Imidazopyridine compound as well as preparation method and application thereof

Abstract

The invention discloses an imidazopyridine compound as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The imidazopyridine compound is shown as a formula V and can be used as an intermediate for preparing a substituted imidazo [1, 2-a] pyridine-2-yl amide compound, and the imidazopyridine compound has the characteristics of high stability and long-term storage when being used as the intermediate, so that the substituted imidazo [1, 2-a] pyridine-2-yl amide compound designed by using the intermediate disclosed by the invention has the advantages of high stability and high yield. The product quality is easy to control according to the synthetic route of the [1, 2-a] pyridine-2-yl amide compound. And the method for preparing the substituted imidazo [1, 2-a] pyridine-2-yl amide compound through the intermediate also has the advantages of high yield and simplicity and convenience in operation, and is suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and particularly relates to an imidazo[1,2-a]pyridine compound, a preparation method thereof and an application thereof. Background Art

[0002] The Janus kinase (JAK) signaling pathway, which is found in interferon-induced receptor-mediated gene expression, has been shown to be a common signaling pathway used by many cytokines and growth factors. The mammalian JAK family of intracellular tyrosine kinases has four members: Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3) and tyrosine kinase 2 (TYK2). JAKs range in size from 120 to 140 kDa and include seven conserved JAK homology (JH) domains that define this kinase superfamily.

[0003] Each JAK isoform can be used by multiple cytokine pathways, and the biological activities of many cytokines can be regulated by the inhibition of one or more JAKs. Inhibition of JAK can be used to prevent, inhibit or treat the progression or onset of various diseases and disorders, including hyperproliferative diseases and cancers such as leukemia and lymphoma, and immune and inflammatory disorders such as transplant rejection, asthma, chronic obstructive pulmonary disease, allergies, rheumatoid arthritis, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis and multiple sclerosis.

[0004] The substituted imidazo[1,2-a]pyridin-2-ylamide compounds represented by Formula I are a class of reported (such as WO2016119700A1) effective JAK inhibitors,

[0005]

[0006] wherein the definitions of each group are: R 1 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl; R 2 and R 3 are independently selected from halogen and C 1 -C 6 alkyl; m and n are each independently 0, 1, 2, 3 or 4.

[0007] In WO2016119700 A1, the following synthetic route 1 of the compound of Formula I is disclosed:

[0008]

[0009] The main steps of the above-mentioned synthetic route 1 are: first, remove the protecting group on the amino group of compound 1, react the obtained amino compound 2 with an alkyl acyl chloride, and then couple it with compound 4 to finally obtain the target compound I.

[0010] However, synthetic route 1 is not suitable for industrial production due to the following problems: (a) the intermediates and final products contain a large number of impurities and by-products, and the purification of the intermediates in each step requires column chromatography, which consumes a large amount of solvent and is difficult to scale up, which is not conducive to industrial production; (b) the coupling reaction of compound 3 and compound 4 requires the use of a heavy metal-containing catalyst, which can easily cause the heavy metal residue in the product to be too high, making the product unqualified.

[0011] On this basis, considering that amino compounds can be salified, and the salified compounds are easy to crystallize, which is more conducive to post-processing and product purification. Therefore, an attempt was made to first prepare an amino compound having a skeleton of formula I (such as formula III), and then obtain the target compound by acylation reaction. After exploration and adjustment, a new synthetic route 2 for preparing compounds of formula I was obtained (see WO2022032644A1), as follows:

[0012]

[0013] However, it is found in practice that the synthetic route 2 has the problem of low yield in scale-up production and is also difficult to be applied to industrial production.

[0014] Therefore, it is necessary to explore a preparation method that is simple to operate, easy to control product quality and suitable for industrial production. Summary of the invention

[0015] In view of the problem of lack of a method suitable for industrial production of substituted imidazo[1,2-a]pyridine-2-ylamide compounds, the present invention provides an intermediate for preparing the above-mentioned substituted imidazo[1,2-a]pyridine-2-ylamide compounds, an imidazopyridine compound shown in Formula V. The imidazopyridine compound has high stability and can be stored for a long time when used as an intermediate, so that the synthetic route of the substituted imidazo[1,2-a]pyridine-2-ylamide compounds designed by the intermediate of the present invention is easy to control the product quality. The method for preparing substituted imidazo[1,2-a]pyridine-2-ylamide compounds by using the intermediate also has the advantages of high yield and simple operation, and is suitable for industrial production.

[0016] A compound represented by the following formula V,

[0017]

[0018] in:

[0019] R1 Selected from: C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl;

[0020] R 2 and R 3 Each independently selected from: halogen and C 1 -C 6 alkyl;

[0021] R 4 Selected from: amino protecting groups;

[0022] m and n are each independently selected from: 0, 1, 2, 3 and 4.

[0023] The inventors found in the previous study that the compound shown in Formula I prepared by the disclosed synthetic route 2 has the problem of low yield. On the one hand, the compound of Formula III is unstable, and the amino group on the imidazopyridine is easily hydrolyzed to form a hydroxyl group, which is not conducive to storage and transportation as an intermediate, thus causing the problem of low yield. On the other hand, the compound of Formula III will form a salt with an acid during the reaction process and precipitate in the reaction system, thereby making the reaction system viscous and not conducive to stirring during the amplification process, and sometimes even causing incomplete reaction, further reducing the yield.

[0024] Based on this, the inventor optimized the synthetic route 2 and found that the compound of formula V has high stability. The inventor adjusted the reaction order of the last two steps, namely, acylation first and then deamination protection. On the one hand, the compound shown in formula V is used as the key intermediate of the reaction, and its high stability is used to develop the key intermediate of the present invention, which can be stored for a long time to prepare the compound of formula I. On the other hand, the method for preparing the compound of formula I using this key intermediate has the characteristics of easy control of product quality, high yield and suitability for industrial production. The present invention can increase the yield by more than 10% based on the synthetic route 2.

[0025] In some embodiments, R 1 In the C 1 -C 6 The alkyl group is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.

[0026] In some embodiments, R 1 In the C 3 -C 8 The cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

[0027] In some embodiments, R 2 and R3 Among them, the described C 1 -C 6 alkyl is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.

[0028] In some embodiments, R 2 and R 3 Among them, the halogen is arbitrarily selected from: iodine, bromine, chlorine or fluorine, preferably fluorine.

[0029] In some embodiments, R 4 Among them, the amino protecting group is tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), phthaloyl (Pht), p-toluenesulfonyl (Tos), trityl (Trt) or benzyl (Bn), preferably tert-butoxycarbonyl.

[0030] In some embodiments, m is 0.

[0031] In some embodiments, n is 1.

[0032] In some embodiments, the compound is:

[0033]

[0034] The present invention also provides a preparation method of the compound shown in the above formula V, including the following steps: in the presence of a base, the compound of formula II reacts with the compound of formula IV or the compound of formula VI in a solvent to carry out the following acylation reaction to obtain the compound of formula V:

[0035]

[0036] Among them, the definitions of R 1 , R 2 and R 3 , m and n are as described above;

[0037] R 5 is F, Cl or Br, preferably Cl.

[0038] It can be understood that the above base can be a conventional base for such reactions.

[0039] In some embodiments, the acylation reaction is carried out under an inert gas atmosphere, and the inert gas can be nitrogen.

[0040] In some embodiments, in the acylation reaction, the base is selected from: organic bases, preferably one or more of triethylamine, N,N-diisopropylethylamine, pyridine, tri-n-butylamine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetramethylguanidine, 4-pyrrolidinopyridine, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, N-methylmorpholine, and more preferably a mixture of N,N-diisopropylethylamine or triethylamine, and most preferably N,N-diisopropylethylamine.

