A preparation method of a substituted imidazo[1,2-a]pyridin-2-ylamide compound and its intermediate

Abstract

A method for preparing a substituted imidazo[1,2-a]pyridine-2-ylamide compound and an intermediate thereof. Specifically disclosed is a method for preparing a compound of formula I: wherein R 1 is C1-C6 alkyl or C3-C8 cycloalkyl; R 2 and R 3 R is independently selected from halogen and C1-C6 alkyl; 4 is Br, I or OTf, preferably Br; m and n are each independently 0, 1, 2, 3 or 4. The preparation method is simple to operate, easy to control product quality, has a high yield and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and specifically relates to a preparation method of a substituted imidazo[1,2-a]pyridine-2-ylamide compound and an intermediate thereof. Background Art

[0002] The Janus kinase (JAK) signaling pathway 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 even the biological activity of many cytokines can be modulated by the inhibition of single or multiple JAKs. The inhibition of JAKs can be used to prevent, inhibit or treat the development or onset of various diseases and disorders, including hyperproliferative diseases and cancers, such as leukemias and lymphomas, 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] Substituted imidazo[1,2-a]pyridine-2-ylamide compounds have been reported to be effective JAK inhibitors. WO2016119700A1 reports the following synthesis method of imidazo[1,2-a]pyridine-2-ylamide compounds:

[0005]

[0006] The method comprises: removing the protecting group on the amino group in compound 1, reacting the obtained amino compound 2 with an alkyl acyl chloride and then coupling the obtained amino compound 2 with compound 4 to obtain the target compound I.

[0007] However, the above synthetic route is not suitable for industrial production due to the following reasons:

[0008] (a) The intermediates and final products contain many impurities and by-products. The purification of each intermediate requires column chromatography, which consumes a large amount of solvent and is difficult to scale up, which is not conducive to industrial production.

[0009] (b) The coupling reaction of compound 3 and compound 4 requires the use of a heavy metal-containing catalyst, which can easily cause excessive heavy metal residues in the product, making the product unqualified.

[0010] Therefore, it is necessary to explore a synthesis method that is simple to operate, easy to control product quality and suitable for industrial production. Summary of the invention

[0011] The present invention provides a preparation method of a substituted imidazo[1,2-a]pyridine-2-ylamide compound and an intermediate thereof. The synthetic route provided by the present invention is easy to control product quality, has a high yield and is suitable for industrial production.

[0012] The present invention provides a method for preparing a compound of formula III, comprising the following steps: subjecting a compound of formula II to an amino group deprotection reaction as shown below in a solvent under acidic conditions to obtain a compound of formula III;

[0013]

[0014] Among them, R 2 and R 3 Independently selected from halogen and C1-C6 alkyl;

[0015] m and n are each independently 0, 1, 2, 3 or 4.

[0016] In some embodiments, when R 2 and R 3 When R is independently a C1-C6 alkyl group, the C1-C6 alkyl group may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group, preferably a methyl group or an ethyl group; 2 and R 3 When independently halogen, the halogen may be iodine, bromine, chlorine or fluorine, preferably fluorine.

[0017] In some embodiments, the acid may be a conventional acid for such reactions in the art, such as an inorganic acid, an organic acid or a mixture thereof, preferably an inorganic acid; wherein the inorganic acid is preferably hydrogen chloride, phosphoric acid or a mixture thereof, more preferably hydrogen chloride; the organic acid is preferably trifluoroacetic acid, formic acid or a mixture thereof, more preferably trifluoroacetic acid.

[0018] In some embodiments, the solvent may be a conventional solvent for such reactions in the art, such as water, C1-C6 alcohol solvents, ester solvents, chlorinated alkane solvents, ether solvents or mixtures thereof, preferably ester solvents, chlorinated alkane solvents or mixtures thereof, and further preferably ester solvents; wherein the C1-C6 alcohol solvent is preferably methanol, ethanol, isopropanol or a mixture thereof, and further preferably ethanol; the ester solvent is preferably methyl acetate, ethyl acetate, propyl acetate or a mixture thereof, and further preferably ethyl acetate; the chlorinated alkane solvent is preferably dichloromethane, chloroform, dichloroethane or a mixture thereof, and further preferably dichloromethane.

[0019] In some embodiments, the molar ratio of the acid to the compound of formula II may be 5-50, preferably 15-25, more preferably 18-20, and even more preferably 19.

[0020] In some embodiments, the molar volume ratio of the acid to the solvent may be 3 to 5 mol / L, preferably 4 mol / L.

[0021] In some embodiments, the reaction temperature of the amino deprotection reaction can be a conventional temperature for such reactions in the art, for example, 0 to 40°C, preferably 10 to 20°C, and more preferably 15°C.

[0022] In some embodiments, the progress of the amino deprotection reaction can be monitored by conventional testing methods in the art (e.g., TLC, GC, HPLC, or NMR, etc.), and the reaction endpoint is generally when the compound of formula II is no longer detected. The reaction time of the amino deprotection reaction is 1 to 24 hours, preferably 12 to 20 hours, and more preferably 16 hours.

[0023] In some embodiments, the amino deprotection reaction may further include a post-treatment step, which includes adding a heavy metal remover, an organic solvent, ammonia water and water to the reaction solution to precipitate the product; wherein the organic solvent is tetrahydrofuran, ethanol, methanol or a mixture thereof.

