Intermediate for pyridyl-substituted thiohydantoin medicine as well as preparation method and application of intermediate

Abstract

The invention belongs to the technical field of medicine synthesis, and relates to a pyridyl-substituted thiohydantoin medicine intermediate as well as a preparation method and application thereof. Specifically, the invention discloses a compound shown as a formula (I), which can be used for preparing thiohydantoin medicines and overcomes the defects of harsh conditions, low yield and the like in the prior art. Also disclosed are various processes for the preparation of compounds of formula (I), where a brand new process involving a portion of the upstream intermediates (e.g., compounds of formula (II) present in the form of carboxylic acids); in addition, the invention further discloses a method for generating the thiohydantoin compound through a ring closing reaction of the compound shown in the formula (I) and an aryl isothiocyanate compound for the first time. # imgabs0 #

Description

Technical Field

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

[0002] Androgen receptor antagonist therapy is one of the main means of clinical treatment of prostate cancer. In recent years, scientists have been committed to developing androgen receptor (AR) small molecule antagonists that can treat cancer, and several drugs have been successfully launched on the market, such as Enzalutamide and Apalutamide. However, the effectiveness of these antagonist drugs as a single agent or combined therapy for resistant prostate cancer is limited. Therefore, there is a medical need for better AR small molecule antagonists, which should have a strong antagonistic effect but no agonistic effect, and also need to reduce the observed side effects.

[0003] CN102757389B discloses a pyridyl-substituted thiohydantoin compound as an AR small molecule antagonist. The patent also discloses a method for preparing the thiohydantoin compound (Example 20), as shown below.

[0004]

[0005] The preparation method uses 3-fluoro-4-isothiocyanato-2-methoxybenzonitrile and 2-methyl-2-(6-methylpyridin-3-yl)aminopropionitrile as raw materials and is carried out under microwave irradiation conditions, with a yield of 23%, which obviously cannot meet the needs of commercial production. In addition, the preparation of 2-methyl-2-(6-methylpyridin-3-yl)aminopropionitrile as an intermediate requires the use of TMSCN (trimethylsilyl cyanide), which is a highly toxic and highly flammable chemical substance, which brings great challenges and hidden dangers to safe production, and TMSCN mainly relies on imports and has high costs.

[0006] The specification of US2012 / 0184580A1, paragraph

[0095] discloses a method for preparing thiohydantoin by ring-closing reaction of (hetero)aryl substituted amino acid and aryl isothiocyanate, but does not provide an example of preparing the corresponding product using heteroaryl (e.g. pyridyl) substituted amino acid. Only in Example 8 of paragraph

[0122] is a ring-closing reaction using sodium salt of aryl (specifically phenyl) substituted amino acid provided. The reaction conditions require a high temperature of about 80°C to 100°C and a duration of more than ten hours, and the yield is low (only 17.02%). Furthermore, in Example 9 of paragraph

[0124] , a method is provided for generating sodium salt of 2-[4-(2-dimethylamino-ethoxy)-phenylamino]-2-methyl-propionic acid by reacting aromatic amine with trichlorobutanol under alkaline conditions in the presence of sodium hydroxide (yield is 63.06%). However, the yield of producing thiohydantoin by first generating the sodium salt of an amino acid and then cyclizing the sodium salt with an aromatic isothiocyanate is obviously low (the total yield of the two steps is only 10.73%), which cannot meet the requirements of industrial production.

[0007] ME Jung et al. (see ME Jung, S. Ouk, D. Yoo, et al., Structure-Activity Relationship for Thiohydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer (CRPC) [J], J. Med. Chem., 2010, 53 (7): 2779-2796) disclosed that when preparing enzalutamide (i.e., compound 92 in the article), the method in CN102757389B was used to perform a microwave-assisted ring-closure reaction, but the yield was significantly higher than that in CN102757389B, reflecting that compounds with the same functional groups (or structural fragments) but different specific structures have poor versatility when prepared by the same method.

[0008] At present, there is no efficient and feasible synthesis method for pyridyl-substituted thiohydantoin drugs, which cannot guarantee the subsequent clinical drug use and subsequent production and supply. Summary of the invention

[0009] Problem that the invention aims to solve

[0010] The present invention aims to provide a pyridyl-substituted thiohydantoin drug intermediate, and to use the intermediate to prepare a pyridyl-substituted thiohydantoin drug (especially a compound of formula (VII)), thereby solving the defects of the prior art in preparing pyridyl-substituted thiohydantoin drugs, such as high toxicity of raw materials, unstable properties of intermediates, low reaction yield, and unsuitability for large-scale production.

[0011] Technical solutions to solve problems

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

[0013]

[0014] Wherein: R is selected from C1-C6 alkyl; A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0015] Preferably, in the compound of formula (I), R is selected from C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably R is methyl, ethyl or tert-butyl, more preferably R is methyl.

[0016] Preferably, in the compound of formula (I), A is selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and C1-C4 haloalkoxy, preferably A is selected from C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably A is methyl, ethyl or tert-butyl, more preferably A is methyl.

[0017] More preferably, in the compound of formula (I), R and A are not methyl groups at the same time.

[0018] According to a second aspect of the present invention, the present invention provides a method for preparing a compound of formula (I) (method A), comprising: subjecting a compound of formula (II) or a pharmaceutically acceptable salt thereof to an esterification reaction with ROH to obtain a compound of formula (I);

[0019]

[0020] wherein: R and A are as defined in formula (I).

[0021] Preferably, in the method A, the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol. At the same time, the ROH is also a solvent for dispersing and dissolving solid reactants in the reaction.