[0041] In some embodiments, in the acylation reaction, the solvent is selected from: a mixed solvent of one or more of chlorinated alkane solvents, ether solvents, and nitrile solvents, preferably chlorinated alkane solvents; wherein, the chlorinated alkane solvents are preferably dichloromethane, dichloroethane, chloroform or a mixture of any two or more thereof, and more preferably dichloromethane; the ether solvents are preferably tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane or a mixture of any two or more thereof; the nitrile solvent is preferably acetonitrile.

[0042] In some embodiments, in the acylation reaction, the molar ratio of the compound of formula IV or the compound of formula VI to the compound of formula II is 1.0 to 3.0, preferably 1.2 to 2.0, more preferably 1.5 to 2.0, most preferably 1.55 to 1.65, and even more preferably 1.59.

[0043] In some embodiments, in the acylation reaction, the volume-mass ratio of the solvent to the compound of formula II can be 4 to 10 L / kg, preferably 6 to 8 L / kg, and most preferably 7 L / kg.

[0044] In some embodiments, in the acylation reaction, the molar ratio of the base to the compound of formula II is 1.0 to 3.0, preferably 1.5 to 2.5, more preferably 1.5 to 2.0, even more preferably 1.8 to 2.2, and most preferably 2.0;

[0045] In some embodiments, the temperature of the acylation reaction is 0 to 60 °C, preferably 20 to 55 °C, and most preferably 20 to 30 °C.

[0046] In some embodiments, the progress of the acylation reaction is monitored by TLC, GC, HPLC, and / or NMR, and the reaction end point is determined when the compound of formula II disappears.

[0047] In some embodiments, the reaction time of the acylation reaction is 0.5 to 12 hours, more preferably 0.5 to 5 hours, and even more preferably 0.5 to 1 hour.

[0048] In some embodiments, after the acylation reaction, a post-treatment step is further included, and the post-treatment step includes: adding water to the reaction solution, stirring and then standing still, taking the organic phase, filtering the organic phase and recovering the solvent to obtain the crude product of the compound of formula V.

[0049] In some embodiments, the organic phase is obtained by liquid separation and / or the solvent is recovered by reduced pressure concentration.

[0050] In some embodiments, the volume ratio of the water added to the reaction solution in the post-treatment step to the solvent used in the acylation reaction is 3:1 to 1:3, preferably 1:1 to 1:2, and further preferably 4:7.

[0051] In some embodiments, the stirring time is 0.2 to 5 hours, preferably 0.4 to 1 hour, and most preferably 0.5 hour.

[0052] In some embodiments, after filtering the organic phase, a step of washing with an organic solvent and then combining the organic solvents is further included, and preferably the same organic solvent as that used in the acylation reaction is used as the washing solvent.

[0053] In some embodiments, after the post-treatment, a preliminary purification step is further included, and the preliminary purification step includes: placing the crude product of the compound of formula V in a mixed organic solvent composed of organic solvent B and organic solvent C, stirring and slurrying, then filtering, collecting the filter cake and drying to obtain the product of the compound of formula V; the organic solvent B is selected from ether solvents, and the organic solvent C is selected from alkane solvents.

[0054] In some embodiments, in the preliminary purification step, the organic solvent B is selected from: methyl tert-butyl ether, 1,4-dioxane or a mixture thereof, preferably methyl tert-butyl ether.

[0055] In some embodiments, in the preliminary purification step, the organic solvent C is selected from: n-heptane, n-hexane or petroleum ether, preferably n-heptane.

[0056] In some embodiments, in the preliminary purification step, the volume percentage of the organic solvent B in the mixed organic solvent is 40% to 80%, preferably 55% to 70%, further preferably 60% to 65%, and most preferably 62.5%.

[0057] In some embodiments, in the preliminary purification step, the slurrying time is 0.4 to 5 hours, preferably 0.4 to 1 hour, and most preferably 0.5 hour.

[0058] In some embodiments, the preliminary purification step further includes a washing step, and / or, a deep purification step is further included after the preliminary purification step.

[0059] In some embodiments, the washing step includes: before filtering and collecting the filter cake for drying, washing the obtained filter cake with the organic solvent C.

[0060] In some embodiments, the deep purification step includes: stirring and pulping the product of the formula V compound obtained in the preliminary purification step with a mixed solvent of an organic solvent D and water, then filtering, collecting the filter cake and drying to obtain a further purified product of the formula V compound, wherein the organic solvent D is a polar solvent.

[0061] In some embodiments, the deep purification step further includes a step of washing the obtained filter cake with water before filtering and collecting the filter cake for drying.

[0062] In some embodiments, in the deep purification step, the organic solvent D is N,N-dimethylformamide, ethanol, THF or acetonitrile, preferably N,N-dimethylformamide.

[0063] In some embodiments, in the deep purification step, the volume percentage of the organic solvent D in the mixed solvent of the organic solvent D and water is 20% - 80%, preferably 40 - 60%, more preferably 45% - 55%, and most preferably 50%.

[0064] In some embodiments, the pulping time in the deep purification step is 0.4 - 5 hours, preferably 0.4 - 1 hour, and most preferably 0.5 hour.

[0065] The present invention also provides the use of the compound shown in the above formula V as an intermediate in the preparation of imidazo[1,2-a]pyridin-2-ylamide compounds.

[0066] The present invention also provides a preparation method of the compound shown in formula I, including the following steps: in the presence of an acid, in a solvent, the compound of formula V undergoes the following deprotection reaction of the amino group in the solvent to obtain the compound of formula I:

[0067]

[0068] Wherein, R 1 , R 2 and R 3 , m and n are as defined above.

[0069] In some embodiments, the compound of formula V is obtained by the above preparation method. That is, the route for preparing the compound of formula I from the compound of formula II is:

[0070]

[0071] In some embodiments, the deprotection reaction of the amino group is carried out in an inert gas atmosphere, and the inert gas can be nitrogen.

[0072] In some embodiments, in the deprotection reaction of the amino group, the acid is selected from: organic acids, inorganic acids or mixtures thereof, preferably inorganic acids; wherein, the inorganic acid is preferably hydrochloric acid, phosphoric acid or mixtures thereof, more preferably hydrochloric acid; the organic acid is preferably trifluoroacetic acid, formic acid or mixtures thereof, more preferably trifluoroacetic acid.

[0073] In some embodiments, in the deprotection reaction of the amino group, the solvent is selected from: ether solvents, chloroalkane solvents, C 1 -C 6 alcohol solvents, ester solvents, water or a mixed solvent of two or more of them, preferably ether solvents, chloroalkane solvents or a mixed solvent thereof, more preferably ether solvents; wherein, the ether solvents are preferably anisole, tert-butyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane or a mixture of two or more of them, preferably anisole, methyl tert-butyl ether or a mixture thereof, more preferably anisole; the chloroalkane solvents are preferably dichloromethane, chloroform, dichloroethane or a mixture of two or more of them, more preferably dichloromethane; the C 1 -C 6 alcohol solvents are preferably methanol, ethanol, isopropanol or a mixture of two or more of them, more preferably ethanol; the ester solvents are preferably methyl acetate, ethyl acetate, propyl acetate or a mixture of two or more of them, more preferably ethyl acetate.

[0074] In some embodiments, in the deprotection reaction of the amino group, the molar ratio of the acid to the compound of formula V is 5 to 50, preferably 5 to 20, more preferably 10 to 12, and even more preferably 10.8 to 11.0.

[0075] In some embodiments, in the deprotection reaction of the amino group, the concentration of the acid in the deprotection reaction system of the amino group is 1 to 3 mol / L, preferably 2 mol / L; and the working concentration of the acid is 3 to 5 mol / L, preferably 4 mol / L.

[0076] In some embodiments, in the deprotection reaction of the amino group, the reaction temperature of the deprotection reaction of the amino group is 0 to 40 °C, preferably 10 to 30 °C, more preferably 20 to 30 °C.

