A preparation method of BTK degradation agent

Abstract

A method for preparing a compound represented by formula (I) and its intermediates. The method has mild reaction conditions, does not involve high temperature or high pressure reactions, uses low-toxic or non-toxic raw materials, is simple to operate, has high reaction yields, high product purity, is easy to post-process, has good reproducibility, and is suitable for industrial production. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a method for preparing a compound represented by formula (I) and an intermediate thereof. Background Art

[0002] Bruton's tyrosine kinase (BTK), a member of the Tec family of non-receptor protein tyrosine kinases, is a key regulator of the B-cell antigen receptor (BCR) signaling pathway, distributed throughout the lymphatic, hematopoietic, and hematologic systems. BTK mutations can activate downstream signaling pathways involved in tumor cell proliferation, differentiation, and angiogenesis, leading to X-linked agammaglobulinemia, non-Hodgkin lymphoma (NHL), and numerous B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and diffuse large B-cell lymphoma. Because BTK is primarily expressed in B cells and myeloid cells, it is a well-targeted and safe target.

[0003] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can induce the target protein to be recognized by the cell's proteasome, causing the degradation of the target protein and effectively reducing the target protein's content in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology has become possible for the treatment of various diseases. This technology has also received widespread attention in recent years.

[0004] PCT / CN2020 / 093455 describes a BTK-Protac small molecule anti-tumor drug (shown in the structure of Compound 1 below). It is a tripartite combination consisting of a small molecule inhibitor targeting the BTK protein, a ligand recruiting the E3 ubiquitin ligase, and a linker connecting the two ligands. On the one hand, it can directly inhibit BTK activity by specifically binding to BTK; on the other hand, it can induce BTK ubiquitination and degradation through the proteasome pathway, thereby blocking the transmission of the BCR signaling pathway and inhibiting the growth and proliferation of B cell lymphoma cells, exerting a dual anti-tumor effect.

[0005] Summary of the Invention

[0006] The present invention aims to provide a method for preparing a compound represented by formula (I) and an intermediate thereof. The method has mild reaction conditions, does not involve high temperature or high pressure reactions, uses low-toxic or non-toxic raw materials, is simple to operate, produces fewer by-products, produces high-purity intermediate products, and facilitates post-processing. The entire process route has good reproducibility and is suitable for industrial production.

[0007] The present invention relates to a method for preparing compound (II), which is prepared by the following reaction formula:

[0008]

[0009] L is selected from trifluoromethanesulfonate, F, Cl, Br, I,

[0010] HX is selected from acetic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid or trifluoroacetic acid;

[0011] n is selected from 0, 1, 1.5, 2, 3 or 4;

[0012] Compound (IV) reacts with compound (III) in the presence of an alkaline reagent and a solvent to obtain compound (II).

[0013] In some embodiments of the method for preparing compound (II) according to the present invention, when n=0, that is, compound (IV) is in the form of a free base, the molar ratio of the alkaline agent to compound (IV) is ≤4.90:1, ≤4.85:1 or ≤4.80:1.

[0014] In some embodiments of the method for preparing compound (II) according to the present invention, the alkaline reagent is selected from organic amine reagents, preferably one or more of triethylamine, diethylamine or N,N-diisopropylethylamine.

[0015] In some embodiments of the method for preparing compound (II) according to the present invention, the alkaline reagent comprises an organic amine reagent, preferably one or more of triethylamine, diethylamine or N,N-diisopropylethylamine.

[0016] In some embodiments of the method for preparing compound (II) according to the present invention, the solvent is selected from polar aprotic solvents, preferably one or more of acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone.

[0017] In some embodiments of the method for preparing compound (II) according to the present invention, the solvent comprises a polar aprotic solvent, preferably one or more of acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone.

[0018] In some embodiments of the method for preparing compound (II) according to the present invention, the solvent is selected from dimethyl sulfoxide.

[0019] In some embodiments of the method for preparing compound (II) according to the present invention, the reaction temperature is optionally 30°C to 120°C, 60°C to 110°C, or 80°C to 100°C.

[0020] In some embodiments of the method for preparing compound (II) according to the present invention, the molar ratio of compound (III) to compound (IV) is ≤10:1, preferably 1:1 to 3:1.

[0021] In some embodiments of the method for preparing compound (II) according to the present invention, when n=0, that is, compound (IV) is in the form of a free base, at this time, the molar ratio of the alkaline agent to compound (IV) is ≤5:1, and the reaction temperature is optionally 60°C to 110°C, 80°C to 100°C, 85°C to 95°C, or 85°C to 90°C.

[0022] In some embodiments of the preparation method of compound (II) according to the present invention, when n=0, that is, compound (IV) is in the form of a free base, the alkaline reagent includes N,N-diisopropylethylamine, the molar ratio of the alkaline reagent to compound (IV) is ≤5:1, and the reaction temperature is optionally 60°C to 110°C, 80°C to 100°C, 85°C to 95°C, or 85°C to 90°C.

[0023] In some embodiments of the method for preparing compound (II) according to the present invention, when n=1, 1.5, 2, 3 or 4, that is, compound (IV) is in the form of a salt, optionally, the molar ratio of the alkaline agent to compound (IV) is ≤10:1 or ≤6:1.

[0024] In some embodiments of the method for preparing compound (II) according to the present invention, when n=1, 1.5, 2, 3 or 4, that is, compound (IV) is in the form of a salt, optionally, the molar ratio of the alkaline agent to compound (IV) is 0.8:1-10:1, 1:1-10:1, 0.8:1-6:1, or 1:1-6:1.

[0025] In some embodiments of the preparation method of compound (II) according to the present invention, after the reaction, compound (II) is obtained by post-treatment, and the post-treatment includes separating the reaction solution into layers, adding the lower layer into water for crystallization, filtering, and slurrying the filtrate and then filtering.

[0026] In some embodiments of the method for preparing compound (II) according to the present invention, compound (II) is obtained by post-treatment after the reaction, and the post-treatment comprises adding the reaction solution into water for crystallization, filtering, and slurrying the filtrate and then filtering.

[0027] In some embodiments of the method for preparing compound (II) according to the present invention, after the reaction, post-treatment includes crystallization and / or beating of compound (II).

[0028] In some embodiments of the method for preparing compound (II) according to the present invention, after the reaction, post-treatment includes crystallization and / or slurrying of compound (II), and the solvent used includes methanol or ethanol.

[0029] The preparation method of compound (II) described in the present invention has the following advantages: compound (IV) is in salt form, has better stability, high reaction yield, few by-products and impurities, and is simple to purify.

[0030] In some embodiments of the method for preparing compound (II), compound (II) is reacted with HY to prepare compound (I).

[0031]

[0032] HY is selected from pharmaceutically acceptable salts, preferably fumaric acid, formic acid, acetic acid, succinic acid, hydrochloric acid, sulfuric acid, tartaric acid, p-toluic acid, methanesulfonic acid, malic acid, maleic acid, succinic acid;

[0033] m is selected from 0.5, 1, 1.5, 2 or 3.

[0034] In some embodiments of the present invention, compound (II) is reacted with HY to prepare compound (I), and the solvent for the reaction of compound (II) with HY is selected from one or a mixed solvent of two or more selected from alkane solvents, halogenated alkane solvents, alcohol solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents and water.

[0035] In some embodiments of the present invention, compound (II) is reacted with HY to prepare compound (I), and the solvent for the reaction of compound (II) with HY comprises one or a mixed solvent of two or more of an alkane solvent, a halogenated alkane solvent, an alcohol solvent, a ketone solvent, an ester solvent, an ether solvent, a nitrile solvent and water.

[0036] In some embodiments of the present invention, the solvent for the reaction of compound (II) with HY to prepare compound (I) is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, acetone, methanol, ethanol, ethylene glycol, polyethylene glycol, isopropanol, diethyl ether, tetrahydrofuran and water, preferably one or more of dichloromethane, methanol and water.

[0037] In some embodiments of the present invention, compound (II) is reacted with HY to prepare compound (I), and the solvent for the reaction of compound (II) with HY includes one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, acetone, methanol, ethanol, ethylene glycol, polyethylene glycol, isopropanol, diethyl ether, tetrahydrofuran and water, preferably one or more of dichloromethane, methanol and water.

[0038] The present invention also relates to a method for preparing compound (IV) or compound (VI-1), which is prepared by the following reaction formula (1) or (2):

[0039]

[0040] P is selected from amino protecting groups, preferably tert-butyloxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, p-methoxybenzyl;

[0041] HX is selected from acetic acid, sulfuric acid, hydrobromic acid, hydroiodic acid or trifluoroacetic acid;

[0042] n is selected from 0, 1, 1.5, 2, 3 or 4;

[0043] Compound (V) reacts in the presence of an acidic reagent HX to obtain compound (IV);

[0044] Compound (VII) reacts in the presence of an acidic reagent HX to obtain compound (VI-1).

[0045] The present invention relates to some embodiments of preparing compound (IV) by reaction formula (1), wherein the reaction includes a solvent, and the solvent is selected from a polar protic solvent, a polar aprotic solvent or a mixture thereof, preferably one or more of methanol, ethanol, water, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran.

