged and the mixture was distilled to a total of 5 volumes. Distillation was continued until less than 0.1% water remained. Proton NMR of the crude lactol was consistent with compound IX.

[0163] 1 H-NMR CDCl3: δ 7.30-7.26(m,1 H); 7.20-7.18(m,1 H); 5.81(d,1 H,J=4 Hz); 4.00(s,3 H); 3.84-3.80(m,1 H); 2.92-2.88(m,1 H); 1.67(s,3 H); 0.83(d,3 H,J=8 Hz)ppm

[0164] Step 4: Synthesis of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate (VIII) [ka]

[0165] The crude product of the above reaction (1055 g of compound IX, 3.23 mol) was pre-dried and then cooled to 20° C. 2The mixture was transferred to a 25 L jacketed reactor, kept under gas. Crude compound IX was rinsed with 6.8 L of anhydrous toluene and the mixture was stirred to ensure complete solution at 20 °C. Triethylamine (466 mL, 3.343 mol, 1.04 equiv) was added, followed by DMAP (3.58 g, 0.0293 mol, 0.01 equiv). Acetic anhydride (313 mL, 3.288 mol, 1.02 equiv) was added over approximately 5-10 min using an addition funnel (T increased from 21.1 °C to T = 26.4 °C during the addition of acetic anhydride). The reaction mixture was stirred at 25 °C for 100 min. Proton NMR of the reaction mixture indicated the reaction was complete at this point.

[0166] The reaction mixture was diluted with 3.5 L of 25% ammonium chloride, followed by 1200 mL of 10% KHCO 3 The aqueous layer was re-extracted with 2 L of toluene, the combined toluene solution was dried over magnesium sulfate, filtered, and the filtered solid was washed with toluene. The resulting toluene solution was concentrated to dryness using first a 20 L RB flask and then a 3 L jacketed reactor (1898 g was transferred) for final concentration. The solution was vacuum distilled to a thick oil and placed under high vacuum at 25°C with stirring until the oil turned to a crystalline mass (a small amount of viscous oil remained). Hexane (900 mL) was added to the reaction vessel (containing the solids and some residual oil) and the mixture was stirred at 20°C overnight. The mixture was cooled to 10°C and stirred for 2 hours, then cooled to 4°C with stirring for 6 hours, after which the mixture was cooled to -10°C overnight (with stirring) and finally cooled to -14°C over the weekend (36-48 hours) to obtain a crystalline slurry. The slurry was filtered through a jacketed filter at -15°C, then the solid was washed with cold (-16°C) hexane (2 x 150 ml, then 100 mL). The crystals were dried under vacuum at room temperature. The resulting solid was dissolved in toluene (total of 1450 mL of solution) and assayed to give 800.2 g in solution.

[0167] Additional product (stuck to the reactor) was dissolved with toluene to give 425 mL of solution. Assay gave 188.4 g of product. The mother liquor was concentrated to 117 g of oil. Proton NMR showed approximately 55% product and 45% impurities.

[0168] The total yield (crystals filtered from the reaction mixture and solids dissolved from the reactor surface) provided 988.6 g, 2.68 mol, 83.1% of compound VIII (acetate ester).

[0169] The product (988.6 g of compound VIII-acetate) was used in the next reaction without further purification. Synthesis of (2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl 4-nitrobenzoate (VIII, 4-nitrobenzoic acid ester) [ka]

[0170] Compound IX in a solution of 5 volumes of toluene was charged to the reactor. An additional 5 volumes of toluene were charged to bring the total volume to 10 volumes. The temperature was adjusted to 20±5° C. 4-Nitrobenzoyl chloride was charged to the reactor as a solid. The temperature was adjusted to 0±5° C. Triethylamine was charged slowly to maintain the temperature at 0±5° C. The temperature was adjusted to 20±5° C. and the reaction mixture was stirred for not less than 3 hours. Upon completion of the reaction, 5 volumes of 2M aqueous NaOH were added to the reactor and the biphasic mixture was stirred for not less than 1 hour, maintaining the temperature at 20±5° C. The stirring was stopped, the phases were allowed to settle and the bottom aqueous phase was drained. 5 volumes of saturated ammonium chloride solution were added to the reactor and the biphasic mixture was stirred for not less than 30 minutes. The stirring was stopped, the phases were allowed to settle and the bottom aqueous phase was drained. 5 volumes of saturated ammonium chloride solution were added to the reactor and the biphasic mixture was stirred for not less than 30 minutes. Five volumes of water were charged to the reactor and the biphasic mixture was stirred for not less than 30 minutes. The phases were allowed to settle and the bottom aqueous layer was drained.

[0171] The organic phase was distilled to a total of 5 volumes while maintaining an internal temperature below 45°C. 5 volumes of toluene were charged and the mixture was distilled to 2.2 volumes. 1.2 volumes of n-heptane were charged to the distilled toluene solution. The mixture was heated to an internal temperature of 70±5°C and stirred for 15 minutes to 1 hour. The solution was cooled to 60±5°C over 30 minutes. The clear solution was seeded with 0.010 w / w equivalents of compound VIII (4-nitrobenzoic acid ester) and stirred for 1 hour to 2 hours. 2.4 volumes of n-heptane were charged at a linear rate over 5 hours. The slurry was cooled to 20±5°C over 5 hours. The slurry was aged for 5 hours. The solids were isolated by filtration. A 2 volume wash solution of 75:25 n-heptane:toluene was used to wash the wet cake. The wet cake was transferred to a drying apparatus and dried under vacuum at a temperature of 40±5°C until a constant weight was observed. Proton NMR of the crude lactol was consistent with the benzoate, 4-nitrobenzoate ester of compound VIII.

[0172] 1 H-NMR CDCl3: δ 8.21(d,2 H,J=8 Hz); 8.10(d,2 H,J=8 Hz); 6.93-6.88(m,1 H); 6.81-6.76(m,1 H)6.73(d,1 H,J=4 Hz); 4.09(d,1 H,J=4 Hz); 3.95-3.91(m,1 H); 3.91(s,3 H); 1.60(s,3 H); 0.86-0.84(d,3 H,J= 8 Hz)ppm.

[0173] Step 5: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile (VII) [ka]

[0174] Compound VIII (acetate ester) (1.87 L of toluene solution containing 987 g of compound VIII obtained in the above step, 2.68 mol) was diluted with N gas four times and then cooled to 50° C. 2Transferred to a gas / vacuum preconditioned 50 L jacketed reactor. Anhydrous toluene (7.0 L) was added, stirred and cooled to -31°C. TMS-CN (385 g; 3.7 mol; 1.4 equiv) was added over 8 min. BF 3 Etherate (380 g = 330 mL, 2.68 mols) was added dropwise over 6 min (temperature -31.5 °C increased to -27.6 °C). The bath temperature was set to -21.6 °C and the reaction was stirred for 2.5 h. Potassium hydroxide (3.5 L of 2.0 M solution) was added over about 5 min (temperature increased to +8 °C). The bath temperature was increased to +20 °C and the reaction mixture was stirred at +20 °C for about 10 min. The layers were separated and the aqueous layer was re-extracted with 6 L of toluene. The toluene solution was re-extracted with 1.5 L of 2 M potassium hydroxide, after which they were concentrated in vacuo to about 900 g of oil. The oil was diluted with 5 L of methanol and re-concentrated to give 887 g (2.65 mol, 98.7% pure) of the final crude compound VII. Proton NMR of this solid was consistent with the expected structure. NMR did not detect any methanol or toluene, suggesting the solid was not solvated.

[0175] Crude compound VII was purified using a preparative silica gel column packed in 85:15 hexane:MTBE. A solution of 0.78 kg of crude product in the packing solvent mixture was transferred to the column and eluted with the packing solvent mixture. The fraction was divided into approximately half, and each half was carried forward separately to the next compound (compound III). The first half of the fraction contained 333 g (or 993 mmol) of compound VII, while the second half of the fraction contained 274 g (or 818 mmol) of compound VII. The following example shows the process of converting compound VII collected from the first half of the fraction. Compound VII obtained in the second half of the fraction was also converted to compound III following the same process, except for the amount of reagents and solvents. Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile (VII) [ka]

[0176] Compound VIII (4-nitrobenzoate ester) solid was charged to the reactor. 10 volumes of toluene were charged to the reactor and the temperature was controlled at 20±5°C. 40% trimethylsilyl cyanide solution in toluene (1.2 equivalents of TMSCN) was added to the reactor while maintaining the temperature at 20±5°C. The batch was cooled to -20±5°C. 1.0 equivalents of boron trifluoride was added slowly while maintaining the temperature at -20±5°C. The batch was stirred at -20±5°C for not less than 3 hours. Upon completion of the reaction, the batch was heated again to 20±5°C. 10 volumes of 20% w / w aqueous potassium hydroxide solution were added to the batch and the biphasic mixture was stirred for not less than 1 hour. 5 volumes of ethanol were added to the batch and the biphasic mixture was stirred for not less than 12 hours. The phases were allowed to settle and the bottom aqueous layer was drained. Ten volumes of 20% w / w aqueous potassium hydroxide was added to the batch and the biphasic mixture was stirred for not less than 1 hour. The phases were allowed to settle and the bottom aqueous layer was drained. Ten volumes of 20% w / w aqueous potassium hydroxide was added to the batch and the biphasic mixture was stirred for not less than 30 minutes. The phases were allowed to settle and the bottom aqueous layer was drained. Ten volumes of water were added to the batch and the biphasic mixture was stirred for not less than 30 minutes. The phases were allowed to settle and the bottom aqueous layer was drained. The top organic layer was distilled to a total of 4 volumes while maintaining an internal temperature below 45° C. Seven volumes of ethanol were charged and the mixture was distilled to a total of 4 volumes. Another seven volumes of ethanol were charged and the mixture was distilled to a total of 4 volumes. Distillation was continued until the residual toluene was below 1.0% w / w. Proton NMR of the crude lactol was consistent with the benzoate ester of compound VII.

[0177] 1 H-NMR CDCl3: δ 6.91-6.85(m,1 H); 6.78-6.73(m,1 H); 5.02(d,1 H,J=9.0 Hz); 4.22(t,1 H,J=8.6 Hz); 4.06(d,3 H,J=3.1 Hz); 2.84(p,1 H,J=7.7 Hz); 1.64(d,3 H,J=1.3 Hz); 0.80(dq,3 H,J=7.3,2.3 Hz)ppm

[0178] Step 6: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (III)

[0179] Step 1: Compound VII (333.06 g, 993.4 mmol) was dissolved in 2.60 L of methanol and 2.60 L of 2.0 M potassium hydroxide in a 25 L jacketed reactor under N2 gas. The mixture was stirred at 55° C. for 20 h. After overnight, the slurry was a clear solution. Proton NMR showed the reaction was complete. The reaction mixture was cooled to +15° C. and 2925 mL of 2 N HCl + 5 L MTBE was added. After stirring for about 5 min, the layers were separated and the aqueous layer was re-extracted with 5 L MTBE. The MTBE solutions were combined, dried over magnesium sulfate, filtered, and washed with MTBE. The combined MTBE solutions were concentrated to an oil and re-concentrated with 4 L toluene to give 360 ​​g of oily product.

