WO2022268218A1 - Preparation method for heterocycloalkyl compound, and intermediate and application thereof heterocycloalkyl compound - Google Patents

Abstract

Disclosed in the present invention are a preparation method for a heterocycloalkyl compound, and an intermediate and an application of the heterocycloalkyl compound. The present invention provides a preparation method for a compound represented by formula IN-06, comprising the following step: carrying out a ring-forming reaction and a deprotection reaction to a compound represented by formula IN-05 in an organic solvent in the presence of an acid-binding agent to obtain a compound represented by formula IN-06, the acid-binding agent being NaOH, NaH or potassium carbonate, wherein R is halogen. The preparation method of the present invention has one or more of the following advantages: having high chiral purity and facilitating industrial production.

Description

A kind of preparation method of heterocycloalkyl compound, its intermediate and its application

This application claims the priority of Chinese patent application 202110705767.4 with a filing date of 2021/6/24. This application cites the full text of the above-mentioned Chinese patent application.

technical field

The invention relates to a preparation method of a heterocycloalkyl compound, an intermediate thereof and an application thereof.

Background technique

ATP receptors are classified into two major families, P2Y- and P2X-purinergic receptors, based on molecular structure, transduction mechanism, and pharmacological properties. P2X-purinergic receptors are a family of ATP-gated cation channels of which several subtypes have been cloned, including: six homomeric receptors, P2X1; P2X2; P2X3; P2X4; P2X5; and P2X7; and three heteromeric receptors Receptors P2X2/3, P2X4/6, P2X1/5. The study found that P2X3 receptors are specifically expressed in the primary afferent nerve fibers of "hollow viscera", such as the lower urinary tract and respiratory tract.

Cough is the main symptom of respiratory diseases. In the outpatient department of respiratory department, 70% to 80% of patients have cough symptoms. With the increasing prevalence of COPD, IPF, etc., and cough as the main symptom of most respiratory diseases, the demand is also increasing. As the body's defensive nerve reflex, coughing helps to clear respiratory secretions and harmful factors, but frequent and severe coughing will seriously affect the work, life and social activities of patients.

There are not many varieties of P2X3 antagonists specifically developed for cough indications. The project that is currently progressing rapidly is Roche’s AF-219 project, which has a better effect on refractory cough in the latest completed phase II clinical trial. But taste disorders are a serious problem.

(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 compound and its use, on page 33 of the description, Example 7 discloses its preparation method, the specific synthetic route is as follows:

The synthetic route disclosed in this patent has an amplification effect, and the chiral purity of the product obtained by amplification will be greatly reduced, which is not conducive to large-scale production, and the raw material used (1-diazo-2-oxopropyl) Dimethyl phosphonate, this compound is expensive, has poor stability, inconvenient transportation and storage, and is easily restricted in production.

Contents of the invention

The technical problem to be solved by the present invention is that there are few preparation methods for the compound shown in the formula SM-03 in the prior art. Therefore, the present invention provides a preparation method of heterocycloalkyl compounds, its intermediates and their applications , the chiral purity of the product obtained by the method is higher, which is beneficial to industrial production. The intermediates corresponding to the present invention can be used in the production of imidazopyridine P2X3 inhibitor compounds.

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

The invention provides a preparation method of the compound shown in the formula IN-06, which comprises the following steps: in an organic solvent, in the presence of an acid-binding agent, subjecting the compound shown in the formula IN-05 to a ring-forming reaction and deprotection Reaction to obtain the compound shown in the formula IN-06; the acid-binding agent is NaOH, NaH or potassium carbonate; wherein, R is a halogen;

In a certain embodiment, R is F, Cl, Br or I, such as Cl.

In a certain scheme, the organic solvent is a conventional organic solvent for this type of reaction in the art, such as a halogenated alkane solvent, a nitrile solvent or an ether solvent. The said halogenated alkanes solvent is preferably dichloromethane. The nitrile solvent is preferably acetonitrile. The ether solvent is preferably tetrahydrofuran. Described organic solvent is preferably THF.

In a certain scheme, the molar ratio of the compound represented by IN-05 to the acid-binding agent may be 1:1.5-4, such as 1:2.

In a certain solution, the mass volume ratio of the compound shown in IN-05 to the organic solvent may be 0.055g/L-0.5g/L, for example 0.1g/L.

In a certain scheme, the mass volume ratio of the compound represented by IN-05 to the organic solvent may be 0.055 g/mL˜0.5 g/mL, for example, 0.1 g/mL.

The temperature of the cyclization reaction and the deprotection reaction is a conventional temperature for this type of reaction in the art, preferably 20-40°C, such as 25°C.

The process of the deprotection reaction is monitored by 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), such as TLC .

The post-processing steps of the deprotection reaction are conventional post-processing steps of this type of reaction in the art, for example: washing, drying, filtering, and column chromatography to obtain the compound represented by the formula IN-06.

The preparation method of the compound shown in the formula IN-06 may further include the following steps: in an organic solvent, mix the compound shown in the formula IN-04A with

Substitution reaction is carried out to obtain the compound of formula IN-05;

R ¹ is F, Cl, Br or I, such as Cl.

In the substitution reaction, 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. Described alkane solvent is preferably dichloromethane.

In the substitution reaction, the

Conventional substituting reagents for this type of reaction in the art, preferably chloroacetyl chloride, bromoacetyl bromide, eg chloroacetyl chloride.