[0077] In some embodiments, the progress of the deprotection reaction of the amino group is monitored by TLC, GC, HPLC and / or NMR, and the reaction end point is detected when the compound of formula V disappears.

[0078] In some embodiments, the reaction time of the amino deprotection reaction is 1 to 24 hours, preferably 1 to 5 hours, more preferably 1 to 2 hours, and most preferably 1 hour.

[0079] In some embodiments, the post-treatment step is also included in the amino deprotection reaction. The post-treatment step is as follows: A metal chelating agent is added to the reaction system, and an alkaline solution is added to adjust its pH to precipitate the product, and then the crude product of the compound of formula I is obtained by filtration. The alkaline solution can be ammonia water, sodium bicarbonate, sodium carbonate or sodium hydroxide.

[0080] In some embodiments, the alkaline solution in the post-treatment step is ammonia water, and the addition method is dropwise addition, and the pH value is adjusted to 8.5 to 9.5, preferably the pH value is adjusted to 9.0.

[0081] In some embodiments, in the amino deprotection reaction, the temperature of the reaction system is controlled to be 5 to 35 °C, preferably 10 to 30 °C, and more preferably 20 to 30 °C when the alkaline solution is added in the post-treatment step.

[0082] In some embodiments, the metal chelating agent added in the post-treatment step is N-acetyl-L-cysteine, preferably added in the form of solid powder and stirred evenly. The mass ratio of N-acetyl-L-cysteine to the compound of formula V is 0.05 to 0.20, preferably 0.10 to 0.15, and more preferably 0.10. It can be understood that the addition of the metal chelating agent is to remove the metal catalysts that may remain in the raw materials. The specific type can be selected according to the actual situation, but the use of N-acetyl-L-cysteine has a better effect in this case.

[0083] Furthermore, the order of adding the metal chelating agent and adding ammonia water to adjust the pH is not limited, that is, adding the metal chelating agent before adding ammonia water to adjust the pH, simultaneously with adding ammonia water to adjust the pH, or after adding ammonia water to adjust the pH can achieve the effect of removing the metal catalysts that may remain in the raw materials. In some embodiments, in the amino deprotection reaction, the post-treatment step also includes the step of washing the filter cake of the crude product of the compound of formula I obtained by filtration with water.

[0084] In some embodiments, a purification step is also included after the post-treatment step. The purification step selects Method 1 or Method 2.

[0085] Method 1 is: The crude product of the compound of formula I obtained in the post-treatment step is heated and stirred in a mixed system of organic solvent A and water, then cooled and filtered, and the filter cake is collected and dried to obtain the product of the compound of formula I.

[0086] The method 2 is as follows: The crude product of the compound of formula I obtained in the post-treatment step is heated and stirred in organic solvent A, then water is added, and then stirring is continued followed by cooling and filtration. The filter cake is collected and dried to obtain the compound product of formula I;

[0087] The organic solvent A is a cyclic ether organic solvent and / or an alcohol organic solvent. The cyclic ether solvent can be tetrahydrofuran or 1,4-dioxane, preferably tetrahydrofuran. The alcohol solvent can be ethanol, isopropanol or tert-butanol, preferably ethanol.

[0088] In some embodiments, in the purification step, the volume-mass ratio of the organic solvent A to the compound of formula V is 3-5 L / Kg, preferably 3.5-4.5 L / Kg, and most preferably 4.0 L / Kg.

[0089] In some embodiments, in the purification step, the volume ratio of the water used to the organic solvent A is 3:1-1:1, preferably 2:1-1.5:1, and most preferably 7:4.

[0090] In some embodiments, in the purification step, the temperature of the heating and stirring is 30-55 °C, preferably 35-50 °C, and further preferably 35-45 °C.

[0091] In some embodiments, in method 1, the time of the heating and stirring is 0.5-10 hours, preferably 2-5 hours, and further preferably 3-4 hours.

[0092] In some embodiments, in method 2, the time for heating and stirring the compound of formula V in the organic solvent A is 0.5-10 hours, preferably 2-5 hours, and further preferably 3-4 hours.

[0093] In some embodiments, in method 2, the time for stirring after adding water is 0.5-10 hours, preferably 1-5 hours, and further preferably 1-2 hours.

[0094] In some embodiments, the purification step further includes a step of washing the filter cake with water before collecting the filter cake.

[0095] In some embodiments, the preparation method of the compound shown in formula I includes the following steps:

[0096] (1) In the presence of a base, the compound of formula II is subjected to the acylation reaction as described above with the compound of formula IV or the compound of formula VI in a solvent to obtain the compound of formula V;

[0097] The acylation reaction satisfies the following conditions:

[0098] The acylation reaction is carried out in an inert gas atmosphere, and the inert gas can be nitrogen;

[0099] The base is selected from: organic bases, preferably N,N-diisopropylethylamine;

[0100] The solvent is selected from: chlorinated alkane solvents, preferably dichloromethane;

[0101] The molar ratio of the compound of formula IV or the compound of formula VI to the compound of formula II is 1.0 to 3.0, preferably 1.2 to 2.0, more preferably 1.5 to 2.0, still more preferably 1.55 to 1.65, and most preferably 1.59;

[0102] The volume-mass ratio of the solvent to the compound of formula II is 4 to 10 L / kg, preferably 6 to 8 L / kg, and most preferably 7 L / kg;

[0103] The molar ratio of the base to the compound of formula II is 1.0 to 3.0, preferably 1.5 to 2.5, more preferably 1.5 to 2.0, still more preferably 1.8 to 2.2, and most preferably 2.0; and

[0104] The temperature of the acylation reaction is 0 to 60 °C, preferably 20 to 55 °C, and most preferably 20 to 30 °C;

[0105] (2) In the presence of an acid, in a solvent, the compound of formula V undergoes the amino deprotection reaction as described above in the solvent to obtain the compound of formula I;

[0106] The amino deprotection reaction satisfies the following conditions:

[0107] The amino deprotection reaction is carried out under an inert gas atmosphere, and the inert gas can be nitrogen;

[0108] The acid is selected from: inorganic acids, preferably hydrochloric acid;

[0109] The solvent is selected from: ether solvents, preferably anisole;

[0110] The molar ratio of the acid to the compound of formula V is 5 to 50, preferably 5 to 20, more preferably 10 to 12, still more preferably 10.8 to 11.0;

[0111] The concentration of the acid in the amino deprotection reaction system is 1 to 3 mol / L, preferably 2 mol / L; and the working concentration of the acid is 3 to 5 mol / L, preferably 4 mol / L; and

[0112] The reaction temperature of the amino deprotection reaction is 0 to 40 °C, preferably 10 to 30 °C, more preferably 20 to 30 °C.

[0113] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0114] The term "C 1 -C 6 -alkyl" means a saturated straight-chain or branched-chain alkyl group having 1 to 6, especially 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., especially methyl or ethyl.

[0115] The term "C 3 -C 8 -cycloalkyl" means a saturated monocyclic or polycyclic cyclic alkyl group having 3 to 8, especially 3 to 6 carbon atoms, wherein the saturated monocyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., especially cyclopropyl.

[0116] The term "working concentration" refers to the concentration in the microenvironment when the reaction occurs. For example, when a 4 mol / L hydrochloric acid solution (3.5 L) is added to anisole (3.5 L) solvent to form a reaction system, the concentration of hydrochloric acid in the reaction system is 2 mol / L. However, since hydrochloric acid aqueous solution and anisole are immiscible, in the microenvironment of the aqueous phase, the working concentration of hydrochloric acid participating in the reaction is still 4 mol / L.

[0117] Abbreviations:

[0118] Pd(dppf)Cl 2 .CH 2 Cl 2 : Dichloromethane complex of dichlorobis[1,1'-bis(diphenylphosphino)ferrocene]palladium(II).

[0119] DIPEA: N,N-Diisopropylethylamine.

[0120] M: Mol / L.

[0121] DCM: Dichloromethane.

