Intermediate for bifunctional medicine as well as preparation method and application of intermediate

Abstract

The invention belongs to the technical field of medicine synthesis, and relates to an intermediate for a bifunctional medicine as well as a preparation method and application thereof. The invention specifically discloses a compound shown as a formula (A), a plurality of preparation methods of the compound and application of the compound shown as the formula (A) in preparation of bifunctional drugs, the defects of high toxicity of raw materials, unstable intermediates, low yield and the like in an existing production process are overcome, the prepared bifunctional drugs are low in impurity content, the quality requirements of the drugs are met, and the application prospect is wide. And the preparation method provided by the invention can also realize industrial large-scale production. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and relates to a bifunctional drug intermediate and a preparation method and application thereof. Background Art

[0002] Androgen receptor (AR) belongs to the family of nuclear hormone receptors activated by androgens. AR is responsible for the development of male sex characteristics and is also a well-documented oncogene in certain cancers, such as prostate cancer. Several AR antagonists have been approved for marketing, such as enzalutamide and apalutamide, and have been successfully used in the treatment of castration-resistant prostate cancer, and have become the main treatment for prostate cancer. However, most patients will develop drug resistance after 0.5-2 years of treatment, leading to further progression of the disease.

[0003] PROTAC (PROteolysis Targeting Chimera) is a bifunctional compound with two different ligands in its structure: one is the ubiquitin ligase E3 ligand, and the other is the target protein binding ligand, and the two ligands are connected by a connecting unit. PROTAC forms a target protein-PROTAC-E3 ternary complex by bringing the target protein and the ubiquitin ligase E3 in the cell closer. Then the E3 ubiquitin ligase marks the target protein with a ubiquitinated protein tag, and then activates the powerful ubiquitination-proteasome system in the cell to specifically degrade the target protein, thereby inhibiting the corresponding protein signaling pathway (Cell Biochem Funct. 2019, 37, 21-30). Compared with traditional AR antagonists, PROTAC has unique advantages: 1) PROTAC does not need to bind to the target protein for a long time and with high intensity, and the process of degrading the target protein is similar to a catalytic reaction. It can cyclically bind and degrade the target protein, thereby reducing the systemic exposure of the drug and reducing the occurrence of toxic side effects; 2) After the target protein is degraded, it needs to be resynthesized to restore its function. Therefore, degrading the target protein shows a more efficient and lasting anti-tumor effect than inhibiting its activity, and there will be no drug resistance caused by target protein mutations.

[0004] CN202110246427.X discloses a novel bifunctional compound to achieve degradation or inhibition of androgen receptor; it also discloses a method for preparing the bifunctional compound (such as Example A46), wherein the preparation methods of intermediates 46-9 and 46-11 are as follows:

[0005]

[0006]

[0007] The raw material trimethylsilyl cyanide (TMSCN) used in the preparation process of intermediate 46-9 is highly flammable and highly toxic; and later the applicant found that intermediate 46-9 has poor stability and is not conducive to storage and transportation; intermediate 46-9 and intermediate 46-10 are subjected to ring closure and hydrolysis reactions to obtain the starting material 46-11 of the bifunctional compound, and the reaction yield of this step is low (38%). Obviously, this method cannot meet the needs of commercial scale-up production.

[0008] When preparing PROTAC molecules, the applicant follows the preparation method in paragraph

[0723] of the CN202110246427.X specification, and conducts a condensation reaction to form an amide bond at room temperature. Although the reaction can be completely converted in a short time, the yield of this step is relatively low and cannot meet the needs of industrial production. Summary of the invention

[0009] Problem that the invention aims to solve

[0010] The purpose of the present invention is to provide an intermediate for a bifunctional drug and a preparation method thereof, and to use the intermediate for preparing a bifunctional drug (especially for preparing a compound of formula (C)-1) to solve the defects of the prior art such as high toxicity of the raw materials, unstable properties of the intermediates, low reaction yield, and unsuitability for large-scale production.

[0011] Solutions for solving problems

[0012] According to the first aspect of the present invention, the present invention provides a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0013]

[0014] in:

[0015] a is an integer selected from 1 to 6;

[0016] b is an integer selected from 0-6, preferably an integer from 1-3;

[0017] If present, each c is independently selected from an integer from 1 to 6;

[0018] Preferably, a is 1, b is 1, and c is 4;

[0019] R 1 , R 2 Each independently selected from C1-C6 alkyl;

[0020] Preferably, R 1 , R 2is selected from C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, more preferably any one of methyl, ethyl, isobutyl or tert-butyl; further preferably, R 1 is tert-butyl, R 2 It is methyl.

[0021] Preferably, a is 1, b is 1, c is 4, R 1 is tert-butyl, R 2 is methyl; that is, the compound of formula (A) has the structure

[0022] According to a second aspect of the present invention, the present invention provides a method for preparing a compound of formula (A) (method one), wherein method one comprises: subjecting a compound of formula (I) or a pharmaceutically acceptable salt thereof to a substitution reaction with a compound of formula (II) to obtain a compound of formula (A);

[0023]

[0024] Where: R 1 , R 2 , a, b, c are as defined in the first aspect;

[0025] X is Cl, Br or I, preferably Cl or Br, more preferably Br.

[0026] Preferably, a is 1, b is 1, c is 4, R 1 is tert-butyl, R 2 is methyl, and X is Br.

[0027] Preferably, the substitution reaction is carried out in the presence of an organic base; further, the organic base is an alkali metal alcoholate or a nitrogen-containing organic base; wherein: the alkali metal alcoholate is sodium tert-butoxide, potassium tert-butoxide, etc., the nitrogen-containing organic base is a high-boiling nitrogen-containing organic base, and the high-boiling nitrogen-containing organic base is any one of N,N-diisopropylethylamine (DIPEA), N,N-diisopropylaniline, 4-dimethylaminopyridine (DMAP), lutidine, imidazole, triethylamine or pyridine, or a combination of two or more thereof.

