Process for producing pyridazinone compounds

Abstract

A method for producing a pyridazinone compound useful for the treatment of Duchenne muscular dystrophy using the Suzuki cross-coupling reaction is disclosed herein. The present disclosure generally relates to a method for producing a compound of Formula 1 such as 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound I). Compound I has been shown to treat neuromuscular conditions by selective inhibition of fast fiber skeletal muscle myosin.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 340,871, filed May 11, 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] background Duchenne muscular dystrophy (DMD) is a genetic disorder that affects skeletal muscle and is characterized by progressive muscle degeneration and weakness. There remains a need for treatments that reduce muscle breakdown in patients with neuromuscular conditions such as DMD. Summary of the Invention [Means for solving the problem]

[0003] overview Methods for making compounds for treating DMD are described herein.

[0004] Formula 1: [ka] (In the formula, X 1 is a halogen, R 1 is C1-C6 haloalkyl) 1. A process for the preparation of a compound of formula (I), Under coupling conditions, in a suitable solvent, in the presence of a metal catalyst and a suitable base, a compound of formula 2: [ka] (In the formula, R 1 is C1-C6 haloalkyl, B is selected from boronic acids and boronic esters with a compound of formula 3: [ka] (In the formula, X 1 is a halogen, Y is a leaving group. to obtain a compound of formula 1 Disclosed herein is a process comprising:

[0005] Formula 2: [ka] (In the formula, R 1 is C1-C6 haloalkyl, B is selected from boronic acids and boronic esters 1. A process for the preparation of a compound of formula (I), In a suitable solvent, in the presence of a metal catalyst and a suitable base, a compound of formula 6: [ka] (In the formula, R 1 is C1-C6 haloalkyl, X 2 is a halogen) with a boron compound, wherein the boron compound contains a boron-boron bond or a boron-hydrogen bond, to obtain a compound of formula 2 Disclosed herein is a process comprising: DETAILED DESCRIPTION OF THE INVENTION

[0006] Detailed Description The present disclosure generally relates to methods of making compounds of Formula 1, such as 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound I). Compound I has been shown to treat neuromuscular conditions through the selective inhibition of fast fiber skeletal muscle myosin.

[0007] Skeletal muscle is primarily composed of two types of fibers: slow-twitch fibers (i.e., type I) and fast-twitch fibers (i.e., type II). Within each muscle, the two types of fibers are arranged in a mosaic-like arrangement, with the fiber type composition varying across different muscles and at various points in growth and development. Slow-twitch fibers have superior aerobic energy-generating capacity. Slow-twitch fibers have a lower contraction rate but are more resistant to fatigue. Slow-twitch fibers typically contain higher concentrations of mitochondria and myoglobin than fast-twitch fibers and are surrounded by more capillaries than fast-twitch fibers. Slow-twitch fibers contract at a slower rate and generate less force than fast-twitch fibers due to lower myosin ATPase activity, but they can maintain contractile function for longer periods, such as during stabilization, postural control, and endurance exercise.

[0008] Fast-twitch fibers in humans are further divided into two main fiber types (type IIa, IIx / d) depending on the specific fast skeletal muscle myosin they express. A third type of fast fiber (type IIb) exists in other mammals but is rarely found in human muscles. Fast-twitch fibers have excellent anaerobic energy-generating capacity and can generate large amounts of tension for short periods of time. Fast-twitch fibers typically have lower concentrations of mitochondria, myoglobin, and capillaries than slow-twitch fibers and therefore can fatigue more quickly. Fast-twitch muscles generate the force required for energy and resistance activities more quickly.

[0009] Because the heart shares some structural components (such as type I myosin) with type I skeletal muscle fibers, inhibitors of skeletal muscle myosin that are not selective for type II fibers may lead to excessive inhibition of skeletal muscle contraction, including respiratory function, and undesirable inhibition of cardiac activity. Without wishing to be bound by a particular mechanistic theory, the present disclosure provides manufacturing protocols and intermediates for producing selective inhibitors of fast-fiber skeletal muscle myosin as a treatment option for DMD and other neuromuscular conditions. Targeted inhibition of type II skeletal muscle myosin can reduce skeletal muscle contraction while minimizing the impact on a subject's daily activities. Preparation of Compound I

[0010] Disclosed herein are novel methods for the synthesis of compounds of Formula 1, such as Compound I. In some embodiments, compounds of Formula 1 are synthesized according to Scheme 1. Scheme 1. Summary of the preparation of compounds of formula 1 [ka]

[0011] Briefly, in some embodiments, compounds of formula 4 and formula 5 are coupled to form formula 3. In some embodiments, a compound of formula 7 is treated with an alcohol of formula 8 to produce a compound of formula 6. In some embodiments, a compound of formula 6 is boronated with a suitable boronating agent under coupling conditions to form a compound of formula 2. In some embodiments, a compound of formula 3 is cross-coupled with a compound of formula 2 under coupling conditions to produce a compound of formula 1. In some embodiments, a compound of formula 2 is produced in situ and further reacted with a compound of formula 3 under coupling conditions to form a compound of formula 1. In some embodiments, a compound of formula 2 is produced, isolated, and then further reacted with a compound of formula 3 under coupling conditions to form a compound of formula 1.

[0012] As disclosed herein, the variables in Scheme 1 are defined as follows: R1 is C1-C6 haloalkyl, and X 1 is a halogen, and X 2 is a halogen, and X 3 is a halogen, Y is a leaving group, and B is selected from boronic acids and boronic esters.

[0013] In some embodiments, R 1 is C1-C3 haloalkyl. In some embodiments, R 1 is selected from -CF, -CHF, -CHF, -CHCF, -CHCHF, and -CHCHF. In some embodiments, R 1 is selected from -CF, -CHF, -CHCF, and -CHCHF. In some embodiments, R 1 is selected from —CHF and —CHCF. In some embodiments, R 1 is -CH2CF3.

[0014] In some embodiments, X 1 is selected from -F, -Cl, and -Br. 1 is selected from -Cl and -Br. 1 is selected from -F and -Cl. 1 is -F. In some embodiments, X 1 is —Cl. In some embodiments, X 1 is -Br.

[0015] In some embodiments, X 2 is selected from -Cl and -Br. 2 is —Cl. In some embodiments, X 2 is -Br.

[0016] In some embodiments, X 3 is selected from -Cl and -Br. 3 is —Cl. In some embodiments, X 3is -Br.

[0017] In some embodiments, Y is selected from halogen and pseudohalides. In some embodiments, Y is selected from halogen, -OTf, -OTs, and -OMs. In some embodiments, Y is selected from halogen and -OTf. In some embodiments, Y is selected from -Cl, -Br, and -I. In some embodiments, Y is selected from -Cl and -Br. In some embodiments, Y is -Cl. In some embodiments, Y is -Br. In some embodiments, Y is -I.

[0018] In some embodiments, B is [ka] In some embodiments, B is selected from: [ka] In some embodiments, B is selected from: [ka] In some embodiments, B is selected from: [ka] In some embodiments, B is [ka] is.

[0019] In some embodiments, the compound of Formula 1 is Compound I. In some embodiments, the compound of Formula 2 is Compound II. In some embodiments, the compound of Formula 3 is Compound III. In some embodiments, the compound of Formula 4 is Compound IV. In some embodiments, the compound of Formula 5 is Compound V. In some embodiments, the compound of Formula 6 is Compound VI. In some embodiments, the compound of Formula 7 is Compound VII. In some embodiments, the compound of Formula 8 is CF3CH2OH. Compounds I-VII are illustrated below. [ka]

[0020] In some embodiments, the isolated yield of the compound of Formula 3 in Step I is about 50% to about 95%. In some embodiments, the isolated yield of the compound of Formula 3 in Step I is about 50% to about 55%, about 50% to about 65%, about 50% to about 70%, about 50% to about 72%, about 50% to about 74%, about 50% to about 76%, about 50% to about 78%, about 50% to about 80%, about 50% to about 85%, about 50% to about 90%, about 50% to about 95%, about 55% to about 65%, about 55% to about 70%, about 55% to about 72%, about 55% ~ about 74%, about 55% to about 76%, about 55% to about 78%, about 55% to about 80%, about 55% to about 85%, about 55% to about 90%, about 55% to about 95%, about 65% to about 70%, about 65% to about 72%, about 65% to about 74%, about 65% to about 76%, about 65% to about 78%, about 65% to about 80%, about 65% to about 85%, about 65% to about 90%, about 65% to about 95%, about 70% to about 72%, about 70% to about 74 %, about 70% to about 76%, about 70% to about 78%, about 70% to about 80%, about 70% to about 85%, about 70% to about 90%, about 70% to about 95%, about 72% to about 74%, about 72% to about 76%, about 72% to about 78%, about 72% to about 80%, about 72% to about 85%, about 72% to about 90%, about 72% to about 95%, about 74% to about 76%, about 74% to about 78%, about 74% to about 80%, about 74% to about 85%, about 7 4% to about 90%, about 74% to about 95%, about 76% to about 78%, about 76% to about 80%, about 76% to about 85%, about 76% to about 90%, about 76% to about 95%, about 78% to about 80%, about 78% to about 85%, about 78% to about 90%, about 78% to about 95%, about 80% to about 85%, about 80% to about 90%, about 80% to about 95%, about 85% to about 90%, about 85% to about 95%, or about 90% to about 95%. In some embodiments, the isolated yield of the compound of Formula 3 in Step I is about 50%, about 55%, about 65%, about 70%, about 72%, about 74%, about 76%, about 78%, about 80%, about 85%, about 90%, or about 95%. In some embodiments, the isolated yield of the compound of Formula 3 in Step I is at least about 50%, about 55%, about 65%, about 70%, about 72%, about 74%, about 76%, about 78%, about 80%, about 85%, or about 90%.In some embodiments, the isolated yield of the compound of Formula 3 in Step I is at most about 55%, about 65%, about 70%, about 72%, about 74%, about 76%, about 78%, about 80%, about 85%, about 90%, or about 95%.

[0021] In some embodiments, the isolated yield of the compound of Formula 6 in Step II is about 70% to about 99%. In some embodiments, the isolated yield of the compound of Formula 6 in Step II is about 70% to about 80%, about 70% to about 90%, about 70% to about 91%, about 70% to about 92%, about 70% to about 93%, about 70% to about 94%, about 70% to about 95%, about 70% to about 96%, about 70% to about 97%, about 70% to about 98%, about 70% to about 99%, about 80% to about 90%, about 80% to about 91%, about 80% to about 92%, about 80% to about 93%. % to about 93%, about 80% to about 94%, about 80% to about 95%, about 80% to about 96%, about 80% to about 97%, about 80% to about 98%, about 80% to about 99%, about 90% to about 91%, about 90% to about 92%, about 90% to about 93%, about 90% to about 94%, about 90% to about 95%, about 90% to about 96%, about 90% to about 97%, about 90% to about 98%, about 90% to about 99%, about 91% to about 92%, about 91% to about 9 3%, about 91% to about 94%, about 91% to about 95%, about 91% to about 96%, about 91% to about 97%, about 91% to about 98%, about 91% to about 99%, about 92% to about 93%, about 92% to about 94%, about 92% to about 95%, about 92% to about 96%, about 92% to about 97%, about 92% to about 98%, about 92% to about 99%, about 93% to about 94%, about 93% to about 95%, about 93% to about 96%, about 93% to about 97%, about 93% to about 98%, about 93% to about 99%, about 94% to about 95%, about 94% to about 96%, about 94% to about 97%, about 94% to about 98%, about 94% to about 99%, about 95% to about 96%, about 95% to about 97%, about 95% to about 98%, about 95% to about 99%, about 96% to about 97%, about 96% to about 98%, about 96% to about 99%, about 97% to about 98%, about 97% to about 99%, or about 98% to about 99%. In some embodiments, the isolated yield of the compound of Formula 6 in Step II is about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the isolated yield of the compound of Formula 6 in Step II is at least about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, or about 98%.In some embodiments, the isolated yield of the compound of Formula 6 in Step II is at most about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%.

[0022] In some embodiments, the unisolated yield of the compound of Formula 6 in Step II is about 70% to about 99%. In some embodiments, the unisolated yield of the compound of Formula 6 in Step II is about 70% to about 80%, about 70% to about 90%, about 70% to about 91%, about 70% to about 92%, about 70% to about 93%, about 70% to about 94%, about 70% to about 95%, about 70% to about 96%, about 70% to about 97%, about 70% to about 98%, about 70% to about 99%, about 80% to about 90%, about 80% to about 91%, about 80% to about 92%, about 80% to about 93%, about 80% to about 94%, about 8 ... 0% to about 93%, about 80% to about 94%, about 80% to about 95%, about 80% to about 96%, about 80% to about 97%, about 80% to about 98%, about 80% to about 99%, about 90% to about 91%, about 90% to about 92%, about 90% to about 93%, about 90% to about 94%, about 90% to about 95%, about 90% to about 96%, about 90% to about 97%, about 90% to about 98%, about 90% to about 99%, about 91% to about 92%, about 91% to about 9 3%, about 91% to about 94%, about 91% to about 95%, about 91% to about 96%, about 91% to about 97%, about 91% to about 98%, about 91% to about 99%, about 92% to about 93%, about 92% to about 94%, about 92% to about 95%, about 92% to about 96%, about 92% to about 97%, about 92% to about 98%, about 92% to about 99%, about 93% to about 94%, about 93% to about 95%, about 93% to about 96%, about 93% to about 97%, about 93% to about 98%, about 93% to about 99%, about 94% to about 95%, about 94% to about 96%, about 94% to about 97%, about 94% to about 98%, about 94% to about 99%, about 95% to about 96%, about 95% to about 97%, about 95% to about 98%, about 95% to about 99%, about 96% to about 97%, about 96% to about 98%, about 96% to about 99%, about 97% to about 98%, about 97% to about 99%, or about 98% to about 99%. In some embodiments, the unisolated yield of the compound of Formula 6 in Step II is about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the unisolated yield of the compound of Formula 6 in Step II is at least about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, or about 98%.In some embodiments, the unisolated yield of the compound of Formula 6 in Step II is at most about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%.