[0122] TEA: Triethylamine.

[0123] THF: Tetrahydrofuran.

[0124] MTBE: Methyl tert-butyl ether.

[0125] EA: Ethyl acetate.

[0126] DMF: N,N-Dimethylformamide.

[0127] On the basis of conforming to the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain the preferred examples of the present invention.

[0128] The reagents and raw materials used in the present invention are all commercially available.

[0129] The positive and progressive effects of the present invention are as follows:

[0130] The imidazopyridine compounds of formula V of the present invention can be used as intermediates for the preparation of substituted imidazo[1,2-a]pyridin-2-ylamide compounds. The imidazopyridine compounds have the characteristics of high stability and can be stored for a long time as intermediates, making the synthetic route of substituted imidazo[1,2-a]pyridin-2-ylamide compounds designed through the intermediates of the present invention easy to control the product quality. Moreover, the method for preparing substituted imidazo[1,2-a]pyridin-2-ylamide compounds through this intermediate also has the advantages of high yield and simple operation, and is suitable for industrial production. In addition, in the preparation method of the present invention, heavy metal impurities and the like that may be introduced by raw materials are removed through steps such as purification and refining, improving the purity and safety of the obtained products. Detailed Description of the Invention

[0131] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. The experimental methods without specific conditions in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0132] In the following examples, the mass spectrometry was performed using a Waters Acquity Xevo G2-XS QTof UPLC / MS ultra-high performance liquid chromatography high-resolution mass spectrometry combined system. 1 1H-NMR was performed using a Bruker AVANCE III 400MHz nuclear magnetic resonance spectrometer or a Bruker AVANCE III HD 300MHz nuclear magnetic resonance spectrometer. HPLC was performed using an Agilent 1260 high-performance liquid chromatograph. IPC-MS detection was performed using a Thermo Fisher iCAP Q inductively coupled plasma mass spectrometer.

[0133] The compound of formula II was synthesized according to the method disclosed in WO2022032644A1. Among them, the compound IIa was synthesized according to the following route:

[0134]

[0135]

[0136] Under a nitrogen atmosphere, 16 L of 1,4-dioxane and 1.6 L of softened water were added to the reaction kettle. While stirring, SM1-1 (1.60 kg, 5.13 mol), SM2-1 (2.27 kg, 6.15 mol) and anhydrous potassium carbonate (1.42 kg, 10.27 mol) were added, and nitrogen protection was provided. Pd(dppf)Cl 2 .CH 2 C1 2(0.125 kg, 0.153 mol). Heat to about 95 °C and keep the reaction for at least 6 hours. After sampling and monitoring by HPLC, the reaction is shown to be complete. Add water and stir for 2 h, then filter to obtain the filter cake. Add acetonitrile (24 L), water (8 L) and the filter cake to the reaction kettle and stir for at least 2 hours. Filter and collect the filter cake. After vacuum drying at 55 °C for 16 hours, the product is collected to obtain Compound IIa (2.167 kg, HPLC purity 98.6%, yield 88.8%).

[0137] 1 Η(400 Hz, DMSO~d 6 ) δ ppm: 7.634 (1H, t), 7.495 (2H, m), 7.425 (1H, d, J = 7.6 Hz), 7.313 (2H, m), 6.920 (1H, d, J = 7.2 Hz), 3.832 (2H, s), 3.180 (4H, s), 2.973 (4H, s), 1.422 (9H, s). LCMS m / z: 475.2 (M+H).

[0138] Example

[0139] This example screens and optimizes the preparation method of Compound Ia.

[0140] Synthesis of Compound Ia: Compound Ia is prepared according to the following route.

[0141]

[0142] Step 1: Synthesis of Compound Va

[0143]

[0144] 1) Reaction condition 1:

[0145] Under a nitrogen atmosphere, add dichloromethane (4.9 L), Compound IIa (700 g, 1.48 mol) and DIPEA (382.9 g, 2.96 mol) to Reaction Flask A. Keep the temperature of the reaction system at 20 - 30 °C and add Compound IVa cyclopropylcarbonyl chloride (246.7 g, 2.36 mol) dropwise to the reaction system. Stir the resulting reaction solution for another 30 minutes. After sampling and analyzing by HPLC, the reaction is shown to be complete.

[0146] Keep the temperature of the reaction system at 20 - 30 °C and add pure water (2.8 L) dropwise to Reaction Flask A. Stir the resulting reaction system for another 30 minutes, then let it stand for 30 minutes. Separate the layers and collect the lower organic phase. Filter the organic phase, wash the filter cake with dichloromethane (0.7 L), combine the organic phases, and then concentrate the resulting organic phase under reduced pressure.

[0147] To the crude product of the concentrated compound, 3.5 L of methyl tert-butyl ether and 2.1 L of n-heptane were added, and the mixture was stirred for 30 minutes. The resulting suspension was filtered, and the filter cake was washed with n-heptane (1.4 L).

[0148] The obtained filter cake was further slurried with DMF (3.5 L) and pure water (3.5 L) by stirring for 30 minutes. The resulting filter cake was filtered and washed with pure water (1.4 L). The filter cake was collected and dried under vacuum at 45 °C to obtain 748.6 g of the white solid compound Va (yield: 93.53%, purity: 99.55%).

[0149] Characterization: 1 H (400 Hz, DMSO-d 6 ) δ ppm: 7.70–7.57 (m, 2H), 7.54 (d, J = 3.0 Hz, 1H), 7.50–7.35 (m, 3H), 7.04 (dd, J = 7.0, 1.2 Hz, 1H), 3.81 (s, 2H), 3.23–3.10 (m, 4H), 2.97 (dd, J = 7.2, 3.5 Hz, 4H), 2.29 (tt, J = 7.1, 5.3 Hz, 1H), 1.39 (s, 9H), 0.92 (dt, J = 8.2, 2.4 Hz, 4H).

[0150] 2) Reaction condition two:

[0151] Under a nitrogen atmosphere, 70 mL of dichloromethane, 10 g (21.07 mmol) of compound IIa, and 3.2 g (31.62 mmol) of triethylamine were added to reaction flask A. While maintaining the temperature of the reaction system at 20–30 °C, cyclopropylcarbonyl chloride (3.30 g, 31.61 mmol) of compound IVa was added dropwise to the reaction system. The resulting reaction solution was continuously stirred for 30 minutes. Sampling for HPLC analysis showed that the reaction was not complete. While maintaining the temperature of the reaction system at 20–30 °C, triethylamine (0.43 g, 4.21 mmol) was added. The reaction was continuously stirred for 10 h until HPLC showed that the reaction was complete.

[0152] 40 mL of pure water was added dropwise to reaction flask A. After the resulting reaction system was continuously stirred for 30 minutes, it was allowed to stand for 30 minutes, and then liquid separation was carried out to collect the lower organic phase. The organic phase was filtered, and the filter cake was washed with 10 mL of dichloromethane. The organic phases were combined. The organic phase was washed once with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was collected and concentrated to obtain a crude solid.

[0153] 40 mL of MTBE and 30 mL of n-heptane were added to the crude solid for slurrying for 1 h. After filtration, the filter cake was collected.

[0154] The obtained filter cake was slurried with DMF (40 mL) and pure water (40 mL) for 1 h. After filtration, the filter cake was collected and dried under vacuum at 45 °C to obtain 10.25 g of a white solid. Confirmed to be compound Va by NMR detection under the same conditions as in Reaction Condition 1 (yield: 89.7%, purity: 97.59%).

[0155] 3) Reaction Condition 3:

[0156] Under a nitrogen atmosphere, add acetonitrile (70 mL), compound IIa (10 g, 21.07 mmol) and DIPEA (5.45 g, 42.14 mmol) to reaction flask A. Keep the temperature of the reaction system at 20 - 30 °C, and add compound IVa cyclopropylcarbonyl chloride (3.30 g, 31.61 mmol) dropwise to the reaction system. Heat up to 45 - 55 °C and stir for 4 h. Sampling for HPLC analysis shows that the reaction is complete.