In the substitution reaction, the compound shown in the formula IN-04A and the

The molar ratio of can be 1:0.8-1.2, for example 1:1.

In the substitution reaction, the mass volume ratio of the compound represented by the formula IN-04A to the organic solvent may be 80g/L-200g/L, such as 100g/L.

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

The progress of the substitution reaction is monitored by 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).

The time for the substitution reaction is subject to the completion of the substitution reaction, for example, 0.1-4 hours, such as 0.3 hours.

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

The preparation method of the compound represented by the formula IN-06 may further include the following steps: neutralizing the compound represented by the formula IN-04 and an acid-binding agent in an organic solvent to obtain the compound represented by the formula IN- 04A compound is enough;

Wherein, R _X is an acid, which can be hydrochloric acid.

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.

The neutralization reaction conditions are conventional conditions for this type of reaction in the art.

In a certain aspect, R _X is an acid conventional in the art, such as hydrochloric acid.

The preparation method of the compound represented by the formula IN-06 may further include the following steps: in an organic solvent, deprotecting the compound represented by the formula IN-03 and a deprotection reagent to obtain the compound represented by the formula IN- 04 compound;

Said R _X is the corresponding acid.

In the deprotection reaction, the organic solvent is a conventional solvent for this type of reaction in the art, such as a halogenated alkane solvent, an ester solvent or an ether solvent. The halogenated alkane 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.

In the deprotection reaction, the deprotection reagent can be hydrochloric acid, hydrochloric acid/dioxane, hydrochloric acid/ethyl acetate, zinc bromide or tert-butyldimethylsilyl trifluoromethanesulfonate.

In the deprotection reaction, the mass volume ratio of the IN-03 to the organic solvent may be 80g/L-300g/L, for example 200g/L.

In the deprotection reaction, the molar ratio of the compound represented by the formula IN-03 to the deprotection reagent may be 3-8:1, such as 5.7:1.

In the deprotection reaction, the molar ratio of the deprotection reagent to the compound represented by the formula IN-03 may be 3-8:1, such as 5.7:1.

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

The progress of the deprotection reaction is monitored by 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).

The preparation method of the compound shown in the described formula IN-06 can further include the following steps: in an organic solvent, the compound shown in the formula IN-02 is mixed with borane methyl sulfide complex ( BH ₃ .Me ₂ S) undergoes a reduction reaction to obtain the compound of formula IN-03;

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

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

In the reduction reaction, the mass volume ratio of the IN-02 to the organic solvent may be 60g/L-150g/L, such as 90g/L or 100g/L.

In the reduction reaction, the molar ratio of the compound represented by the formula IN-02 to the BH ₃ .Me ₂ S may be (0.5-1.2):1, such as 0.91:1.

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

The progress of the reduction reaction is monitored by 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).

The preparation method of the compound represented by the formula IN-06 may further include the following steps: in an organic solvent, in the presence of a Grignard reagent, perform a Grignard reaction on the compound represented by the formula IN-01 and trimethylsilylacetylene , to obtain the compound of formula IN-02;

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

In the Grignard reaction, the Grignard reagent can be a conventional reagent for this type of reaction in the art, such as isopropylmagnesium chloride lithium chloride solution.

In the Grignard reaction, the mass volume ratio of the IN-01 to the organic solvent may be 70g/L-150g/L, such as 92g/L or 96g/L.

In the Grignard reaction, the molar ratio of the compound represented by the formula IN-01 to the Grignard reagent may be 0.2-0.8:1, such as 0.4:1.

In the Grignard reaction, the molar ratio of the compound represented by the formula IN-01 to the trimethylsilylacetylene can be 0.2-0.6:1, such as 0.3:1.

The temperature of the Grignard reaction may be a conventional temperature for this type of reaction in the art, preferably -20 to 0°C, for example -10°C.

The progress of the Grignard reaction can be monitored by 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).

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

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

In the esterification reaction, the base is a conventional base for this type of reaction in the art, such as triethylamine.

In the esterification reaction, the catalyst is a conventional catalyst for this type of reaction in the art, 4-dimethylaminopyridine (DMAP) and 1-ethyl-(3-dimethylaminopropyl) carbonyl di imine hydrochloride (EDCl).

In the esterification reaction, the mass volume ratio of the SM-01 to the organic solvent may be 40g/L˜100g/L, such as 66.7g/L.

In the esterification reaction, the molar ratio of the N, O-dimethylhydroxylamine hydrochloride to the compound represented by the formula SM-01 may be 1-1.5:1, for example, 1.2:1.

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

In the esterification reaction, the molar ratio of the compound represented by the formula SM-01 to the base may be 1:1.5-2.5, for example, 1:2.1.

In the esterification reaction, the molar ratio of the compound represented by the formula SM-01 to the EDCl may be 1:1.1-1.4, such as 1:1.2.

In the esterification reaction, the molar ratio of the compound represented by the formula SM-01 to the DMAP may be 1:0.05-0.2, such as 1:0.1.

The temperature of the esterification reaction is a conventional temperature for this type of reaction in the art, preferably 10-30°C, for example 20°C.

The progress of the esterification reaction can be monitored by 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).

The present invention also provides a preparation method of the compound shown in formula SM-03, which comprises the following steps:

Step 1: Prepare the compound shown as formula IN-06 according to the above-mentioned preparation method;

Step 2: In an organic solvent, the compound shown in the formula IN-06 is subjected to a reduction reaction with a reducing agent, and then, in the presence of an acid-binding agent, is subjected to a protection reaction with a protection reagent to obtain the SM-03;

In the protection reaction, the organic solvent is a conventional solvent for this type of reaction in the art, such as tetrahydrofuran.