[0024] In some embodiments, in the post-treatment step, the heavy metal remover can be N-acetyl-L-cysteine, diatomaceous earth, 2,4,6-trimercapto-1,3,5-triazine, Si-Thiol, diethylenetriamine, sodium ethylenediaminetetraacetate, tributylphosphine or a mixture thereof, preferably N-acetyl-L-cysteine.

[0025] In some embodiments, in the post-treatment step, the organic solvent may be methanol.

[0026] In some embodiments, in the post-treatment step, the molar ratio of the aqueous ammonia to the acid in the amino deprotection reaction may be 1.2 to 2.0, preferably 1.2 to 1.5.

[0027] In some embodiments, in the post-treatment step, the volume ratio of the organic solvent to the aqueous ammonia can be 0.5-2.0, preferably 1.0-1.5, and more preferably 1.2.

[0028] In some embodiments, in the post-treatment step, the volume ratio of the water to the aqueous ammonia can be 0.5-1.5, preferably 0.8-1.2, and more preferably 0.8.

[0029] The preparation method of the compound of formula III may further include a preparation method of the compound of formula II, which comprises the following steps: in the presence of a base and a palladium catalyst, in a solvent, SM1 and SM2 are subjected to a coupling reaction as shown below to obtain a compound of formula II,

[0030]

[0031] Among them, R 4 is Br, I or OTf, preferably Br;

[0032] R 2 , R 3 , m and n are as described above.

[0033] In some embodiments, in the method for preparing the compound of formula II, the palladium catalyst may be a conventional palladium catalyst for such reactions in the art, for example, Pd(PPh3)4, Pd(OAc)2, Pd(dtbpf)Cl2, (Pd(dppf)Cl2.CH2Cl2 or a mixture thereof, preferably (Pd(dppf)Cl2.CH2Cl2.

[0034] In some embodiments, in the preparation method of the compound of formula II, the base can be a conventional base for such reactions in the art, such as an inorganic base, an organic base or a mixture thereof, preferably an inorganic base; wherein the inorganic base is preferably an alkali metal hydroxide, an alkali metal carbonate, an alkali metal phosphate or a mixture thereof, further preferably potassium phosphate, potassium carbonate, potassium hydroxide, cesium carbonate or a mixture thereof, further preferably potassium carbonate; the organic base is preferably tert-butyl potassium, triethylamine or a mixture thereof.

[0035] In some embodiments, in the preparation method of the compound of formula II, the solvent may be a conventional solvent for such reactions in the art, for example, a mixed system of an organic solvent and water; wherein the organic solvent is selected from C1-C6 alcohol solvents, aromatic hydrocarbon solvents, ether solvents or mixtures thereof, preferably ether solvents; wherein the C1-C6 alcohol solvent is preferably methanol, ethanol or a mixture thereof; the aromatic hydrocarbon solvent is preferably toluene; the ether solvent is preferably 1,4-dioxane, tetrahydrofuran or a mixture thereof, further preferably 1,4-dioxane.

[0036] In some embodiments, in the method for preparing the compound of formula II, in the mixed system of the organic solvent and water, the volume ratio of the organic solvent to water can be 2:1 to 15:1, preferably 10:3 to 10:1, and more preferably 10:1.

[0037] In some embodiments, in the method for preparing the compound of formula II, the molar ratio of SM2 to SM1 can be 1.0 to 2.0, preferably 1.1 to 1.3, and more preferably 1.2.

[0038] In some embodiments, in the method for preparing the compound of formula II, the molar ratio of the catalyst to SM1 can be 0.01 to 0.5, preferably 0.02 to 0.05, and more preferably 0.03.

[0039] In some embodiments, in the method for preparing the compound of formula II, the molar ratio of the base to SM1 can be 1.0 to 5.0, preferably 1.8 to 2.2, and more preferably 2.0.

[0040] In some embodiments, in the method for preparing the compound of formula II, the reaction temperature of the coupling reaction can be a conventional temperature for such reactions in the art, for example, 60 to 120°C, preferably 90 to 100°C.

[0041] In some embodiments, in the method for preparing the compound of formula II, the progress of the coupling reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.), and the end point of the reaction is generally when SM1 and SM2 no longer react. The reaction time of the coupling reaction can be 2 to 12 hours, preferably 6 to 8 hours.

[0042] In some embodiments, in the method for preparing the compound of formula II, the coupling reaction is preferably carried out under gas protection. The gas in the gas protection does not participate in the reaction, such as argon, helium or nitrogen, for example nitrogen.

[0043] The present invention also provides a method for preparing the compound of formula I, which comprises the following steps: in a solvent under alkaline conditions, subjecting the compound of formula III to an acylation reaction with the compound of formula IV as shown below:

[0044]

[0045] Among them, R 1 is a C1-C6 alkyl group or a C3-C8 cycloalkyl group;

[0046] R 2 , R 3 , R 4 , m and n are as described above.

[0047] In some embodiments, when R 1 When R is a C1-C6 alkyl group, the C1-C6 alkyl group may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group, preferably a methyl group or an ethyl group; 1When it is a C3-C8 cycloalkyl group, the C3-C8 cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, and is preferably a cyclopropyl group.

[0048] In some embodiments, the preparation method of the compound of formula III is preferably as described above.

[0049] In some embodiments, in the preparation method of the compound of formula I, the base can be a conventional base for such reactions, for example, an organic base, preferably triethylamine, N,N-diisopropylethylamine, pyridine, tri-n-butylamine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, 4-pyrrolidinylpyridine, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, N-methylmorpholine or a mixture thereof, further preferably triethylamine.