[0046] The present invention relates to some embodiments of preparing compound (IV) by reaction formula (1), wherein a solvent is included in the reaction, and the solvent includes a polar protic solvent, a polar aprotic solvent or a mixture thereof, preferably including one or more of methanol, ethanol, water, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran.

[0047] In some embodiments of the present invention for preparing compound (IV) via reaction formula (1), the reaction temperature is optionally 0°C to 60°C, 10°C to 40°C, or 20°C to 30°C.

[0048] In some embodiments of the present invention for preparing compound (IV) via reaction formula (1), post-reaction treatment includes concentration of the reaction solution (e.g., reduced pressure concentration, normal pressure concentration), organic solvent crystallization and / or slurrying, filtration, and filter cake drying.

[0049] In some embodiments of the present invention, the solvent is selected from a polar protic solvent, a polar aprotic solvent or a mixture thereof, preferably one or more of methanol, ethanol, water, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran.

[0050] In some embodiments of the present invention for preparing compound (VI-1) by reaction formula (2), the solvent includes a polar protic solvent, a polar aprotic solvent or a mixture thereof, preferably including one or more of methanol, ethanol, water, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran.

[0051] In some embodiments of the present invention, the compound (VI-1) is prepared by reaction formula (2), wherein the reaction temperature is optionally 0°C to 60°C, 10°C to 40°C, or 20°C to 30°C.

[0052] In some embodiments of the present invention, compound (VI-1) is prepared by reaction formula (2), and the post-reaction treatment includes concentrating the reaction solution under reduced pressure, crystallizing with an organic solvent and / or beating the solution, filtering, and drying the filter cake.

[0053] The present invention also relates to a method for preparing compound (IV) or compound (VI-1), which is prepared by the following reaction formula (3) or (4):

[0054]

[0055] P is selected from amino protecting groups, preferably tert-butyloxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, p-methoxybenzyl;

[0056] HX is selected from hydrochloric acid;

[0057] n is selected from 0, 1, 1.5, 2, 3 or 4;

[0058] Compound (V) reacts in the presence of hydrochloric acid and a polar protic solvent to obtain compound (IV);

[0059] Compound (VII) is reacted in the presence of hydrochloric acid and a polar protic solvent to give compound (VI-1).

[0060] The present invention relates to some embodiments of preparing compound (IV) by reaction formula (3), wherein the solvent is selected from polar protic solvents, preferably one or more of methanol, ethanol and water, and a polar aprotic solvent is optionally further added during the reaction, wherein the polar aprotic solvent is preferably one or more of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran.

[0061] In some embodiments of the present invention, compound (IV) is prepared by reaction formula (3), wherein the solvent comprises a polar protic solvent, preferably one or more of methanol, ethanol and water, and the reaction optionally further comprises adding a polar aprotic solvent, wherein the polar aprotic solvent preferably comprises one or more of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran.

[0062] In some embodiments of the present invention, the reaction temperature is 0°C to 60°C, 10°C to 40°C, or 20°C to 30°C.

[0063] The present invention relates to some embodiments of preparing compound (VI-1) by reaction formula (4), wherein the solvent is selected from polar protic solvents, preferably one or more of methanol, ethanol and water, and a polar aprotic solvent is optionally further added during the reaction, wherein the polar aprotic solvent is preferably one or more of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran.

[0064] The present invention relates to some embodiments of preparing compound (VI-1) by reaction formula (4), wherein the solvent includes a polar protic solvent, preferably includes one or more of methanol, ethanol and water, and the reaction optionally further includes adding a polar aprotic solvent, wherein the polar aprotic solvent preferably includes one or more of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran.

[0065] In some embodiments of the present invention, the compound (VI-1) is prepared by reaction formula (4), wherein the reaction temperature is optionally 0°C to 60°C, 10°C to 40°C, or 20°C to 30°C.

[0066] The present invention also relates to a method for preparing compound (V) or (VII), which is prepared by the following reaction formula:

[0067]

[0068] P is selected from amino protecting groups, preferably tert-butyloxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, p-methoxybenzyl;

[0069] Compound (VI) reacts with 1a in the presence of an acidic reagent and a reducing agent to obtain compound (V);

[0070] Compound (VIII) reacts with 1a in the presence of an acidic reagent and a reducing agent to obtain compound (VII).

[0071] In some embodiments of the present invention for preparing compound (V) or (VII), the desiccant is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate or molecular sieves.

[0072] In some embodiments of the present invention for preparing compound (V) or (VII), the desiccant comprises one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate or molecular sieves.

[0073] In some embodiments of the present invention for preparing compound (V) or (VII), compound (VI) reacts with 1a in the presence of an acidic reagent, a drying agent and a reducing agent to obtain compound (V).

[0074] Compound (VIII) reacts with 1a in the presence of an acidic reagent, a drying agent and a reducing agent to obtain compound (VII).

[0075] In some embodiments of the present invention for preparing compound (V) or (VII), the reaction temperature is 0°C to 40°C, preferably 20°C to 40°C.

[0076] In some embodiments of the present invention for preparing compound (V) or (VII), compound (VI) and 1a are reacted in the presence of an acidic reagent and a reducing agent, optionally with the addition of a desiccant, and then post-treated to obtain compound (V). Preferably, the reaction temperature is 0°C to 40°C, and more preferably, the reaction temperature is 20°C to 40°C.

[0077] Compound (VIII) and 1a are reacted in the presence of an acidic reagent and a reducing agent, optionally with the addition of a desiccant, and then post-treated to obtain compound (VII). The reaction temperature is preferably 0°C to 40°C, more preferably 20°C to 40°C.

[0078] In some embodiments of the present invention for preparing compound (V) or (VII), the reaction includes a solvent, which is selected from polar aprotic solvents, preferably one or more of 1,2-dichloroethane, chloroform or dichloromethane.

[0079] In some embodiments of the present invention for preparing compound (V) or (VII), the reaction includes a solvent, which includes a polar aprotic solvent, preferably one or more of 1,2-dichloroethane, chloroform or dichloromethane.

[0080] In some embodiments of the present invention for preparing compound (V) or (VII), the acidic reagent is optionally one or more of hydrochloric acid, acetic acid, formic acid, propionic acid, butyric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and trifluoroacetic acid.

[0081] In some embodiments of the present invention for preparing compound (V) or (VII), the acidic reagent includes one or more of hydrochloric acid, acetic acid, formic acid, propionic acid, butyric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and trifluoroacetic acid.

[0082] In some embodiments of the present invention for preparing compound (V) or (VII), the reducing agent is selected from a boron reducing agent, preferably one or more of sodium borohydride, sodium triacetoxyborohydride, sodium triethylborohydride, sodium cyanoborohydride, potassium borohydride or lithium borohydride.

[0083] In some embodiments of the present invention for preparing compound (V) or (VII), the reducing agent comprises a boron reducing agent, preferably one or more of sodium borohydride, sodium triacetoxyborohydride, sodium triethylborohydride, sodium cyanoborohydride, potassium borohydride or lithium borohydride.

[0084] In some embodiments of the present invention for preparing compound (V) or (VII), the preparation method further comprises post-treatment, wherein the post-treatment comprises adjusting the pH of the reaction system to neutral to weakly alkaline, extracting, and concentrating the organic phase to obtain compound (V) or (VII).

[0085] In some embodiments of the present invention for preparing compound (V) or (VII), the post-treatment further comprises crystallizing or / and slurrying compound (V) or (VII) with a solvent, filtering, and drying the filter cake. Optionally, the slurrying solvent is preferably methyl tert-butyl ether or diethyl ether.

[0086] In some embodiments of the present invention for preparing compound (V) or (VII), the post-treatment further comprises crystallizing or / and slurrying compound (V) or (VII) with a solvent, filtering, and drying the filter cake, wherein the slurrying solvent preferably comprises methyl tert-butyl ether or diethyl ether.

[0087] In some embodiments of the present invention for preparing compound (V), when P is selected from tert-butyloxycarbonyl, the molar ratio of the reducing agent to compound (VI) is ≤5:1, preferably 2:1 to 4:1.

[0088] In some embodiments of the present invention for preparing compound (V), when P is selected from tert-butyloxycarbonyl, the molar ratio of the acidic reagent to compound (VI) is ≤5:1, preferably 2:1 to 4:1.

[0089] In some embodiments of the present invention for preparing compound (V), when P is selected from tert-butyloxycarbonyl, the molar ratio of compound 1a to compound (VI) is ≤5:1, preferably 2:1 to 4:1.

[0090] In some embodiments of the present invention for preparing compound (VII), when P is selected from tert-butyloxycarbonyl, the molar ratio of the reducing agent to compound (VIII) is ≤5:1, preferably 2:1 to 4:1.

[0091] In some embodiments of the present invention for preparing compound (VII), when P is selected from tert-butyloxycarbonyl, the molar ratio of the acidic reagent to compound (VIII) is ≤5:1, preferably 2:1 to 4:1.

[0092] In some embodiments of the present invention for preparing compound (VII), when P is selected from tert-butyloxycarbonyl, the molar ratio of compound 1a to compound (VIII) is ≤5:1, preferably 2:1 to 4:1.

[0093] The preparation method of compound (VII), compound (V), compound (IV) or compound (VI-1) described in the present invention has the following advantages: mild reaction conditions, no high temperature or high pressure reaction involved, low or non-toxic raw materials, simple operation, few by-products, high product purity, and convenient post-processing.