[0022] Preferably, in the method A, the esterification reaction is carried out in the presence of a catalyst; the catalyst is a chlorinating agent, an alkylating agent or an inorganic acid; the chlorinating agent is thionyl chloride (SOCl2), phosphorus oxychloride (POCl3), phosphorus pentachloride (PCl5) or phosgene (COCl2), etc.; the alkylating agent is iodomethane, dimethyl sulfate or dimethyl carbonate, etc.; the inorganic acid is sulfuric acid, phosphoric acid or hydrochloric acid, etc., preferably a chlorinating agent.

[0023] More preferably, in the method A, the compound of formula (II) or a pharmaceutically acceptable salt thereof is subjected to an esterification reaction with methanol in the presence of thionyl chloride; further, calculated on the basis of the prototype compound, the molar ratio of the thionyl chloride to the compound of formula (II) is 1.5-5.0:1, for example 2.0:1, 2.5:1, 3.0:1 or 5.0:1.

[0024] Preferably, the method A further comprises: reacting the compound of formula (III) or a pharmaceutically acceptable salt thereof with chlorobutanol or a hydrate thereof to obtain a compound of formula (II);

[0025]

[0026] wherein: n is 0, 0.5 or 1; and A is as defined in formula (I).

[0027] Furthermore, the hydrate of chlorobutanol is chlorobutanol hemihydrate.

[0028] Preferably, calculated on the basis of the prototype compound, the molar ratio of the compound of formula (III) to the chlorobutanol is 1:1.1-3.0, such as 1:1.5, 1:2, 1:2.5 or 1:3.0.

[0029] Preferably, the reaction is carried out in the presence of a solvent and a base, and after the reaction is completed, an acid is used for post-treatment.

[0030] Furthermore, the solvent is a mixture of any one or more of an aprotic solvent or a protic solvent, 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., and the protic solvent includes chain or cyclic C1-C6 aliphatic alcohols (such as methanol, ethanol, isopropanol, tert-butanol). Preferably, the solvent is one of acetone, tetrahydrofuran, tert-butanol or a combination thereof.

[0031] Furthermore, the base is an alkali metal hydroxide, preferably sodium hydroxide.

[0032] Preferably, the molar ratio of the base to the compound of formula (III) is 2-10:1, such as 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1, calculated on the basis of the prototype compound.

[0033] Furthermore, the acid is an inorganic acid or an organic acid, preferably an inorganic acid, such as hydrochloric acid, phosphoric acid or sulfuric acid.

[0034] More preferably, in the method A, the compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with chlorobutanol hemihydrate, and the reaction is carried out in the presence of acetone, tetrahydrofuran and sodium hydroxide. After the reaction is completed, hydrochloric acid is used for post-treatment; further, calculated based on the prototype compound, the molar ratio of the compound of formula (III) to the chlorobutanol hemihydrate is 1:1.1-3.0, for example, 1:1.5, 1:2 or 1:2.5; the molar ratio of the sodium hydroxide to the compound of formula (III) is 2-10:1, for example, 3:1, 4:1, 5:1.

[0035] Alternatively, preferably, the method A further comprises: performing a substitution reaction between the compound of formula (III) or a pharmaceutically acceptable salt thereof and the compound of formula (IV) to obtain a compound of formula (II);

[0036]

[0037] Wherein: X is Cl, Br or I, preferably Cl or Br, more preferably Br; A is as defined in formula (I).

[0038] Preferably, calculated on the basis of the prototype compound, the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1.1-2.0:1, such as 1.1:1, 1.35:1, 1.5:1 or 1.8:1.

[0039] Preferably, the substitution reaction is carried out in the presence of a solvent.

[0040] Furthermore, the solvent is a mixture of any one or more of an aprotic solvent or a protic solvent, wherein: the aprotic solvent includes aromatic hydrocarbons (such as benzene, toluene, dimethylbenzene, etc.), and the protic solvent includes chain or cyclic C1-C6 aliphatic alcohols (such as methanol, ethanol, isopropanol, tert-butanol, etc.).

[0041] Preferably, the substitution reaction is carried out in the presence of a base.

[0042] 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., preferably potassium tert-butoxide; the alkali metal carbonate includes sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, etc., preferably cesium carbonate; the alkali metal hydroxide includes sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., preferably sodium hydroxide or potassium hydroxide; the nitrogen-containing organic base includes triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), etc.; the base is preferably a nitrogen-containing organic base, more preferably N,N-diisopropylethylamine or triethylamine. Preferably, calculated on the basis of the prototype compound, the molar ratio of the base to the compound of formula (III) is 1-6:1, for example, 1.5:1, 2:1, 3:1, 4:1 or 5:1.

[0043] More preferably, the compound of formula (III) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with 2-bromo-2-methylpropionic acid in the presence of isopropanol and triethylamine; further, calculated on the basis of the prototype compound, the molar ratio of the 2-bromo-2-methylpropionic acid to the compound of formula (III) is 1.1-2.0:1, for example, 1.1:1, 1.35:1, 1.5:1 or 1.8:1; the molar ratio of the triethylamine to the compound of formula (III) is 1-6:1, for example, 1.5:1, 2:1, 3:1, 4:1 or 5:1.

[0044] According to the third aspect of the present invention, the present invention provides a method for preparing a compound of formula (I) (method B), which comprises: subjecting a compound of formula (III) or a pharmaceutically acceptable salt thereof to a substitution reaction with a compound of formula (V) to obtain a compound of formula (I);

[0045]

[0046] wherein: X is Cl, Br or I, preferably Cl or Br, more preferably Br; R and A are as defined in formula (I).

[0047] Preferably, calculated on the basis of the prototype compound, the molar ratio of the compound of formula (V) to the compound of formula (III) is 1.1-2.0:1, such as 1.1:1, 1.35:1, 1.5:1 or 2.0:1.

