An intermediate for thiohydantoin drugs and its preparation method and use

Abstract

The present application relates to a kind of thiohydantoin drug intermediates and its preparation method and purposes, specifically disclosed the compound of formula (I) and various preparation methods thereof, and first adopt the compound of formula (I) and the compound of formula (V) are prepared by ring closing reaction, such as the thiohydantoin drug shown in formula (VI).

Description

[0001] REFERENCE TO RELATED APPLICATIONS

[0002] The present application claims priority to the invention patent application filed in China on January 29, 2021, entitled "A Thiohydantoin Drug Intermediate and Its Preparation Method and Use", application number 202110128887.2, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present application belongs to the technical field of drug synthesis, and relates to a thiohydantoin drug intermediate and its preparation method and use. BACKGROUND

[0004] Thiohydantoin compounds can be used to prepare androgen receptor antagonists, and a variety of androgen receptor antagonist drugs have been reported, such as enzalutamide, apalutamide and proxalutamide. The synthesis methods of enzalutamide are disclosed in WO2006124118A1, WO2011106570A1 and CN103910679A; the synthesis method of apalutamide is disclosed in WO2007126765A2 and US20110003839A1; and the synthesis method of proxalutamide is disclosed in US9216957B2. Although enzalutamide, apalutamide and proxalutamide all contain thiohydantoin structural fragments, due to the large differences in other structural fragments, there are significant differences between the above-mentioned methods, and the versatility is not very ideal.

[0005]

[0006] The preparation process of proxalutamide disclosed in US9216957B2 is as shown below:

[0007]

[0008] The above route has many reaction steps, and includes many reaction steps which can be dangerous on a production scale and / or produce unacceptable levels of by-products in the final drug substance, for example, TMSCN (trimethylsilyl cyanide) is an extremely toxic, highly flammable chemical, which poses great challenges and risks to production and safety; in addition, in the ring-closing reaction step for constructing the thiohydantoin fragment, the yield of 15.7% is obviously unable to meet the needs of commercial production. Although M.E. Jung et al. (see M.E. 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) discloses that in the preparation of enzalutamide (i.e. compound 92 in the article), the ring-closing reaction can also be carried out by the above method, and the yield is significantly higher than that of US9216957B2, but microwave-assisted reaction is required, which also reflects that different compounds with the same functional group (or structural fragment) have poor universality for the same method in preparation, and a specific preparation method needs to be developed for a certain type of specific compound structure. SUMMARY

[0009] Problem to be solved by the invention

[0010] The object of the present application is to provide a thiohydantoin intermediate for drug use, and to prepare thiohydantoin drugs (especially to prepare plinabulin), which solves the defects of great toxicity of raw materials, low reaction yield and unsuitability for production expansion in the preparation process of thiohydantoin drugs in the prior art.

[0011] Solution for solving the problem

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

[0013]

[0014] wherein: R is selected from C1-C6 alkyl.

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

[0016] 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);

[0017]

[0018] Where R is defined as in equation (I).

[0019] Preferably, in method A, the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, with methanol being preferred.

[0020] Preferably, in method A, the esterification reaction is carried out in the presence of an acid; further, the acid is sulfuric acid, hydrochloric acid, phosphoric acid, or thionyl chloride, preferably thionyl chloride.

[0021] 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, 2.2:1, 2.5:1 or 3.0:1, preferably 3.0:1, calculated based on the prototype compound.

[0022] 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).

[0023]

[0024] Furthermore, the hydrate of trichloro-tert-butanol is a trichloro-tert-butanol hemihydrate.

[0025] Preferably, the molar ratio of the compound of formula (III) to the trichlorotert-butanol is 1:1.1-2.0, for example 1:1.4, 1:1.5 or 1:1.6, preferably 1:1.5, calculated based on the prototype compound.

[0026] 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.

[0027] Further, the solvent is any one or more of an aprotic solvent or a mixture of protic solvents, wherein: the aprotic solvent includes chain-like or cyclic C... 1-C6aliphatic ketones (e.g. acetone, butanone), chain or cyclic C1-C6aliphatic ethers (e.g. tetrahydrofuran, dimethyl ether) and the like, the protic solvents include chain or cyclic C1-C6aliphatic alcohols (e.g. methanol, ethanol, isopropanol, tert-butanol), preferably the solvent is one or a combination of acetone, tetrahydrofuran, tert-butanol.

[0028] Further, the base is an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide; 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, preferably 5:1, calculated as the prototype compound.

[0029] Further, the acid is an inorganic acid or an organic acid, preferably an inorganic acid, for example hydrochloric acid, phosphoric acid or sulfuric acid.

[0030] More preferably, in the method A, the compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with t-butyl hydroperoxide, the reaction is carried out in the presence of a solvent and a base, after the reaction is completed, an acid is used for the post-treatment; further, the molar ratio of the compound of formula (III) to the t-butyl hydroperoxide is 1:1.1-2.0, for example 1:1.4, 1:1.5 or 1:1.6; 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.

[0031] Correspondingly, the present application also provides a preparation method of a compound of formula (II), which comprises: reacting a compound of formula (III) or a pharmaceutically acceptable salt thereof with t-butyl hydroperoxide or a hydrate thereof to obtain a compound of formula (II).

[0032]

[0033] Further, the hydrate of t-butyl hydroperoxide is t-butyl hydroperoxide hemihydrate.

