Preparation method of heterocyclic alkyl compound, intermediates thereof and application thereof

Abstract

The application discloses a preparation method of a heterocyclic alkyl compound, an intermediate thereof and application of the intermediate. The application provides a preparation method of a compound shown in a formula IN-06, which comprises the following steps: performing ring formation reaction and deprotection reaction on a compound shown in a formula IN-05 in an organic solvent in the presence of an acid-binding agent to obtain the compound shown in the formula IN-06, and the acid-binding agent is NaOH, NaH or potassium carbonate; wherein R is halogen. The preparation method has one or more advantages of higher chiral purity and being beneficial to industrial production.

Description

[0001] This application claims priority to Chinese patent application 202110705767.4, filed on June 24, 2021. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to a method for preparing heterocyclic alkyl compounds, their intermediates, and their applications. Background Technology

[0003] ATP receptors are classified into two main families based on their molecular structure, transduction mechanism, and pharmacological properties: P2Y- and P2X-purine receptors. P2X-purine receptors are a family of ATP-gated cation channels, and several subtypes have been cloned, including: six homopolymers, P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7; and three heteropolymers, P2X2 / 3, P2X4 / 6, and P2X1 / 5. Studies have found that P2X3 receptors are particularly expressed in primary afferent nerve fibers of "hollow viscera," such as the lower urinary tract and respiratory tract.

[0004] Coughing is a major symptom of respiratory diseases, affecting 70% to 80% of patients in respiratory clinics. With the increasing prevalence of conditions like COPD and IPF, and given that coughing is a primary symptom of most exhaled airway diseases, the demand for treatment is also growing. As a defensive reflex, coughing helps clear respiratory secretions and harmful agents; however, frequent and severe coughing can seriously impact a patient's work, daily life, and social activities.

[0005] There are not many P2X3 antagonists specifically developed for the indication of cough. The project that is progressing the fastest is Roche's AF-219 project. Its latest completed Phase II clinical trial showed good efficacy for refractory cough, but the taste disorder problem is serious.

[0006] (S)-2-ethynylmorpholine-4-carboxylic acid tert-butyl ester is an important intermediate in the synthesis of imidazopyridine P2X3 inhibitors. Chinese patent WO2014117274A-CN105246888A, "Imidazopyridine Compounds and Their Uses," page 33, Example 7, discloses its preparation method. The specific synthetic route is as follows:

[0007]

[0008] The synthetic route disclosed in this patent has a scale-up effect, and the chiral purity of the product obtained by scale-up will be significantly reduced, which is not conducive to large-scale production. In addition, the raw material used is dimethyl phosphonate (1-diazo-2-oxopropyl)phosphonate, which is expensive, has poor stability, and is inconvenient to transport and store, making production easily restricted. Summary of the Invention

[0009] The technical problem this invention aims to solve is the scarcity of existing methods for preparing compounds of formula SM-03. Therefore, this invention provides a method for preparing heterocyclic alkyl compounds, its intermediate, and its applications. The product obtained by this method has higher chiral purity, which is beneficial for industrial production. The intermediate corresponding to this invention can be used in the production of imidazopyridine P2X3 inhibitor compounds.

[0010] The present invention mainly solves the above-mentioned technical problems through the following technical solutions.

[0011] This invention provides a method for preparing the compound shown in formula IN-06, comprising the following steps: in an organic solvent, in the presence of an acid-binding agent, the compound shown in formula IN-05 undergoes a cyclization reaction and a deprotection reaction to obtain the compound shown in formula IN-06; wherein the acid-binding agent is NaOH, NaH, or potassium carbonate; and R is a halogen.

[0012]

[0013] In a certain scheme, R is F, Cl, Br or I, for example Cl.

[0014] In one embodiment, the organic solvent is a conventional organic solvent for this type of reaction in the art, such as a haloalkane solvent, a nitrile solvent, or an ether solvent. The haloalkane solvent is preferably dichloromethane. The nitrile solvent is preferably acetonitrile. The ether solvent is preferably tetrahydrofuran. The organic solvent is preferably tetrahydrofuran.

[0015] In one embodiment, the molar ratio of the compound shown in IN-05 to the acid-binding agent can be 1:1.5 to 4, for example, 1:2.

[0016] In one embodiment, the mass-to-volume ratio of the compound shown in IN-05 to the organic solvent can be 0.055 g / L to 0.5 g / L, for example, 0.1 g / L.

[0017] In one embodiment, the mass-to-volume ratio of the compound shown in IN-05 to the organic solvent can be 0.055 g / mL to 0.5 g / mL, for example, 0.1 g / mL.

[0018] The temperatures for the cyclization reaction and the deprotection reaction are conventional temperatures for this type of reaction in the art, preferably 20–40°C, for example 25°C.

[0019] The progress of the deprotection reaction is monitored using conventional detection methods in the art, such as thin-layer chromatography (TLC), gas chromatography (GC), nuclear magnetic resonance spectroscopy (NMR), or high-performance liquid chromatography (HPLC), for example, TLC.

[0020] The post-processing steps of the deprotection reaction are conventional post-processing steps for this type of reaction in the art, such as washing, drying, filtration, and column chromatography, to obtain the compound shown in formula IN-06.

[0021] The method for preparing the compound shown in formula IN-06 may further include the following steps: in an organic solvent, mixing the compound shown in formula IN-04A with... The compound of formula IN-05 can be obtained by carrying out a substitution reaction.

[0022]

[0023] R 1 It can be F, Cl, Br, or I, for example, Cl.

[0024] In the substitution reaction described above, the organic solvent is a conventional solvent for this type of reaction in the art, preferably a nitrile solvent or an alkane solvent. The nitrile solvent is preferably acetonitrile. The alkane solvent is preferably dichloromethane.

[0025] In the aforementioned substitution reaction, the The preferred substitutes for this type of reaction are chloroacetyl chloride and bromoacetyl bromide, such as chloroacetyl chloride.

[0026] In the substitution reaction described above, the compound represented by formula IN-04A reacts with the compound described above. The molar ratio can be 1:0.8-1.2, for example 1:1.

[0027] In the substitution reaction, the mass-to-volume ratio of the compound represented by formula IN-04A to the organic solvent can be 80 g / L to 200 g / L, for example, 100 g / L.

[0028] The temperature of the substitution reaction is the conventional temperature for this type of reaction in the art, preferably -5 to 5°C, for example 0°C.

[0029] The progress of the substitution reaction is monitored using conventional detection methods in the art, such as thin-layer chromatography (TLC), gas chromatography (GC), nuclear magnetic resonance spectroscopy (NMR), or high-performance liquid chromatography (HPLC).

[0030] The duration of the substitution reaction is determined by the completeness of the substitution reaction, for example, 0.1 to 4 hours, or for example, 0.3 hours.

[0031] The post-processing steps of the substitution reaction are conventional post-processing steps for this type of reaction in the art, such as washing, drying, filtering, and column chromatography, to obtain the compound shown in IN-05.

[0032] The preparation method of the compound shown in formula IN-06 may further include the following steps: in an organic solvent, the compound shown in formula IN-04 is neutralized with an acid-binding agent to obtain the compound shown in formula IN-04A.

[0033]

[0034] Among them, R X It is an acid, and can be hydrochloric acid.