[0050] In some embodiments, in the method for preparing the compound of formula I, the solvent may be a conventional solvent for such reactions, such as a chlorinated alkane solvent, an ether solvent, a nitrile solvent or a mixture thereof, preferably a chlorinated alkane solvent; wherein the chlorinated alkane solvent is preferably dichloromethane, dichloroethane, chloroform or a mixture thereof, further preferably dichloromethane; the ether solvent is preferably tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane or a mixture thereof; the nitrile solvent is preferably acetonitrile.

[0051] In some embodiments, in the method for preparing the compound of formula I, the molar ratio of the compound of formula IV to the compound of formula III can be 1.0 to 3.0, preferably 1.0 to 1.5, and more preferably 1.15.

[0052] In some embodiments, in the method for preparing the compound of formula I, the volume mass ratio of the solvent to the compound of formula III can be 8 to 12 L / kg, preferably 10 L / kg.

[0053] In some embodiments, in the method for preparing the compound of formula I, the acylation reaction temperature can be a conventional temperature for such reactions in the art, for example, 0 to 40°C, preferably 0 to 10°C.

[0054] In some embodiments, in the method for preparing the compound of formula I, the progress of the acylation reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.), and the reaction endpoint is generally when the compound of formula III is no longer detected. The reaction time of the acylation reaction can be 0.5 to 12 hours, more preferably 0.5 to 5 hours, and even more preferably 1 hour.

[0055] In some embodiments, in the preparation method of the compound of formula I, a post-treatment step may be further included after the acylation reaction, and the post-treatment step includes: after the acylation reaction is completed, adding a heavy metal remover, an organic solvent and ammonia water to the reaction solution to precipitate the product; wherein the organic solvent is a mixed solvent of an alkane solvent and a C1-C6 alcohol solvent.

[0056] In some embodiments, in the preparation method of the compound of formula I, in the post-treatment step, the heavy metal remover can be N-acetyl-L-cysteine, diatomaceous earth, 2,4,6-trimercapto-1,3,5-triazine, Si-Thiol, diethylenetriamine, sodium ethylenediaminetetraacetate, tributylphosphine or a mixture thereof, preferably N-acetyl-L-cysteine.

[0057] In some embodiments, in the method for preparing the compound of formula I, in the post-treatment step, the alkane solvent can be n-hexane, cyclohexane, n-heptane or a mixture thereof, preferably n-heptane.

[0058] In some embodiments, in the method for preparing the compound of formula I, in the post-treatment step, the C1-C6 alcohol solvent is preferably methanol, ethanol or isopropanol, and more preferably methanol.

[0059] In some embodiments, in the method for preparing the compound of formula I, in the post-treatment step, the volume ratio of the alkane solvent to the solvent used in the acylation reaction can be 1 to 2, preferably 1.3 to 1.4.

[0060] In some embodiments, in the method for preparing the compound of formula I, in the post-treatment step, the volume ratio of the C1-C6 alcohol solvent to the solvent used in the acylation reaction can be 0.05 to 0.25, preferably 0.05 to 0.15, and more preferably 0.1.

[0061] In some embodiments, in the method for preparing the compound of formula I, in the post-treatment step, the molar ratio of the aqueous ammonia to the compound of formula III can be 15-40, preferably 20-30, and more preferably 25.

[0062] In some embodiments, in the preparation method of the compound of formula I, after the post-treatment step, a purification step may be further included, and the purification step includes: in a mixed system of an organic solvent and water, using an acid to remove insoluble impurities in the product obtained in the post-treatment step, and then adding ammonia water to precipitate a pure product; wherein the organic solvent is ethanol, acetonitrile, acetone or a mixture thereof, preferably ethanol.

[0063] In some embodiments, in the method for preparing the compound of formula I, in the purification step, the acid can be hydrochloric acid, sulfuric acid, methanesulfonic acid or a mixture thereof, preferably concentrated hydrochloric acid.

[0064] In some embodiments, in the method for preparing the compound of formula I, in the purification step, the volume ratio of the organic solvent to the solvent used in the acylation reaction can be 0.8 to 1.2, preferably 1.0.

[0065] In some embodiments, in the method for preparing the compound of formula I, in the purification step, the volume ratio of the water to the volume of the solvent used in the acylation reaction can be 0.5 to 1.0, preferably 0.6 to 0.7.

[0066] In some embodiments, in the method for preparing the compound of formula I, in the purification step, the molar ratio of the hydrochloric acid to the compound of formula III can be 1.5 to 3.0, preferably 2.2 to 2.3.

[0067] In some embodiments, in the method for preparing the compound of formula I, in the purification step, the amount of ammonia water used can be sufficient to adjust the pH of the system to 8-9.

[0068] The present invention also provides a method for preparing a compound of formula II, comprising the following steps: in the presence of a base and a palladium catalyst, in a solvent, subjecting SM1 and SM2 to a coupling reaction as shown below to obtain a compound of formula II,

[0069]

[0070] Among them, R 2 , R 3 , m and n are as described above;

[0071] The reaction conditions for the preparation of the compound of formula II are all as described above.

[0072] In some embodiments, the preparation method of the compound of formula I can be as follows:

[0073]

[0074] Among them, R 1 , R 2 , R 3 , m and n are as described above; and the reaction conditions in each step are the same as described above.

[0075] The present invention also provides a compound of formula II:

[0076]

[0077] Among them, R 2 and R3 The definitions of , m and n are the same as described above.

