Process for preparation of pyridazinone compounds

Abstract

Disclosed herein are methods of preparing pyridazinone compounds for the treatment of Duchenne muscular dystrophy using a Suzuki cross-coupling reaction.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 340,871, filed May 11, 2023, which is incorporated herein by reference in its entirety. Background Art

[0003] Duchenne muscular dystrophy (DMD) is a genetic disorder affecting skeletal muscle 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

[0004] Described herein are methods of preparing compounds useful for treating DMD.

[0005] Disclosed herein is a method for preparing a compound of formula 1:

[0006]

[0007] Where X 1 is a halogen; and

[0008] R 1 is a C1-C6 haloalkyl group;

[0009] The method comprises:

[0010] reacting a compound of Formula 2 with a compound of Formula 3 under coupling conditions in the presence of a metal catalyst, a suitable base, in a suitable solvent to provide a compound of Formula 1;

[0011]

[0012] Where R 1 is a C1-C6 haloalkyl group; and

[0013] B is selected from boric acid and boric acid esters;

[0014]

[0015] Where X 1 is a halogen; and

[0016] Y is a leaving group.

[0017] Disclosed herein is a method for preparing a compound of formula 2:

[0018]

[0019] Where R 1 is a C1-C6 haloalkyl group; and

[0020] B is selected from boric acid and boric acid esters;

[0021] The method comprises:

[0022] contacting a compound of Formula 6 with a boron compound in the presence of a metal catalyst, a suitable base, in a suitable solvent to provide a compound of Formula 2, wherein the boron compound comprises a boron-boron bond or a boron-hydrogen bond;

[0023]

[0024] Where R 1 is a C1-C6 haloalkyl group; and

[0025] X 2 It's a halogen. DETAILED DESCRIPTION

[0026] The present disclosure generally relates to methods of preparing 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 by selectively inhibiting fast fiber skeletal muscle myosin.

[0027] Skeletal muscle is composed primarily 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 pattern, with the composition of fiber types varying in different muscles and at different points in growth and development. Slow-twitch fibers have excellent aerobic energy production capabilities. Slow-twitch fibers have a low rate of contraction but a high tolerance to fatigue. Slow-twitch fibers typically have higher mitochondrial and myoglobin concentrations than fast-twitch fibers and are surrounded by more capillaries than fast-twitch fibers. Due to lower myosin ATPase activity, slow-twitch fibers contract more slowly and produce less energy than fast-twitch fibers, but they are able to maintain contractile function for longer periods of time, such as in stabilization, postural control, and endurance exercise.

[0028] Human fast-twitch muscle fibers are further divided into two major fiber types (type IIa, type IIx / d) based on the specific fast skeletal myosins they express. A third type of fast fiber (type IIb) is present in other mammals but is rarely found in human muscle. Fast-twitch muscle fibers have excellent anaerobic energy production capabilities and are able to generate large amounts of tension in a short period of time. In general, fast-twitch muscle fibers have lower mitochondrial, myoglobin, and capillary concentrations than slow-twitch muscle fibers and can therefore fatigue more quickly. Fast-twitch muscle fibers generate the faster forces required for force and resistance activities.

[0029] Skeletal muscle myosin inhibitors that are not selective for type II fibers can lead to excessive inhibition of skeletal muscle contraction, including inhibition of respiratory function and undesirable cardiac activity, because the heart shares multiple structural components (such as type I myosin) with type I skeletal muscle fibers. Although not wishing to be bound by a particular mechanistic theory, the present disclosure provides preparation schemes and intermediates therein to generate 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 the subject's daily activities.

[0030] Preparation of Compound I

[0031] Disclosed herein are novel methods for synthesizing compounds of Formula 1, such as Compound I. In some embodiments, the compound of Formula 1 is synthesized as Scheme 1.

[0032] Scheme 1. Overview of the preparation of compounds of Formula 1

[0033]

[0034] 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 borylated with a suitable borylation agent under coupling conditions to form a compound of Formula 2. In some embodiments, a compound of Formula 3 is cross-linked 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 generated 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 generated and isolated, and then further reacted with a compound of Formula 3 under coupling conditions to form a compound of Formula 1.

[0035] As disclosed herein, the variables in Scheme 1 are defined as follows: R 1 is a C1-C6 haloalkyl group; 1 is a halogen; X 2 is a halogen; X 3 is a halogen; Y is a leaving group; and B is selected from the group consisting of boronic acid and boronic ester.

[0036] In some embodiments, R 1 is C1-C3 haloalkyl. 1 is selected from -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2 and -CH2CHF2. In some embodiments, R 1 is selected from -CF3, -CHF2, -CH2CF3 and -CH2CHF2. In some embodiments, R1 is selected from CHF2 and -CH2CF3. In some embodiments, R 1 It is -CH2CF3.

[0037] In some embodiments, X 1 In some embodiments, X 1 In some embodiments, X 1 In some embodiments, X 1 In some embodiments, X 1 In some embodiments, X 1 Yes -Br.

[0038] In some embodiments, X 2 In some embodiments, X 2 In some embodiments, X 2 Yes -Br.

[0039] In some embodiments, X 3 In some embodiments, X 3 In some embodiments, X 3 Yes -Br.

[0040] In some embodiments, Y is selected from halogen and pseudohalide. 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.

[0041] In some embodiments, B is selected from In some embodiments, B is selected from In some embodiments, B is selected from In some embodiments, B is In some embodiments, B is

[0042] 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 depicted below.

[0043]

[0044] 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% 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% to about 78%. 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 7 4%, 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 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 74% 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%.

[0045] 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 8 ...80% 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 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 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 93%, 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%.

[0046] 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 8 ...80% 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 9 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 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 93%, 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%.

[0047] In some embodiments, the isolated yield of the compound of Formula 2 in Step III is from about 50% to about 85%. In some embodiments, the isolated yield of the compound of Formula 2 in Step III is from about 50% to about 55%, from about 50% to about 60%, from about 50% to about 62%, from about 50% to about 64%, from about 50% to about 66%, from about 50% to about 68%, from about 50% to about 70%, from about 50% to about 73%, from about 50% to about 75%, from about 50% to about 80%, from about 50% to about 85%, from about 55% to about 60%, from about 55% to about 62%, from about 55% to about 64%, from about 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 66%, 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 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%.

[0048] 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 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%. 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 78%, 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%.

[0049] In some embodiments, the total isolated yield of the compound of Formula 1 starting with the compound of Formula 7 is from about 35% to about 65%. In some embodiments, the total isolated yield of the compound of Formula 1 starting with the compound of Formula 7 is from about 35% to about 40%, from about 35% to about 45%, from about 35% to about 50%, from about 35% to about 55%, from about 35% to about 60%, from about 35% to about 65%, from about 40% to about 45%, from about 40% to about 50%, from about 40% to about 55%, from about 40% to about 60%, from about 40% to about 65%, from about 45% to about 50%, from about 45% to about 55%, from about 45% to about 60%, from about 45% to about 65%, from about 50% to about 55%, from about 50% to about 60%, from about 50% to about 65%, from about 55% to about 60%, from about 55% to about 65%, or from 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%.

[0050] Step I: Preparation of the compound of formula 3

[0051]

[0052] In some embodiments, compounds of Formula 4 and Formula 5 are reacted to provide compounds of Formula 3 in the presence of a suitable base in a suitable solvent.

[0053] In some embodiments, the compound of Formula 5 is an acidic salt. In some embodiments, the compound of Formula 5 is an HCl salt, an HBr salt, an HNO3 salt, or an H2SO4 salt. In some embodiments, the compound of Formula 5 is an HCl salt.

[0054] In some embodiments, the suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO3, NaOAc, KOAc, KOMe, KOtBu Ba(OH)2, Li2CO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, Na3PO4, K3PO4, KF and CsF. In some embodiments, the suitable base is selected from KOAc, NaHCO3 and K2CO3. In some embodiments, the suitable base is selected from NaHCO3, K2CO3 and Cs2CO3. In some embodiments, the suitable base is K2CO3. In some embodiments, the suitable base is K2CO3. In some embodiments, the suitable base is Cs2CO3.