[0035] In the neutralization reaction, the acid-binding agent is a conventional base in the art, preferably a strong organic base, such as triethylamine or N,N-diisopropylethylamine.

[0036] The neutralization reaction conditions described are conventional conditions for this type of reaction in the art.

[0037] In one particular scheme, R X It is an acid commonly used in the field, such as hydrochloric acid.

[0038] The preparation method of the compound shown in formula IN-06 may further include the following steps: in an organic solvent, the compound shown in formula IN-03 is reacted with a deprotecting agent to obtain the compound shown in formula IN-04;

[0039]

[0040] The R mentioned X For the corresponding acid.

[0041] In the deprotection reaction described above, the organic solvent is a conventional solvent for this type of reaction in the art, such as a haloalkane solvent, an ester solvent, or an ether solvent. The haloalkane solvent is preferably dichloromethane. The ester solvent is preferably ethyl acetate. The ether solvent is preferably 1,4-dioxane. The organic solvent is preferably dichloromethane.

[0042] In the deprotection reaction, the deprotection reagent may be hydrochloric acid, hydrochloric acid / dioxane, hydrochloric acid / ethyl acetate, zinc bromide, or tert-butyldimethylsilyltrifluoromethanesulfonate.

[0043] In the deprotection reaction, the mass-to-volume ratio of IN-O3 to the organic solvent can be 80 g / L to 300 g / L, for example, 200 g / L.

[0044] In the deprotection reaction, the molar ratio of the compound represented by formula IN-03 to the deprotection reagent can be 3-8:1, for example 5.7:1.

[0045] In the deprotection reaction, the molar ratio of the deprotection reagent to the compound represented by formula IN-03 can be 3-8:1, for example 5.7:1.

[0046] The temperature of the deprotection reaction is the conventional temperature for this type of reaction in the art, preferably 20-40°C, for example 25°C.

[0047] The progress of the deprotection reaction is monitored using conventional detection methods in the art, such as thin-layer chromatography (TLC), gas chromatography (GC), nuclear magnetic resonance spectroscopy (NMR), or high-performance liquid chromatography (HPLC).

[0048] The preparation method of the compound shown in formula IN-06 may further include the following steps: in an organic solvent, the compound shown in formula IN-02 is reduced with a boron methyl sulfide complex (BH3.Me2S) under the action of a catalyst to obtain the compound shown in formula IN-03;

[0049]

[0050] In the reduction reaction, the catalyst is a conventional catalyst for this type of reaction in the art, such as (R)-2-methyl-CBS-oxazolborane.

[0051] In the reduction reaction described, the organic solvent is a conventional solvent for this type of reaction in the art, such as tetrahydrofuran.

[0052] In the reduction reaction, the mass-to-volume ratio of IN-O2 to the organic solvent can be 60 g / L to 150 g / L, for example, 90 g / L or 100 g / L.

[0053] In the reduction reaction, the molar ratio of the compound represented by formula IN-02 to BH3.Me2S can be (0.5-1.2):1, for example 0.91:1.

[0054] The temperature of the reduction reaction is the conventional temperature for this type of reaction in the art, preferably -5 to 5°C, for example 0°C.

[0055] The progress of the reduction reaction is monitored using conventional detection methods in the art, such as thin-layer chromatography (TLC), gas chromatography (GC), nuclear magnetic resonance spectroscopy (NMR), or high-performance liquid chromatography (HPLC).

[0056] The preparation method of the compound shown in formula IN-06 may further include the following steps: in an organic solvent, in the presence of a Grignard reagent, the compound shown in formula IN-01 is subjected to a Grignard reaction with trimethylsilylacetylene to obtain the compound shown in formula IN-02.

[0057]

[0058] In the described reaction, the organic solvent can be a conventional solvent for this type of reaction in the art, such as tetrahydrofuran.

[0059] In the described Grignard reaction, the Grignard reagent can be a conventional reagent for this type of reaction in the art, such as isopropyl magnesium chloride and lithium chloride solution.

[0060] In the aforementioned reaction, the mass-to-volume ratio of IN-01 to the organic solvent can be 70 g / L to 150 g / L, for example, 92 g / L or 96 g / L.

[0061] In the Grignard reaction, the molar ratio of the compound represented by formula IN-01 to the Grignard reagent can be 0.2-0.8:1, for example 0.4:1.

[0062] In the described reaction, the molar ratio of the compound represented by formula IN-01 to the trimethylsilylacetylene reagent can be 0.2-0.6:1, for example 0.3:1.

[0063] The temperature of the reaction can be the conventional temperature for this type of reaction in the art, preferably -20 to 0°C, for example -10°C.

[0064] The progress of the described reaction can be monitored using conventional detection methods in the art, such as thin-layer chromatography (TLC), gas chromatography (GC), nuclear magnetic resonance spectroscopy (NMR), or high-performance liquid chromatography (HPLC).

[0065] The preparation method of the compound shown in formula IN-06 may further include the following steps: in an organic solvent, in the presence of a base, the compound shown in formula SM-01 is subjected to an esterification reaction with N,O-dimethylhydroxylamine hydrochloride under the condition of a catalyst to obtain the compound of formula IN-01.

[0066]

[0067] In the esterification reaction described above, the organic solvent is a conventional solvent for this type of reaction in the art, such as dichloromethane.

[0068] In the esterification reaction described herein, the base is a base conventional for this type of reaction in the art, such as triethylamine.

[0069] In the esterification reaction described herein, the catalyst is a conventional catalyst for such reactions in the art, 4-dimethylaminopyridine (DMAP) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl).

[0070] In the esterification reaction, the mass-to-volume ratio of SM-01 to the organic solvent can be 40 g / L to 100 g / L, for example, 66.7 g / L.

[0071] In the esterification reaction, the molar ratio of the N,O-dimethylhydroxylamine hydrochloride to the compound of formula SM-01 can be 1-1.5:1, for example 1.2:1.

[0072] In the esterification reaction, the mass-to-volume ratio of the compound of formula SM-01 to the base can be (300-900:1) g / L, for example 600:1 g / L.

[0073] In the esterification reaction, the molar ratio of the compound of formula SM-01 to the base can be 1:1.5-2.5, for example, 1:2.1.

[0074] In the esterification reaction, the molar ratio of the compound represented by formula SM-01 to EDCl can be 1:1.1-1.4, for example 1:1.2.

[0075] In the esterification reaction, the molar ratio of the compound represented by formula SM-01 to the DMAP can be 1:0.05-0.2, for example 1:0.1.

[0076] The temperature of the esterification reaction is the conventional temperature for this type of reaction in the art, preferably 10 to 30°C, for example 20°C.

[0077] The esterification reaction process can be monitored using conventional detection methods in the art, such as thin-layer chromatography (TLC), gas chromatography (GC), nuclear magnetic resonance spectroscopy (NMR), or high-performance liquid chromatography (HPLC).

[0078] The present invention also provides a method for preparing a compound as shown in formula SM-03, comprising the following steps:

[0079] Step 1: Prepare the compound as shown in formula IN-06 by the preparation method described above;

[0080] Step 2: In an organic solvent, the compound shown in formula IN-06 is reduced with a reducing agent, and then protected with a protecting agent in the presence of an acid-binding agent to obtain SM-03.