[0157] Most of the solvent was removed by rotary evaporation under reduced pressure. Add pure water (40 mL) and dichloromethane (100 mL) dropwise to reaction flask A. After stirring for 30 minutes, let it stand for 30 minutes, separate the layers, and collect the lower organic phase. The organic phase was washed once with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was collected and concentrated to obtain a crude solid. 40 mL of MTBE and 30 mL of n - heptane were added to the crude product and slurried for 1 h. After filtration, the filter cake was collected. The obtained filter cake was slurried with DMF (40 mL) and pure water (40 mL) for 1 h. After filtration, the filter cake was collected and dried under vacuum at 45 °C. Characterized by NMR detection under the same conditions as in Reaction Condition 1, 9.87 g of white solid compound Va was confirmed to be obtained (yield: 86.33%, purity: 96.46%).

[0158] 4) Reaction Condition 4:

[0159] Under a nitrogen atmosphere, add DCM (3.0 mL) and THF (3.0 mL), compound IIa (1.0 g, 2.11 mmol) and triethylamine (0.32 g, 3.16 mmol) to reaction flask A. Keep the temperature of the reaction system at 20 - 30 °C, and add compound IVa cyclopropylcarbonyl chloride (0.33 g, 3.16 mmol) dropwise to the reaction system. Heat up to 45 - 55 °C and stir for 4 h. Sampling for HPLC analysis shows that the reaction is not complete. While keeping the temperature of the reaction system at 20 - 30 °C, add additional triethylamine (0.06 g, 0.60 mmol) and cyclopropylcarbonyl chloride (0.07 g, 0.67 mmol). Continue to stir the reaction for 20 h until HPLC shows that the reaction is complete.

[0160] Most of the solvent was removed under reduced pressure. Pure water (4 mL) and dichloromethane (10 mL) were added dropwise to reaction flask A. After stirring for 30 minutes, it was allowed to stand for 30 minutes. Liquid separation was carried out, and the lower organic phase was collected. The organic phase was washed once with 5 mL of saturated brine. The organic phase was concentrated to obtain a crude solid. 4 mL of MTBE and 3 mL of n-heptane were added to the crude product for slurrying for 1 h. Filtration was carried out, and the filter cake was collected. The obtained filter cake was slurried again with DMF (4 mL) and pure water (4 mL) for 1 h. Filtration was carried out, and the filter cake was collected and dried under vacuum at 45 °C. After characterization by the same NMR detection as in Reaction Condition 1, it was confirmed that 0.89 g of white solid compound Va was obtained (yield: 77.73%, purity: 97.46%).

[0161] 5) Reaction Condition 5:

[0162] Under a nitrogen atmosphere, DMF (7.0 mL), compound IIa (1.0 g, 2.11 mmol), and triethylamine (0.32 g, 3.16 mmol) were added to reaction flask A. While maintaining the temperature of the reaction system at 20 - 30 °C, cyclopropylcarbonyl chloride (0.33 g, 3.16 mmol) was added dropwise to the reaction system. The temperature was raised to 45 - 55 °C and stirred for 24 h. Sampling for HPLC analysis showed no product formation, and the reaction was stopped.

[0163] 6) Reaction Condition 6:

[0164] Under a nitrogen atmosphere, dichloromethane (7.0 mL), compound IIa (1.0 g, 2.11 mmol), and DBU (0.48 g, 3.16 mmol) were added to reaction flask A. While maintaining the temperature of the reaction system at 20 - 30 °C, cyclopropylcarbonyl chloride (0.33 g, 3.16 mmol) was added dropwise to the reaction system. The temperature was raised to 45 - 55 °C and stirred for 24 h. Sampling for HPLC analysis showed no product formation, and the reaction was stopped.

[0165] 7) Reaction Condition 7:

[0166] Under a nitrogen atmosphere, THF (7.0 mL), compound IIa (1.0 g, 2.11 mmol), and DIPEA (0.55 g, 4.21 mmol) were added to reaction flask A. While maintaining the temperature of the reaction system at 20 - 30 °C, cyclopropylcarbonyl chloride (0.33 g, 3.16 mmol) was added dropwise to the reaction system. The temperature was raised to 45 - 55 °C and stirred for 24 h. Sampling for HPLC analysis showed that the reaction was not complete. While maintaining the temperature of the reaction system at 20 - 30 °C, DIPEA (0.14 g, 1.05 mmol) and cyclopropylcarbonyl chloride (0.11 g, 1.05 mmol) were added. Stirring the reaction was continued for 24 h until HPLC showed that the reaction was complete.

[0167] Most of the solvent was removed by rotary evaporation under reduced pressure. Pure water (4 mL) and dichloromethane (10 mL) were added dropwise to reaction flask A. After stirring for 30 minutes, it was allowed to stand for 30 minutes, and then liquid separation was carried out to collect the lower organic phase. The organic phase was washed once with 5 mL of saturated brine. The organic phase was concentrated to obtain a crude solid. 4 mL of MTBE and 3 mL of n-heptane were added to the crude product and slurried for 1 h. Filtration was carried out to collect the filter cake. The obtained filter cake was further slurried with DMF (4 mL) and pure water (4 mL) for 1 h. Filtration was carried out to collect the filter cake and dried under vacuum at 45 °C. After characterization by the same NMR detection as in Reaction Condition 1, 0.91 g of white solid compound Va was confirmed to be obtained (yield: 79.58%, purity: 98.11%).

[0168] 8) Reaction Condition 8:

[0169] Under a nitrogen atmosphere, THF (7.0 mL), compound IIa (1.0 g, 2.11 mmol), DMAP (0.25 g, 0.21 mmol) and DIPEA (0.55 g, 4.21 mmol) were added to reaction flask A. While maintaining the temperature of the reaction system at 20 - 30 °C, cyclopropylcarbonyl chloride (0.33 g, 3.16 mol) was added dropwise to the reaction system. The temperature was raised to 45 - 55 °C and stirred for 24 h. Sampling for HPLC analysis showed that the reaction was not complete. While maintaining the temperature of the reaction system at 20 - 30 °C, DIPEA (0.14 g, 1.05 mmol) and cyclopropylcarbonyl chloride (0.11 g, 1.05 mmol) were added. Stirring was continued for 24 h until HPLC showed that the reaction was complete.

[0170] Most of the solvent was removed by rotary evaporation under reduced pressure. Pure water (4 mL) and dichloromethane (10 mL) were added dropwise to reaction flask A. After stirring for 30 minutes, it was allowed to stand for 30 minutes, and then liquid separation was carried out to collect the lower organic phase. The organic phase was washed once with 5 mL of saturated brine. The organic phase was concentrated to obtain a crude solid. 4 mL of methyl tert-butyl ether and 3 mL of n-heptane were added to the crude product and slurried for 1 h. Filtration was carried out to collect the filter cake. The obtained filter cake was further slurried with DMF (4 mL) and pure water (4 mL) for 1 h. Filtration was carried out to collect the filter cake and dried under vacuum at 45 °C. After characterization by the same NMR detection as in Reaction Condition 1, 0.92 g of white solid compound Va was confirmed to be obtained (yield: 80.46%, purity: 95.87%).

[0171] Step 2: Synthesis of compound Ia

[0172]

[0173] 1) Reaction Condition 1:

[0174] Under a nitrogen atmosphere, anisole (3.5 L) and compound Va (700.0 g, 1.29 mol) were added to reaction flask A. While stirring at room temperature, 4M hydrochloric acid solution (3.5 L) was added to reaction flask A. Then, while maintaining the temperature of the reaction system at 20 - 30 °C, stirring was continued for 1 hour. Sampling for HPLC analysis showed that the reaction was complete.