[0078] In some embodiments, the compound of formula II is

[0079] definition

[0080] In the present invention, the term "C1-C6 alkyl" refers to a saturated straight or branched alkyl group comprising 1-6, especially 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., especially methyl or ethyl.

[0081] In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

[0082] In the present invention, the term "C3-C8 cycloalkyl" refers to a saturated cyclic alkyl group comprising 3-8, especially 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., especially cyclopropyl.

[0083] abbreviation

[0084] <![CDATA[Pd(OA c )2]]> Palladium acetate <![CDATA[Pd(dtbpf)Cl2]]> [1,1′-Bis(diphenylphosphino)ferrocene]palladium dichloride <![CDATA[Pd(dppf)Cl2.CH2Cl2]]> [1,1′-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex M Mole / L DCM Dichloromethane TEA Triethylamine EA Ethyl acetate Si-Thiol Thiols immobilized on silica or polymer

[0085] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0086] The reagents and raw materials used in the present invention are commercially available.

[0087] The positive and progressive effect of the present invention is to provide a novel preparation method of a substituted imidazo[1,2-a]pyridine-2-ylamide compound and an intermediate thereof. The preparation method is simple to operate, easy to control product quality, high in yield and suitable for industrial production. DETAILED DESCRIPTION

[0088] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0089] In the following examples, mass spectrometry was performed using a Waters Acquity Xevo G2-XS QTof UPLC / MS ultra-high performance liquid chromatography high-resolution mass spectrometry system. 1H-NMR was performed using a BrukerAVANCE III 400 MHz nuclear magnetic resonance instrument or a BrukerAVANCE III HD 300 MHz nuclear magnetic resonance instrument, HPLC was performed using an Agilent 1260 high performance liquid chromatograph, and IPC-MS was performed using a Thermo Fisher iCAP Q inductively coupled plasma mass spectrometer.

[0090] SM1 and SM2 can be synthesized according to the method of patent application WO2016119700A1.

[0091] Example 1: Synthesis of Compound 1

[0092] Step 1: Synthesis of compound 2

[0093]

[0094] Under nitrogen environment, add 16L of 1,4-dioxane and 1.6L of demineralized water to reactor A, add SM1-1 (1.60kg, 5.13mol), SM2-1 (2.27kg, 6.15mol) and anhydrous potassium carbonate (1.42kg, 10.27mol) under stirring, and protect with nitrogen. Add Pd(dppf)Cl2.CH2Cl2 (0.125kg, 0.153mol). Heat to about 95°C, keep warm for at least 6 hours, and sample HPLC monitoring shows that the reaction is complete. After adding water and stirring for 2h, filter to obtain a filter cake. Add acetonitrile (24L), water (8L) and filter cake to reactor A and stir for at least 2 hours. Filter and collect the filter cake. After vacuum drying at 55°C for 16 hours, the material is collected to obtain compound 2 (2.167kg, HPLC purity is 98.6%, yield 88.8%).

[0095] 1 H (400 Hz, DMSO-d 6 )δppm: 7.634 (1H, t), 7.495 (2H, m), 7.425 (1H, d, J = 7.6Hz), 7.313 (2H, m), 6.9 20(1H,d,J=7.2Hz), 3.832(2H,s), 3.180(4H,s), 2.973(4H,s), 1.422(9H,s). LCMS m / z: 475.2(M+H).

[0096] Step 2: Synthesis of compound 3

[0097]

[0098] Under nitrogen protection, add ethyl acetate solution of hydrogen chloride (4M, 20L) to reactor A, cool to 15°C, and add compound 2 (2.0kg, 4.21mol) in batches while stirring under heat preservation. After addition, control the temperature to 15°C, stir for at least 16 hours, and sample HPLC monitoring shows that the reaction is complete. Add methanol (12L), water (8L), 25% ammonia water (10L) and N-acetyl-L-cysteine ​​(0.2kg) to reactor B, cool to 5°C, and drop the reaction solution in reactor A into reactor B under stirring. After addition, stir for at least 2 hours. Filter, collect the filter cake, and vacuum dry at 55°C. Collect the material after 16 hours, weigh, and obtain compound 3 (1.50kg, purity 98.6%, yield 95.0%).

[0099] 1 H (300 Hz, DMSO-d 6 )δppm: 7.592 (1H, m), 7.429 (2H, m), 7.274 (1H, d, J = 8.7Hz), 7.130 (1H, m), 6.752 (1H, m), 6 .494 (1H, d, J = 2.7Hz), 5.079 (1H, s), 3.815 (2H, s), 3.170 (4H, d, J = 5.1Hz), 3.649 (4H, t). LCMSm / z 375.1(M+H).

[0100] Step 3: Synthesis of compound 1

[0101]

[0102] Under nitrogen protection, add dichloromethane (15L) to reactor A, add compound 3 (1.5kg, 4.0mol) and triethylamine (0.81kg, 8.0mol) under stirring, then control the temperature in the reactor to about 5°C, add cyclopropylcarbonyl chloride (0.48kg, 4.59mol) dropwise to reactor A, keep warm and stir for at least 1 hour after the addition, take a sample and send it to HPLC for analysis to show that the reaction is complete. Add n-heptane (20L), methanol (1.5L), 25% ammonia water (7.5L) and N-acetyl-L-cysteine ​​(0.15kg) to reactor A, adjust the temperature to 15°C, keep warm and stir for at least 8 hours. Filter and collect the filter cake. Add ethanol (15L), water (10L) and filter cake to reactor A, drop concentrated hydrochloric acid (0.75L), and stir for at least 2 hours. Filter and collect the filtrate. 25% ammonia water was added dropwise to the filtrate to adjust the pH value to 8-9, and stirred for 1 hour. The filter cake was collected by filtration. The filter cake was transferred to an oven and dried under vacuum at 55°C. After 8 hours, the material was collected and weighed to obtain compound 1 (1.28 kg, HPLC purity of 99.4%, yield of 72.2%). IPC-MS detection showed that the palladium residue was 6.4 ppm.