[0023] In some embodiments, the isolated yield of the compound of Formula 2 in Step III is about 50% to about 85%. In some embodiments, the isolated yield of the compound of Formula 2 in Step III is about 50% to about 55%, about 50% to about 60%, about 50% to about 62%, about 50% to about 64%, about 50% to about 66%, about 50% to about 68%, about 50% to about 70%, about 50% to about 73%, about 50% to about 75%, about 50% to about 80%, about 50% to about 85%, about 55% to about 60%, about 55% to about 62%, about 55% to about 64%, about 50% to about 68%. 5% to about 66%, about 55% to about 68%, about 55% to about 70%, about 55% to about 73%, about 55% to about 75%, about 55% to about 80%, about 55% to about 85%, about 60% to about 62%, about 60% to about 64%, about 60% to about 66%, about 60% to about 68%, about 60% to about 70%, about 60% to about 73%, about 60% to about 75%, about 60% to about 80%, about 60% to about 85%, about 62% to about 64%, about 62% to about 6 6%, about 62% to about 68%, about 62% to about 70%, about 62% to about 73%, about 62% to about 75%, about 62% to about 80%, about 62% to about 85%, about 64% to about 66%, about 64% to about 68%, about 64% to about 70%, about 64% to about 73%, about 64% to about 75%, about 64% to about 80%, about 64% to about 85%, about 66% to about 68%, about 66% to about 70%, about 66% to about 73%, about 66% to about 75%, about 66% to about 80%, about 66% to about 85%, about 68% to about 70%, about 68% to about 73%, about 68% to about 75%, about 68% to about 80%, about 68% to about 85%, about 70% to about 73%, about 70% to about 75%, about 70% to about 80%, about 70% to about 85%, about 73% to about 75%, about 73% to about 80%, about 73% to about 85%, about 75% to about 80%, about 75% to about 85%, or about 80% to about 85%. In some embodiments, the isolated yield of the compound of Formula 2 in Step III is about 50%, about 55%, about 60%, about 62%, about 64%, about 66%, about 68%, about 70%, about 73%, about 75%, about 80%, or about 85%. In some embodiments, the isolated yield of the compound of Formula 2 in Step III is at least about 50%, about 55%, about 60%, about 62%, about 64%, about 66%, about 68%, about 70%, about 73%, about 75%, or about 80%.In some embodiments, the isolated yield of the compound of Formula 2 in Step III is at most about 55%, about 60%, about 62%, about 64%, about 66%, about 68%, about 70%, about 73%, about 75%, about 80%, or about 85%.

[0024] In some embodiments, the isolated yield of the compound of Formula I in Step IV is about 60% to about 95%. In some embodiments, the isolated yield of the compound of Formula I in Step IV is about 60% to about 65%, about 60% to about 70%, about 60% to about 73%, about 60% to about 76%, about 60% to about 78%, about 60% to about 80%, about 60% to about 82%, about 60% to about 85%, about 60% to about 88%, about 60% to about 90%, about 60% to about 95%, about 65% to about 70%, about 65% to about 73%, about 65% to about 76%, about 65% to about 78%, about 65 ... % to about 78%, about 65% to about 80%, about 65% to about 82%, about 65% to about 85%, about 65% to about 88%, about 65% to about 90%, about 65% to about 95%, about 70% to about 73%, about 70% to about 76%, about 70% to about 78%, about 70% to about 80%, about 70% to about 82%, about 70% to about 85%, about 70% to about 88%, about 70% to about 90%, about 70% to about 95%, about 73% to about 76%, about 73% to about 7 8%, about 73% to about 80%, about 73% to about 82%, about 73% to about 85%, about 73% to about 88%, about 73% to about 90%, about 73% to about 95%, about 76% to about 78%, about 76% to about 80%, about 76% to about 82%, about 76% to about 85%, about 76% to about 88%, about 76% to about 90%, about 76% to about 95%, about 78% to about 80%, about 78% to about 82%, about 78% to about 85%, about 78% to about 88%, about 78% to about 90%, about 78% to about 95%, about 80% to about 82%, about 80% to about 85%, about 80% to about 88%, about 80% to about 90%, about 80% to about 95%, about 82% to about 85%, about 82% to about 88%, about 82% to about 90%, about 82% to about 95%, about 85% to about 88%, about 85% to about 90%, about 85% to about 95%, about 88% to about 90%, about 88% to about 95%, or about 90% to about 95%. In some embodiments, the isolated yield of the compound of Formula I in Step IV is about 60%, about 65%, about 70%, about 73%, about 76%, about 78%, about 80%, about 82%, about 85%, about 88%, about 90%, or about 95%. In some embodiments, the isolated yield of the compound of Formula I in Step IV is at least about 60%, about 65%, about 70%, about 73%, about 76%, about 78%, about 80%, about 82%, about 85%, about 88%, or about 90%.In some embodiments, the isolated yield of the compound of Formula I in Step IV is at most about 65%, about 70%, about 73%, about 76%, about 78%, about 80%, about 82%, about 85%, about 88%, about 90%, or about 95%. In some embodiments, the overall isolated yield of the compound of Formula 1 starting from the compound of Formula 7 is about 35% to about 65%. In some embodiments, the overall isolated yield of the compound of Formula 1 starting with the compound of Formula 7 is about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 35% to about 55%, about 35% to about 60%, about 35% to about 65%, about 40% to about 45%, about 40% to about 50%, about 40% to about 55%, about 40% to about 60%, about 40% to about 65%, about 45% to about 50%, about 45% to about 55%, about 45% to about 60%, about 45% to about 65%, about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 55% to about 60%, about 55% to about 65%, or about 60% to about 65%. In some embodiments, the total isolated yield of the compound of Formula 1 starting from the compound of Formula 7 is about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, or about 65%. In some embodiments, the total isolated yield of the compound of Formula 1 starting from the compound of Formula 7 is at least about 35%, about 40%, about 45%, about 50%, about 55%, or about 60%. In some embodiments, the total isolated yield of the compound of Formula 1 starting from the compound of Formula 7 is at most about 40%, about 45%, about 50%, about 55%, about 60%, or about 65%. Step I: Preparation of Compounds of Formula 3 [ka]

[0025] In some embodiments, compounds of formula 4 and formula 5 are reacted in a suitable solvent in the presence of a suitable base to provide a compound of formula 3.

[0026] In some embodiments, the compound of formula 5 is an acid salt. In some embodiments, the compound of formula 5 is a salt of HCl, HBr, HNO3, or H2SO4. In some embodiments, the compound of formula 5 is an HCl salt.

[0027] In some embodiments, a suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO, NaOAc, KOAc, KOMe, KOtBu, Ba(OH), LiCO, NaCO, KCO, KHCO, CsCO, NaPO, KPO, KF, and CsF. In some embodiments, a suitable base is selected from KOAc, NaHCO, and KCO. In some embodiments, a suitable base is selected from NaHCO, KCO, and CsCO. In some embodiments, a suitable base is KCO. In some embodiments, a suitable base is KCO. In some embodiments, a suitable base is CsCO.

[0028] In some embodiments, the suitable solvent is selected from N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropyl alcohol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl t-butyl ether, water, and any combination thereof. In some embodiments, the suitable solvent is selected from N-methyl-2-pyrrolidone, tetrahydrofuran, methyl t-butyl ether, tetrahydropyran, 1,4-dioxane, 2-methyltetrahydrofuran, water, and any combination thereof. In some embodiments, the suitable solvent is a combination of N-methyl-2-pyrrolidone and water.

[0029] In some embodiments, the reaction conditions include a stirring time of about 0.1 hours to about 24 hours. In some embodiments, the reaction conditions include a stirring time of about 0.1 hours to about 12 hours. In some embodiments, the reaction conditions include a stirring time of about 0.5 hours to about 5 hours. In some embodiments, the reaction conditions include a stirring time of about 3 hours to about 5 hours.

[0030] In some embodiments, the reaction conditions include a reaction temperature of about 10°C to about 50°C. In some embodiments, the reaction conditions include a reaction temperature of about 10°C to about 40°C. In some embodiments, the reaction conditions include a reaction temperature of about 15°C to about 30°C. In some embodiments, the reaction conditions include a reaction temperature of about 20°C to about 30°C. In some embodiments, the reaction conditions include a reaction temperature of about 20°C to about 25°C.

[0031] In some embodiments, the compound of Formula 3 is Compound III, the compound of Formula 4 is Compound IV, and the compound of Formula 5 is Compound V. In some embodiments, the molar ratio of Compound IV to Compound V is about 1.0:1.0 to about 1.0:1.5. In some embodiments, the molar ratio of Compound IV to Compound V is about 1.0:1.0 to about 1:1.2. In some embodiments, the molar ratio of Compound IV to Compound V is about 1.0:1.0. In some embodiments, the suitable base is K2CO3. In some embodiments, the molar ratio of Compound IV to the suitable base is about 1.0:5.0 to about 1.0:1.0. In some embodiments, the molar ratio of Compound IV to the suitable base is about 1.0:4.0 to about 1.0:2.0. In some embodiments, the molar ratio of Compound IV to the suitable base is about 1.0:3.0. Step II: Preparation of compounds of formula 6. [ka]

[0032] In some embodiments, a compound of formula 7 is reacted with an alcohol of formula 8 in the presence of a suitable base in a suitable solvent to provide a compound of formula 6.

[0033] In some embodiments, a suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO, NaOAc, KOAc, KOMe, KOtBu, Ba(OH), LiCO, NaCO, KCO, KHCO, CsCO, NaPO, KPO, KF, and CsF. In some embodiments, a suitable base is selected from KOAc, NaHCO, and KCO. In some embodiments, a suitable base is KCO.

[0034] In some embodiments, the suitable solvent is selected from N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropyl alcohol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl t-butyl ether, water, and any combination thereof. In some embodiments, the suitable solvent is selected from dimethylformamide, N-methyl-2-pyrrolidone, tetrahydrofuran, methyl t-butyl ether, tetrahydropyran, 1,4-dioxane, 2-methyltetrahydrofuran, water, and any combination thereof. In some embodiments, the suitable solvent is dimethylformamide.

[0035] In some embodiments, the reaction conditions include a stirring time of about 0.1 hours to about 24 hours. In some embodiments, the reaction conditions include a stirring time of about 0.1 hours to about 12 hours. In some embodiments, the reaction conditions include a stirring time of about 0.5 hours to about 5 hours. In some embodiments, the reaction conditions include a stirring time of about 3 hours to about 5 hours.

[0036] In some embodiments, the reaction conditions include a reaction temperature of about 10°C to about 50°C. In some embodiments, the reaction conditions include a reaction temperature of about 10°C to about 40°C. In some embodiments, the reaction conditions include a reaction temperature of about 15°C to about 30°C. In some embodiments, the reaction conditions include a reaction temperature of about 20°C to about 30°C. In some embodiments, the reaction conditions include a reaction temperature of about 20°C to about 25°C.

[0037] In some embodiments, the compound of Formula 6 is Compound VI, the compound of Formula 7 is Compound VII, and the compound of Formula 8 is CF3CH2OH. In some embodiments, the molar ratio of Compound VII to CF3CH2OH is about 1.0:1.0 to about 1.0:1.5. In some embodiments, the molar ratio of Compound VII to CF3CH2OH is about 1.0:1.0 to about 1:1.2. In some embodiments, the molar ratio of Compound VII to CF3CH2OH is about 1.0:1.1. In some embodiments, the suitable base is K2CO3. In some embodiments, the molar ratio of Compound VII to the suitable base is about 1.0:5.0 to about 1.0:1.0. In some embodiments, the molar ratio of Compound VII to the suitable base is about 1.0:4.0 to about 1.0:1.0. In some embodiments, the molar ratio of Compound VII to the suitable base is about 1.0:1.6.

[0038] In some embodiments, the compound of Formula 6 is not isolated before use in a subsequent step. In some embodiments, the compound of Formula 6 is carried over in the solution used in Step III. In some embodiments, water is removed from the solution of Formula 6 before use in Step III. Step III: Preparation of Compounds of Formula 2 [ka]

[0039] In some embodiments, the compound of formula 6 is boronated with a boron compound in the presence of a metal catalyst, a suitable base, in a suitable solvent to give the compound of formula 2.