[0081]

[0082] In the described protective reaction, the organic solvent is a conventional solvent for this type of reaction in the art, such as tetrahydrofuran.

[0083] In the protective reaction, the mass-to-volume ratio of the compound of formula IN-06 to the organic solvent can be 40 g / L to 100 g / L, for example, 66.7 g / L.

[0084] In the protective reaction described above, the reducing agent is a conventional reducing agent for this type of reaction in the art, such as lithium aluminum hydride.

[0085] In the protective reaction, the molar ratio of the compound represented by formula IN-06 to the reducing agent can be 1:0.5-3, for example 1:2.

[0086] In the protective reaction described above, the reaction temperature is the conventional reaction temperature for this type of reaction in the art, for example, 20-40°C, or 25°C.

[0087] In the protective reaction described above, the acid-binding agent is a base commonly used in this type of reaction in the art, such as sodium carbonate or potassium carbonate.

[0088] In the described protective reaction, the protecting agent is a conventional protecting agent for this type of reaction in the art, such as di-tert-butyl carbonate.

[0089] In the protective reaction, the molar ratio of the compound of formula IN-06 to the base can be 1:0.5-3, for example 1:2.

[0090] In the protection reaction, the molar ratio of the compound represented by formula IN-06 to the protecting reagent can be 1:0.5-3, for example 1:2.

[0091] The temperature of the protective reaction is the conventional temperature for this type of reaction in the art, preferably 20 to 40°C, for example 25°C.

[0092] The progress of the protective reaction is monitored using conventional detection methods in the art, such as thin-layer chromatography (TLC), gas chromatography (GC), nuclear magnetic resonance spectroscopy (NMR), or high-performance liquid chromatography (HPLC).

[0093] The post-processing steps of the protection reaction are conventional post-processing steps for this type of reaction in the art, such as filtration and column chromatography, to obtain the compound shown in SM-03.

[0094] In one embodiment, the method for preparing the compound as shown in formula SM-03 includes the following steps:

[0095] Step 1: Prepare the compound as shown in formula IN-06 by the preparation method described above;

[0096] Step 2: In an organic solvent, the compound shown in formula IN-06 is reduced with a reducing agent, and then protected with a protecting agent in the presence of an acid-binding agent to obtain SM-03.

[0097]

[0098] In the described protective reaction, the organic solvent is a conventional solvent for this type of reaction in the art, such as tetrahydrofuran.

[0099] In the protective reaction, the mass-to-volume ratio of the compound of formula IN-06 to the organic solvent can be 40 g / L to 100 g / L, for example, 66.7 g / L.

[0100] In the protective reaction described above, the reducing agent is lithium aluminum hydride.

[0101] In the protective reaction, the molar ratio of the compound represented by formula IN-06 to the reducing agent can be 1:0.5-3, for example 1:2.

[0102] In the protective reaction described above, the reaction temperature is the conventional reaction temperature for this type of reaction in the art, for example, 20-40°C, or 25°C.

[0103] In the protective reaction described above, the acid-binding agent is sodium carbonate or potassium carbonate.

[0104] In the protection reaction described above, the protecting agent is di-tert-butyl carbonate anhydride.

[0105] In the protective reaction, the molar ratio of the compound of formula IN-06 to the base can be 1:0.5-3, for example 1:2.

[0106] In the protection reaction, the molar ratio of the compound represented by formula IN-06 to the protecting reagent can be 1:0.5-3, for example 1:2.

[0107] The temperature of the protective reaction is the conventional temperature for this type of reaction in the art, preferably 20 to 40°C, for example 25°C.

[0108] The progress of the protective reaction is monitored using conventional detection methods in the art, such as thin-layer chromatography (TLC), gas chromatography (GC), nuclear magnetic resonance spectroscopy (NMR), or high-performance liquid chromatography (HPLC).

[0109] The post-processing steps of the protection reaction are conventional post-processing steps for this type of reaction in the art, such as filtration and column chromatography, to obtain the compound shown in SM-03.

[0110] The present invention also provides a method for preparing the compound shown in formula IN-05, comprising the following steps: in an organic solvent, in the presence of an acid-binding agent, reacting the compound shown in formula IN-04A with... The compound of formula IN-05 can be obtained by carrying out a substitution reaction.

[0111]

[0112] Where R is F, Cl, Br, or I, for example, Cl; R 1 It can be F, Cl, Br, or I, for example, Cl;

[0113] The conditions for the substitution reactions are all as described above;

[0114] The preparation method of the compound shown in formula IN-05 may further include the following steps: in an organic solvent, the compound shown in formula IN-04 is neutralized with an acid-binding agent to obtain the compound shown in formula IN-04A.

[0115]

[0116] Among them, R X It is an acid, and can be hydrochloric acid;

[0117] The conditions for the neutralization reaction are as described above;

[0118] The preparation method of the compound shown in formula IN-05 may further include the following steps: in an organic solvent, the compound shown in formula IN-03 is reacted with a deprotecting agent to obtain the compound shown in formula IN-04;

[0119]

[0120] The R mentioned X For the corresponding acid;

[0121] The conditions for the deprotection reactions are all as described above;

[0122] The preparation method of the compound shown in formula IN-05 may further include the following steps: in an organic solvent, the compound shown in formula IN-02 is reduced with a boron methyl sulfide complex (BH3.Me2S) to obtain the compound shown in formula IN-03;

[0123]

[0124] The conditions for the reduction reactions are as described above;

[0125] The preparation method of the compound shown in formula IN-05 may further include the following steps: in an organic solvent, in the presence of a Grignard reagent, the compound shown in formula IN-01 is subjected to a Grignard reaction with trimethylsilylacetylene to obtain the compound shown in formula IN-02.

[0126]

[0127] The conditions for the described reaction are as described above;

[0128] The preparation method of the compound shown in formula IN-05 may further include the following steps: in an organic solvent, in the presence of a base, the compound shown in formula SM-01 is subjected to an esterification reaction with N,O-dimethylhydroxylamine hydrochloride under the condition of a catalyst to obtain the compound of formula IN-01.

[0129]

[0130] The conditions for the esterification reactions are as described above.

[0131] The present invention also provides a method for preparing the compound shown in formula IN-05, comprising the following steps: in an organic solvent, in the presence of an acid-binding agent, reacting the compound shown in formula IN-04A with... The compound of formula IN-05 can be obtained by carrying out a substitution reaction.

[0132]

[0133] Where R is F, Cl, Br, or I, for example, Cl; R 1 It can be F, Cl, Br, or I, for example, Cl;

[0134] The conditions for the substitution reactions described above are all as described above.

[0135] The present invention also provides a method for preparing a compound as shown in formula SM-03, which includes the following steps: in an organic solvent, a compound as shown in formula IN-06 is subjected to a reduction reaction with a reducing agent, and then a protecting group reaction is carried out with a protecting agent in the presence of an acid-binding agent to obtain SM-03;

[0136]

[0137] The conditions for both the reduction reaction and the protecting group reaction are as described above.

[0138] In one embodiment, the preparation method of the compound shown in formula SM-03 includes the following steps: in an organic solvent, the compound shown in formula IN-06 is reduced with a reducing agent, and then, in the presence of an acid-binding agent, it is reacted with a protecting agent to obtain SM-03.