[0180] The oil was dissolved in 4.0 L of anhydrous toluene and stirred at 60° C. To the solution was added (R)-(+)-α-methylbenzylamine (142 mL, 1.1156 mol, 1.12 equiv.) rapidly. The solution was seeded and after about 5 min the solution began to deposit crystals. The slurry was cooled to 45° C. and stirred for 1.5 h, then cooled to 35° C. and stirred for an additional 1.5 h. The temperature was then reduced to 25° C. (stirred for an additional 1.5 h) and finally reduced to 15° C. and stirred overnight. The product was filtered, washed with 2×200 mL of toluene (15° C.) and dried at 50° C., 1 mm overnight to give 431.37 g of the (R)-(+)-α-methylbenzylamine salt of compound III.

[0181] Step 2: 4.5 volumes of 10% w / w KOH solution were charged to a solution of compound VII in 4 volumes ethanol at 20° C. The reaction mixture was heated to 55° C. and stirred for 12 hours. Upon completion of the reaction, the mixture was cooled to 20° C. and charged with 5 volumes of toluene. After stirring for 30 minutes, the phases were separated and the organic phase was discarded. The aqueous phase was extracted with toluene and 9.5 volumes of 7% HCl solution. After stirring for 60 minutes, the phases were separated and the aqueous phase was discarded. The organic phase was washed twice with 7.3 volumes of water. The organic phase was distilled to 6 volumes under vacuum at an internal temperature of less than 40° C. 6 volumes of toluene were charged and the solution was distilled to 5 volumes under vacuum at an internal temperature of less than 40° C. to give compound III. Proton NMR of the crude lactol was consistent with compound III.

[0182] 1 H-NMR d6-DMSO: δ 13.00(s,1 H); 7.27-7.08(m,2 H); 4.98(d,1 H,J=10.5 Hz); 4.08(dd,1 H,J=10.5,7.6 Hz); 3.93(d,3 H,J=2.1 Hz); 2.66(p,1 H,J=7.5 Hz); 1.53(d,3 H,J=1.4 Hz); 0.73-0.64(m,3 H)ppm.

[0183] Step 7: Synthesis of the quinine salt of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (IV) [ka] [ka] [ka]

[0184] Compound III (2 g) was dissolved in 10 mL of toluene at 60° C. Separately, (R)-AMB (1.2 eq.) was dissolved in 2 mL of toluene and added to the compound III solution over 1 h. The resulting solution was then cooled to 50° C. over 1 h and held for 1 h for self-nucleation to occur. The slurry was then cooled to 20° C. over 5 h, stirred at 20° C. for about 8 h, and filtered under vacuum. The resulting wet cake was washed with 5 mL of toluene and dried at 40° C. under vacuum to give a yield of about 70% compared to the input compound III free form. The resulting solid was identified as (R)-(+)-α-methylbenzylamine salt of compound III form A from XRPD.

[0185] Form A of the (R)-(+)-α-methylbenzylamine salt of Compound III exhibits the following XRPD peaks in a standard X-ray powder diffraction experiment:

[0186] [Table 1]

[0187] In Table 1, the term "priority" indicates the perceived importance of a particular diffraction peak based on its relative intensity. One skilled in the art will appreciate that the relative intensity of the diffraction peaks may be affected by experimental conditions. The overall diffraction pattern, such as that shown in FIG. 1, may be equally important for characterizing a solid form.

[0188] Fill the container with isopropyl alcohol (27.8 L) and infuse the solvent with N 2 The mixture was stirred continuously and the vessel was saturated with N 2 While purging with gas, n-heptane (47.2 L) was added to the vessel. The n-heptane / isopropyl alcohol mixture was transferred to a clean drum. The (R)-(+)-α-methylbenzylamine salt of compound III (10.42 Kg) was added to the 2 The solvent mixture was added while purging with gas. The reactor was sealed and vacuum / N 2A gas cycle was performed. Methylene chloride (80 L) was added to the reaction mixture, then the agitator was started slowly to suspend and slurried the solids. Hydrochloric acid (full carboy of 2.0 M) was added. The mixture was stirred for 15 minutes and the phases were allowed to separate (approximately 10 minutes). Compound III was in the lower phase. The phases were separated and then the organic phase was returned to the reactor. The washing procedure was repeated with two more portions of 2 M HCl (19 L each). The lower organic phase was dried by stirring with anhydrous magnesium sulfate (1 kg) and then the supernatant was filtered. The mixture was distilled to a volume of approximately 11 L and then isopropanol (10 L) was added to the reactor. The distillation and isopropanol addition were repeated two more times. Quinine (7.11 kg) was added to the mixture. The remaining solution was diluted with a mixture of isopropanol and n-heptane (57 L total) and then the resulting mixture was heated to approximately 60-65 °C to dissolve all the solids. The mixture was cooled to 45° C. over 90 minutes. During the cooling period, when the mixture temperature was about 56-58° C., the quinine salt of Compound IV species material was added. The mixture was cooled to 20° C. over 3 hours. The mixture was stirred for 100 minutes and filtered. The filter cake was washed with an isopropanol / n-heptane mixture (8 L) and the solid was then dried at 75° C. The product was recrystallized from isopropanol / n-heptane to give 8.7 kg of IV.

[0189] Quinine (1 eq.) was added to compound III (2 g) in about 4 mL of dichloromethane. The resulting slurry / solution was then solvent exchanged into 2-propanol (4 mL) and heated to 70° C. to allow complete dissolution. The solution was then cooled to 65° C. and n-heptane (12 mL) was added over 1 hour. During this heptane addition, self-nucleation was observed and the resulting slurry was stirred at 65° C. for 1 hour. The slurry was then cooled to 20° C. over 3 hours and stirred at 20° C. for 2 hours. The slurry was filtered and washed with 3 mL of a 75 V% heptane in 2-propanol mixture. The wet solid was analyzed by XRPD and identified as the 2-propanol solvate of compound III quinine salt Form A (i.e., compound IV). The wet cake was then dried at 50° C. for 24 hours to give compound IV Form A in about 85% yield.

[0190] Form A of compound IV may be characterized by the following XRPD peaks in a standard X-ray powder diffraction experiment:

[0191] [Table 2]

[0192] In Table 2, the term "priority" indicates the perceived importance of a particular diffraction peak based on its relative intensity. One skilled in the art will appreciate that the relative intensity of the diffraction peaks may be affected by experimental conditions. The overall diffraction pattern, such as that shown in FIG. 2, may be equally important for characterizing a solid form.

[0193] Step 8: Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide) methyl picolinate (II) [ka]

[0194] Step 1: Compound IV (quinine salt of compound III, 2.8 kg) was added to a flask containing 1The mixture was dried in a tray dryer at 50°C for at least 24 hours until 0.5% or less by H NMR analysis. The dried quinine salt was charged to a 100 L jacketed reactor followed by the addition of dichloromethane (DCM, 30.1 kg). 2.5 M hydrochloric acid solution (9.0 kg) was charged and the mixture was stirred at 20±5°C for at least 15 minutes. The layers were separated and the aqueous layer was discarded (this step was repeated two more times). The organic layer was washed with water (5.6 kg), the layers were separated and the aqueous layer was discarded. A sample was taken from the organic layer to determine the amount of quinine (IPC). If quinine was greater than 1.0%, the organic layer was washed with aqueous hydrochloric acid, the layers were separated and the aqueous layer was discarded. The organic layer was transferred to a rotary evaporator and distilled down to 4 volumes. DCM was charged to a 20 L rotary evaporator round bottom flask (rbf) and the mixture was distilled down to 4 volumes. Samples were taken (IPC) and analyzed for moisture content (KF) for reference.

[0195] The mixture was transferred to a 100 L jacketed reactor. N,N-Dimethylformamide (DMF, 33.1 g) was charged followed by oxalyl chloride (682.4 g) and the mixture was stirred at 20±5° C. for at least 3 hours or until the amount of compound III present in the reaction mixture was <0.50%. The mixture was transferred to a 20 L rotary evaporator rbf and distilled down to 2 volumes. DCM was charged to the rotary evaporator rbf and the mixture was distilled down to 3 volumes (this step was repeated). A sample was taken (IPC) to determine the amount of oxalyl chloride (derivatization). If the amount of oxalyl chloride was determined to be greater than 0.50%, DCM was charged to the mixture and the mixture was distilled down to 3 volumes (if necessary, this step was repeated three times until the amount of oxalyl chloride was less than 0.50%).

[0196] Compound VI (690.7 g) was charged to a 100 L jacketed reactor, followed by DCM. The mixture was stirred and the temperature of the mixture was adjusted to 10±5° C. Triethylamine (TEA, 501.5 g) was charged to a 100 L jacketed reactor, followed by the contents of the 20 L rbf containing the acid chloride (i.e., compound V). The temperature of the reactor was adjusted to 20° C. over at least 30 minutes and stirred at 20±5° C. for at least 3 hours. A sample was taken (IPC) to determine the amount of compound III. If compound III was present in an amount greater than 1.5%, the reaction was allowed to continue at 20±5° C. for at least 1 hour. The process of taking a sample, determining compound III content, followed by stirring for an additional hour was repeated as necessary.

[0197] Water (11.2 kg) was charged to the reactor and the mixture was stirred for at least 15 minutes. The layers were allowed to separate and the aqueous layer was discarded. The organic layer was washed with 18% aqueous citric acid (9.5 kg) followed by water (5.7 kg), discarding the aqueous layer after each wash. The 100 L jacketed reactor was washed. The organic layer was transferred to the washed 100 L jacketed reactor and the mixture was distilled down to 4 volumes. Methanol was charged to the 100 L jacketed reactor and the mixture was distilled down to 4 volumes (this step was repeated). For reference, the DCM content ( 1 A sample was taken to determine H NMR (IPC). Additional methanol (2.8 kg) was charged followed by water (4.9 kg). The temperature was adjusted to 60±5° C. and the mixture was stirred. The temperature of the mixture was adjusted to 55±5° C. and the mixture was stirred at 55±5° C. for at least 15 minutes. If necessary, compound II seed crystals were charged and the mixture was stirred at 55±5° C. for at least 30 minutes. Water (4.9 kg) was charged over at least 5 hours. The mixture was stirred at 55±5° C. for at least 30 minutes followed by adjusting the temperature to 20±5° C. for at least 5 hours. The mixture was stirred at 20±5° C. for at least 8 hours. The solids were collected by filtration and washed with water / methanol. The product (1.7 kg) was dried and packaged.