[0040] In some embodiments, the boron compound comprises a boron-boron bond or a boron-hydrogen bond. [ka] In some embodiments, the boron compound is selected from: [ka] In some embodiments, the boron compound is selected from: [ka] In some embodiments, the boron compound is [ka] In some embodiments, the boron compound is [ka] In some embodiments, the boron compound is [ka] is.

[0041] In some embodiments, B is [ka] In some embodiments, B is selected from: [ka] In some embodiments, B is selected from: [ka] In some embodiments, B is selected from: [ka] In some embodiments, B is [ka] is.

[0042] In some embodiments, the metal catalyst is suitable for Suzuki cross-coupling. In some embodiments, the metal catalyst is a palladium catalyst. In some embodiments, the metal catalyst is selected from palladium(0) or palladium(II) catalysts. In some embodiments, the metal catalyst comprises palladium and one or more ligands. In some embodiments, the ligand is selected from N-heterocyclic carbenes, phosphines, phosphites, and bis-phosphines. In some embodiments, the ligand is selected from phosphines, phosphites, and bis-phosphines. In some embodiments, the ligand is selected from phosphines and bis-phosphines.

[0043] In some embodiments, the phosphine is selected from the group consisting of trimethylphosphine, tricyclohexylphosphine, tri-(tert-butyl)-phosphine, XantPhos, DPEPhos, XPhos, SPhos, JohnPhos, Cy-JohnPhos, Amphos, triphenylphosphine, methyldiphenylphosphine, Me4 t-BuXphos, t-BuXPhos, t-BuXantPhos, RuPhos, DavePhos, sSPhos, AdBrettPhos, BrettPhos, JackiePhos, t-BuBrettPhos, TrixiePos, t-BuDavePhos, t-BuMePhos, MePhos, PhDavePhos, VPhos, PhCPhos, XPhos-SO3Na, water-soluble SPhos, CPhos, EtCPhos, RockPhos, AlPhos, t-Bu In some embodiments, the phosphine is selected from tricyclohexylphosphine, XantPhos, DPEPhos, XPhos, SPhos, Cy-JohnPhos, Amphos, and PhDavePhos.

[0044] In some embodiments, the phosphite is selected from trimethyl phosphite and triphenyl phosphite.

[0045] In some embodiments, the bis-phosphine is selected from bis(diphenylphosphino)methane (dppm), 1,2′-bis(diphenylphosphino)ethane (dppe), 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,1′-bis(di-cyclohexylphosphino)ferrocene (dcypf), 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf), and 1,1′-bis(di-isopropylphosphino)ferrocene (dippf). In some embodiments, the bis-phosphine is selected from 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,1′-bis(di-cyclohexylphosphino)ferrocene (dcypf), 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf), and 1,1′-bis(di-isopropylphosphino)ferrocene (dippf).

[0046] In some embodiments, the metal catalyst is selected from Pd(dppf)Cl, Pd(Amphos)Cl, Pd(dcypf)Cl, Pd(dtbpf)Cl, Pd(XantPhos)Cl, PdCl(DPEPhos), Pd(PCy)Cl, XPhosPd G, and RuPhos-Pd-G. In some embodiments, the metal catalyst is Pd(dppf)Cl. In some embodiments, the metal catalyst is Pd(Amphos)Cl.

[0047] In some embodiments, the metal catalyst is a palladacycle. In some embodiments, the metal catalyst is formed in solution.

[0048] In some embodiments, the metal catalysts described herein have two monodentate phosphine ligands. In some embodiments, the active metal catalyst may not be coordinated to one of the monodentate phosphine ligands and / or may form a palladacycle. For example, the compound Pd(Amphos)Cl is assumed to encompass Pd(Amphos)Cl and / or an equivalent palladacycle.

[0049] In some embodiments, a suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO, NaOAc, KOAc, KOMe, KOtBu, Ba(OH), LiCO, NaCO, KCO, KHCO, CsCO, NaPO, KPO, KF, and CsF. In some embodiments, a suitable base is selected from KOAc, NaHCO, and KCO. In some embodiments, a suitable base is KCO. In some embodiments, a suitable base is KOAc.

[0050] In some embodiments, the suitable solvent is selected from N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropyl alcohol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl t-butyl ether, water, and any combination thereof. In some embodiments, the suitable solvent is selected from dimethylformamide, N-methyl-2-pyrrolidone, tetrahydrofuran, methyl t-butyl ether, tetrahydropyran, 1,4-dioxane, 2-methyltetrahydrofuran, water, and any combination thereof. In some embodiments, the suitable solvent is 2-methyltetrahydrofuran.

[0051] In some embodiments, the reaction conditions include a stirring time of about 0.5 hours to about 48 hours. In some embodiments, the reaction conditions include a stirring time of about 1 hour to about 36 hours. In some embodiments, the reaction conditions include a stirring time of about 5 hours to about 30 hours. In some embodiments, the reaction conditions include a stirring time of about 10 hours to about 20 hours.

[0052] In some embodiments, the reaction conditions include a reaction temperature of about 50°C to about 120°C. In some embodiments, the reaction conditions include a reaction temperature of about 60°C to about 110°C. In some embodiments, the reaction conditions include a reaction temperature of about 60°C to about 100°C. In some embodiments, the reaction conditions include a reaction temperature of about 70°C to about 90°C. In some embodiments, the reaction conditions include a reaction temperature of about 80°C to about 85°C.

[0053] In some embodiments, the compound of Formula 2 is Compound II, the compound of Formula 6 is Compound VI, and the boron compound is [ka] In some embodiments, the molar ratio of Compound VI to the boron compound is about 1.0:1.0 to about 1.0:1.5. In some embodiments, the molar ratio of Compound VI to the boron compound is about 1.0:1.0 to about 1:1.2. In some embodiments, the molar ratio of Compound VI to the boron compound is about 1.0:1.0. In some embodiments, the suitable base is KOAc. In some embodiments, the molar ratio of Compound VI to the suitable base is about 1.0:5.0 to about 1.0:1.0. In some embodiments, the molar ratio of Compound VI to the suitable base is about 1.0:4.0 to about 1.0:2.0. In some embodiments, the molar ratio of Compound VI to the suitable base is about 1.0:3.0. In some embodiments, the metal catalyst is Pd(dppf)2Cl2. In some embodiments, the metal catalyst is Pd(Amphos)2Cl. In some embodiments, the molar ratio of Compound VI to the metal catalyst is between about 1.0:0.0001 and about 1.0:0.1. In some embodiments, the molar ratio of Compound VI to the metal catalyst is between about 1.0:0.001 and about 1.0:0.05. In some embodiments, the molar ratio of Compound VI to the metal catalyst is between about 1.0:0.05 and about 1.0:0.04. In some embodiments, the molar ratio of Compound VI to the metal catalyst is between about 1.0:0.01 and about 1.0:0.02. In some embodiments, the molar ratio of Compound VI to the metal catalyst is about 1.0:0.015.

[0054] In some embodiments, water is removed from the solution of Formula 6 before adding the catalyst and boron compound. In some embodiments, after removing the water, the homocoupling impurity of Formula 6 is reduced. In some embodiments, the homocoupling impurity is reduced by about 1% to about 15%. In some embodiments, the homocoupling impurity is about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1% to about 6%, about 1% to about 7%, about 1% to about 8%, about 1% to about 9%, about 1% to about 10%, about 1% to about 15%, about 2% to about 3%, about 2% to about 4%, about 2% to about 5%, about 2% to about 6%, about 2% to about 7%, about 2% to about 8%, about 2% to about 9%, about 2% to about 10%, about 2% to about 15%, about 3% to about 4%, about 3% to about 5%, about 3% to about 6%, about 3% to about 7%, about 3% to about 8%, about 3% to about 9%, about 3% to about 10%, about 3% to about 15%, It decreases by about 4% to about 5%, about 4% to about 6%, about 4% to about 7%, about 4% to about 8%, about 4% to about 9%, about 4% to about 10%, about 4% to about 15%, about 5% to about 6%, about 5% to about 7%, about 5% to about 8%, about 5% to about 9%, about 5% to about 10%, about 5% to about 15%, about 6% to about 7%, about 6% to about 8%, about 6% to about 9%, about 6% to about 10%, about 6% to about 15%, about 7% to about 8%, about 7% to about 9%, about 7% to about 10%, about 7% to about 15%, about 8% to about 9%, about 8% to about 10%, about 8% to about 15%, about 9% to about 10%, about 9% to about 15%, or about 10% to about 15%. In some embodiments, homocoupling impurities are reduced by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, or about 15%. In some embodiments, homocoupling impurities are reduced by at least about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%. In some embodiments, homocoupling impurities are reduced by at most about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, or about 15%. [ka]

[0055] In some embodiments, water is removed from the solution of Formula 6 before adding the catalyst and boron compound. In some embodiments, removing water from the solution of Formula 6 improves the yield of the compound of Formula 2. In some embodiments, the yield is improved by about 1% to about 15%. In some embodiments, the yield is about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1% to about 6%, about 1% to about 7%, about 1% to about 8%, about 1% to about 9%, about 1% to about 10%, about 1% to about 15%, about 2% to about 3%, about 2% to about 4%, about 2% to about 5%, about 2% to about 6%, about 2% to about 7%, about 2% to about 8%, about 2% to about 9%, about 2% to about 10%, about 2% to about 15%, about 3% to about 4%, about 3% to about 5%, about 3% to about 6%, about 3% to about 7%, about 3% to about 8%, about 3% to about 9%, about 3% to about 10%, about 3% to about 15%, about 4% to about 5%, about 4% to about 6%, about 4% to about 7%, about 4% to about 8%, about 4% to about 9%, about 4% to about 10%, about 4% to about 15%, about 5% to about 6%, about 5% to about 7%, about 5% to about 8%, about 5% to about 9%, about 5% to about 10%, about 5% to about 15%, about 6% to about 7%, about 6% to about 8%, about 6% to about 9%, about 6% to about 10%, about 6% to about 15%, about 7% to about 8%, about 7% to about 9%, about 7% to about 10%, about 7% to about 15%, about 8% to about 9%, about 8% to about 10%, about 8% to about 15%, about 9% to about 10%, about 9% to about 15%, or about 10% to about 15% improvement. In some embodiments, the yield is improved by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, or about 15%. In some embodiments, the yield is improved by at least about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%. In some embodiments, the yield is improved by at most about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, or about 15%. Step IV: Preparation of Compounds of Formula 1 [ka]

[0056] In some embodiments, a compound of formula 2 is reacted with a compound of formula 3 in the presence of a metal catalyst, a suitable base, in a suitable solvent to provide a compound of formula 1.

[0057] In some embodiments, the metal catalyst is suitable for Suzuki cross-coupling. In some embodiments, the metal catalyst is a palladium catalyst. In some embodiments, the metal catalyst is selected from palladium(0) or palladium(II) catalysts. In some embodiments, the metal catalyst comprises palladium and one or more ligands. In some embodiments, the ligand is selected from N-heterocyclic carbenes, phosphines, phosphites, and bis-phosphines. In some embodiments, the ligand is selected from phosphines, phosphites, and bis-phosphines. In some embodiments, the ligand is selected from phosphines and bis-phosphines.

[0058] In some embodiments, the phosphine is selected from the group consisting of trimethylphosphine, tricyclohexylphosphine, tri-(tert-butyl)-phosphine, XantPhos, DPEPhos, XPhos, SPhos, JohnPhos, Cy-JohnPhos, Amphos, triphenylphosphine, methyldiphenylphosphine, Me4 t-BuXphos, t-BuXPhos, t-BuXantPhos, RuPhos, DavePhos, sSPhos, AdBrettPhos, BrettPhos, JackiePhos, t-BuBrettPhos, TrixiePos, t-BuDavePhos, t-BuMePhos, MePhos, PhDavePhos, VPhos, PhCPhos, XPhos-SO3Na, water-soluble SPhos, CPhos, EtCPhos, RockPhos, AlPhos, t-Bu In some embodiments, the phosphine is selected from tricyclohexylphosphine, XantPhos, DPEPhos, XPhos, SPhos, Cy-JohnPhos, Amphos, and PhDavePhos. In some embodiments, the phosphine is Amphos.

[0059] In some embodiments, the phosphite is selected from trimethyl phosphite and triphenyl phosphite.

[0060] In some embodiments, the bis-phosphine is selected from bis(diphenylphosphino)methane (dppm), 1,2′-bis(diphenylphosphino)ethane (dppe), 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,1′-bis(di-cyclohexylphosphino)ferrocene (dcypf), 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf), and 1,1′-bis(di-isopropylphosphino)ferrocene (dippf). In some embodiments, the bis-phosphine is selected from 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,1′-bis(di-cyclohexylphosphino)ferrocene (dcypf), 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf), and 1,1′-bis(di-isopropylphosphino)ferrocene (dippf).

[0061] In some embodiments, the metal catalyst is selected from Pd(dppf)Cl, Pd(Amphos)Cl, Pd(dcypf)Cl, Pd(dtbpf)Cl, Pd(XantPhos)Cl, PdCl(DPEPhos), Pd(PCy)Cl, XPhosPd G, and RuPhos-Pd-G. In some embodiments, the metal catalyst is Pd(Amphos)Cl.