[0028] Preferably, the substitution reaction is carried out in the presence of a high-boiling nitrogen-containing organic base without solvent or in an organic solvent, and it is further preferred to carry out the reaction without solvent. The solvent-free reaction refers to adding only the compound of formula (I) or its pharmaceutically acceptable salt, the compound of formula (II) and the nitrogen-containing organic base without adding an additional solvent. The applicant was surprised to find in the experiment that when a high-boiling nitrogen-containing organic base was used, solvents such as isopropanol, xylene, anisole or pyridine were tried for reaction, and the reaction was monitored by thin layer chromatography (TLC). After isopropanol, xylene and anisole reacted for 24 hours between 80-100°C, no product was generated, and only the pyridine system generated the product. The reason why the pyridine system generates the product may be that pyridine itself belongs to a high-boiling nitrogen-containing organic base.

[0029] Preferably, the reaction temperature of the substitution reaction is 80-135° C., preferably 90-110° C., and more preferably 90-100° C. The experimental results during the applicant's early research and development process showed that in a solvent-free system, too low a temperature would lead to incomplete reaction of formula (I) and low conversion rate; but when the temperature is higher than 135° C., impurities increase significantly, and the reaction temperature is a key control indicator for the reaction of the present invention.

[0030] Preferably, in the substitution reaction, the molar ratio of the compound of formula (I) or its pharmaceutically acceptable salt to the compound of formula (II) is 1:(1-6); more preferably 1:(2-5), for example 1:2, 1:3, 1:4, 1:5.

[0031] More preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with the compound of formula (II), X is Br, R 1 is tert-butyl, R 2 The substitution reaction is carried out in the presence of a high boiling point nitrogen-containing organic base.

[0032] According to the third aspect of the present invention, the present invention provides a method for preparing a compound of formula (A) (method 2), which comprises: performing a substitution reaction between a compound of formula (I) or a pharmaceutically acceptable salt thereof and a compound of formula (III) in the presence of an organic solvent to obtain a compound of formula (IV) or a pharmaceutically acceptable salt thereof, and then reacting the compound with R 2 OH undergoes esterification reaction to obtain a compound of formula (A);

[0033]

[0034] Where: R 1 , R 2 , a, b, c are as defined in the first aspect;

[0035] X is Cl, Br or I, preferably Cl or Br, more preferably Br.

[0036] Preferably, the substitution reaction is carried out in the presence of a base; further, the base is an alkali metal alcoholate, an alkali metal carbonate, an alkali metal hydroxide or a nitrogen-containing organic base, wherein: the alkali metal alcoholate includes sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; the alkali metal carbonate is sodium carbonate, potassium carbonate, cesium carbonate or lithium carbonate; the alkali metal hydroxide is sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.; the nitrogen-containing organic base includes triethylamine, N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), etc.; the base is preferably a nitrogen-containing organic base, such as triethylamine.

[0037] Preferably, the organic solvent is a linear or cyclic C1-C6 aliphatic alcohol (such as methanol, ethanol, isopropanol, tert-butanol), an aromatic hydrocarbon (such as benzene, toluene, dimethylbenzene), preferably isopropanol.

[0038] More preferably, the compound of formula (I) or its pharmaceutically acceptable salt is subjected to a substitution reaction with the compound of formula (III), X is Br, and the substitution reaction is carried out in the presence of a nitrogen-containing organic base to obtain a compound of formula (IV) or its pharmaceutically acceptable salt. The molar ratio of the compound of formula (III) to the compound of formula (I) or its pharmaceutically acceptable salt is (1.1-2.0):1, for example 1.1:1, 1.35:1, 1.5:1, 1.8:1. The molar ratio of the nitrogen-containing organic base to the compound of formula (I) is (1-6):1, for example 1.5:1, 2:1, 3:1, 4:1, 5:1.

[0039] The esterification reaction is carried out in the presence of a catalyst, and the catalyst can be selected from a chlorination agent, an alkylation agent or an inorganic acid; the chlorination agent is SOCl 2 POCl 5 or COCl 2 The alkylating agent is iodomethane, dimethyl sulfate or dimethyl carbonate; the inorganic acid is sulfuric acid, phosphoric acid or hydrochloric acid. A person skilled in the art can select the most suitable catalyst based on the reaction rate and product yield.

[0040] According to the fourth aspect of the present invention, the present invention provides a method for preparing a compound of formula (A) (method three), which comprises: subjecting a compound of formula (I) or a pharmaceutically acceptable salt thereof to a Jocic reaction with chlorobutanol or a hydrate thereof to obtain a compound of formula (IV) or a pharmaceutically acceptable salt thereof, and then reacting the compound with R 2 OH undergoes esterification reaction to obtain a compound of formula (A);

[0041]

[0042] Where: R 1 , R2 , a, b, c are as defined in the first aspect; n is 0, 0.5 or 1.

[0043] Preferably, the Jocic reaction is carried out in the presence of a solvent and a base, and after the reaction, an acid is used for post-treatment; the solvent can be any one or more combinations of aprotic solvents or protic solvents, wherein: the aprotic solvent includes chain or cyclic C1-C6 aliphatic ketones (such as acetone, butanone), chain or cyclic C1-C6 aliphatic ethers (such as tetrahydrofuran, dimethyl ether), etc., the protic solvent includes chain or cyclic C1-C6 aliphatic alcohols (such as methanol, ethanol, isopropanol, tert-butanol), and the solvent is preferably a combination of one or more of acetone, tetrahydrofuran, and tert-butanol; the base can be an alkali metal hydroxide; the acid can be an inorganic acid or an organic acid, preferably an inorganic acid, such as hydrochloric acid, phosphoric acid or sulfuric acid.

[0044] The esterification reaction is carried out in the presence of a catalyst, and the catalyst can be selected with reference to the type of catalyst in the esterification reaction in method 2.

[0045] According to a fifth aspect of the present invention, the present invention provides a method for preparing a compound of formula (VI) (method A), wherein method A comprises: reacting a compound of formula (A) or a pharmaceutically acceptable salt thereof, a compound of formula (B-1), and a thiogenating agent in an organic solvent through a one-pot reaction to generate a compound of formula (VI);

[0046]

[0047] Where: R 1 , R 2 , a, b, c are as defined in the first aspect;

[0048] Z 1 is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens, and C1-C4 alkoxy optionally substituted by one or more halogens; preferably C1-C4 alkyl optionally substituted by one or more halogens; more preferably CF 3 ;

[0049] Z 2 is selected from halogen, hydroxy, cyano and C1-C4 alkoxy optionally substituted by one or more halogens; preferably halogen; more preferably F.

[0050] Preferably, a is 1, b is 1, c is 4, R 1 is tert-butyl, R 2 is methyl, Z 1 For CF 3 , Z 2 For F.