[0055] In some embodiments, the suitable solvent is selected from N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropanol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl-tert-butyl ether, water, and any combination thereof. In some embodiments, the suitable solvent is selected from N-methyl-2-pyrrolidone, tetrahydrofuran, methyl-tert-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.

[0056] In some embodiments, the reaction conditions include a stirring time of about 0.1 h to about 24 h. In some embodiments, the reaction conditions include a stirring time of about 0.1 h to about 12 h. In some embodiments, the reaction conditions include a stirring time of about 0.5 h to about 5 h. In some embodiments, the reaction conditions include a stirring time of about 3 h to about 5 h.

[0057] 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.

[0058] 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 from about 1.0:1.0 to about 1.0:1.5. In some embodiments, the molar ratio of Compound IV to Compound V is from 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 a suitable base is from about 1.0:5.0 to about 1.0:1.0. In some embodiments, the molar ratio of Compound IV to a suitable base is from about 1.0:4.0 to about 1.0:2.0. In some embodiments, the molar ratio of Compound IV to a suitable base is about 1.0:3.0.

[0059] Step II: Preparation of the compound of formula 6

[0060]

[0061] 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.

[0062] In some embodiments, the suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO3, NaOAc, KOAc, KOMe, KOtBu Ba(OH)2, Li2CO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, Na3PO4, K3PO4, KF and CsF. In some embodiments, the suitable base is selected from KOAc, NaHCO3 and K2CO3. In some embodiments, the suitable base is K2CO3.

[0063] In some embodiments, the suitable solvent is selected from N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropanol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl-tert-butyl ether, water, and any combination thereof. In some embodiments, the suitable solvent is selected from dimethylformamide, N-methyl-2-pyrrolidone, tetrahydrofuran, methyl-tert-butyl ether, tetrahydropyran, 1,4-dioxane, 2-methyltetrahydrofuran, water, and any combination thereof. In some embodiments, the suitable solvent is dimethylformamide.

[0064] In some embodiments, the reaction conditions include a stirring time of about 0.1 h to about 24 h. In some embodiments, the reaction conditions include a stirring time of about 0.1 h to about 12 h. In some embodiments, the reaction conditions include a stirring time of about 0.5 h to about 5 h. In some embodiments, the reaction conditions include a stirring time of about 3 h to about 5 h.

[0065] 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.

[0066] 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 from about 1.0:1.0 to about 1.0:1.5. In some embodiments, the molar ratio of compound VII to CF3CH2OH is from 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 a suitable base is from about 1.0:5.0 to about 1.0:1.0. In some embodiments, the molar ratio of compound VII to a suitable base is from about 1.0:4.0 to about 1.0:1.0. In some embodiments, the molar ratio of compound VII to a suitable base is about 1.0:1.6.

[0067] In some embodiments, the compound of Formula 6 is not isolated prior to use in subsequent steps. In some embodiments, the compound of Formula 6 is carried on in the solution used in Step III. In some embodiments, water is removed from the solution of Formula 6 prior to use in Step III. Step III: Preparation of Compound of Formula 2

[0068]

[0069] In some embodiments, the compound of Formula 6 is borylated with a boron compound in the presence of a metal catalyst, a suitable base, in a suitable solvent to provide a compound of Formula 2.

[0070] In some embodiments, the boron compound comprises a boron-boron bond or a boron-hydrogen bond. In some embodiments, the boron compound is selected from In some embodiments, the boron compound is selected from In some embodiments, the boron compound is In some embodiments, the boron compound is In some embodiments, the boron compound is In some embodiments, the boron compound is

[0071] In some embodiments, B is selected from In some embodiments, B is selected from In some embodiments, B is selected from In some embodiments, B is In some embodiments, B is

[0072] 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) catalyst. 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 bisphosphines. In some embodiments, the ligand is selected from phosphines, phosphites and bisphosphines. In some embodiments, the ligand is selected from phosphines and bisphosphines.

[0073] In some embodiments, the phosphine is selected from 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-BuPhCPhos, AlPhos. In some embodiments, the phosphine is selected from tricyclohexylphosphine, XantPhos, DPEPhos, XPhos, SPhos, Cy-JohnPhos, Amphos, and PhDavePhos.

[0074] In some embodiments, the phosphite is selected from trimethyl phosphite and triphenyl phosphite.

[0075] In some embodiments, the bisphosphine is selected from bis(diphenylphosphino)methane (dppm), 1,2'-bis(diphenylphosphino)ethane (dppe), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(dicyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 1,1'-bis(diisopropylphosphino)ferrocene (dippf). In some embodiments, the bisphosphine is selected from 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(dicyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 1,1'-bis(diisopropylphosphino)ferrocene (dippf).

[0076] In some embodiments, the metal catalyst is selected from Pd(dppf)Cl2, Pd(Amphos)2Cl2, Pd(dcypf)Cl2, Pd(dtbpf)Cl2, Pd(XantPhos)Cl2, PdCl2(DPEPhos), Pd(PCy3)Cl2, XPhosPd G2 and RuPhos-Pd-G2. In some embodiments, the metal catalyst is Pd(dppf)Cl2. In some embodiments, the metal catalyst is Pd(Amphos)2Cl2.

[0077] In some embodiments, the metal catalyst is a palladium cycle. In some embodiments, the metal catalyst is formed in solution.

[0078] In some embodiments, the metal catalyst described herein has two monodentate phosphine ligands. In some embodiments, the active metal catalyst can be deligated and / or form a palladium ring with one of the monodentate phosphine ligands. For example, it is envisioned that the compound Pd(Amphos)2Cl2 includes Pd(Amphos)Cl2 and / or an equivalent palladium ring.

[0079] In some embodiments, the suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO3, NaOAc, KOAc, KOMe, KOtBu Ba(OH)2, Li2CO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, Na3PO4, K3PO4, KF and CsF. In some embodiments, the suitable base is selected from KOAc, NaHCO3 and K2CO3. In some embodiments, the suitable base is K2CO3. In some embodiments, the 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, isopropanol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl-tert-butyl ether, water, and any combination thereof. In some embodiments, the suitable solvent is selected from dimethylformamide, N-methyl-2-pyrrolidone, tetrahydrofuran, methyl-tert-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 h to about 48 h. In some embodiments, the reaction conditions include a stirring time of about 1 h to about 36 h. In some embodiments, the reaction conditions include a stirring time of about 5 h to about 30 h. In some embodiments, the reaction conditions include a stirring time of about 10 h to about 20 h.

[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 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.

[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 In some embodiments, the molar ratio of compound VI to the boron compound is from 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 from 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 from 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 from 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.

[0084] In some embodiments, water is removed from the solution of Formula 6 prior to adding the catalyst and the boron compound. In some embodiments, after the water is removed, the homocoupled impurities of Formula 6 are reduced. In some embodiments, the homocoupled impurities are reduced by about 1% to about 15%. In some embodiments, the homocoupled impurities are reduced by 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%. In some embodiments, the homocoupled 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, the homocoupled 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, the homocoupled 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%.

[0085]

[0086] In some embodiments, water is removed from the solution of Formula 6 prior to adding the catalyst and boron compound. In some embodiments, removing water from the solution of Formula 6 increases the yield of the compound of Formula 2. In some embodiments, the yield is increased by about 1% to about 15%. In some embodiments, the yield is improved by 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 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 3% to about 1 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, the yield is increased 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 increased 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 increased by at most about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, or about 15%.

[0087] Step IV: Preparation of the compound of formula 1

[0088]

[0089] 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.

[0090] 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) catalyst. 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 bisphosphines. In some embodiments, the ligand is selected from phosphines, phosphites and bisphosphines. In some embodiments, the ligand is selected from phosphines and bisphosphines.

[0091] In some embodiments, the phosphine is selected from 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-BuPhCPhos, AlPhos. 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.