[0094] The present invention relates to a method for preparing compound (I), comprising the following steps:

[0095]

[0096] L is selected from trifluoromethanesulfonate, F, Cl, Br, I,

[0097] HX is selected from acetic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid or trifluoroacetic acid;

[0098] n is selected from 0, 1, 1.5, 2, 3 or 4;

[0099] HY is selected from pharmaceutically acceptable salts, preferably fumarate, formate, acetate, succinate, hydrochloride, sulfate, tartrate, p-toluate, methanesulfonate, malate, maleate, succinate;

[0100] m is selected from 0.5, 1, 1.5, 2 or 3;

[0101] Step (1) Compound (VI) and 1a are reacted in the presence of an acidic reagent and a reducing agent, optionally with the addition of a desiccant, and then post-treated to obtain compound (V);

[0102] Step (2) Compound (V) reacts in the presence of an acidic reagent HX to obtain Compound (IV), wherein HX is selected from acetic acid, sulfuric acid, hydrobromic acid, hydroiodic acid or trifluoroacetic acid;

[0103] Step (3) Compound (V) reacts in the presence of hydrochloric acid and a polar protic solvent to obtain compound (IV), wherein HX is HCl;

[0104] Step (4) Compound (IV) reacts with compound (III) in the presence of an alkaline reagent to obtain compound (II);

[0105] Step (5) Compound (II) reacts with HY to prepare compound (I).

[0106] In some embodiments of the present invention for preparing compound (I), in step (2), compound (IV) is reacted in the presence of an acidic reagent HX and a solvent. After the reaction is completed, optionally, a basic reagent is added to neutralize the acid in the system to obtain the free base form of compound (IV) (i.e., n=0 in this case).

[0107] In some embodiments of the present invention for preparing compound (I), step (3) is to react in the presence of hydrochloric acid and a polar protic solvent to obtain compound (IV), wherein HX is HCl. After the reaction is completed, optionally, an alkaline agent is added to neutralize the acid in the system to obtain the free base form of compound (IV) (i.e., n=0 in this case).

[0108] The present invention relates to some embodiments of preparing compound (I),

[0109] The acidic reagent in step (1) is selected from one or more of hydrochloric acid, acetic acid, formic acid, propionic acid, butyric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and trifluoroacetic acid; the reducing agent is selected from a boron reducing agent, preferably one or more of sodium borohydride, sodium triacetoxyborohydride, sodium triethylborohydride, sodium cyanoborohydride, potassium borohydride, or lithium borohydride; the desiccant is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate, or molecular sieves;

[0110] The alkaline reagent in step (4) is selected from organic amine reagents, preferably one or more of triethylamine, diethylamine or N,N-diisopropylethylamine.

[0111] The present invention relates to some embodiments of preparing compound (I),

[0112] The acidic reagent in step (1) includes one or more of hydrochloric acid, acetic acid, formic acid, propionic acid, butyric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and trifluoroacetic acid; the reducing agent includes a boron reducing agent, preferably including one or more of sodium borohydride, sodium triacetoxyborohydride, sodium triethylborohydride, sodium cyanoborohydride, potassium borohydride, or lithium borohydride; the desiccant includes one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate, or molecular sieves;

[0113] The alkaline reagent in step (4) includes an organic amine reagent, preferably one or more of triethylamine, diethylamine or N,N-diisopropylethylamine.

[0114] The present invention relates to some embodiments of preparing compound (I),

[0115] Step (1) includes a solvent, wherein the solvent is selected from one or more of 1,2-dichloroethane, chloroform or dichloromethane;

[0116] Step (2) includes a solvent, wherein the solvent is selected from a polar aprotic solvent or a polar protic solvent, preferably one or more of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, methanol, ethanol and water;

[0117] The solvent in step (3) is selected from one or more of methanol, ethanol and water, and a polar aprotic solvent is optionally further added during the reaction, wherein the polar aprotic solvent is preferably one or more of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran;

[0118] Step (4) includes a solvent, wherein the solvent is selected from a polar aprotic solvent, preferably one or more of N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone;

[0119] Step (5) includes a solvent, and the solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, acetone, methanol, ethanol, ethylene glycol, polyethylene glycol, isopropanol, ether, tetrahydrofuran and water.

[0120] The present invention relates to some embodiments of preparing compound (I),

[0121] Step (1) includes a solvent, wherein the solvent includes one or more of 1,2-dichloroethane, chloroform or dichloromethane;

[0122] Step (2) includes a solvent, wherein the solvent is selected from a polar aprotic solvent or a polar protic solvent, preferably one or more of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, methanol, ethanol and water;

[0123] The solvent in step (3) includes one or more of methanol, ethanol and water, and a polar aprotic solvent is optionally further added during the reaction, wherein the polar aprotic solvent includes one or more of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran;

[0124] Step (4) includes a solvent, wherein the solvent includes a polar aprotic solvent, preferably including one or more of N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone;

[0125] The step (5) includes a solvent, and the solvent includes one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, acetone, methanol, ethanol, ethylene glycol, polyethylene glycol, isopropanol, ether, tetrahydrofuran and water.

[0126] The present invention relates to some embodiments of preparing compound (I),

[0127] The reaction temperature of step (1) is 0°C to 40°C, preferably 20°C to 40°C;

[0128] The reaction temperature of step (2) is 0°C to 40°C, preferably 20°C to 40°C;

[0129] The reaction temperature of step (3) is 0°C to 40°C, preferably 20°C to 40°C;

[0130] The reaction temperature of step (4) is 30°C to 120°C, preferably 60°C to 110°C, more preferably 80°C to 100°C;

[0131] The reaction temperature of step (5) is 0°C to 40°C, preferably 10°C to 30°C.

[0132] The present invention relates to a compound as shown below,

[0133]

[0134] HX is selected from acetic acid, sulfuric acid, hydrobromic acid, hydroiodic acid or trifluoroacetic acid;

[0135] n is selected from 1, 1.5, 2, 3 or 4.

[0136] The compound of formula (IV) of the present invention has better stability and is suitable for long-term storage. The use of the compound as an intermediate in preparing compound (II) has the advantages of high reaction yield, few by-products and impurities, and simple purification.

[0137] The present invention relates to a method for purifying a compound represented by formula (I), comprising mixing the compound represented by formula (I) with a solvent comprising methanol, ethanol, isopropanol, ethyl acetate, acetone, methyl tert-butyl ether, diethyl ether or water, and crystallizing or / and beating the mixture.

[0138]

[0139] HY is selected from pharmaceutically acceptable salts, preferably fumaric acid, formic acid, acetic acid, succinic acid, hydrochloric acid, sulfuric acid, tartaric acid, p-toluic acid, methanesulfonic acid, malic acid, maleic acid, succinic acid;

[0140] m is selected from 0.5, 1, 1.5, 2 or 3.

[0141] The present invention relates to a method for refining a compound represented by formula (I), comprising mixing the compound represented by formula (I) with one or more solvents selected from methanol, ethanol, isopropanol, ethyl acetate, acetone, methyl tert-butyl ether, diethyl ether or water, and performing crystallization and / or slurrying.

[0142] The present invention relates to a method for purifying a compound represented by formula (II), comprising mixing the compound represented by formula (II) with a solvent comprising methanol, ethanol, isopropanol, ethyl acetate, acetone, methyl tert-butyl ether, diethyl ether or water, and crystallizing or / and beating the mixture.

[0143]

[0144] The present invention relates to a method for refining a compound represented by formula (II), comprising mixing the compound represented by formula (II) with one or more solvents selected from methanol, ethanol, isopropanol, ethyl acetate, acetone, methyl tert-butyl ether, diethyl ether or water, and performing crystallization and / or slurrying.

[0145] The present invention relates to a method for purifying a compound represented by formula (IV), comprising mixing the compound represented by formula (IV) with a solvent comprising methanol, ethanol, isopropanol, ethyl acetate, acetone, methyl tert-butyl ether, diethyl ether or water, and crystallizing or / and beating the mixture.

[0146]

[0147] HX is selected from hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid, hydroiodic acid or trifluoroacetic acid;

[0148] n is selected from 0, 1, 1.5, 2, 3 or 4.

[0149] The present invention relates to a method for refining a compound represented by formula (IV), comprising mixing the compound represented by formula (IV) with one or more solvents selected from methanol, ethanol, isopropanol, ethyl acetate, acetone, methyl tert-butyl ether, diethyl ether or water, and performing crystallization and / or slurrying.

[0150] The present invention relates to a method for purifying a compound represented by formula (V) or (VII), comprising mixing the compound represented by formula (V) or (VII) with a solvent comprising methanol, ethanol, isopropanol, ethyl acetate, acetone, methyl tert-butyl ether, diethyl ether or water, and crystallizing or / and beating the mixture.

[0151]

[0152] P is selected from amino protecting groups, preferably tert-butyloxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, p-methoxybenzyl.

[0153] The present invention relates to a method for purifying a compound represented by formula (V) or (VII), comprising mixing the compound represented by formula (V) or (VII) with one or more solvents selected from methanol, ethanol, isopropanol, ethyl acetate, acetone, methyl tert-butyl ether, diethyl ether or water, and performing crystallization and / or slurrying.