[0103] 1 H (400 Hz, DMSO-d 6 )δppm: 8.05 (1H, dd, J=9.2, 7.2Hz), 8.01 (1H, dd, J=9.2, 1.6Hz), 7.85-7.77 (3H, m), 7.58 (1H, dd, J=7. 2, 1.6Hz), 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).

[0104] Example 2: Synthesis of Compound 2

[0105]

[0106] Under nitrogen environment, 300 mL of 1,4-dioxane and 90 mL of demineralized water were added to a 1L round-bottom flask, and SM1-1 (30.0 g, 96.1 mmol), SM2-1 (46.1 g, 124.9 mol), anhydrous potassium carbonate (26.56 g, 192.2 mmol) and Pd(dppf)Cl2.CH2Cl2 (3.93 g, 4.81 mmol) were added under stirring. The temperature was raised to about 95°C, and the reaction was kept warm for at least 6 hours. After sampling, HPLC monitoring showed that the reaction was complete. After adding water and stirring for 2 hours, the filter cake was filtered. Acetonitrile (450 mL), water (150 mL) and the filter cake were added to a 1L round-bottom flask and stirred for at least 2 hours. Filter and collect the filter cake. After vacuum drying at 55°C for 16 hours, the material was collected to obtain compound 2 (29.0 g, HPLC purity of 98.3%, yield of 78.2%).

[0107] Example 3: Synthesis of Compound 3

[0108]

[0109] 4.74 g of compound 2 (100 mmol) and 25 mL of DCM were added to a 100 mL round-bottom flask, cooled to about 0°C, and trifluoroacetic acid (269 mmol, 20 mL) was slowly added dropwise. After the addition, the mixture was stirred at room temperature for 16 hours. HPLC showed that the reaction was complete. The trifluoroacetic acid was removed in vacuo, 50 mL of DCM was added for dilution, the mixture was washed with an aqueous solution of NaHCO3, dried and concentrated, and purified by silica gel column chromatography to obtain compound 3 (1.45 g, yield 38.7%) as a white solid.

[0110] 1 H (400 Hz, DMSO-d 6)δppm: 8.08 (1H, dd, J=9.2, 7.2Hz), 8.03 (1H, dd, J=9.2, 1.6Hz), 7.84-7.78 (3H, m), 7.60 (1H, dd, J=7. 1, 1.6Hz), 4.66 (2H, s), 3.90-3.89, (4H, m), 3.70-3.68 (4H, m), 1.97-1.94 (1H, m), 1.08-1.04 (4H, m). LCMS m / z: 443.2(M+H).

[0111] Example 4: Synthesis of Compound 1

[0112]

[0113] Under nitrogen protection, add dichloromethane (100 mL) to a 250 mL round-bottom flask, add compound 3 (10.0 g, 26.71 mmol) and triethylamine (5.41 g, 53.5 mmol) under stirring, then cool to about 5 ° C, slowly add cyclopropylcarbonyl chloride (3.21 g, 30.72 mmol). After the addition, keep warm and stir for at least 1 hour, take a sample and send it to HPLC for analysis to show that the reaction is complete. Add n-heptane (135 mL), methanol (10 mL), 25% ammonia water (50 mL) and N-acetyl-L-cysteine ​​(1.0 g) to the round-bottom flask, adjust the temperature to 15 ° C, keep warm and stir for at least 8 hours. Filter and collect the filter cake. Add acetonitrile (170 mL), water (30 mL) and the filter cake to a 500 mL round-bottom flask, drop concentrated hydrochloric acid (5 mL), and stir for at least 2 hours. Filter and collect the filtrate. 25% ammonia water was added dropwise to the filtrate to adjust the pH value to 8-9, and stirred for 1 hour. The filter cake was collected by filtration. The filter cake was dried under vacuum at 55°C and weighed to obtain compound 1 (6.48 g, HPLC purity 99.2%, yield 54.8%).

[0114] Comparative Example 1 (Preparation method of imidazo[1,2-a]pyridine-2-ylamide compound in WO2016119700A1)

[0115] Step 1: Synthesis of compound 4

[0116]

[0117] SM1-1 (54.60 g, 175.0 mmol) and dichloromethane (1 L) were added to a 3 L round-bottom flask. After cooling to about 0 ° C, trifluoroacetic acid (200 mL) was slowly added dropwise. The mixture was stirred at room temperature for 10 hours. HPLC showed that the reaction was complete, and the trifluoroacetic acid was removed in vacuo, and then diluted with dichloromethane (500 mL). After washing with NaHCO3 aqueous solution, the mixture was dried and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain white solid compound 4 (23.00 g, HPLC purity was 99.2%, yield 62.0%).

[0118] 1 H NMR (400 MHz, DMSO-d 6 ) δppm: 7.24 (d, J=8.4Hz, 1H), 7.05 (dd, J=1.1Hz, 6.8Hz, 1H), 6.97-7.01 (m, 2H), 5.31 (br, 2H).