[0034] Preferably, the molar ratio of the compound of formula (III) to the t-butyl hydroperoxide is 1:1.1-2.0, for example 1:1.4, 1:1.5 or 1:1.6, preferably 1:1.5, calculated as the prototype compound.

[0035] 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 the post-treatment.

[0036] Further, the solvent is any one or a mixture of more than one of aprotic solvents or protic solvents, wherein: the aprotic solvents include chain or cyclic C1-C6aliphatic ethers (e.g. tetrahydrofuran, dimethyl ether), C6aliphatic ketones (e.g. acetone, butanone) and the like, the protic solvents include chain or cyclic C1-C6aliphatic alcohols (e.g. methanol, ethanol, isopropanol, tert-butanol), preferably the solvent is one or a combination of acetone, tetrahydrofuran, tert-butanol. 1-C6 aliphatic ketones (e.g., acetone, butanone), chain- or cyclic C1-C6 aliphatic ethers (e.g., tetrahydrofuran, dimethyl ether), etc., wherein the protic solvent includes chain- or cyclic C1-C6 aliphatic alcohols (e.g., methanol, ethanol, isopropanol, tert-butanol), preferably one or a combination of acetone, tetrahydrofuran, and tert-butanol.

[0037] Further, the alkali is an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide; preferably, the molar ratio of the alkali 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, preferably 5:1, calculated based on the prototype compound.

[0038] Furthermore, the acid is an inorganic acid or an organic acid, preferably an inorganic acid, such as hydrochloric acid, phosphoric acid, or sulfuric acid.

[0039] More preferably, in the method, the compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with chlorobutanol hemihydrate in the presence of a mixed solvent 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 1:1.1-2.0, for example 1:1.4, 1:1.5 or 1:1.6, 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, 5:1, 6:1, 7:1 or 8:1.

[0040] 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 (IV) to obtain a compound of formula (I);

[0041]

[0042] Where: X is Cl, Br or I; R is as defined in formula (I).

[0043] Preferably, in method B, X is Cl or Br, preferably Br; R is methyl or isopropyl, preferably methyl.

[0044] Preferably, in method B, the substitution reaction is carried out in the presence of a base; further, the base is an alkali metal alkoxide or a nitrogen-containing organic base, wherein: the alkali metal alkoxide includes sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; the nitrogen-containing organic base includes N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), etc.; preferably, a nitrogen-containing organic base, such as N,N-diisopropylethylamine.

[0045] More preferably, in the method B, the compound of formula (III) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with a compound of formula (IV), X is Br, R is methyl, in the presence of N,N-diisopropylethylamine.

[0046] According to a fourth aspect of the present application, the present application provides a method (method C) for preparing a compound of formula (I), which comprises: subjecting a compound of formula (III) or a pharmaceutically acceptable salt thereof to a substitution reaction with a compound of formula (IV-OH) to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof, and then subjecting the compound of formula (II) or a pharmaceutically acceptable salt thereof to an esterification reaction with ROH to obtain a compound of formula (I);

[0047]

[0048] wherein: X is Cl, Br or I; R is as defined in formula (I).

[0049] Preferably, in the method C, X is Cl or Br, preferably Br; R is methyl or isopropyl, preferably methyl.

[0050] Preferably, in the method C, the substitution reaction is carried out in the presence of a base; further, the base is an alkali metal alcoholate or a nitrogen-containing organic base, wherein: the alkali metal alcoholate includes sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; the nitrogen-containing organic base includes triethylamine, N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), etc.; preferably a nitrogen-containing organic base, such as diisopropylethylamine or triethylamine. Preferably, in the method C, the esterification reaction is carried out in the presence of an acid; further, the acid is sulfuric acid, hydrochloric acid, phosphoric acid or thionyl chloride, preferably thionyl chloride.

[0051] More preferably, in the method C, the compound of formula (III) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with a compound of formula (IV-OH), X is Br, R is methyl, in the presence of N,N-diisopropylethylamine and / or triethylamine to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof, and then the compound of formula (II) or a pharmaceutically acceptable salt thereof is subjected to an esterification reaction with ROH in the presence of thionyl chloride to obtain a compound of formula (I).

[0052] According to a fifth aspect of the present application, the present application provides a method for preparing a compound of formula (VI), which comprises: subjecting a compound of formula (I) or a pharmaceutically acceptable salt thereof to a ring closure reaction with a compound of formula (V) to obtain a compound of formula (VI);

[0053]

[0054] wherein: Y is selected from the group consisting of hydrogen, halogen, C1-C3alkoxy, hydroxyl, CF3O and cyano; Z is selected from the group consisting of halogen, cyano, C1-C4alkyl, C1-C4alkoxy, C1-C4alkyl optionally substituted with one or more halogens and C1-C4alkoxy optionally substituted with one or more halogens; R is as defined in formula (I).

[0055] Preferably, in said process of preparation, Y is H or F; Z is CF3or CH3O; R is as defined in formula (I).

[0056] More preferably, in said process of preparation, Y is H or F, preferably F; Z is CF3or CH3O, preferably CF3; R is methyl or isopropyl, preferably methyl.

[0057] Preferably, in said process of preparation, the molar ratio of said compound of formula (I) to said compound of formula (V) is 1.0:1.0-5.0, for example 1.0:2.0, 1.0:2.2, 1.0:2.5 or 1.0:3.0, preferably 1.0:2.2.