[0154] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0155] The method of using extraction in the post-treatment of the reaction in the present invention is a conventional method in the art. The solvent for extraction can be selected according to the solubility of the product and the solubility of the organic solvent in water. Common extraction solvents include but are not limited to dichloromethane, chloroform, ethyl acetate, methyl acetate, isopropyl acetate, ether, isopropyl ether, methyl tert-butyl ether, methanol and ethanol, or a mixed solvent of two or more. The number of extractions can be appropriately increased or decreased according to the amount of product remaining in the aqueous phase. The organic phase after extraction is optionally further subjected to conventional washing and / or drying treatment in the art.

[0156] The elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the elements carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by 1 to 5 of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, an isotope of fluorine 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0157] "Alcohol solvent" refers to a solvent containing hydroxyl groups in its molecular structure. Non-limiting examples include ethylene glycol, methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, sec-pentanol, 3-pentanol, isopentanol, tert-pentanol, n-hexanol and cyclohexanol.

[0158] "Ether solvent" refers to a solvent with an ether bond in its molecular structure. Non-limiting examples include tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, diisopropyl ether, ethyl butyl ether, dibutyl ether, diamyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether and anisole.

[0159] "Aromatic hydrocarbon solvents" refer to solvents containing 0-3 heteroatoms (heteroatoms selected from O, S or N) and aromatic rings in their molecular structure. Non-limiting examples include benzene, pyridine, toluene, ethylbenzene, xylene, chlorobenzene and o-dichlorobenzene.

[0160] “Halogenated alkane solvents” refer to alkane solvents containing halogens (fluorine, chlorine, bromine, iodine) in their molecular structure. Non-limiting examples include dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, carbon tetrachloride, pentachlorohexane, 1-chlorobutane, and bromoform.

[0161] "Alkane solvent" refers to a solvent containing only alkanes in its molecular structure, and non-limiting examples include n-hexane, n-heptane, n-octane, n-pentane, cyclohexane, and cycloheptane.

[0162] "Ester solvents" refer to solvents containing carboxylic acid esters in their molecular structure. Non-limiting examples include ethyl acetate, isopropyl acetate, triacetin, ethyl acetoacetate, isoamyl acetate, isopropyl acetate, n-butyl acetate, n-propyl acetate, n-amyl acetate, methyl acetate, sec-butyl acetate, butyl formate, propyl formate, n-amyl formate and diethyl carbonate.

[0163] "Ketone solvents" refer to solvents containing a ketone carbonyl group in their molecular structure. Non-limiting examples include acetone, butanone, acetophenone, methyl isobutyl ketone, 2,6-dimethyl-2,5-heptadien-4-one, 3,5,5-trimethyl-2-cyclohexenone, and mesityl oxide.

[0164] "Nitrile solvent" refers to a solvent containing a cyano group in its molecular structure, non-limiting examples of which include acetonitrile, propionitrile, butyronitrile, and benzyl cyanide.

[0165] "Amide solvents" refer to solvents containing amides in their molecular structure, non-limiting examples of which include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, hexamethylphosphoramide, and N-methylpyrrolidone.

[0166] A "polar aprotic solvent" refers to a solvent that does not contain hydrogen atoms directly attached to electronegative atoms and does not have hydrogen bonding capability. Non-limiting examples include acetone, dimethyl sulfoxide, HMF (hydroxymethylfurfural), crown ethers, acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methyl-2-pyrrolidone.

[0167] "Polar protic solvents" refer to solvents capable of hydrogen bonding (because they contain at least one hydrogen atom directly attached to an electronegative atom (e.g., an OH or NH bond)), non-limiting examples of which include methanol, water, ethanol, ammonia, acetic acid, and the like.

[0168] "Optionally" or "as an option" means that the subsequently described event or circumstance can but need not occur, including instances where the event or circumstance occurs or does not occur.

[0169] The reaction process of the present invention is tracked by HPLC, HNMR or thin layer chromatography to determine whether the reaction is completed.

[0170] In the present invention, the internal temperature refers to the temperature of the reaction system. DETAILED DESCRIPTION

[0171] The following describes in detail the implementation process of the present invention and the beneficial effects produced by specific embodiments, which is intended to help readers better understand the essence and characteristics of the present invention and is not intended to limit the scope of implementation of this case.

[0172] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The units of ppm are given. NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and deuterated acetonitrile (CD3CN), with tetramethylsilane (TMS) as the internal standard. MS measurements were performed using an Agilent 6120 Quadrupole MS spectrometer.

[0173] Example 1

[0174] (1) Synthesis of Compound 1B (tert-butyl 3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidine-1-carboxylate)

[0175]

[0176] To a 2L three-necked flask equipped with a thermometer and mechanical stirring, 350 g of dichloromethane was added sequentially with stirring. At approximately 25°C, 69.9 g (0.181 mol) of compound 1A, 62.3 g (0.364 mol) of tert-butyl 3-oxoazetidine-1-carboxylate, 25.0 g (0.416 mol) of acetic acid, and 86.2 g (0.607 mol) of anhydrous sodium sulfate were added. After stirring for 1 hour, 79.9 g (0.377 mol) of sodium triacetoxyborohydride was slowly added portionwise at 15°C to 20°C. After the addition was complete, the mixture was reacted at 25°C to 35°C for approximately 3 to 5 hours.

[0177] After completion of the reaction, the reaction mixture was filtered and the resulting filtrate was neutralized with a 15% aqueous sodium hydroxide solution to a pH of about 10. After separation, the aqueous phase was extracted, and the combined organic phases were washed with water and dried, and then concentrated under reduced pressure at about 40°C to obtain a yellow viscous substance. The product was then crystallized from methyl tert-butyl ether to obtain a white solid, which was dried under reduced pressure at 40 to 50°C to obtain 94.4 g of compound 1B, i.e., tert-butyl 3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidine-1-carboxylate, in a yield of 96.2% and a purity of 98.9%.

[0178] 1 HNMR(DMSO-d6): δ8.25(s,1H),7.67(d,2H),7.45(t,2H),7.21-7.11(br,m,7H),4.70(s,1H),3.86-3.69(br,4H ),3.13-3.07(m,1H),2.96-2.89(m,2H),2.05-1.99(m,2H),2.26-2.19(m,2H),1.93-1.90(m,2H),1.40(s,9H).

[0179] (+)ESI-MS:542.2[M+1].

[0180] (2) Synthesis of Compound 1C (i.e., 1-(1-(azetidin-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine)

[0181]

[0182] To a 2 L three-necked flask equipped with a thermometer and mechanical stirring was added 539 g of dichloromethane and 107.8 g (0.200 mol) of compound 1B in sequence with stirring. After dissolution, 318.0 g (2.789 mol) of trifluoroacetic acid was added while controlling the temperature at 10 to 15°C, and the mixture was reacted at 25 to 30°C for about 3 hours.

[0183] After the reaction is completed, the mixture is concentrated under reduced pressure at 30 to 45°C to obtain a light yellow viscous substance, which is then dissolved in 500 g of dichloromethane and the temperature is controlled at 0 to 15°C. The mixture is neutralized with 20% aqueous sodium hydroxide solution to a pH of about 11 in the aqueous phase.

[0184] After separation, the aqueous phase was extracted again, and the combined organic phases were washed with water, dried, and concentrated under reduced pressure at 30 to 45°C. Finally, the solid was crystallized from methyl tert-butyl ether to obtain a white solid, which was dried under reduced pressure at 40 to 50°C to obtain 76.3 g of compound 1C, i.e., 1-(1-(azetidin-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, in a yield of 86.9% and a purity of 98.4%.

[0185] 1 HNMR(DMSO-d6): δ1.9(m,2H),2.0(m,2H),2.2(m,2H),2.8(m,2H),2.9(m,1H),3.0(m,2H ),3.5(m,2H),4.7(m,1H),7.1-7.2(m,5H),7.4-7.5(t,2H),7.6-7.7(d,2H),8.2(s,1H).

[0186] 1 HNMR(DMSO-d6): δ8.25(s,1H),7.67(d,2H),7.45-7.42(m,2H),7.21-7.11(m,5H),6.93(br,2H),4.70-4.64(m,1 H),3.97(br,1H),3.53-3.52(m,2H),3.17-3.05(m,2H),2.89-2.84(m,3H),2.24-2.16(m,2H),2.00-1.90(m,4H).

[0187] (+)ESI-MS:442.2[M+1].

[0188] (3) Synthesis of Compound 1E (tert-butyl 3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3']-diazetidine-1'-carboxylate)

[0189]

[0190] To a 2L three-necked flask equipped with a thermometer and mechanical stirring, 600 g of dichloromethane was added sequentially with stirring. At approximately 25°C, 99.8 g (0.226 mol) of 1C, 78.1 g (0.456 mol) of tert-butyl 3-oxoazetidine-1-carboxylate (1D), 32.0 g (0.533 mol) of acetic acid, and 86.9 g (0.612 mol) of anhydrous sodium sulfate were added. After stirring for 1 hour, 96.0 g (0.453 mol) of sodium triacetoxyborohydride was slowly added in portions. After the addition was complete, the reaction was allowed to proceed at 25 to 35°C for approximately 3 to 5 hours.