[0062] In some embodiments, the metal catalyst is a palladacycle. In some embodiments, the metal catalyst is formed in solution.

[0063] In some embodiments, a suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO, NaOAc, KOAc, KOMe, KOtBu, Ba(OH), LiCO, NaCO, KCO, KHCO, CsCO, NaPO, KPO, KF, and CsF. In some embodiments, a suitable base is selected from KOAc, NaHCO, and KCO. In some embodiments, a suitable base is KCO. In some embodiments, a suitable base is NaHCO.

[0064] In some embodiments, the suitable solvent is selected from N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropyl alcohol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl t-butyl ether, water, and any combination thereof. In some embodiments, the suitable solvent is selected from dimethylformamide, N-methyl-2-pyrrolidone, tetrahydrofuran, methyl t-butyl ether, tetrahydropyran, 1,4-dioxane, 2-methyltetrahydrofuran, water, and any combination thereof. In some embodiments, the suitable solvent is 2-methyltetrahydrofuran.

[0065] In some embodiments, B is [ka] In some embodiments, B is selected from: [ka] In some embodiments, B is selected from: [ka] In some embodiments, B is selected from: [ka] In some embodiments, B is [ka] is.

[0066] In some embodiments, the reaction conditions include a stirring time of about 0.5 hours to about 48 hours. In some embodiments, the reaction conditions include a stirring time of about 1 hour to about 36 hours. In some embodiments, the reaction conditions include a stirring time of about 5 hours to about 30 hours. In some embodiments, the reaction conditions include a stirring time of about 10 hours to about 20 hours.

[0067] In some embodiments, the reaction conditions include a reaction temperature of about 50°C to about 120°C. In some embodiments, the reaction conditions include a reaction temperature of about 60°C to about 110°C. In some embodiments, the reaction conditions include a reaction temperature of about 60°C to about 90°C. In some embodiments, the reaction conditions include a reaction temperature of about 60°C to about 80°C. In some embodiments, the reaction conditions include a reaction temperature of about 70°C to about 80°C.

[0068] In some embodiments, the compound of Formula 1 is Compound I, the compound of Formula 2 is Compound II, and the compound of Formula 3 is Compound III. In some embodiments, the molar ratio of Compound II to Compound III is about 1.0:1.0 to about 1.0:1.5. In some embodiments, the molar ratio of Compound II to Compound III is about 1.0:1.0 to about 1.0:1.2. In some embodiments, the molar ratio of Compound II to Compound III is about 1.0:1.0. In some embodiments, the metal catalyst is Pd(Amphos)2Cl2. In some embodiments, the molar ratio of Compound II to Metal Catalyst is between about 1.0:0.0001 and about 1.0:0.1. In some embodiments, the molar ratio of Compound II to Metal Catalyst is between about 1.0:0.001 and about 1.0:0.05. In some embodiments, the molar ratio of Compound II to Metal Catalyst is between about 1.0:0.05 and about 1.0:0.04. In some embodiments, the molar ratio of compound II to the metal catalyst is between about 1.0:0.01 and about 1.0:0.02. In some embodiments, the molar ratio of compound II to the metal catalyst is about 1.0:0.015. In some embodiments, the suitable base is NaHCO3. In some embodiments, the molar ratio of compound II to the suitable base is about 1.0:5.0 to about 1.0:1.0. In some embodiments, the molar ratio of compound II to the suitable base is about 1.0:3.0 to about 1.0:1.0. In some embodiments, the molar ratio of compound II to the suitable base is about 1.0:2.0.

[0069] In some embodiments, the compound of Formula 1 is recrystallized. In some embodiments, the compound of Formula 1 is recrystallized in a suitable solvent. In some embodiments, the suitable solvent is N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropyl alcohol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl t-butyl ether, water, and any combination thereof. In some embodiments, the suitable solvent is selected from dimethylformamide, N-methyl-2-pyrrolidone, tetrahydrofuran, methyl t-butyl ether, tetrahydropyran, 1,4-dioxane, 2-methyltetrahydrofuran, water, and any combination thereof. In some embodiments, the suitable solvent is 2-methyltetrahydrofuran. In some embodiments, the suitable solvent is isopropanol. Step IIIa and Step IVa: Short Preparation of Compounds of Formula 1 [ka]

[0070] In some embodiments, the compound of Formula 6 is reacted in situ with a boron compound in the presence of a metal catalyst and a suitable base in a suitable solvent to provide the compound of Formula 2. In situ, the compound of Formula 2 is reacted with a compound of Formula 3 in the presence of a metal catalyst and a suitable base in a suitable solvent to provide the compound of Formula 1.

[0071] In some embodiments, the boron compound comprises a boron-boron bond or a boron-hydrogen bond. [ka] In some embodiments, the boron compound is selected from: [ka] In some embodiments, the boron compound is selected from: [ka] In some embodiments, the boron compound is [ka] In some embodiments, the boron compound is [ka] In some embodiments, the boron compound is [ka] is.

[0072] In some embodiments, B is [ka] In some embodiments, B is selected from: [ka] In some embodiments, B is selected from: [ka] In some embodiments, B is selected from: [ka] In some embodiments, B is [ka] is.

[0073] In some embodiments, the metal catalyst is suitable for Suzuki cross-coupling. In some embodiments, the metal catalyst is a palladium catalyst. In some embodiments, the metal catalyst is selected from palladium(0) or palladium(II) catalysts. In some embodiments, the metal catalyst comprises palladium and one or more ligands. In some embodiments, the ligand is selected from N-heterocyclic carbenes, phosphines, phosphites, and bis-phosphines. In some embodiments, the ligand is selected from phosphines, phosphites, and bis-phosphines. In some embodiments, the ligand is selected from phosphines and bis-phosphines.

[0074] In some embodiments, the phosphine is selected from the group consisting of trimethylphosphine, tricyclohexylphosphine, tri-(tert-butyl)-phosphine, XantPhos, DPEPhos, XPhos, SPhos, JohnPhos, Cy-JohnPhos, Amphos, triphenylphosphine, methyldiphenylphosphine, Me4 t-BuXphos, t-BuXPhos, t-BuXantPhos, RuPhos, DavePhos, sSPhos, AdBrettPhos, BrettPhos, JackiePhos, t-BuBrettPhos, TrixiePos, t-BuDavePhos, t-BuMePhos, MePhos, PhDavePhos, VPhos, PhCPhos, XPhos-SO3Na, water-soluble SPhos, CPhos, EtCPhos, RockPhos, AlPhos, t-Bu In some embodiments, the phosphine is selected from tricyclohexylphosphine, XantPhos, DPEPhos, XPhos, SPhos, Cy-JohnPhos, Amphos, and PhDavePhos. In some embodiments, the phosphine is Amphos.

[0075] In some embodiments, the phosphite is selected from trimethyl phosphite and triphenyl phosphite.

[0076] In some embodiments, the bis-phosphine is selected from bis(diphenylphosphino)methane (dppm), 1,2′-bis(diphenylphosphino)ethane (dppe), 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,1′-bis(di-cyclohexylphosphino)ferrocene (dcypf), 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf), and 1,1′-bis(di-isopropylphosphino)ferrocene (dippf). In some embodiments, the bis-phosphine is selected from 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,1′-bis(di-cyclohexylphosphino)ferrocene (dcypf), 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf), and 1,1′-bis(di-isopropylphosphino)ferrocene (dippf).

[0077] In some embodiments, the metal catalyst is selected from Pd(dppf)Cl, Pd(Amphos)Cl, Pd(dcypf)Cl, Pd(dtbpf)Cl, Pd(XantPhos)Cl, PdCl(DPEPhos), Pd(PCy)Cl, XPhosPd G, and RuPhos-Pd-G. In some embodiments, the metal catalyst is Pd(Amphos)Cl. In some embodiments, the metal catalyst is Pd(dppf)Cl.

[0078] In some embodiments, the metal catalyst is a palladacycle. In some embodiments, the metal catalyst is formed in solution.

[0079] In some embodiments, a suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO, NaOAc, KOAc, KOMe, KOtBu, Ba(OH), LiCO, NaCO, KCO, KHCO, CsCO, NaPO, KPO, KF, and CsF. In some embodiments, a suitable base is selected from KOAc, NaHCO, and KCO. In some embodiments, a suitable base is KCO. In some embodiments, a suitable base is NaHCO. In some embodiments, a suitable base is KOAc.

[0080] In some embodiments, the suitable solvent is selected from N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropyl alcohol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl t-butyl ether, water, and any combination thereof. In some embodiments, the suitable solvent is selected from dimethylformamide, N-methyl-2-pyrrolidone, tetrahydrofuran, methyl t-butyl ether, tetrahydropyran, 1,4-dioxane, 2-methyltetrahydrofuran, water, and any combination thereof. In some embodiments, the suitable solvent is 2-methyltetrahydrofuran.

[0081] In some embodiments, the reaction conditions include a stirring time of about 0.5 hours to about 48 hours. In some embodiments, the reaction conditions include a stirring time of about 1 hour to about 36 hours. In some embodiments, the reaction conditions include a stirring time of about 5 hours to about 30 hours. In some embodiments, the reaction conditions include a stirring time of about 10 hours to about 20 hours.

[0082] In some embodiments, the reaction conditions include a reaction temperature of about 50°C to about 120°C. In some embodiments, the reaction conditions include a reaction temperature of about 60°C to about 110°C. In some embodiments, the reaction conditions include a reaction temperature of about 60°C to about 90°C. In some embodiments, the reaction conditions include a reaction temperature of about 60°C to about 80°C. In some embodiments, the reaction conditions include a reaction temperature of about 70°C to about 80°C.

[0083] In some embodiments, the compound of Formula 2 is Compound II, the compound of Formula 6 is Compound VI, and the boron compound is [ka] In some embodiments, the molar ratio of Compound VI to the boron compound is about 1.0:1.0 to about 1.0:1.5. In some embodiments, the molar ratio of Compound VI to the boron compound is about 1.0:1.0 to about 1.0:1.2. In some embodiments, the molar ratio of Compound VI to the boron compound is about 1.0:1.0. In some embodiments, the suitable base is KOAc. In some embodiments, the molar ratio of Compound VI to the suitable base is about 1.0:5.0 to about 1.0:1.0. In some embodiments, the molar ratio of Compound VI to the suitable base is about 1.0:4.0 to about 1.0:2.0. In some embodiments, the molar ratio of Compound VI to the suitable base is about 1.0:3.0. In some embodiments, the metal catalyst is Pd(dppf)2Cl2. In some embodiments, the molar ratio of Compound VI to the metal catalyst is between about 1.0:0.0001 and about 1.0:0.1. In some embodiments, the molar ratio of Compound VI to the metal catalyst is between about 1.0:0.001 and about 1.0:0.05. In some embodiments, the molar ratio of Compound VI to the metal catalyst is between about 1.0:0.05 and about 1.0:0.04. In some embodiments, the molar ratio of Compound VI to the metal catalyst is between about 1.0:0.01 and about 1.0:0.02. In some embodiments, the molar ratio of Compound VI to the metal catalyst is about 1.0:0.015.

[0084] In some embodiments, the compound of Formula 1 is Compound I, the compound of Formula 2 is Compound II, and the compound of Formula 3 is Compound III. In some embodiments, the molar ratio of Compound II to Compound III is about 1.0:1.0 to about 1.0:1.5. In some embodiments, the molar ratio of Compound II to Compound III is about 1.0:1.0 to about 1.0:1.2. In some embodiments, the molar ratio of Compound II to Compound III is about 1.0:1.0. In some embodiments, the metal catalyst is Pd(Amphos)2Cl2. In some embodiments, the molar ratio of Compound II to Metal Catalyst is between about 1.0:0.0001 and about 1.0:0.1. In some embodiments, the molar ratio of Compound II to Metal Catalyst is between about 1.0:0.001 and about 1.0:0.05. In some embodiments, the molar ratio of Compound II to Metal Catalyst is between about 1.0:0.05 and about 1.0:0.04. In some embodiments, the molar ratio of compound II to the metal catalyst is between about 1.0:0.01 and about 1.0:0.02. In some embodiments, the molar ratio of compound II to the metal catalyst is about 1.0:0.015. In some embodiments, the suitable base is NaHCO3. In some embodiments, the molar ratio of compound II to the suitable base is about 1.0:5.0 to about 1.0:1.0. In some embodiments, the molar ratio of compound II to the suitable base is about 1.0:3.0 to about 1.0:1.0. In some embodiments, the molar ratio of compound II to the suitable base is about 1.0:2.0.

[0085] In some embodiments, the compounds described herein are synthesized as outlined in the Examples. compound

[0086] In some embodiments, Formula 9: [ka] (In the formula, R 1 are -CF3, -CHF2, -CH2CF3 and -CH2CHF2, B is selected from boronic acids and boronic esters or a salt thereof.