[0058] Preferably, in said process of preparation, said ring closure reaction is carried out in the presence of a polar organic solvent; further, said polar organic solvent is selected from the group consisting of acetonitrile (ACN), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), tetrahydrofuran (THF) and 2-methyltetrahydrofuran (2-MTHF), preferably N,N-dimethylformamide.

[0059] More preferably, in said process of preparation, after the reaction is completed, said compound of formula (VI) is purified by salification with an acid; further, the acid forming said acid addition salt is an inorganic acid or an organic acid, wherein: said inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; said organic acid is formic acid, acetic acid, oxalic acid, propionic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, succinic acid, tartaric acid, 1,5-naphthalenedisulfonic acid, citric acid or nicotinic acid, preferably hydrochloric acid and / or 1,5-naphthalenedisulfonic acid.

[0060] Preferably, in the above process of preparation, said compound of formula (I) is prepared from said process A.

[0061] According to a sixth aspect of the present application, the present application provides the use of a compound of formula (I) for the preparation of a compound of formula (VI);

[0062]

[0063] wherein: Y is selected from the group consisting of hydrogen, halogen, C1-C3 alkoxy, hydroxyl, CF3O and cyano; Z is selected from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl optionally substituted with one or more halogens and C1-C4 alkoxy optionally substituted with one or more halogens.

[0064] Preferably, in the use, Y is H or F, and Z is CF3 or CH3O.

[0065] More preferably, in the use, Y is F, and Z is CF3.

[0066] According to a seventh aspect of the present application, the present application provides use of a compound of formula (I) as an impurity control and / or standard for analysis of a compound of formula (VI).

[0067]

[0068] wherein: Y is selected from the group consisting of hydrogen, halogen, C1-C3 alkoxy, hydroxyl, CF3O and cyano; Z is selected from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl optionally substituted with one or more halogens and C1-C4 alkoxy optionally substituted with one or more halogens.

[0069] Preferably, in the use, Y is H or F, and Z is CF3 or CH3O.

[0070] More preferably, in the use, Y is F, and Z is CF3.

[0071] Effects of the invention

[0072] Compared with the prior art, the present application has the following beneficial effects:

[0073] 1) The present application provides a thiohydantoin drug intermediate, i.e. a compound of formula (I), which can be used for preparing a thiohydantoin drug such as a compound of formula (VI), solving the defects of harsh reaction conditions and low product yield in the ring-closing reaction of the existing production process; compared with the preparation method in US9216957B2 (especially the preparation method of prucalopride), the present application not only avoids the use of dangerous reagents (such as TMSCN, metal salt, etc.), but also has a ring-closing reaction yield of up to 80% or more, which is significantly improved.

[0074] 2) The present application first uses a compound of formula (III) or a pharmaceutically acceptable salt thereof to prepare a compound of formula (II) with trichloro-t-butyl alcohol or a hydrate thereof, which has a high yield, and provides a basis for the production scale-up of the compound of formula (I) and its subsequent application (such as the preparation of a compound of formula (VI), especially prucalopride).

[0075] 3) The present application first adopts the direct cyclization of the compound of formula (I) with 4-cyano-2-fluoro-3-(trifluoromethyl)phenyl isothiocyanate to generate prucalopride, which belongs to the key impurity quality control point of prucalopride. When the method of the present application is used to prepare prucalopride, the compound of formula (I) can also be used as a key organic impurity for quality control analysis. BRIEF DESCRIPTION OF DRAWINGS

[0076] Figure 1 The reaction formula for the cyclization reaction of the compound as shown in formula (V) with the compound as shown in formula (I) to generate the thiohydantoin drug as shown in formula (VI). DETAILED DESCRIPTION

[0077] <Intermediate for thiohydantoin drug>

[0078] The present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0079]

[0080] wherein: R can be selected from C1-C6 alkyl.

[0081] In an embodiment of the present application, R in the compound of formula (I) can be selected from C1-C4 alkyl, preferably methyl.

[0082] <Method for preparing intermediate for thiohydantoin drug>

[0083] Firstly, the present application provides a method for preparing the compound of formula (I) (Method A).

[0084] Method A comprises: the compound of formula (II) or a pharmaceutically acceptable salt thereof can be subjected to esterification with ROH to obtain the compound of formula (I).

[0085]

[0086] wherein: R can be selected from C1-C6 alkyl, preferably methyl.

[0087] In an embodiment of the present application, ROH in Method A can be methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, preferably methanol.

[0088] In an embodiment of the present application, the esterification reaction in Method A can be carried out in the presence of an acid; further, the acid can be sulfuric acid, hydrochloric acid, phosphoric acid or sulfurous acid chloride, preferably sulfurous acid chloride.

[0089] In an embodiment of the present application, the compound of formula (II) or a pharmaceutically acceptable salt thereof in Method A can be subjected to esterification reaction with methanol in the presence of thionyl chloride; further, the molar ratio of thionyl chloride to the compound of formula (II) can be 1.5-5.0:1, preferably 3.0:1, calculated on the basis of the prototype compound.

[0090] In a preferred embodiment of the present application, Method A further comprises: the compound of formula (III) or a pharmaceutically acceptable salt thereof can be subjected to reaction (Jocic reaction) with trichloro-tert-butanol or a hydrate thereof to obtain the compound of formula (II).

[0091]

[0092] In an embodiment of the present application, the hydrate of trichloro-tert-butanol in Method A can be trichloro-tert-butanol hemihydrate.

[0093] In an embodiment of the present application, the molar ratio of the compound of formula (III) to trichloro-tert-butanol in Method A can be 1:1.1-2.0, preferably 1:1.5, calculated on the basis of the prototype compound.