[0191] After completion of the reaction, the reaction mixture was filtered and the resulting filtrate was neutralized with a 15% aqueous sodium hydroxide solution to a pH of approximately 11. After separation, the aqueous phase was extracted, and the combined organic phases were washed with water, dried, and concentrated under reduced pressure to obtain a yellow viscous substance. This was then crystallized from methyl tert-butyl ether to obtain a white solid, which was dried under reduced pressure at 40 to 50° C. to obtain 100.3 g of compound 1E, i.e., tert-butyl 1-carboxylate-3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-diazetidine], in a yield of 74.2% and a purity of 89.1%.

[0192] 1 HNMR(DMSO-d6): δ8.23(s,1H),7.67-7.65(m,2H),7.46-7.42(m,2H),7.21-7.12(m,5H),6.93(br,2H),4.69-4.63(m,1H),3.82(m,4 H),3.39-3.35(m,3H),2.97-2.92(m,2H),2.88-2.82(m,2H),2.02-1.96(m,2H),2.23-2.15(m,2H),1.91-1.89(m,2H),1.37(s,9H).

[0193] (+)ESI-MS:597.3[M+1].

[0194] (4) Synthesis of Compound 1F (i.e., 1-(1-([1,3'-diazaalkane]-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolino[3,4-d]pyrimidin-4-amine tetrakis trifluoroacetate)

[0195]

[0196] To a 2 L three-necked flask equipped with a thermometer and mechanical stirring, 350 g of dichloromethane and 69.8 g (0.117 mol) of compound 1E were added sequentially with stirring. After dissolution, 209.8 g (1.84 mol) of trifluoroacetic acid was added while controlling the temperature at 15 to 35°C, and the reaction was continued at 25 to 30°C for about 3 hours.

[0197] After completion of the reaction, the mixture was concentrated under reduced pressure at 30 to 45°C to obtain a light yellow viscous substance, which was then slurried three times with methyl tert-butyl ether to obtain a white solid. The solid was then dried under reduced pressure at 40 to 50°C to obtain 105.2 g of compound 1F, i.e., 1-(1-([1,3'-diazaalkane]-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolino[3,4-d]pyrimidin-4-amine tetrakistrifluoroacetate, in a yield of 94.4% and a purity of 88.9%.

[0198] 1 HNMR(DMSO-d6): δ8.23(s,1H),7.69-7.65(m,2H),7.46-7.41(m,2H),7.21-7.11(m,5H),6.89(br,2H),4.70-4.62(m,1 H),3.44-3.30(m,7H),2.98-2.81(m,1H),2.88-2.82(m,2H),2.24-2.14(m,2H),2.00-1.94(m,6H),1.91-1.88(m,2H).

[0199] (+)ESI-MS:497.3[M+1].

[0200] The amount of trifluoroacetic acid in compound 1F was determined by HPLC, and the results are shown below:

[0201]

[0202] (5) Synthesis of Compound 1 (i.e., 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione)

[0203]

[0204] To a 2 L three-necked flask equipped with a thermometer and mechanical stirring, 90 g of dimethyl sulfoxide, 90.8 g (0.095 mol) of compound 1F, and 82.0 g (0.63 mol) of N,N-diisopropylethylamine were added sequentially at about 20°C with stirring to form a solution. The solution was then added to a 60-70°C solution containing 400 g of dimethyl sulfoxide and 36.0 g (0.13 mol) of compound 1G (i.e., 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione), and the mixture was reacted at 85-95°C for 6-8 hours.

[0205] After the reaction, the temperature was lowered to 15 to 25° C., the upper layer containing most of the N,N-diisopropylethylamine was separated and removed, and the lower reaction liquid was poured into 2.7 L of water for crystallization. After filtration, it was slurried with 0.54 kg of anhydrous ethanol for 1 hour. After filtration, 56.2 g of yellow solid compound 1 was obtained, namely 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione, with a yield of 67.9% and a purity of 85.1%.

[0206] 1 HNMR(DMSO-d6): δ11.06(s,1H),8.24(s,1H),7.68~7.62(m,3H),7.46~7.41(m,2H),7 .21~7.11(m,5H),6.79(d,1H),6.65(dd,1H),5.06(dd,1H),4.69~4.64(m,1H),4.04( t,2H),3.81(dd,2H),3.66~3.63(m,1H),3.42(s,2H),2.99~2.92(m,3H),2.88~2.84( m,3H),2.61~2.54(m,1H),2.51(d,1H),2.24~2.16(m,2H),2.00(dd,3H),1.90(d,2H).

[0207] (+)ESI-MS:753.3[M+1].

[0208] (6) Synthesis of Compound 1-1 (i.e., 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione dimaleate)

[0209]

[0210] To a 2 L three-necked flask equipped with a thermometer and mechanical stirring, 747.5 g of dichloromethane, 18.5 g of methanol and 56.2 g (0.075 mol) of compound 1 were added in sequence with stirring at about 20°C. Then, a solution containing 22.5 g of methanol and 17.4 g (0.15 mol) of maleic acid was added at 10 to 20°C, and the temperature was then lowered to about 0°C for crystallization for about 4 hours.

[0211] After filtration, the crude product was dried under reduced pressure at 40 to 50° C., and further refined and purified to obtain 41.9 g of yellow solid compound 1-1, i.e., 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione dimaleate, with a yield of 56.7% and a purity of 99.1%.

[0212] 1HNMR(DMSO-d6): δ11.09(s,1H),8.27(s,1H),7.70~7.66(m,3H),7.47~7.43(m,2H),7.22~7.13(m,5 H),6.87(d,1H),6.74~6.71(m,1H),6.16(s,4H),5.10~5.05(m,1H),4.97~4.92(m,1H),4.20~4.17( m,2H),4.05(br,1H),3.99~3.97(m,2H),3.87(br,2H),3.70(br,3H),3.32~3.30(m,2H),2.94~2.84 (m,1H),2.87(br,2H),2.62~2.54(m,2H),2.44~2.35(m,2H),2.14~2.11(m,2H),2.04~2.01(m,1H).

[0213] (+)ESI-MS:753.3[M+1].

[0214] Example 2

[0215] (1) Synthesis of Compound 1B (tert-butyl 3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidine-1-carboxylate)

[0216]

[0217] To a 2L three-necked flask equipped with a thermometer and mechanical stirring, 450 g of dichloromethane was added sequentially with stirring. At approximately 25°C, 100.1 g (0.259 mol) of compound 1A, 96.6 g (0.564 mol) of tert-butyl 3-oxoazetidine-1-carboxylate, 23.8 g (0.518 mol) of formic acid, and 80.9 g (0.570 mol) of anhydrous sodium sulfate were added. After stirring for 1 hour, 120.8 g (0.570 mol) of sodium triacetoxyborohydride was slowly added portionwise at 15°C to 20°C. After the addition was complete, the reaction was allowed to proceed at 25°C to 35°C for approximately 3 to 5 hours.

[0218] After completion of the reaction, the reaction mixture was filtered and the resulting filtrate was neutralized with a 15% aqueous sodium hydroxide solution to a pH of about 10. After separation, the aqueous phase was extracted, and the combined organic phases were washed with water and dried, and then concentrated under reduced pressure at about 40°C to obtain a yellow viscous substance. The product was then crystallized from methyl tert-butyl ether to obtain a white solid, which was dried under reduced pressure at 40 to 50°C to obtain 77.6 g of compound 1B, i.e., tert-butyl 3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidine-1-carboxylate, in a yield of 95.2% and a purity of 99.2%.

[0219] (2) Synthesis of Compound 1C (i.e., 1-(1-(azetidin-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine)

[0220]

[0221] To a 2 L three-necked flask equipped with a thermometer and mechanical stirring was added 539 g of dichloromethane and 107.8 g (0.200 mol) of compound 1B in sequence with stirring. After dissolution, 318.0 g (2.789 mol) of trifluoroacetic acid was added while controlling the temperature at 10 to 15°C, and the mixture was reacted at 25 to 30°C for about 3 hours.

[0222] After the reaction is completed, the mixture is concentrated under reduced pressure at 30 to 45°C to obtain a light yellow viscous substance, which is then dissolved in 500 g of dichloromethane and the temperature is controlled at 0 to 15°C. The mixture is neutralized with 20% aqueous sodium hydroxide solution to a pH of about 11 in the aqueous phase.

[0223] After separation, the aqueous phase was extracted again, and the combined organic phases were washed with water, dried, and concentrated under reduced pressure at 30 to 45°C. Finally, the solid was crystallized from methyl tert-butyl ether to obtain a white solid, which was dried under reduced pressure at 40 to 50°C to obtain 76.3 g of compound 1C, i.e., 1-(1-(azetidin-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, in a yield of 86.9% and a purity of 98.4%.

[0224] (3) Synthesis of Compound 1E (tert-butyl 3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3']-diazetidine-1'-carboxylate)

[0225]

[0226] To a 2 L three-necked flask equipped with a thermometer and mechanical stirring was added 600 g of dichloromethane and 99.8 g of compound 1C (0.226 mol). 85.1 g (0.497 mol) of tert-butyl 3-oxoazetidine-1-carboxylate (1D), 28.5 g (0.62 mol) of formic acid, and 90.0 g (0.634 mol) of anhydrous sodium sulfate were added at about 25°C. After stirring for 1 h, 100.0 g (0.472 mol) of sodium triacetoxyborohydride was slowly added in batches. After the addition was complete, the mixture was reacted at 25 to 35°C for about 3 to 5 hours.