[0092] In some embodiments, the phosphite is selected from trimethyl phosphite and triphenyl phosphite.

[0093] In some embodiments, the bisphosphine is selected from bis(diphenylphosphino)methane (dppm), 1,2'-bis(diphenylphosphino)ethane (dppe), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(dicyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 1,1'-bis(diisopropylphosphino)ferrocene (dippf). In some embodiments, the bisphosphine is selected from 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(dicyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 1,1'-bis(diisopropylphosphino)ferrocene (dippf).

[0094] In some embodiments, the metal catalyst is selected from Pd(dppf)Cl2, Pd(Amphos)2Cl2, Pd(dcypf)Cl2, Pd(dtbpf)Cl2, Pd(XantPhos)Cl2, PdCl2(DPEPhos), Pd(PCy3)Cl2, XPhosPd G2 and RuPhos-Pd-G2. In some embodiments, the metal catalyst is Pd(Amphos)2Cl2.

[0095] In some embodiments, the metal catalyst is a palladium cycle. In some embodiments, the metal catalyst is formed in solution.

[0096] In some embodiments, the suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO3, NaOAc, KOAc, KOMe, KOtBu Ba(OH)2, Li2CO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, Na3PO4, K3PO4, KF and CsF. In some embodiments, the suitable base is selected from KOAc, NaHCO3 and K2CO3. In some embodiments, the suitable base is K2CO3. In some embodiments, the suitable base is NaHCO3.

[0097] In some embodiments, the suitable solvent is selected from N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropanol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl-tert-butyl ether, water, and any combination thereof. In some embodiments, the suitable solvent is selected from dimethylformamide, N-methyl-2-pyrrolidone, tetrahydrofuran, methyl-tert-butyl ether, tetrahydropyran, 1,4-dioxane, 2-methyltetrahydrofuran, water, and any combination thereof. In some embodiments, the suitable solvent is 2-methyltetrahydrofuran.

[0098] In some embodiments, B is selected from In some embodiments, B is selected from In some embodiments, B is selected from In some embodiments, B is In some embodiments, B is

[0099] In some embodiments, the reaction conditions include a stirring time of about 0.5 h to about 48 h. In some embodiments, the reaction conditions include a stirring time of about 1 h to about 36 h. In some embodiments, the reaction conditions include a stirring time of about 5 h to about 30 h. In some embodiments, the reaction conditions include a stirring time of about 10 h to about 20 h.

[0100] 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.

[0101] 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 from about 1.0:1.0 to about 1.0:1.5. In some embodiments, the molar ratio of compound II to compound III is from about 1.0:1.0 to about 1:1.2. 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 the 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 the 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 the 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 to 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 from 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 from 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.

[0102] 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, isopropanol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl-tert-butyl ether, water, and any combination thereof. In some embodiments, the suitable solvent is selected from dimethylformamide, N-methyl-2-pyrrolidone, tetrahydrofuran, methyl-tert-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.

[0103] Step IIIa and Step Iva: Simplified Preparation of Compounds of Formula 1

[0104]

[0105] In some embodiments, the compound of Formula 6 is reacted with a boron compound in the presence of a metal catalyst, a suitable base, in a suitable solvent to provide in situ the compound of Formula 2. The in situ 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.

[0106] In some embodiments, the boron compound comprises a boron-boron bond or a boron-hydrogen bond. In some embodiments, the boron compound is selected from In some embodiments, the boron compound is selected from In some embodiments, the boron compound is In some embodiments, the boron compound is In some embodiments, the boron compound is In some embodiments, the boron compound is

[0107] In some embodiments, B is selected from In some embodiments, B is selected from In some embodiments, B is selected from In some embodiments, B is In some embodiments, B is

[0108] 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) catalyst. 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 bisphosphines. In some embodiments, the ligand is selected from phosphines, phosphites and bisphosphines. In some embodiments, the ligand is selected from phosphines and bisphosphines.

[0109] In some embodiments, the phosphine is selected from 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-BuPhCPhos, AlPhos. 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.

[0110] In some embodiments, the phosphite is selected from trimethyl phosphite and triphenyl phosphite.

[0111] In some embodiments, the bisphosphine is selected from bis(diphenylphosphino)methane (dppm), 1,2'-bis(diphenylphosphino)ethane (dppe), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(dicyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 1,1'-bis(diisopropylphosphino)ferrocene (dippf). In some embodiments, the bisphosphine is selected from 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(dicyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 1,1'-bis(diisopropylphosphino)ferrocene (dippf).

[0112] In some embodiments, the metal catalyst is selected from Pd(dppf)Cl2, Pd(Amphos)2Cl2, Pd(dcypf)Cl2, Pd(dtbpf)Cl2, Pd(XantPhos)Cl2, PdCl2(DPEPhos), Pd(PCy3)Cl2, XPhosPd G2 and RuPhos-Pd-G2. In some embodiments, the metal catalyst is Pd(Amphos)2Cl2. In some embodiments, the metal catalyst is Pd(dppf)Cl2.

[0113] In some embodiments, the metal catalyst is a palladium cycle. In some embodiments, the metal catalyst is formed in solution.

[0114] In some embodiments, the suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO3, NaOAc, KOAc, KOMe, KOtBu Ba(OH)2, Li2CO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, Na3PO4, K3PO4, KF and CsF. In some embodiments, the suitable base is selected from KOAc, NaHCO3 and K2CO3. In some embodiments, the suitable base is K2CO3. In some embodiments, the suitable base is NaHCO3. In some embodiments, the suitable base is KOAc.

[0115] In some embodiments, the suitable solvent is selected from N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, isopropanol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl-tert-butyl ether, water, and any combination thereof. In some embodiments, the suitable solvent is selected from dimethylformamide, N-methyl-2-pyrrolidone, tetrahydrofuran, methyl-tert-butyl ether, tetrahydropyran, 1,4-dioxane, 2-methyltetrahydrofuran, water, and any combination thereof. In some embodiments, the suitable solvent is 2-methyltetrahydrofuran.

[0116] In some embodiments, the reaction conditions include a stirring time of about 0.5 h to about 48 h. In some embodiments, the reaction conditions include a stirring time of about 1 h to about 36 h. In some embodiments, the reaction conditions include a stirring time of about 5 h to about 30 h. In some embodiments, the reaction conditions include a stirring time of about 10 h to about 20 h.

[0117] 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.

[0118] In some embodiments, the compound of Formula 2 is Compound II, the compound of Formula 6 is Compound VI, and the boron compound is In some embodiments, the molar ratio of compound VI to the boron compound is from 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 from 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 from 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 from 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.

[0119] 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 from about 1.0:1.0 to about 1.0:1.5. In some embodiments, the molar ratio of Compound II to Compound III is from 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 the 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 the 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 the 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 to 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 from 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 from 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.

[0120] In some embodiments, the compounds described herein are synthesized as outlined in the Examples.

[0121] Compound

[0122] In some embodiments, disclosed herein are compounds represented by Formula 9:

[0123]

[0124] or a salt thereof, wherein:

[0125] R 1 is -CF3, -CHF2, -CH2CF3 and -CH2CHF2; and

[0126] B is selected from boric acid and boric acid esters.

[0127] In some embodiments, R 1 is -CH2CF3. In some embodiments, B is selected from

[0128] In some embodiments, B is selected from In some embodiments, the compound is Compound II depicted as follows:

[0129]

[0130] MIDA borate

[0131] In some embodiments, methyliminodiacetic acid (MIDA) boronate is conjugated to the heteroaryl group prior to palladium catalyzed transmetalation.For example, the following compound A can be synthesized and utilized in place of compound II.

[0132]

[0133] Compound A can be synthesized via the reaction of BCl3, N-methyliminodiacetic acid and compound VI.

[0134] Heavy metal remover

[0135] In some embodiments, the compound of Formula 1 (such as Compound I) or the compound of Formula 2 (such as Compound II) is further treated with a metal scavenger to remove residual palladium. In some embodiments, the metal scavenger includes SiO2, activated carbon, an aqueous solution of L-cysteine, Silicycle metal scavengers, Si-thiols, SiliaBond DMT, SiliaBond cysteine, or 3-mercaptopropylethyl sulfide silica. In some embodiments, the ratio of metal catalyst to scavenger (w / w) 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.