In the protection reaction, the mass volume ratio of the compound represented by the formula IN-06 to the organic solvent may be 40g/L˜100g/L, for example, 66.7g/L.

In the protection reaction, the reducing agent is a conventional reducing agent for this type of reaction in the art, such as lithium aluminum hydride.

In the protection reaction, the molar ratio of the compound represented by the formula IN-06 to the reducing agent may be 1:0.5-3, such as 1:2.

In the protection reaction, the reaction temperature is a conventional reaction temperature for this type of reaction in the art, such as 20-40°C, and for example 25°C.

In the protection reaction, the acid-binding agent is a conventional base for this type of reaction in the art, such as sodium carbonate or potassium carbonate.

In the protection reaction, the protection reagent is a conventional protection reagent for this type of reaction in the art, such as di-tert-butyl carbonic anhydride.

In the protection reaction, the molar ratio of the compound represented by the formula IN-06 to the base may be 1:0.5-3, such as 1:2.

In the protection reaction, the molar ratio of the compound represented by the formula IN-06 to the protection reagent may be 1:0.5-3, such as 1:2.

The temperature of the protection reaction is a conventional temperature for this type of reaction in the art, preferably 20-40°C, such as 25°C.

The progress of the protection reaction is monitored by 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).

The post-processing steps of the protection reaction are conventional post-processing steps of this type of reaction in the art, for example: filtration, column chromatography, to obtain the compound represented by SM-03.

In a certain scheme, the preparation method of the compound shown in formula SM-03 comprises the following steps:

Step 1: Prepare the compound shown as formula IN-06 according to the above-mentioned preparation method;

Step 2: In an organic solvent, the compound shown in the formula IN-06 is subjected to a reduction reaction with a reducing agent, and then, in the presence of an acid-binding agent, is subjected to a protection reaction with a protection reagent to obtain the SM-03;

In the protection reaction, the organic solvent is a conventional solvent for this type of reaction in the art, such as tetrahydrofuran.

In the protection reaction, the mass volume ratio of the compound represented by the formula IN-06 to the organic solvent may be 40g/L˜100g/L, for example, 66.7g/L.

In the protection reaction, the reducing agent is lithium aluminum hydride.

In the protection reaction, the molar ratio of the compound represented by the formula IN-06 to the reducing agent may be 1:0.5-3, such as 1:2.

In the protection reaction, the reaction temperature is a conventional reaction temperature for this type of reaction in the art, such as 20-40°C, and for example 25°C.

In the protection reaction, the acid-binding agent is sodium carbonate or potassium carbonate.

In the protection reaction, the protection reagent is di-tert-butyl carbonic anhydride.

In the protection reaction, the molar ratio of the compound represented by the formula IN-06 to the base may be 1:0.5-3, such as 1:2.

In the protection reaction, the molar ratio of the compound represented by the formula IN-06 to the protection reagent may be 1:0.5-3, such as 1:2.

The temperature of the protection reaction is a conventional temperature for this type of reaction in the art, preferably 20-40°C, for example 25°C.

The progress of the protection reaction is monitored by 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).

The post-processing steps of the protection reaction are conventional post-processing steps of this type of reaction in the art, for example: filtration, column chromatography, to obtain the compound represented by SM-03.

The present invention also provides a preparation method of the compound represented by the formula IN-05, which comprises the following steps: in an organic solvent, in the presence of an acid-binding agent, mix the compound represented by the formula IN-04A with

Substitution reaction is carried out to obtain the compound of formula IN-05;

Wherein, R is F, Cl, Br or ^I , such as Cl; R is F, Cl, Br or I, such as Cl;

The conditions of the substitution reaction are as described above;

The preparation method of the compound represented by the formula IN-05 may further include the following steps: neutralizing the compound represented by the formula IN-04 and an acid-binding agent in an organic solvent to obtain the compound represented by the formula IN- 04A compound is enough;

Wherein, R _X is an acid, which can be hydrochloric acid;

The conditions of the neutralization reaction are as described above;

The preparation method of the compound represented by the formula IN-05 may further include the following steps: in an organic solvent, deprotecting the compound represented by the formula IN-03 and a deprotection reagent to obtain the compound represented by the formula IN- 04 compound;

The R _X is the corresponding acid;

The conditions of the deprotection reaction are all as above;

The preparation method of the compound represented by the formula IN-05 may further include the following steps: in an organic solvent, the compound represented by the formula IN-02 and the borane methyl sulfide complex (BH ₃ .Me ₂ S) performing a reduction reaction to obtain the compound of formula IN-03;

The conditions of the reduction reaction are all as above;

The preparation method of the compound represented by the formula IN-05 may further include the following steps: in an organic solvent, in the presence of a Grignard reagent, perform a Grignard reaction on the compound represented by the formula IN-01 and trimethylsilylacetylene , to obtain the compound of formula IN-02;

The conditions of the format reaction are all as above;

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

The conditions of the esterification reaction are all as above.

The present invention also provides a preparation method of the compound represented by the formula IN-05, which comprises the following steps: in an organic solvent, in the presence of an acid-binding agent, mix the compound represented by the formula IN-04A with

Substitution reaction is carried out to obtain the compound of formula IN-05;

Wherein, R is F, Cl, Br or ^I , such as Cl; R is F, Cl, Br or I, such as Cl;

The conditions of the substitution reaction are all as above.