[0051] The thio-source reagent is selected from:

[0052]

[0053] Preferably, the thio-source reagent is selected from:

[0054]

[0055] Furthermore, the compound of formula (VI) is subjected to a hydrolysis reaction in an organic solvent under acidic conditions to obtain a compound of formula (VII); further preferably, after the compound of formula (VI) is generated in a one-pot process, an acid is directly added for a hydrolysis reaction to obtain the compound of formula (VII) without post-treatment.

[0056]

[0057] Preferably, in the one-pot method and / or hydrolysis reaction method, the organic solvent is an alkyl acid ester, a linear or branched alkyl ether, a cyclic ether, an aryl ether, a halogenated hydrocarbon, an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, an alkyl ketone, a linear or branched C2-C6 nitrile, a sulfoxide solvent or a chain or cyclic amide; the alkyl acid ester is ethyl acetate, isopropyl acetate or n-propyl acetate; the linear or branched alkyl ether is ethyl ether or methyl tert-butyl ether; the cyclic ether is 1,4-dioxane, tetrahydrofuran or 2-methyltetrahydrofuran; the aryl ether is anisole ; The chlorinated hydrocarbon is dichloromethane (DCM), chloroform or 1,2-dichloroethane; the aromatic hydrocarbon is toluene or xylene; the halogenated aromatic hydrocarbon is chlorobenzene; the alkyl ketone is acetone, butanone or methyl isobutyl ketone; the straight-chain or branched C2-C6 nitrile is acetonitrile, propionitrile, n-butyronitrile or isobutyronitrile; the sulfoxide solvent is dimethyl sulfoxide, diethyl sulfoxide, n-propyl sulfoxide and other reagents; the chain amide is N,N-dimethylformamide or N,N-dimethylacetamide, and the cyclic amide is N-methyl-2-pyrrolidone.

[0058] Further preferably, the organic solvent is a chlorinated hydrocarbon, a cyclic ether, a linear or branched C2-C6 nitrile or an aromatic hydrocarbon.

[0059] More preferably, the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran, toluene or 1,4-dioxane.

[0060] Preferably, in the method, the molar ratio of the compound of formula (A) or a pharmaceutically acceptable salt thereof, the compound of formula (B-1) and the thiogenating agent is 1:(1-5):(1-5); more preferably 1:(1-3):(2-4).

[0061] Preferably, in the one-pot preparation method, the compound of formula (A) or its pharmaceutically acceptable salt, the compound of formula (B-1) and the thiolate source reagent are added to the organic solvent at the same time for stirring reaction; or the compound of formula (A) or its pharmaceutically acceptable salt and the compound of formula (B-1) are first added to the organic solvent for stirring, and then the thiolate source reagent is added in batches for reaction; or the compound of formula (A) or its pharmaceutically acceptable salt and the thiolate source reagent are first added to the organic solvent for stirring, and then the compound of formula (B-1) is added in batches for reaction.

[0062] Preferably, in the one-pot preparation method, the reaction temperature is from 0°C to below the boiling point, preferably from 20°C to below the boiling point, for example, 20-100°C, 30-90°C, 40-80°C or 50-70°C, 70-80°C, 35-40°C. A person skilled in the art can determine the appropriate reaction temperature based on the reaction rate and the specific reaction solvent.

[0063] Preferably, the acid of the hydrolysis reaction is an inorganic acid or an organic acid, the inorganic acid is hydrochloric acid, sulfuric acid, nitric acid, etc.; the organic acid is sulfonic acid, formic acid, trifluoroacetic acid, etc.; preferably hydrochloric acid.

[0064] More preferably, the compound of formula (A) (R 1 is tert-butyl, R 2 is methyl, a is 1, b is 1, c is 4) or a pharmaceutically acceptable salt thereof and 4-amino-3-fluoro-2-trifluoromethylbenzonitrile, The reaction is carried out in the presence of a halogenated hydrocarbon to obtain a compound of formula (VI) (R 1 is tert-butyl, Z 1 For CF 3 , Z 2 is F, a is 1, b is 1, c is 4), and then an acidic hydrolysis reaction is carried out at 70-80°C to obtain a compound of formula (VII) (Z 1 For CF 3 , Z 2 is F, a is 1, b is 1, and c is 4).

[0065] According to the sixth aspect of the present invention, the present invention provides a method for preparing a compound of formula (VI) (method B), wherein method B comprises: subjecting a compound of formula (A) or a pharmaceutically acceptable salt thereof and a compound of formula (B-2) to a ring-closing reaction in an organic solvent to generate a compound of formula (VI);

[0066]

[0067] Where: R 1 , R 2 , a, b, c are as defined in the first aspect; Z 1, Z 2 As defined in the fifth aspect.

[0068] Preferably, a is 1, b is 1, c is 4, R 1 is tert-butyl, R 2 is methyl, Z 1 For CF 3 , Z 2 For F.

[0069] Furthermore, the compound of formula (VI) is subjected to a hydrolysis reaction in an organic solvent under acidic conditions to obtain a compound of formula (VII); further preferably, after the ring-closure reaction to generate the compound of formula (VI), an acid is directly added for a hydrolysis reaction to obtain the compound of formula (VII) without post-treatment.

[0070]

[0071] The ring closure and / or hydrolysis reaction is carried out in the presence of an organic solvent; further, the organic solvent can be a combination of one or more of an ether solvent, an amide solvent, a sulfoxide solvent, and an ester solvent; the ether solvent is ether, methyl tert-butyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, anisole and other reagents; the amide solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-ethylformamide and other reagents; the sulfoxide solvent is dimethyl sulfoxide, diethyl sulfoxide, n-propyl sulfoxide and other reagents; the ester solvent is ethyl acetate, propyl acetate, isopropyl acetate and other reagents. Preferably, the organic solvent can be selected from a combination of one or more of 1,4-dioxane, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO), more preferably 1,4-dioxane, DMF or a combination of the two.

[0072] Preferably, the reaction temperature of the ring-closure reaction is 15-70°C, more preferably 30-60°C, further preferably 35-40°C.

[0073] Preferably, the acid of the hydrolysis reaction is an inorganic acid or an organic acid, the inorganic acid is hydrochloric acid, sulfuric acid, nitric acid, etc.; the organic acid is sulfonic acid, formic acid, trifluoroacetic acid, etc.; preferably hydrochloric acid.