[0136] In some of these embodiments, the palladium level is reduced to about 10 ppm. In some of these embodiments, the palladium level is sufficiently reduced to be undetectable.

[0137] 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 U.S. Pharmacopoeia Appendix <231> Heavy Metals (US Pharmacopeia General Chapter <231> Heavy Metals) to determine the presence of residual heavy metal (e.g., palladium) impurities.

[0138] Terms and Definitions

[0139] 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 the present disclosure belongs.

[0140] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Any reference to "or" herein is intended to include "and / or" unless stated otherwise.

[0141] As used herein, the term "about" in some instances refers to an amount that is approximately the stated amount.

[0142] As used herein, the term "about" refers to an amount that is approximately 10%, 5%, or 1% of the stated amount, including increments therein.

[0143] As used herein, the term "about" with respect to a percentage refers to an amount that is 10%, 5%, or 1% greater or less than the stated percentage, including increments therein.

[0144] As used herein, "pharmaceutically acceptable" refers to a material such as a carrier or diluent that does not abrogate the biological activity or properties of the compound and is relatively nontoxic, i.e., the material does not cause undesirable biological effects when administered to a subject or interact in a deleterious manner with any component of a composition containing the material.

[0145] The term "C x-y " or "C x -C y " when used with a chemical moiety such as haloalkyl, is intended to include groups containing from x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight chain alkyl and branched chain alkyl groups containing 1 to 6 carbon atoms.

[0146] The term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the haloalkyl group is optionally further substituted as described herein.

[0147] The term "halo" or "halogen" or "halide" means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro or bromo.

[0148] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that is a combination of a cationic form of the therapeutically active agent and a suitable anion, or in an alternative embodiment, a combination of an anionic form of the therapeutically active agent and a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bigley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002. Pharmaceutically acceptable salts are generally more soluble and more rapidly soluble in gastric and intestinal fluids than non-ionic substances, and are therefore used in solid dosage forms. Furthermore, because their solubility is often a function of pH, selective dissolution in one or another part of the digestive tract is possible, and this ability can be manipulated as an aspect of delayed and sustained release behavior. Moreover, because salt-forming molecules can equilibrate with the neutral form, passage through biological membranes can be modulated.

[0149] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound disclosed herein with an acid. In some embodiments, the compound disclosed herein (i.e., the free base form) is alkaline and reacts with an organic acid or an 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 (+); decanoic acid (capric acid / decanoic acid); caproic acid (caproic acid / hexanoic acid); octanoic acid (caprylic acid / octanoic acid); acid); carbonic acid; cinnamic acid; citric acid; cyclohexanesulfamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic 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.

[0150] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with a base. In some embodiments, the compound disclosed herein is acidic and reacts with a base. In this case, the acidic protons of the compound disclosed herein are replaced by metal ions (e.g., lithium ions, sodium ions, potassium ions, magnesium ions, calcium ions, or aluminum ions). In some cases, the compound described herein is coordinated with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compound described herein forms a salt with an amino acid (such as, but not limited to, arginine, lysine, etc.). The acceptable inorganic bases for forming a salt with a compound containing an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, etc. In some embodiments, the compound provided herein is prepared as a sodium salt, a calcium salt, a potassium salt, a magnesium salt, a meglumine salt, an N-methylglucamine salt, or an ammonium salt.

[0151] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms. In some embodiments, solvates contain stoichiometric or non-stoichiometric amounts of solvents and are formed during the process of crystallization with pharmaceutically acceptable solvents (such as water, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, sec-butanol, etc.). Hydrates are formed when the solvent is water, or alkoxides are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein are optionally present in non-solvated and solvated forms.

[0152] Therapeutic agents that can be applied to mammals (such as humans) must be prepared in accordance with regulatory guidelines. Such government-regulated guidelines are called Good Manufacturing Practice (GMP). GMP guidelines outline acceptable levels of contamination for active therapeutic agents, such as the amount of residual solvents in the final product. Preferred solvents are those that are suitable for GMP facilities and meet industrial safety considerations. The categories of solvents are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C (R3), (November 2005).

[0153] Solvents are divided into three categories. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents with limited use during the preparation of therapeutic agents. Class 3 solvents are solvents with low toxicity potential and low risk to human health. Data for Class 3 solvents show that they are less toxic in acute or short-term studies and are negative in genotoxicity studies.

[0154] Class 1 solvents that should be avoided include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethylene; and 1,1,1-trichloroethane.

[0155] Examples of Class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethylene, 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-trichloroethylene and xylene.

[0156] Class 3 solvents with low toxicity include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), isopropylbenzene, 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.

[0157] Residual solvents in active pharmaceutical ingredients (APIs) originate from the preparation of the API. In some cases, the solvent cannot be completely removed by practical preparation techniques. Appropriate selection of solvents for the synthesis of APIs can improve yield or determine characteristics such as crystal form, purity, and solubility. Therefore, solvents are key parameters in the synthesis process.

[0158] In some embodiments, the composition comprising compound A comprises one or more organic solvents. In some embodiments, the composition comprising compound A includes one or more organic solvents in a residual amount. In some embodiments, the composition comprising compound A comprises a residual amount of the third class solvent. In some embodiments, the third class solvent is selected from acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, isopropylbenzene, dimethyl sulfoxide, ethanol, ethyl acetate, 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 third class solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropyl alcohol and ethanol.

[0159] In some embodiments, the composition comprising Compound A includes a detectable amount of an organic solvent. In some embodiments, the organic solvent is a Class 3 solvent.

[0160] In other embodiments, the composition comprises compound A, wherein the composition comprises a detectable amount of solvent less than about 1%, wherein the solvent is selected from acetone, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, heptane and 2-propanol. In a further embodiment, the composition comprises compound A, wherein the composition comprises a detectable amount of solvent less than about 5000ppm. In another embodiment, the composition comprises compound A, wherein the detectable amount of solvent is less than about 5000ppm, less than about 4000ppm, less than about 3000ppm, less than about 2000ppm, less than about 1000ppm, less than about 500ppm or less than about 100ppm.

[0161] Example

[0162] The following illustrative examples represent embodiments of the methods described herein and are not meant to be limiting in any way.

[0163] 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)

[0164]

[0165] Step 1. Synthesis of 6-chloro-2-((5-fluoropyridin-3-yl)methyl)pyridazin-3(2H)-one (Compound III)

[0166] The preparation of compound III was accomplished 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. During the addition of water, the reaction temperature increased from 20°C to 34°C and off-gassing (CO2 release) was observed during the addition of K2CO3 (which was added over 10 min). HPLC analysis after 15 h showed HPLC A% <1 for compound IV. (PDF). After filtering the inorganics from the reactor, the filter cake was washed with IPAc (10 vols). The filtrate and washings were combined and washed with aqueous LiCl solution and the layers were separated. The aqueous layer was back extracted with IPAc (2 vols). The organic layers were combined and washed with water. The layer separation was rapid, requiring <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 obtained semi-solid was treated with deionized water (10 volumes) in a Büchi ball and stirred by a rotating distillation ball at atmospheric pressure until a uniform slurry was obtained and filtered. The filtered solid was dried on a filter funnel for several hours under a nitrogen hood by applying a vacuum, and then dried in a vacuum oven at 35° C. until constant weight was reached. After drying, a total of 817.5 g of compound III (78% yield) was isolated as a tan solid. The isolated compound III was found to be 97.8A% pure by HPLC, and was found to be 99wt.% pure by quantitative NMR analysis. It was found that the isolated compound III did not contain compound V.