[0048] Preferably, in the method B, the substitution reaction is carried out in the presence of a solvent.

[0049] Furthermore, the solvent is a chain or cyclic C1-C6 aliphatic amide (such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.).

[0050] Preferably, in the method B, the substitution reaction is carried out in the presence of a base.

[0051] Further, the base is an alkali metal carbonate or a nitrogen-containing organic base, wherein: the alkali metal carbonate includes sodium carbonate, potassium carbonate, etc., and the nitrogen-containing organic base includes N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), etc.; preferably, the base is an alkali metal carbonate, preferably potassium carbonate; more preferably, calculated on the basis of the prototype compound, the molar ratio of the base to the compound of formula (III) is 1-6:1, for example 1.5:1, 2:1, 3:1, 4:1 or 5:1.

[0052] More preferably, in the method B, the compound of formula (III) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with 2-bromo-2-methylpropionic acid in the presence of N,N-dimethylformamide and potassium carbonate; further, calculated on the basis of the prototype compound, the molar ratio of methyl 2-bromo-2-methylpropanoate to the compound of formula (III) is 1.1-2.0:1, for example, 1.1:1, 1.35:1, 1.5:1 or 2.0:1, preferably 2.0:1; the molar ratio of potassium carbonate to the compound of formula (III) is 1-6:1, for example, 1.5:1, 2:1, 3:1, 4:1 or 5:1.

[0053] According to the fourth aspect of the present invention, the present invention provides a method for preparing a compound of formula (I) (method C), which comprises: reacting a compound of formula (III) or a pharmaceutically acceptable salt thereof with chlorobutanol or a hydrate thereof in the presence of a base to obtain a compound of formula (II)-M, and then reacting the compound with ROH to obtain a compound of formula (I);

[0054]

[0055] Wherein: n is 0, 0.5 or 1; m is 1 or 2, preferably 1; M m+ is an alkali metal or alkaline earth metal cation, preferably Na + , K + or Ca 2+ , preferably Na + ; R and A are as defined in formula (I).

[0056] Furthermore, in the first step of the method C, the hydrate of chlorobutanol is chlorobutanol hemihydrate.

[0057] Preferably, in the first step of the method C, the molar ratio of the compound of formula (III) to the chlorobutanol is 1:1.1-3.0, such as 1:1.5, 1:2, 1:2.5 or 1:3.0, calculated based on the prototype compound.

[0058] Preferably, in the first step of the method C, the reaction is carried out in the presence of a solvent.

[0059] Furthermore, the solvent is a mixture of any one or more aprotic 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., preferably, the solvent is one of acetone and tetrahydrofuran or a combination thereof.

[0060] Further, in the first step of the method C, the base is an alkali metal hydroxide or an alkaline earth metal hydroxide, preferably sodium hydroxide, potassium hydroxide or calcium hydroxide, more preferably sodium hydroxide. In other words, the compound of formula (II)-M is the sodium salt, potassium salt or calcium salt corresponding to the compound of formula (II).

[0061] Preferably, in the first step of the method C, the molar ratio of the base to the compound of formula (III) is 2-10:1, such as 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1, calculated on the basis of the prototype compound.

[0062] More preferably, in the first step of the method C, the compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with chlorobutanol hemihydrate, and the reaction is carried out in the presence of acetone and sodium hydroxide; further, calculated on the basis of the prototype compound, the molar ratio of the compound of formula (III) to the chlorobutanol hemihydrate is 1:1.1-3.0, for example, 1:1.5, 1:2 or 1:2.5; the molar ratio of the sodium hydroxide to the compound of formula (III) is 2-10:1, for example, 3:1, 4:1, 5:1.

[0063] Preferably, in the second step of the method C, the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol. At the same time, the ROH is also a solvent for dispersing and dissolving solid reactants in the reaction.

[0064] Preferably, in the second step of method C, the esterification reaction is carried out in the presence of a catalyst; the catalyst is a chlorinating agent, an alkylating agent or an inorganic acid; the chlorinating agent is SOCl2, POCl3 or COCl2, etc.; the alkylating agent is iodomethane, dimethyl sulfate or dimethyl carbonate, etc.; the inorganic acid is sulfuric acid, phosphoric acid or hydrochloric acid, etc., preferably a chlorinating agent, more preferably SOCl2.

[0065] More preferably, in the second step of the method C, the compound of formula (II) or a pharmaceutically acceptable salt thereof is subjected to an esterification reaction with methanol in the presence of thionyl chloride; further, calculated on the basis of the prototype compound, the molar ratio of the thionyl chloride to the compound of formula (II) is 1.5-5.0:1, for example 2.0:1, 2.5:1, 3.0:1 or 5.0:1.

[0066] According to the fifth aspect of the present invention, the present invention provides a method for preparing a compound of formula (I) (method D), which comprises: reacting a compound of formula (III) or a pharmaceutically acceptable salt thereof with trichlorobutanol or a hydrate thereof in a one-pot manner in the presence of a base and ROH to obtain a compound of formula (I).

[0067]

[0068] wherein: n is 0, 0.5 or 1; R and A are as defined in formula (I).

[0069] Furthermore, in the method D, the hydrate of chlorobutanol is chlorobutanol hemihydrate.

[0070] Preferably, in the method D, the molar ratio of the compound of formula (III) to the chlorobutanol is 1:1.1-3.0, such as 1:1.5, 1:2, 1:2.5 or 1:3.0, calculated based on the prototype compound.

[0071] Preferably, in the method D, the base is an alkali metal alcoholate, preferably sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide.

[0072] Preferably, in the method D, the molar ratio of the base to the compound of formula (III) is 2-10:1, such as 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1, calculated on the basis of the prototype compound.