[0074] More preferably, the compound of formula (A) or a pharmaceutically acceptable salt thereof is subjected to a ring-closing reaction with a compound of formula (B-2) in the presence of 1,4-dioxane and / or DMF to obtain a compound of formula (VI), and then subjected to an acidic hydrolysis reaction at 60-80° C. to obtain a compound of formula (VII), wherein R 1 is tert-butyl, R 2 is methyl, Z 1 For CF 3 , Z 2is F, a is 1, b is 1, and c is 4; further, the molar ratio of the compound of formula (A) or its pharmaceutically acceptable salt to the compound of formula (B-2) is 1:(1.0-5.0); preferably 1:(1.5-3.0).

[0075] According to the seventh aspect of the present invention, the present invention provides a method for preparing a compound of formula (VII), comprising: subjecting a compound of formula (I) or a pharmaceutically acceptable salt thereof to a substitution reaction with a compound of formula (II) to generate a compound of formula (A); subjecting the compound of formula (A) to a ring-closing reaction with a compound of formula (B-2) in an organic solvent to generate a compound of formula (VI); subjecting the compound of formula (VI) to a hydrolysis reaction in an organic solvent under acidic conditions to obtain a compound of formula (VII);

[0076]

[0077] Where: R 1 , R 2 , a, b, c are as defined in the first aspect; Z 1 , Z 2 as defined in the fifth aspect;

[0078] X is Cl, Br or I, preferably Cl or Br, more preferably Br;

[0079] Preferably, a is 1, b is 1, c is 4, R 1 is tert-butyl, R 2 is methyl, Z 1 For CF 3 , Z 2 For F.

[0080] Preferably, the substitution reaction is carried out according to the preparation method described in the second aspect;

[0081] Preferably, the ring-closure reaction and hydrolysis reaction are carried out according to the preparation method described in the sixth aspect.

[0082] According to an eighth aspect of the present invention, the present invention provides the use of a compound of formula (A) for preparing a compound of formula (VII) or as an impurity reference substance and / or standard substance for analyzing a compound of formula (VII);

[0083]

[0084] Wherein: a, b, c are as defined in the first aspect; Z 1 , Z 2 As defined in the fifth aspect.

[0085] According to the ninth aspect of the present invention, the present invention provides a method for preparing a bifunctional compound of formula (C), which comprises carrying out a condensation reaction of a compound of formula (VII) or a pharmaceutically acceptable salt thereof with a compound of formula (VIII) or a pharmaceutically acceptable salt thereof in the presence of a base, an organic solvent and an amide condensation agent at low temperature to obtain a compound of formula (C).

[0086]

[0087] Wherein: a, b, c are as defined in the first aspect; Z 1 , Z 2 as defined in the fifth aspect;

[0088] Preferably, a is 1, b is 1, c is 4, and Z 1 For CF 3 , Z 2 For F.

[0089] ULM is a hydroxycerebroside E3 ubiquitin ligase binding moiety (CLM) or a VHLE3 ligase binding moiety (VLM).

[0090] The CLM is

[0091] The VLM is defined in paragraphs

[0167] -

[0295] of the CN113387930A specification, and the exemplary structure is as follows:

[0092]

[0093] Preferably, the VLM is

[0094] Among them, in the above structure Indicates the connection point of the connected parts.

[0095] Preferably, the base is an organic base; further, the organic base is an alkali metal alcoholate or a nitrogen-containing organic base, wherein: the alkali metal alcoholate is sodium tert-butoxide, potassium tert-butoxide, etc., and the nitrogen-containing organic base is N,N-diisopropylethylamine (DIPEA), N,N-diisopropylaniline, 4-dimethylaminopyridine (DMAP), lutidine, imidazole, triethylamine, etc.; preferably a nitrogen-containing organic base, such as N,N-diisopropylethylamine.

[0096] Preferably, the organic solvent is an amide, a chlorinated hydrocarbon or a mixture thereof; the amide solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-ethylformamide and the like; the chlorinated hydrocarbon is dichloromethane, dichloroethane, chloroform and the like.

[0097] Preferably, the amide condensation agent is carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate Phosphate (HCTU), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), 2-succinimidyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU) or 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate quaternary ammonium salt (TNTU), or any one or a combination of two or more thereof.

[0098] Preferably, the condensation reaction at low temperature refers to the condensation reaction at -40°C to 10°C; more preferably, the reaction is carried out at -30°C to 10°C, and more preferably at -30°C to -10°C. Although the preparation method in paragraph

[0723] of the CN202110246427.X specification can completely convert the reaction in a short time at room temperature, the yield of this step is relatively low (only 26%), and the impurity content is also relatively high; the present invention surprisingly found that the temperature is between 0-10°C, the impurity with RRT = 0.99 (relative to the compound of formula (C)-1, Z 1 For CF 3 , Z 2 is F, a is 1, b is 1, c is 4) is basically controlled between 1.4-1.6%, especially when the temperature is controlled below -25°C, the impurities with RRT=0.99 are controlled below 0.5%, and the yield of the reaction is also greatly improved (can be increased to more than 98%).

[0099] Further preferably, the order of adding materials for the condensation reaction is: adding an amide condensation agent and a base to a system of the compound of formula (VII) or a pharmaceutically acceptable salt thereof and an organic solvent, stirring the mixture, and then adding the compound of formula (VIII) or a pharmaceutically acceptable salt thereof to react.

[0100] Preferably, the compound of formula (VII) or a pharmaceutically acceptable salt thereof is subjected to a condensation reaction with the compound of formula (VIII) or a pharmaceutically acceptable salt thereof to prepare the compound of formula (C), wherein Z 1 For CF 3 , Z 2is F, a is 1, b is 1, and c is 4. Further, the molar ratio of the compound of formula (VII) or a pharmaceutically acceptable salt thereof to the compound of formula (VIII) or a pharmaceutically acceptable salt thereof is 1.0:(1.0-2.0), for example 1.0:1.2, 1.0:1.5, 1.0:1.6.

[0101] Preferably, in the preparation method of the compound (C), the compound of formula (VII) is prepared by the method A or method B. Further preferably, the compound of formula (A) in the method A or method B is prepared by any one of the methods 1 to 3. Even more preferably, the compound of formula (A) is prepared by the method 1.

