Pyridyl substituted thiohydantoin intermediates for pharmaceuticals and processes for their preparation and use

Abstract

The application belongs to the technical field of medicine synthesis, and relates to a pyridyl-substituted thiohydantoin intermediate for medicine, and a preparation method and application thereof. Specifically, the application discloses a compound of formula (I) which can be used for preparing a thiohydantoin medicine, and solves the defects of harsh conditions and low yield in the prior art. The application also discloses multiple preparation methods of the compound of formula (I), wherein a brand-new process of some upstream intermediates (for example, a compound of formula (II) in the form of a carboxylic acid) is involved. In addition, the application also discloses a method for generating a thiohydantoin compound through a ring-closing reaction of the compound of formula (I) and an aryl isothiocyanate compound.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and relates to a pyridyl-substituted thiohydantoin pharmaceutical intermediate, its preparation method, and its uses. Background Technology

[0002] Androgen receptor antagonist therapy is one of the main clinical treatments for prostate cancer. In recent years, scientists have been dedicated to developing small-molecule androgen receptor (AR) antagonists to treat cancer, and several drugs have been successfully marketed, such as enzalutamide and apalutamide. However, the efficacy of these antagonist drugs as single or combination therapy against resistant prostate cancer is limited. Therefore, there is a medical need for better AR small-molecule antagonists that should have potent antagonistic effects without any agonistic effects, and also reduce the observed side effects.

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

[0004]

[0005] The current preparation method uses 3-fluoro-4-isothiocyanate-2-methoxybenzonitrile and 2-methyl-2-(6-methylpyridin-3-yl)aminopropionitrile as raw materials under microwave irradiation, with a yield of 23%, which is clearly insufficient for commercial production. Furthermore, the preparation of the intermediate 2-methyl-2-(6-methylpyridin-3-yl)aminopropionitrile requires TMSCN (trimethylcyanosilane), which is a highly toxic and flammable chemical, posing a significant challenge and hazard to safe production. Moreover, TMSCN is mainly imported, resulting in high costs.

[0006] US2012 / 0184580A1 discloses a method for preparing thiohydantoin via a cyclization reaction of a (hetero)aryl-substituted amino acid and an aryl isothiocyanate in paragraph

[0095] . However, it does not provide examples of preparing the corresponding product using heteroaryl-substituted (e.g., pyridyl) amino acids. Only in Example 8 of paragraph

[0122] is a cyclization reaction using a sodium salt of an aryl (specifically phenyl) substituted amino acid given, requiring a high temperature of approximately 80°C to 100°C and a reaction time of more than ten hours, with a low yield (only 17.02%). Further, Example 9 of paragraph

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

[0007] MEJung et al. (see MEJung, S. Ouk, D. Yoo, et al., Structure-ActivityRelationship 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), they used the method in CN102757389B to carry out a microwave-assisted ring-closing reaction, but the yield was significantly higher than that in CN102757389B. This reflects that although compounds have the same functional groups (or structural fragments) but different specific structures have poor universality for the same method when preparing them.

[0008] Currently, there is no efficient and feasible synthetic method for pyridyl-substituted thiohydantoin drugs, which makes it impossible to guarantee the subsequent clinical use of the drugs and their subsequent production and supply. Summary of the Invention

[0009] The problem the invention aims to solve

[0010] The purpose of this invention is to provide a pyridyl-substituted thiohydantoin drug intermediate for the preparation of pyridyl-substituted thiohydantoin drugs (especially compounds of formula (VII)). This invention solves the defects of the prior art in the preparation of 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 for solving the problem

[0012] According to a first aspect of the invention, the 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 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, more preferably R is methyl, ethyl or tert-butyl, and 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, and more preferably A is selected from C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, and more preferably A is methyl, ethyl or tert-butyl.

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

[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: reacting a compound of formula (II) or a pharmaceutically acceptable salt thereof with ROH to obtain a compound of formula (I);

[0019]

[0020] Where R and A are as defined in equation (I).