[0175] While still maintaining the temperature of the reaction system at 20 - 30 °C, N-acetyl-L-cysteine (70.0 g of solid powder, used to remove any potentially residual metals in the raw materials) was added to the reaction system, and ammonia water was added dropwise to adjust the pH to around 9. The resulting reaction system was stirred for an additional 30 minutes and then filtered. The filter cake was washed with pure water (1.4 L), and then the filter cake was collected.

[0176] THF (2.8 L), pure water (4.9 L) and the filter cake were added to reaction flask B. The resulting reaction system was heated to 35 - 45 °C and stirred for 3 hours. The resulting reaction solution was cooled to room temperature, filtered, the filter cake was washed with pure water (1.4 L), and the collected filter cake was dried under vacuum at 45 °C to obtain 501.71 g of white solid compound Ia (yield 87.89%, purity 99.87%).

[0177] Characterization: 1 H (400 Hz, DMSO-d 6 ) δ ppm: 8.05 (1H, dd, J = 9.2, 7.2 Hz), 8.01 (1H, dd, J = 9.2, 1.6 Hz), 7.85 - 7.77 (3H, m), 7.58 (1H, dd, J = 7.2, 1.6 Hz), 4.65 (2H, s), 3.91 - 3.88, (4H, m), 3.69 - 3.68 (4H, m), 1.96 - 1.92 (1H, m), 1.06 - 1.03 (4H, m). LCMS m / z: 443.2 (M + H).

[0178] 2) Reaction condition two:

[0179] Under a nitrogen atmosphere, compound Va (5.0 g, 9.21 mmol), DCM (25 mL) and anisole (10 mL) were added to reaction flask A. While stirring at room temperature, 4M hydrochloric acid solution (25 mL) was added to reaction flask A. Then, while maintaining the temperature of the reaction system at 20 - 30 °C, stirring was continued for 12 hours. Sampling for HPLC analysis showed that the reaction was complete.

[0180] While still maintaining the temperature of the reaction system at 20 - 30 °C, N-acetyl-L-cysteine (0.5 g) was added to the reaction system, and ammonia water was added dropwise to adjust the pH to around 9. The resulting reaction system was stirred for an additional 30 minutes and then filtered. The filter cake was washed with pure water, and then the filter cake was collected.

[0181] Add THF (20 mL), pure water (35 mL) and the filter cake into reaction flask B. Heat the resulting reaction system to 35 - 45 °C and stir for 3 hours. Cool to room temperature, filter, wash the filter cake with pure water, collect the obtained filter cake and dry it under vacuum at 45 °C. After characterization by the same NMR detection as in Reaction Condition 1, it was confirmed that 2.71 g of white solid compound Ia was obtained (yield 66.57%, purity 99.9%).

[0182] 3) Reaction Condition 3:

[0183] Under a nitrogen atmosphere, add compound Va (5.0 g, 9.21 mmol), DCM (25 mL) and anisole (10 mL) into reaction flask A. While stirring at room temperature, add 6 M hydrochloric acid solution (10 mL) into reaction flask A, and then continue to stir the reaction system at 20 - 30 °C for 12 hours. Sampling for HPLC analysis shows that the reaction is complete.

[0184] Continue to maintain the reaction system temperature at 20 - 30 °C, add N-acetyl-L-cysteine (0.5 g) into the reaction system, and adjust the pH to about 9 by dropping ammonia water. The resulting reaction system is stirred for another 30 minutes and then filtered. The filter cake is washed with pure water, and then the filter cake is collected. Add THF (20 mL) and the filter cake into reaction flask B. Heat the resulting reaction system to 35 - 45 °C and stir for 3 hours. Then add pure water (35 mL) into the reaction system and continue to stir at 35 - 45 °C for 1 hour. Cool the resulting reaction solution to room temperature, filter, wash the filter cake with pure water, collect the obtained filter cake and dry it under vacuum at 45 °C. After characterization by the same NMR detection as in Reaction Condition 1, it was confirmed that 2.38 g of white solid compound Ia was obtained (yield 58.46%, purity 99.5%).

[0185] 4) Reaction Condition 4:

[0186] Under a nitrogen atmosphere, add compound Va (5.0 g, 9.21 mmol), DCM (25 mL) and anisole (10 mL) into reaction flask A. While stirring at room temperature, add 0.5 M hydrochloric acid solution (10 mL) into reaction flask A, and then continue to stir the reaction system at 20 - 30 °C for 24 hours. Sampling for HPLC analysis shows that only 3.32% of compound Ia is obtained. The reaction rate is too slow, so the reaction is terminated.

[0187] 5) Reaction Condition 5:

[0188] Under a nitrogen atmosphere, compound Va (5.0 g, 9.21 mmol), DCM (25 mL) and anisole (10 mL) were added to reaction flask A. While stirring at room temperature, 0.5 M hydrochloric acid solution (30 mL) was added to reaction flask A, and then the reaction system was continuously stirred at 20 - 30 °C for 24 hours. A sample was taken for HPLC analysis, and the analysis showed that 53.17% of compound Ia was obtained. The reaction rate was too slow, and the reaction was terminated.

[0189] 6) Reaction condition six:

[0190] Under a nitrogen atmosphere, compound Va (5.0 g, 9.21 mmol), DCM (25 mL) and anisole (10 mL) were added to reaction flask A. While stirring at room temperature, 3 M hydrochloric acid solution (10 mL) was added to reaction flask A, and then the reaction system was continuously stirred at 20 - 30 °C for 12 hours. Sampling for HPLC analysis showed that the reaction was complete.

[0191] While maintaining the reaction system temperature at 20 - 30 °C, N-acetyl-L-cysteine (0.5 g) was added to the reaction system, and ammonia water was added dropwise to adjust the pH to about 9. The resulting reaction system was continuously stirred for 30 minutes and then filtered. The filter cake was washed with pure water, and then the filter cake was collected. THF (20 mL) and the filter cake were added to reaction flask B, and the resulting reaction system was heated to 35 - 45 °C and stirred for 3 hours. Then pure water (35 mL) was added to the reaction system, and it was continuously stirred at 35 - 45 °C for 1 hour. The resulting reaction solution was cooled to room temperature, filtered, the filter cake was washed with pure water, and the collected filter cake was dried under vacuum at 45 °C. After characterization by the same NMR detection as in reaction condition one, it was confirmed that 2.16 g of white solid compound Ia was obtained (yield 52.97%, purity 99.3%).

[0192] 7) Reaction condition seven:

[0193] Under a nitrogen atmosphere, compound Va (5.0 g, 9.21 mmol), THF (25 mL) and anisole (10 mL) were added to reaction flask A. While stirring at room temperature, 4 M hydrochloric acid solution (25 mL) was added to reaction flask A, and then the reaction system was continuously stirred at 20 - 30 °C for 12 hours. Sampling for HPLC analysis showed that the reaction was not complete. Stirring was continued for 24 hours, and sampling for HPLC analysis showed that 8.53% of compound A of formula A appeared, and the reaction was terminated.

[0194]

[0195] 8) Reaction condition eight:

[0196] Under a nitrogen atmosphere, compound Va (5.0 g, 9.21 mmol), THF (25 mL) and anisole (10 mL) were added to reaction flask A. Under stirring at room temperature, 4 M hydrochloric acid solution (25 mL) was added to reaction flask A, and then the reaction system was continuously stirred at 20 - 30 °C for 12 hours. Sampling for HPLC analysis showed that the reaction was not complete. Stirring was continued for 24 hours, and sampling for HPLC analysis showed the appearance of 12.09% of compound A of formula A, and the reaction was terminated.