[0102] According to the tenth aspect of the present invention, the present invention provides the use of the compound of formula (VII) for preparing the compound of formula (C) or as an impurity reference substance and / or standard substance for analyzing the compound of formula (C);

[0103]

[0104] Wherein: a, b, c are as defined in the first aspect; Z 1 , Z 2 As defined in the fifth aspect; the ULM is as defined in the ninth aspect.

[0105] Preferably, a is 1, b is 1, c is 4, and Z 1 For CF 3 , Z 2 is F, ULM is

[0106] In each reaction step described in the present invention, a post-treatment step can be taken to further separate and / or purify the product, such as extracting and concentrating the reaction solution; crystallizing and beating the separated product; unit operations such as activated carbon / silica gel decolorization, adsorption of impurities, and filtering aids; for example, using an organic solvent to dissolve the product by heating and cooling for crystallization; or using a good solvent to dissolve it and then adding a poor solvent for crystallization; or using a solvent to stir for a certain period of time without dissolving the product and then filtering it; or using a salt-forming operation for purification.

[0107] Effects of the Invention

[0108] Compared with the prior art, the present invention has the following excellent effects:

[0109] 1) The present invention provides an intermediate for a bifunctional drug, namely a compound of formula (A), which can be used to prepare a bifunctional drug as shown in formula (C), thereby solving the defects of unstable intermediates and low yield in the existing production process; compared with the preparation method in CN202110246427.X, the present method abandons the use of hazardous raw materials such as trimethylsilyl cyanide, and the yields of the ring-closure and condensation reactions are significantly improved, reaching 77% and 98% or more.

[0110] 2) The present invention uses the compound of formula (A) and the isothiocyanate compound of formula (B-2) for the first time to carry out ring closure and hydrolysis to generate the compound of formula (VII), and the yield is 77.4%, which is significantly improved compared with CN202110246427.X (the yield is 38%). When the method of the present invention is used to prepare the compound of formula (VII), the compound of formula (A) can also be used as a key organic impurity for quality control analysis.

[0111] 3) The present invention adopts the compound of formula (A), the compound of formula (B-1) and the thiogenating agent for the first time to prepare the intermediate compound of formula (VI) of the bifunctional drug by a one-pot method. Compared with the preparation method of first preparing isothiocyanate and then performing ring closing, this method does not need to prepare isothiocyanate, thus overcoming the defects of isothiocyanate such as poor stability and inconvenience in storage and transportation; at the same time, the production period is greatly shortened and the production cost is reduced.

[0112] 4) The present invention optimizes the preparation process of the compound of formula (C), and surprisingly finds that the RRT=0.99 impurity (relative to the compound of formula (C)-1, Z 1 For CF 3 , Z 2 The content of F, a is 1, b is 1, and c is 4), especially when the temperature is controlled below -25°C, RRT=0.99 impurities can be controlled below 0.5%, meeting the drug quality control requirements. At the same time, compared with CN202110246427.X (condensation reaction yield is 26%), the condensation reaction yield in the present invention is also increased to more than 98%.

[0113] 5) The preparation method of the present invention has been verified and can be scaled up, and has a technical effect that is better than or substantially equivalent to that of the embodiments of the present invention. DETAILED DESCRIPTION

[0114] The "RRT" in the present invention refers to the ratio of the calibrated retention time of a component to the calibrated retention time of the corresponding standard sample. In the present invention, it refers to the ratio of the impurity in the condensation reaction to the compound of formula (C)-1 (Z 1 For CF 3 , Z 2 is the ratio of the retention times of F, a is 1, b is 1, and c is 4).

[0115] The "good solvent" in the present invention refers to a solvent that has good solubility for a certain substance, and vice versa, it is a "poor solvent" for this substance.

[0116] Example

[0117] The technical solution of the present invention will be further described below based on specific examples. Unless otherwise specified, the instruments, consumables and reagents used in the following examples can be obtained through conventional commercial means.

[0118] The HPLC detection conditions used for content detection or purity analysis in the examples are as follows:

[0119] HPLC detection condition 1:

[0120] Chromatographic column: C18 (150mm×4.6mm×3.5μm); mobile phase: binary mobile phase system, mobile phase A is 10mM ammonium acetate solution (pH=4.50±0.05), mobile phase B is acetonitrile; elution time: 35min; elution mode: gradient elution (the maximum volume percentage of mobile phase A during gradient elution is 60%, and the minimum volume percentage is 20%); detection wavelength: UV270nm.

[0121] HPLC test condition 2:

[0122] Chromatographic column: C18 (150mm×4.6mm×3.5μm); mobile phase: binary mobile phase system, mobile phase A is 10mM ammonium acetate solution (pH=4.50±0.05), mobile phase B is acetonitrile; elution time: 40min; elution mode: gradient elution (the maximum volume percentage of mobile phase A during gradient elution is 60%, and the minimum volume percentage is 20%); detection wavelength: UV270nm.

[0123] HPLC detection condition three:

[0124] Chromatographic column: C18 (150mm×4.6mm×3.5μm); mobile phase: binary mobile phase system, mobile phase A is 10mM ammonium acetate solution (pH=4.50±0.05), mobile phase B is acetonitrile; elution time: 50min; elution mode: gradient elution (the maximum volume percentage of mobile phase A during gradient elution is 75%, and the minimum volume percentage is 10%); detection wavelength: UV270nm.

[0125] Example 1 Preparation of the compound of formula (A)-1 (R 1 is tert-butyl, R 2 is methyl, a is 1, b is 1, c is 4)

[0126] Method 1: Compound (I)-1 and compound (II)-1 (X is Br, R 2 methyl) as a raw material, and carry out a substitution reaction to prepare a compound of formula (A)-1

[0127]

[0128] Under nitrogen protection, the compound of formula (I)-1 (12.0 g, 32 mmol), DIPEA (16.8 g, about 4 eq) and methyl 2-bromoisobutyrate (24.0 g, about 4 eq) were added to the reaction bottle, and the temperature was raised to 95-100° C. with stirring. The reaction was carried out for 48-56 hours, and the reaction control results were monitored by HPLC (area normalization method) until the compound of formula (I)-1 was <5.0%, and the reaction was completed.