[0198] Step 2: Compound IV (quinine salt of compound III, 10 g) was stirred with 60 mL of toluene and 30 mL of aqueous hydrochloric acid (2 M) at 20 °C for 30 min. The resulting emulsion was phase separated and the organic phase (compound III) was stirred with 30 mL of aqueous hydrochloric acid (2 M) at 20 °C for 30 min. The resulting emulsion was phase separated and the organic phase (containing compound III) was stirred with 20 mL of distilled water at 20 °C for 30 min. The resulting emulsion was phase separated and the organic phase (containing compound III) was distilled (chased with 60 mL of toluene) to approximately 30 mL. To the latter solution, 30 mL of dichloromethane was charged together with 200 μL of N,N-dimethylformamide and the resulting mixture was stirred at 30 °C. To this solution, separately prepared oxalyl chloride (1.6 mL) mixed with 10 mL of dichloromethane was slowly added over 1 h. The reaction was allowed to proceed for 3 hours to form compound V. After the reaction, a series of put-take distillation cycles must be performed to remove residual oxalyl chloride (100 mL toluene, followed by a chase with 100 mL dichloromethane). The resulting solution is 50 mL of compound V in dichloromethane, which is charged (over 1 hour) with a separately prepared solution of compound VI (2.5 g) + 40 mL dichloromethane + 2.5 mL triethylamine. The reaction is carried out at 25°C for 4 hours, followed by a series of washes [1) 40 mL water wash, 2) 26 mL citric acid solution wash, and 3) 20 mL water wash]. A solvent exchange is performed via put-take distillation to exchange toluene with methanol, resulting in 70 mL of compound II solution in methanol. A premixed mixture of 12.5 mL methanol and 5 mL water is added to the latter solution. The batch is heated to 35-40°C and Compound II crystals are added, then 15 mL of water is slowly charged over 3 hours and cooled to 20°C over 5 hours. The slurry is aged for 8 hours or more and filtered under vacuum. The resulting wet cake is washed with a 30% by volume water in methanol solution and dried at 40°C under vacuum to give Compound II in about 85-90% yield. The form isolated is Form C.

[0199] Step 9 Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (I) [ka]

[0200] Step 1: Compound II (1.6 kg) was charged to a 100 L reactor, followed by 7 M ammonia solution in methanol (10.7 kg). The temperature of the mixture was adjusted to 20±5° C. The mixture was stirred at 20±5° C. for at least 24 hours or until the amount of starting material present was <0.5% (additional amounts of ammonia solution may be added as necessary to reduce Compound II to less than 0.5%). The reaction mixture was transferred to a rotary evaporator and distilled to 4 volumes. Methanol was charged to the rotary evaporator rbf and the mixture was distilled to 4 volumes. The mixture was transferred to a 100 L reactor and charged with methanol. The temperature was adjusted to 55±5° C. and the mixture was stirred at 55±5° C. for at least 10 minutes. If no solution was present in the reactor, the temperature of the mixture was adjusted to 60±5° C. and the mixture was stirred for at least 10 minutes, followed by adjusting the temperature to 55±5° C. Water (7.9 kg) was charged to the reactor over at least 2 hours while maintaining the temperature at 55±5° C. The mixture was stirred at 55±5° C. for at least 1 hour, followed by adjusting the temperature to 20±5° C. for at least 12 hours. The mixture was stirred at 20±5° C. for at least 5 hours, and the solids were collected by filtration. The reactor was rinsed with methanol / water, and the rinse was transferred through the filter cake. The solids were transferred to a lined tray and dried in a tray dryer at up to 45° C. for at least 12 hours to give 1.3 kg of crude Compound (I).

[0201] Step 2: Ammonia gas is bubbled through a 30% by volume tetrahydrofuran in methanol solution to obtain a concentrated solution of about 6M. Compound II (10 g) is dissolved in 102 mL of the prepared ammonia solution and the reaction is carried out at 20° C. for 20 hours. The resulting compound I solution is slowly charged with 12.5 mL of water at 25° C. over 1 hour. Seeding is carried out with 0.5% by weight compound I crystals at 25° C. and aged for 1 hour. 87.5 mL of water is charged at 25° C. over 4.5 hours. The slurry is aged for more than 8 hours and filtered under vacuum. The resulting wet cake is washed with methanol / tetrahydrofuran / water (volume ratio 35 / 15 / 50) and dried at 40° C. under vacuum to obtain compound I in about 92-94% yield. The isolated form is Form B.

[0202] Step 10: Purification of Compound I

[0203] Step 1: Crude Compound I (1.23 kg) was charged to a 22 L rbf followed by acetone (5.01 kg). The mixture was stirred and the temperature was adjusted to 40±5° C. The mixture was polish filtered into a 20 L jacketed reactor. The temperature was adjusted to 35±5° C. and the mixture was stirred at 35±5° C. for at least 5 minutes. If the mixture was not a solution, the temperature was adjusted to 40±5° C. and the mixture was stirred at 40±5° C. for at least another 5 minutes. The temperature was adjusted to 35±5° C. and water (1.90 kg) was charged to the solution over 1.5 hours and then the solution was seeded. The mixture was stirred at 35±5° C. for at least 1 hour. Water (2.49 kg) was charged to the reactor over at least 2 hours while maintaining a temperature of 35±5° C. and the mixture was stirred at 35±5° C. for at least 30 minutes. The temperature was adjusted to 20±5° C. for at least 5 hours and the mixture was stirred at 20±5° C. for at least 5 hours. The solids were collected by filtration and the reactor was rinsed with acetone / water, passing the rinse through the filter cake. The solids were collected by filtration and washed with N 2 The gas was used to dry on the filter for at least 30 minutes. The product was transferred to a lined tray and dried in a tray dryer to give 1.10 kg of recrystallized Compound (I).

[0204] Step 2: Compound I (10 g) obtained above was dissolved in 70 mL of methanol and 30 mL of tetrahydrofuran at 25° C. Then, polishing filtration was performed. 12.5 mL of water was slowly charged at 25° C. over 1 hour. Seeding was performed with 0.5 wt % of compound I crystals at 25° C. and aged for 1 hour. 87.5 mL of water was charged at 25° C. over 4.5 hours. The slurry was aged for 8 hours or more and filtered under vacuum. The resulting wet cake was washed with methanol / tetrahydrofuran / water (volume ratio 35 / 15 / 50) and dried under vacuum at 40° C. to obtain compound I with a yield of about 95%. The isolated form was form B. Example 2

[0205] Synthesis of Compound III Alternatively, compound III may be synthesized according to Scheme 2. [ka]

[0206] Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid III

[0207] Step 1 Synthesis of (3S,4S,5S)-4-(3,4-difluoro-2-methoxy-phenyl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-2-one (XX) [ka]

[0208] A solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3,4-difluoro-2-methoxyphenyl)-3-methylfuran-2(5H)-one XXI (1.064 g, 3.937 mmol) and NiCl in methanol (40 mL). 2 .6H 2 A solution of 2,4-dichlorophenyl ether (112.0 mg, 0.4712 mmol) was cooled to -15 °C (NaCl / ice). 4(730 mg, 19.30 mmol) was added in portions over 10 min and stirred for an additional 20 min upon complete addition. The reaction mixture was diluted with cold NH 4 Poured into Cl(sat) solution, separated the phases and further extracted the aqueous phase with DCM (x2). The combined organic phases were washed with water and brine. The crude product was purified by silica gel chromatography (eluted with 0%-30% EtOAc in heptane) to give (3S,4S,5S)-4-(3,4-difluoro-2-methoxy-phenyl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-2-one XX (501 mg, 47%). 1 H NMR(400 MHz,chloroform-d)δ 6.81 - 6.69(m,1H),6.64(ddd,J=8.7,5.6,2.2 Hz,1H),4.74 - 4.62(m,1H),3.91(d,J=3.4 Hz,3H),3.52(dd,J=12.1,7.9 Hz,1H),3.28(dd,J=12.1,4.6 Hz,1H),3.14 - 2.92(m,1H),1.84(d,J=1.8 Hz,1H),0.93(d,J=7.2 Hz,3H)ppm. ESI-MS m / z calculated value 272.08603, actual value 273.4(M+1)+; retention time: 1.32 minutes.

[0209] Step 2 Synthesis of (3S,4S,5S)-5-(benzyloxymethyl)-4-(3,4-difluoro-2-methoxy-phenyl)-3-methyl-tetrahydrofuran-2-one (XIX) [ka]

[0210] To a solution of (3S,4S,5S)-4-(3,4-difluoro-2-methoxy-phenyl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-2-one XX (17.7 g, 65.02 mmol) and benzyl 2,2,2-trichloroethaneimidate (34 g, 134.6 mmol) in 1,4-dioxane (200 mL) was added trifluoromethanesulfonic acid (1 mL, 11.30 mmol) dropwise at room temperature (a mild exotherm occurs even with slow addition, reaching 28 °C), the reaction was cooled in an ice bath and the addition was continued. The mixture was stirred at room temperature overnight. The solution was diluted with TBME and quenched by the addition of NaOH 1M. The phases were separated and the organic phase was washed twice with NaOH 2M. The combined organic extracts were washed with water, brine and MgSO 4 The crude product was purified by silica gel chromatography (220 g column, gradient: 0-20% EtOAc in heptane) to give impure product. The product was dissolved in DCM and washed twice with NaOH 2M, then with water, dried (MgSO 4 ), filtered and concentrated in vacuo to give (3S,4S,5S)-5-(benzyloxymethyl)-4-(3,4-difluoro-2-methoxy-phenyl)-3-methyl-tetrahydrofuran-2-one XIX (18.7 g, 79%). 1 H NMR(400 MHz,chloroform-d)δ 7.34 - 7.27(m,1H),7.31 - 7.17(m,2H),7.21 - 7.13(m,2H),6.79(td,J=9.1,7.2 Hz,1H),6.70(ddd,J=8.5,5.7,2.1 Hz,1H),4.87 - 4.78(m,1H),4.44(d,J=11.8 Hz,1H),4.28(d,J=11.9 Hz,1H),3.89(d,J=3.2 Hz,3H),3.51(dd,J=10.3,6.8 Hz,1H),3.25(s,1H),3.04(s,1H),0.97(d,J=7.1 Hz, 3H) ppm; ESI-MS m / z calculated 362.13297, found 363.4 (M+1)+; retention time: 0.95 min.

[0211] Steps 3 and 4 : Synthesis of (2S,3S,4S,5S)-5-(benzyloxymethyl)-4-(3,4-difluoro-2-methoxy-phenyl)-3-methyl-2-(trifluoromethyl)tetrahydrofuran-2-ol (XVII) [ka]

[0212] (3S,4S,5S)-5-(benzyloxymethyl)-4-(3,4-difluoro-2-methoxy-phenyl)-3-methyl-tetrahydrofuran-2-one XIX (948 mg, 2.616 mmol) was charged into a round-bottom flask and N 2 The mixture was backfilled with gas / vacuum three times. Trimethyl(trifluoromethyl)silane (1.7 mL, 11.50 mmol) was added via syringe. THF (0.4 mL) was added followed by anhydrous CsF (97.5 mg, 0.6419 mmol) (oven dried). The mixture was flushed with N 2 Refilled with gas / vacuum three times. The resulting mixture was stirred at room temperature over the weekend. Additional THF (9.5 mL) was added followed by TBAF (2.6 mL of 1M, 2.600 mmol) at room temperature and stirred for 10 min. The crude mixture was dissolved in DCM and washed with water (2 times) and brine. The solvent was removed in vacuo to give crude (2S,3S,4S,5S)-5-(benzyloxymethyl)-4-(3,4-difluoro-2-methoxy-phenyl)-3-methyl-2-(trifluoromethyl)tetrahydrofuran-2-ol XVII (367 mg, 32%). 1H NMR(500 MHz,chloroform-d)δ 7.25 - 7.12(m,3H),7.12 - 7.02(m,2H),6.72(dtt,J=11.1,7.0,3.8 Hz,2H),4.47(qd,J=6.1,2.3 Hz,1H),4.35(d,J=11.9 Hz,1H),4.22 - 4.14(m,1H),3.98(dd,J=8.5,6.0 Hz,1H),3.76(t,J=1.6 Hz,3H),3.46 - 3.35(m,1H),3.20(ddd,J=10.1,5.8,2.1 Hz,1H),2.95(p,J=7.5 Hz,1H),1.27 - 1.11(m,3H),0.81(td,J=7.0,2.1 Hz,1H),0.75(dd,J=7.2,1.7 Hz,3H)ppm; ESI-MS m / z calculated value 432.136, actual value 431.5(M-1)-; Retention time: 1.01 min.