[0119] Step 2: Synthesis of compound 5

[0120]

[0121] Compound 4 (23.00 g, 108.5 mmol), triethylamine (39.46 g, 390.0 mmol) and acetonitrile (400 mL) were added to a 2 L round bottom flask. The mixture was cooled to about 0 ° C and cyclopropyl chloride (40.23 g, 384.9 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 8 hours after the addition. HPLC showed that the reaction was complete. The mixture was concentrated to dryness, then washed with water and filtered to obtain a solid. The obtained solid was subjected to column chromatography to obtain a white solid compound 5 (29.46 g, HPLC purity of 99.6%, yield 97.0%).

[0122] 1 H NMR (400 MHz, DMSO-d 6 )δppm: 11.14 (br, 1H), 8.05 (s, 1H), 7.50-7.52 (m, 1H), 7.19-7.28 (m, 2H), 1.92-1.99 (m, 1H), 0.82-0.84 (m, 4H).

[0123] Step 3: Synthesis of compound 1

[0124]

[0125] Compound 5 (29.46 g, 105.2 mmol), SM2-1 (41.88 g, 113.4 mmol), K2CO3 (26.12 g, 189.0 mmol), Pd(dppf)Cl2.CH2Cl2 (6.91 g, 8.5 mmol), H2O (120 mL) and 1,4-dioxane (600 mL) were added to a 2 L round bottom flask. The mixture was refluxed for 10 hours under N2 protection. HPLC showed that the reaction was complete, ice water was added to quench the reaction, and the solid was filtered. The obtained solid was subjected to column chromatography to obtain white solid compound 1 (27.42 g, HPLC purity was 98.9%, yield was 58.9%). IPC-MS detection showed that the palladium residue was 314 ppm.

[0126] 1 H (400 Hz, DMSO-d 6 ) δppm: 8.08 (1H, dd, J = 9.2, 7.3Hz), 8.03 (1H, dd, J = 9.3, 1.6Hz), 7.84-7.78 (3H, m), 7.60 (1H, dd, J = 7. 1, 1.6Hz), 4.66 (2H, s), 3.90-3.89, (4H, m), 3.70-3.68 (4H, m), 1.97-1.94 (1H, m), 1.08-1.04 (4H, m). LCMS m / z: 443.2(M+H).

Claims

1. A method for preparing a compound of formula III, comprising the following steps: subjecting a compound of formula II to an amino deprotection reaction as shown below in a solvent under acidic conditions to obtain a compound of formula III; in, R 2 and R 3 Independently selected from halogen and C1-C6 alkyl; m and n are each independently 0, 1, 2, 3 or 4; The acid is hydrogen chloride; The molar ratio of the acid to the compound of formula II is 5 to 50; The molar volume ratio of the acid to the solvent is 3 to 5 mol / L; The reaction temperature of the amino deprotection reaction is 0 to 40°C; The amino deprotection reaction further includes a post-treatment step, which includes adding a heavy metal remover, an organic solvent, ammonia water and water to the reaction solution to precipitate the product; wherein the organic solvent is tetrahydrofuran, ethanol, methanol or a mixture thereof.

2. The preparation method according to claim 1, characterized in that When R 2 and R 3 When R is independently C1-C6 alkyl, the C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; 2 and R 3 When independently halogen, the halogen is iodine, bromine, chlorine or fluorine; And / or, the solvent is water, a C1-C6 alcohol solvent, an ester solvent, a chlorinated alkane solvent, an ether solvent or a mixture thereof; And / or, the reaction time of the amino deprotection reaction is 1 to 24 hours.

3. The preparation method according to claim 2, characterized in that: When R 2 and R 3 When R is independently C1-C6 alkyl, the C1-C6 alkyl is methyl or ethyl; 2 and R 3 When independently halogen, the halogen is fluorine; And / or, the solvent is a C1-C6 alcohol solvent, a chlorinated alkane solvent or a mixture thereof; and / or, the molar ratio of the acid to the compound of formula II is 15 to 25; and / or, the molar volume ratio of the acid to the solvent is 4 mol / L; And / or, the reaction temperature of the amino deprotection reaction is 10 to 20°C; And / or, the reaction time of the amino deprotection reaction is 12 to 20 hours.

4. The preparation method according to claim 2, characterized in that: The solvent is an ester solvent; and / or, the molar ratio of the acid to the compound of formula II is 18 to 20; And / or, the reaction temperature of the amino deprotection reaction is 15°C; And / or, the reaction time of the amino deprotection reaction is 16 hours.

5. The preparation method according to claim 2, characterized in that: The C1-C6 alcohol solvent is methanol, ethanol, isopropanol or a mixture thereof; The ester solvent is methyl acetate, ethyl acetate, propyl acetate or a mixture thereof; The chlorinated alkane solvent is dichloromethane, chloroform, dichloroethane or a mixture thereof; And / or, the molar ratio of the acid to the compound of formula II is 19.

6. The preparation method according to claim 5, characterized in that: The C1-C6 alcohol solvent is ethanol; The ester solvent is ethyl acetate; The chlorinated alkane solvent is dichloromethane.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The organic solvent in the post-treatment step is ethanol, methanol or a mixture thereof.

8. The preparation method according to claim 7, characterized in that: In the post-treatment step, the heavy metal remover is N-acetyl-L-cysteine, diatomaceous earth, 2,4,6-trimercapto-1,3,5-triazine, Si-Thiol, diethylenetriamine, sodium ethylenediaminetetraacetate, tributylphosphine or a mixture thereof; And / or, in the post-treatment step, the organic solvent is methanol; and / or, in the post-treatment step, the molar ratio of the aqueous ammonia to the acid in the amino deprotection reaction is 1.2 to 2.0; and / or, in the post-treatment step, the volume ratio of the organic solvent to the aqueous ammonia is 0.5-2.0; And / or, in the post-treatment step, the volume ratio of the water to the ammonia water is 0.5-1.