[0197] Based on the above experimental results, using the optimized conditions of Example 1 above (reaction condition 1 was selected for both acylation reaction and amino deprotection reaction), the yield of compound Va formed from compound IIa was 93.53%, the yield of compound Ia obtained by further reaction was 87.89%, the purity was 99.87%, and the total yield was 82.20%. According to the content of Example 1 of WO2022032644 A1, the optimal yield of deaminoprotection of compound IIa was 95.0%, the purity was 98.6%, the yield of compound Ia obtained by subsequent acylation was 72.7%, the purity was 99.4%, and the total yield was 69.07%. Through the adjustment of the reaction route and optimization of the reaction conditions of the present invention, the yield was increased from 69.07% to 82.20%, an increase of 19.01%.

Claims

1. A compound as shown in Formula V below, wherein: R 1 Selected from: C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl; R 2 and R 3 each independently selected from: halogen and C 1 -C 6 alkyl; R 4 Selected from: amino protecting groups; m and n are each independently selected from: 0, 1, 2, 3, and 4.

2. The compound according to claim 1, characterized in that it satisfies one or more of the following conditions: (1)R 1 Among them, the C 1 -C 6 alkyl group is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl; (2)R 1 Among them, the C 3 -C 8 The cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl; (3)R 2 and R 3 In, the C 1 -C 6 alkyl group is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl; (4)R 2 and R 3 wherein the halogen is optionally selected from iodine, bromine, chlorine or fluorine, preferably fluorine; (5)R 4 In the formula, the amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, phthaloyl, p-toluenesulfonyl, trityl or benzyl, preferably tert-butoxycarbonyl.

3. The compound according to claim 1, characterized in that the compound is:

4. A method for preparing the compound according to any one of claims 1 to 3, characterized in that it includes the following steps: In the presence of a base, the compound of Formula II reacts with the compound of Formula IV or the compound of Formula VI in a solvent to carry out the following acylation reaction to obtain the compound of Formula V: Among them, R 1 , R 2 and R 3 , the definitions of m and n are as described in any one of claims 1 to 3; R 5 is F, Cl or Br, preferably Cl.

5. The preparation method according to claim 4, characterized in that the acylation reaction satisfies at least one of the following conditions: 1) The acylation reaction is carried out under an inert gas atmosphere, and the inert gas can be nitrogen; 2) The base is selected from: organic bases, preferably one or a mixture of two or more of triethylamine, N,N - diisopropylethylamine, pyridine, tri - n - butylamine, N,N - dimethylaniline, N,N - diethylaniline, 2,6 - dimethylpyridine, 4 - dimethylaminopyridine, tetramethylguanidine, 4 - pyrrolidinopyridine, 1 - hydroxybenzotriazole, 1 - hydroxy - 7 - azabenzotriazole, N - hydroxysuccinimide, N - hydroxyphthalimide, N - methylmorpholine, more preferably N,N - diisopropylethylamine or triethylamine, and most preferably N,N - diisopropylethylamine; 3) The solvent is selected from: one or a mixture of two or more of chlorinated alkane solvents, ether solvents, and nitrile solvents, preferably chlorinated alkane solvents; wherein, the chlorinated alkane solvents are preferably dichloromethane, dichloroethane, chloroform or a mixture of any two or more of them, more preferably dichloromethane; the ether solvents are preferably tetrahydrofuran, methyl tert - butyl ether, 1,4 - dioxane or a mixture of any two or more of them; the nitrile solvent is preferably acetonitrile; 4) The molar ratio of the compound of Formula IV or the compound of Formula VI to the compound of Formula II is 1.0 - 3.0, preferably 1.2 - 2.0, more preferably 1.5 - 2.0, even more preferably 1.55 - 1.65, and most preferably 1.59; 5) The volume - mass ratio of the solvent to the compound of Formula II is 4 - 10 L / kg, preferably 6 - 8 L / kg, and most preferably 7 L / kg; 6) The molar ratio of the base to the compound of Formula II is 1.0 - 3.0, preferably 1.5 - 2.5, more preferably 1.5 - 2.0, even more preferably 1.8 - 2.2, and most preferably 2.0; 7) The temperature of the acylation reaction is 0 - 60 °C, preferably 20 - 55 °C, and most preferably 20 - 30 °C; 8) The progress of the acylation reaction is monitored by TLC, GC, HPLC, and / or NMR, and the reaction end point is when the compound of Formula II disappears.

6. The preparation method according to claim 4, characterized in that After the acylation reaction, a post-treatment step is further included, and the post-treatment step includes: adding water to the reaction solution, stirring, standing still, taking the organic phase, filtering, and recovering the solvent to obtain the crude product of the compound of formula V.

7. The preparation method according to claim 6, wherein, the post-treatment step satisfies at least one of the following conditions: 1) The volume ratio of the water added to the reaction solution in the post-treatment step to the solvent used in the acylation reaction is 3:1 to 1:3, preferably 1:1 to 1:2, and more preferably 4:7; 2) The stirring time is 0.2 to 5 hours, preferably 0.4 to 1 hour, and most preferably 0.5 hour; 3) After filtering the organic phase, a step of washing with an organic solvent and then combining the organic solvents is further included, and preferably the same organic solvent as that used in the acylation reaction is used as the washing solvent.

8. The preparation method according to claim 6, wherein, after the post-treatment, a preliminary purification step is further included, and the preliminary purification step includes: placing the crude product of the compound of formula V in a mixed organic solvent composed of organic solvent B and organic solvent C, stirring and slurrying, filtering, collecting the filter cake, and drying to obtain the product of the compound of formula V; the organic solvent B is selected from ether solvents, and the organic solvent C is selected from alkane solvents.

9. The preparation method according to claim 8, wherein, the preliminary purification step satisfies at least one of the following conditions: 1) The organic solvent B is selected from: methyl tert-butyl ether, 1,4-dioxane or a mixture thereof, preferably methyl tert-butyl ether; 2) The organic solvent C is selected from: n-heptane, n-hexane or petroleum ether, preferably n-heptane; 3) The volume percentage of the organic solvent B in the mixed organic solvent is 40% to 80%, preferably 55% to 70%, more preferably 60% to 65%, and most preferably 62.5%; 4) The slurrying time is 0.4 to 5 hours, preferably 0.4 to 1 hour, and most preferably 0.5 hour.

10. The preparation method according to claim 8, wherein, a washing step is further included in the preliminary purification step, and / or a deep purification step is further included after the preliminary purification step, the washing step includes: washing the obtained filter cake with the organic solvent C before filtering, collecting the filter cake, and drying; the deep purification step includes: stirring and slurrying the product of the compound of formula V obtained in the preliminary purification step with a mixed solvent of organic solvent D and water, filtering, collecting the filter cake, and drying to obtain the further purified product of the compound of formula V, and the organic solvent D is a polar solvent.

11. The preparation method according to claim 10, wherein, the deep purification satisfies at least one of the following conditions: (1) A step of washing the obtained filter cake with water before filtering, collecting the filter cake, and drying is further included in the deep purification step; (2) The organic solvent D is N,N-dimethylformamide, ethanol, THF or acetonitrile, preferably N,N-dimethylformamide; (3) The volume percentage of the organic solvent D in the mixed solvent of the organic solvent D and water is 20% to 80%, preferably 40% to 60%, more preferably 45% to 55%, and most preferably 50%. (4) The time for pulping in the deep purification step is 0.4 to 5 hours, preferably 0.4 to 1 hour, and most preferably 0.5 hour.

12. Use of the compound shown by formula V according to any one of claims 1 to 3 as an intermediate in the preparation of imidazo[1,2-a]pyridin-2-ylamide compounds.

13. Preparation method of the compound shown by formula I Characterized in that It includes the following steps: In the presence of an acid, in a solvent, the compound of formula V undergoes the following amino deprotection reaction in the solvent to obtain the compound of formula I: wherein, R 1 , R 2 and R 3 , m and n are defined as described in claim 1.

14. The preparation method according to claim 13 Characterized in that It further includes the following steps: The compound of formula V is prepared according to the preparation method according to any one of claims 4 to 11.