[0073] Preferably, in the method D, the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol. At the same time, the ROH is also a solvent for dispersing and dissolving solid reactants in the reaction.

[0074] More preferably, in the method D, the compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with chlorobutanol hemihydrate, and the reaction is carried out in the presence of sodium methoxide and methanol; further, calculated on the basis of the prototype compound, the molar ratio of the compound of formula (III) to the chlorobutanol hemihydrate is 1:1.1-3.0, for example, 1:1.5, 1:2 or 1:2.5; the molar ratio of the sodium methoxide to the compound of formula (III) is 2-10:1, for example, 3:1, 4:1, 5:1.

[0075] According to a sixth 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 ring-closing reaction with a compound of formula (VI) to obtain a compound of formula (VII);

[0076]

[0077] in:

[0078] Z 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 alkoxy, more preferably methoxy;

[0079] Y is selected from halogen, cyano, hydroxy and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;

[0080] R and A are as defined in formula (I).

[0081] Preferably, in the preparation method, the molar ratio of the compound of formula (I) to the compound of formula (VI) is 1.0:1.0-2.0, such as 1.0:1.3, 1.0:1.5, 1.0:1.6 or 1.0:1.7.

[0082] Preferably, in the preparation method, the ring-closing reaction is carried out in the presence of a polar organic solvent; further, the polar organic solvent is a nitrile, an amide, a sulfoxide, an ester or a mixture thereof, wherein: the nitrile solvent is acetonitrile, propionitrile, acrylonitrile, butyronitrile 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; further, the solvent is acetonitrile (ACN), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), isopropyl acetate (IPAc) or a mixture thereof, preferably DMF.

[0083] More preferably, in the preparation method, the compound of formula (I) or a pharmaceutically acceptable salt thereof is subjected to a ring-closing reaction with 3-fluoro-4-isothiocyanato-2-methoxybenzonitrile, and the reaction is carried out in the presence of DMF. Further, the molar ratio of the compound of formula (I) to 3-fluoro-4-isothiocyanato-2-methoxybenzonitrile is 1.0:1.0-2.0, for example, 1.0:1.3, 1.0:1.5, 1.0:1.6 or 1.0:1.7.

[0084] According to the seventh aspect of the present invention, the present invention provides a method for preparing a compound of formula (VII), comprising: using a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (VIII) and a thiogenating agent as raw materials, and performing a ring-closing reaction in an organic solvent by a one-pot method to obtain a compound of formula (VII);

[0085]

[0086] in:

[0087] Z 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 alkoxy, more preferably methoxy;

[0088] Y is selected from halogen, cyano, hydroxy and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;

[0089] R and A are as defined in formula (I).

[0090] Preferably, in the preparation method, Z and Y also satisfy the following conditions:

[0091] When Y is fluorine and is in the ortho position to Z, Z is not methoxy; and

[0092] When Y is at the ortho position to Z, Y and Z are neither fluorine nor methoxy at the same time.

[0093] Preferably, in the preparation method, the thiocarbonyl reagent is selected from 1,1'-thiocarbonyldi(pyridin-2(1H)-one) Thiophosgene O,O'-Bis(pyridin-2-yl)thiocarbonate Bis(1H-imidazol-1-yl)methylthioketone Bis(1H-benzotriazol-1-yl)methylthioketone One of the aromatic thiochloroformate (for example, phenyl thiochloroformate), preferably

[0094] Preferably, in the preparation method, the organic solvent is an alkyl ester, an alkyl ether, a cyclic ether, an aryl ether, a chlorinated hydrocarbon, an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, an alkyl ketone, a C2-C6 nitrile or a chain or cyclic amide, wherein: the alkyl ester is ethyl acetate or isopropyl acetate; the alkyl ether is ethyl ether or methyl tert-butyl ether; the cyclic ether is 1,4-dioxane or 2-methyltetrahydrofuran; the aryl ether is anisole; the chlorinated hydrocarbon is dichloromethane, chloroform or 1,2-dichloroethane; the aromatic hydrocarbon is toluene or xylene; the chlorinated aromatic hydrocarbon is chlorobenzene; the alkyl ketone is acetone, butanone or methyl isobutyl ketone; the C2-C6 nitrile is acetonitrile, propionitrile, n-butyronitrile or isobutyronitrile; the chain amide is N,N-dimethylformamide or N,N-dimethylacetamide; the cyclic amide is N-methyl-2-pyrrolidone.

[0095] More preferably, the organic solvent is an alkyl ester, a chlorinated hydrocarbon, an aromatic hydrocarbon or an alkyl ketone.

[0096] More preferably, the organic solvent is ethyl acetate, dichloromethane, chloroform, toluene or acetone.

[0097] Preferably, in the method, the molar ratio of compound of formula (I): compound of formula (VIII): thiogenating agent = 1:0.5-5:1-5, preferably 1:0.5-2:1-5, more preferably 1:1.5-2:2-5, for example 1:2:3.

[0098] Furthermore, in the preparation method of the sixth aspect or the seventh aspect, the compound of formula (I) is prepared by any one method of the second aspect to the fifth aspect.

[0099] Preferably, in the preparation method of the sixth aspect or the seventh aspect, the compound of formula (I) is prepared by the method of the second aspect, which comprises: esterifying the compound of formula (II) or a pharmaceutically acceptable salt thereof with ROH to obtain the compound of formula (I);

[0100]

[0101] wherein: the definitions of R and A and the conditions for the esterification reaction are as described in the second aspect.

[0102] More preferably, the method further comprises: performing a substitution reaction between the compound of formula (III) or a pharmaceutically acceptable salt thereof and the compound of formula (IV) to obtain a compound of formula (II);

[0103]

[0104] wherein: the definitions of A and X and the conditions for the substitution reaction are as described in the second aspect.