[0213] Step 5 Synthesis of (2S,3S,4S,5S)-6-benzyloxy-4-(3,4-difluoro-2-methoxy-phenyl)-1,1,1-trifluoro-2,3-dimethyl-hexane-2,5-diol (XVI) [ka]

[0214] (2S,3S,4S,5S)-5-(benzyloxymethyl)-4-(3,4-difluoro-2-methoxy-phenyl)-3-methyl-2-(trifluoromethyl)tetrahydrofuran-2-ol XVII (415 mg, 0.9598 mmol) was dissolved in THF (8.5 mL) and cooled to 0° C. before adding MeMgCl (1.6 mL of 3M, 4.800 mmol) dropwise. The reaction mixture was allowed to reach room temperature and then heated to 60° C. in a sealed vial until the reaction was complete. The reaction was allowed to cool to room temperature and quenched by the addition of HCl 2M, extracted with EtOAc and purified by evaporation with MgSO 4The crude product was purified by silica gel chromatography (12 g column, gradient: 0-20% EtOAc in heptane) to give the desired product (2R,3S,4S,5S)-6-benzyloxy-4-(3,4-difluoro-2-methoxy-phenyl)-1,1,1-trifluoro-2,3-dimethyl-hexane-2,5-diol XVI (300 mg, 70%). 1 H NMR(400 MHz,chloroform-d)δ 7.30 - 7.12(m,7H),6.74(td,J=9.3,7.5 Hz,1H),4.33(d,J=3.2 Hz,2H),4.30 - 4.21(m,1H),3.88(d,J=2.7 Hz,3H),3.47(dd,J=7.3,2.8 Hz,1H),3.29(dd,J=9.3,3.7 Hz,1H),2.91(t,J=8.9 Hz,1H),2.42(s,1H),2.37 - 2.25(m,1H),2.19(q,J=6.1,5.1 Hz,1H),1.28(d,J=1.2 Hz,3H),1.24(dq,J=7.3,1.8 Hz,3H)ppm; ESI-MS m / z calculated value 448.1673, actual value 447.5(M+1)+; Retention time: 0.96 minutes.

[0215] Step 6 Synthesis of (2R,3S,4S,5R)-5-(benzyloxymethyl)-4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)tetrahydrofuran (XV) [ka]

[0216] (2R,3S,4S,5S)-6-Benzyloxy-4-(3,4-difluoro-2-methoxy-phenyl)-1,1,1-trifluoro-2,3-dimethyl-hexane-2,5-diol XVI (218 mg, 0.4861 mmol) and Et 3N (0.34 mL, 2.439 mmol) was dissolved in DCM (2.5 mL) and cooled to 0° C. using an ice / water bath. Mesyl chloride (0.12 mL, 1.521 mmol) was then added dropwise and the reaction was stirred at 0° C. until deemed complete. The reaction was quenched by the addition of MeOH (1.5 mL). The cold mixture was allowed to warm to room temperature and water (20 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (2×15 mL). The combined organic phase was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give 264 mg of the crude mesylate intermediate as a yellow oil. The crude mesylated product was diluted with 2,6-lutidine (5 mL) and heated at 120° C. for 1 h. The mixture was diluted with water (20 mL) and DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3×20 mL). The combined organic phase was washed with saturated CuSO 4 Wash with aqueous solution (20 mL x 4) and add Na 2 SO 4 After drying at 40° C., filtering and concentrating under reduced pressure, the crude product was purified by silica gel chromatography using a gradient of 0-10% EtOAc in heptane, then 20% EtOAc:80% heptane to give (2R,3S,4S,5R)-5-(benzyloxymethyl)-4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)tetrahydrofuran XV (100 mg, 48%). 1 H NMR(500 MHz,chloroform-d)δ 7.28 - 7.11(m,5H),6.76 - 6.56(m,2H),4.61 - 4.38(m,3H),3.90 - 3.75(m,4H),3.57(ddd,J=11.0,2.6,1.4 Hz,1H),3.42(ddd,J=11.1,4.7,1.4 Hz,1H),2.52(pd,J=7.7,1.4 Hz,1H),1.48 - 1.41(m,3H),0.67(dt,J=7.2,2.2 Hz,3H)ppm. ESI-MS m / z calculation value 430.15674, found 431.5 (M+1)+; retention time: 1.21 min.

[0217] Step 7 Synthesis of [(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]methanol (XIV) [ka]

[0218] Pd(OH) 2 (Degussa, 23.7 mg, 0.03375 mmol) was dissolved in N 2 The flask was filled with N 2 The flask was refilled with gas three times. Then, (2R,3S,4S,5R)-5-(benzyloxymethyl)-4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)tetrahydrofuran XV (76 mg, 0.1766 mmol) in EtOH (2 mL) was added and the flask was again filled with N 2 The reaction flask was refilled with N2. A balloon of hydrogen was bubbled through the resulting solution until it was empty. The balloon was refilled and the mixture was stirred vigorously at room temperature overnight. The reaction flask was refilled with N2. 2 Flush with gas three times (vacuum / N 2 The catalyst was then filtered by passing the mixture through a Celite cartridge pre-wetted with EtOH, and the solvent was removed in vacuo to give [(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]methanol XIV (68 mg, quantitative yield based on a purity of approximately 94%). 1H NMR(400 MHz,chloroform-d)δ 6.76(td,J=9.2,7.3 Hz,1H),6.67(ddd,J=8.6,5.6,2.1 Hz,1H),4.46(ddd,J=11.3,4.0,2.5 Hz,1H),3.92(d,J=2.5 Hz,3H),3.89 - 3.70(m,2H),3.41(dd,J=12.3,4.0 Hz,1H),2.56(p,J=7.7 Hz,1H),2.12 - 1.83(m,1H),1.46(d,J=1.4 Hz,3H),0.69(dq,J=7.4,2.4 Hz,3H)ppm. Quantitative yield based on ESI-MS m / z calculations 340.10977, found 358.5 (M+1)+; retention time: 0.94 min.

[0219] Step 8 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (III) [ka]

[0220] [(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]methanol XIV (45 mg, 0.1322 mmol) was dissolved in CH 2 Cl 2 (0.5 mL) and cooled to 0° C. Then, NaBr (8.6 mg, 0.08358 mmol), tetrabutylammonium bromide (45.3 mg, 0.1405 mmol), TEMPO (7.7 mg, 0.04928 mmol), and NaHCO 3 Saturated water (0.4 mL) was added. The resulting mixture was treated with NaOCl (9 μL, 0.1326 mmol) with vigorous stirring and allowed to warm to room temperature over 1 h. HCl (0.13 mL of 1 M, 0.1300 mmol) was added until the pH was neutralized to 6-7. Then tBuOH (2 mL), 2-methylbut-2-ene (0.5 mL of 2 M, 1.000 mmol) followed by NaClO 2 (12.6 mg, 0.1393 mmol) and NaH 2PO 4 (0.02 mL, 0.3192 mmol) was added and the mixture was stirred at room temperature for 1-2 h. The mixture was diluted with saturated NaH 2 PO 4 The mixture was diluted with aqueous solution (5 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined and washed with MgSO 4 The mixture was dried at 4° C., filtered and concentrated in vacuo to give the crude product. The product was purified by reverse phase HPLC. Method: C18 Waters X-bridge column (19×150 mm, 5 micron), gradient: H 2 O containing 0.1% ammonium hydroxide. 2 MeCN in O. 19 mL / min + 1 mL / min MeCN on column dilution injection, gradient 15.8% to 30.5% over 9 min, gave (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid III (17 mg, 36%). 1 H NMR(400 MHz, methanol-d4)δ 7.11(ddd,J=8.3,5.6,2.2 Hz,1H),6.96(ddd,J=9.9,8.9,7.5 Hz,1H),4.96(d,J=10.5 Hz,1H),4.16(dd,J=10.5,7.8 ESI-MS m / z calculated value 354.08905, actual value 353.4 (M-1)-; retention time: 0.59 minutes. Example 3

[0221] Synthesis of Compound X Alternatively, compound XX may be synthesized according to Scheme 4. [ka]

[0222] In some embodiments, compound XXVI may be decarboxylated, followed by a hydrogenation reaction to give compound XXIV.

[0223] Step 1 Synthesis of (R)-4,5-dimethyl-2-oxo-5-(trifluoromethyl)-2,5-dihydrofuran-3-carboxylate (XXVII) [ka]

[0224] Step 1: A 10 L vessel equipped with an overhead stirrer, nitrogen inlet, and temperature probe was flushed with nitrogen and charged with 200.14 g (1.282 mol) of compound XXVIII, 450 mL (520 g, 3.94 mol, 3.07 equiv.) of dimethyl malonate, and 6.0 L of methanol. To the clear solution was added 1003.16 g (3.079 mol, 2.4 equiv.) of cesium carbonate in portions. The addition was slightly exothermic, with the internal temperature rising from 22° C. to 29° C. (when all the Cs2CO3 had been added). A thin white suspension was obtained. After 1.5 h, the mixture became a clear, colorless solution. The mixture was stirred under nitrogen at room temperature over the weekend.

[0225] An orange-brown solution was obtained. The solution was cooled to 2-3° C. and 3N HCl(aq) was added until pH 6-7. Approximately 1300 mL of 3N HCl(aq) was required. Most of the methanol was removed under reduced pressure (52° C. water bath, vacuum to 170 mbar). The remaining liquid was extracted with EtOAc (1.5 L, 3×500 mL). The combined organic phase was washed with brine (500 mL) and diluted with Na 2 SO 4 After filtration, the solvent was removed under reduced pressure.

[0226] A brown oil was obtained. Yield: 362 g. NMR 1 (CDCl 3 : 18% w / w dimethyl malonate present. The material was purified by fractional distillation at 9-12 mbar to give 256 g (1.075 mol, 84%) of compound XXVII.

[0227] Step 2: To a solution of compound XXVIII (249.5 g, 1.2786 mol), dimethyl malonate (509.9 g, 3.8595 mol) in methanol (6 L) was added cesium carbonate (1000 g, 3.0692 mol) in portions over 1 h. The mixture was stirred overnight. After the mixture was cooled to 5 °C, 1% aqueous hydrochloric acid was added in portions such that the temperature did not exceed 10 °C until a pH of 6-7 was obtained. The methanol was removed in vacuo and the resulting solution was extracted with ethyl acetate (2 x 1.5 L). The combined organic extracts were washed with brine (1 L), dried (sodium sulfate), and concentrated. The reaction was repeated three times on the above scale and once on this scale, and all batches were combined to give compound XXVII (283.2 g, 93%) as a black oil, which was used in the next step without purification. 1 Based on 1 H NMR, the oil was contaminated with 20% dimethyl malonate and 3% toluene.