The present invention also provides a preparation method of the compound shown in formula SM-03, which comprises the following steps: reducing the compound shown in formula IN-06 with a reducing agent in an organic solvent, In the presence of , carry out protecting group reaction with protecting reagent to obtain SM-03;

The conditions of the reduction reaction and the protecting group reaction are as above.

In a certain scheme, the preparation method of the compound shown in the formula SM-03 comprises the following steps: in an organic solvent, the compound shown in the formula IN-06 is subjected to a reduction reaction with a reducing agent, and then in the presence of the acid-binding agent In the presence of a protecting group reaction with a protecting reagent to obtain SM-03;

The conditions of the reduction reaction and the protecting group reaction are as above.

The present invention also provides a compound represented by the formula IN-06,

The present invention also provides a compound represented by formula IN-05,

Wherein, R is F, Cl, Br or I, such as Cl.

The present invention also provides an application of a compound of formula IN-06 for preparing the compound shown in formula SM-03 or preparing substance A via SM03, and the substance A is compound A1

Compound A2

Compound A3

Compound A4

Preferably, the preparation methods of compound A1, compound A2, compound A3, and compound A4 are as follows:

method one:

Method Two:

Method three:

Method four:

The present invention also provides the application of a compound of formula IN-06 for preparing the compound shown in formula SM-03 or preparing substance A via SM03, and the substance A is compound A5

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

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

The invention provides a preparation method of a heterocycloalkyl compound, an intermediate thereof and an application thereof. The product obtained by the method has higher chiral purity and is beneficial to industrial production.

Description of drawings

Fig. 1 is the liquid chromatogram test figure of the compound shown in formula SM-03.

detailed description

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

The compound of the general formula of the present invention and its preparation method and application will be further described in detail below in conjunction with specific examples. The following examples are only to illustrate and explain the present invention, but should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.

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

The following abbreviations are used throughout this disclosure:

MeOH (methanol), EA (ethyl acetate), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide), g (gram), mg (milligram), mol (mol), mmol (mmol), h (hour ), min (minutes), mL (milliliters), μL (microliters).

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

In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated.

Testing instruments and methods

X-ray powder diffractometer (XRPD): Instrument model: PANalytical Empyrean, the system is equipped with a PIXcel ^1D detector, the instrument parameters are: scanning range 3-40° (2θ), step size 0.013° (2θ), light tube voltage 45KV light The tube current is 40mA.

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 pan, and accurately record the weight. After equilibrating at 25°C, the sample was heated to 250°C at a heating rate of 10°C/min.

Thermogravimetric Analyzer (TGA): Instrument model: Discovery TGA 55 (TA Instruments, US), the sample is placed in an open tared aluminum pan, weighed automatically, and inserted into the TGA furnace. After the mass of the sample was automatically weighed in the TGA heating furnace, the sample was heated to 250°C at a heating rate of 10°C/min.

Polarizing Light Microscope (PLM): Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN).

Dynamic moisture sorption instrument (DVS): instrument model: DVS (ProUmid GmbH&Co.KG, Germany), the sample is put into the sample box that is equipped with asphalt, and weighs automatically.

Proton nuclear magnetic resonance ( ¹ H-NMR): Instrument model: AVANCE III HD 300, equipped with an automatic sampler (SampleXpress 60).

Example 1:

1. Synthesis of IN-01

Dissolve SM-01 (45g, 256.87mmol, 1.0eq), N, O-dimethylhydroxylamine hydrochloride (30g, 308.25mmol, 1.2eq), DMAP (3.1g, 25.68mmol, 0.1eq) in DCM ( 675mL), cooled to 0°C, added TEA (75ml), stirred for 1h, then added EDCl (59g, 1.2eq), naturally warmed to room temperature (20°C) and reacted overnight. The TLC plate was spotted, and the raw materials were consumed. Adjust the pH from 3 to 4 with 1M HCl, separate the layers, wash the organic phase with 1M HCl (150mL), water (150mL), and saturated brine (100mL) successively, dry over anhydrous Na ₂ SO ₄ , filter and concentrate to obtain 52.5 g of a white solid , yield 93%. ¹ H NMR (400MHz, CDCl ₃ ) δ5.25(s, 1H), 4.07(d, J=4.0Hz, 2H), 3.70(s, 3H), 3.19(s, 3H), 1.44(s, 9H) .

2. Synthesis of IN-02

The three-necked flask was replaced with nitrogen and protected, trimethylsilylacetylene (32.4g, 329.89mmol) was added, and isopropylmagnesium chloride lithium chloride solution (211mL, 1.3M, 274.9mmol, in THF ), after the dropwise addition was complete, the ice bath reaction was continued for 1 h. Take IN-01 (24g, 109.96mmol) into a three-necked flask, add anhydrous tetrahydrofuran (50ml) to dissolve, and perform nitrogen replacement. At room temperature, the above-mentioned reaction solution was added dropwise into the tetrahydrofuran solution, and the reaction was continued for 2 h. Samples were taken for TLC detection, and the reaction was basically complete. Add saturated ammonium chloride solution (150ml) to quench, extract with EA, wash with saturated brine, dry over anhydrous sodium sulfate, and spin to dry the solvent to obtain 29g of red oily liquid with a yield of 100%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.16 (s, 1H), 4.15-4.02 (m, 2H), 1.42 (s, 9H), 0.23 (s, 9H).