[0105] According to an eighth aspect of the present invention, the present invention provides the use of a compound of formula (I) in preparing a compound of formula (VII);

[0106]

[0107] in:

[0108] Z 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 alkoxy, more preferably methoxy;

[0109] Y is selected from halogen, cyano, hydroxy and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;

[0110] A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, preferably C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and C1-C4 haloalkoxy, more preferably C1-C4 alkyl, further preferably methyl, ethyl and tert-butyl, further preferably methyl.

[0111] According to the ninth aspect of the present invention, the present invention provides the use of the compound of formula (I) as an impurity reference substance and / or standard substance for analysis of the compound of formula (VII);

[0112]

[0113] in:

[0114] Z 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 alkoxy, more preferably methoxy;

[0115] Y is selected from halogen, cyano, hydroxy and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;

[0116] A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, preferably C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and C1-C4 haloalkoxy, more preferably C1-C4 alkyl, further preferably methyl, ethyl and tert-butyl, further preferably methyl.

[0117] Effects of the Invention

[0118] Compared with the prior art, the present invention has the following excellent effects:

[0119] 1) The present invention provides a thiohydantoin drug intermediate, namely a compound of formula (I), which can be used to prepare a thiohydantoin drug as shown in formula (VII), solving the defects of harsh ring-closing reaction conditions and low product yield in the existing production process; compared with the method in CN102757389B, the present method abandons the use of hazardous raw materials such as sodium cyanide and trimethylsilyl cyanide, and the ring-closing yield is significantly improved, which can reach more than 60%;

[0120] 2) The present invention is the first to use a compound of formula (III) or a pharmaceutically acceptable salt thereof and a halogenated carboxylic acid (i.e., a compound of formula (IV)) to prepare a compound of formula (II). The method has a high yield of up to 90%, which provides a basis for the production scale-up of the compound of formula (I) and its subsequent application (e.g., the preparation of a compound of formula (VII));

[0121] 3) The present invention is the first to directly carry out a ring-closing reaction between the compound of formula (I) and 3-fluoro-4-isothiocyanato-2-methoxybenzonitrile to generate the compound of formula (VII). When the method of the present invention is used to prepare the compound of formula (VII), the compound of formula (I) can also be used as a key organic impurity for quality control analysis.

[0122] 4) The preparation method of the present invention is suitable for industrial production and can be scaled up to kilogram-level production. The reaction effect is better than or basically equivalent to the small-scale level in the embodiments of the present invention. DETAILED DESCRIPTION

[0123] 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.

[0124] The HPLC conditions used for content detection or purity analysis in the examples are as follows:

[0125] ●HPLC test condition 1:

[0126] Chromatographic column: C18 (150 mm × 4.6 mm × 2.7 μm);

[0127] Mobile phase: binary mobile phase system, mobile phase A is 100 mM ammonium acetate aqueous solution (pH = 7.8), mobile phase B is acetonitrile;

[0128] Elution time: 45min;

[0129] Elution mode: gradient elution (during gradient elution, the maximum volume percentage of mobile phase A is 95% and the minimum volume percentage is 25%);

[0130] Detection wavelength: 268nm.

[0131] ●HPLC test condition 2:

[0132] Chromatographic column: C18 (150 mm × 4.6 mm × 5 μm);

[0133] Mobile phase: binary mobile phase system, mobile phase A is acetonitrile, mobile phase B is 0.1% v / v formic acid aqueous solution;

[0134] Elution time: 25min;

[0135] Elution mode: gradient elution (during gradient elution, the maximum volume percentage of mobile phase A is 30% and the minimum volume percentage is 10%);

[0136] Detection wavelength: 220nm.

[0137] ●HPLC test condition three:

[0138] Chromatographic column: C18 (150 mm × 4.6 mm × 5 μm);

[0139] Mobile phase: binary mobile phase system, mobile phase A is acetonitrile, mobile phase B is 0.1% v / v formic acid aqueous solution;

[0140] Elution time: 37min;

[0141] Elution mode: gradient elution (during gradient elution, the maximum volume percentage of mobile phase A is 95% and the minimum volume percentage is 30%);

[0142] Detection wavelength: 268nm.

[0143] Example 1: Preparation of compound of formula (II) (A is methyl)

[0144] Method 1: Using the compound of formula (III) (A is methyl) and chlorobutanol or its hydrate (semihydrate) as raw materials

[0145]

[0146] To the reaction flask, 6-methylpyridin-3-amine (21.62 g, about 0.2 mol), chlorobutanol hemihydrate (93.19 g, 2.5 eq), acetone (32.05 g) and tetrahydrofuran (72.15 g) were added in sequence, and the mixture was stirred to dissolve under ice bath. Sodium hydroxide (40.10 g, 5 eq) was added, and the mixture was stirred for 30 min. The reaction was monitored by TLC.

[0147] After the raw material disappears, filter, concentrate the filtrate to no liquid, add acetone and dichloromethane to extract and wash, separate the layers, take the product layer (HPLC purity is 89.3%), add hydrogen chloride methanol solution, adjust the pH to 6, filter, collect the filtrate, and concentrate under reduced pressure to obtain a brown-red oil (46.54g, the purity is 89.3% calculated based on the HPLC test result of the corresponding carboxylic acid sodium salt). The product is directly used in the subsequent reaction without further purification. The product weight exceeds the theoretical yield, and it is speculated that the product may contain unremoved methanol and unreacted trichlorobutanol.

[0148] In addition, in method 1, when the layering operation is performed before adding the methanol solution of hydrogen chloride, since the product at this time is the corresponding sodium carboxylate, the layering operation is more difficult to handle, but the subsequent acidification can still be achieved.