[0129] Post-treatment: Control the system temperature to 0-10°C, pour into a mixed solution of ethyl acetate and water under stirring, stand for stratification, extract the aqueous phase with ethyl acetate, combine the organic phases and wash with saturated brine, add 2 volumes of n-heptane, stir, stand for phase separation, the lower layer is a black oily substance, add ethyl acetate to dissolve the separated lower layer, add 2 volumes of n-heptane and stir, stand for phase separation, repeat the operation twice for the lower black oily substance, combine the upper clear liquid and pass through a silica gel pad, concentrate and dry the filtrate to obtain 14.7 g of a brown oily product, with a yield of 97.1% and an HPLC purity of 85.4% (using HPLC detection condition 1, retention time of 17.72 min). After purification, the structure was identified, and the results are as follows:

[0130] LC-MS: m / z=473.4[M+H] + .

[0131] 1 H-NMR (400MHz, CDCl 3 )δ8.06(d,J=2.8Hz,1H),7.81(d,J=8.8Hz,2H),7.46(d,J=8.6Hz,1H),6.90-6.95(m,3H),4.18(br,1H),4.03( t,J=6.3Hz,2H),3.97(s,2H),3.73(s,3H),3.59(t,J=6.3Hz,2H),1.78-1.94(m,4H),1.59(s,6H),1.48(s,9H).

[0132] The applicant surprisingly found in the experiment that when a high boiling point nitrogen-containing organic base (DIPEA) was used, and solvents such as isopropanol, xylene, anisole or pyridine were added to react, and the reaction was monitored by thin layer chromatography (TLC), no product was generated after the isopropanol, xylene and anisole system reacted at 80-100°C for 24 hours; only the pyridine system generated a product (where DIPEA was not added to the pyridine system, and only pyridine was added as both a solvent and an organic base). The reason why pyridine generated a product may be that pyridine itself is a high boiling point nitrogen-containing organic base.

[0133] Method 2: The compound of formula (I)-1 is subjected to substitution reaction with the compound of formula (III)-1 (X is Br) to obtain the compound of formula (IV)-1; the compound of formula (IV)-1 is subjected to substitution reaction with CH 3 OH undergoes esterification reaction to obtain a compound of formula (A)-1

[0134]

[0135] The compound of formula (I)-1 (2.2 g, 5.9 mmol) and bromoisobutyric acid (1.48 g, about 1.5 eq) were added to 25 mL of isopropanol, and finally triethylamine (1.79 g, 3 eq) was added, and the mixture was heated to 80°C and reacted overnight. TLC showed that the raw material was not completely reacted. (2M) HCl aqueous solution was added to adjust the pH to 5, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL*4), washed with saturated sodium chloride (300 mL*3), dried with anhydrous sodium sulfate, filtered, and evaporated to remove ethyl acetate. Silica gel was added to mix the sample, and column chromatography was performed to obtain 0.7 g of the compound of formula (IV)-1 with a yield of 26.0%.

[0136] The compound of formula (A)-1 (R is methyl) can be prepared by esterification reaction of the compound of formula (IV)-1 with methanol; those skilled in the art are familiar with the fact that the esterification reaction is carried out in the presence of a catalyst, and a suitable yield and rate can be obtained by selecting from known catalysts through experiments; for example, the catalyst can be selected from a chlorination agent, an alkylation agent or an inorganic acid; the chlorination agent can be SOCl 2 POCl 5 or COCl 2 etc.; the alkylating agent may be iodomethane, dimethyl sulfate or dimethyl carbonate etc.; the inorganic acid may be sulfuric acid, phosphoric acid or hydrochloric acid.

[0137] Example 2 Preparation of Compound of Formula (C)-1

[0138] Step 1: Preparation of intermediate compound of formula (VII)-1

[0139] Method 1: The compound of formula (A) or a pharmaceutically acceptable salt thereof, the compound of formula (B-1), and a thiogenating agent are reacted in an organic solvent in a one-pot process to generate a compound of formula (VI), which is then hydrolyzed under acidic conditions to obtain a compound of formula (VII):

[0140] Preparation of exemplary compound of formula (VII)-1:

[0141]

[0142] The compound of formula (A)-1 (5.00 g, 10.6 mmol), the compound of formula (B-1)-1 (3.89 g, about 1.8 eq) and (5.65 g, about 2.3 eq) was added to the reaction bottle, DCM (40 mL) was added, the temperature was raised to 40°C, and the reaction was kept warm for 20 hours. The results of the reaction control were monitored by HPLC (area normalization method). The content of the compound of formula (VI)-1 was 60.82%.

[0143] Add DCM, wash with 40 mL 0.5 N HCl, and NaHCO 3 The mixture was neutralized, washed with saturated brine, and the organic phase was concentrated to obtain 11.2 g of an oily product with an HPLC purity of 79.9%.

[0144] The product weight exceeds the theoretical value, and the product contains unreacted compounds of formula (A)-1 and formula (B-1)-1.

[0145] The compound of formula (VI)-1 (500 mg, 72.8 mmol), DCM (5 ml) and 6N hydrochloric acid were added to the reaction bottle, the temperature was raised to 75°C ~ 80°C and stirred for reaction, and the reaction control results were monitored by HPLC (area normalization method) (HPLC detection condition 2) and the compound of formula (VII)-1 was 61.2% (retention time was 12.22 min), and the compound of formula (VI)-1 was 0.49% (retention time was 27.81 min), and no post-treatment was done.

[0146] In addition, the applicant tried to expand the solvents in the above one-pot reaction, and selected acetonitrile, THF, toluene, and 1,4-dioxane respectively. The reactions can basically achieve the same technical effects of the present invention.

[0147] Method 2: The compound of formula (A) or its pharmaceutically acceptable salt is subjected to a ring-closing reaction with the compound of formula (B-2), and then hydrolyzed under acidic conditions to obtain a compound of formula (VII):

[0148] Preparation of exemplary compound of formula (VII)-1:

[0149]

[0150] Add the compound of formula (A)-1 (9.83 g, 0.02 mol), 1,4-dioxane (39.32 g, about 38 mL), DMF (9.34 g, about 9.90 mL) and the compound of formula (B-2)-1 (12.8 g, 2.5 eq) to the reaction bottle, heat to 35-40°C with stirring, react for about 18 hours, and detect the compound of formula (A)-1 by HPLC control ≤1.0%, and proceed to the next step; add 6N hydrochloric acid, heat to 70°C-80°C, stir and react for about 3 hours, and detect the compound of formula (VI)-1 by HPLC control ≤1.0%, cool to 15-25°C, add water and isopropyl acetate, separate the layers, extract the aqueous phase twice with isopropyl acetate, then combine the organic phases, wash twice with 3N hydrochloric acid, and then wash once with brine, and concentrate the organic phase to obtain a crude compound of formula (VII)-1. Column chromatography, concentration, slurrying with n-heptane and ethyl acetate, and then drying, 10.16 g of compound (VII)-1 was obtained with a yield of 77.4% and an HPLC purity of 98.5% (using HPLC detection condition 2, the product retention time was 11.23 min).