[0167] Step 2. Synthesis of 5-bromo-2-(2,2,2-trifluoroethoxy)pyrimidine (Compound VI)

[0168] At 19 ° C, 20g of compound VII, 1.6 equivalents of K2CO3 and 1.1 equivalents of 2,2,2-trifluoroethanol in DMF were used to synthesize compound VI. The reaction needs to be stirred overnight (>18h) to obtain compound VI with>99% HPLC A%. After the reaction is completed, adding cold H2O to the reaction will not dissolve all salts. Ethyl acetate is added to the mixture and when transferred to a separatory funnel, three layers are formed. Finally, compound VI is isolated after concentration. This material needs to be washed with an additional round of water to remove excess DMF. The material is azeotropically dried with PhMe. 22.3g of compound VI (98.8% isolated yield) is obtained. The procedure is expanded using 5.945kg of compound VII, 6.90kg of K2CO3 and 3.4kg of 2,2,2-trifluoroethanol to obtain 8.45kg of compound VI (97.5% isolated yield).

[0169] Step 3. 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl Synthesis of (2-(2-oxy)pyrimidine (Compound II)

[0170] Under N2, compound VI (1.80 kg, 7.00 mol, 1 eq.), B2Pin2 (1.79 kg, 7.01 mol, 1 eq.), KOAc (2.06 kg, 20.99 mol, 3 eq.) and 10.8 L of 2-MeTHF were added to a 50 L reactor. Under N2, the mixture was stirred for 1 hour. Metal catalyst Pd (dppf) Cl2 (77 g, 0.11 mol, 0.015 eq.) was added to the reactor. The reactor was heated to 80-85 ° C and the progress of the reaction was monitored by HPLC. After completion, H2O was added. The organic layer was washed, filtered and evaporated. The crude product was recrystallized from heptane to obtain 1.2 kg of compound II in a yield of 55%. The isolated compound II was found to be 99A% by HPLC analysis and 94wt.% by QNMR analysis.

[0171] The crude product was dissolved in MTBE and filtered through a pad of silica gel before recrystallization from heptane. MTBE was removed and replaced with heptane to form a suspension, which was filtered and cooled to produce crystalline compound II. Compound II was isolated by filtration and washed with cold heptane (≤0°C) and dried.

[0172] After concentration, filtration and washing with cold heptane, a second crop was isolated from the mother liquor to give an additional 0.21 kg for a 6.6% yield. The isolated Compound II was found to be >99A% by HPLC analysis and >65 wt.% by QNMR analysis.

[0173] Step 4. 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazine-3-yl Synthesis of (2H)-Ketone (Compound I)

[0174] Under N2, compound II (1186.6 g, 95 wt.%, 1.0 eq.), compound III (888.4 g, 1.0 eq.) and degassed 2-MeTHF (11.0 L) were added to a 50 L reactor. After stirring for a few minutes, degassed water (5.9 L) and NaHCO3 (622.9 g, 2.0 eq.) were added, followed by Pd(Amphos)2Cl2 (39.37 g, 0.015 eq.). The contents of the 50 L reactor were heated to 70 ° C, and a slight reflux was observed. The reaction mixture was maintained at 70 ° C for 3 h and monitored by HPLC. The reaction was cooled to room temperature, the aqueous layer was discarded and the organic layer was reduced.

[0175] 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 uniform and then cooled to give a slurry. The solid was collected via filtration to give 1126 g of Compound I (isolated yield 79.6%). Compound I was found to be a product of 99.36% HPLC A% by HPLC.

[0176] 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 4L of 2-propanol was added. The solution was heated until uniform and then cooled to give a slurry. The solid was collected by filtration to give 1126g of Compound I (isolated yield 79.6%). Compound I was found to be a product of 99.36% HPLC A% by HPLC.

[0177] 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)

[0178]

[0179] 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)

[0180] A streamlined procedure was developed for the generation of compound I. On a small scale, 1 g of compound VI was treated with B2pin2 (1 eq) in the presence of Pd(dppf)Cl2 (1.5 mol%) and KOAc (3 eq) in 2-MeTHF at 80° C. The borylation reaction was completed in 3.5 h.

[0181] Step 2. 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazine-3-yl Synthesis of (2H)-Ketone (Compound I)

[0182] After concentration, the reaction mixture containing compound II was Suzuki coupled with compound III (0.9 eq.) in dioxane at 80°C in the presence of 1.0 mol% Pd(Amphos)2Cl2, NaHCO3 (3 eq.) and water (5V) for 19 h to obtain a final reaction mixture in which the product compound I was 92.5% LCAP and the homo-coupling product of compound VI (2,2'-bis(2,2,2-trifluoroethoxy)-5,5'-bipyrimidine) was 3.6% LCAP. After the reaction was completed, the product was isolated from 2-propanol (1.08 g, 73% yield). HPLC showed that the product was 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.

[0183] The scaled-up, 20 g streamlined method using Pd(dppf)Cl2 / 2-MeTHF for the borylation step and Pd(Amphos)2Cl2 / 1,4-dioxane for the Suzuki reaction step encountered a significantly slower rate (23 h) in the borylation step.

[0184] Purification 1: The reaction was completed as usual and after the crystallization step, the isolated compound I (14.3 g) was found to be only 92.3% LCAP, with 6.0% impurity produced by homo-coupling of compound III (1,1'-bis((5-fluoropyridin-3-yl)methyl)-[3,3'-bipyridazine]-6,6'(1H,1'H)-dione). The overall yield was 54%.

[0185] 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)

[0186]

[0187] Step 1. Preparation of 6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one (Compound IX) synthesis

[0188] Compound IV (3.31 g, 18.916 mmol, 1.00 equiv.), Pd (dppf) Cl2 (0.69 g, 0.943 mmol, 0.05 equiv.), K2CO3 (3.92 g, 28.387 mmol, 1.5 equiv.) and H2O (4 mL) were added to a mixture of compound II (4.2 g, 18.93 mmol, 1.0 equiv.) in dioxane (40 mL). The flask was purged with an inert atmosphere of nitrogen and maintained. The resulting solution was stirred at 90 ° C for 2 h. The solution was diluted with water and extracted with EtOAc (30 mLx3). The combined organics were washed with brine, dried over Na2SO4 and the solvent was removed in vacuo. Compound IX (3.0 g, 58.24%) was obtained as a brown solid by chromatography on silica gel (Flash 300 g, 50-100% EtOAc: cyclohexane). LC / MS(ESI):273[M+H] + Scaling up this procedure to kilogram scale resulted in reduced yields. In addition, Compound IX was found to have limited solubility as shown in Table 1 below.

[0189] Table 1

[0190]

[0191] Step 2. 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazine-3-yl Synthesis of (2H)-Ketone (Compound I) Compound IX (0.736kg, 4.04mol) was added to a jacketed 10L reactor, followed by NMP (4L). The jacket temperature of the reactor was set to 15°C. Stirring was started and DI water (1L) was added. Heat release was observed to be about 26°C. Potassium carbonate (1.523kg, 11mol, 3.01 equivalents) was added in batches so that the temperature did not rise above 25°C. Compound V (1.0kg) was added using a funnel at one time. The resulting mixture was allowed to stir for 15-20min at 23±2°C, and then an additional 1L of 1:4 (v / v) water:NMP was added to assist stirring. The reaction mixture was continued to stir at 23±2°C and the progress of the reaction was monitored by HPLC. After judging that the reaction was complete, the jacket temperature of the reactor was set to 10°C and 5L water was added, resulting in a mild heat release. The reaction mixture was discharged and poured into 90L water in a 100L reactor. The mixture was allowed to stir at room temperature for 60 minutes, and then the solid was filtered through a glass filter funnel sintered with medium frit. The off-white cake was washed with 6.5 L of water. Two additional runs were completed using the same procedure using 1.0 and 0.695 kg of compound IX, respectively. The solid was recrystallized from EtOH to give 3.35 kg of compound I (88% yield). The isolated material was found to be >99.9A% by HPLC.