[0094] In an embodiment of the present application, the reaction (Jocic reaction) in Method A can be carried out in the presence of a solvent and a base, and after the reaction is completed, an acid can be used for post-treatment; further, the solvent can be any one or a mixture of more than one of aprotic solvents or protic solvents, wherein: the aprotic solvents can include chain or cyclic C1-C6 aliphatic ketones (such as acetone, butanone), chain or cyclic C1-C6 aliphatic ethers (such as tetrahydrofuran, dimethyl ether) and the like, and the protic solvents can include chain or cyclic C1-C6 aliphatic alcohols (such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol), preferably one or a combination of acetone, tetrahydrofuran, tert-butyl alcohol; further, the base can be an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide; preferably, the molar ratio of the base to the compound of formula (III) can be 2-10:1, preferably 5:1, calculated on the basis of the prototype compound; further, the acid can be an inorganic acid or an organic acid, preferably an inorganic acid (such as hydrochloric acid, phosphoric acid or sulfuric acid).

[0095] In a preferred embodiment of the present application, the reaction (Jocic reaction) of the compound of formula (III) or a pharmaceutically acceptable salt thereof with trichloro-tert-butanol hemihydrate in Method A can be carried out in the presence of a mixture of acetone / tetrahydrofuran and sodium hydroxide, and after the reaction is completed, hydrochloric acid can be used for post-treatment; further, the molar ratio of the compound of formula (III) to trichloro-tert-butanol hemihydrate is 1:1.1-2.0, and the molar ratio of the base to the compound of formula (III) is 2-10:1, calculated on the basis of the prototype compound.

[0096] In addition, the above method of reacting a compound of formula (III) or a pharmaceutically acceptable salt thereof with t-butyl hypochlorite or a hydrate thereof (Jocic reaction) to obtain a compound of formula (II) is also within the scope of the present application.

[0097] Secondly, the present application provides a method (Method B) for preparing a compound of formula (I).

[0098] Method B comprises: a compound of formula (III) or a pharmaceutically acceptable salt thereof can be subjected to a substitution reaction with a compound of formula (IV) to obtain a compound of formula (I).

[0099]

[0100] wherein: X can be Cl, Br or I; R can be selected from C1-C6 alkyl, preferably methyl.

[0101] In an embodiment of the present application, in Method B, X can be Cl or Br, preferably Br; R can be methyl or isopropyl, preferably methyl.

[0102] In an embodiment of the present application, the substitution reaction in Method B can be carried out in the presence of a base; further, the base can be an alkali metal alcoholate or a nitrogen-containing organic base, wherein: the alkali metal alcoholate can include sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; the nitrogen-containing organic base can include triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, etc.; preferably the nitrogen-containing organic base (such as N,N-diisopropylethylamine or triethylamine).

[0103] In a preferred embodiment of the present application, in Method B, the compound of formula (III) or a pharmaceutically acceptable salt thereof can be subjected to a substitution reaction with a compound of formula (IV), X can be Br, R can be methyl, and the substitution reaction can be carried out in the presence of N,N-diisopropylethylamine.

[0104] Finally, the present application provides a method (Method C) for preparing a compound of formula (I).

[0105] Method C comprises: a compound of formula (III) or a pharmaceutically acceptable salt thereof can be subjected to a substitution reaction with a compound of formula (IV-OH) to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof, and then subjected to an esterification reaction with ROH to obtain a compound of formula (I).

[0106]

[0107] wherein: X can be Cl, Br or I; R can be selected from C1-C6 alkyl, preferably methyl.

[0108] In an embodiment of the present application, X in Method C can be Cl or Br, preferably Br; R can be methyl or isopropyl, preferably methyl.

[0109] In an embodiment of the present application, the substitution reaction in Method C can be carried out in the presence of a base; further, the base can be an alkali metal alcoholate or a nitrogen-containing organic base, wherein: the alkali metal alcoholate can include sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and the like; the nitrogen-containing organic base can include triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, and the like; preferably the nitrogen-containing organic base (such as triethylamine or diisopropylethylamine); the esterification reaction in Method C can be carried out in the presence of an acid; further, the acid is sulfuric acid, hydrochloric acid, phosphoric acid, or thionyl chloride, preferably thionyl chloride.

[0110] In a preferred embodiment of the present application, the compound of formula (III) or a pharmaceutically acceptable salt thereof in Method C can be subjected to a substitution reaction with a compound of formula (IV-OH), X can be Br, R can be methyl, the substitution reaction can be carried out in the presence of N,N-diisopropylethylamine to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof, and then subjected to an esterification reaction with ROH, the esterification reaction can be carried out in the presence of thionyl chloride to obtain a compound of formula (I).

[0111] <Thiohydantoin drugs>

[0112] The present application provides a preparation method of a compound of formula (VI) (thiohydantoin drug).

[0113] The preparation method comprises: a compound of formula (I) or a pharmaceutically acceptable salt thereof can be subjected to a ring closure reaction with a compound of formula (V) to obtain a compound of formula (VI);

[0114]

[0115] wherein: Y can be selected from hydrogen, halogen, C1-C3 alkoxy, hydroxyl, CF3O, and cyano; Z can be selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl optionally substituted with one or more halogens, and C1-C4 alkoxy optionally substituted with one or more halogens; R can be selected from C1-C6 alkyl, preferably methyl.