5.

9. The preparation method according to claim 7, characterized in that: The heavy metal remover is N-acetyl-L-cysteine; and / or, in the post-treatment step, the molar ratio of the aqueous ammonia to the acid in the amino deprotection reaction is 1.2 to 1.5; and / or, in the post-treatment step, the volume ratio of the organic solvent to the aqueous ammonia is 1.0-1.5; And / or, in the post-treatment step, the volume ratio of the water to the ammonia water is 0.8-1.

2.

10. The preparation method according to claim 9, characterized in that: In the post-treatment step, the volume ratio of the organic solvent to the ammonia water is 1.2; And / or, in the post-treatment step, the volume ratio of the water to the ammonia water is 0.

8.

11. The preparation method according to any one of claims 1 to 6, characterized in that: It further includes a method for preparing the compound of formula II: in the presence of a base and a palladium catalyst, in a solvent, SM1 and SM2 are subjected to a coupling reaction as shown below to obtain the compound of formula II, Among them, R 4 is Br, I or OTf; R 2 , R 3 , m and n as described in claim 1 or 2.

12. The preparation method according to claim 11, characterized in that: In the preparation method of the compound of formula II, the palladium catalyst is Pd(PPh3)4, Pd(OAc)2, Pd(dtbpf)Cl2, (Pd(dppf)Cl2.CH2Cl2 or a mixture thereof; And / or, in the method for preparing the compound of formula II, the base is an inorganic base, an organic base or a mixture thereof; And / or, in the method for preparing the compound of formula II, the solvent is a mixed system of an organic solvent and water; And / or, in the method for preparing the compound of formula II, in the mixed system of the organic solvent and water, the volume ratio of the organic solvent to water is 2:1 to 15:1; and / or, in the method for preparing the compound of formula II, the molar ratio of SM2 to SM1 is 1.0 to 2.0; and / or, in the method for preparing the compound of formula II, the molar ratio of the catalyst to SM1 is 0.01 to 0.5; and / or, in the method for preparing the compound of formula II, the molar ratio of the base to SM1 is 1.0 to 5.0; And / or, in the method for preparing the compound of formula II, the reaction temperature of the coupling reaction is 60 to 120°C; And / or, in the method for preparing the compound of formula II, the reaction time of the coupling reaction is 2 to 12 hours.

13. The preparation method according to claim 12, characterized in that: In the preparation method of the compound of formula II, the palladium catalyst is (Pd(dppf)Cl2.CH2Cl2; and / or, in the method for preparing the compound of formula II, the base is an inorganic base; And / or, in the method for preparing the compound of formula II, the organic base is tert-butyl potassium, triethylamine or a mixture thereof; And / or, the organic solvent is selected from C1-C6 alcohol solvents, aromatic hydrocarbon solvents, ether solvents or mixtures thereof; And / or, in the method for preparing the compound of formula II, in the mixed system of the organic solvent and water, the volume ratio of the organic solvent to water is 10:3 to 10:1; and / or, in the method for preparing the compound of formula II, the molar ratio of SM2 to SM1 is 1.1 to 1.3; and / or, in the method for preparing the compound of formula II, the molar ratio of the base to SM1 is 1.8 to 2.2; And / or, in the method for preparing the compound of formula II, the reaction temperature of the coupling reaction is 90-100°C; And / or, in the method for preparing the compound of formula II, the reaction time of the coupling reaction is 6 to 8 hours.

14. The preparation method according to claim 13, characterized in that: The inorganic base is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal phosphate or a mixture thereof; And / or, the C1-C6 alcohol solvent is methanol, ethanol or a mixture thereof; And / or, the ether solvent is 1,4-dioxane, tetrahydrofuran or a mixture thereof; And / or, in the method for preparing the compound of formula II, in the mixed system of the organic solvent and water, the volume ratio of the organic solvent to water is 10:1; and / or, in the method for preparing the compound of formula II, the molar ratio of SM2 to SM1 is 1.2; and / or, in the method for preparing the compound of formula II, the molar ratio of the catalyst to SM1 is 0.02 to 0.05; And / or, in the method for preparing the compound of formula II, the molar ratio of the base to SM1 is 2.

0.

15. The preparation method according to claim 14, characterized in that: The inorganic base is potassium phosphate, potassium carbonate, potassium hydroxide, cesium carbonate or a mixture thereof, And / or, the aromatic hydrocarbon solvent is toluene; And / or, the ether solvent is 1,4-dioxane; And / or, in the method for preparing the compound of formula II, the molar ratio of the catalyst to SM1 is 0.

03.

16. A method for preparing a compound of formula I, comprising the following steps: in a solvent under alkaline conditions, subjecting a compound of formula III to an acylation reaction with a compound of formula IV as shown below; in, R 1 is a C1-C6 alkyl group or a C3-C8 cycloalkyl group; R 2 , R 3 , m and n are as described in claim 1 or 2; The compound of formula III is prepared by the preparation method as described in any one of claims 1 to 5.