[0227] After completion of the reaction, the reaction mixture was filtered and the resulting filtrate was neutralized with a 15% aqueous sodium hydroxide solution to a pH of about 11. After separation, the aqueous phase was extracted and the combined organic phases were washed with water and dried. The combined organic phases were concentrated under reduced pressure at about 40°C to obtain a yellow viscous substance. The solid was crystallized from methyl tert-butyl ether to obtain a white solid, which was dried under reduced pressure at 40 to 50°C to obtain 112.0 g of compound 1E, i.e., tert-butyl 1-carboxylate-3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-diazetidine], in a yield of 83.0% and a purity of 89.2%.

[0228] (4) Synthesis of Compound 1F-1 (i.e., 1-(1-([1,3'-diazaalkane]-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolino[3,4-d]pyrimidin-4-amine)

[0229]

[0230] To a 2 L three-necked flask equipped with a thermometer and mechanical stirring was added 320 g of dichloromethane and 69.8 g (0.117 mol) of compound 1E in sequence with stirring. After dissolution, the temperature was controlled at 15 to 35°C. 199.5 g (1.75 mol) of trifluoroacetic acid was added, and the mixture was reacted at 25 to 35°C for approximately 3 hours.

[0231] After the reaction is completed, the mixture is concentrated under reduced pressure at 30 to 45°C to obtain a light yellow viscous substance, which is then dissolved in 300 g of dichloromethane and the temperature is controlled at 0 to 15°C. The mixture is neutralized with 20% aqueous sodium hydroxide solution to a pH of about 11 in the aqueous phase.

[0232] After separation, the aqueous phase was extracted again, and the combined organic phases were washed with water, dried, and concentrated under reduced pressure at 30 to 45°C. Finally, the solid was crystallized from methyl tert-butyl ether to obtain a white solid, which was dried under reduced pressure at 40 to 50°C to obtain 48.0 g of compound 1F-1, i.e., 1-(1-([1,3'-diazaalkane]-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolino[3,4-d]pyrimidin-4-amine, with a yield of 82.6% and a purity of 90.1%.

[0233] (5) Synthesis of Compound 1 (i.e., 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione)

[0234]

[0235] In a 2 L three-necked flask equipped with a thermometer and mechanical stirring, 150 g of dimethyl sulfoxide, 35.5 g (0.0715 mol) of compound 1F-1, and 42.6 g (0.33 mol) of N,N-diisopropylethylamine were added in sequence at about 20°C with stirring to form a solution. The solution was then added to a 60 to 70°C solution containing 300 g of dimethyl sulfoxide and 24.0 g (0.087 mol) of compound 1G, and the mixture was reacted at 85 to 90°C for 6 to 8 hours.

[0236] After the reaction, the temperature was lowered to 15 to 25° C., the upper layer containing most of the N,N-diisopropylethylamine was separated and removed, and the lower reaction liquid was poured into 3 L of water for crystallization. After filtration, it was slurried with 0.5 L of anhydrous ethanol for 1 hour, and 38.2 g of yellow solid compound 1 was obtained, namely 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione, with a yield of 71.0% and a purity of 84.5%.

[0237] (6) Synthesis of Compound 1-1 (i.e., 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione dimaleate)

[0238]

[0239] To a 2L three-necked flask equipped with a thermometer and mechanical stirring, 1200 g of dichloromethane, 30 g of methanol and 70.1 g (0.09 mol) of compound 1 were added in sequence with stirring at about 20°C. Then, a solution containing 45 g of methanol and 35.2 g (0.3 mol) of maleic acid was added at 10 to 20°C, and the temperature was then lowered to about 0°C for crystallization for 4 hours.

[0240] After filtration, the crude product was dried under reduced pressure at 40 to 50° C., and further refined and purified to obtain 53.2 g of yellow solid compound 1-1, i.e., 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione dimaleate, with a yield of 60.0% and a purity of 99.2%.

[0241] Example 3

[0242] (1) Synthesis of Compound 1B (tert-butyl 3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidine-1-carboxylate)

[0243]

[0244] To a 2L three-necked flask equipped with a thermometer and mechanical stirring, 400 g of dichloromethane was added sequentially with stirring. At approximately 25°C, 69.9 g (0.181 mol) of compound 1A, 62.3 g (0.364 mol) of tert-butyl 3-oxoazetidine-1-carboxylate, 18.3 g (0.398 mol) of formic acid, and 61.0 g (0.507 mol) of anhydrous magnesium sulfate were added. After stirring for 1 hour, 27.3 g (0.435 mol) of sodium cyanoborohydride was slowly added in portions. After the additions were completed, the mixture was reacted at 25 to 35°C for approximately 3 to 5 hours.

[0245] After completion of the reaction, the reaction mixture was filtered and the resulting filtrate was neutralized with a 15% aqueous sodium hydroxide solution to a pH of about 10. After separation, the aqueous phase was extracted, and the combined organic phases were washed with water and dried, and then concentrated under reduced pressure at about 40°C to obtain a yellow viscous substance. The product was then crystallized from methyl tert-butyl ether to obtain a white solid, which was dried under reduced pressure at 40 to 50°C to obtain 94.4 g of compound 1B, i.e., tert-butyl 3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidine-1-carboxylate, in a yield of 96.2% and a purity of 98.9%.

[0246] (2) Synthesis of Compound 1C (i.e., 1-(1-(azetidin-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine)

[0247]

[0248] To a 2L three-necked flask equipped with a thermometer and mechanical stirring was added 539 g of methanol and 80.2 g (0.148 mol) of compound 1B in sequence with stirring. After dissolution, 270.5 g (2.223 mol) of 30% concentrated hydrochloric acid was added at a temperature of 10 to 15°C, and the mixture was reacted at 25 to 35°C for 2 to 3 hours.

[0249] After the reaction is completed, the mixture is concentrated under reduced pressure at 30 to 45°C to obtain a light yellow viscous substance, which is then dissolved in 500 g of dichloromethane and the temperature is controlled at 0 to 15°C. The mixture is neutralized with 20% aqueous sodium hydroxide solution to a pH of about 9 in the aqueous phase.

[0250] After separation, the aqueous phase was extracted again, and the combined organic phases were washed with water, dried, and concentrated under reduced pressure at 30 to 45°C. Finally, the solid was crystallized from methyl tert-butyl ether to obtain a white solid, which was dried under reduced pressure at 40 to 50°C to obtain 56.7 g of compound 1C, i.e., 1-(1-(azetidin-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, in a yield of 86.8% and a purity of 98.1%.

[0251] (3) Synthesis of Compound 1E (tert-butyl 3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3']-diazetidine-1'-carboxylate)

[0252]

[0253] To a 2L three-necked flask equipped with a thermometer and mechanical stirring was added 600 g of dichloromethane in sequence with stirring. At about 25°C, 99.8 g (0.226 mol) of compound 1C, 85.6 g (0.500 mol) of tert-butyl 3-oxoazetidine-1-carboxylate (1D), 36.0 g (0.600 mol) of acetic acid, and 100.0 g (0.704 mol) of anhydrous sodium sulfate were added. After stirring for 1 h, 106.0 g (0.500 mol) of sodium triacetoxyborohydride was slowly added in batches. After the addition was complete, the reaction was carried out at 25 to 30°C for 3 to 5 hours.

[0254] After completion of the reaction, the reaction mixture was filtered and the resulting filtrate was neutralized with a 15% aqueous sodium hydroxide solution to a pH of 9 to 11. After separation, the aqueous phase was extracted, and the combined organic phases were washed with water and dried. The combined organic phases were concentrated under reduced pressure at about 40°C to obtain a yellow viscous substance. The solid was crystallized from methyl tert-butyl ether to obtain a white solid, which was dried under reduced pressure at 40 to 50°C to obtain 112.0 g of compound 1E, i.e., tert-butyl 1-carboxylate-3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-diazetidine], in a yield of 83.0% and a purity of 89.3%.

[0255] (4) Synthesis of Compound 1F-1 (i.e., 1-(1-([1,3'-diazaalkane]-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolino[3,4-d]pyrimidin-4-amine)

[0256]

[0257] To a 2 L three-necked flask equipped with a thermometer and mechanical stirring, 300 g of methanol and 101.4 g (0.17 mol) of compound 1E were added sequentially with stirring. After dissolution, the temperature was controlled at 15 to 35°C. 165.5 g (1.36 mol) of 30% mass concentration hydrochloric acid was added, and the mixture was reacted at 25 to 35°C for about 3 hours.

[0258] After the reaction is completed, the mixture is concentrated under reduced pressure at 30 to 45°C to obtain a light yellow viscous substance, which is then dissolved in 300 g of dichloromethane and the temperature is controlled at 0 to 15°C. The mixture is neutralized with 20% aqueous sodium hydroxide solution to a pH of about 11 in the aqueous phase.