[0116] In an embodiment of the present application, Y in the preparation method can be H or F; Z can be CF3 or CH3O; R can be selected from C1-C6 alkyl, preferably methyl.

[0117] In an embodiment of the present application, Y in the preparation method can be H or F, preferably F; Z can be CF3 or CH3O, preferably CF3; R can be methyl or isopropyl, preferably methyl.

[0118] In an embodiment of the present application, the molar ratio of the compound of formula (I) to the compound of formula (V) in the preparation method can be 1.0:1.0-5.0, preferably 1.0:2.2.

[0119] In an embodiment of the present application, the ring-closing reaction in the preparation method can be carried out in the presence of a polar organic solvent; further, the polar organic solvent can be selected from acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran and 2-methyltetrahydrofuran, preferably N,N-dimethylformamide.

[0120] In an embodiment of the present application, the compound of formula (VI) in the preparation method can be purified by acid salt formation; further, the acid for forming the acid addition salt can be an inorganic acid or an organic acid, wherein: the inorganic acid can be hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; the organic acid can be formic acid, acetic acid, oxalic acid, propionic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, succinic acid, tartaric acid, 1,5-naphthalenedisulfonic acid, citric acid or nicotinic acid, preferably hydrochloric acid and / or 1,5-naphthalenedisulfonic acid.

[0121] In an embodiment of the present application, the compound of formula (I) in the preparation method can be prepared by method A, i.e. the preparation method of the compound of formula (VI) can comprise the following steps:

[0122] The compound of formula (III) or a pharmaceutically acceptable salt thereof can be reacted with trichloro-tert-butanol or a hydrate thereof to obtain the compound of formula (II);

[0123]

[0124] Preferably, the preparation method can further comprise the following step: the compound of formula (II) or a pharmaceutically acceptable salt thereof can be esterified with ROH to obtain the compound of formula (I);

[0125]

[0126] Preferably, the preparation method can further comprise the following step: the compound of formula (I) or a pharmaceutically acceptable salt thereof can be subjected to ring-closing reaction with the compound of formula (V) to obtain the compound of formula (VI);

[0127]

[0128] wherein:

[0129] Y can be selected from hydrogen, halogen, C1-C3alkoxy, hydroxyl, CF3O and cyano, preferably H or F, more preferably F;

[0130] Z can be selected from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl optionally substituted with one or more halogens and C1-C4 alkoxy optionally substituted with one or more halogens, preferably CF3 or CH3O, more preferably CF3;

[0131] R can be selected from the group consisting of C1-C6 alkyl, preferably C1-C4 alkyl, more preferably methyl.

[0132] Use of thiohydantoin pharmaceutical intermediates

[0133] The present invention provides the use of a compound of formula (I) in the preparation of a compound of formula (VI);

[0134]

[0135] wherein: Y can be selected from the group consisting of hydrogen, halogen, C1-C3 alkoxy, hydroxy, CF3O and cyano; Z can be selected from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl optionally substituted with one or more halogens and C1-C4 alkoxy optionally substituted with one or more halogens.

[0136] In one embodiment of the present invention, Y in the use can be H or F and Z can be CF3 or CH3O.

[0137] In a preferred embodiment of the present invention, Y in the use can be F and Z can be CF3.

[0138] Use of thiohydantoin pharmaceutical intermediates

[0139] The present invention provides the use of a compound of formula (I) as an impurity control and / or standard for the analysis of a compound of formula (VI);

[0140]

[0141] wherein: Y can be selected from the group consisting of hydrogen, halogen, C1-C3 alkoxy, hydroxy, CF3O and cyano; Z can be selected from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl optionally substituted with one or more halogens and C1-C4 alkoxy optionally substituted with one or more halogens.

[0142] In one embodiment of the present invention, Y in the use can be H or F and Z can be CF3 or CH3O.

[0143] In a preferred embodiment of the present invention, Y in the use can be F and Z can be CF3.

[0144] The technical solutions of the present application will be further described below in combination with the drawings and specific examples. Unless otherwise specified, the instruments, consumables and reagents used in the following examples can be obtained through conventional commercial means.

[0145] The HPLC conditions for content detection or purity analysis in the examples are as follows:

[0146] Chromatographic column: Agilent ZORBAX SB-C18 (4.6 x 150 mm, 3.5 μm);

[0147] Mobile phase: binary mobile phase system, mobile phase A is 0.02 vol% trifluoroacetic acid aqueous solution, mobile phase B is acetonitrile;

[0148] Elution time: 18 min;

[0149] Elution mode: gradient elution, the specific procedure is shown in Table 1;

[0150] Table 1. Gradient elution table

[0151] Time (min) Mobile phase A (vol%) Mobile phase B (vol%) 0.00 90 10 1.000 90 10 4.000 70 30 6.000 30 70 8.000 0 100 13.000 0 100 13.010 90 10 18.000 90 10

[0152] Detection wavelength: 220 nm.

[0153] Example 1: Preparation of the compound of formula (II).

[0154] Method 1: using trichloro-t-butyl alcohol or its hydrate as raw material

[0155]

[0156] Into a reaction bottle, a compound of formula (III) (4.50 g, about 22.2 mmol) and trichloro-t-butyl alcohol hemihydrate (6.2 g, about 1.5 eq) dissolved in a mixture of acetone and tetrahydrofuran (50 ml, equal volume of acetone and tetrahydrofuran) were added, stirred and dissolved, then sodium hydroxide (4.4 g, about 5.2 eq) was added in batches, and the reaction was carried out at 10-30°C for 12-18 h.