[0021] Preferably, in method A, the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or tert-butanol. Simultaneously, the ROH also serves as a solvent used to disperse and dissolve the solid reactants in the reaction.

[0022] Preferably, in 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 method A, the compound of formula (II) or its pharmaceutically acceptable salt is esterified with methanol in the presence of thionyl chloride; further, 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, calculated based on the prototype compound.

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

[0025]

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

[0027] Furthermore, the hydrate of trichloro-tert-butanol is a trichloro-tert-butanol hemihydrate.

[0028] Preferably, the molar ratio of the compound of formula (III) to the trichlorotert-butanol is 1:1.1-3.0, for example, 1:1.5, 1:2, 1:2.5 or 1:3.0, calculated based on the prototype compound.

[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] Further, the solvent is any one or a mixture of aprotic solvents or protic solvents, wherein: the aprotic solvent includes chain-like or cyclic C1-C6 aliphatic ketones (e.g., acetone, butanone), chain-like or cyclic C1-C6 aliphatic ethers (e.g., tetrahydrofuran, dimethyl ether), etc., and the protic solvent includes chain-like or cyclic C1-C6 aliphatic alcohols (e.g., methanol, ethanol, isopropanol, tert-butanol), preferably the solvent is one or a combination of acetone, tetrahydrofuran, and tert-butanol.

[0031] Furthermore, the alkali 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, for example 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1, calculated based on 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 method A, the compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with chlorobutanol hemihydrate in the presence of acetone, tetrahydrofuran and sodium hydroxide, and after the reaction is completed, post-treatment is performed with hydrochloric acid; furthermore, 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, calculated based on the prototype compound; the molar ratio of the sodium hydroxide to the compound of formula (III) is 2-10:1, for example 3:1, 4:1 or 5:1.

[0035] Alternatively, preferably, method A further includes: reacting the compound of formula (III) or a pharmaceutically acceptable salt thereof with the compound of formula (IV) to obtain the 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, the molar ratio of the compound of formula (IV) 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, calculated based on the prototype compound.

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

[0040] Furthermore, the solvent is any one or more of aprotic solvents or protic solvents, wherein: the aprotic solvent includes aromatic hydrocarbons (e.g., benzene, toluene, dimethylbenzene, etc.), and the protic solvent includes chain or cyclic C1-C6 aliphatic alcohols (e.g., 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 alkoxide, an alkali metal carbonate, an alkali metal hydroxide, or a nitrogen-containing organic base, wherein: the alkali metal alkoxide 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 based on 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 undergoes a substitution reaction with 2-bromo-2-methylpropionic acid in the presence of isopropanol and triethylamine; further, 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, calculated based on the prototype compound; and 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 a third aspect of the present invention, the present invention provides a method for preparing a compound of formula (I) (method B), comprising: 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, the molar ratio of the compound of formula (V) 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, calculated based on the prototype compound.

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

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

[0050] Preferably, in 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, 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, calculated based on the prototype compound.

[0052] More preferably, in method B, the compound of formula (III) or a pharmaceutically acceptable salt thereof undergoes a substitution reaction with 2-bromo-2-methylpropionic acid in the presence of N,N-dimethylformamide and potassium carbonate; furthermore, the molar ratio of the methyl 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 2.0:1, preferably 2.0:1, calculated based on the prototype compound; and the molar ratio of the 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 a fourth aspect of the present invention, the present invention provides a method for preparing a compound of formula (I) (method C), comprising: reacting a compound of formula (III) or a pharmaceutically acceptable salt thereof with chlorobutanol or its hydrate in the presence of a base to obtain a compound of formula (II)-M, and then subjecting it to an esterification reaction with ROH to obtain a compound of formula (I);

[0054]

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

[0056] Furthermore, in the first step of method C, the hydrate of trichloro-tert-butanol is trichloro-tert-butanol hemihydrate.