[0087] In some embodiments, R 1 In some embodiments, B is -CHCF. [ka] In some embodiments, B is selected from: [ka] In some embodiments, the compound is selected from Compound II, as depicted below: [ka] is. MIDA Boronate

[0088] In some embodiments, methyliminodiacetic acid (MIDA) boronic ester is attached to the heteroaryl group prior to palladium-catalyzed transmetallation. For example, compound A below can be synthesized and utilized in place of compound II. [ka] Compound A can be synthesized from the reaction of BCl3, N-methyliminodiacetic acid and compound VI. Heavy metal scavengers

[0089] In some embodiments, a compound of Formula 1 (e.g., Compound I) or a compound of Formula 2 (e.g., Compound II) is further treated with a metal scavenger to remove residual palladium. In some embodiments, the metal scavenger comprises SiO, charcoal, an aqueous solution of L-cysteine, a Silicycle metal scavenger, Si-thiol, SiliaBond DMT, SiliaBond cysteine, or 3-mercaptopropylethylsulfide silica. In some embodiments, the ratio (w / w) of metal catalyst to scavenger is about 1:100, 1:50, 1:30, 1:25, 1:20, 1:15, 1:10, 1:5, 1:3, 1:2, or about 1:1.

[0090] In some of these embodiments, the palladium level is reduced to about 10 ppm, hi some of these embodiments, the palladium level is reduced sufficiently to be undetectable.

[0091] In some embodiments, the presence of residual heavy metal (e.g., palladium) impurities is determined by utilizing methods known in the art. In some embodiments, the presence of residual heavy metal (e.g., palladium) impurities is determined by using inductively coupled plasma mass spectrometry (ICP-MS). In some embodiments, the presence of residual heavy metal (e.g., palladium) impurities is determined by using ... <231> Heavy metals are determined by using the techniques described in Terms and Definitions

[0092] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0093] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. As used herein, any reference to "or" is intended to include "and / or" unless specifically stated otherwise.

[0094] As used herein, the term "about" refers, in some instances, to an amount that is approximately the stated amount.

[0095] As used herein, the term "about" refers to an amount that is closer to the stated amount by 10%, 5%, or 1%, including increments thereof.

[0096] As used herein, the term "about" in reference to percentages refers to amounts that are 10%, 5%, or 1% greater or less than the stated percentage, including increments thereof.

[0097] "Pharmaceutically acceptable," as used herein, refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the substance may be administered to an individual without causing undesired biological effects or deleterious interactions with any of the components contained in the composition.

[0098] The term “C x~y " or "C x ~C y " when used in connection with a chemical moiety such as haloalkyl, is intended to include groups containing x to y carbons in the chain. For example, the term "C 1~6 "Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain and branched-chain alkyl groups containing from 1 to 6 carbons.

[0099] The term "haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, e.g., trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the haloalkyl radical is optionally further substituted as described herein.

[0100] The term "halo" or alternatively "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0101] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent combined with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zuerich:Wiley-VCH / VHCA, 2002. Pharmaceutical salts are generally more soluble and rapidly dissolving than non-ionic species in gastric and intestinal fluids and are therefore useful in solid dosage forms. Furthermore, the solubility of pharmaceutical salts is often a function of pH, allowing for selective dissolution in one part of the gastrointestinal tract or another, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Similarly, salt-forming molecules can be in equilibrium with neutral forms, thereby modulating passage through biological membranes.

[0102] In some embodiments, pharmaceutically acceptable salts can be obtained by reacting the compounds disclosed herein with acid.In some embodiments, the compounds disclosed herein (i.e., free base form) are basic and react with organic or inorganic acid.Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecyl sulfuric acid; ethane-1,2-dicarboxylic acid; Sulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0103] In some embodiments, pharmaceutically acceptable salts can be obtained by reacting a compound disclosed herein with a base. In some embodiments, the compounds disclosed herein are acidic and react with a base. In such situations, the acidic protons of the compounds disclosed herein are replaced by metal ions, such as lithium, sodium, potassium, magnesium, calcium, or aluminum ions. In some cases, the compounds described herein coordinate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids, such as, but not limited to, arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, and lithium hydroxide. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0104] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms.In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and are formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in both unsolvated and solvated forms, as needed.

[0105] Therapeutic agents that can be administered to mammals, such as humans, must be prepared by following regulatory guidelines. These government-mandated guidelines are called Good Manufacturing Practice (GMP). GMP guidelines outline acceptable levels of contamination of active therapeutic agents, such as the amount of residual solvents in the final product. Preferred solvents are suitable for use in GMP facilities and are consistent with industrial safety concerns. Solvent classifications are defined, for example, in the International Conference on Harmonization (ICH) Technical Requirements for Registration of Pharmaceuticals for Human Use, "Impurities: Guidelines for Residual Solvents, Q3C(R3)," (November 2005).

[0106] Solvents are divided into three classes: Class 1 solvents are toxic and should be avoided; Class 2 solvents are solvents that should be limited to use during the manufacture of therapeutic agents; and Class 3 solvents are solvents that have low potential toxicity and pose a lower risk to human health. Data on Class 3 solvents indicates that these solvents have low toxicity in acute or short-term studies and negative genotoxicity studies.

[0107] Class 1 solvents to be avoided include benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethene; and 1,1,1-trichloroethane.

[0108] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0109] Class 3 solvents with low toxicity include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydropyran, and tetrahydrofuran.

[0110] Residual solvents in active pharmaceutical ingredients (APIs) result from the manufacturing of the APIs. In some cases, the solvents are not completely removed by the actual manufacturing techniques. The appropriate selection of solvents for the synthesis of APIs can improve the yield or determine characteristics such as crystalline form, purity, and solubility. Therefore, the solvent is an important parameter in the synthesis process.

[0111] In some embodiments, the composition comprising Compound A comprises an organic solvent. In some embodiments, the composition comprising Compound A comprises a residual amount of an organic solvent. In some embodiments, the composition comprising Compound A comprises a residual amount of a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

[0112] In some embodiments, the composition comprising Compound A comprises a detectable amount of an organic solvent. In some embodiments, the organic solvent is a Class 3 solvent.

[0113] In other embodiments, the composition comprises Compound A, wherein the composition comprises less than about 1% detectable amount of solvent, wherein the solvent is selected from acetone, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, heptane, and 2-propanol. In further embodiments, the composition comprises Compound A, wherein the composition comprises a detectable amount of solvent that is less than about 5000 ppm. In further embodiments, the composition comprises Compound A, wherein the detectable amount of solvent is less than about 5000 ppm, less than about 4000 ppm, less than about 3000 ppm, less than about 2000 ppm, less than about 1000 ppm, less than about 500 ppm, or less than about 100 ppm. [Example]

[0114] The following illustrative examples are representative of embodiments of the methods described herein and are not intended to be limiting in any way. Example 1 Synthesis of 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound I) [ka] Step 1. Synthesis of 6-chloro-2-((5-fluoropyridin-3-yl)methyl)pyridazin-3(2H)-one (Compound III)

[0115] The preparation of compound III was completed using 0.570 kg (4.38 mol) of compound IV and compound V (0.788 kg, 4.32 mol, 0.99 equiv.) and K2CO3 (1.81 kg, 13.1 mol, 3 equiv.) in NMP / water. The reaction temperature increased from 20 °C to 34 °C during the water addition, and gas evolution (CO2 evolution) was observed during the K2CO3 addition, which was added over 10 min. HPLC analysis after 15 h revealed compound IV at less than 1% HPLC A (PDF). After filtering the inorganics from the reactor, the cake was washed with IPAc (10 vol.). The filtrate and washings were combined and washed with aqueous LiCl, and the layers were separated. The aqueous layer was back-extracted with IPAc (2 vol.). The organic layers were combined and washed with water. Layer separation was rapid and required less than 10 min. The final IPAc layer containing the product was filtered using a 0.45 micron filter cartridge and then concentrated to dryness on a Büchi rotary evaporator. The resulting semi-solid was treated with deionized water (10 volumes) in a Büchi bulb, stirred by rotating the distillation bulb under atmospheric pressure until a homogeneous slurry was obtained, and filtered. The filtered solid was dried on the filter funnel under reduced pressure under a nitrogen tent for several hours and then dried in a vacuum oven at 35°C until a constant weight was reached. After drying, a total of 817.5 g of compound III was isolated as a tan solid in 78% yield. The isolated compound III was found to be 97.8 A% pure by HPLC and 99% pure by weight by quantitative NMR analysis. The isolated compound III was found to be free of compound V. Step 2. Synthesis of 5-bromo-2-(2,2,2-trifluoroethoxy)pyrimidine (Compound VI)

[0116] The synthesis of compound VI was carried out in DMF at 19 °C using 20 g of compound VII, 1.6 equivalents of KCO, and 1.1 equivalents of 2,2,2-trifluoroethanol. The reaction required overnight (>18 hours) stirring to yield compound VI with a 99% HPLC A% yield. Upon completion, adding cold H2O to the reaction mass did not dissolve all of the salts. Ethyl acetate was added to the mixture, which was then transferred to a separatory funnel, forming three layers. Compound VI was finally isolated after concentration. This material required an additional water wash to remove excess DMF. This material was azeotropically dried with PhMe. 22.3 g of compound VI was obtained (98.8% isolated yield). Scaling up the procedure utilizing 5.945 kg of compound VII, 6.90 kg of K2CO3 and 3.4 kg of 2,2,2-trifluoroethanol gave 8.45 kg of compound VI (97.5% isolated yield). Step 3. Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine (Compound II)

[0117] A 50 L reactor was charged with compound VI (1.80 kg, 7.00 mol, 1 equiv.), B2Pin2 (1.79 kg, 7.01 mol, 1 equiv.), KOAc (2.06 kg, 20.99 mol, 3 equiv.), and 10.8 L of 2-MeTHF under N2. The mixture was stirred under N2 for 1 h. The metal catalyst Pd(dppf)Cl2 (77 g, 0.11 mol, 0.015 equiv.) was added to the reactor. The reactor was heated to 80-85 °C, and the reaction progress was monitored by HPLC. Upon completion, HO was added. The organic layer was washed, filtered, and evaporated. The crude product was recrystallized from heptane to give 1.2 kg of compound II in 55% yield. The isolated compound II was found to be 99% pure by HPLC analysis and 94% pure by weight by QNMR analysis.

[0118] The crude product was dissolved in MTBE and filtered through a silica gel pad before being recrystallized from heptane. MTBE was removed and replaced with heptane, forming a suspension that was filtered and cooled to give crystalline Compound II. Compound II was isolated by filtration, washed with cold heptane (below 0°C), and dried.

[0119] A second crop was isolated from the mother liquor after concentration, filtration, and washing with cold heptane to give an additional 0.21 kg in 6.6% yield. The isolated Compound II was found to be >99 A% by HPLC analysis and 65 wt% by QNMR analysis. Step 4. Synthesis of 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound I)

[0120] A 50 L reactor was charged with compound II (1186.6 g, 95 wt%, 1.0 equiv.), compound III (888.4 g, 1.0 equiv.), and degassed 2-MeTHF (11.0 L) under N2. After stirring for several minutes, degassed water (5.9 L) and NaHCO3 (622.9 g, 2.0 equiv.) were added, followed by Pd(Amphos)2Cl2 (39.37 g, 0.015 equiv.). The contents of the 50 L reactor were heated to 70 °C, and a gentle reflux was observed. The reaction mixture was maintained at 70 °C for 3 hours and monitored by HPLC. The reaction was cooled to room temperature, the aqueous layer was discarded, and the organic layer was reduced.

[0121] Purification 1: The solid was dissolved in EtOAc and filtered through a silica gel plug. The solution was concentrated to a slurry, and 4 L of 2-propanol was added. The solution was heated until homogeneous and then cooled to give a slurry. The solid was collected by filtration to give 1126 g of Compound I (79.6% isolated yield). Compound I was determined by HPLC to be 99.36% HPLC A% product.

[0122] Alternative Purification 2: The solid was dissolved in EtOAc and treated with functionalized silica gel and DARCO activated carbon. The functionalized silica gel and DARCO activated carbon were removed by filtration. The solution was concentrated to a slurry, and 4 L of 2-propanol was added. The solution was heated until homogeneous and then cooled to give a slurry. The solid was collected by filtration to give 1126 g of Compound I (79.6% isolated yield). Compound I was determined by HPLC to be 99.36% HPLC A%. Example 2 Alternative synthesis of 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (compound I) [ka] Step 1. In situ generation of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine (Compound II)

[0123] A shortened procedure for the preparation of compound I was developed. On a small scale, 1 g of compound VI was treated with B2pin2 (1 equivalent) in the presence of Pd(dppf)Cl2 (1.5 mol%) and KOAc (3 eq) in 2-MeTHF at 80 °C. The boronation reaction was complete in 3.5 h. Step 2. Synthesis of 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound I)

[0124] After concentration, the reaction mixture containing compound II underwent Suzuki coupling with compound III (0.9 equiv.) in dioxane in the presence of 1.0 mol% Pd(Amphos)2Cl2, NaHCO3 (3 equiv.), and water (5 V) at 80 °C for 19 h. The final reaction mixture contained the product, compound I, in 92.5% LCAP and the homocoupling product, compound VI, 2,2'-bis(2,2,2-trifluoroethoxy)-5,5'-bipyrimidine, in 3.6% LCAP. After reaction workup, the product was isolated from 2-propanol (1.08 g, 73% yield). HPLC showed the product to be 99.8% LCAP. After treatment with 10% methylthiourea silica gel to remove palladium, a total of 0.7 g (47% yield) of compound I was obtained, which contained 31 ppm Pd.