3. Synthesis of IN-03

Dissolve (R)-2-methyl-CBS-oxazoboridine (6.3g, 22.71mmol, 0.2eq) in THF (70mL), carry out nitrogen replacement and protection, cool to 0°C, add BH3.Me ₂ S (12.5ml, 10M, 124.9mmol), then IN-02 (29g, 113.55mmol) dissolved in THF (220ml) was added dropwise into the reaction system, the temperature was controlled at 0°C, and the dropwise addition time was longer than 25min. ℃ reaction, sampling TLC detection, the raw material reaction is complete. Add MeOH (50ml) dropwise to quench, react for half an hour, concentrate, and purify by column chromatography (PE/EA=15/1) chromatography to obtain 20g of light brown oily liquid with a yield of 70.6% and a chiral purity of 77.8% . ¹ H NMR (400MHz, CDCl ₃ ) 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).

4. Synthesis of IN-04

IN-03 (20 g, 77.69 mmol, 1 eq) was dissolved in DCM (100 mL), and 4M HCl (100 mL) was added to react at room temperature. TLC plate detection showed that the reaction was complete, and it was directly concentrated to dryness to obtain 16 g of the crude product as a brown solid (15 g in theory), with a yield of 100%, which was directly put into the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 2H), 4.90 (s, 1H), 3.34 (s, 2H), 0.19 (s, 9H).

5. Synthesis of IN-05

Method 1: Dissolve IN-04 (16g, 93.7%, 77.42mmol, 1eq), TEA (19.6g, 193.55mmol, 2.5eq) in DCM (150mL), N ₂ displacement protection, cool to 0°C, then add dropwise Chloroacetyl chloride (8.7g, 77.42mmol, 1.0eq, dissolved in 10ml DCM), reacted for 20min. The TLC monitoring plate shows that the raw material has completely reacted, aftertreatment, washing with saturated NaCl solution, drying, filtration and concentration, column chromatography (PE/EA from 5/1 to 2/1) purification to obtain product 12g, light brown oil, yield 66%. ¹ H NMR (400MHz, CDCl ₃ ) 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).

Method 2: Dissolve IN-04 (1.7g, 1eq), TEA (2.5eq) in DCM (15mL), protect by N2 displacement, cool down to 0°C, then add chloroacetyl chloride (1.05eq, dissolved in 2ml DCM) dropwise ), react for 20min. The TLC plate showed that the raw materials were completely reacted. After the post-treatment, the reaction solution was washed with saturated NaCl solution, dried, filtered and concentrated to obtain 2.8 g of the crude product as a light yellow oil with a chiral purity of 78.8% and no racemization.

6. Synthesis of IN-06

IN-05 (12g, 51.33mmol, 1eq) was dissolved in 120ml of THF, and NaH (2.46g, 102.67mmol, 2.0eq) was added to react at room temperature. The TLC plate showed that the raw materials were completely reacted, after treatment, the reaction solution was adjusted to pH ~ 5 with 1M HCl, the aqueous phase and the organic phase were concentrated to dryness (IN-06 has a certain water solubility), filtered and concentrated, and column chromatography (PE/EA =1/2) 4.5 g of the product was obtained as a light yellow solid with a yield of 70.3%. ¹ H NMR (400MHz, DMSO-d6) δ8.07(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).

7. Synthesis of SM-03

method one:

IN-06 (4.5g, 35.96mmol, 1eq) was dissolved in THF (67.5mL), then LAH (2.73g, 71.93mmol, 2.0eq) was added and reacted at room temperature. TLC monitoring shows that after the reaction of the raw materials is complete, add K ₂ CO ₃ (2.0eq) solution dissolved in 20ml of water, Boc ₂ O (15.7g, 71.93mmol, 2.0eq), react at room temperature, TLC plate shows that the reaction is complete, filter, EA Extracted, washed with saturated NaCl solution, dried, concentrated by filtration, column chromatography (PE/EA=10/1) obtained 2.3g product, white solid, yield 30.2%, chiral purity 78.9%, retention time 8.051min . 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).

Method Two:

Dissolve IN-06 (80mg, 1eq) in THF (3mL), then add LAH (3.0eq) and react at room temperature. After-treatment of the reaction solution, add 10mL NH ₄ Cl solution to quench, then add K ₂ CO ₃ (2.0eq), Boc ₂ O (2.0eq), react at room temperature, after the reaction is completed, filter, extract with EA, wash with saturated NaCl solution, and dry , concentrated by filtration, and obtained 40 mg of the product by column chromatography, with a chiral purity of 81.8%, and an HPLC 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).

The detection method of the product SM-03 prepared by method 1 and method 2:

Instrument: liquid chromatograph (Shimadzu LC-20AT or equivalent);

Column model: CHIRALPAK AD-H (250*4.6mm, 5μm);

Column temperature: 30°C;

Flow rate: 1mL/min;

Wavelength: 210nm;

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

Isocratic elution: 20min;

Thinner: ethanol;

Sample solution: 2mg/mL;

The test results are shown in Table 1 and Figure 1.