[0259] After separation, the aqueous phase was extracted, and the combined organic phases were washed with water, dried, and concentrated under reduced pressure at 30 to 45°C. Finally, the solid was crystallized from methyl tert-butyl ether to obtain a white solid, which was dried under reduced pressure at 40 to 50°C to obtain 67.5 g of compound 1F-1, i.e., 1-(1-([1,3'-diazaalkane]-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolino[3,4-d]pyrimidin-4-amine, with a yield of 80.0% and a purity of 90.3%.

[0260] (5) Synthesis of Compound 1 (i.e., 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione)

[0261]

[0262] In a 2 L three-necked flask equipped with a thermometer and mechanical stirring, 150 g of dimethyl sulfoxide, 64.5 g (0.13 mol) of compound 1F-1 and 33.4 g (0.33 mol) of triethylamine were sequentially added with stirring at about 20°C to form a solution. The solution was then added to a 60 to 70°C solution containing 300 g of dimethyl sulfoxide and 55.2 g (0.2 mol) of compound 1G (i.e., 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione, CAS NO.: 835616-61-0), and the mixture was reacted at 85 to 90°C for 6 to 8 hours.

[0263] After the reaction, the temperature was lowered to 15 to 25°C. The upper layer containing the majority of N,N-diisopropylethylamine was separated and removed. The lower reaction liquid was poured into 3 L of water for crystallization. After filtration, the mixture was slurried with 1.0 L of anhydrous ethanol for 1 hour. After filtration, 68.5 g of yellow solid Compound 1 (5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione) was obtained, with a yield of 70.0% and a purity of 87.1%.

[0264] (6) Synthesis of Compound 1-1 (i.e., 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione fumarate)

[0265]

[0266] To a 2L three-necked flask equipped with a thermometer and mechanical stirring, 1200 g of dichloromethane, 30 g of methanol and 70.1 g (0.09 mol) of compound 1 were added in sequence at about 20°C with stirring. Then, a solution containing 45 g of methanol and 34.8 g (0.3 mol) of fumaric acid was added. The temperature was then lowered to about 0°C for crystallization for 3 hours.

[0267] After filtration, the crude product was dried under reduced pressure at 40 to 50° C., and further refined and purified to obtain 50.3 g of yellow solid compound 1-1, i.e., 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione difumarate, with a yield of 56.7% and a purity of 99.2%.

[0268] 1HNMR(DMSO-d6): δ11.09(s,1H),8.27(s,1H),7.70~7.66(m,3H),7.47~7.43(m,2H),7.22~7.13(m,5 H),6.87(d,1H),6.74~6.71(m,1H),6.16(s,4H),5.10~5.05(m,1H),4.97~4.92(m,1H),4.20~4.17( m,2H),4.05(br,1H),3.99~3.97(m,2H),3.87(br,2H),3.70(br,3H),3.32~3.30(m,2H),2.94~2.84 (m,1H),2.87(br,2H),2.62~2.54(m,2H),2.44~2.35(m,2H),2.14~2.11(m,2H),2.04~2.01(m,1H).

[0269] (+)ESI-MS:753.3[m+1].

[0270] BTK degradation assay in Mino cells

[0271] Mino human mantle cell lymphoma cell line was purchased from ATCC. Culture conditions: RPMI-1640 + 15% FBS + 1% double-antibody, cultured at 37°C in a 5% CO2 incubator. Cells were plated in 6-well plates, 5 × 10 5 / well. After plating, different concentrations of compounds were added and cultured in a 37°C, 5% CO2 incubator for 48 hours. After the culture was completed, the cells were collected and lysed on ice for 15 minutes with RIPA lysis buffer (beyotime, Cat.P0013B). The cells were centrifuged at 12000 rpm and 4°C for 10 minutes to collect the supernatant protein sample. After protein quantification using a BCA kit (Beyotime, Cat.P0009), the protein was diluted to 0.25 mg / mL and the expression of BTK (CST, Cat.8547S) and the internal reference β-actin (CST, Cat.3700S) was detected using a fully automatic protein blot quantitative analyzer (Proteinsimple) using a kit (Proteinsimple, Cat.SM-W004). The expression of BTK relative to the internal reference was calculated using compass software and DC was calculated using Origen9.2 software according to formula (1) 50 The BTK administration group refers to the BTK expression level in different dose groups, and the BTK vehicle group refers to the BTK expression level in the vehicle control group.

[0272] BTK% = BTK dosage / BTK solvent × 100 Formula (1)

[0273] Table 1 DCs of BTK degradation in Mino cells 50 value

[0274] Serial number Compound number <![CDATA[DC 50 (nM)]]> 1 Compound 1 10.9

[0275] Conclusion: Compounds 1 and 2 have significant degradation effects on BTK in Mino cells.

[0276] Detection of BTK protein degradation in mouse spleen

[0277] Female ICR mice, 6-8 weeks old, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. and the experiment began after 3 days of acclimatization. After oral administration of different doses of the compound for 3 consecutive days, the spleen of the mice was removed, spleen cells were collected, lysed on ice for 15 minutes with RIPA lysis buffer (beyotime, Cat.P0013B), centrifuged at 12000 rpm, 4°C for 10 minutes, and supernatant protein samples were collected. After protein quantification using a BCA kit (Beyotime, Cat.P0009), the protein was diluted to 0.25 mg / mL and the expression of BTK (CST, Cat.8547S) and the internal reference β-actin (CST, Cat.3700S) was detected using an automatic protein blot quantitative analyzer (Proteinsimple). The expression of BTK relative to the internal reference was calculated using compass software and the DD was calculated using Origen9.2 software according to formula (2) 50 Value. Among them, BTK 给药 is the BTK expression level in different dose groups, BTK 溶媒 is the BTK expression level in the vehicle control group.

[0278] BTK% = BTK 给药 / BTK 溶媒 ×100 formula (2)

[0279] Table 2 DD of BTK protein degradation in mouse spleen by compounds 50 value

[0280] Serial number Compound number <![CDATA[DD 50 (mg / kg)]]> 2 Compound 1 3.8

[0281] Conclusion: Compounds 1 and 2 have a significant degradation effect on BTK protein in mouse spleen.

[0282] In vitro kinase assays

[0283] Kinases BTK wt (Carna, Cat. No. 08-180) and BTK C481S (Carna, Cat. No. 08-547) were prepared into a 2.5× kinase solution, and substrates FAM-P2 (GL Biochem, Cat. No. 112394) and ATP (Sigma, Cat. No. A7699-1G) were prepared into a 2.5× substrate solution. 5 μL of compound at different concentrations was added to a 384-well plate, followed by 10 μL of 2.5× kinase solution and incubation at room temperature for 10 minutes. 10 μL of 2.5× substrate solution was added, and after incubation at 28°C for an appropriate time, the reaction was terminated by adding 30 μL of stop solution and detected using a Caliper EZ reader2 instrument. IC was calculated using XLFit Excel add-in version 5.4.0.8 software. 50 The inhibition rate calculation formula is shown in formula (3), where max is the DMSO control reading, min is the negative control reading, and conversion is the compound reading.

[0284] Inhibition rate % = (max-conversion) / (max-min)*100. Formula (3)

[0285] The results are shown in Table 3:

[0286] Table 3 IC of BTK wt / C481S kinase inhibition 50 value

[0287] Serial number Compound number <![CDATA[BTK C481S IC 50 (nM)]]> <![CDATA[BTK wt IC 50 (nM)]]> 1 Compound 1 8 6.3

[0288] Conclusion: Compound 1 has a significant inhibitory effect on BTK wt / C481S kinase.

Claims

1. A method for preparing compound (II), which is prepared by the following reaction formula: L is selected from trifluoromethanesulfonate, F, Cl, Br, I, HX is selected from acetic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid or trifluoroacetic acid; n is selected from 0, 1, 1.5, 2, 3 or 4; Compound (IV) reacts with compound (III) in the presence of an alkaline reagent and a solvent to obtain compound (II); When n=0, that is, compound (IV) is in the form of a free base, at this time, the molar ratio of the alkaline agent to compound (IV) is ≤4.90:

1.

2. The preparation method according to claim 1, wherein the alkaline reagent is selected from organic amine reagents.

3. The preparation method according to claim 1, wherein the alkaline reagent is selected from one or more of triethylamine, diethylamine or N,N-diisopropylethylamine.

4. The preparation method according to claim 1, wherein the solvent is selected from polar aprotic solvents.

5. The preparation method according to claim 1, wherein the solvent is selected from one or more of acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone. The preparation method according to claim 1 , wherein the reaction temperature is 30° C. to 120° C. The preparation method according to claim 1 , wherein the reaction temperature is 60° C. to 110° C. The preparation method according to claim 1 , wherein the reaction temperature is 80° C. to 100° C.

9. The preparation method according to claim 1, wherein compound (II) is reacted with HY to prepare compound (I), HY is selected from pharmaceutically acceptable acids; m is selected from 0.5, 1, 1.5, 2 or 3.

10. The preparation method according to claim 9, wherein HY is selected from fumaric acid, formic acid, acetic acid, succinic acid, hydrochloric acid, sulfuric acid, tartaric acid, p-toluic acid, methanesulfonic acid, malic acid, maleic acid or succinic acid.

11. The preparation method according to claim 9 or 10, wherein the solvent for the reaction of compound (II) with HY is selected from one or a mixture of two or more of alkane solvents, halogenated alkane solvents, alcohol solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents and water.