[0228] 1 H NMR(400MHz,CDCl3)δ 3.90(s,3H),2.44(s,3H),1.70(s,3H)ppm.

[0229] Step 2 [ka] Synthesis of (R)-4,5-dimethyl-2-oxo-5-(trifluoromethyl)-2,5-dihydrofuran-3-carboxylic acid (XXVI)

[0230] Step 1: A 9 L jacketed glass reactor was charged with 5.7 L (10.43 kg, 106.4 mol, 44.5 equiv.) >95% sulfuric acid and 569.0 g (2.389 mol) of compound XXVII. The colorless solution was heated to 78-79 °C. After 4 h, a dark orange clear solution was obtained. The sample was mixed with ice and DCM, and the separated organic phase was washed with water and diluted with Na. 2 SO 4 and concentrated for NMR aliquots ( 1 H, 19 FCDCl 3): 34-35% conversion. The mixture was stirred at 78-79 °C overnight. After 21 h the internal temperature was 78.7 °C and the mixture was slightly darker in color. The sample was mixed with ice and DCM and the separated organic phase was washed with water and added Na 2 SO 4 and concentrated for NMR aliquots ( 1 H, 19 FCDCl 3 ): 94% conversion. The mixture was cooled to 0-3°C (took 2 h). The mixture was siphoned into a stirred mixture of 20 kg ice and 9 L DCM (transfer took 4-5 min). The mixture was stirred vigorously for 10 min to allow the phases to settle. After phase separation, the aqueous phase was extracted with DCM (3 x 3 L, 3 x 2 L). The combined organic phase was washed with water (3.0 L), brine (1.5 L) and added Na 2 SO 4 The organic phase was filtered and concentrated under reduced pressure (55° C. water bath, vacuum to 42 mbar) to give a light beige solid, 525 g. The crude product was dissolved in TBME (2.2 L). The solution was diluted with 3.8 L of saturated NaHCO 3 The aqueous solution was added carefully (gas evolution and foaming). A thick suspension was obtained and 3.5 L of water was added, giving a clear two-phase system. The phases were separated and the organic phase was washed with 1 / 2 saturated NaHCO 3 The combined aqueous phase was washed with TBME (2×400 mL) and acidified to pH 1-2 with concentrated aqueous HCl. A pinkish suspension was obtained that became more opaque. The opaque mixture was extracted with TBME (7×1 L). The combined organic phase was washed with brine (200 mL) and diluted with Na 2 SO 4 After filtration, the solvent was removed under reduced pressure (61°C water bath, reduced pressure to 8 mbar) to give a cream-colored solid of compound XXVII. Yield 489.5 g (2.184 mol, 91.4%). NMR ( 1 H, 19 FCDCl 3 ): 19 97.2% pure by F NMR, no TBME remaining. HPLC-MS (ACN): 98.12% pure, some decarboxylation product present.

[0231] Step 2: A solution of compound XXVII (284.8 g, 920.79 mmol) in concentrated sulfuric acid (2.5760 kg, 1.4 L, 26.264 mol) was stirred at 78° C. overnight. The reaction was cooled to 0° C. and poured onto ice (6 kg) with vigorous stirring. The mixture was extracted with dichloromethane (3×2 L). The combined organic extracts were washed with brine (1 L) and concentrated. The residue was taken up in toluene (2 L) and partially concentrated to a volume of 0.5 L. The solution was cooled to 0° C. and filtered. The product was washed with cold toluene (0.2 L), followed by heptane (0.3 L) and air-dried. The reaction was repeated five times and all materials were combined to give compound XXVI (786.4 g, 62%) as an off-white solid.

[0232] 1 H-NMR (400 MHz, chloroform-D) δ 2.60 (d, 3H), 1.77 (d, 3H) ppm, no acid protons observed.

[0233] The combined mother liquors were concentrated to give a dark oil, which was treated with concentrated sulfuric acid (1.8400 kg, 1 L, 18.760 mol) and stirred at 78° C. overnight. The reaction was cooled to 0° C. and poured onto ice (4 kg) with vigorous stirring. The mixture was extracted with dichloromethane (3×1.5 L). The combined organic extracts were washed with brine (1 L) and concentrated. The residue was taken up in toluene (2 L) and partially concentrated to a volume of 0.5 L. The solution was cooled to 0° C. and filtered. The product was washed with cold toluene (0.2 L) followed by heptane (0.3 L) and air-dried to give compound XXVI (226.5 g, 18%) as a light brown solid.

[0234] 1 H-NMR (400 MHz, chloroform-D) δ 2.61(d,3H), 1.77(d,3H) ppm, no acid protons observed.

[0235] Steps 3 and 4 [ka]

[0236] Step 3 Synthesis of (R)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one (XXIX) [ka]

[0237] A 250 mL 3-neck RBF equipped with an air condenser connected to a temperature probe and bubble counter was charged with 76.29 g (340.4 mmol) of compound XXVI. The solids were allowed to melt (heating mantle set at 120 °C). Once all solids were melted (dissolved at 95-97 °C), the heat was set to 175 °C, the internal temperature reached 168-199 °C, and a steady evolution of gas was observed. After 30 min, the heat was set to 170 °C to maintain the internal temperature at 165-166 °C. From that time, gas evolution increased slowly, and 45 min after gas evolution began, gas evolution increased considerably and the mixture turned reddish brown in 10-15 s. After discoloration, gas evolution stopped abruptly. The liquid was cooled to room temperature. A yield of 60.62 g (336.5 mmol, 98.9%) of (R)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one (XXIX) was isolated.

[0238] Step 4 Hydrogenation of (R)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one [ka]

[0239] Pd / C (8.16 g, 7.668 mmol) was dissolved in N 2 The RBF was charged under vacuum. EtOH (140 mL) was added followed by compound XXIX (13.9479 g, 77.43 mmol). The flask was then subjected to three cycles of N 2 / Purge with vacuum. 2 The balloon filled with H was connected to a three-way valve adapter, and the suspension was 2 The mixture was then refilled with vacuum three times. Then, H was added until complete by TLC. 2 Stirred under a balloon.2 The charged balloon was removed and the reaction was placed under vacuum to remove the hydrogen. Three cycles of N 2 / Vacuum is applied and the suspension is then pumped with N using an inverted funnel 2 Filtration through a pad of Celite under air flow gave an orange oil, confirmed by NMR to be a single diastereomer, 12.17 g of compound XXIV, containing 1.1% residual EtOH.

[0240] 1 H NMR (400 MHz, chloroform-d) δ 2.73 - 2.64(m,1H), 2.64 - 2.54(m,1H), 2.54 - 2.42(m,1H), 1.62(q,J=1.0 Hz,3H), 1.29(dt,J=6.7,2.2 Hz,3H)ppm.

[0241] Alternative Step 3 Synthesis of (3S,4S,5R)-4,5-dimethyl-2-oxo-5-(trifluoromethyl)tetrahydrofuran-3-carboxylic acid (XXV) [ka]

[0242] A slurry of palladium on carbon (101 g, 5% w / w, 47.453 mmol) in toluene (100 mL) was added to a solution of compound XXVI (1012 g, 4.4474 mol) in THF (5 L) in an autoclave. The mixture was charged with hydrogen to 600 psi and stirred at room temperature for 18 h. The reaction was filtered and the filtrate was concentrated to give crude compound XXV as a colorless oil, which was 1 Based on 1 H NMR it was contaminated with THF (5.11% w / w), the methyl ester of the desired product (1.92% w / w), and the isopropyl ester of the desired product (15.6% w / w).

[0243] Alternative Step 4 Synthesis of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (XXIV) [ka]

[0244] A solution of compound XXV (1.124 kg, 3.8454 mol) in toluene (6 L) was heated at 110° C. for 42 h. Upon cooling, the solution was concentrated. Vacuum distillation (92-96° C., 18 mbar) afforded compound XXIV (625 g, 86%) as a colorless liquid. 1 H-NMR (400 MHz, chloroform-D) δ 2.69-2.42(m,3H), 1.62-1.55(m,3H), 1.30-1.21(m,3H)ppm.

[0245] GC (DB1-1HT column, constant flow method from 40 to 360 °C, 25 °C / min, injector 250 °C) room temperature for 2.750 min, 96.1%.

[0246] Step 5 Synthesis of (3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (XXIII) [ka]

[0247] Step 1 A solution of LiHMDS in tetrahydrofuran (84 mL of 1 M, 84.000 mmol) was added over 15 min to a solution of compound XXIV (14.2 g, 74.064 mmol) in tetrahydrofuran (100 mL) at −50° C. under nitrogen. After 1 h, a solution of zinc chloride in tetrahydrofuran (335 mL of 0.5 M, 167.50 mmol) was added over 40 min and the reaction mixture was stirred at −52 to −45° C. After 75 min, Pd(dba) 2A solution of (12.880 mg, 0.0224 mmol), QPhos (1.08 g, 1.5196 mmol), and 1-bromo-3,4-difluoro-2-methoxy-benzene (11.04 g, 49.503 mmol) was added over 5 min and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was cooled to 5° C. and 20% aqueous ammonium chloride solution (100 mL) was added. Methyl tert-butyl ether (100 mL) and water (50 mL) were added. The aqueous layer was diluted with water (100 mL) and extracted with methyl tert-butyl ether (100 mL). The combined organic layers were washed with 15% aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Toluene (100 mL) was added and the organic mixture was washed with 30% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was preabsorbed onto silica gel (25 g) using dichloromethane. Flash chromatography on silica gel (125 g) using 0-6% methyl tert-butyl ether in heptane gave compound XXIII (10 g, 62%) as a red solid. ESI-MS m / z calculated 324.0785, found 325.1 (M+1)+; retention time: 2.101 min. The mixed fractions were combined and the solvent removed under vacuum. The residue was preabsorbed onto silica gel (4.0 g) using dichloromethane. A second purification by flash chromatography on silica gel (40 g, 25 μm) using 0-20% methyl tert-butyl ether in heptane gave compound XXIII (2.755 g, 17%) as a red solid. ESI-MS m / z calculated 324.0785, found 325.1 (M+1)+; retention time: 2.101 min. Total yield = 79%.

[0248] 1 H NMR (400 MHz, CDCl 3 )δ 6.91 - 6.80(m,2H),3.98(d,J=2.7 Hz,3H),3.53(d,J=12.0 Hz,1H),2.77 - 2.62(m,1H),1.67(s,3H),1.19 - 1.14(m,3H)ppm. 19F NMR (377 MHz, CDCl 3 )δ -76.10(s,3F),-135.14 - -135.71(m,1F),-153.19(dd,J=19.8,3.4 Hz,1F)ppm.