[0149] 1 H-NMR (400MHz, DMSO-d6): δ7.77-7.78(d,J=2.88,1H), 6.93(d,J=8.4Hz,1H), 6.72-6.75(dd,J1=2.88Hz, J2=8.36Hz,1H), 2.27(s,3H), 1.41(s,6H).

[0150] Method 2: Using the compound of formula (III) (A is methyl) and the compound of formula IV (X is Br) as raw materials

[0151]

[0152] 6-Methylpyridin-3-amine (32.4 g, 1.0 eq) was put into a reaction flask, and isopropanol and triethylamine (125 ml, about 3.0 eq) were added. After stirring, 2-bromo-2-methylpropionic acid (75.2 g, about 1.5 eq) was added. Under nitrogen protection, the temperature was raised and refluxed for 3 to 4 hours. Sampling was performed for central control and HPLC detection (HPLC detection condition 1 and area normalization statistics were used). The product compound of formula (II) was 91.04% (retention time was 6.69 min), and the raw material compound of formula (III) was 3.89% (retention time was 6.20 min), and the reaction was completed.

[0153] After cooling, the mixture was filtered, and the filtrate was concentrated to a solvent-free state. Anhydrous methanol was added and the mixture was distilled under reduced pressure until the water content was ≤ 0.3% to obtain a reddish brown oily substance, i.e., a methanol solution (95.2 g) of the compound of formula (II). The product was detected by HPLC (using HPLC detection condition 1 and area normalization method), and the product was 91.19% (retention time 6.75 min) and the raw material was 4.11% (retention time 6.24 min). The product was used directly in the subsequent reaction without further purification.

[0154] In the early stage of research and development, the inventors referred to the above reaction conditions, and under different feeding amounts (2-5 g) of the compound of formula (III), using isopropanol as the solvent, and fixing the amount of 2-bromo-2-methylpropionic acid to 1.5 times the molar amount of the compound of formula (III) (i.e., 1.5 eq, based on the compound of formula (III) as the calculation basis), screened different types of bases and their amounts, specifically triethylamine (3.0 eq), cesium carbonate (1.5 eq), potassium hydroxide (2.5 eq), sodium hydroxide (2.5 eq), potassium tert-butoxide (2.5 eq), and sodium hydroxide (2.5 eq). eq) to investigate the effects of different types of bases on the reaction process, and the results of the HPLC monitoring reaction control (using HPLC detection condition 1, area normalization method statistics) are: triethylamine (90.58%, retention time 9.79min), cesium carbonate (87.47%, retention time 7.33min), potassium hydroxide (88.05%, retention time 7.30min), sodium hydroxide (82.89%, retention time 7.29min), potassium tert-butoxide (71.62%, retention time 6.80min). The results show that different types of bases can achieve excellent conversion rates, among which the preferred nitrogen-containing organic base (triethylamine) is the most excellent.

[0155] In addition, during the early research and development process, the inventors also expanded the solvents (for example, replacing isopropanol with methanol, toluene, etc.) to examine the effects of different types of solvents on the reaction process. The results of the HPLC monitoring reaction control (using HPLC detection condition 1, area normalization method statistics) showed that there was a certain difference between the reaction results of methanol and toluene and isopropanol. The results of the methanol system control test were 80.82% (retention time 9.66min) and 79.48% (retention time 9.64min) for the toluene system, which were basically able to meet the requirements of the later reaction before further optimization.

[0156] Example 2: Preparation of the compound of formula (I) (R is methyl, A is methyl)

[0157] Method 1: Using the compound of formula (II) (A is methyl) and alcohol (methanol) as raw materials

[0158]

[0159] The methanol solution of the compound of formula (II) obtained by method 2 in Example 1 (the theoretical value of the compound of formula (II) is 58.3 g, 0.3 mol) was transferred to a reaction bottle, stirred under nitrogen protection, the temperature was controlled at 0-5°C, thionyl chloride (107.1 g, 3.0 eq) was added dropwise, and after the addition was completed, the mixture was stirred for 0.5-1 h, the temperature was raised to 25-30°C, and the reaction was allowed to react overnight.

[0160] The temperature was controlled at 40-50°C, the reaction solution was concentrated until no solvent was distilled off, methanol was added to the concentrated material, and it was concentrated to dryness again. Methyl tert-butyl ether (400ml) and water (400g) were added, and stirred for 10min. Sodium carbonate was added for neutralization, the pH was adjusted to 8-9, the liquid was separated by standing, the organic phase was collected, the aqueous phase was extracted twice with methyl tert-butyl ether (200ml*2), the organic phases were combined, saturated sodium chloride aqueous solution (200ml) was added for washing, stirred for 10min, the liquid was separated by standing, anhydrous sodium sulfate (45g) was added to the organic phase, stirred, filtered, the filter cake was rinsed with methyl tert-butyl ether, and the filtrate was concentrated until no solvent was distilled off to obtain a light yellow oil (34.36g, the total yield of the two steps was 55.0%, the purity was 95.64% by HPLC detection (HPLC detection condition one, area normalization method statistics), and the retention time was 14.78min).

[0161] 1 H-NMR (400MHz, CDCl3): δ7.94(d,J=2.8Hz,1H),6.94(d,J=8.36Hz,1H),6.81-6.84( dd, J1=2.92Hz, J2=8.36Hz,1H),4.01(s,1H),3.71(s,3H),2.42(s,3H),1.54(s,6H).