[0157] After the reaction was completed, filtration was carried out, the filter cake was washed with 10 ml of acetone, and the washing liquid and filtrate were collected and concentrated to obtain an oil. The oil was washed with an appropriate amount of a mixture of acetone / dichloromethane (the oil was insoluble in acetone / dichloromethane, and the main purpose of the washing was to remove the unreacted compound of formula (III)). After washing, the oil was separated, methanol was added and stirred, and a methanolic hydrochloric acid solution was added dropwise at room temperature, the pH of the system was adjusted to 4-6, filtration was carried out, and the filtrate was concentrated to obtain 5.85 g of the compound of formula (II) with a yield of 91.3%.

[0158] 1H-NMR (400 MHz, DMSO-d6): δ 7.97 (s, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.08 (s, 1H), 3.17 (s, 1H), 2.80 (dt, J = 15.3, 7.5 Hz, 4H), 2.05 (p, J = 7.5 Hz, 2H), 1.47 (s, 6H).

[0159] For Method 1, sodium hydroxide used as base was replaced by triethylamine, sodium methoxide, potassium carbonate and cesium carbonate to investigate the effect of different kinds of base on the reaction progress, and the results are shown in Table 2.

[0160] Table 2. Effect of different bases on the reaction progress

[0161]

[0162] As can be seen from Table 2, in Method 1, the yield of the reaction is more ideal when alkali metal hydroxide is used as base.

[0163] For Method 1, acetone / tetrahydrofuran used as solvent was replaced by N-methylpyrrolidone, N,N-dimethylformamide, 1,4-dioxane, dimethyl ether / water, isopropanol and tert-butanol to investigate the effect of different kinds of solvent on the reaction progress, and the results are shown in Table 3.

[0164] Table 3. Effect of different solvents on the reaction progress

[0165]

[0166] As can be seen from Table 3, in Method 1, the yield of the reaction is more ideal when aliphatic ketone, ether and / or alcohol, etc. is used as solvent.

[0167] Method 2: using compound of formula (IV-OH) (X is Br) as raw material

[0168]

[0169] Into a reaction bottle, compound of formula (III) (200 mg, 0.984 mmol), 2-bromoisobutyric acid (246 mg, 1.476 mmol), triethylamine (300 mg, 2.95 mmol) and isopropanol (2.5 ml) were added, stirred and dissolved, and reacted at 85°C for 5h. According to the peak area percentage calculated by HPLC detection, compound of formula (II) was 70%, and compound of formula (III) was 30%, without further separation and purification.

[0170] Alternatively, a pharmaceutically acceptable salt of the compound of formula (III) (e.g. 1,5-naphthalenedisulfonate salt) can also be used as the starting material, the free form of the compound of formula (III) is obtained by adjusting the pH with a basic substance (e.g. sodium carbonate) and using a two-phase extraction system (e.g. water / dichloromethane), and then the compound of formula (II) is prepared.

[0171] Example 2: Preparation of the compound of formula (I).

[0172] Method 1: using the compound of formula (II) and an alcohol as the starting material

[0173]

[0174] 1-1: R is methyl

[0175]

[0176] The compound of formula (II) (5.08 g, 17.57 mmol) was dissolved in 50 ml of methanol, stirred at room temperature, then cooled to 0-10°C, and sulfurous chloride (52.7 mmol, about 3.0 eq) was added dropwise, and the stirring was continued overnight.

[0177] The stirring was stopped, the reaction solution was rotary evaporated at 50°C, 50 ml of methyl tert-butyl ether and 50 ml of water were added, and the stirring was continued at room temperature until complete dissolution, sodium carbonate was added, the pH was adjusted to 8-9, the layers were separated, the aqueous layer was extracted with methyl tert-butyl ether (30 ml*2), the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain the target product 4.1 g with a yield of 77.0%.

[0178] 1 H-NMR (400 MHz, DMSO-d6): δ 7.96 (d, J = 0.9 Hz, 1H), 7.78 (dd, J = 3.0, 0.7 Hz, 1H), 7.08 (d, J = 0.8 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.67 (dd, J = 8.4, 2.9 Hz, 1H), 6.03 (s, 1H), 3.61 (s, 3H), 2.73 (t, J = 7.5 Hz, 2H), 2.63-2.56 (m, 2H), 1.99 (p, J = 7.5 Hz, 2H), 1.44 (s, 6H).

[0179] 1-2: R is isopropyl

[0180]

[0181] Compound (II) (200 mg, 0.691 mmol) was mixed with 2 ml of isopropanol, and thionyl chloride (approximately 3.0 eq) was added dropwise at 5-10 °C. After the addition was complete, the temperature was raised to 35 °C and the reaction was allowed to proceed overnight. LC-MC analysis showed that the content of the target product was only 10.8% based on the peak area percentage. Thionyl chloride (approximately 6 eq) was added, and the temperature was raised to 70-80 °C and the reaction was allowed to proceed overnight. LC-MC analysis showed that the content of the target product was 74.7% based on the peak area percentage.

[0182] After the reaction was completed, the mixture was concentrated to dryness, and 5 ml of water and 10 ml of methyl tert-butyl ether were added. The pH was then adjusted to 9 with sodium carbonate, and the layers were separated. The aqueous layer was extracted with methyl tert-butyl ether (10 ml * 2). The organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by preparative thin-layer chromatography to obtain the target product with a yield of 43.7% and an HPLC purity of 93.3%.