[0139]

[0140] The conditions for both the reduction reaction and the protecting group reaction are as described above.

[0141] The present invention also provides a compound of formula IN-06.

[0142]

[0143] The present invention also provides a compound of formula IN-05.

[0144]

[0145] Where R is F, Cl, Br or I, for example Cl.

[0146] The present invention also provides the use of a compound of formula IN-06 for the preparation of a compound of formula SM-03 or for the preparation of substance A via SM03, wherein substance A is compound A1. Compound A2 Compound A3 Compound A4

[0147]

[0148]

[0149] Preferably, the preparation methods of compounds A1, A2, A3, and A4 are as follows:

[0150] Method 1:

[0151]

[0152] Method 2:

[0153]

[0154] Method 3:

[0155]

[0156] Method 4:

[0157]

[0158] The present invention also provides an application of a compound of formula IN-06 for the preparation of a compound of formula SM-03 or for the preparation of substance A via SM-03, wherein substance A is compound A5.

[0159] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0160] The reagents and raw materials used in this invention are all commercially available.

[0161] This invention provides a method for preparing heterocyclic alkyl compounds, their intermediates, and their applications. The products obtained by this method have higher chiral purity, which is beneficial for industrial production. Attached Figure Description

[0162] Figure 1 The liquid chromatography chromatogram is shown for the compound represented by formula SM-03. Detailed Implementation

[0163] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0164] The following detailed description, in conjunction with specific embodiments, illustrates the general formula compounds of the present invention, their preparation methods, and applications in further detail. The following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0165] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0166] The following abbreviations are used throughout this invention:

[0167] MeOH (methanol), EA (ethyl acetate), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide), g (gram), mg (milligram), mol (mol), mmol (millimole), h (hour), min (minute), mL (milliliter), μL (microliter).

[0168] Overnight refers to 8 to 15 hours, such as 12 hours; room temperature refers to 20°C to 30°C; solvent ratio, such as PE / EA, refers to the volume ratio.

[0169] Unless otherwise stated, all temperatures described in the embodiments below are in degrees Celsius.

[0170] Testing instruments and methods

[0171] X-ray powder diffractometer (XRPD): Instrument model: PANalytical Empyrean, system equipped with PIXcel 1D The detector and instrument parameters are as follows: scanning range 3-40° (2θ), step size 0.013° (2θ), phototube voltage 45KV, and phototube current 40mA.

[0172] Differential Scanning Calorimeter (DSC): Instrument model: Discovery DSC 250 (TA Instruments, US). Accurately weigh 2-3 mg of solid sample into an aluminum pinhole sealed dish and record the weight accurately. After the sample equilibrates at 25°C, heat it to 250°C at a heating rate of 10°C / min.

[0173] Thermogravimetric Analysis (TGA): Instrument model: Discovery TGA 55 (TA Instruments, US). The sample is placed in an open, tare aluminum pan, automatically weighed, and then inserted into the TGA furnace. After the sample mass is automatically weighed inside the TGA furnace, it is heated to 250°C at a heating rate of 10°C / min.

[0174] Polarizing Microscope (PLM): ECLIPSE LV100POL (Nikon, JPN).

[0175] Dynamic Moisture Adsorption Analyzer (DVS): Instrument model: DVS (ProUmid GmbH & Co. KG, Germany). The sample is placed in a sample box containing tar and automatically weighed.

[0176] Hydrogen nuclear magnetic resonance (HNMR) 1 H-NMR: Instrument model: AVANCE III HD 300, equipped with an autosampler (SampleXpress 60).

[0177] Example 1:

[0178] I. Synthesis of IN-01

[0179]

[0180] SM-01 (45 g, 256.87 mmol, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (30 g, 308.25 mmol, 1.2 eq), and DMAP (3.1 g, 25.68 mmol, 0.1 eq) were dissolved in DCM (675 mL). The mixture was cooled to 0 °C, and TEA (75 mL) was added. The mixture was stirred for 1 h, followed by the addition of EDCl (59 g, 1.2 eq). The mixture was then allowed to warm naturally to room temperature (20 °C) and reacted overnight. The reaction mixture was spotted onto a TLC plate, and the starting material was consumed. The pH was adjusted to 3-4 with 1 M HCl. The mixture was separated into liquid and liquid phases. The organic phase was washed successively with 1 M HCl (150 mL), distilled water (150 mL), and saturated brine (100 mL). The solution was dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain 52.5 g of a white solid, with a yield of 93%. 1 H NMR (400MHz, CDCl3) δ5.25 (s, 1H), 4.07 (d, J = 4.0Hz, 2H), 3.70 (s, 3H), 3.19 (s, 3H), 1.44 (s, 9H).

[0181] II. Synthesis of IN-02

[0182]

[0183] In a three-necked flask, under nitrogen purging and protection, trimethylsilylacetylene (32.4 g, 329.89 mmol) was added. Then, under ice bath conditions, isopropyl magnesium chloride and lithium chloride solution (211 mL, 1.3 M, 274.9 mmol, in THF) was added dropwise. After complete addition, the reaction was continued in an ice bath for 1 h. IN-01 (24 g, 109.96 mmol) was added to the three-necked flask and dissolved in anhydrous tetrahydrofuran (50 mL), followed by nitrogen purging. At room temperature, the above reaction solution was added dropwise to the tetrahydrofuran solution, and the reaction was continued for 2 h. TLC analysis showed that the reaction was essentially complete. The mixture was quenched with saturated ammonium chloride solution (150 mL), extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness, yielding 29 g of a red oily liquid (100% yield). 1 H NMR (400MHz, CDCl3) δ5.16 (s, 1H), 4.15-4.02 (m, 2H), 1.42 (s, 9H), 0.23 (s, 9H).

[0184] III. Synthesis of IN-03

[0185]

[0186] (R)-2-methyl-CBS-oxazolium borane (6.3 g, 22.71 mmol, 0.2 eq) was dissolved in THF (70 mL), purged with nitrogen and protected, and cooled to 0 °C. BH3·Me2S (12.5 mL, 10 M, 124.9 mmol) was added, followed by the addition of IN-O2 (29 g, 113.55 mmol) dissolved in THF (220 mL). The temperature was maintained at 0 °C, and the addition time exceeded 25 min. After the reaction was complete, the mixture was reacted again at 0 °C. TLC analysis showed that the starting material reacted completely. The reaction was quenched by adding MeOH (50 mL), and after half an hour, the mixture was concentrated and purified by column chromatography (PE / EA = 15 / 1) to obtain 20 g of a light brown oily liquid, with a yield of 70.6% and a chiral purity of 77.8%. 1 HNMR (400MHz, CDCl3) δ4.99 (s, 1H), 4.42 (s, 1H), 3.45 (s, 1H), 3.31-3.18 (m, 1H), 2.88 (s, 1H), 1.44 (s, 9H), 0.16 (d, J = 0.6Hz, 8H).

[0187] IV. Synthesis of IN-04

[0188]

[0189] IN-03 (20 g, 77.69 mmol, 1 eq) was dissolved in DCM (100 mL), followed by the addition of 4 M HCl (100 mL). The reaction was allowed to proceed at room temperature. TLC analysis showed that the reaction was complete. The solution was then concentrated to dryness to yield 16 g of crude product, a brown solid (theoretically yielding 15 g), with a 100% yield. This product was then directly used in the next step. 1 H NMR (400MHz, CDCl3) δ7.98 (s, 2H), 4.90 (s, 1H), 3.34 (s, 2H), 0.19 (s, 9H).