[0151] The applicant also investigated the effect of the addition method of the compound of formula (B-2)-1 on the reaction. When batch addition and dissolution and dropwise addition were adopted, the TLC detection results showed that they were consistent with the above-mentioned one-time addition reaction results.

[0152] Step 2: The compound of formula (VII) and the compound of formula (VIII) are subjected to condensation reaction in the presence of a solvent and HATU to obtain a bifunctional compound of formula (C):

[0153] Preparation of Example Compound Formula (C)-1:

[0154]

[0155] Add the compound of formula (VII)-1 (45.00 g, 0.071 mol) and DCM (450 mL, 10 mL DCM per gram of raw material) to a four-necked glass bottle, reduce the internal temperature to ≤-25°C, add HATU (40.7 g, about 1.5 eq) under stirring, drop DIPEA (27.6 g, about 3.0 eq), stir and react for about 1 hour, add the compound of formula (VIII)-1 (40.00 g, about 1.2 eq) in batches, stir for 1-3 hours after addition, and the reaction is completed according to liquid chromatography; add water, stir and separate, and the organic phase is obtained. The phase was washed with water, concentrated, and purified by silica gel column chromatography (eluent: DCM: MeOH = 20: 1). The crude product was dissolved in dimethyl sulfoxide and then added dropwise to water, stirred, and filtered. The crude product was slurried with water for 3 times, then filtered and dried to obtain 72.72 g of an off-white powder product with a yield of 98.2%. The HPLC purity was 99.3% (using HPLC detection condition three, with a retention time of 30.20 min), RRT = 0.99 (relative to the compound of formula (C)-1), and the impurity content was 0.09%, which met the requirements of drug quality control.

[0156] In addition, the applicant has previously investigated the effect of the reaction temperature of this step on the impurity of RRT=0.99 (relative to the compound of formula (C)-1). While keeping the usage ratio of each raw material and reagent consistent with the usage ratio in the above embodiment, when the reaction temperature is controlled at 10°C and 0°C, respectively, the HPLC monitoring reaction results (area normalization method) statistics (using HPLC detection condition three) show that the content of RRT=0.99 impurities is 1.4% and 1.6%, respectively. The impurity content is small and can be controlled below 2%.

Claims

1. A compound of formula (A) or a pharmaceutically acceptable salt thereof: in: a is selected from an integer of 1-6; b is selected from an integer of 0-6, preferably an integer of 1-3; if present, each c is independently selected from an integer of 1-6; preferably, a is 1, b is 1, and c is 4; R 1 , R 2 Each is independently selected from C1-C6 alkyl; preferably, R 1 , R 2 Each is independently selected from C1-C4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, further preferably methyl, ethyl, isopropyl or tert-butyl.

2. A method for preparing the compound of formula (A) according to claim 1, comprising: The compound of formula (I) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with the compound of formula (II) to obtain a compound of formula (A); in: R 1 , R 2 , a, b, c as defined in claim 1; X is Cl, Br or I; Preferably, the substitution reaction is carried out in the presence of an organic base; further, the organic base is an alkali metal alcoholate or a nitrogen-containing organic base; further, the nitrogen-containing organic base is a high-boiling point nitrogen-containing organic base; More preferably, the substitution reaction is carried out in the presence of a high-boiling nitrogen-containing organic base without a solvent.

3. A method for preparing the compound of formula (A) according to claim 1, comprising: The compound of formula (IV) or a pharmaceutically acceptable salt thereof and R 2 OH undergoes esterification reaction to obtain a compound of formula (A); in: R 1 , R 2 , a, b, c as defined in claim 1.

4. The preparation method according to claim 3, characterized in that: The preparation method also includes a preparation method of a compound of formula (IV); The preparation method of the compound of formula (IV) is: a compound of formula (I) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with a compound of formula (III) in the presence of an organic solvent to obtain a compound of formula (IV); in: R 1 , a, b, c as defined in claim 1; X is Cl, Br or I; Preferably, the substitution reaction is carried out in the presence of a base; Preferably, the organic solvent is a chain or cyclic C1-C6 aliphatic alcohol or aromatic hydrocarbon; or, The preparation method of the compound of formula (IV) is: the compound of formula (I) or a pharmaceutically acceptable salt thereof is subjected to a Jocic reaction with a compound of formula (V) to obtain a compound of formula (IV); in: R 1 , a, b, c as defined in claim 1; n is 0, 0.5 or 1.

5. A method for preparing a compound of formula (VI), comprising: The compound of formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, the compound of formula (B-1) and a thiogenating agent are reacted in an organic solvent by a one-pot reaction to generate a compound of formula (VI); in: R 1 , R 2 , a, b, c as defined in claim 1; Z1 is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens, and C1-C4 alkoxy optionally substituted by one or more halogens; preferably C1-C4 alkyl optionally substituted by one or more halogens; more preferably trifluoromethyl; Z2 is selected from halogen, hydroxy, cyano and C1-C4 alkoxy optionally substituted by one or more halogens; preferably halogen; more preferably fluorine; The thio-source reagent is selected from: Preferably, the thio-source reagent is selected from: Preferably, the compound of formula (A) is prepared according to the method according to any one of claims 2 to 4, more preferably prepared according to the method according to claim 2; Preferably, the organic solvent is an alkyl ester, a linear or branched alkyl ether, a cyclic ether, an aryl ether, a halogenated hydrocarbon, an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, an alkyl ketone, a linear or branched C2-C6 nitrile, a sulfoxide solvent, or a chain or cyclic amide; Preferably, the molar ratio of the compound of formula (A) or a pharmaceutically acceptable salt thereof, the compound of formula (B-1) and the thiogenating agent is 1:(1-5):(1-5), more preferably 1:(1-3):(2-4).