[0125] Scaling up, i.e., a 20 g scale-up shortened process using Pd(dppf)Cl / 2-MeTHF for the boronation step and Pd(Amphos)Cl / 1,4-dioxane for the Suzuki reaction step, was met with a significantly slower rate (23 h) for the boronation step.

[0126] Purification 1: The reaction was worked up as usual, and after a crystallization step, the isolated compound I (14.3 g) was found to be only 92.3% LCAP and contained 6.0% of 1,1'-bis((5-fluoropyridin-3-yl)methyl)-[3,3'-bipyridazine]-6,6'(1H,1'H)-dione, an impurity resulting from the homocoupling of compound III. The overall yield was 54%. Example 3 Synthesis of 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound I) [ka] Step 1. Synthesis of 6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one (Compound IX)

[0127] To a mixture of compound II (4.2 g, 18.93 mmol, 1.0 equiv.) in dioxane (40 mL) was added compound IV (3.31 g, 18.916 mmol, 1.00 equiv.), Pd(dppf)Cl (0.69 g, 0.943 mmol, 0.05 equiv.), KCO (3.92 g, 28.387 mmol, 1.5 equiv.), and HO (4 mL). The flask was purged with and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 90 °C for 2 h. The solution was diluted with water and extracted with EtOAc (30 mL × 3). The combined organics were washed with brine, dried over NaSO, and the solvent was removed in vacuo. Purification by silica gel chromatography (Flash 300 g, 50-100% EtOAc:cyclohexane) afforded compound IX as a brown solid (3.0 g, 58.24%). LC / MS (ESI): 273 [M+H] + Scaling up the procedure to kilogram scale resulted in a loss of yield. Additionally, compound IX was found to have limited solubility, as seen in Table 1 below. [Table 1] Step 2. Synthesis of 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound I) A 10 L jacketed reactor was charged with Compound IX (0.736 kg, 4.04 mol) followed by NMP (4 L). The reactor jacket temperature was set to 15 °C. Stirring was initiated, and DI water (1 L) was charged. An exotherm to approximately 26 °C was observed. Potassium carbonate (1.523 kg, 11 mol, 3.01 equiv.) was charged in small portions to prevent the temperature from rising above 25 °C. Compound V (1.0 kg) was added in one portion using an addition funnel. The resulting mixture was stirred at 23 ± 2 °C for 15-20 minutes, after which an additional 1 L of 1:4 (v / v) water:NMP was charged to aid stirring. The reaction mixture was continued to stir at 23 ± 2 °C, and the reaction progress was monitored by HPLC. After the reaction was deemed complete, the reactor jacket temperature was set to 10 °C, and 5 L of water was added, resulting in a slight exotherm. The reaction mixture was drained and poured into 90 L of water in a 100 L reactor. The mixture was stirred at room temperature for 60 minutes, after which the solid was filtered through a medium-frit sintered glass filter funnel. The off-white cake was washed with 6.5 L of water. Using the same procedure, two more runs were completed using 1.0 kg and 0.695 kg of compound IX, respectively. The solid was recrystallized from EtOH to give 3.35 kg of compound I in 88% yield. The isolated material was found to be >99.9 A% by HPLC. Example 4 Alternative synthesis of 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (compound I) [ka] Step 1. Synthesis of 6-chloro-2-((5-fluoropyridin-3-yl)methyl)pyridazin-3(2H)-one (Compound III)

[0128] A 12 L, three-necked round-bottom flask equipped with a nitrogen inlet, mechanical stirrer, and internal thermocouple was charged with HO (1.60 kg) and KCO (325 mesh; 0.740 kg). This solution was diluted with NMP (0.80 kg), and compound V (0.322 kg) was charged to the stirred solution in four approximately equal portions every 5 minutes. After all solids had dissolved, a solution of compound IV in NMP (0.235 kg in 0.850 kg NMP) was charged to the mixture over 1 hour, maintaining the reaction temperature below 40°C. The mixture was cooled to 25°C and stirred at about this temperature for 18.5 hours. IPC analysis by HPLC indicated that less than 1% compound V remained. After this time, the reaction mixture was diluted with HO (6.40 kg), and the resulting tan / orange slurry was adjusted to 6-10°C and stirred for 3 hours. The reaction mixture was filtered through a Buchner filter funnel, and when the pH of the filtrate reached 7.5-7.0, the solid was washed with water (2 x 2 kg). The solid was allowed to dry on the funnel for 30 minutes and then transferred to a vacuum drying oven. The solid was dried at 50 °C for 21 hours until it reached a constant weight (less than 1% difference between subsequent weighings). 0.314 kg (74.1% yield; 100% AUC) of a tan solid, Compound III, was isolated. Step 2. Synthesis of 5-bromo-2-(2,2,2-trifluoroethoxy)pyrimidine (Compound VI)

[0129] A reaction flask was charged with 507 g of Compound VII (2.62 mol, lot 73197) followed by N,N-dimethylformamide (3.28 L). While stirring the reactor contents at 300 rpm, 2,2,2-trifluoroethanol (lot 72775) was added in one portion as a neat liquid (2.88 mol, 1.1 equiv.). K2CO3 (325 mesh, 4.19 mol, 1.6 equiv.) was added as a solid in small portions over 10 minutes. The reaction mixture was allowed to cool to 30°C and stirred overnight (18 h stirring time), at which point another aliquot of the reaction mixture was diluted 1 / 40 in 50:50 MeCN / HO for HPLC analysis. The reaction mixture was filtered through a 7 μm polypropylene filter cloth, and the salts were washed with 2-MeTHF (2.5 kg). The washes were combined with the filtrate, and the mixture was diluted with 10% aqueous LiCl (2.5 kg). The resulting mixture was stirred at 25-30°C for 15 minutes. Stirring was stopped, and the layers were separated. After resuming slow stirring (<20 rpm) for an additional 20 minutes, the layers settled, with the desired product in the lower layer. The layers were then separated, and additional 2.5 kg of 2-MeTHF was added to the upper aqueous layer for extraction. The combined organic layers were washed sequentially with USP water (2 x 2.5 kg) and 10% aqueous LiCl (2.5 kg). In each case, the lower layer was removed, leaving the organic product in the upper layer. The washed organic layer was concentrated under vacuum to approximately 1.2 L (bath temperature 35-45°C) as an azeotrope against the remaining water, and 2.5 kg of 2-MeTHF was added. An aliquot of this solution was submitted for Karl Fischer analysis (result: 0.4% HO content, target: 1% or less). This solution was then collected and weighed 3.80 kg. HPLC assay determined 17.1% w / w Compound VI (0.65 kg in solution; 96.4% isolated yield). 99.7% AUC. This solution was carried on directly to step 3. Step 3. Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine (Compound II)

[0130] A 12 L, three-necked, round-bottom flask equipped with a mechanical stirrer, N2 inlet, internal thermocouple, and mechanical stirrer was charged with 3.8 kg of Compound VI solution (17.3% w / w in 2-MeTHF; 0.65 kg; 2.53 mol). While stirring, B2pin2 (0.71 kg, 2.79 mol) was added as a solid in one portion. KOAc (0.75 kg, 7.68 mol) was charged to the mixture, and N2 was sparged below the surface of the vessel contents for 10 minutes. Under nitrogen, Pd(dppf)Cl2 catalyst (0.028 kg, 0.038 mol) was added as a solid, and the vessel contents were heated to 70-75 °C for 22 hours using an external heating mantle. The mixture was cooled to 40 °C, and USP water (2 kg) was added. The mixture was stirred for 25 minutes. After this, the aqueous (lower) layer was removed and the organic layer was washed twice with 5% aqueous NaCl (3.25 kg per wash). The organic layer was diluted with n-heptane (6.2 kg) and stirred for 30 minutes. To this suspension, silica (Siliaflash TM(Silicycle, 60-200 μm size, 0.65 kg) was charged and the slurry was stirred for 20 minutes. The suspension was filtered through a Celite pad (0.2 kg). The solid on the pad was washed with 3:1 v / v n-heptane:2-MeTHF (1.4 kg), and the washings were combined with the filtrate. The combined filtrate and washings were distilled under partial vacuum (external heating temperature 40-45 °C) to a concentrate of approximately 2 L. To this concentrate, n-heptane (4.5 kg) was charged, and distillation was repeated to approximately 2 L. The concentrate was diluted again with n-heptane (1.8 kg). 1H NMR analysis indicated that no 2-MeTHF remained in solution. The slurry was cooled to 0-5 °C with stirring. Once at this temperature, a small amount of 2-MeTHF (0.08 kg) was added, and the slurry was aged at temperature for 2 hours. After this time, the slurry was filtered through a 10" Buchner funnel (7 μm polypropylene filter cloth). The mother liquor was cycled back to the original vessel and any remaining solids were collected and deposited on the filter cake. The cake was vacuum dried under a nitrogen blanket for 20 minutes and the partially dried solid was transferred to a vacuum drying oven set at 40°C. After 3 days, an off-white solid was removed from the drying oven and weighed 0.49 kg (63.3% isolated yield) of Compound II (94.7% AUC).

[0131] Alternative route: A 20 L jacketed reaction vessel equipped with a 22 mm glass stirring shaft (PTFE blade), mechanical stirrer, nitrogen inlet, pressure-equalizing dropping funnel, Dean-Stark adapter (vented to a mineral oil bubbler) equipped with a reflux condenser, and thermocouple was charged sequentially with B2Pin2 (0.971 kg), 2-MeTHF (6.60 kg), and KOAc (0.982 kg). The mixture was stirred (160 rpm) and heated to reflux (approximately 80 °C). Approximately 1.4 kg of 2-MeTHF distillate was collected and drained via the Dean-Stark trap over 3 hours. After distillation was complete, Pd(dppf)Cl2 (0.036 kg) was added as a solid in one portion under a nitrogen blanket, and the solution of compound VI was transferred to the dropping funnel and added in small portions over 45 minutes. The reaction was heated to 75-80°C and sampled after 16 hours to confirm completion. A kicker charge of B2pin2 (90 g), KOAc (90 g), and Pd(dppf)Cl2 (3.7 g) was added, and after an additional 4 hours of reaction time, the reaction was resampled. After completion of the reaction, the crude product was worked up as described above. After 3 days, an off-white solid was removed from the drying oven and weighed 0.674 kg (66.3% isolated yield) of compound II (99.9% AUC).

[0132] Azeotropic removal of water to form compound II before initiating the Miyaura boronation, followed by controlled addition of compound VI (41% w / w, HO <0.1% w / w) to the heated mixture, successfully minimized the formation of undesired by-products, such as the homocoupling impurity of compound VI (see below). Azeotropic removal under nitrogen also served as a means of degassing the mixture before initiating the reaction. Reduction of the homocoupling impurity and degassing the solvent resulted in a 3.0% improvement in isolated yield and a 5.2% improvement in purity, as determined by HPLC, in the above procedure. Azeotropic removal of water typically reduces the amount of homocoupling impurity to less than 1% (0.07% in the above procedure). Failure to remove water typically results in a homocoupling impurity of 4–7%, although values ​​up to 45% have been observed during the development of the manufacturing procedure. Thus, azeotropic removal of water serves to reduce yield variability in the manufacturing procedure. [ka] Step 4. Synthesis of 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound I)

[0133] A 12 L, three-necked round-bottom flask equipped with a mechanical stirrer (glass rod with a PTFE stir blade), nitrogen inlet, internal thermocouple, and external heating mantle was charged with Compound III (0.30 kg), 2-MeTHF (3.3 kg), and Compound II (0.41 kg). The contents of the reactor were set to stir, and NaHCO (0.21 kg) was added, followed by HO (2.0 kg). Nitrogen was sparged below the surface of the mixture for 10 minutes, after which Pd(amphos)Cl (0.013 kg) was added as a solid in one portion under a nitrogen blanket. The injection needle was removed, and the mixture was heated to 70-80 °C under a gentle nitrogen blanket. The mixture was stirred vigorously at temperature for 4 hours, at which point IPC analysis indicated that 0.1% Compound III remained (target specification: 1% or less relative to Compound I). The mixture was allowed to cool to room temperature with stirring for 13 hours, overnight.

[0134] Stirring was stopped and the layers were allowed to settle. The aqueous (lower) layer was removed, and the organic layer was concentrated under vacuum to approximately 2.2 L. Ethyl acetate (3.6 kg) was charged to the vessel, and the concentration was repeated once more, removing approximately 4.5 L of distillate. An additional 3.7 kg of EtOAc was charged. The organic layer was washed with aqueous 5% (w / w) brine (2.0 kg). Then, silica-supported thiourea metal scavenger (Carbosynth, 0.066 kg) was charged to the organic layer, and the mixture was stirred under nitrogen at room temperature for 24 hours. At this point, additional silica (Siliaflash®, 60-200 μm 60 Å, 0.48 kg) was charged to the stirred reaction mixture and stirred for 30 minutes. The mixture was then filtered through a Buchner filter funnel, and the solid was washed twice with EtOAc (1.4 kg per wash). The filtrate and washings were cartridge filtered under vacuum into the receiving flask of a 20 L rotary evaporator. An external heating bath was set to 42-45°C and EtOAc was removed to an approximate volume of about 1.5 L.