[0190] V. Synthesis of IN-05

[0191]

[0192] Method 1: IN-04 (16g, 93.7%, 77.42mmol, 1eq) and TEA (19.6g, 193.55mmol, 2.5eq) were dissolved in DCM (150mL). The mixture was protected by N2 displacement and cooled to 0℃. Then, chloroacetyl chloride (8.7g, 77.42mmol, 1.0eq, dissolved in 10mL DCM) was added dropwise, and the reaction was allowed to proceed for 20 min. TLC monitoring showed complete reaction of the starting material. After post-processing, the mixture was washed with saturated NaCl solution, dried, filtered, concentrated, and purified by column chromatography (PE / EA ratio from 5 / 1 to 2 / 1) to obtain 12g of the product, a light brown oily substance, with a yield of 66%. 1 HNMR (400MHz, CDCl3) δ7.02 (s, 1H), 4.50 (s, 1H), 4.09 (s, 2H), 3.72-3.66 (m, 1H), 3.47-3.41 (m, 1H), 2.58 (s, 1H), 0.18 (d, J = 0.7Hz, 9H).

[0193] Method 2: 1.7 g (1 eq) of IN-04 and 2.5 eq of TEA were dissolved in 15 mL of DCM under N2 displacement protection and cooled to 0 °C. Then, 1.05 eq of chloroacetyl chloride (dissolved in 2 mL of DCM) was added dropwise, and the reaction was allowed to proceed for 20 min. TLC showed complete reaction of the starting materials. After post-processing, the reaction solution was washed with saturated NaCl solution, dried, filtered, and concentrated to obtain 2.8 g of crude product, a light yellow oily substance with a chiral purity of 78.8% and no racemization.

[0194] VI. Synthesis of IN-06

[0195]

[0196] IN-05 (12 g, 51.33 mmol, 1 eq) was dissolved in 120 mL of THF, and then NaH (2.46 g, 102.67 mmol, 2.0 eq) was added. The reaction was carried out at room temperature. TLC plate showed that the starting material was completely reacted. After post-processing, the pH of the reaction solution was adjusted to 5 with 1 M HCl. The aqueous and organic phases were concentrated to dryness (IN-06 has some water solubility), filtered, concentrated, and then subjected to column chromatography (PE / EA = 1 / 2) to give 4.5 g of product, a light yellow solid, with a yield of 70.3%. 1 H NMR (400MHz, DMSO-d6) δ 8.07 (s, 1H), 4.70-4.67 (m, 1H), 4.04 (d, J=1.6Hz, 2H), 3.61 (d, J=2.2Hz, 1H), 3.45-3.39 (m, 1H), 3.23-3.18 (m, 1H).

[0197] VII. Synthesis of SM-03

[0198] Method 1:

[0199]

[0200] IN-06 (4.5 g, 35.96 mmol, 1 eq) was dissolved in THF (67.5 mL), followed by LAH (2.73 g, 71.93 mmol, 2.0 eq), and the reaction was carried out at room temperature. After the starting material was completely reacted by TLC, K2CO3 (2.0 eq) solution dissolved in 20 mL of water and Boc2O (15.7 g, 71.93 mmol, 2.0 eq) were added, and the reaction was carried out at room temperature. After the reaction was completed by TLC, the mixture was filtered, extracted with EA, washed with saturated NaCl solution, dried, filtered and concentrated, and column chromatography (PE / EA = 10 / 1) was performed to obtain 2.3 g of product, a white solid, with a yield of 30.2%, a chiral purity of 78.9%, and a retention time of 8.051 min. 1 H NMR (400MHz, CDCl3) δ4.76 (d, J=8.9Hz, 1H), 4.16 (d, J=13.4Hz, 1H), 4.04 (d, J=9.4Hz, 1H), 3.47 (d, J=12.1Hz, 1H), 3.28 (s, 1H), 3.15 (s, 2H), 2.66 (s, 1H).

[0201] Method 2:

[0202] IN-06 (80 mg, 1 eq) was dissolved in THF (3 mL), followed by the addition of LAH (3.0 eq), and the reaction was carried out at room temperature. The reaction solution was then post-treated by quenching with 10 mL of NH4Cl solution, followed by the addition of K2CO3 (2.0 eq) and Boc2O (2.0 eq), and the reaction was carried out at room temperature. After the reaction was complete, the mixture was filtered, extracted with EA, washed with saturated NaCl solution, dried, filtered, concentrated, and column chromatography was performed to obtain 40 mg of product with a chiral purity of 81.8% and an HPLC retention time of 8.051 min.

[0203] 1 H NMR (400MHz, CDCl3) δ4.76 (d, J=8.9Hz, 1H), 4.16 (d, J=13.4Hz, 1H), 4.04 (d, J=9.4Hz, 1H), 3.47 (d, J=12.1Hz, 1H), 3.28 (s, 1H), 3.15 (s, 2H), 2.66 (s, 1H).

[0204] Detection methods for product SM-03 obtained by methods one and two:

[0205] Instrument: Liquid chromatograph (Shimadzu LC-20AT or equivalent);

[0206] Column type: CHIRALPAK AD-H (250*4.6mm, 5μm);

[0207] Column temperature: 30℃;

[0208] Flow rate: 1 mL / min;

[0209] Wavelength: 210nm;

[0210] Mobile phase: n-hexane:ethanol = 98:2 (V / V);

[0211] Isocratic elution: 20 min;

[0212] Diluent: Ethanol;

[0213] Sample solution: 2 mg / mL;

[0214] The test results are shown in Table 1 and Figure 1 As shown.

[0215] Table 1. Analysis Results and Preliminary Quality Standards

[0216] name retention time min Relative Retention Time (RRT) SM-03(R) 8.051 0.89

[0217] SM-03(S) 9.009 1.00

[0218] Example 2

[0219] Preparation of methyl (S)-2-((2-(2,6-difluoro-4-aminosulfonylphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

[0220]

[0221] Step 1: In a 100 mL round-bottom flask, add intermediate A1-4 (18.2 g, 39.4 mmol, 1.0 eq), 4-methylpyridin-2-amine (4.26 g, 39.4 mmol, 1.0 eq, compounds 1-5), (S)-2-ethynylmorpholine-4-carboxylic acid tert-butyl ester (8.33 g, 39.4 mmol, 1.0 eq, SM-03), CuCl (1.17 g, 11.8 mmol, 0.3 eq), Cu(OIf)2 (4.34 g, 11.8 mmol, 0.3 eq), toluene (200 mL), and DMA (12 mL). Purge with nitrogen three times, heat in an oil bath at 85 °C overnight (12 h). TLC analysis shows that starting material compounds 1-5 have disappeared, while intermediate A1-4 remains and the reaction is incomplete. After cooling the reaction solution to room temperature, ammonia (100 mL) and water (150 mL) were added, and the mixture was stirred for 5 min. The mixture was separated, and the toluene phase was collected. The aqueous phase was extracted twice with DCM (150 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness before column chromatography to obtain intermediate A1-5 (11.2 g, yellow solid, purity 96%, yield 37%). LC-MS: [M+H] + =761.9.