[0057] Preferably, in the first step of method C, the molar ratio of the compound of formula (III) to the trichlorotert-butanol is 1:1.1-3.0, for example, 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 method C, the reaction is carried out in the presence of a solvent.

[0059] Furthermore, the solvent is any one or a mixture of aprotic solvents, wherein: the aprotic solvent includes chain-like or cyclic C1-C6 aliphatic ketones (e.g., acetone, butanone), chain-like or cyclic C1-C6 aliphatic ethers (e.g., tetrahydrofuran, dimethyl ether), etc., preferably the solvent is one or a combination of acetone, tetrahydrofuran.

[0060] Further, in the first step of 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 method C, the molar ratio of the base to the compound of formula (III) is 2-10:1, for example 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1, calculated based on the prototype compound.

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

[0063] Preferably, in the second step of method C, the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or tert-butanol. Simultaneously, the ROH also serves as a solvent used to disperse and dissolve the 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 method C, the compound of formula (II) or its pharmaceutically acceptable salt is esterified with methanol in the presence of thionyl chloride; further, 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, calculated based on the prototype compound.

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

[0067]

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

[0069] Furthermore, in method D, the hydrate of trichloro-tert-butanol is trichloro-tert-butanol hemihydrate.

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

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

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

[0073] Preferably, in method D, the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or tert-butanol. Simultaneously, the ROH also serves as a solvent used to disperse and dissolve the solid reactants in the reaction.

[0074] More preferably, in method D, the compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with chlorobutanol hemihydrate in the presence of sodium methoxide and methanol; furthermore, 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, calculated based on the prototype compound; and the molar ratio of the sodium methoxide to the compound of formula (III) is 2-10:1, for example 3:1, 4:1 or 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: reacting a compound of formula (I) or a pharmaceutically acceptable salt thereof with a compound of formula (VI) in a cyclization reaction to obtain a compound of formula (VII);

[0076]

[0077] in:

[0078] Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted with one or more halogens, and C1-C4 alkoxy optionally substituted with one or more halogens, preferably C1-C4 alkoxy, more preferably methoxy;

[0079] Y is selected from halogens, cyano groups, hydroxyl groups, and C1-C4 alkoxy groups optionally substituted with one or more halogens, preferably halogens, more preferably fluorine;

[0080] R and A are as defined in equation (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, for example 1.0:1.3, 1.0:1.5, 1.0:1.6 or 1.0:1.7.

[0082] Preferably, in the preparation method, the cyclization reaction is carried out in the presence of a polar organic solvent; further, the polar organic solvent is a nitrile, amide, sulfoxide, ester, or a mixture thereof, wherein: the nitrile solvent is acetonitrile, propionitrile, acrylonitrile, butyronitrile, etc.; the amide solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-ethylformamide, etc.; the sulfoxide solvent is dimethyl sulfoxide, diethyl sulfoxide, n-propyl sulfoxide, etc.; the ester solvent is ethyl acetate, propyl acetate, isopropyl acetate, etc.; 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 undergoes a cyclization reaction with 3-fluoro-4-isothiocyanate-2-methoxybenzonitrile, the reaction being carried out in the presence of DMF. Further, the molar ratio of the compound of formula (I) to 3-fluoro-4-isothiocyanate-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 a 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 thiogenous reagent as raw materials, and carrying out a cyclization reaction in an organic solvent in a one-pot manner to obtain a compound of formula (VII);

[0085]

[0086] in:

[0087] Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted with one or more halogens, and C1-C4 alkoxy optionally substituted with one or more halogens, preferably C1-C4 alkoxy, more preferably methoxy;

[0088] Y is selected from halogens, cyano groups, hydroxyl groups, and C1-C4 alkoxy groups optionally substituted with one or more halogens, preferably halogens, more preferably fluorine;

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

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

[0091] When Y is fluorine and is ortho-positioned to Z, Z is not methoxy; and

[0092] When Y is adjacent to Z, Y and Z are neither both fluorine nor both methoxy.