[0249] Step 2 To lithium bis(trimethylsilyl)amide in THF (1 L of 1 M, 1000.0 mmol) under argon at −25° C. was added a solution of compound XXIV (156.1 g, 857.03 mmol) in tetrahydrofuran (500 mL) with cooling such that the temperature was maintained below −25° C. Upon stirring at −25° C. for 0.5 h, zinc chloride in THF (3.955 L of 0.5 M, 1.9775 mol) was added such that the temperature was maintained below −25° C. Upon stirring at -25°C for 0.5 h, a solution of XPhos (9.5 g, 19.928 mmol) and bis(dibenzylideneacetone)palladium(0) (7.6 g, 13.217 mmol) in tetrahydrofuran (500 mL) was added, followed by a solution of 1-bromo-3,4-difluoro-2-methoxybenzene (147 g, 659.15 mmol) in tetrahydrofuran (250 mL). The reaction mixture was stirred at -25°C for 1 h and then allowed to warm to room temperature and stirred overnight. The reaction mixture was then cooled to 0°C and saturated aqueous ammonium chloride solution (4 L) was added. The mixture was extracted with TBME (2 x 1.5 L) and the combined organic extracts were washed with brine (1 L), dried (anhydrous sodium sulfate) and concentrated. Purification by flash chromatography on silica gel (0-5% TBME in heptane) followed by crystallization from heptane (300 mL) upon cooling to 10° C. afforded compound XXIII (96.1 g, 45%) as a white solid.

[0250] 1 H-NMR (400 MHz, chloroform-D) δ 6.83(m,2H), 3.97(m,3H), 3.52(d,1H), 2.68(m,1H), 1.65(m,3H), 1.17(m,3H) ppm.

[0251] Step 6 Synthesis of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (X) [ka]

[0252] Step 1: To lithium bis(trimethylsilyl)amide in THF (480 mL of 1 M, 480.00 mmol) at -25° C. under argon was added a solution of compound XXIII (100 g, 308.41 mmol) in tetrahydrofuran (500 mL) dropwise. After stirring at -25° C. for 0.5 h, the solution was allowed to warm to 0° C. and stirred for 1 h. The solution was then cooled to -25° C. and added to a solution of pivalic acid (315 g, 3.0842 mol) in tetrahydrofuran (1 L) at -25° C. under argon. After stirring at -25° C. for 0.5 h, TBME (1 L) was added in small portions so that the temperature did not exceed -15° C., followed by 2 M aqueous hydrochloric acid (1.5 L) so that the temperature did not exceed 0° C. Sodium chloride (480 g, 8.2132 mol) was added and the mixture was allowed to warm to room temperature. The organic layer was separated, concentrated, treated with heptane (1 L) and further concentrated. The resulting oil was dissolved in TBME (1 L) and washed with saturated aqueous sodium bicarbonate (6×1 L), then 0.5 M aqueous hydrochloric acid (500 mL), then brine (500 mL), dried (sodium sulfate) and concentrated to give crude compound X (129.3 g, 92%) as a yellow oil. 1 Based on 1 H NMR, the oil was contaminated with 29% pivalic acid.

[0253] 1 H-NMR (400 MHz, chloroform-d) δ 6.89(m,2H), 4.49(m,1H), 3.99(d,3H), 2.88(m,1H), 1.70(m,3H), 0.79(m,3H)ppm [ka]

[0254] Step 2: A solution of n-butyllithium in hexane (0.95 mL of 2.5 M, 2.3750 mmol) was slowly added to a solution of mesityl bromide (503 mg, 2.5265 mmol) in tetrahydrofuran (6.5 mL) at -78 °C and the reaction mixture was warmed to -50 °C. After stirring at this temperature for 45 min, the reaction mixture was cooled to -78 °C and a solution of compound XXIII (503 mg, 1.5498 mmol) in tetrahydrofuran (5 mL) was slowly added over 15 min. After 1.5 h, a room temperature solution of salicylic acid (535 mg, 3.8734 mmol) in tetrahydrofuran (2.2 mL) was slowly added. After 30 min, formic acid (244.00 mg, 0.2 mL, 5.3014 mmol) was added and the reaction mixture was warmed to room temperature and concentrated under vacuum. The residue was dissolved in methyl tert-butyl ether (20 mL) and the organic mixture was washed with 10% aqueous sodium carbonate (2×15 mL). The basic aqueous washes were combined and re-extracted with methyl tert-butyl ether (20 mL). The organic layers were combined, washed with 15% aqueous sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound X (545 mg, 74%) as a pale yellow oil. ESI-MS m / z calculated 324.0785, found 325.1 (M+1)+; retention time: 3.217 min. Example 4

[0255] Alternatively, compound XXIV may be synthesized according to Scheme 5. [ka]

[0256] Step 1 Synthesis of (2S,3R)-4,4,4-trifluoro-2,3-dimethylbutane-1,3-diol (XXX)

[0257] A solution of (2R,3R)-4,4,4-trifluoro-3-hydroxy-2,3-dimethyl-butanoic acid (XXIX) (357.3 g, 1.9196 mol) in tetrahydrofuran (750 mL) was added dropwise over 2 h at 45-55 °C to a solution of lithium aluminum hydride in tetrahydrofuran (2.4 L of 2.4 M, 5.7600 mol) under argon. Upon complete addition, the mixture was heated under reflux for 0.5 h and then cooled to 0 °C3. 1:1 tetrahydrofuran-water (750 mL) was added dropwise over 1 h at 0-20 °C. 5M aqueous HCl (4.5 L) was then added dropwise over 40 min at 0-20 °C and the product was extracted into TBME (2 × 2 L). The combined organic extracts were washed with brine (1 L), dried (Na 2 SO 4 ) and concentrated. The reaction was repeated five times and all batches were combined to give compound XXX (1934 g, 96%) as a pale yellow oil, which was used in the next step without purification. 1 Based on 1 H NMR the oil was contaminated with 1.6% THF.

[0258] 1 H-NMR (400 MHz, chloroform-D) δ 3.90-3.66(m,4H), 2.07(m,1H), 1.38(s,3H), 1.03(m,3H)ppm.

[0259] Step 2 Synthesis of (2S,3R)-4,4,4-trifluoro-3-hydroxy-2,3-dimethylbutyl 4-methylbenzenesulfonate (XXXI)

[0260] To a solution of compound XXX (322.3 g, 1.8423 mol) in pyridine (1.6 L) under argon at 0° C. was added p-toluenesulfonyl chloride (439 g, 2.3027 mol) in portions over 1.5 h at 0-5° C. Upon complete addition, the mixture was stirred at 0-5° C. for 4 h and then at 10° C. overnight. The mixture was then cooled to 0° C. and treated with water (6.5 L). The mixture was extracted with TBME (2×1.5 L) and the combined organics were washed with 2M aqueous HCl (2×2 L), followed by saturated aqueous copper sulfate (2 L), dried (Na 2 SO 4The reaction was repeated five times and all batches were combined to give compound XXXI (3399 g, 93%) as an orange oil, which was used in the next step without purification. 1 Based on 1 H NMR, the oil was contaminated with 1.6% TBME.

[0261] 1 H-NMR (400 MHz, chloroform-D) δ 7.77(m,2H), 7.30(m,2H), 4.26(m,1H), 3.91(m,1H), 2.44(s,3H), 2.19(m,2H), 1.33(s,3H), 1.08(m,3H) ppm.

[0262] Step 3 Synthesis of (3S,4R)-5,5,5-trifluoro-4-hydroxy-3,4-dimethyl-pentanenitrile (XXXII)

[0263] To a solution of compound XXXI (566.5 g, 1.7082 mol) in dimethyl sulfoxide (2.2 L) was added sodium cyanide (125.6 g, 2.5629 mol) and the reaction mixture was stirred at 80° C. overnight. Upon cooling to room temperature, water (6.6 L) was added and the product was extracted into dichloromethane (3×2 L). The combined organics were concentrated in vacuo and the resulting oil was dissolved in TBME (2 L), washed with brine (500 mL), dried (sodium sulfate) and concentrated. The reaction was repeated five times and all batches were combined to give compound XXXII (1371 g, 66%) as a brown oil, which was used in the next step without purification. 1 Based on 1 H NMR the oil was contaminated with 10% DMSO.

[0264] 1 H-NMR (400 MHz, chloroform-D) δ 2.89 (m, 1H), 2.14 (m, 2H), 1.28 (m, 3H), 1.15 (m, 3H) ppm, no hydroxyl protons observed.

[0265] Step 4 Synthesis of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-one / (3S,4R)-5,5,5-trifluoro-4-hydroxy-3,4-dimethyl-pentanoic acid (XXIV)

[0266] To a solution of XXXII (228.5 g, 1.1352 mol) in ethanol (IMS) (1.1 L) and water (1.1 L) was added potassium hydroxide (85%, 299.2 g, 4.5408 mol). The resulting solution was heated under reflux overnight. Upon cooling to room temperature, the ethanol was removed in vacuo and the resulting aqueous solution was washed with TBME (2 x 500 mL). The aqueous solution was cooled to 0 °C, acidified with 36% aqueous hydrochloric acid (250 mL) at 0-4 °C with cooling to pH 5.0, extracted with TBME (3 x 1.5 L) and the combined extracts were washed with brine (500 mL), dried (Na 2 SO 4 The reaction was repeated five times and all batches were combined to give compound XXIV and impurity (3S,4R)-5,5,5-trifluoro-4-hydroxy-3,4-dimethyl-pentanoic acid (1122 g, ca. 86%) as an orange oil, which was used in the next step without purification. 1 Based on 1 H NMR, the oil was contaminated with 0.5% TBME.

[0267] Compound XXIV was isolated from (3S,4R)-5,5,5-trifluoro-4-hydroxy-3,4-dimethyl-pentanoic acid using the following procedure.

[0268] A mixture of compound XXIV and (3S,4R)-5,5,5-trifluoro-4-hydroxy-3,4-dimethyl-pentanoic acid (561 g, ca. 2.8 mol1), hydrogen form 2 of Amberlyst 15 (10 g), and toluene (2 L) was heated under reflux for 2 h using a Dean-Stark apparatus. Upon cooling, the reaction mixture was decanted from the resin and concentrated. The reaction was repeated and both batches were combined. Vacuum distillation (102-108 °C, 30 mbar) afforded the liquid of compound XXIV (903 g, ca. 84%) as a pale yellow liquid.

[0269] 1 H-NMR (400 MHz, chloroform-D) δ 2.58-2.31(m,3H), 1.47(d,3H), 1.14(m,3H)ppm.

[0270] GC (DB1-1HT column, constant flow rate of 40-360°C, 25°C / min, injector 250°C) room temperature 3.008 min, 99.8%

[0271] 19 F-NMR (400 MHz, chloroform-D) δ -76.4 ppm

[0272] As will be apparent to those skilled in the art, many modifications and variations of the embodiments described herein may be made without departing from the scope thereof. The specific embodiments described herein are offered by way of example only.

Claims

1. A method for preparing a compound of formula I or a salt thereof, comprising 【Chemical 1】 converting a compound of formula III or a salt thereof 【Chemical 2】 to the compound of formula I, and optionally, said converting of the compound of formula III to the compound of formula I comprises preparing a compound of formula IV 【Chemical Formula 3】 A method.

2. Said converting of the compound of formula III to the compound of formula I comprises reacting the compound of formula III or the compound of formula IV with a chlorinating agent to obtain a compound of formula V, [Chemical Formula 4] in the compound of formula V, the parentheses around the compound indicate that the compound of formula V is not isolated, optionally, said chlorinating agent is selected from the group consisting of phosgene, thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, isobutyl chloroformate (IBCF), pivaloyl chloride (PivCl), and diphenylphosphinic acid chloride (DPPCl); or said chlorinating agent is phosgene, oxalyl chloride, or thionyl chloride, The method according to claim 1.