[0222] Step 2: Dissolve intermediate A1-5 (11.2 g, 14.7 mol) in DCM (33 mL), then add dioxane hydrochloride solution (4 M, 33 mL), stir at room temperature for 1.0 h, and monitor the reaction by TLC until complete. Add water (100 mL) and dichloromethane (200 mL) to the reaction solution, and adjust the pH with sodium carbonate until the aqueous phase is weakly alkaline (pH = 9–10). Separate the DCM phase, and extract the aqueous phase twice with DCM (100 mL). Combine the DCM phases, wash with saturated brine, dry and evaporate to dryness to obtain intermediate A1-6 (9.7 g, white solid), which is directly added to the next step in 100% yield. LC-MS: [M+H] + =622.2.

[0223] Step 3: Intermediate A1-6 (9.7 g, 14.7 mmol, 1.0 eq) was dissolved in DCM (40 mL), and Et3N (2.96 g, 29.3 mmol, 2.0 eq) was added. Methyl chloroformate (2.08 g, 22 mmol, 1.5 eq) was added dropwise. After 1.0 h, TLC showed that the reaction was complete. After the reaction was complete, water (150 mL) and DCM (200 mL) were added. After stirring for 10 min, the DCM phase was separated, and the aqueous phase was extracted twice with DCM (50 mL). The combined DCM phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain intermediate A1-7 (9.4 g, white solid, yield 89%). LC-MS: [M+H] + =720.9.

[0224] Step 4: Intermediate A1-7 (9.4 g) was dissolved in DCM (30 mL), and TFA (30 mL) was added. The mixture was stirred overnight at 35 °C. LC-MS showed 80% product. TFA (10 mL) was added, and the reaction was continued at 40 °C for 4.0 h. The reaction solution was evaporated to dryness, and the crude product was dissolved in acetonitrile and evaporated to dryness to obtain compound A1 as a white solid (3.165 g, yield 50.6%). LC-MS: [M+H] + =481.1.

[0225] 1 H NMR (400MHz, DMSO-d6) δ8.41 (d, J=7.11Hz, 1H), 7.69 (s, 2H), 7.59 (d, J=6.6, 2H), 7.33 (s, 1H), 6.84-6.78 (m, 1H), 3.76 (d, J=12.5Hz, 1H), 3.60 (d, J=11.6Hz, 2H), 3.53 (s, 3H), 3.44 (d, J=3.6Hz, 1H), 3.31 (s, 1H), 3.2 4-3.14 (m, 1H), 3.02 (qd, J=15.7, 6.1Hz, 2H), 2.77 (s, 1H), 2.34 (s, 3H).

[0226] Example 3

[0227] Preparation of methyl (S)-2-((7-chloro-2-(2,6-difluoro-4-aminosulfonylphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate

[0228]

[0229] Step 1: In a 100 mL round-bottom flask, add tert-butyl (S)-2-ethynylmorpholine-4-carboxylate (3.1 g, 1.0 eq, SM-03), 4-bromo-2,6-difluorobenzaldehyde (2.76 g, 1.0 eq, compound A2-1), 4-chloropyridin-2-amine (1.61 g, 1.0 eq, compound A2-2), CuCl (0.37 g, 0.3 eq), Cu(OTf)2 (1.36 g, 0.3 eq), and isopropanol (50 mL). Purge with nitrogen three times, heat in an oil bath at 80 °C overnight, and TLC analysis shows the disappearance of starting material compound A2-2. Recycle the isopropanol to dryness, extract successively with EA and ammonia, collect the EA phase, wash successively with saturated brine and citric acid, dry to anhydrous sodium sulfate, and evaporate to dryness before column chromatography to obtain intermediate A2-3, a white solid (3.0 g, purity 78%). LC-MS: [M+H] + =542.2.

[0230] Step 2: Dissolve intermediate A2-3 (2.67 g) in dichloromethane (24 mL), then add dioxane hydrochloride (24 mL), stir at room temperature for 1.0 h, and monitor the reaction complete by LC-MS. Dry the reaction mixture, add water (15 mL) and dichloromethane (15 mL) to the reaction mixture, extract, discard the aqueous phase, and adjust the pH of the aqueous phase to weakly alkaline (pH = 8-9) with sodium bicarbonate solution. Separate the dichloromethane phase, and extract the aqueous phase again with dichloromethane (10 mL × 2). Combine the dichloromethane phases, wash with saturated brine, and dry to obtain intermediate A2-4, a white solid (1.70 g, purity 88.6%). LC-MS: [M+H] + =442.1.

[0231] Step 3: Intermediate A2-4 (1.4 g, 1.0 eq) was dissolved in dichloromethane (10 mL), triethylamine (480 mg, 1.5 eq) was added, and methyl chloroacetate (388 mg, 1.3 eq) was added dropwise. After reacting for 1.0 h, LC-MS showed product formation. After the reaction was complete, water (10 mL) was added and stirred for 30 min. The dichloromethane phase was separated, and the aqueous phase was extracted again with dichloromethane (10 mL × 2). The dichloromethane phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The solution was then passed through a column to obtain intermediate A2-5, a white solid (1.01 g, purity 93.02%). LC-MS: [M+H] + =499.8.

[0232] Step 4: Dissolve intermediate A2-5 (0.73 g, 1.0 eq) in dioxane (4 mL), add BnSH (0.24 g, 1.3 eq), Pd2(dba)3 (0.04 g, 0.03 eq), Xantphos (0.04 g, 0.05 eq), and DIEA (0.60 g, 3.0 eq), and replace N2 three times. React overnight at 80 °C. LC-MS monitoring showed complete disappearance of the starting material. Add dichloromethane (10 mL) and water (10 mL) to the reaction mixture, separate the dichloromethane phase, and extract the aqueous phase again with dichloromethane (10 mL × 2). Combine the dichloromethane phases, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, and evaporate to dryness. Column chromatography yields intermediate A2-6, a white solid (0.82 g, purity 91.53%). LC-MS: [M+H] + =544.2.

[0233] In step five, intermediate A2-6 (510 mg) was added to a reaction flask, dissolved in acetonitrile (3 mL), followed by glacial acetic acid (281 mg, 5.0 eq). Then, 8O2Cl2 (506 mg, 4.0 eq) was added dropwise under ice bath conditions. The reaction was carried out at 0 °C for 1 h. LC-MS showed the disappearance of the starting material and the formation of intermediate A2-7. No further treatment was performed, and the reaction solution was used directly in the next step.

[0234] Step Six: At 0°C, ammonia water (2 mL) diluted with acetonitrile (1 mL) was added dropwise to the above reaction solution, and the reaction was carried out at room temperature for 0.5 h. LC-MS showed that the starting material disappeared completely and the target product was formed. The reaction solution was extracted twice with water and ethyl acetate, washed with saline solution, dried over anhydrous sodium sulfate, concentrated, and sent for preparative separation and purification. Compound A2 was obtained as a white solid (185 mg, purity 99.74%). LC-MS: [M+H] + =501.1.