[0093] Preferably, in the preparation method, the thiogenin is selected from 1,1'-thiocarbonyl di(pyridine-2(1H)-one). Phosgene O,O'-Di(pyridin-2-yl)thiocarbonate bis(1H-imidazol-1-yl)meththione bis(1H-benzotriazol-1-yl)meththione Aromatic esters of thiochloroformic acid (e.g., phenyl thiochloroformic acid ester), preferably

[0094] Preferably, in the preparation method, the organic solvent is an alkyl ester, alkyl ether, cyclic ether, aryl ether, chlorinated hydrocarbon, aromatic hydrocarbon, halogenated aromatic hydrocarbon, alkyl ketone, C2-C6 nitrile, or a chain or cyclic amide, wherein: the alkyl ester is ethyl acetate or isopropyl acetate; the alkyl ether is diethyl 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; and 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 (I): compound (VIII): thiogenous reagent is 1:0.5-5:1-5, more 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 or seventh aspect, the compound of formula (I) is prepared by any one of the methods of the second to fifth aspects.

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

[0100]

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

[0102] More preferably, the method further includes: reacting the compound of formula (III) or a pharmaceutically acceptable salt thereof with the compound of formula (IV) to obtain the compound of formula (II);

[0103]

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

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

[0106]

[0107] in:

[0108] Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted with one or more halogens, and C1-C4 alkoxy optionally substituted with one or more halogens, preferably C1-C4 alkoxy, more preferably methoxy;

[0109] Y is selected from halogens, cyano groups, hydroxyl groups, and C1-C4 alkoxy groups optionally substituted with one or more halogens, preferably halogens, more preferably fluorine;

[0110] A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-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, and even more preferably methyl.

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

[0112]

[0113] in:

[0114] Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted with one or more halogens, and C1-C4 alkoxy optionally substituted with one or more halogens, preferably C1-C4 alkoxy, more preferably methoxy;

[0115] Y is selected from halogens, cyano groups, hydroxyl groups, and C1-C4 alkoxy groups optionally substituted with one or more halogens, preferably halogens, more preferably fluorine;

[0116] A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-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, and even more preferably methyl.

[0117] The effects of the invention

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

[0119] 1) This invention provides an intermediate for the preparation of thiohydantoin drugs, namely the compound of formula (I), which can be used to prepare thiohydantoin drugs as shown in formula (VII). This invention solves the defects of the existing production process, such as harsh conditions and low product yield in the ring-closing reaction. Compared with the method in CN102757389B, this method eliminates the use of hazardous raw materials such as sodium cyanide and trimethylcyanosilane, and the ring-closing yield is significantly improved, reaching more than 60%.

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

[0121] 3) This invention is the first to use the compound of formula (I) to directly undergo a cyclization reaction with 3-fluoro-4-isothiocyanate-2-methoxybenzonitrile to generate compound (VII). When compound (VII) is prepared by the method of this invention, compound (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 the kilogram level. The reaction effect is better than or basically equivalent to the small-scale level in the embodiments of the present invention. Detailed Implementation

[0123] The technical solution of the present invention will be further described below with reference to specific embodiments. Unless otherwise stated, the instruments, consumables, and reagents used in the following embodiments can all 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 detection condition one:

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

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

[0128] Washing time: 45 min;

[0129] Elution method: 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 detection condition two:

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

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

[0134] Washing time: 25 min;

[0135] Elution method: 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 detection condition three:

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

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

[0140] Washing time: 37 min;

[0141] Elution method: 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 (II) (A is methyl)

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

[0145]

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

[0147] After the raw materials disappeared, the mixture was filtered, and the filtrate was concentrated until no liquid remained. Acetone and dichloromethane were added for extraction and washing, and the layers were separated. The product layer (HPLC purity 89.3%) was collected, and a methanol solution of hydrogen chloride was added to adjust the pH to 6. The mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain a brownish-red oily substance (46.54 g, purity calculated to be 89.3% based on HPLC results of the corresponding sodium carboxylate). The product was used directly in subsequent reactions without further purification. The product weight exceeded the theoretical yield, suggesting that the product may contain residual methanol and unreacted chlorobutanol.