[0192] 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)

[0193]

[0194] Step 1. Synthesis of 6-chloro-2-((5-fluoropyridin-3-yl)methyl)pyridazin-3(2H)-one (Compound III)

[0195] To a 12L 3-necked round bottom flask equipped with a nitrogen inlet, a mechanical stirrer and an internal thermocouple was added H2O (1.60 kg) and K2CO3 (325 mesh; 0.740 kg). The solution was diluted with NMP (0.80 kg) and compound V (0.322 kg) was added to the stirred solution in approximately 4 equal portions every 5 minutes. After all solids were dissolved, a solution of compound IV in NMP (0.235 kg in 0.850 kg NMP) was added to the mixture over 1 hour while maintaining the reaction temperature ≤ 40°C. The mixture was cooled to 25°C and stirred for 18.5 hours near this temperature. IPC analysis by HPLC showed that the remaining compound V was <1%. After this, the reaction mixture was diluted with H2O (6.40 kg) and the resulting tan / orange slurry was adjusted to 6-10°C and then stirred for 3 hours. The reaction mixture was filtered on a Buchner filter funnel, and when the pH of the filtrate was 7.5-7.0, the solid was washed with water (2 x 2 kg). The solid was dried on the funnel for 30 minutes and then transferred to a vacuum drying oven. At 50 ° C, the solid was dried to constant weight (difference between subsequent weighings < 1%) over 21 hours. 0.314 kg of tan solid compound III was isolated (74.1% yield; 100% AUC).

[0196] Step 2. Synthesis of 5-bromo-2-(2,2,2-trifluoroethoxy)pyrimidine (Compound VI)

[0197] 507g of compound VII (2.62mol, lot number 73197) is added to the reaction flask, and then N, N-dimethylformamide (3.28L) is added. With 300rpm stirring reactor contents, 2,2,2-trifluoroethanol (lot number 72775) in pure liquid (2.88mol, 1.1 equivalents) is added at once. K2CO3 (325 mesh, 4.19mol, 1.6 equivalents) is added in batches over 10 minutes as solid. The reaction mixture is naturally cooled to 30 ℃ and stirred overnight (stirring time 18 hours), and another aliquot of the reaction mixture is now diluted with 1 / 40 in 50:50MeCN / H2O for HPLC analysis. The reaction mixture is filtered through 7 μm polypropylene filter cloth and the salt is washed with 2-MeTHF (2.5kg). The washings were combined with the filtrate, and the mixture was diluted with a 10% aqueous LiCl solution (2.5 kg), and the resulting phase was stirred for 15 minutes at 25-30°C. Stirring was stopped and the layers were allowed to separate. After restarting the low stirring speed (<20 rpm) and stirring for another 20 minutes, the layers were precipitated with the desired product at the bottom layer. The layers were then separated, and additional 2-MeTHF was added to the top aqueous layer for extraction (2.5 kg). The combined organic layers were washed with USP water (2x 2.5 kg) and a 10% aqueous LiCl solution (2.5 kg) in turn. In each case, the bottom layer was removed with the organic product of the top layer. The washed organic layer was azeotroped with the remaining water and an additional 2.5 kg of 2-MeTHF concentrated under vacuum to about 1.2 L (bath temperature 35-45°C). An aliquot of the solution was submitted for Karl Fischer analysis (result: 0.4% H2O content. Target: ≤1%). The solution was then collected and weighed to 3.80 kg. HPLC assay determined 17.1% w / w Compound VI (0.65 kg in solution; 96.4% isolated yield;). 99.7% AUC. The solution was carried directly into Step 3 as is.

[0198] Step 3. 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl Synthesis of (2-(2-oxy)pyrimidine (Compound II)

[0199] To a 12L 3-neck round-bottom flask equipped with a mechanical stirrer, N2 inlet, internal thermocouple and mechanical stirrer was added 3.8 kg of Compound VI solution (17.3% w / w solution in 2-MeTHF; 0.65 kg; 2.53 mol). The solution was stirred and B2pin2 (0.71 kg, 2.79 mol) was added as a solid in one portion. KOAc (0.75 kg, 7.68 mol) was added to the mixture and the contents of the vessel were sparged subsurface with N2 for 10 minutes. Pd(dppf)Cl2 catalyst (0.028 kg, 0.038 mol) was added as a solid under nitrogen and the contents of the vessel were heated to 70-75°C via an external heating mantle for 22 hours. 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 (bottom) layer was removed and the organic layer was washed twice with 5% aqueous NaCl solution (3.25 kg each time). The organic layer was diluted with n-heptane (6.2 kg) and stirred for 30 minutes. Silica flash was added to the suspension. TM (Silicycle, 60-200 μm size, 0.65 kg) and stirred the slurry for 20 minutes. The suspension was filtered through a diatomaceous earth 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 to about 2 L of concentrate under partial vacuum (external heating temperature 40-45 ° C). N-heptane (4.5 kg) was added to the concentrate, and the distillation was repeated to about 2 L. The concentrate was diluted with n-heptane (1.8 kg) again. 1H NMR analysis showed that there was no remaining 2-MeTHF in the solution. The slurry was cooled to 0-5 ° C while stirring. Once this temperature was reached, a small amount of 2-MeTHF (0.08 kg) was added, and the slurry was aged at this temperature for 2 hours. After this, the slurry was filtered on a 10" Buchner funnel (7 μm polypropylene filter cloth). The mother liquor was recycled back to the original container to collect any remaining solids and deposited on the filter cake. The filter cake was vacuum dried under a nitrogen blanket for 20 minutes, and the partially dried solids were transferred to a vacuum oven set at 40°C. After 3 days, the off-white solid was removed from the oven and weighed 0.49 kg (63.3% isolated yield) of Compound II (94.7% AUC).

[0200] Alternative Pathway:B2Pin2 (0.971 kg), 2-MeTHF (6.60 kg), KOAc (0.982 kg) were added to a 20L jacketed reaction vessel equipped with a 22 mm glass stirring rod (PTFE blade), a mechanical stirrer, a nitrogen inlet, a pressure equalizing feeding funnel, a Dean-stark adapter with a reflux condenser (to a mineral oil bubbler) and a thermocouple. The mixture was stirred (160 rpm) and heated to reflux (about 80 ° C). About 1.4 kg of 2-MeTHF distillate was collected and discharged via a Dean-Stark water separator within 3 hours. After the distillation was completed, Pd (dppf) Cl2 (0.036 kg) was added as a solid at one time under a nitrogen blanket and the compound VI solution was transferred to the feeding funnel and added in batches within 45 minutes. The reactants were heated at 75-80 ° C and sampled after 16 hours to detect the completion of the reaction. A supplemental charge of B2pin2 (90 g), KOAc (90 g), and Pd(dppf)Cl2 (3.7 g) was added and the reaction was resampled after an additional 4 hours of reaction time. After completion of the reaction, the crude product was processed as described above. After 3 days, the off-white solid was removed from the drying oven and weighed 0.674 kg (66.3% isolated yield) of Compound II (99.9% AUC).

[0201] Azeotropic removal of water prior to initiation of Miyaura borylation to form compound II, followed by controlled addition of compound VI (41% w / w, H2O<0.1% w / w) to the heated mixture, successfully minimized the formation of undesirable byproducts such as homo-coupled impurities of compound VI (as follows). Azeotropic removal under nitrogen is also a way to degas the mixture before the reaction begins. As determined by HPLC in the above procedure, the reduction of homo-coupled impurities and solvent degassing resulted in an increase in isolated yield of 3.0% and an increase in purity of 5.2%. When water is azeotropically removed, the amount of homo-coupled impurities is typically reduced to less than 1% (0.07% in the above procedure). Failure to remove water typically results in 4-7% homo-coupled impurities, but values ​​as high as 45% were observed during the development of the preparation procedure. Therefore, azeotropic removal of water helps to reduce yield variation in the preparation procedure.