6. A method for preparing a compound of formula (VI), comprising: The compound of formula (A) or a pharmaceutically acceptable salt thereof according to claim 1 is subjected to a ring-closing reaction with a compound of formula (B-2) in an organic solvent to generate a compound of formula (VI); in: R 1 , R 2 , a, b, c as defined in claim 1; Z1 is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens, and C1-C4 alkoxy optionally substituted by one or more halogens; preferably C1-C4 alkyl optionally substituted by one or more halogens; more preferably trifluoromethyl; Z2 is selected from halogen, hydroxy, cyano and C1-C4 alkoxy optionally substituted by one or more halogens; preferably halogen; more preferably fluorine; Preferably, the compound of formula (A) is prepared according to the method according to any one of claims 2 to 4, more preferably prepared according to the method according to claim 2.

7. A method for preparing a compound of formula (VII), comprising: The compound of formula (VI) is subjected to a hydrolysis reaction in an organic solvent under acidic conditions to obtain a compound of formula (VII); in: a is selected from an integer of 1-6; b is selected from an integer of 0-6, preferably an integer of 1-3; if present, each c is independently selected from an integer of 1-6; preferably, a is 1, b is 1, and c is 4; R 1 is selected from C1-C6 alkyl; preferably, R 1 is selected from C1-C4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, further preferably methyl, ethyl, isopropyl or tert-butyl; Z1 is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens, and C1-C4 alkoxy optionally substituted by one or more halogens; preferably C1-C4 alkyl optionally substituted by one or more halogens; more preferably trifluoromethyl; Z2 is selected from halogen, hydroxy, cyano and C1-C4 alkoxy optionally substituted by one or more halogens; preferably halogen; more preferably fluorine; Preferably, the compound of formula (VI) is prepared according to the method of claim 5 or 6; Preferably, the preparation method comprises: preparing the compound of formula (VI) according to the method of claim 5 or 6, and then directly adding an acid to carry out a hydrolysis reaction without post-treatment to obtain the compound of formula (VII).

8. A method for preparing a compound of formula (VII), comprising: The compound of formula (I) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with the compound of formula (II) to generate a compound of formula (A); The compound of formula (A) and the compound of formula (B-2) undergo a ring-closing reaction in an organic solvent to generate a compound of formula (VI); The compound of formula (VI) is subjected to a hydrolysis reaction in an organic solvent under acidic conditions to obtain a compound of formula (VII); in: a is selected from an integer of 1-6; b is selected from an integer of 0-6, preferably an integer of 1-3; if present, each c is independently selected from an integer of 1-6; preferably, a is 1, b is 1, and c is 4; R 1 , R 2 Each is independently selected from C1-C6 alkyl; preferably, R 1 , R 2 Each is independently selected from C1-C4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, further preferably methyl, ethyl, isopropyl or tert-butyl; X is Cl, Br or I; Z1 is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens, and C1-C4 alkoxy optionally substituted by one or more halogens; preferably C1-C4 alkyl optionally substituted by one or more halogens; more preferably trifluoromethyl; Z2 is selected from halogen, hydroxy, cyano and C1-C4 alkoxy optionally substituted by one or more halogens; preferably halogen; more preferably fluorine; Preferably, the substitution reaction is carried out according to the method of claim 2; Preferably, the ring-closing reaction is carried out according to the method of claim 6; Preferably, the hydrolysis reaction is carried out according to the method of claim 7.

9. The use of the compound of formula (A) according to claim 1, for preparing the compound of formula (VII) or as an impurity reference substance and / or standard substance for analysis of the compound of formula (VII); in: a is selected from an integer of 1-6; b is selected from an integer of 0-6, preferably an integer of 1-3; if present, each c is independently selected from an integer of 1-6; preferably, a is 1, b is 1, and c is 4; Z1 is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens, and C1-C4 alkoxy optionally substituted by one or more halogens; preferably C1-C4 alkyl optionally substituted by one or more halogens; more preferably trifluoromethyl; Z2 is selected from halogen, hydroxy, cyano and C1-C4 alkoxy optionally substituted by one or more halogens; preferably halogen; more preferably fluorine.

10. A method for preparing a compound of formula (C), comprising: The compound of formula (VII) or a pharmaceutically acceptable salt thereof and the compound of formula (VIII) or a pharmaceutically acceptable salt thereof are subjected to condensation reaction in the presence of a base, an organic solvent and an amide condensation agent at low temperature to obtain a compound of formula (C); in: a is selected from an integer of 1-6; b is selected from an integer of 0-6, preferably an integer of 1-3; if present, each c is independently selected from an integer of 1-6; preferably, a is 1, b is 1, and c is 4; Z1 is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens, and C1-C4 alkoxy optionally substituted by one or more halogens; preferably C1-C4 alkyl optionally substituted by one or more halogens; more preferably trifluoromethyl; Z2 is selected from halogen, hydroxy, cyano and C1-C4 alkoxy optionally substituted by one or more halogens; preferably halogen; more preferably fluorine; ULM is a hydroxycerebroside E3 ubiquitin ligase binding portion or a VHLE3 ligase binding portion; Preferably, the hydroxycerebroside E3 ubiquitin ligase binding moiety is Preferably, the VHLE3 ligase binding moiety is in Indicates the connection point of the connected parts; Further, the low temperature is -40°C to 10°C, preferably -30°C to 10°C, more preferably -30°C to -10°C; Preferably, the compound of formula (VII) is prepared according to the method of claim 7 or 8.

11. Use of the compound of formula (VII) for preparing the compound of formula (C) or as an impurity reference substance and / or standard substance for analyzing the compound of formula (C); in: a is selected from an integer of 1-6; b is selected from an integer of 0-6, preferably an integer of 1-3; if present, each c is independently selected from an integer of 1-6; preferably, a is 1, b is 1, and c is 4; Z1 is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens, and C1-C4 alkoxy optionally substituted by one or more halogens; preferably C1-C4 alkyl optionally substituted by one or more halogens; more preferably trifluoromethyl; Z2 is selected from halogen, hydroxy, cyano and C1-C4 alkoxy optionally substituted by one or more halogens; preferably halogen; more preferably fluorine; ULM is a hydroxycerebroside E3 ubiquitin ligase binding portion or a VHLE3 ligase binding portion.

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