15. The preparation method according to claim 13 Characterized in that The amino deprotection reaction satisfies at least one of the following conditions: 1) The amino deprotection reaction is carried out under an inert gas atmosphere, and the inert gas can be nitrogen; 2) The acid is selected from: organic acids, inorganic acids or mixtures thereof, preferably inorganic acids; wherein, the inorganic acid is preferably hydrochloric acid, phosphoric acid or mixtures thereof, more preferably hydrochloric acid; the organic acid is preferably trifluoroacetic acid, formic acid or mixtures thereof, more preferably trifluoroacetic acid; 3) The solvent is selected from: ether solvents, chloroalkane solvents, C 1 -C 6 alcohol solvents, ester solvents, water, or a mixed solvent of two or more of them. Preferably, it is an ether solvent, a chloroalkane solvent, or a mixed solvent thereof. More preferably, it is an ether solvent; wherein, the ether solvent is preferably anisole, tert-butyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, or a mixed solvent of two or more of them. Preferably, it is anisole, methyl tert-butyl ether, or a mixed solvent thereof. More preferably, it is anisole; the chloroalkane solvent is preferably dichloromethane, chloroform, dichloroethane, or a mixed solvent of two or more of them. More preferably, it is dichloromethane; the C 1 -C 6 alcohol solvent is preferably methanol, ethanol, isopropanol, or a mixed solvent of two or more of them. More preferably, it is ethanol; the ester solvent is preferably methyl acetate, ethyl acetate, propyl acetate, or a mixed solvent of two or more of them. More preferably, it is ethyl acetate; 4) The molar ratio of the acid to the compound of formula V is 5 to 50, preferably 5 to 20, more preferably 10 to 12, and even more preferably 10.8 to 11.0; 5) The concentration of the acid in the amino deprotection reaction system is 1 to 3 mol / L, preferably 2 mol / L; and the working concentration of the acid is 3 to 5 mol / L, preferably 4 mol / L; 6) The reaction temperature of the amino deprotection reaction is 0 to 40 °C, preferably 10 to 30 °C, more preferably 20 to 30 °C; 7) The progress of the amino deprotection reaction is monitored by TLC, GC, HPLC and / or NMR, and the reaction end point is when the compound of formula V disappears.

16. The preparation method according to claim 15 Characterized in that The amino deprotection reaction further includes a post-treatment step, and the post-treatment step is: adding a metal chelating agent to the reaction system, and adding an alkali solution to adjust its pH to precipitate the product, and then filtering to obtain the crude product of the compound of formula I, and the alkali solution can be ammonia water, sodium bicarbonate, sodium carbonate or sodium hydroxide.

17. The preparation method according to claim 16 Characterized in that The post-treatment step satisfies at least one of the following conditions: 1) The alkali solution in the post-treatment step is ammonia water, and the addition method is dropwise addition, and the pH value is adjusted to 8.5 to 9.5, preferably the pH value is adjusted to 9.0; 2) When adding the alkali solution in the post-treatment step, the temperature of the reaction system is controlled to be 5 to 35 °C, preferably 10 to 30 °C, more preferably 20 to 30 °C; 3) The metal chelating agent added in the post-treatment step is N-acetyl-L-cysteine, preferably added in the form of solid powder and stirred evenly. The mass ratio of N-acetyl-L-cysteine to the compound of formula V is 0.05 to 0.20, preferably 0.10 to 0.15, and further preferably 0.10; 4) The post-treatment step further includes a step of washing the crude cake of the compound of formula I obtained by filtration with water.

18. The preparation method according to claim 16, characterized in that, after the post-treatment step, a refining step is further included. The refining step adopts Method 1 or Method 2, Method 1 is: heating and stirring the crude product of the compound of formula I obtained in the post-treatment step in a mixed system of organic solvent A and water, then cooling and filtering, collecting the filter cake and drying to obtain the product of the compound of formula I; Method 2 is: heating and stirring the crude product of the compound of formula I obtained in the post-treatment step in organic solvent A, then adding water, continuing to stir, then cooling and filtering, collecting the filter cake and drying to obtain the product of the compound of formula I; The organic solvent A is a cyclic ether organic solvent and / or an alcohol organic solvent. The cyclic ether solvent can be tetrahydrofuran or 1,4-dioxane, preferably tetrahydrofuran. The alcohol solvent can be ethanol, isopropanol or tert-butanol, preferably ethanol.

19. The preparation method according to claim 18, characterized in that, the refining step satisfies at least one of the following conditions: 1) In Method 1 and Method 2, the volume-mass ratio of the organic solvent A to the compound of formula V is 3 to 5 L / Kg, preferably 3.5 to 4.5 L / Kg, and most preferably 4.0 L / Kg; 2) In Method 1 and Method 2, the volume ratio of the water used to the organic solvent A is 3:1 to 1:1, preferably 2:1 to 1.5:1, and most preferably 7:4; 3) In Method 1 and Method 2, the temperature of the heating and stirring is 30 to 55 °C, preferably 35 to 50 °C, and further preferably 35 to 45 °C; 4) In Method 1, the heating and stirring time is 0.5 to 10 hours, preferably 2 to 5 hours, and further preferably 3 to 4 hours; 5) In Method 2, the heating and stirring time of the compound of formula V in the organic solvent A is 0.5 to 10 hours, preferably 2 to 5 hours, and further preferably 3 to 4 hours; 6) In Method 2, the stirring time after adding water is 0.5 to 10 hours, preferably 1 to 5 hours, and further preferably 1 to 2 hours; 7) In the refining step, a step of washing the filter cake with water before collecting the filter cake is further included.

20. The preparation method according to claim 13, characterized in that, it includes the following steps: (1) Under the condition of the presence of a base, reacting the compound of formula II with the compound of formula IV or the compound of formula VI in a solvent to carry out the acylation reaction as described in claim 4 to obtain the compound of formula V; The acylation reaction satisfies the following conditions: The acylation reaction is carried out in an inert gas atmosphere, and the inert gas can be nitrogen; The base is selected from: organic bases, preferably N,N-diisopropylethylamine; The solvent is selected from: chlorinated alkane solvents, preferably dichloromethane; The molar ratio of the compound of formula IV or formula VI to the compound of formula II is 1.0 to 3.0, preferably 1.2 to 2.0, more preferably 1.5 to 2.0, still more preferably 1.55 to 1.65, and most preferably 1.59; The volume-mass ratio of the solvent to the compound of formula II is 4 to 10 L / kg, preferably 6 to 8 L / kg, and most preferably 7 L / kg; The molar ratio of the base to the compound of formula II is 1.0 to 3.0, preferably 1.5 to 2.5, more preferably 1.5 to 2.0, still more preferably 1.8 to 2.2, and most preferably 2.0; and The temperature of the acylation reaction is 0 to 60 °C, preferably 20 to 55 °C, and most preferably 20 to 30 °C; (2) In the presence of an acid, in a solvent, the compound of formula V undergoes the deprotection reaction of the amino group as described in claim 13 in the solvent to obtain the compound of formula I; The deprotection reaction of the amino group satisfies the following conditions: The deprotection reaction of the amino group is carried out in an inert gas atmosphere, and the inert gas can be nitrogen; The acid is selected from: inorganic acids, preferably hydrochloric acid; The solvent is selected from: ether solvents, preferably anisole; The molar ratio of the acid to the compound of formula V is 5 to 50, preferably 5 to 20, more preferably 10 to 12, still more preferably 10.8 to 11.0; The concentration of the acid in the deprotection reaction system of the amino group is 1 to 3 mol / L, preferably 2 mol / L; and the working concentration of the acid is 3 to 5 mol / L, preferably 4 mol / L; and The reaction temperature of the deprotection reaction of the amino group is 0 to 40 °C, preferably 10 to 30 °C, more preferably 20 to 30 °C.

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