[0183] 1 H-NMR (400MHz, DMSO-d6) δ7.96(d,J=0.9Hz,1H),7.79(d,J=2.8Hz,1H),7.08(d,J=0.9Hz,1H),6.93(d,J=8.4Hz,1H),6.70(dd,J=8.4,2.9Hz,1H) ,5.96(s,1H),4.87(hept,J=6.2Hz,1H),2.71(t,J=7.5Hz,2H),2.59(t,J=7.5Hz,2H),1.98(p,J=7.6Hz,2H),1.43(s,6H),1.08(d,J=6.2Hz,6H).

[0184] Method 2: Using compounds of formula (III) and formula (IV) (X is Br, R is methyl) as raw materials

[0185]

[0186] Compound (III) (100 mg, 0.492 mmol), methyl 2-bromoisobutyrate (178 mg, 2 eq), and N,N-diisopropylethylamine (95 mg, 1.5 eq) were placed in a sealed container and reacted at 110 °C for 2 h. HPLC analysis showed that the target product comprised 51.2% of the total product, calculated based on peak area percentage.

[0187] For Method 2, replacing N,N-diisopropylethylamine, which is used as the base, with 4-dimethylaminopyridine yields comparable results.

[0188] Method 3: Compound of formula (I) is prepared in a one-pot reaction with chlorobutanol or its hydrate under alkaline conditions using compound (III).

[0189]

[0190] 3-1: using methanol as solvent

[0191] Take the compound of formula (III) 100mg, methanol 2ml and semi-hydrated trichloro-t-butyl alcohol 138mg, add part of sodium hydroxide 102mg (about 2eq) at room temperature, after 30min, add methanol 2ml, after 20min, add the rest of sodium hydroxide, react at room temperature for more than 12h. HPLC detection, according to the peak area percentage, the target product is 13.8%, the compound of formula (III) is 19.7%, the intermediate transition state, i.e. the compound of formula (II) is 47.4%, and the rest is unknown impurities.

[0192] 3-2: using acetone as solvent

[0193] Take the compound of formula (III) 100mg, methanol 2ml and semi-hydrated trichloro-t-butyl alcohol 138mg, add part of sodium hydroxide 102mg (about 2eq) at room temperature, after 30min, add methanol 2ml, after 20min, add the rest of sodium hydroxide, react at room temperature for more than 12h. HPLC detection, according to the peak area percentage, the target product is 13.8%, the compound of formula (III) is 19.7%, the intermediate transition state, i.e. the compound of formula (II) is 47.4%, and the rest is unknown impurities.

[0194] 3-3: using dichloromethane as solvent

[0195] Take dichloromethane 3ml and semi-hydrated trichloro-t-butyl alcohol (275mg, 3eq), add sodium hydroxide (197mg, 10eq) at room temperature, mix and stir for 30min, then add the compound of formula (III) 100mg, stir for 20min, then add methanol (157mg, 10eq), heat to reflux, and react for more than 12h. HPLC detection, according to the peak area percentage, the target product is 4.3%, the intermediate transition state, i.e. the compound of formula (II) is 90.5%, and the rest is unknown impurities.

[0196] From the above, the yield of the method for preparing the compound of formula (I) by one-pot method using trichloro-t-butyl alcohol and the compound of formula (III) as raw materials under alkaline conditions is low; compared with this, the yield of the method for preparing the compound of formula (I) by two-step method in the present application is significantly improved.

[0197] Example Three: Preparation of the compound of formula (VI).

[0198]

[0199] Preparation 1 of Example Compound 1:

[0200]

[0201] To the compound of formula (I)-1 (100 mg, 0.302 mmol), the compound of formula (V)-1 (163 mg, 2.2 eq) was added into N,N-dimethylformamide 0.5 ml, stirred at room temperature, and reacted overnight. After the reaction was completed, methyl tert-butyl ether 10 ml and water 5 ml were added to extract the layers, the water layer was extracted with methyl tert-butyl ether (10 ml*2), the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by preparative thin layer chromatography to obtain the target product 130 mg with a yield of 83.2% and a HPLC purity of 90.3%.

[0202] Preparation 2 of Example Compound 1:

[0203]

[0204] To the compound of formula (I)-2 (3.63 g, 12 mmol), the compound of formula (V)-1 (6.5 g, 26.4 mmol) was added into N,N-dimethylformamide 100 ml, stirred at room temperature, and reacted overnight. After the reaction was completed, methyl tert-butyl ether 80 ml and deionized water 100 ml were added to extract the layers, the water layer was extracted with methyl tert-butyl ether (60 ml*2), the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, dissolved in dichloromethane 80 ml, then 6M hydrochloric acid 60 ml was added to extract, the water layer was collected, the water layer was adjusted to pH 8-9 with aqueous sodium carbonate solution, and methyl tert-butyl ether was added dropwise to extract, the layers were separated, the organic layer was collected, concentrated, and dried to obtain the target product 5.0 g with a yield of 80.6%.

[0205] LC-MS: m / z = 518 [M+H] + .

[0206] 1 H-NMR (400 MHz, DMSO-d6) δ 8.57-8.58 (d, J = 2.45 Hz, 1H), 8.27-8.34 (m, 2H), 7.99 (s, 1H), 7.84-7.87 (dd, J1 = 2.55 Hz, J2 = 8.25 Hz, 1H), 7.50-7.53 (d, J = 8.25 Hz, 1H), 7.12 (s, 1H), 2.91-2.95 (t, J = 7.5 Hz, 2H), 2.84-2.88 (t, J = 7.45 Hz, 2H), 2.17-2.21 (m, 2H), 1.57 (s, 6H).