[0235] 1 H NMR (400MHz, DMSO-d6) δ = 8.11 (d, J = 7.4Hz, 1H), 7.29 (d, J = 1.6Hz, 1H), 7.22 (s, 2H), 7.14 (d, J = 6.6Hz, 2H), 6.60 (dd, J = 7.4Hz, 2.1Hz, 1H), 3.33 (d, J=12.8Hz, 1H), 3.13 (d, J=11.3Hz, 2H), 3.07 (s, 3H), 2.97 (d, J=7.8Hz, 1H), 2.77-2.69 (m, 1H), 2.69-2.61 (m, 1H), 2.53 (dd, J=15.5Hz, 8.3Hz, 1H).

[0236] Example 4

[0237] Preparation of (S)-4-(3-((4-acetylmorpholin-2-yl)methyl)-7-methylimidazo[1,2-a]pyridin-2-yl)-3,5-difluorobenzenesulfonamide

[0238]

[0239] Step 1: Following the steps in Example 2, intermediate A1-6 was prepared. Intermediate A1-6 (620 mg, 0.94 mmol, 1.0 eq) was dissolved in DCM (5 mL), and Et3N (236 mg, 2.34 mmol, 2.5 eq) was added. Acetic anhydride (191 mg, 1.88 mmol, 2 eq) was added dropwise. After 1.0 h of reaction, TLC showed that the reaction was complete. After the reaction was complete, water (30 mL) was added, and DCM (50 mL) was stirred for 10 min. The DCM phase was separated, and the aqueous phase was extracted twice with DCM (20 mL). The combined DCM phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain product intermediate A3-1, a white solid (450 mg, yield 68.3%). LC-MS: [M+H] + =705.2.

[0240] Step 2: Dissolve intermediate A3-1 (420 mg) in DCM (2 mL), add TFA (2 mL), and stir overnight at room temperature. Heat to 35 °C and react for 4.0 h, then post-process. Add water (20 mL) and DCM (20 mL) to the reaction solution, and adjust the pH of the aqueous phase to 9 with sodium carbonate. Separate the DCM phase, and extract the aqueous phase again with DCM (20 mL × 2). Combine the DCM phases, wash with saturated brine, and dry to dryness with anhydrous sodium sulfate. Pass the product through a column and then slurry with DCM / PE (1:10) to obtain compound A3, a white solid (104 mg, yield 37.5%).

[0241] 1 H NMR (400MHz, CDCl3) δ8.23 (1H, dd, J=36.9Hz, 6.8Hz), 7.60 (1H, s), 7.53 (2H, t, J=6.0Hz), 6.80 ( 2H, t, J=12.6Hz), 6.57 (1H, s), 4.37 (1H, t, J=11.4Hz), 3.91-3.72 (1H, m), 3.51 (2H, d, J=12.1Hz ), 3.35 (1H, dd, J = 21.8Hz, 11.9Hz), 3.16 (0.5H, t, J = 11.6Hz), 3.09-2.78 (2H, m), 2.66 (0.5H, t, J=11.1Hz), 2.47 (3H, d, J=3.8Hz), 2.44-2.32 (0.5H, m), 2.04 (2H, s), 1.98 (1H, s), 1.82 (2H, s).

[0242] Example 5

[0243] Preparation of (S)-4-(3-((4-acetylmorpholin-2-yl)methyl)-7-chloroimidazolo[1,2-a]pyridin-2-yl)-3,5-difluorobenzenesulfonamide

[0244]

[0245] In step one, 3,5-difluoro-4-aldehyde-N,N-bis(4-methoxybenzyl)benzenesulfonamide (29 g, 62.84 mmol), 4-chloropyridin-2-amine (8.08 g, 62.84 mmol), and (S)-tert-butyl-2-ethynylmorpholine-4-carboxylic acid ester (13.28 g, 62.84 mmol) were dissolved in toluene (150 mL) and dimethylacetamide (150 mL) and stirred until homogeneous. Then, cuprous chloride (1.87 g, 18.85 mmol) and copper(II) trifluoromethanesulfonate (6.82 g, 18.85 mmol) were added to the reaction solution, and the reaction was carried out at 85 °C for 16 h under nitrogen protection. 750 mL of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (150 mL). The organic phase was washed once with ammonia (100 mL) and twice with saturated brine (100 mL). The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (10:1-3:1)) to give intermediate A4-1, a brownish-yellow foamy solid (18 g, purity 85%, yield 39%). LC-MS: [M+H] + =783.0.

[0246] Step 2: Intermediate A4-1 (17 g, 21.7 mmol) was dissolved in dichloromethane (60 mL), and a hydrochloric acid-ethyl acetate salt solution (60 mL, 3 M) was added dropwise, controlling the addition temperature at 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. TLC (PE / EA = 3 / 1, Rf = 0.1) was used to detect the depletion of the starting material. The mixture was concentrated under reduced pressure, and the crude product was adjusted to pH ~8 with sodium bicarbonate aqueous solution. It was extracted twice with ethyl acetate (150 mL), dried over anhydrous sodium sulfate with stirring for 20 min, filtered, and concentrated to obtain intermediate A4-2, a brown foamy solid (13 g, purity 90%, yield 87%). LC-MS [M+H] was performed. + =683.0.

[0247] Step 3: Intermediate A4-2 (1.5 g, 2.2 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (444 mg, 4.39 mmol) was added at 0°C. Then, acetic anhydride (336 g, 3.29 mmol) was added dropwise, and the reaction was carried out at 0°C for 1 h. A saturated sodium chloride aqueous solution (40 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (50 mL). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 4–1 / 2) to obtain intermediate A4-3, a yellowish-white solid (1.1 g, yield 69%). LC-MS: [M+H] + =725.1.

[0248] Step 4: Intermediate A4-3 (1.1 g, 1.52 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (3 mL) was added at 0 °C. The reaction mixture was reacted at room temperature for 16 h. The reaction solution was added dropwise to an aqueous sodium bicarbonate solution to adjust the pH to ~8, and extracted with dichloromethane (50 mL × 3). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and sent to the preparation phase. The prepared phase (acetonitrile, water, trifluoroacetic acid) was concentrated, adjusted to pH ~8 with sodium bicarbonate, extracted three times with ethyl acetate (300 mL), washed twice with saturated brine (100 mL), dried over anhydrous sodium sulfate with stirring for 20 min, filtered, concentrated, and the concentrated solid was rinsed three times with acetonitrile, then acetonitrile (10 mL) and pure water (30 mL) were added, and lyophilized to obtain compound A4, a white solid (358 mg, purity 97%). LC-MS: [M+H] + =484.2.

[0249] 1 H NMR (400MHz, DMSO-d6) δ8.62 (t, J=7.3Hz, 1H), 7.82-7.77 (m, 1H), 7.73 (d, J=2.3Hz, 2H), 7.64 (d, J=6.6Hz, 2 H), 7.10 (td, J=7.3, 2.3Hz, 1H), 4.26-4.19 (m, 1H), 4.05 (d, J=13.3Hz, 1H), 3.78 (d, J=12.7Hz, 1H), 3.69-3.6 0 (m, 1H), 3.56 (d, J = 13.3Hz, 1H), 3.52-3.37 (m, 1H), 3.25 (td, J = 11.5, 2.3Hz, 1H), 3.20-2.97 (m, 3H), 2.80 ( dd, J=12.9, 10.5Hz, 1H), 2.54 (dd, J=12.7, 2.9Hz, 1H), 2.29 (dd, J=12.8, 10.9Hz, 1H), 1.94 (d, J=4.2Hz, 3H).