17. The preparation method according to claim 16, characterized in that: When R 1 When R is a C1-C6 alkyl group, the C1-C6 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group; 1 When it is a C3-C8 cycloalkyl group, the C3-C8 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group; and / or, the base is an organic base; And / or, the solvent is a chlorinated alkane solvent, an ether solvent, a nitrile solvent or a mixture thereof and / or, the molar ratio of the compound of formula IV to the compound of formula III is 1.0 to 3.0; and / or, the volume mass ratio of the solvent to the compound of formula III is 8 to 12 L / Kg; and / or, the acylation reaction temperature is 0 to 40°C; And / or, the reaction time of the acylation reaction is 0.5 to 12 hours; And / or, the preparation method of the compound of formula III is as described in any one of claims 1-6.

18. The preparation method according to claim 17, characterized in that: When R 1 When R is C1-C6 alkyl, the C1-C6 alkyl is methyl or ethyl; 1 When it is a C3-C8 cycloalkyl group, the C3-C8 cycloalkyl group is a cyclopropyl group; and / or the base is triethylamine, N,N-diisopropylethylamine, pyridine, tri-n-butylamine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, 4-pyrrolidinylpyridine, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, N-methylmorpholine or a mixture thereof; And / or, the solvent is a chlorinated alkane solvent; and / or, the molar ratio of the compound of formula IV to the compound of formula III is 1.0 to 1.5; And / or, the volume mass ratio of the solvent to the compound of formula III is 10 L / kg; And / or, the acylation reaction temperature is 0 to 10°C; And / or, the reaction time of the acylation reaction is 0.5 to 5 hours.

19. The preparation method according to claim 17, characterized in that: The base is triethylamine; The chlorinated alkane solvent is dichloromethane, dichloroethane, chloroform or a mixture thereof; The ether solvent is tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane or a mixture thereof; and / or, the molar ratio of the compound of formula IV to the compound of formula III is 1.15; And / or, the reaction time of the acylation reaction is 1 hour.

20. The preparation method according to claim 17, characterized in that: The chlorinated alkane solvent is dichloromethane; The nitrile solvent is acetonitrile.

21. The preparation method according to claim 16, characterized in that: The acylation reaction further includes a post-treatment step, which includes: after the acylation reaction is completed, adding a heavy metal remover, an organic solvent and ammonia water to the reaction solution to precipitate the product; wherein the organic solvent is a mixed solvent of an alkane solvent and a C1-C6 alcohol solvent.

22. The preparation method according to claim 21, characterized in that: In the post-treatment step, the heavy metal remover is N-acetyl-L-cysteine, diatomaceous earth, 2,4,6-trimercapto-1,3,5-triazine, Si-Thiol, diethylenetriamine, sodium ethylenediaminetetraacetate, tributylphosphine, or a mixture thereof; And / or, in the post-treatment step, the alkane solvent is n-hexane, cyclohexane, n-heptane or a mixture thereof; And / or, in the post-treatment step, the C1-C6 alcohol solvent is methanol, ethanol or isopropanol; and / or, in the post-treatment step, the volume ratio of the alkane solvent to the solvent used in the acylation reaction is 1 to 2; and / or, in the post-treatment step, the volume ratio of the C1-C6 alcohol solvent to the solvent used in the acylation reaction is 0.05 to 0.25; And / or, in the post-treatment step, the molar ratio of the aqueous ammonia to the compound of formula III is 15-40.

23. The preparation method according to claim 22, characterized in that: The heavy metal remover is N-acetyl-L-cysteine; In the post-treatment step, the alkane solvent is n-heptane; And / or, in the post-treatment step, the C1-C6 alcohol solvent is methanol; and / or, in the post-treatment step, the volume ratio of the alkane solvent to the solvent used in the acylation reaction is 1.3 to 1.4; and / or, in the post-treatment step, the volume ratio of the C1-C6 alcohol solvent to the solvent used in the acylation reaction is 0.05 to 0.15; And / or, in the post-treatment step, the molar ratio of the aqueous ammonia to the compound of formula III is 20-30.

24. The preparation method according to claim 23, characterized in that: In the post-treatment step, the volume ratio of the C1-C6 alcohol solvent to the solvent used in the acylation reaction is 0.1; And / or, in the post-treatment step, the molar ratio of the aqueous ammonia to the compound of formula III is 25.

25. The preparation method according to claim 21 or 22, characterized in that: After the post-treatment step, a purification step may be further included, which includes: in a mixed system of an organic solvent and water, using an acid to remove insoluble impurities in the product obtained in the post-treatment step, and then adding ammonia water to precipitate a pure product; wherein the organic solvent is ethanol, acetonitrile, acetone or a mixture thereof; and the acid is hydrochloric acid.

26. The preparation method according to claim 25, characterized in that: In the purification step, the organic solvent is ethanol; and / or, in the purification step, the volume ratio of the organic solvent to the solvent used in the acylation reaction is 0.8 to 1.2; and / or, in the purification step, the volume ratio of the water to the volume of the solvent used in the acylation reaction is 0.5 to 1.0; and / or, in the purification step, the molar ratio of the hydrochloric acid to the compound of formula III is 1.5 to 3.0; And / or, in the purification step, the amount of ammonia water used is sufficient to adjust the pH of the system to 8-9.

27. The preparation method according to claim 26, characterized in that: In the purification step, the acid is concentrated hydrochloric acid; and / or, in the purification step, the volume ratio of the organic solvent to the solvent used in the acylation reaction is 1.0; and / or, in the purification step, the volume ratio of the water to the volume of the solvent used in the acylation reaction is 0.6 to 0.7; And / or, in the purification step, the molar ratio of hydrochloric acid to the compound of formula III is 2.2 to 2.3.

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