[0148] In addition, in Method 1, when performing the layering operation before adding the methanol solution of hydrogen chloride, the product is the corresponding sodium carboxylate, making the layering operation more difficult to handle, but 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 compound (III) (A is methyl) and compound (IV) (X is Br) as raw materials

[0151]

[0152] 32.4 g (1.0 eq) of 6-methylpyridin-3-amine was added to a reaction flask, followed by isopropanol and triethylamine (125 ml, approximately 3.0 eq). The mixture was stirred, and then 75.2 g (approximately 1.5 eq) of 2-bromo-2-methylpropionic acid was added. The mixture was refluxed under nitrogen protection for 3–4 h. Samples were taken for control and HPLC analysis was performed (using HPLC detection condition one, with area normalization statistics). The product compound (II) was 91.04% (retention time 6.69 min), and the reactant compound (III) was 3.89% (retention time 6.20 min). The reaction was then complete.

[0153] After cooling, the solution was filtered, and the filtrate was concentrated until solvent-free. Anhydrous methanol was added, and the solution was distilled under reduced pressure until the water content was ≤0.3%, yielding a reddish-brown oily substance, namely a methanol solution (95.2 g) of compound (II). HPLC analysis was performed (using HPLC detection condition one, area normalization method for statistical analysis). The product was 91.19% (retention time 6.75 min), and the starting material was 4.11% (retention time 6.24 min). The product was used directly in subsequent reactions without further purification.

[0154] During the early stages of research and development, the inventors, referring to the above reaction conditions, screened different types of bases and their amounts under different feed amounts (2-5 g) of compound (III), using isopropanol as the solvent and fixing the amount of 2-bromo-2-methylpropionic acid at 1.5 times the molar amount of compound (III) (i.e., 1.5 eq, based on compound (III)). Specifically, they screened triethylamine (3.0 eq), cesium carbonate (1.5 eq), potassium hydroxide (2.5 eq), sodium hydroxide (2.5 eq), and potassium tert-butoxide (2.5 eq). The effects of different types of bases on the reaction process were investigated using HPLC monitoring (HPLC detection condition 1, area normalization method for statistical analysis). The results were as follows: triethylamine (90.58%, retention time 9.79 min), cesium carbonate (87.47%, retention time 7.33 min), potassium hydroxide (88.05%, retention time 7.30 min), sodium hydroxide (82.89%, retention time 7.29 min), and potassium tert-butoxide (71.62%, retention time 6.80 min). The results showed that different types of bases could achieve excellent conversion rates, with nitrogen-containing organic base (triethylamine) being the most effective.

[0155] In addition, during the early stages of research and development, the inventors expanded the range of solvents (e.g., replacing isopropanol with methanol, toluene, etc.) to investigate the impact of different solvents on the reaction process. HPLC monitoring of the reaction control results (using HPLC detection condition one, statistical analysis using area normalization method) showed that the reaction results of methanol and toluene differed somewhat from those of isopropanol. The control detection results for the methanol system were 80.82% (retention time 9.66 min), and for the toluene system, they were 79.48% (retention time 9.64 min). Even without further optimization, these results generally met the requirements for later stages of the reaction.

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

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

[0158]

[0159] A methanol solution of compound (II) obtained by method 2 in Example 1 (equivalent to 58.3 g, 0.3 mol of compound (II)) was transferred to a reaction flask, stirred under nitrogen protection, and the temperature was controlled at 0-5°C. Thionyl chloride (107.1 g, 3.0 eq) was added dropwise. After the addition was complete, the mixture was stirred for 0.5-1 h, and the temperature was raised to 25-30°C. The reaction was carried out overnight.