Claims

1. A method for preparing a compound of formula IN-06, comprising the following steps: in an organic solvent, in the presence of an acid-binding agent, subjecting the compound of formula IN-05 to a cyclization reaction and a deprotection reaction to obtain the compound of formula IN-06; wherein the acid-binding agent is NaOH, NaH, or potassium carbonate; wherein, R is a halogen; 。 2. The preparation method according to claim 1, characterized in that, The preparation method satisfies one or more of the following conditions; 1) The R mentioned is F, Cl, Br or I; 2) The organic solvent is a haloalkane solvent, a nitrile solvent, or an ether solvent; 3) The molar ratio of the compound shown in IN-05 to the acid-binding agent is 1:1.5~4; 4) The mass-to-volume ratio of the compound shown in IN-05 to the organic solvent is 0.055 g / L to 0.5 g / L; 5) The cyclization reaction and the deprotection reaction are carried out at temperatures of 20~40℃; 6) The mass-to-volume ratio of the compound shown in IN-05 to the organic solvent is 0.055 g / mL to 0.5 g / mL.

3. The preparation method according to claim 2, characterized in that, The preparation method satisfies one or more of the following conditions; 1) The R mentioned above is Cl; 2) The haloalkane solvent mentioned is dichloromethane; 3) The nitrile solvent mentioned is acetonitrile; 4) The ether solvent is tetrahydrofuran; 5) The molar ratio of the compound shown in IN-05 to the acid-binding agent is 1:2; 6) The mass-to-volume ratio of the compound shown in IN-05 to the organic solvent is 0.1 g / L; 7) The cyclization reaction and the deprotection reaction are carried out at a temperature of 25°C; 8) The mass-to-volume ratio of the compound shown in IN-05 to the organic solvent is 0.1 g / mL.

4. The preparation method according to claim 2, characterized in that, The organic solvent is tetrahydrofuran.

5. The preparation method according to claim 1, characterized in that, The method for preparing the compound shown in formula IN-06 further includes the following steps: in an organic solvent, mixing the compound shown in formula IN-04A with... The compound of formula IN-05 can be obtained by carrying out a substitution reaction. ； R 1 It can be F, Cl, Br or I.

6. The preparation method according to claim 5, characterized in that, The R mentioned 1 It is Cl.

7. The preparation method according to claim 5, characterized in that, The preparation method satisfies one or more of the following conditions: 1) The organic solvent is a nitrile solvent or an alkane solvent; 2) The above It is chloroacetyl chloride and bromoacetyl bromide; 3) The compound represented by formula IN-04A and the compound represented by IN-04A The molar ratio is 1:0.8-1.2; 4) The mass-to-volume ratio of the compound represented by formula IN-04A to the organic solvent is 80 g / L to 200 g / L; 5) The temperature for the substitution reaction is -5~5℃; 6) The substitution reaction takes 0.1 to 4 hours.

8. The preparation method according to claim 7, characterized in that, The preparation method satisfies one or more of the following conditions: 1) The nitrile solvent mentioned is acetonitrile; 2) The alkane solvent mentioned is dichloromethane; 3) The above It is chloroacetyl chloride; 4) The compound represented by formula IN-04A and the compound represented by IN-04A The molar ratio is 1:1; 5) The mass-to-volume ratio of the compound represented by formula IN-04A to the organic solvent is 100 g / L; 6) The temperature of the substitution reaction is 0℃; 7) The substitution reaction takes 0.3 hours.

9. The preparation method according to claim 5, characterized in that, The preparation method of the compound shown in formula IN-06 further includes the following steps: neutralizing the compound shown in formula IN-04 with an acid-binding agent in an organic solvent to obtain the compound shown in formula IN-04A. ； Among them, R X It is acidic.

10. The preparation method according to claim 9, characterized in that, The preparation method satisfies one or more of the following conditions; 1) The R mentioned above X It is hydrochloric acid; 2) The acid-binding agent is an organic strong base.

11. The preparation method according to claim 9, characterized in that, The acid-binding agent is triethylamine or N,N-diisopropylethylamine.

12. A method for preparing a compound as shown in formula SM-03, comprising the following steps: In an organic solvent, a compound as shown in formula IN-06 is reduced with a reducing agent, and then protected with a protecting agent in the presence of an acid-binding agent. 。 13. The preparation method according to claim 12, characterized in that, The IN-06 is prepared according to the preparation method described in any one of claims 1-11.

14. The preparation method according to claim 12, characterized in that, The preparation method satisfies one or more of the following conditions; 1) The organic solvent is tetrahydrofuran; 2) The reducing agent is lithium aluminum hydride; 3) The reaction temperature is 20-40℃; 4) The acid-binding agent is sodium carbonate or potassium carbonate; 5) The protective reagent is di-tert-butyl carbonate anhydride; 6) The molar ratio of the compound represented by formula IN-06 to the acid-binding agent is 1:0.5-3; 7) The molar ratio of the compound represented by formula IN-06 to the protective reagent is 1:0.5-3; 8) The molar ratio of the compound represented by formula IN-06 to the reducing agent is 1:0.5-3; 9) The temperature of the protective reaction is 20~40℃.

15. The preparation method according to claim 14, characterized in that, The preparation method satisfies one or more of the following conditions; 1) The reaction temperature is 25℃; 2) The molar ratio of the compound shown in formula IN-06 to the acid-binding agent is 1:2; 3) The molar ratio of the compound represented by formula IN-06 to the protective reagent is 1:2; 4) The molar ratio of the compound represented by formula IN-06 to the reducing agent is 1:2; 5) The temperature of the protective reaction is 25℃.

16. A method for preparing a compound of formula IN-05, comprising the following steps: in an organic solvent, in the presence of an acid-binding agent, reacting the compound of formula IN-04A with... The compound of formula IN-05 can be obtained by carrying out a substitution reaction. ； in, R is F, Cl, Br, or I; R 1 It can be F, Cl, Br or I.

17. The preparation method according to claim 16, characterized in that, The preparation method satisfies one or more of the following conditions; 1) The R mentioned above is Cl; 2) The R 1 For Cl; 3) The conditions for the substitution reaction are as described in claim 7 or 8; 4) The preparation method of IN-04A is as described in any one of claims 9-11.

18. A compound having the structural formula shown in formula IN-06 or IN-05, 、 ， in, The R mentioned is F, Cl, Br or I.

19. The compound of claim 18, characterized in that, R is Cl.

20. A compound of formula IN-06 For the preparation of the compound shown in formula SM-03 Applications.

21. A compound of formula IN-06 Used via SM-03 The application of preparing substance A, wherein substance A is compound A1 Compound A2 Compound A3 Compound A4 Compound A5 Compound A6 Compound A7 Compound A8 Compound A9 Compound A10 Compound A11 .

22. The use of the compound of formula IN-06 as described in claim 21 for the preparation of substance A via SM-03, characterized in that, The preparation methods of compounds A1, A2, A3, and A4 are as follows: ， ， Method 1: ； Method 2: ； Method 3: ； Method 4: 。

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