Table 1 Analysis results and preliminary quality standards

name	retention timemin	Relative retention time RRT
SM-03(R)	8.051	0.89

SM-03(S)

9.009

1.00

Example 2

(S)-2-((2-(2,6-difluoro-4-sulfamoylphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl) Preparation of phen-4-carboxylic acid methyl ester

Step 1 Add intermediate A1-4 (18.2g, 39.4mmol, 1.0eq), 4-methylpyridin-2-amine (4.26g, 39.4mmol, 1.0eq, compound 1-5) in sequence in a 100mL round bottom flask , (S)-tert-butyl 2-ethynylmorpholine-4-carboxylate (8.33g, 39.4mmol, 1.0eq, SM-03), CuCl (1.17g, 11.8mmol, 0.3eq), Cu(OIf) ₂ (4.34g, 11.8mmol, 0.3eq), toluene (200mL), DMA (12mL), nitrogen replacement 3 times, heating in an oil bath at 85°C overnight (12h), TLC detection of starting compound 1-5 disappeared, intermediate A1-4 There will be unfinished reactions left. After the reaction solution was cooled to room temperature, ammonia water (100 mL) was added, and water (150 mL) was stirred for 5 min, separated, and the toluene phase was taken. The aqueous phase was extracted 2 more times with DCM (150 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried and passed through the column to obtain intermediate A1-5 (11.2 g, yellow solid, purity 96%, yield 37%). LC-MS: [M+H] ⁺ = 761.9.

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 TLC detects that the reaction is complete. Water (100 mL) and dichloromethane (200 mL) were added to the reaction solution, and the pH was adjusted with sodium carbonate until the aqueous phase was slightly alkaline (pH=9-10). The DCM phase was obtained by liquid separation, and the aqueous phase was extracted twice with DCM (100 mL). The DCM phases were combined, washed with saturated brine, dried and spin-dried to obtain intermediate A1-6 (9.7 g, white solid), which was directly submitted to the next step with a 100% yield. LC-MS: [M+H] ⁺ = 622.2.

Step 3 Intermediate A1-6 (9.7g, 14.7mmol, 1.0eq) was dissolved in DCM (40mL), Et ₃ N (2.96g, 29.3mmol, 2.0eq) was added, and methyl chloroformate (2.08g, 22mmol, 1.5eq). After 1.0 h of reaction, TLC showed that the reaction was complete. After the reaction, water (150 mL) was added, DCM (200 mL) was stirred for 10 min, and then the DCM phase was obtained by liquid separation, and the water phase was extracted twice with DCM (50 mL). The DCM phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spin-dried, and passed through a column to obtain intermediate A1-7 (9.4 g, white solid, yield 89%). LC-MS: [M+H] ⁺ = 720.9.

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

¹ H NMR (400MHz, DMSO-d ₆ ) 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), 3.24-3.14(m, 1H), 3.02(qd, J=15.7, 6.1Hz, 2H), 2.77(s, 1H), 2.34(s, 3H).

Example 3

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

Step 1 Add (S)-2-ethynylmorpholine-4-carboxylic acid tert-butyl ester (3.1g, 1.0eq, SM-03), 4-bromo-2,6-difluorobenzene successively into a 100mL round bottom flask Formaldehyde (2.76g, 1.0eq, compound A2-1), 4-chloropyridin-2-amine (1.61g, 1.0eq, compound A2-2), CuCl (0.37g, 0.3eq), Cu(OTf) ₂ ( 1.36g, 0.3eq), isopropanol (50mL), replaced with nitrogen 3 times, heated in an oil bath at 80°C overnight, TLC detected that the starting material compound A2-2 disappeared. Spin-dry isopropanol, extract with EA and ammonia water successively, take the EA phase, successively wash with saturated saline, citric acid, dry with anhydrous sodium sulfate, and spin-dry through the column to obtain intermediate A2-3, a white solid (3.0g, The purity is 78%). LC-MS: [M+H] ⁺ = 542.2.

Step 2 Dissolve intermediate A2-3 (2.67g) in dichloromethane (24mL), then add dioxane hydrochloride (24mL), stir at room temperature for 1.0h, and LC-MS detects that the reaction is complete. Spin the reaction solution to dryness, add water (15mL) and dichloromethane (15mL) to the reaction solution, remove the aqueous phase after extraction, adjust the pH with aqueous sodium bicarbonate until the aqueous phase is weakly alkaline (pH=8-9) . The dichloromethane phase was obtained by liquid separation, and the aqueous phase was extracted with dichloromethane (10 mL×2). The dichloromethane phases were combined, washed with saturated brine, and spin-dried to obtain intermediate A2-4 as a white solid (1.70 g, purity 88.6%). LC-MS: [M+H] ⁺ = 442.1.

Step 3 Intermediate A2-4 (1.4g, 1.0eq) was dissolved in dichloromethane (10mL), triethylamine (480mg, 1.5eq) was added, and methyl chloroacetate (388mg, 1.3eq) was added dropwise. After 1.0 h of reaction, LC-MS showed that the product was formed. After the reaction, add water (10 mL) and stir for 30 min, then separate the layers to get the dichloromethane phase, and then extract the water phase with dichloromethane (10 mL×2). The dichloromethane phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spin-dried, and passed through a column to obtain intermediate A2-5 as a white solid (1.01 g, purity 93.02%). LC-MS: [M+H] ⁺ = 499.8.