[0162] Method 2: First, the salt (sodium salt) of the compound of formula (II) is prepared using the compound of formula (III) (A is methyl) and chlorobutanol or its hydrate (semihydrate) as raw materials, and then the salt (sodium salt) of the compound of formula (II) is used as a raw material to prepare the compound of formula (I) (R is methyl, A is methyl)

[0163] Step (1):

[0164]

[0165] Add acetone (200 ml), 6-methylpyridin-3-amine (21.6 g, 0.2 mol) and trichlorobutanol hemihydrate (93.2 g, 0.5 mol) into a three-necked flask, stir and dissolve under nitrogen protection, control the system temperature below 30°C, add sodium hydroxide (40.1 g, 1.0 mol) in batches, and after the addition, stir and react at 10°C for 1 h, heat to 25°C and react for about 15 h, and the reaction is completed.

[0166] The reaction solution was filtered, and the filter cake was washed with acetone (20 ml × 2), the temperature was controlled at ≤ 50 ° C, the filtrate was concentrated under reduced pressure until no liquid was evaporated, dichloromethane (100 ml) was added, stirred for 10 min, and allowed to stand for separation. The obtained product layer was washed with dichloromethane (100 ml × 1), stirred for 10 min, allowed to stand for separation, and the upper layer was collected to obtain about 42 g of the sodium salt of the compound of formula (II), with a yield of about 97.1% and an HPLC purity of 91.6% (using HPLC detection condition two, area normalization method, retention time of 2.70 min).

[0167] Step (2):

[0168]

[0169] The sodium salt of the compound of formula (II) obtained in step (1) (42 g, about 0.2 mol) and methanol (200 ml) were added to a 500 ml three-necked flask. Under nitrogen protection, the mixture was stirred to dissolve. The temperature was controlled at ≤ 20°C. Sulfoxide chloride (63.5 g, 0.53 mol) was added dropwise. After the addition was completed, the temperature was raised to 25°C and the reaction was carried out for about 15 hours. The reaction was then terminated.

[0170] The reaction solution was concentrated under reduced pressure and dried by spin-drying, and methyl tert-butyl ether (200 ml) and water (200 ml) were added, stirred for 10 min, and the pH was adjusted to 8-9 with anhydrous sodium carbonate, and the mixture was allowed to stand for separation to obtain an organic phase. The aqueous phase was extracted with methyl tert-butyl ether (100 ml×2), and the mixture was allowed to stand for separation. The obtained organic phases were combined, washed with saturated aqueous sodium chloride solution (200 ml), and the mixture was allowed to stand for separation. Anhydrous sodium sulfate (42 g) was added to the organic phase, filtered, and the filter cake was rinsed with a small amount of methyl tert-butyl ether. The filtrate was concentrated under reduced pressure until no liquid was evaporated to obtain 21 g of a brown oil. The total yield of the two steps was about 50%, and the HPLC purity was 91.3% (using HPLC detection condition two, area normalization method for statistics, retention time was 7.36 min).

[0171] Method 2 can achieve a higher yield of the compound of formula (I), but the stratification in the post-treatment process of step (2) is difficult to operate, the water cannot be removed, and the difficulty of mass production is relatively high.

[0172] Method 3: Using the compound of formula (III) (A is methyl) and trichlorobutanol or its hydrate (semihydrate) as raw materials, in the presence of a base (sodium methoxide) and an alcohol (methanol), a one-pot method is used to prepare the compound of formula (I) (R is methyl, A is methyl)

[0173]

[0174] 6-Methylpyridin-3-amine (0.5 g, 4.62 mmol) and methanol (5 ml) were added to a 50 mL reaction bottle, and sodium methoxide (1.25 g, 23.15 mmol) was added under stirring at room temperature. The mixture was cooled in an ice-water bath, and a mixed solution of tert-chlorobutanol hemihydrate (2.16 g, 2.15 mmol) and methanol (2.5 ml) was added dropwise. After the addition was completed, the reaction was continued with stirring for 10 min. The system was heated to 40° C. and kept for 3 h. The reaction was completed after TLC monitoring. According to the TLC spot plate controlled during the reaction, the area ratio of the product to the raw material was approximately 20%.

[0175] The experimental results show that the specific structure of the compound of formula (III) is likely to directly affect whether it is suitable for the above-mentioned one-pot reaction. Although the compound of formula (I) can also be obtained, the room for further optimization in terms of yield is also relatively limited.

[0176] Method 4: Using the compound of formula (III) (A is methyl) and the compound of formula (V) (X is Br, R is methyl) as raw materials

[0177]

[0178] 6-Methylpyridin-3-amine (0.5 g, 4.62 mmol), methyl 2-bromo-2-methylpropionate (1.67 g, 9.07 mmol), potassium carbonate (1.92 g, 13.91 mmol) and DMF (5 mL) were mixed in a 50 ml reaction bottle, heated to 50 ° C under stirring, potassium iodide (0.1 g, 0.60 mmol) was added, and the temperature was continued to rise to 70 ° C. The reaction was reacted for about 5 hours, and the reaction was completed by TLC monitoring. According to the TLC spot plate controlled during the reaction, the area ratio of the product to the raw material was about 20%.

[0179] In order to further improve the yield of method 4, the inventors have tried to replace the potassium carbonate used as a base with an organic base (such as triethylamine, pyridine, etc.), but no reaction occurred.

[0180] The experimental results show that the specific structure of the compound of formula (III) is likely to directly affect whether it is suitable for direct substitution reaction with the corresponding halogenated ester. Although the compound of formula (I) can also be obtained, the room for further optimization in terms of yield is relatively limited.

[0181] Example 3: Preparation of the compound of formula (VII) (R is methyl, A is methyl)

[0182]

[0183] To a 50 ml reaction bottle, add the compound of formula (I)-1 (9.85 g, 0.047 mol) and DMF (13.3 ml), stir at room temperature until completely dissolved, then add the compound of formula (VI)-1 (16.74 g, 1.7 eq), and stir at room temperature for 23 h; after the reaction, add ethyl acetate and water for extraction, combine the organic layers; wash with water and saturated brine in sequence, dry over anhydrous sodium sulfate, filter, and rinse with ethyl acetate; combine the filtrate, remove ethyl acetate by rotary evaporation, add DCM (30 ml), stir, filter, add ethanol to the obtained solid, filter, and dry the filter cake to obtain 11.7 g of the target product with a yield of 64.4% and an HPLC purity of 99.8% (using HPLC detection condition three, retention time of 12.97 min).