[0202]

[0203] Step 4. 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazine-3-yl Synthesis of (2H)-Ketone (Compound I)

[0204] Compound III (0.30 kg), 2-MeTHF (3.3 kg) and Compound II (0.41 kg) were added to a 12L 3-neck round-bottom flask equipped with a mechanical stirrer (glass rod with PTFE stirring blades), a nitrogen inlet, an internal thermocouple and an external heating jacket. The reactor contents were set to stir and NaHCO (0.21 kg) was added, followed by H O (2.0 kg). The mixture was sprayed subsurface with nitrogen for 10 minutes, and then solid Pd (amphos) Cl (0.013 kg) was added once under a nitrogen blanket. The spray needle was removed, and the mixture was heated to 70-80 ° C under a gentle nitrogen blanket. When IPC analysis showed that 0.1% of Compound III remained (with respect to Compound I, target specification ≤ 1%), the mixture was vigorously stirred at temperature for 4 hours. The mixture was cooled to room temperature and stirred overnight for 13 hours.

[0205] Stirring was stopped and the layers were allowed to settle. The aqueous (bottom) layer was removed and the organic layer was concentrated to about 2.2 L under vacuum. Ethyl acetate (3.6 kg) was added to the vessel and the concentration was repeated again to remove about 4.5 L of distillate. An additional 3.7 kg of EtOAc was added. The organic layer was washed with 5% (w / w) aqueous brine (2.0 kg), and then a silica-loaded thiourea metal scavenger (Carbosynth, 0.066 kg) was added to the organic layer and the mixture was stirred at room temperature under nitrogen for 24 hours. At this point, additional silica ( 60-200μm 0.48kg) and stirred for 30 minutes.Then the mixture was filtered through a Buchner filter funnel and the solid was washed twice with EtOAc (1.4kg each time).The filtrate and washings were cartridge filtered under vacuum into a 20L rotary evaporator receiving bottle.The external heating bath was set to 42-45°C and the EtOAc was removed to a volume of about 1.5L.

[0206] Isopropanol (0.98kg) is added to the bulk mixture, and concentration is continued under vacuum until a volume of about 1.5L is reached. Two additional chase-distillation cycles (0.92kg isopropanol is added each time), and a volume of about 1.5L is reached. The bulk stream is diluted with additional isopropanol (0.92kg), and the mixture is transferred to a 5L 3-neck round-bottom flask equipped with a mechanical stirrer, a nitrogen inlet, and an internal thermocouple. The mixture is heated to 60 ± 5 ° C via an external heating jacket, and stirred at this temperature until the complete dissolution of the solid is noted. The solution is then cooled to 50-55 ° C. The seed of ground compound I (3.3g, 1.1% w / w relative to the input of compound III) is incorporated into the batch and maintained at this temperature for 1 hour. Turn off the heat source and cool the reaction mixture to ambient temperature and stir for 16 hours. At this point, the concentration of compound I in the supernatant evaluated by HPLC is 24.2mg / mL. The bulk slurry was filtered on a 7 micron polypropylene filter cloth under vacuum 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 with a nitrogen blanket for 45 minutes. The bulk solid was then transferred to a vacuum drying oven with nitrogen venting and dried at 45° C. for 2 days. The white solid was weighed as 382.8 g of Compound I (80.2% yield; 99.7% AUC5).

[0207] Although preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Without departing from the present disclosure, those skilled in the art will now appreciate that many variations, changes and substitutions may be employed in the implementation of the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed.

Claims

1. A method for preparing a compound of formula 1: Where X 1 is a halogen; and R 1 is a C1-C6 haloalkyl group; The method comprises: reacting a compound of Formula 2 with a compound of Formula 3 under coupling conditions in the presence of a metal catalyst, a base, in a suitable solvent to provide a compound of Formula 1; Where R 1 is a C1-C6 haloalkyl group; and B is selected from boric acid and boric acid esters; Where X 1 is a halogen; and Y is a leaving group.

2. The method of claim 1, wherein R 1 It is a C1-C3 haloalkyl group.

3. The method of claim 2, wherein R 1 Selected from -CF3, -CHF2, -CH2CF3 and -CH2CHF2.

4. The method of any one of claims 1 to 3, wherein B is selected from 5. The method of claim 4, wherein B is selected from 6. The method of any one of claims 1 to 5, wherein Y is selected from halogens and pseudohalides.

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

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

9. The method of any one of claims 1 to 8, wherein X 1 Selected from -F and -Cl.

10. The process of any one of claims 1 to 9, wherein the metal catalyst is a palladium catalyst.

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

13. The method of claim 12, wherein 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, TrixiePhos, t-BuDavePhos, t-BuMePhos, MePhos, PhDavePhos, VPhos, PhCPhos, XPhos-SO3Na, water-soluble SPhos, CPhos, EtCPhos, RockPhos, AlPhos and t-BuPhCPhos.

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

15. The method of claim 12, wherein the phosphite is selected from the group consisting of trimethyl phosphite and triphenyl phosphite.

16. The method of claim 12, wherein the bisphosphine is selected from bis(diphenylphosphino)methane (dppm), 1,2'-bis(diphenylphosphino)ethane (dppe), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(dicyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 1,1'-bis(diisopropylphosphino)ferrocene (dippf).

17. The method of claim 16, wherein the bisphosphine is selected from 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(dicyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 1,1'-bis(diisopropylphosphino)ferrocene (dippf).

18. The method of claim 12, wherein the metal catalyst is selected from Pd(dppf)Cl2, Pd(Amphos)2Cl2, Pd(dcypf)Cl2, Pd(dtbpf)Cl2, Pd(XantPhos)Cl2, PdCl2(DPEPhos), Pd(PCy3)Cl2, XPhos-Pd-G2 and RuPhos-Pd-G2.

19. The method of claim 18, wherein the metal catalyst is Pd(Amphos)2Cl2.

20. The method of claim 12, wherein the metal catalyst is a palladium cycle.

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

22. The process of any one of claims 1 to 21, wherein the suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO3, NaOAc, KOAc, KOMe, KOtBu Ba(OH)2, Li2CO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, Na3PO4, K3PO4, KF, Na2HPO4 and CsF.

23. The process of claim 22, wherein the suitable base is selected from KOAc, NaHCO3 and K2CO3.

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

25. 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, isopropanol, 1,4-dioxane, toluene, cyclopentyl methyl ether, water, and any combination thereof.

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

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

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

30. The method of any one of claims 1 to 29, wherein the reaction conditions include a stirring time of about 0.1 h to about 24 h.

31. The method of claim 30, wherein the reaction conditions include a stirring time of about 0.5 h to about 5 h.

32. The method of any one of claims 1 to 31, wherein 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 depicted as follows:

33. The method 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. The method 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. The method of claim 34, wherein the molar ratio of Compound II to Compound III is about 1.0:1.

0.

36. The method of any one of claims 32 to 35, wherein the metal catalyst is Pd(Amphos)2Cl2.

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

05.

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

04.

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

02.

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

015.

42. The process of any one of claims 32 to 41, wherein the suitable base is selected from NaHCO3, K2CO3 and Cs2CO3.

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. 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. The method of claim 44, wherein the molar ratio of Compound II to the suitable base is about 1.0:2.

0.

46. ​​The method of any one of claims 32 to 45, wherein the solvent is a combination of 2-MeTHF and H2O.

47. The method of claim 46, wherein the ratio of 2-MeTHF to H2O is about 2:

1.

48. The method of any one of claims 1 to 31, wherein the compound of Formula 3 is prepared by contacting a compound of Formula 4 with a compound of Formula 5 or a salt thereof in the presence of a suitable base in a suitable solvent to provide a compound of Formula 3: Y is a leaving group; Where X 1 is a halogen; and X 3 It's a halogen.

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

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

51. The method of any one of claims 48 to 50, wherein X 1 Selected from -F and -Cl.

52. The method of any one of claims 48 to 51, wherein X 3 Selected from -Cl and -Br.

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

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

55. The method of any one of claims 48 to 54, wherein the suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO3, NaOAc, KOAc, KOMe, KOtBu Ba(OH)2, Li2CO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, Na3PO4, K3PO4, KF and CsF.