Step 4 Dissolve intermediate A2-5 (0.73g, 1.0eq) in dioxane (4mL), add BnSH (0.24g, 1.3eq), Pd ₂ (dba) ₃ (0.04g, 0.03eq), Xantphos (0.04g, 0.05eq), DIEA (0.60g, 3.0eq), and N ₂ were replaced three times, and reacted overnight at 80°C. Complete disappearance of starting material monitored by LCMS. Dichloromethane (10mL) and water (10mL) were added to the reaction solution, and the dichloromethane phase was separated, and the aqueous phase was extracted with dichloromethane (10mL×2). The dichloromethane phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spin-dried, and passed through a column to obtain intermediate A2-6 as a white solid (0.82 g, purity 91.53%). LC-MS: [M+H] ⁺ = 544.2.

Step 5 Add intermediate A2-6 (510mg) to the reaction flask, add acetonitrile (3mL) to dissolve, then add glacial acetic acid (281mg, 5.0eq), add dropwise 8O ₂ Cl ₂ (506mg, 4.0eq ). And react at 0°C for 1h. LCMS showed disappearance of starting material and formation of intermediate A2-7. The reaction was not processed, and the reaction solution was directly used in the next step.

Step 6 At 0° C., ammonia water (2 mL) was diluted with acetonitrile (1 mL) and added dropwise to the above reaction solution, and reacted at room temperature for 0.5 h. LCMS 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 to preparation for separation and purification. Compound A2 was obtained as a white solid (185 mg, purity 99.74%). LC-MS: [M+H] ⁺ = 501.1.

¹ H NMR (400MHz, DMSO-d ₆ ) 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).

Example 4

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

Step 1: Intermediate A1-6 was prepared by referring to the steps of Example 2. Intermediate A1-6 (620 mg, 0.94 mmol, 1.0 eq) was dissolved in DCM (5 mL), and Et ₃ N (236 mg, 2.34 mmol, 2.5 eq)), and 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, water (30 mL) was added, DCM (50 mL) was stirred for 10 min, and then the DCM phase was obtained by liquid separation, and the water phase was extracted twice with DCM (20 mL). The DCM phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spin-dried, and passed through the column to obtain the product intermediate A3-1 as a white solid (450 mg, yield 68.3%). LC-MS: [M+H] ⁺ = 705.2.

Step 2 Intermediate A3-1 (420mg) was dissolved in DCM (2mL), TFA (2mL) was added, and stirred overnight at room temperature. Raise the temperature to 35°C to react for 4.0h, and post-treatment. Water (20 mL) and DCM (20 mL) were added to the reaction solution, and sodium carbonate was added to adjust the pH of the aqueous phase to 9. The DCM phase was obtained by liquid separation, and the aqueous phase was extracted with DCM (20 mL×2). The DCM phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and spin-dried. The obtained product was passed through the column and then slurried with DCM/PE (1:10) to obtain compound A3 as a white solid (104 mg, yield 37.5%).

¹ H NMR (400MHz, CDCl ₃ ) 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).

Example 5

(S)-4-(3-((4-acetylmorpholin-2-yl)methyl)-7-chloroimidazo[1,2-a]pyridin-2-yl)-3,5-di Preparation of fluorobenzenesulfonamide

Step 1: 3,5-difluoro-4-formyl-N,N-bis(4-methoxybenzyl)benzenesulfonamide (29g, 62.84mmol), 4-chloropyridin-2-amine (8.08g, 62.84mmol), (S)-tert-butyl-2-ethynylmorpholine-4-carboxylate (13.28g, 62.84mmol) was dissolved in toluene (150mL) and dimethylacetamide (150mL), stirred After uniformity, cuprous chloride (1.87g, 18.85mmol) and copper (II) trifluoromethanesulfonate (6.82g, 18.85mmol) were added to the reaction solution, and reacted at 85°C under nitrogen protection for 16h. Add 750 mL of water to the reaction solution, extract twice with ethyl acetate (150 mL), wash the organic phase once with ammonia water (100 mL), wash twice with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate by filtration. The crude product was purified by silica gel column (petroleum ether: ethyl acetate (10:1-3:1)) to obtain intermediate A4-1 as a brown-yellow foamy solid (18 g, purity 85%, yield 39%). LC-MS: [M+H] ⁺ = 783.0.

Step 2 Intermediate A4-1 (17g, 21.7mmol) was dissolved in dichloromethane (60mL), hydrochloric acid·ethyl acetate salt solution (60mL, 3M) was added dropwise, and the dropping temperature was controlled at 0°C. After the dropwise addition was completed, the reaction was carried out at room temperature for 2 hours. The starting material was consumed as detected by TLC (PE/EA=3/1, Rf=0.1). Concentrate under reduced pressure, add aqueous sodium bicarbonate solution to the crude product to adjust pH to 8, extract twice with ethyl acetate (150 mL), stir and dry with anhydrous sodium sulfate for 20 min, filter and concentrate to obtain intermediate A4-2, brown foamy solid (13 g, Purity 90%, yield 87%), LC-MS [M+H] ⁺ = 683.0.

Step 3 Intermediate A4-2 (1.5g, 2.2mmol) was dissolved in dichloromethane (15mL), triethylamine (444mg, 4.39mmol) was added at zero degree, and then acetic anhydride (336g, 3.29mmol) was added dropwise, Reaction at 0°C for 1h. Add saturated sodium chloride aqueous solution (40mL) to the reaction solution, extract twice with dichloromethane (50mL), dry over anhydrous sodium sulfate, filter and concentrate, and the crude product is purified by silica gel column (PE/EA=1/4～1/ 2) Intermediate A4-3 was obtained as a yellow-white solid (1.1 g, yield 69%), LC-MS: [M+H] ⁺ =725.1.