[0160] The reaction mixture was concentrated at 40–50 °C until no solvent was distilled off. Methanol was added to the concentrated material, and the mixture was concentrated again to dryness. Methyl tert-butyl ether (400 ml) and water (400 g) were added, and the mixture was stirred for 10 min. Sodium carbonate was added to neutralize the mixture, and the pH was adjusted to 8–9. The mixture was allowed to stand and separated. The organic phase was collected, and the aqueous phase was extracted twice with methyl tert-butyl ether (200 ml * 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (200 ml), stirred for 10 min, allowed to stand and separated, and anhydrous sodium sulfate (45 g) was added to the organic phase. The mixture was stirred, filtered, and the filter cake was washed with methyl tert-butyl ether. The filtrate was concentrated until no solvent was distilled off, yielding a pale yellow oily substance (34.36 g, total yield of the two steps was 55.0%, purity of 95.64% and retention time of 14.78 min according to HPLC analysis (using HPLC analysis condition 1, area normalization method).

[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, prepare the salt (sodium salt) of compound (II) using compound (III) (A is methyl) and chlorobutanol or its hydrate (hemihydrate) as raw materials. Then, prepare compound (I) (R is methyl, A is methyl) using the salt (sodium salt) of compound (II) as raw materials.

[0163] Step (1):

[0164]

[0165] Acetone (200 ml), 6-methylpyridin-3-amine (21.6 g, 0.2 mol), and trichloro-tert-butanol hemihydrate (93.2 g, 0.5 mol) were added to a three-necked flask and stirred to dissolve under nitrogen protection. The system temperature was controlled below 30 °C. Sodium hydroxide (40.1 g, 1.0 mol) was added in portions. After the addition was complete, the mixture was stirred at 10 °C for 1 h and then heated to 25 °C for about 15 h to complete the reaction.

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

[0167] Step (2):

[0168]

[0169] Add the sodium salt (42g, about 0.2mol) of the compound of formula (II) obtained in step (1) and methanol (200ml) to a 500ml three-necked flask. Under nitrogen protection, stir to dissolve and control the temperature to ≤20℃. Add thionyl chloride (63.5g, 0.53mol) dropwise. After the addition is complete, raise the temperature to 25℃ and react for about 15h. The reaction is then complete.

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

[0171] Method 2 can achieve a high yield of compound (I), but the layering process in step (2) is difficult to operate, the moisture cannot be removed, and the scale-up production is difficult.

[0172] Method 3: Using compound (III) (A is methyl) and chlorobutanol or its hydrate (hemihydrate) as raw materials, compound (I) (R is methyl, A is methyl) is prepared in a one-pot process in the presence of alkali (sodium methoxide) and alcohol (methanol).

[0173]

[0174] 6-Methylpyridin-3-amine (0.5 g, 4.62 mmol) and methanol (5 mL) were added to a 50 mL reaction flask. Sodium methoxide (1.25 g, 23.15 mmol) was added with stirring at room temperature. The mixture was cooled in an ice-water bath. A mixture of chlorobutanol hemihydrate (2.16 g, 11.58 mmol) and methanol (2.5 mL) was added dropwise. After the addition was complete, the mixture was stirred for another 10 min. The system was then heated to 40 °C and kept at this temperature for 3 h. The reaction was monitored by TLC until it was complete. Based on the TLC spotting during the reaction, the area ratio of the product to the starting material was approximately 20%.

[0175] Experimental results show that the specific structure of compound (III) likely directly affects its suitability for the above one-pot reaction. Although compound (I) can also be obtained, the space for further optimization of yield is relatively limited.

[0176] Method 4: Using compound (III) (A is methyl) and compound (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 flask and heated to 50 °C with stirring. Potassium iodide (0.1 g, 0.60 mmol) was added, and the temperature was further increased to 70 °C. The reaction was allowed to proceed for approximately 5 hours, and the reaction was stopped by TLC monitoring. Based on the intra-reaction TLC spotting, the product-to-starter area ratio was approximately 20%.