3. Said converting of the compound of formula III to the compound of formula I further comprises reacting the compound of formula V with a compound of formula VI to obtain 【Chemical Formula 5】 a compound of formula II 【Chemical Formula 6】 The method according to claim 2.

4. Said converting of the compound of formula III to the compound of formula I further comprises reacting the compound of formula II with ammonia to obtain the compound of formula I, optionally, said ammonia is in the form of a solution of ammonia in a solvent, ammonia gas in gaseous form bubbled into the reaction mixture, or ammonia in the form of ammonium hydroxide or ammonium salt generated in situ, said in situ generation of ammonia optionally comprising reacting ammonium hydroxide or said ammonium salt with an acid; and / or said reacting of the compound of formula II with ammonia is carried out in a solvent, said solvent optionally comprising methanol, ethanol, IPA, MeCN, THF, water, or a mixture thereof, and optionally, said solvent comprises methanol or ethanol, The method according to claim 3.

5. further comprising recrystallizing the compound of formula I from a solvent system containing acetone to obtain the compound of formula I as a solid, The method according to claim 1, wherein the solvent system comprises acetone and water as needed.

6. Further comprising hydrolyzing the cyano compound of formula VII to 【Chemical Formula 7】 obtain the compound of formula III, and as needed, (a) the hydrolysis of the cyano compound is enzymatically hydrolyzed using nitrilase, and as needed, the hydrolysis is carried out in a solvent comprising ethanol, methanol, 1-propanol, 2-propanol, dioxane, water, THF, or a mixture thereof, and / or (b) the hydrolysis is carried out at about 25 to about 75 °C, about 30 to about 70 °C, about 35 to about 65 °C, about 40 to about 60 °C, about 45 to about 60 °C, about 50 to about 60 °C, or about 55 °C, the method according to claim 1.

7. A compound of formula VIII, 【Chemical 8】 In the formula, OR is OC(=O)-Z, OC(=O)OZ, OC(=O)CH=CH-Z, or OP(=O)Z ２ wherein Z is unsubstituted aryl, or aryl substituted by CN, halo, NO ２ and may also be a short-chain alkyl, alkoxy, haloalkyl, or haloalkoxy group, said short chain containing 1, 2, 3, or 4 carbon atoms, and a compound of formula VIII further comprising reacting with a cyanating agent to obtain the compound of formula VII, and as needed, Z is a C1-C4 alkyl or C1-C4 haloalkyl group; or Z is phenyl or naphthyl; and / or the cyanating agent is selected from the group consisting of trimethylsilyl cyanide, diethylaluminum cyanide, KCN, NaCN, TBACN, HCN, and as needed, the cyanating agent is trimethylsilyl cyanide; and / or the reaction between compound VIII and the cyanating agent is carried out in the presence of a Lewis acid, and as needed, the Lewis acid is selected from the group consisting of boron trifluoride ethyl etherate (BF3OEt2), TiCl4, InCl3, AgSbF6, iodine, ZnBr2, Al(O iPr)3, MgCl2, Mn(acac)2, MnCl2, TMSOTf, and SnCl4, or the Lewis acid is BF3OEt2; and / or the reaction between compound VIII and the cyanating agent is carried out in a solvent comprising toluene, dichloromethane, 2-methyl THF, acetonitrile, methanol, 1,2-dichloroethane, nitromethane, or a mixture thereof, the method according to claim 6.

8. Reacting a compound of formula IX with 【Chemical Formula 9】 an acid anhydride or acid chloride to obtain the compound of formula VIII, further comprising the method according to claim 7.

9. Reacting a compound of formula X with 【Chemical Formula 10】 a reducing agent to obtain the compound of formula IX, and as needed, The reducing agent is selected from the group consisting of diisobutylaluminum hydride, Red-Al, NaBH4 / BF3, a titanocene containing polymethylhydrosiloxane, and phenylsilane, or the reducing agent is diisobutylaluminum hydride; and / or, The reduction of the compound of formula X is carried out in an organic solvent or a solvent mixture, and optionally, the solvent contains toluene, dichloromethane, 2-methyl THF, THF, TFT, MTBE, CPME, heptane, or a mixture thereof; and / or, The reduction of the compound of formula X is carried out at about -78 °C to about 0 °C, about -60 °C to about 0 °C, about -50 °C to about -10 °C, about 40 °C to about -10 °C, about 30 °C to about -10 °C, about -30 °C to about -15 °C, about 25 °C to about -15 °C, or about -20 °C; and / or, The reduction reaction is carried out in the presence of CuCl, CuI, CuTol, CuBr, CuF, Cu(II)Cl, DMAP, 2,6-lutidine, LiI, or pyridine, the method according to claim 8.

10. Performing asymmetric hydrogenation of a compound of formula XI to 【Chemical 11】 further comprising obtaining a compound of formula X, optionally, (a) The asymmetric hydrogenation is carried out in the presence of a hydrogenation catalyst, and optionally, the catalyst is selected from the group consisting of Pd / C, Pd / Al2O3, Pt / C, Ni(Raney), Co(Raney), Rh / C, Ir / C, Ru / C, Pd(OH)2, homogeneous chiral Ru and Rh; and / or, (b) The asymmetric hydrogenation is carried out using a suitable hydrogen source, and optionally, the hydrogen source is selected from the group consisting of H2 gas, NiCl2 / NaBH4 in methanol, and Et3SiH; and / or, (c) The asymmetric hydrogenation is carried out in the presence of H2 gas using Pd / C as a catalyst; and / or, (d) The asymmetric hydrogenation reaction is carried out in an organic solvent at about 20 - 40 bar, and / or the hydrogenation is carried out in an organic solvent or a solvent mixture, and optionally, the solvent contains IPA, EtOAc, MeOH, nBuOH, THF, MTBE, CPME, IPAC, nBuAc, toluene, ethanol, or a mixture thereof; and / or, (e) The method according to claim 9, wherein the asymmetric hydrogenation reaction is carried out in a reaction mixture containing TFA, AcOH, H₂SO₄, H₃PO₄, MSA, Cs₂CO₃, CuCl, MgF₂, LiBr, CsF, ZnI, LiOTf, imidazole, KF, Bu₄NOAc, or NH₄BF₄.

11. The compound of formula XIII is 【Chemical 12】 coupled with the compound of formula XII to 【Chemical 13】 further obtain the compound of formula XI, optionally, the coupling reaction between the compound of formula XII and the compound of formula XIII is carried out in the presence of a coupling agent or a chlorinating agent, and optionally, (a) the coupling agent is selected from the group consisting of CDI and T3P; or (b) the chlorinating agent converts the compound XIII into an acid chloride, which is not isolated before reacting with the compound of formula XII; or (c) the chlorinating agent is selected from oxalyl chloride and thionyl chloride, the method according to claim 10.

12. further comprising oxidizing the compound of formula XIV to 【Chemical Formula 14】 obtain the compound of formula III, optionally, the oxidation comprises reacting the compound XIV with TEMPO in the presence of NaCl; and / or the oxidation is carried out in an organic solvent; and / or the oxidation is carried out at about -10 °C to about 40 °C, about -10 °C to about 35 °C, about -5 °C to about 35 °C, about 0 °C to about 30 °C, about 0 °C to 25 °C, about 5 °C, about 10 °C, about 15 °C, or about 20 °C in the presence of a weak base, the method according to claim 1.

13. the compound of formula XIV is obtained by 【Chemical Formula 15】 deprotecting the obtained compound of formula XV following the ring closure of the compound of formula XVI, 【Chemical Formula 16】 to obtain the compound of formula XIV, optionally, the ring closure reaction comprises reacting the compound XVI with methanesulfonyl chloride in the presence of a non-nucleophilic base, and optionally, the non-nucleophilic base is a tertiary amine; and / or the reaction is carried out at about -5 °C to about 5 °C, the method according to claim 12.

14. The compound of formula XV is further reacted with H in the presence of a Pd / C catalyst to obtain the compound of formula XIV, according to the method of claim 13. ２ The method according to claim 13, further comprising reacting with to obtain the compound of formula XIV.

15. A method for preparing a compound of formula I or a salt thereof, comprising 【Chemical 17】 converting the compound of formula IX into 【Chemical Formula 18】 the compound of formula I.

16. converting the compound of formula IX into the compound of formula I comprises reacting the compound of formula IX with an acid anhydride or an acid chloride to obtain a compound of formula VIII, 【Chemical Formula 19】 In the formula, OR is OC(=O)-Z, OC(=O)OZ, OC(=O)CH=CH-Z, or OP(=O)Z ２ where Z is unsubstituted aryl, or aryl substituted by CN, halo, NO ２ and may also be a short-chain alkyl, alkoxy, haloalkyl, or haloalkoxy group, said short chain containing 1, 2, 3, or 4 carbon atoms optionally, Z is a C1-C4 alkyl or C1-C4 haloalkyl group; alternatively, Z is phenyl or naphthyl, the method according to claim 15.

17. further comprising reacting the compound of formula VIII with a cyanating agent to obtain a compound of formula VII 【Chemical 20】 and, optionally, the cyanating agent is selected from the group consisting of trimethylsilyl cyanide, diethylaluminum cyanide, KCN, NaCN, TBACN, HCN; alternatively, optionally, the cyanating agent is trimethylsilyl cyanide; and / or, the reaction between the compound VIII and the cyanating agent is carried out in the presence of a Lewis acid, optionally, the Lewis acid is selected from the group consisting of boron trifluoride ethyl etherate (BF3OEt2), TiCl4, InCl3, AgSbF6, iodine, ZnBr2, Al(O iPr)3, MgCl2, Mn(acac)2, MnCl2, TMSOTf, and SnCl4; alternatively, optionally, the Lewis acid is BF3OEt2; and / or, the reaction between the compound VIII and the cyanating agent is carried out in a solvent comprising toluene, dichloromethane, 2-methyl THF, acetonitrile, methanol, 1,2-dichloroethane, nitromethane, or a mixture thereof, the method according to claim 16.

18. further comprising hydrolyzing the compound of formula VII to obtain the compound of formula III 【Chemical 21】 and, optionally, the hydrolysis of the cyano compound is enzymatically hydrolyzed using nitrilase; and / or, the hydrolysis is carried out in a solvent comprising ethanol, methanol, 1-propanol, 2-propanol, dioxane, water, THF, or a mixture thereof; and / or, the hydrolysis of the cyano compound is carried out at about 25 to about 75 °C, about 30 to about 70 °C, about 35 to about 65 °C, about 40 to about 60 °C, about 45 to about 60 °C, about 50 to about 60 °C, or about 55 °C, the method according to claim 17.

19. the converting the compound of formula IX to the compound of formula I comprises preparing a compound of formula IV 【Chemical 22】 the method according to claim 15.

20. Converting the compound of formula IX to the compound of formula I involves reacting the compound of formula III or the compound of formula IV with a chlorinating agent to obtain a compound of formula V, 【Chemical 23】 In the compound of formula V, the parentheses around the compound indicate that the compound of formula V is not isolated, Optionally, the chlorinating agent is selected from the group consisting of phosgene, thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, isobutyl chloroformate (IBCF), pivaloyl chloride (PivCl), and diphenylphosphinic acid chloride (DPPCl); or the chlorinating agent is phosgene, oxalyl chloride, or thionyl chloride, according to the method of claim 15.