[0135] Isopropanol (0.98 kg) was charged to the bulk mixture, and concentration under vacuum was continued until an approximate volume of 1.5 L was reached. Two additional chase distillation cycles were completed (0.92 kg of isopropanol was added per chase) to reach an approximate volume of 1.5 L. The bulk stream was diluted with additional isopropanol (0.92 kg), and the mixture was transferred to a 5 L, three-necked round-bottom flask equipped with a mechanical stirrer, nitrogen inlet, and internal thermocouple. The mixture was heated to 60 ± 5 °C using an external heating mantle and stirred at this temperature until complete dissolution of the solid was observed. The solution was then cooled to 50–55 °C. Milled crystal grains of Compound I (3.3 g, 1.1% w / w relative to the Compound III input) were added to the batch and maintained at this temperature for 1 hour. The heat source was turned off, and the reaction mixture was allowed to cool to ambient temperature and stirred for 16 hours. At this point, the concentration of Compound I in the supernatant was assessed by HPLC to be 24.2 mg / mL. The bulk slurry was filtered under vacuum through a 7-micron polypropylene filter cloth, and the filter cake was washed with cold IPA (2 x 0.32 kg, maintained at 3-5°C). The washed solid was dried under vacuum for 45 minutes with a nitrogen blanket. The bulk solid was then transferred to a vacuum drying oven with a nitrogen flow and dried at 45°C for 2 days. The white solid weighed 382.8 g of Compound I (80.2% yield; 99.7% AUC5).

[0136] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be used in practicing the present disclosure.

Claims

1. Formula 1: 【Chemistry 58】 (In the formula, X １ is a halogen, R １ is C １ ~C ６ haloalkyl) 1. A process for the preparation of a compound of formula (I), Under coupling conditions, in a suitable solvent, in the presence of a metal catalyst and a base, a compound of formula 2: 【Chemistry 59】 (In the formula, R １ is C １ ~C ６ is haloalkyl, B is selected from boronic acids and boronic esters. The compound of formula 3: 【Chemistry 60】 (In the formula, X １ is a halogen, Y is a leaving group. to obtain a compound of formula 1 The process includes:

2. R １ But, C １ ~C ３ 2. The process of claim 1, wherein the alkyl group is a haloalkyl group.

3. R １ But -CF ３ , -CHF ２ , -CH ２ CF ３ and -CH ２ CHF ２ The process of claim 2, wherein the

4. B, 【Chemistry 61】 The process according to any one of claims 1 to 3, wherein the process is selected from the group consisting of

5. B, 【Chemistry 62】 The process of claim 4, wherein the

6. 6. The process of claim 1, wherein Y is selected from halogens and pseudohalides.

7. The process of claim 6, wherein Y is selected from halogen and -OTf.

8. The process of claim 7, wherein Y is selected from -Cl and -Br.

9. X １ The process of any one of claims 1 to 8, wherein is selected from -F and -Cl.

10. 10. The process of claim 1, wherein the metal catalyst is a palladium catalyst.

11. 11. The process of any one of claims 1 to 10, wherein the metal catalyst is selected from palladium (0) or palladium (II) catalysts.

12. 12. The process of any one of claims 1 to 11, wherein the metal catalyst comprises palladium and one or more ligands, the one or more ligands being selected from phosphines, phosphites, bis-phosphines and N-heterocyclic carbenes.

13. The phosphine may be trimethylphosphine, tricyclohexylphosphine, tri-(tert-butyl)-phosphine, XantPhos, DPEPhos, XPhos, SPhos, JohnPhos, Cy-JohnPhos, Amphos, triphenylphosphine, methyldiphenylphosphine, Me4 t-BuXphos, t-BuXPhos, t-BuXantPhos, RuPhos, DavePhos, sSPhos, AdBrettPhos, BrettPhos, JackiePhos, t-BuBrettPhos, TrixiePhos, t-BuDavePhos, t-BuMePhos, MePhos, PhDavePhos, VPhos, PhCPos, XPhos-SO ３ 13. The process of claim 12, wherein the phosphate phosphide is selected from Na, water soluble SPhos, CPhos, EtCPhos, RockPhos, AlPhos, and t-Bu PhCPhos.

14. 14. The process of claim 13, wherein the phosphine is selected from tricyclohexylphosphine, XantPhos, DPEPhos, XPhos, SPhos, Cy-JohnPhos, Amphos and PhDavePhos.

15. 13. The process of claim 12, wherein the phosphite is selected from trimethyl phosphite and triphenyl phosphite.

16. 13. The process of claim 12, wherein the bis-phosphine is selected from bis(diphenylphosphino)methane (dppm), 1,2'-bis(diphenylphosphino)ethane (dppe), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(di-cyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 1,1'-bis(di-isopropylphosphino)ferrocene (dippf).

17. 17. The process of claim 16, wherein the bis-phosphine is selected from 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(di-cyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 1,1'-bis(di-isopropylphosphino)ferrocene (dippf).

18. The metal catalyst is Pd(dppf)Cl ２ , Pd(Amphos) ２ C ２ , Pd(dcypf)Cl ２ , Pd(dtbpf)Cl ２ , Pd(XantPhos)Cl ２ , PdCl ２ (DPEPhos), Pd(PCy ３ ) Cl ２ , XPhos-Pd-G2 and RuPhos-Pd-G2.

19. The metal catalyst is Pd(Amphos) ２ C ２ 20. The process of claim 18, wherein

20. The process of claim 12, wherein the metal catalyst is a palladacycle.

21. 21. The process of any one of claims 1 to 20, wherein the metal catalyst is formed in solution.

22. The preferred bases are triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO ３ , NaOAc, KOAc, KOMe, KOtBu Ba(OH) ２ , Li ２ CO ３ , Na ２ CO ３ , K ２ CO ３ , KHCO ３ , Cs ２ CO ３ , Na ３ P.O. ４ , K ３ P.O. ４ , KF, Na ２ H.P.O. ４ 22. The process of claim 1, wherein the fluorine atom is selected from the group consisting of CsF and CsF.

23. The preferred base is KOAc, NaHCO ３ and K. ２ CO ３ 23. The process of claim 22, wherein the

24. 24. The process of any one of claims 1 to 23, wherein the suitable solvent is selected from polar protic solvents, polar aprotic solvents, and any combination thereof.

25. 24. The process of any one of claims 1 to 23, wherein the suitable solvent is selected from acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropyl alcohol, 1,4-dioxane, toluene, cyclopentyl methyl ether, water, and any combination thereof.

26. 26. The process of claim 25, wherein the suitable solvent is selected from tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 2-methyltetrahydrofuran, cyclopentyl methyl ether, water, and any combination thereof.

27. 27. The process of any one of claims 1 to 26, wherein the coupling conditions comprise a reaction temperature of from about 60°C to about 100°C.

28. 27. The process of any one of claims 1 to 26, wherein the coupling conditions comprise a reaction temperature of from about 70°C to about 90°C.

29. 30. The process of claim 28, wherein the coupling conditions comprise a reaction temperature of about 70°C.

30. 30. The process of any one of claims 1 to 29, wherein the reaction conditions comprise a stirring time of about 0.1 hours to about 24 hours.

31. 31. The process of claim 30, wherein the reaction conditions comprise a stirring time of about 0.5 hours to about 5 hours.

32. The compound of formula 1 is compound I, the compound of formula 2 is compound II, and the compound of formula 3 is compound III, each of which is as follows: 【Chemistry 63】 32. The process of any one of claims 1 to 31, as illustrated in:

33. 33. The process of claim 32, wherein the molar ratio of compound II to compound III is from about 1.0:1.0 to about 1.0:1.

5.

34. 34. The process of claim 33, wherein the molar ratio of compound II to compound III is from about 1.0:1.0 to about 1:1.

2.

35. 35. The process of claim 34, wherein the molar ratio of compound II to compound III is about 1.0:1.

0.

36. The metal catalyst is Pd(Amphos) ２ C ２ 36. The process of any one of claims 32 to 35, wherein

37. 37. The process of claim 36, wherein the molar ratio of compound II to the metal catalyst is between about 1.0:0.0001 and about 1.0:0.

1.

38. 38. The process of claim 37, wherein the molar ratio of compound II to the metal catalyst is between about 1.0:0.001 and about 1.0:0.

05.

39. 39. The process of claim 38, wherein the molar ratio of compound II to the metal catalyst is between about 1.0:0.05 and about 1.0:0.

04.

40. 40. The process of claim 39, wherein the molar ratio of compound II to the metal catalyst is between about 1.0:0.01 and about 1.0:0.

02.

41. 41. The process of claim 40, wherein the molar ratio of compound II to the metal catalyst is about 1.0:0.

015.

42. The suitable base is NaHCO ３ , K ２ CO ３ and Cs ２ CO ３ 42. The process of any one of claims 32 to 41, wherein the process is selected from:

43. 43. The process of claim 42, wherein the molar ratio of compound II to the suitable base is from about 1.0:5.0 to about 1:1.

0.

44. 44. The process of claim 43, wherein the molar ratio of compound II to the suitable base is from about 1.0:3.0 to about 1.0:1.

0.

45. 45. The process of claim 44, wherein the molar ratio of compound II to the suitable base is about 1.0:2.

0.

46. The solvent is 2-MeTHF and H ２ 46. The process of any one of claims 32 to 45, in combination with O.

47. 2-MeTHF vs. H ２ 47. The process of claim 46, wherein the ratio of O is about 2:

1.

48. Formula 3: 【Chemistry 64】 is reacted with a compound of formula 4: 【Chemistry 65】 (Y is a leaving group). The compound of formula 5: 【Chemistry 66】 (In the formula, X １ is a halogen, X ３ is a halogen) or a salt thereof to obtain a compound of formula 3.

49. 49. The process of claim 48, wherein Y is selected from halogen.

50. 50. The process of claim 49, wherein Y is selected from -Cl and -Br.

51. X １ The process of any one of claims 48 to 50, wherein is selected from -F and -Cl.

52. X ３ 52. The process of any one of claims 48 to 51, wherein is selected from -Cl and -Br.

53. 53. The process of any one of claims 48 to 52, wherein the compound of formula 5 is an acid salt.

54. 54. The process of claim 53, wherein the compound of formula 5 is an HCl salt.

55. The preferred bases are triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO ３ , NaOAc, KOAc, KOMe, KOtBu Ba(OH) ２ , Li ２ CO ３ , Na ２ CO ３ , K ２ CO ３ , KHCO ３ , Cs ２ CO ３ , Na ３ P.O. ４ , K ３ P.O. ４ 55. The process of any one of claims 48 to 54, wherein the fluorine atom is selected from the group consisting of KF and CsF.

56. The preferred base is KOAc, NaHCO ３ and K. ２ CO ３ 56. The process of claim 55, wherein the

57. 57. The process of any one of claims 48 to 56, wherein the suitable solvent is selected from N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropyl alcohol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl t-butyl ether, water, and any combination thereof.

58. 58. The process of claim 57, wherein the suitable solvent is selected from N-methyl-2-pyrrolidone, tetrahydrofuran, methyl-t-butyl ether, tetrahydropyran, 1,4-dioxane, 2-methyltetrahydrofuran, water, and any combination thereof.

59. 59. The process of any one of claims 48 to 58, wherein the reaction conditions comprise a stirring time of from about 0.1 hours to about 24 hours.

60. 60. The process of claim 59, wherein the reaction conditions comprise a stirring time of about 0.5 hours to about 5 hours.

61. The compound of formula 3 is compound III, the compound of formula 4 is compound IV, and the compound of formula 5 is compound V, each of which is as follows: 【Chemistry 67】 61. The process of any one of claims 48 to 60, as illustrated in:

62. 62. The process of claim 61, wherein the molar ratio of compound IV to compound V is from about 1.0:1.0 to about 1.0:1.

5.

63. 63. The process of claim 62, wherein the molar ratio of compound IV to compound V is from about 1.0:1.0 to about 1.0:1.

2.

64. 64. The process of claim 63, wherein the molar ratio of compound IV to compound V is about 1.0:1.

0.

65. The preferred base is K ２ CO ３ 65. The process of any one of claims 61 to 64, wherein

66. 66. The process of claim 65, wherein the molar ratio of compound IV to the suitable base is from about 1.0:5.0 to about 1.0:1.

0.

67. 66. The process of claim 65, wherein the molar ratio of compound IV to the suitable base is from about 1.0:4.0 to about 1.0:2.

0.

68. 66. The process of claim 65, wherein the molar ratio of compound IV to the suitable base is about 1.0:3.

0.