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

[0180] Experimental results show that the specific structure of compound (III) likely directly affects its suitability for direct substitution reaction with the corresponding haloester. Although compound (I) can be obtained in the same way, the potential for further optimization in terms of yield is relatively limited.

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

[0182]

[0183] Compound (I)-1 (9.85 g, 0.047 mol) and DMF (13.3 ml) were added to a 50 ml reaction flask and stirred at room temperature until completely dissolved. Then, compound (VI)-1 (16.74 g, 1.7 eq) was added and the mixture was stirred at room temperature for 23 h. After the reaction was completed, ethyl acetate and water were added for extraction, and the organic layers were combined. The mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and rinsed with ethyl acetate. The filtrates were combined, and ethyl acetate was removed by rotary evaporation. DCM (30 ml) was added, stirred, and filtered. Ethanol was added to the obtained solid, and the mixture was filtered and the filter cake was dried to obtain 11.7 g of the target product, with a yield of 64.4% and an HPLC purity of 99.8% (HPLC detection under condition 3, retention time 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 mixtures thereof) under fixed reaction conditions (20-25℃) and molar ratio of compound (VI)-1 to compound (I)-1 (1.5 eq). Excellent conversion rates can be achieved in all cases. When acetonitrile is used as a solvent, heating at 40-80℃ is required for complete conversion.

Claims

1. A method for preparing a compound of formula (II), comprising: The compound of formula (III) or its pharmaceutically acceptable salt is subjected to a substitution reaction with the compound of formula (IV) to give the compound of formula (II); Where: X is Cl, Br or I; A is a C1-C6 alkyl group; The substitution reaction is carried out in the presence of a solvent, namely isopropanol; The substitution reaction is carried out in the presence of a base, which is a nitrogen-containing organic base.

2. The preparation method according to claim 1, characterized in that, The base is triethylamine.

3. The preparation method according to claim 1 or 2, characterized in that, A is a C1-C4 alkyl group.

4. The preparation method according to claim 3, characterized in that, A is methyl, ethyl, or tert-butyl.

5. The preparation method according to claim 4, characterized in that, A stands for methyl group.

6. The preparation method according to claim 1 or 2, characterized in that, X is either Cl or Br.

7. The preparation method according to claim 6, characterized in that, X is Br.

8. A method for preparing a compound of formula (I), comprising: Compound of formula (II) or its pharmaceutically acceptable salt is esterified with ROH to obtain compound of formula (I); in: The preparation method further includes the step of preparing compound (II) by the preparation method according to any one of claims 1-7; R is a C1-C6 alkyl group, and A is as defined in any one of claims 1 and 3-5.

9. The preparation method according to claim 8, characterized in that, R is a C1-C4 alkyl group.

10. The preparation method according to claim 9, characterized in that, R is methyl, ethyl, or tert-butyl.

11. The preparation method according to claim 10, characterized in that, R stands for methyl.

12. A method for preparing a compound of formula (VII), comprising: A compound of formula (I) or a pharmaceutically acceptable salt thereof undergoes a ring-closure reaction with a compound of formula (VI) to give a compound of formula (VII); in: The preparation method further includes the step of preparing compound (I) by the preparation method according to any one of claims 8-11; Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted with one or more halogens, and C1-C4 alkoxy optionally substituted with one or more halogens; Y is selected from halogens, cyano groups, hydroxyl groups, and C1-C4 alkoxy groups optionally substituted with one or more halogens; R is as defined in claim 8; A is as defined in any one of claims 8-11.

13. The preparation method according to claim 12, characterized in that, Z represents a C1-C4 alkoxy group.

14. The preparation method according to claim 13, characterized in that, Z stands for methoxy group.

15. The preparation method according to any one of claims 12-14, characterized in that, Y represents halogen.

16. The preparation method according to claim 15, characterized in that, Y stands for fluorine.

17. A method for preparing a compound of formula (VII), comprising: Using a compound of formula (I) or its pharmaceutically acceptable salt, a compound of formula (VIII) and a thiogenous reagent as raw materials, a one-pot cyclization reaction is carried out in an organic solvent to obtain a compound of formula (VII). in: The preparation method further includes the step of preparing compound (I) by the preparation method according to any one of claims 8-11; Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted with one or more halogens, and C1-C4 alkoxy optionally substituted with one or more halogens; Y is selected from halogens, cyano groups, hydroxyl groups, and C1-C4 alkoxy groups optionally substituted with one or more halogens; R is as defined in claim 8; A is as defined in any one of claims 8-11.