21. Converting the compound of formula IX to the compound of formula I further involves reacting the compound of formula V with a compound of formula VI to 【Chemical 24】 obtain a compound of formula II 【Chemical 25】 according to the method of claim 15.

22. Converting the compound of formula IX to the compound of formula I further involves reacting the compound of formula II with ammonia to obtain the compound of formula I, Optionally, the ammonia is in the form of a solution of ammonia in a solvent, ammonia gas in gaseous form bubbled into the reaction mixture, or ammonia in the form of ammonium hydroxide or ammonium salt generated in situ, and optionally, the in situ generation of ammonia involves reacting ammonium hydroxide or the ammonium salt with an acid; and / or reacting the compound of formula II with ammonia is carried out in a solvent, and optionally, the solvent includes methanol, ethanol, IPA, MeCN, THF, water, or a mixture thereof, according to the method of claim 21.

23. The method of claim 15 further includes recrystallizing the compound of formula I from a solvent system containing acetone to obtain the compound of formula I as a solid, Optionally, the solvent system includes acetone and water, according to the method of claim 15.

24. Reducing the compound of formula X with 【Chemical 26】 a reducing agent to obtain the compound of formula IX, Optionally, The reducing agent is selected from the group consisting of diisobutylaluminum hydride, Red-Al, NaBH4 / BF3, a titanocene containing polymethylhydrosiloxane, and phenylsilane, or the reducing agent is diisobutylaluminum hydride; and / or, The reduction of the compound of formula X is carried out in an organic solvent, and optionally, the solvent contains toluene, dichloromethane, 2-methyl THF, THF, TFT, MTBE, CPME, heptane, or a mixture thereof; and / or, The reduction of the compound of formula X is carried out at about -78 °C to about 0 °C, about -60 °C to about 0 °C, about -50 °C to about -10 °C, about 40 °C to about -10 °C, about 30 °C to about -10 °C, about -30 °C to about -15 °C, about 25 °C to about -15 °C, or about -20 °C; and / or, The reduction reaction is carried out in the presence of CuCl, CuI, CuTol, CuBr, CuF, Cu(II)Cl, DMAP, 2,6-lutidine, LiI, or pyridine, the method according to claim 15.

25. Performing asymmetric hydrogenation of a compound of formula XI, 【Chemical 27】 Further comprising obtaining a compound of formula X, Optionally, The asymmetric hydrogenation is carried out in the presence of a hydrogenation catalyst, and optionally, the catalyst is selected from the group consisting of Pd / C, Pd / Al2O3, Pt / C, Ni (Raney), Co (Raney), Rh / C, Ir / C, Ru / C, Pd(OH)2, homogeneous chiral Ru and Rh; and / or, The asymmetric hydrogenation is carried out using a hydrogen source, and optionally, the hydrogen source is selected from the group consisting of H2 gas, NiCl2 / NaBH4 in methanol, and Et3SiH; and / or, The asymmetric hydrogenation is carried out in the presence of H2 gas using Pd / C as a catalyst; and / or, The asymmetric hydrogenation reaction is carried out at about 20 to 40 bar in an organic solvent or a solvent mixture, and optionally, the solvent contains IPA, EtOAc, MeOH, nBuOH, THF, MTBE, CPME, IPAc, nBuAc, toluene, ethanol, or a mixture thereof; and / or, The method according to claim 24, wherein the asymmetric hydrogenation reaction is carried out in a reaction mixture containing TFA, AcOH, H₂SO₄, H₃PO₄, MSA, Cs₂CO₃, CuCl, MgF₂, LiBr, CsF, ZnI, LiOTf, imidazole, KF, Bu₄NOAc, or NH₄BF₄.

26. The compound of formula XIII is 【Chemical 28】 esterified with the compound of formula XII to 【Chemical 29】 further comprising obtaining the compound of formula XI, optionally, the esterification reaction between the compound of formula XII and the compound of formula XIII is carried out in the presence of a coupling agent or a chlorinating agent, and optionally, the coupling agent is selected from the group consisting of CDI and T3P; and / or the chlorinating agent converts the compound of formula XIII into an acid chloride, which is not isolated before reacting with the compound of formula XII, and optionally, the chlorinating agent is selected from oxalyl chloride and thionyl chloride, the method according to claim 25.

27. A method for preparing a compound of formula I or a salt thereof, comprising 【Chemical 30】 converting the compound of formula XI into 【Chemical 31】 the compound of formula I.

28. The converting of the compound of formula XI into the compound of formula I comprises performing asymmetric hydrogenation of the compound of formula XI to obtain a compound of formula X 【Chemical 32】 the method according to claim 27.

29. The converting of the compound of formula XI into the compound of formula I further comprises reducing the compound of formula X with a reducing agent to obtain a compound of formula IX 【Chemical 33】 and optionally, optionally, the reducing agent is selected from the group consisting of diisobutylaluminum hydride, Red-Al, NaBH₄ / BF₃, a titanocene containing polymethylhydrosiloxane, and phenylsilane, and optionally, the reducing agent is diisobutylaluminum hydride; and / or the reducing of the compound of formula X is carried out in an organic solvent, and optionally, the solvent comprises toluene, dichloromethane, 2-methyl THF, THF, TFT, MTBE, CPME, heptane, or a mixture thereof; and / or the reducing of the compound of formula X is carried out at about -78°C to about 0°C, about -60°C to about 0°C, about -50°C to about -10°C, about 40°C to about -10°C, about 30°C to about -10°C, about -30°C to about -15°C, about 25°C to about -15°C, or about -20°C; and / or The method according to claim 28, wherein the reduction reaction is carried out in the presence of CuCl, CuI, CuTol, CuBr, CuF, Cu(II)Cl, DMAP, 2,6-lutidine, LiI, or pyridine.

30. Converting the compound of formula XI to the compound of formula I is carried out by further reacting the compound of formula IX with an acid anhydride or acid chloride to obtain a compound of formula VIII, 【Chemical 34】 wherein OR is OC(=O)-Z, OC(=O)OZ, OC(=O)CH=CH-Z, or OP(=O)Z ２ wherein Z is unsubstituted aryl, or aryl substituted by CN, halo, NO ２ and may also be short-chain alkyl, alkoxy, haloalkyl, or haloalkoxy groups, said short-chain containing 1, 2, 3, or 4 carbon atoms, optionally, Z is a C1-C4 alkyl or C1-C4 haloalkyl group; or Z is phenyl or naphthyl, the method according to claim 29.

31. The method further includes reacting the compound of formula VIII with a cyanating agent to obtain a compound of formula VII 【Chemical 35】 and, optionally, the cyanating agent is selected from the group consisting of trimethylsilyl cyanide, diethylaluminum cyanide, KCN, NaCN, TBACN, HCN, and optionally, the cyanating agent is trimethylsilyl cyanide; and / or the reaction between the compound VIII and the cyanating agent is carried out in the presence of a Lewis acid, and optionally, the Lewis acid is selected from the group consisting of boron trifluoride ethyl etherate (BF3OEt2), TiCl4, InCl3, AgSbF6, iodine, ZnBr2, Al(O iPr)3, MgCl2, Mn(acac)2, MnCl2, TMSOTf, and SnCl4, and optionally, the Lewis acid is BF3OEt2; and / or the reaction between the compound VIII and the cyanating agent is carried out in a solvent containing toluene, dichloromethane, 2-methyl THF, acetonitrile, methanol, 1,2-dichloroethane, nitromethane, or a mixture thereof, the method according to claim 30.

32. The method further includes hydrolyzing the cyano compound of formula VII to obtain a compound of formula III 【Chemical Formula 36】 and, optionally, the hydrolysis of the cyano compound is enzymatically hydrolyzed using nitrilase; and / or the hydrolysis is carried out in a solvent containing ethanol, methanol, 1-propanol, 2-propanol, dioxane, water, THF, or a mixture thereof; and / or The method according to claim 31, wherein the hydrolysis of the cyano compound is carried out at about 25 to about 75 °C, about 30 to about 70 °C, about 35 to about 65 °C, about 40 to about 60 °C, about 45 to about 60 °C, about 50 to about 60 °C, or about 55 °C.

33. The method according to claim 29, wherein converting the compound of formula IX to the compound of formula I comprises preparing a compound of formula IV. 【Chemical 37】

34. Converting the compound of formula IX to the compound of formula I comprises reacting the compound of formula III or the compound of formula IV with a chlorinating agent to obtain a compound of formula V, wherein in the compound of formula V, the parentheses around the compound indicate that the compound of formula V is not isolated, and optionally, the chlorinating agent is selected from the group consisting of phosgene, thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, isobutyl chloroformate (IBCF), pivaloyl chloride (PivCl), and diphenylphosphinic acid chloride (DPPCl), and optionally, the chlorinating agent is phosgene, oxalyl chloride, or thionyl chloride. 【Chemical Formula 38】 Optionally,

35. The method according to claim 34, wherein converting the compound of formula IX to the compound of formula I further comprises reacting the compound of formula V with a compound of formula VI to obtain a compound of formula II. 【Chemical Formula 39】 【Chemical Formula 40】

36. The method according to claim 35, wherein converting the compound of formula IX to the compound of formula I further comprises reacting the compound of formula II with ammonia to obtain the compound of formula I, and optionally, the ammonia is in the form of a solution of ammonia in a solvent, ammonia gas in a gaseous form that is bubbled into the reaction mixture, or ammonia in the form of ammonium hydroxide or an ammonium salt that is generated in situ, and optionally, the in situ generation of ammonia comprises reacting ammonium hydroxide or the ammonium salt with an acid; and / or the reaction of the compound of formula II with ammonia is carried out in a solvent or a solvent mixture, and optionally, the solvent comprises methanol, ethanol, IPA, MeCN, THF, water, or a mixture thereof; and / or the reaction of the compound of formula II with ammonia is carried out in the presence of methanol or ethanol. Optionally,

37. The method further comprises recrystallizing the compound of formula I from a solvent system containing acetone to obtain the compound of formula I as a solid. The method according to claim 27, wherein optionally, the solvent system contains acetone and water.

38. The method further comprises coupling a compound of formula XIII 【Chemical 41】 with a compound of formula XII to obtain 【Chemical 42】 the compound of formula XI. Optionally, the coupling reaction between the compound of formula XII and the compound of formula XIII is carried out in the presence of a coupling agent or a chlorinating agent, and optionally, the coupling agent is selected from the group consisting of CDI and T3P; or the chlorinating agent converts the compound of formula XIII into an acid chloride, which is not isolated before reacting with the compound of formula XII, and optionally, the chlorinating agent is selected from oxalyl chloride and thionyl chloride. The method according to claim 28.

39. A compound of the following formula 【Chemical Formula 43】

40. A compound having the following formula as claimed in claim 39. 【Chemical 44】

41. A compound having the following formula as claimed in claim 39. 【Chemical 45】

42. A compound of formula VII

43. 【Chemical Formula 46】 A compound of the following formula ​ ​ 【Chemical 47】 ​

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