56. The process of claim 55, wherein the suitable base is selected from the group consisting of KOAc, NaHCO3 and K2CO3.

57. The method 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, isopropanol, 1,4-dioxane, toluene, cyclopentyl methyl ether, methyl-tert-butyl ether, water, and any combination thereof.

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

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

60. The method of claim 59, wherein the reaction conditions include a stirring time of about 0.5 h to about 5 h.

61. The method of any one of claims 48 to 60, wherein 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 depicted as follows: and 62. The method 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. The method 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. The method of claim 63, wherein the molar ratio of Compound IV to Compound V is about 1.0:1.

0.

65. The method of any one of claims 61 to 64, wherein the suitable base is K2CO3.

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

0.

69. The method of any one of claims 61 to 68, wherein the solvent is a combination of NMP and H2O.

70. The method of claim 69, wherein the solvent combination is 20% H2O by volume.

71. The method of any one of claims 61 to 68, wherein the solvent is a combination of NMP 2-methylTHF and H2O.

72. The method of claim 71, wherein the solvent combination is 50% H2O by volume.

73. The method of any one of claims 1 to 72, further comprising preparing a compound of formula 2: Where R 1 is a C1-C6 haloalkyl group; and B is selected from boric acid and boric acid esters; The method comprises: contacting a compound of Formula 6 with a boron compound in the presence of a metal catalyst, a suitable base, in a suitable solvent to provide a compound of Formula 2, wherein the boron compound comprises a boron-boron bond or a boron-hydrogen bond; Where R 1 is a C1-C6 haloalkyl group; and X 2 It's a halogen.

74. A method for preparing a compound of formula 2: Where R 1 is a C1-C6 haloalkyl group; and B is selected from boric acid and boric acid esters; The method comprises: contacting a compound of Formula 6 with a boron compound in the presence of a metal catalyst, a suitable base, in a suitable solvent to provide a compound of Formula 2, wherein the boron compound comprises a boron-boron bond or a boron-hydrogen bond; Where R 1 is a C1-C6 haloalkyl group; and X 2 It's a halogen.

75. The method of claim 73 or 74, wherein R 1 It is a C1-C3 haloalkyl group.

76. The method of claim 75, wherein R 1 Selected from -CF3, -CHF2, -CH2CF3 and -CH2CHF2.

77. The method of any one of claims 71 to 74, wherein B is selected from 78. The method of claim 77, wherein B is selected from 79. The method of any one of claims 73 to 78, wherein X 2 is selected from -Cl, -Br and -I.

80. The method of any one of claims 73 to 79, wherein the boron compound is selected from 81. The method of claim 80, wherein the boron compound is selected from 82. The method of any one of claims 73 to 81, wherein the metal catalyst is a palladium catalyst.

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. The method of any one of claims 73 to 83, wherein the metal catalyst comprises palladium and one or more ligands, wherein the one or more ligands are selected from phosphines, phosphites, and bisphosphines.

85. The method of claim 84, wherein the phosphine is selected from 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 PhCPhos, AlPhos.

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

87. The method of claim 84, wherein the phosphite is selected from the group consisting of trimethyl phosphite and triphenyl phosphite.

88. The method of claim 84, wherein the bisphosphine is selected from bis(diphenylphosphino)methane (dppm), 1,2'-bis(diphenylphosphino)ethane (dppe), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(dicyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf), and 1,1'-bis(diisopropylphosphino)ferrocene (dippf).

89. The method of claim 88, wherein the bisphosphine is selected from 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(dicyclohexylphosphino)ferrocene (dcypf), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf), and 1,1'-bis(diisopropylphosphino)ferrocene (dippf).

90. The method of claim 84, wherein the metal catalyst is selected from the group consisting of Pd(dppf)Cl2, Pd(Amphos)2Cl2, Pd(dcypf)Cl2, Pd(dtbpf)Cl2, Pd(XantPhos)Cl2, PdCl2(DPEPhos), Pd(PCy3)Cl2, XPhosPd G2 and RuPhos-Pd-G2.

91. The method of claim 84, wherein the metal catalyst is Pd(dppf)Cl2.

92. The method of claim 84, wherein the metal catalyst is Pd(Amphos)2Cl2.

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

94. The method of any one of claims 73 to 90, wherein the suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO3, NaOAc, KOAc, KOMe, KOtBu Ba(OH)2, Li2CO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, Na3PO4, K3PO4, KF and CsF.

95. The method of claim 91, wherein the suitable base is selected from the group consisting of KOAc, NaHCO3 and K2CO3.

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

97. The method 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, isopropanol, 1,4-dioxane, toluene, cyclopentyl methyl ether, water, and any combination thereof.

98. The method 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, isopropanol, 1,4-dioxane, toluene, cyclopentyl methyl ether, and any combination thereof.

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

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

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

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

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

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. The method of claim 104, wherein the borate ester or acid, the suitable base and the suitable solvent are heated to reduce water from the solvent prior to adding the metal catalyst and the compound of Formula 2.

107. The method of any one of claims 104 to 106, wherein the removal of water reduces the formation of the homocoupled impurity of Formula 6 by 1% to 10%.

108. The method of claim 107, wherein the removal of water reduces the formation of the homo-coupled impurity of Formula 6 by 1% to 5%.

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

110. The method of claim 109, wherein the removal of water increases the yield of the compound of Formula 2 by 1% to 5%.

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

112. The method of claim 111, wherein the reaction conditions include a stirring time of about 0.5 h to about 24 h.

113. The method of any one of claims 73 to 112, wherein the compound of Formula 2 is Compound II, the compound of Formula 6 is Compound VI and each is depicted as follows: and The boron compound is 114. The method 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. The method 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. The method of claim 115, wherein the molar ratio of Compound VI to the boron compound is about 1.0:1.

0.

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

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

0.

121. The process of any one of claims 113 to 120, wherein said metal catalyst is Pd(dppf)2Cl2.

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

05.

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

04.

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

02.

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

015.

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

128. The method of any one of claims 73 to 127, wherein the compound of Formula 6 is prepared by contacting a compound of Formula 7 with a compound of Formula 8 in the presence of a suitable base in a suitable solvent to provide a compound of Formula 6; Where X 2 is a halogen; and X 3 It is a halogen; HOR1 Formula 8; Where R 1 It is a C1-C6 haloalkyl group.

129. The method of claim 128, wherein R 1 It is a C1-C3 haloalkyl group.

130. The method of claim 129, wherein R 1 Selected from -CF3, -CHF2, -CH2CF3 and -CH2CHF2.

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

132. The method of any one of claims 128 to 131, wherein X 3 Selected from -Cl and -Br.

133. The process of any one of claims 128 to 132, wherein the suitable base is selected from triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaHCO3, NaOAc, KOAc, KOMe, KOtBu Ba(OH)2, Li2CO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, Na3PO4, K3PO4, KF and CsF.

134. The process of claim 133, wherein the suitable base is selected from the group consisting of KOAc, NaHCO3 and K2CO3.

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

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

137. The method of claim 136, wherein the suitable solvent is selected from the group consisting of acetonitrile, dimethyl sulfoxide, tetrahydrofuran, N-methyl-2-pyrrolidone, dimethylformamide, methyl-tert-butyl ether, 1,4-dioxane, water, and any combination thereof.

138. The method of any one of claims 128 to 137, wherein the compound of Formula 6 is Compound VI and the compound of Formula 7 is Compound VII, each depicted as follows: And the compound of formula 8 is CF3CH2OH.

139. The method of claim 138, wherein the molar ratio of Compound VII to CF3CH2OH is from about 1.0:1.0 to about 1.0:1.

5.

140. The method of claim 139, wherein the molar ratio of Compound VII to CF3CH2OH is from about 1.0:1.0 to about 1.0:1.

2.

141. The method of claim 140, wherein the molar ratio of Compound VII to CF3CH2OH is about 1.0:1.

1.

142. The process of any one of claims 138 to 141, wherein said suitable base is K2CO3.

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. 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. The method of claim 144, wherein the molar ratio of Compound VII to the suitable base is about 1.0:1.

6.

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

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

Images