18. The preparation method according to claim 17, characterized in that, Z represents a C1-C4 alkoxy group.

19. The preparation method according to claim 18, characterized in that, Z stands for methoxy group.

20. The preparation method according to any one of claims 17-19, characterized in that, Y represents halogen.

21. The preparation method according to claim 20, characterized in that, Y stands for fluorine.

22. The preparation method according to claim 17, characterized in that, Z and Y also satisfy the following conditions: When Y is fluorine and is ortho-positioned to Z, Z is not methoxy; and When Y is adjacent to Z, Y and Z are neither both fluorine nor both methoxy.

23. A method for preparing a compound of formula (VII), comprising: A compound of formula (I) or a pharmaceutically acceptable salt thereof undergoes a ring-closure reaction with a compound of formula (VI) to give a compound of formula (VII); in: Z is a C1-C4 alkoxy group; Y represents a halogen; R is a C1-C6 alkyl group; A is a C1-C6 alkyl group; The cyclization reaction is carried out at room temperature; The ring-closing reaction is carried out in the presence of a polar organic solvent, which is an amide solvent, a sulfoxide solvent, an ester solvent, or a mixture thereof.

24. The preparation method according to claim 23, characterized in that, The amide solvent is N,N-dimethylformamide, N,N-dimethylacetamide, or N-ethylformamide; the sulfoxide solvent is dimethyl sulfoxide, diethyl sulfoxide, or n-propyl sulfoxide; and the ester solvent is ethyl acetate, propyl acetate, or isopropyl acetate.

25. The preparation method according to claim 23, characterized in that, The polar organic solvent is N,N-dimethylformamide, dimethyl sulfoxide, isopropyl acetate, or a mixture thereof.

26. The preparation method according to claim 23, characterized in that, The cyclization reaction was carried out at 20-25°C.

27. The preparation method according to any one of claims 23-26, characterized in that, R is a C1-C4 alkyl group.

28. The preparation method according to claim 27, characterized in that, R is methyl, ethyl, or tert-butyl.

29. The preparation method according to claim 28, characterized in that, R stands for methyl.

30. The preparation method according to any one of claims 23-26, characterized in that, A is a C1-C4 alkyl group.

31. The preparation method according to claim 30, characterized in that, A is methyl, ethyl, or tert-butyl.

32. The preparation method according to claim 31, characterized in that, A stands for methyl group.

33. The preparation method according to any one of claims 23-26, characterized in that, Z stands for methoxy group.

34. The preparation method according to any one of claims 23-26, characterized in that, Y stands for fluorine.

35. A method for preparing a compound of formula (VII), comprising: Using a compound of formula (I) or its pharmaceutically acceptable salt, a compound of formula (VIII) and a thiogenous reagent as raw materials, a one-pot cyclization reaction is carried out in an organic solvent to obtain a compound of formula (VII). in: Z is a C1-C4 alkoxy group; Y represents a halogen; R is a C1-C6 alkyl group; A is a C1-C6 alkyl group; Furthermore, R and A are not both methyl groups.

36. The preparation method according to claim 35, characterized in that, Z stands for methoxy group.

37. The preparation method according to claim 35, characterized in that, Y stands for fluorine.

38. The preparation method according to claim 35, characterized in that, Z and Y also satisfy the following conditions: When Y is fluorine and is ortho-positioned to Z, Z is not methoxy; and When Y is adjacent to Z, Y and Z are neither both fluorine nor both methoxy.

Images