69. The solvent is NMP and H ２ 69. The process of any one of claims 61 to 68, in combination with O.

70. The solvent combination is 20% H by volume. ２ 70. The process of claim 69, wherein

71. The solvent is NMP 2-methylTHF and H ２ 69. The process of any one of claims 61 to 68, in combination with O.

72. The solvent combination is 50% H by volume. ２ 72. The process of claim 71, wherein

73. The process comprises reacting a compound of formula 2: 【Chemistry 68】 (In the formula, R １ is C １ ~C ６ is haloalkyl, B is selected from boronic acids and boronic esters. The method further includes preparing a compound of In a suitable solvent, in the presence of a metal catalyst and a suitable base, a compound of formula 6: 【Chemistry 69】 (In the formula, R １ is C １ ~C ６ is haloalkyl, X ２ is a halogen) with a boron compound, wherein said boron compound contains a boron-boron bond or a boron-hydrogen bond, to obtain a compound of formula 2.

73. The process of any one of claims 1 to 72, comprising:

74. Formula 2: 【Chemistry 70】 (In the formula, R １ is C １ ~C ６ is haloalkyl, B is selected from boronic acids and boronic esters.

1. A process for the preparation of a compound of formula (I), In a suitable solvent, in the presence of a metal catalyst and a suitable base, a compound of formula 6: 【Chemistry 71】 (In the formula, R １ is C １ ~C ６ is haloalkyl, X ２ is a halogen) with a boron compound, wherein said boron compound contains a boron-boron bond or a boron-hydrogen bond, to obtain a compound of formula 2. The process includes:

75. R １ But, C １ ~C ３ 75. The process of claim 73 or 74, wherein the alkyl group is haloalkyl.

76. R １ But -CF ３ , -CHF ２ , -CH ２ CF ３ and -CH ２ CHF ２ 76. The process of claim 75, wherein the

77. B, 【Chemical 72】 75. The process of any one of claims 71 to 74, wherein the process is selected from:

78. B, 【Chemical 73】 78. The process of claim 77, wherein the

79. X ２ 79. The process of any one of claims 73 to 78, wherein is selected from -Cl, -Br, and -I.

80. The boron compound is 【Chemical 74】 80. The process of any one of claims 73 to 79, selected from:

81. The boron compound is 【Chemistry 75】 81. The process of claim 80, wherein the

82. 82. The process of any one of claims 73 to 81, wherein the metal catalyst is a palladium catalyst.

83. 83. The process of any one of claims 73 to 82, wherein the metal catalyst is selected from a palladium (0) or palladium (II) catalyst.

84. 84. The process of any one of claims 73 to 83, wherein the metal catalyst comprises palladium and one or more ligands, the one or more ligands being selected from phosphines, phosphites and bis-phosphines.

85. The phosphine may be trimethylphosphine, tricyclohexylphosphine, tri-(tert-butyl)-phosphine, XantPhos, DPEPhos, XPhos, SPhos, JohnPhos, Cy-JohnPhos, Amphos, triphenylphosphine, methyldiphenylphosphine, Me4 t-BuXphos, t-BuXPhos, t-BuXantPhos, RuPhos, DavePhos, sSPhos, AdBrettPhos, BrettPhos, JackiePhos , t-BuBrettPhos, TrixiePos, t-BuDavePhos, t-BuMePhos, MePhos, PhDavePhos, VPhos, PhCPos, XPhos-SO ３ 85. The process of claim 84, wherein the phosphate phosphide is selected from Na, water soluble SPhos, CPhos, EtCPhos, RockPhos, AlPhos, t-Bu PhCPhos, AlPhos.

86. 86. The process of claim 85, wherein the phosphine is selected from tricyclohexylphosphine, XantPhos, DPEPhos, XPhos, SPhos, Cy-JohnPhos, Amphos and PhDavePhos.

87. 85. The process of claim 84, wherein the phosphite is selected from trimethyl phosphite and triphenyl phosphite.

88. 85. The process of claim 84, wherein the bis-phosphine is selected from bis(diphenylphosphino)methane (dppm), 1,2'-bis(diphenylphosphino)ethane (dppe), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(di-cyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf), and 1,1'-bis(di-isopropylphosphino)ferrocene (dippf).

89. 89. The process of claim 88, wherein the bis-phosphine is selected from 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(di-cyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 1,1'-bis(di-isopropylphosphino)ferrocene (dippf).

90. The metal catalyst is Pd(dppf)Cl ２ , Pd(Amphos) ２ C ２ , Pd(dcypf)Cl ２ , Pd(dtbpf)Cl ２ , Pd(XantPhos)Cl ２ , PdCl ２ (DPEPhos), Pd(PCy ３ ) Cl ２ , XPhosPd G2 and RuPhos-Pd-G2.

91. The metal catalyst is Pd(dppf)Cl ２ 85. The process of claim 84, wherein

92. The metal catalyst is Pd(Amphos) ２ C ２ 85. The process of claim 84, wherein

93. 93. The process of any one of claims 73 to 92, wherein the metal catalyst is formed in solution.

94. The preferred bases are triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO ３ , NaOAc, KOAc, KOMe, KOtBu Ba(OH) ２ , Li ２ CO ３ , Na ２ CO ３ , K ２ CO ３ , KHCO ３ , Cs ２ CO ３ , Na ３ P.O. ４ , K ３ P.O. ４ 91. The process of any one of claims 73 to 90, wherein the fluorine atom is selected from the group consisting of KF and CsF.

95. The preferred base is KOAc, NaHCO ３ and K. ２ CO ３ 92. The process of claim 91, wherein the process is selected from:

96. 96. The process of any one of claims 73 to 95, wherein the suitable solvent is selected from polar protic solvents, polar aprotic solvents, and any combination thereof.

97. 97. The process of any one of claims 73 to 96, wherein the suitable solvent is selected from N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropyl alcohol, 1,4-dioxane, toluene, cyclopentyl methyl ether, water, and any combination thereof.

98. 97. The process of any one of claims 73 to 96, wherein the suitable solvent is selected from N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropyl alcohol, 1,4-dioxane, toluene, cyclopentyl methyl ether, and any combination thereof.

99. 99. The process of claim 97 or 98, wherein the suitable solvent is selected from N-methyl-2-pyrrolidone, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 2-methyltetrahydrofuran, water, and any combination thereof.

100. 100. The process of claim 99, wherein the suitable solvent is 2-methyltetrahydrofuran.

101. 101. The process of any one of claims 73 to 100, wherein the boronation reaction conditions comprise a reaction temperature of from about 60°C to about 100°C.

102. 102. The process of claim 101, wherein the boronation reaction conditions comprise a reaction temperature of from about 70°C to about 90°C.

103. 103. The process of claim 102, wherein the boronation reaction conditions comprise a reaction temperature of about 85°C.

104. 99. The process of claim 98, wherein any water present in the suitable solvent is reduced.

105. 105. The process of claim 104, wherein the suitable solvent is 2-methyltetrahydrofuran, and any water in the suitable solvent is reduced by azeotropic distillation.

106. 105. The process of claim 104, wherein the boronic ester or boronic acid, the suitable base and the suitable solvent are heated to reduce the water from the solvent prior to addition of the metal catalyst and the compound of formula 2.

107. 107. The process of claims 104 to 106, wherein removal of water reduces the formation of the homocoupling impurity of formula 6 by between 1-10%.

108. 108. The process of claim 107, wherein removal of water reduces the formation of the homocoupling impurity of formula 6 by between 1-5%.

109. 109. The process of claims 104-108, wherein removal of water increases the yield of the compound of formula 2 by 1-10%.

110. 110. The process of claim 109, wherein removal of water increases the yield of the compound of formula 2 by 1-5%.

111. 111. The process of any one of claims 73 to 110, wherein the reaction conditions comprise a stirring time of from about 0.1 hours to about 48 hours.

112. 112. The process of claim 111, wherein the reaction conditions comprise a stirring time of about 0.5 hours to about 24 hours.

113. The compound of formula 2 is compound II, and the compound of formula 6 is compound VI, each of which is as follows: 【Chemical 76】 As illustrated in The boron compound is 【Chemical 77】 That is, 113. The process of any one of claims 73 to 112.

114. 114. The process of claim 113, wherein the molar ratio of compound VI to the boron compound is from about 1.0:1.0 to about 1.0:1.

5.

115. 115. The process of claim 114, wherein the molar ratio of compound VI to the boron compound is from about 1.0:1.0 to about 1:1.

2.

116. 116. The process of claim 115, wherein the molar ratio of compound VI to the boron compound is about 1.0:1.

0.

117. 117. The process of any one of claims 113 to 116, wherein the suitable base is KOAc.

118. 114. The process of claim 113, wherein the molar ratio of compound VI to the suitable base is from about 1.0:5.0 to about 1.0:1.

0.

119. 119. The process of claim 118, wherein the molar ratio of compound VI to the suitable base is from about 1.0:4.0 to about 1.0:2.

0.

120. 120. The process of claim 119, wherein the molar ratio of compound VI to the suitable base is about 1.0:3.

0.

121. The metal catalyst is Pd(dppf) ２ C ２ 121. The process of any one of claims 113 to 120, wherein

122. 122. The process of claim 121, wherein the molar ratio of compound VI to the metal catalyst is between about 1.0:0.0001 and about 1.0:0.

1.

123. 123. The process of claim 122, wherein the molar ratio of compound VI to the metal catalyst is between about 1.0:0.001 and about 1.0:0.

05.

124. 123. The process of claim 122, wherein the molar ratio of compound VI to the metal catalyst is between about 1.0:0.05 and about 1.0:0.

04.

125. 123. The process of claim 122, wherein the molar ratio of compound VI to the metal catalyst is between about 1.0:0.01 and about 1.0:0.

02.

126. 123. The process of claim 122, wherein the molar ratio of compound VI to the metal catalyst is about 1.0:0.

015.

127. 127. The process of any one of claims 113 to 126, wherein the solvent is 2-MeTHF.

128. Formula 6: 【Chemical 78】 is reacted with a compound of formula 7: 【Chemical 79】 (In the formula, X ２ is a halogen, X ３ is a halogen) The compound of formula 8: 【Chemistry 80】 (In the formula, R １ is C １ ~C ６ haloalkyl) to obtain a compound of formula 6.

129. R １ But, C １ ~C ３ 129. The process of claim 128, wherein the alkyl group is haloalkyl.

130. R １ But -CF ３ , -CHF ２ , -CH ２ CF ３ and -CH ２ CHF ２ 130. The process of claim 129, wherein the process is selected from:

131. X ２ The process of any one of claims 128 to 130, wherein is selected from -Cl, -Br, and -I.

132. X ３ The process of any one of claims 128 to 131, wherein is selected from -Cl and -Br.

133. The preferred bases are triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO ３ , NaOAc, KOAc, KOMe, KOtBu Ba(OH) ２ , Li ２ CO ３ , Na ２ CO ３ , K ２ CO ３ , KHCO ３ , Cs ２ CO ３ , Na ３ P.O. ４ , K ３ P.O. ４ 133. The process of any one of claims 128 to 132, wherein the fluorine atom is selected from the group consisting of KF, KF and CsF.

134. The preferred base is KOAc, NaHCO ３ and K. ２ CO ３ The process of claim 133, wherein the process is selected from the group consisting of

135. 135. The process of any one of claims 128 to 134, wherein the suitable solvent is selected from polar protic solvents, polar aprotic solvents, and any combination thereof.

136. 136. The process of any one of claims 128 to 135, wherein the suitable solvent is selected from acetonitrile, dimethylsulfoxide, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, N-methyl-2-pyrrolidone, methyl-t-butyl ether, isopropyl alcohol, 1,4-dioxane, toluene, cyclopentyl methyl ether, water, and any combination thereof.

137. 137. The process of claim 136, wherein the suitable solvent is selected from acetonitrile, dimethylsulfoxide, tetrahydrofuran, N-methyl-2-pyrrolidone, dimethylformamide, methyl-t-butyl ether, 1,4-dioxane, water, and any combination thereof.

138. The compound of formula 6 is compound VI, and the compound of formula 7 is compound VII, each of which is as follows: 【Chemistry 81】 As illustrated in The compound of formula 8 is CF ３ CH ２ OH, 138. The process of any one of claims 128 to 137.

139. Compound VII vs. CF ３ CH ２ 139. The process of claim 138, wherein the molar ratio of OH is from about 1.0:1.0 to about 1.0:1.

5.

140. Compound VII vs. CF ３ CH ２ 140. The process of claim 139, wherein the molar ratio of OH is from about 1.0:1.0 to about 1.0:1.

2.

141. Compound VII vs. CF ３ CH ２ 141. The process of claim 140, wherein the molar ratio of OH is about 1.0:1.

1.

142. The preferred base is K ２ CO ３ 142. The process of any one of claims 138 to 141, wherein

143. 143. The process of claim 142, wherein the molar ratio of compound VII to the suitable base is from about 1.0:5.0 to about 1.0:1.

0.

144. 144. The process of claim 143, wherein the molar ratio of compound VII to the suitable base is from about 1.0:4.0 to about 1.0:1.

0.

145. 145. The process of claim 144, wherein the molar ratio of compound VII to the suitable base is about 1.0:1.

6.

146. 146. The process of any one of claims 138 to 145, wherein the solvent is dimethylformamide.

147. 146. The process of any one of claims 138 to 145, wherein the solvent is N-methyl-2-pyrrolidone.

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