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

¹ H NMR (400MHz, DMSO-d ₆ ) 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, 2H), 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=12.7 Hz, 1H), 3.69-3.60(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 (10)

1. A preparation method for a compound shown in formula IN-06, which comprises the following steps: in an organic solvent, in the presence of an acid-binding agent, subjecting the compound shown in formula IN-05 to a ring-forming reaction and a deprotection group reaction to obtain The compound shown in formula IN-06 is enough; the acid-binding agent is NaOH, NaH or potassium carbonate; wherein, R is a halogen;

   
2. The preparation method according to claim 1, wherein the preparation method meets one or more of the following conditions;

   1) The R is F, Cl, Br or I, such as Cl;

   2) described organic solvent is halogenated alkanes solvent, nitrile solvent or ether solvent; Described halogenated alkanes solvent is preferably dichloromethane; Described nitrile solvent is preferably acetonitrile; Described ether solvent Preferably tetrahydrofuran; Described organic solvent is preferably tetrahydrofuran;

   3) The molar ratio of the compound shown in IN-05 to the acid-binding agent is 1:1.5-4, such as 1:2;

   4) The mass volume ratio of the compound shown in IN-05 to the organic solvent is 0.055g/L-0.5g/L, such as 0.1g/L;

   5) The temperature of the cyclization reaction and the deprotection reaction is 20-40°C, such as 25°C;

   6) The mass volume ratio of the compound shown in IN-05 to the organic solvent is 0.055g/mL-0.5g/mL, for example 0.1g/mL.
3. The preparation method according to claim 1, characterized in that, the preparation method of the compound shown in the formula IN-06 further comprises the following steps: in an organic solvent, the compound shown in the formula IN-04A and

   

   Substitution reaction is carried out to obtain the compound of formula IN-05;

   

   R ¹ is F, Cl, Br or I, such as Cl.
4. The preparation method according to claim 3, wherein the preparation method meets one or more of the following conditions:

   1) described organic solvent is nitrile solvent or alkane solvent, and described nitrile solvent is preferably acetonitrile, and described alkane solvent is preferably dichloromethane;

   2) as stated

   

   is chloroacetyl chloride, bromoacetyl bromide, for example chloroacetyl chloride;

   3) the compound shown in the formula IN-04A and the

   

   The molar ratio is 1:0.8-1.2, such as 1:1;

   4) The mass volume ratio of the compound represented by the formula IN-04A to the organic solvent is 80g/L-200g/L, such as 100g/L;

   5) The temperature of the substitution reaction is -5 to 5°C, such as 0°C;

   6) The time for the substitution reaction is 0.1 to 4 hours, such as 0.3 hours.
5. The preparation method according to claim 3, characterized in that, the preparation method of the compound shown in the formula IN-06 further comprises the following steps: in an organic solvent, the compound shown in the formula IN-04 and the acid-binding The agent is neutralized to obtain the compound of formula IN-04A;

   

   Wherein, R _X is an acid, preferably hydrochloric acid;

   The acid-binding agent can be an organic strong base, such as triethylamine or N,N-diisopropylethylamine.
6. A preparation method of the compound shown in formula SM-03, which includes the following steps: in an organic solvent, reducing the compound shown in formula IN-06 with a reducing agent, and then in the presence of an acid-binding agent, and The protection reagent carries out the protection reaction;

   

   Preferably, the IN-06 is prepared according to the preparation method described in any one of claims 1-5.
7. The preparation method according to claim 6, wherein the preparation method meets 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°C, for example 25°C;

   4) the acid-binding agent is sodium carbonate or potassium carbonate;

   5) The protecting reagent is di-tert-butyl carbonic anhydride;

   6) The molar ratio of the compound represented by the formula IN-06 to the acid-binding agent is 1:0.5-3, such as 1:2;

   7) The molar ratio of the compound represented by the formula IN-06 to the protective reagent is 1:0.5-3, for example 1:2;

   8) The molar ratio of the compound represented by the formula IN-06 to the reducing agent is 1:0.5-3, for example 1:2;

   9) The temperature of the protection reaction is 20-40°C, such as 25°C.
8. A preparation method of the compound shown in the formula IN-05, which comprises the following steps: in an organic solvent, in the presence of an acid-binding agent, mix the compound shown in the formula IN-04A with

   

   Substitution reaction is carried out to obtain the compound of formula IN-05;

   

   Wherein, R is F, Cl, Br or ^I , such as Cl; R is F, Cl, Br or I, such as Cl;

   The condition of described substitution reaction can be as described in claim 4;

   Preferably, the preparation method of IN-04A is as described in claim 5.
9. A compound whose structural formula is shown in formula IN-06 or IN-05,

   

   Wherein, said R is F, Cl, Br or I, such as Cl.
10. A compound shown in formula IN-06 is used to prepare the compound shown in formula SM-03 or the application of preparing substance A via SM03, and the substance A can be compound A1, compound A2, compound A3, compound A4, compound A5, compound A6, Compound A7, Compound A8, Compound A9, Compound A10, Compound A11;

    Preferably, the preparation methods of compound A1, compound A2, compound A3, and compound A4 are as follows:

    

    method one:

    

    Method Two:

    

    Method three:

    

    Method four:

    

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