12. The preparation method according to claim 9 or 10, wherein the solvent for the reaction of compound (II) with HY is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, acetone, methanol, ethanol, ethylene glycol, polyethylene glycol, isopropanol, ether, tetrahydrofuran and water.

13. A method for preparing compound (VI-1), which is prepared by the following reaction formula: P is selected from amino protecting groups; HX is selected from acetic acid, sulfuric acid, hydrobromic acid, hydroiodic acid or trifluoroacetic acid; n is selected from 0, 1, 1.5, 2, 3 or 4; Compound (VII) reacts in the presence of an acidic reagent HX to obtain compound (VI-1).

14. The method according to claim 13, wherein P is selected from tert-butyloxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl or p-methoxybenzyl.

15. According to the preparation method according to claim 13, a solvent is included in the reaction, and the solvent is selected from a polar protic solvent, a polar aprotic solvent or a mixture thereof.

16. The preparation method according to claim 15, wherein the solvent is selected from one or more of methanol, ethanol, water, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran.

17. According to the preparation method according to claim 13, the reaction temperature is 0°C to 60°C.

18. According to the preparation method according to claim 17, the reaction temperature is 10°C to 40°C.

19. A method for preparing compound (IV) or compound (VI-1), which is prepared by the following reaction formula: P is selected from amino protecting groups; HX is selected from hydrochloric acid; n is selected from 0, 1, 1.5, 2, 3 or 4; Compound (V) reacts in the presence of hydrochloric acid and a polar protic solvent to obtain compound (IV); Compound (VII) is reacted in the presence of hydrochloric acid and a polar protic solvent to give compound (VI-1).

20. The preparation method according to claim 19, wherein P is selected from tert-butyloxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, and p-methoxybenzyl.

21. The preparation method according to claim 19, wherein the solvent is selected from polar protic solvents, and a polar aprotic solvent is optionally further added during the reaction.

22. The preparation method according to claim 21, wherein the polar protic solvent is selected from one or more of methanol, ethanol and water.

23. The preparation method according to claim 21, wherein the polar aprotic solvent is one or more of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran. The preparation method according to claim 21 , wherein the reaction temperature is 0° C. to 60° C. The preparation method according to claim 24 , wherein the reaction temperature is 10° C. to 40° C.

26. A method for preparing compound (V) or (VII), which is prepared by the following reaction formula: P is selected from tert-butyloxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, p-methoxybenzyl; Compound (VI) and 1a are reacted in the presence of an acidic reagent and a reducing agent, optionally with a desiccant, and then post-treated to obtain compound (V), wherein the reaction contains a solvent selected from one or more of chloroform and dichloromethane; Compound (VIII) and 1a are reacted in the presence of an acidic reagent and a reducing agent, optionally with the addition of a desiccant, and then post-treated to obtain compound (VII). When P is selected from tert-butyloxycarbonyl, the molar ratio of compound 1a to compound (VIII) is selected from 2:1 to 4:

1.

27. The preparation method according to claim 26, wherein the reaction temperature of compound (VI) and 1a is 0°C to 40°C; and the reaction temperature of compound (VIII) and 1a is 0°C to 40°C.

28. The preparation method according to claim 26, wherein the reaction temperature of compound (VI) and 1a is 20°C to 40°C; and the reaction temperature of compound (VIII) and 1a is 20°C to 40°C.

29. The preparation method according to claim 26, wherein the desiccant is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate or molecular sieves.

30. The preparation method according to claim 26, The acidic reagent is selected from one or more of hydrochloric acid, acetic acid, formic acid, propionic acid, butyric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and trifluoroacetic acid; The reducing agent is selected from boron reducing agents.

31. The preparation method according to claim 30, wherein the reducing agent is selected from one or more of sodium borohydride, sodium triacetoxyborohydride, sodium triethylborohydride, sodium cyanoborohydride, potassium borohydride or lithium borohydride.

32. The preparation method according to claim 26, wherein the post-treatment comprises adjusting the pH of the reaction system to neutral to weakly alkaline, extracting, and concentrating the organic phase to obtain compound (V) or (VII).

33. The preparation method according to claim 32, wherein the post-treatment further comprises crystallization with a solvent and / or beating, filtering, and drying the filter cake. The preparation method according to claim 33 , wherein the solvent is methyl tert-butyl ether or diethyl ether.

35. A method for preparing compound (I), comprising the following steps: L is selected from trifluoromethanesulfonate, F, Cl, Br, I, HX is selected from acetic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid or trifluoroacetic acid; n is selected from 0, 1, 1.5, 2, 3 or 4; HY is selected from pharmaceutically acceptable acids; m is selected from 0.5, 1, 1.5, 2 or 3; Step (1) Compound (VI) and 1a are reacted in the presence of an acidic reagent and a reducing agent, optionally with the addition of a desiccant, and then post-treated to obtain Compound (V); the reaction contains a solvent, which is selected from one or more of chloroform and dichloromethane; Step (2) Compound (V) reacts in the presence of an acidic reagent HX to obtain Compound (IV), wherein HX is selected from acetic acid, sulfuric acid, hydrobromic acid, hydroiodic acid or trifluoroacetic acid; Step (3) Compound (V) reacts in the presence of hydrochloric acid and a polar protic solvent to obtain compound (IV), wherein HX is HCl; Step (4) Compound (IV) reacts with compound (III) in the presence of an alkaline reagent to obtain compound (II); Step (5) Compound (II) reacts with HY to prepare compound (I).

36. The preparation method according to claim 35, wherein HY is selected from fumaric acid, formic acid, acetic acid, succinic acid, hydrochloric acid, sulfuric acid, tartaric acid, p-toluic acid, methanesulfonic acid, malic acid, maleic acid or succinic acid.

37. The preparation method according to claim 35, wherein The acidic reagent in step (1) is selected from one or more of hydrochloric acid, acetic acid, formic acid, propionic acid, butyric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and trifluoroacetic acid; the reducing agent is selected from a boron reducing agent; and the desiccant is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate, or a molecular sieve; The alkaline reagent in step (4) is selected from organic amine reagents.

38. The preparation method according to claim 37, wherein The reducing agent in step (1) is selected from one or more of sodium borohydride, sodium triacetoxyborohydride, sodium triethylborohydride, sodium cyanoborohydride, potassium borohydride or lithium borohydride; the alkaline reagent in step (4) is selected from one or more of triethylamine, diethylamine or N,N-diisopropylethylamine.

39. The preparation method according to claim 35, wherein Step (2) includes a solvent, wherein the solvent is selected from a polar aprotic solvent or a polar protic solvent; The solvent in step (3) is selected from one or more of methanol, ethanol and water, and a polar aprotic solvent is optionally further added during the reaction; Step (4) includes a solvent, wherein the solvent is selected from a polar aprotic solvent; Step (5) includes a solvent, and the solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, acetone, methanol, ethanol, ethylene glycol, polyethylene glycol, isopropanol, ether, tetrahydrofuran and water.

40. The preparation method according to claim 39, wherein The solvent in step (2) is selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, methanol, ethanol and water; The polar aprotic solvent in step (3) is selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran; The solvent in step (4) is selected from one or more of N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone.

41. The preparation method according to claim 35, wherein The reaction temperature of step (1) is 0°C to 40°C; The reaction temperature of step (2) is 0°C to 40°C; The reaction temperature of step (3) is 0°C to 40°C; The reaction temperature of step (4) is 30°C to 120°C; The reaction temperature of step (5) is 0°C to 40°C.

42. The preparation method according to claim 41, wherein The reaction temperature of step (1) is 20°C to 40°C; The reaction temperature of step (2) is 20°C to 40°C; The reaction temperature of step (3) is 20°C to 40°C; The reaction temperature of step (4) is 60° C. to 110° C.; The reaction temperature of step (5) is 10°C to 30°C.

43. The preparation method according to claim 41, wherein The reaction temperature of step (4) is 80°C to 100°C.

44. A compound as shown below, HX is selected from acetic acid, sulfuric acid, hydrobromic acid, hydroiodic acid or trifluoroacetic acid; n is selected from 1, 1.5, 2, 3 or 4.

45. A method for purifying a compound represented by formula (II), comprising mixing the compound represented by formula (II) with one or more solvents selected from methanol, isopropanol, acetone, methyl tert-butyl ether, diethyl ether or water, and crystallizing or / and slurrying the mixture.

46. ​​A method for purifying a compound of formula (IV), comprising mixing the compound of formula (IV) with one or more solvents selected from methanol, ethanol, isopropanol, ethyl acetate, acetone, methyl tert-butyl ether, diethyl ether, or water, followed by crystallization or / and slurrying. HX is selected from hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid, hydroiodic acid or trifluoroacetic acid; n is selected from 0, 1, 1.5, 2, 3 or 4.

47. A method for purifying a compound of formula (V) or (VII), comprising mixing the compound of formula (V) or (VII) with one or more solvents selected from methanol, ethanol, isopropanol, ethyl acetate, acetone, methyl tert-butyl ether, diethyl ether, or water, followed by crystallization and / or slurrying. P is selected from amino protecting groups. The purification method according to claim 47, wherein P is selected from the group consisting of tert-butyloxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, and p-methoxybenzyl.

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