[0184] 1 H-NMR (400MHz, DMSO-d6): δ8.50 (s, 1H), 7.79-7.86 (dd, J1=7.6Hz, J2=17.6Hz ,2H),7.49(t,J=10Hz,2H),4.13(s,3H),2.54(d,J=22.4Hz,3H),1.52(s,6H).

[0185] In addition, the inventors have tried to investigate different solvents (such as acetonitrile, isopropyl acetate, dimethyl sulfoxide or a mixture thereof) under fixed reaction conditions such as reaction temperature (20-25°C) and feed molar ratio of compound (VI)-1 to compound (I)-1 (1.5eq), and all of them were able to achieve excellent conversion rates. When acetonitrile was used as the solvent, heating at 40-80°C was required for complete conversion.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof; in: R is selected from C1-C6 alkyl, preferably C1-C4 alkyl, more preferably methyl, ethyl or tert-butyl, further preferably methyl; A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, preferably C1-C4 alkyl, more preferably methyl, ethyl or tert-butyl, further preferably methyl; Preferably, R and A are not methyl at the same time.

2. A method for preparing a compound of formula (I) according to claim 1, comprising: The compound of formula (II) or a pharmaceutically acceptable salt thereof is subjected to an esterification reaction with ROH to obtain a compound of formula (I); wherein: R and A are as defined in formula (I).

3. The preparation method according to claim 2, characterized in that: The method further comprises: reacting a compound of formula (III) or a pharmaceutically acceptable salt thereof with chlorobutanol or a hydrate thereof to obtain a compound of formula (II); Wherein: n is 0, 0.5 or 1; A is as defined in formula (I); Alternatively, the compound of formula (III) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with the compound of formula (IV) to obtain a compound of formula (II); Wherein: X is Cl, Br or I, preferably Cl or Br, more preferably Br; A is as defined in formula (I).

4. A method for preparing the compound of formula (I) according to claim 1, comprising: The compound of formula (III) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with the compound of formula (V) to obtain a compound of formula (I); wherein: X is Cl, Br or I, preferably Cl or Br, more preferably Br; R and A are as defined in formula (I).

5. A method for preparing the compound of formula (I) according to claim 1, comprising: The compound of formula (III) or a pharmaceutically acceptable salt thereof is first reacted with chlorobutanol or a hydrate thereof in the presence of a base to obtain a compound of formula (II)-M, and then esterified with ROH to obtain a compound of formula (I); Wherein: n is 0, 0.5 or 1; m is 1 or 2, preferably 1; M m+ is an alkali metal or alkaline earth metal cation, preferably Na + , K + or Ca 2+ , preferably Na + ; R and A are as defined in formula (I).

6. A method for preparing the compound of formula (I) according to claim 1, comprising: The compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with chlorobutanol or a hydrate thereof in a one-pot manner in the presence of a base and ROH to obtain a compound of formula (I); wherein: n is 0, 0.5 or 1; R and A are as defined in formula (I).

7. A method for preparing a compound of formula (II), comprising: The compound of formula (III) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with the compound of formula (IV) to obtain a compound of formula (II); Wherein: X is Cl, Br or I, preferably Cl or Br, more preferably Br; A is as defined in formula (I).

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 ring-closing reaction with the compound of formula (VI) to obtain a compound of formula (VII); in: Z 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 alkoxy, more preferably methoxy; Y is selected from halogen, cyano, hydroxy and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine; R and A are as defined in formula (I); Preferably, the compound of formula (I) is prepared by the preparation method according to any one of claims 2 to 6; More preferably, the compound of formula (I) is prepared by the preparation method according to claim 2; Further preferably, the compound of formula (I) is prepared by the preparation method according to claim 3.

9. A method for preparing a compound of formula (VII), comprising: Using the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound of formula (VIII) and a thiogenating agent as raw materials, a ring-closing reaction is carried out in an organic solvent by a one-pot method to obtain a compound of formula (VII); in: Z 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 alkoxy, more preferably methoxy; Y is selected from halogen, cyano, hydroxy and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine; R and A are as defined in formula (I); Preferably, Z and Y also satisfy the following conditions: When Y is fluorine and is in the ortho position to Z, Z is not methoxy; and When Y is in the ortho position of Z, Y and Z are neither fluorine nor methoxy at the same time; or, Preferably, the compound of formula (I) is prepared by the preparation method according to any one of claims 2 to 6; More preferably, the compound of formula (I) is prepared by the preparation method according to claim 2; Further preferably, the compound of formula (I) is prepared by the preparation method according to claim 3.

10. Use of the compound of formula (I) according to claim 1 for preparing a compound of formula (VII); in: Z 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 alkoxy, more preferably methoxy; Y is selected from halogen, cyano, hydroxy and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine; A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, preferably C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and C1-C4 haloalkoxy, more preferably C1-C4 alkyl, further preferably methyl, ethyl and tert-butyl, further preferably methyl.

11. The use of the compound of formula (I) according to claim 1, which is used as an impurity reference substance and / or standard substance for analysis of the compound of formula (VII); in: Z 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 alkoxy, more preferably methoxy; Y is selected from halogen, cyano, hydroxy and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine; A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, preferably C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and C1-C4 haloalkoxy, more preferably C1-C4 alkyl, further preferably methyl, ethyl and tert-butyl, further preferably methyl.

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