[0207] For Preparation 2, N,N-dimethylformamide used as solvent was replaced by isopropyl acetate, toluene, acetonitrile and ethyl acetate to investigate the effect of different kinds of solvents on the reaction progress, and the results are shown in Table 4.

[0208] Table 4. Effect of different solvents on the reaction progress

[0209]

[0210] As can be seen from Table 4, when acetonitrile is used as the solvent, the yield of the reaction is close to that of N,N-dimethylformamide, which is suitable for mass production.

[0211] In addition, the target product of the above preparation method can also be formed into an acid addition salt with an acid (for example, 1,5-naphthalene disulfonic acid) in a solvent (for example, ethanol).

[0212] Preparation method of example compound 2:

[0213]

[0214] The compound of formula (I)-2 (100 mg, 0.330 mmol), the compound of formula (V)-2 (165 mg, about 2.2 eq) were added to N,N-dimethylformamide 1 ml, stirred at room temperature, and the reaction was carried out overnight; after the reaction was completed, methyl tert-butyl ether 20 ml and water 10 ml were added to extract and separate the layers, the water layer was extracted with methyl tert-butyl ether (10 ml), the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to preparative thin layer chromatography to obtain 97 mg of the target product with a yield of 58.8%.

[0215] 1 H-NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.5 Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 1.9 Hz, 1H), 8.09 (dd, J = 8.4, 1.9 Hz, 1H), 7.99 (d, J = 0.9 Hz, 1H), 7.76 (dd, J = 8.2, 2.5 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 1.0 Hz, 1H), 2.86 (dt, J = 25.0, 7.5 Hz, 4H), 2.20 - 2.11 (m, 2H), 1.53 (s, 6H).

[0216] Preparation method of example compound 3:

[0217]

[0218] The compound of formula (I)-2 (100 mg, 0.330 mmol), the compound of formula (V)-3 (151 mg, about 2.2 eq) were added into N,N-dimethylformamide 1 ml, stirred at room temperature, and the reaction was carried out overnight; after the reaction was completed, methyl tert-butyl ether 20 ml and water 10 ml were added to extract the layers, the water layer was extracted with methyl tert-butyl ether (10 ml), the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then subjected to preparative thin layer chromatography to obtain the target product 90 mg with a yield of 57.0%.

[0219] 1 H-NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 2.5, 0.8 Hz, 1H), 7.99 (d, J = 0.9 Hz, 1H), 7.83 (ddd, J = 8.3, 5.3, 2.1 Hz, 2H), 7.54 - 7.46 (m, 2H), 7.10 (d, J = 0.9 Hz, 1H), 4.12 (d, J = 2.6 Hz, 3H), 4.06 (d, J = 2.2 Hz, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.15 (p, J = 7.5 Hz, 2H), 1.52 (s, 6H).

[0220] Based on the method 1 of Example 1, item 1-1 of the method 1 of Example 2 and the method 2 of Example 3 of the compound 1 of the present application, the production process of the compound of formula (VI) (Y is F, Z is CF3, i.e. pukaline) is obtained. The reaction yield of each step is 91.3%, 77.0% and 80.6% respectively, and the total yield of the method involving Jocic reaction, esterification and ring closure reaction is up to 56.7%, which is much higher than the total yield of 11.8% of the method involving only substitution and ring closure reaction in US9216957B2.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof; in: R is selected from C1-C6 alkyl groups.

2. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from C1-C4 alkyl groups.

3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R is selected from methyl.

4. A method for preparing the compound of formula (I) according to claim 1, comprising: The compound of formula (II) or its pharmaceutically acceptable salt is esterified with ROH to obtain the compound of formula (I); Wherein: R is as defined in claim 1.

5. The preparation method according to claim 4, characterized in that: The preparation method 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); 6. A method for preparing the compound of formula (I) according to claim 1, comprising: A compound of formula (III) or a pharmaceutically acceptable salt thereof undergoes a substitution reaction with a compound of formula (IV) to yield a compound of formula (I); in: X is Cl, Br, or I; R is as defined in claim 1.

7. The method for preparing the compound of formula (I) according to claim 6, wherein X is Cl or Br.

8. The method for preparing the compound of formula (I) according to claim 6, wherein X is Br.

9. A method for preparing the compound of formula (I) according to claim 1, comprising: The compound of formula (III) or its pharmaceutically acceptable salt undergoes a substitution reaction with the compound of formula (IV-OH) to obtain the compound of formula (II) or its pharmaceutically acceptable salt, which is then subjected to an esterification reaction with ROH to obtain the compound of formula (I). in: X is Cl, Br, or I; R is as defined in claim 1.

10. The method for preparing the compound of formula (I) according to claim 9, wherein X is Cl or Br.

11. The method for preparing the compound of formula (I) according to claim 10, wherein X is Br.

12. A method for preparing a compound of formula (II), comprising: The compound of formula (III) or its pharmaceutically acceptable salt is reacted with chlorobutanol or its hydrate to give the compound of formula (II); 13. A method for preparing a compound of formula (VI), comprising: The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof undergoes a cyclization reaction with the compound of formula (V) to obtain the compound of formula (VI); in: Y is selected from hydrogen, halogen, C1-C3 alkoxy, hydroxyl, CF3O and cyano; Z is selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl optionally substituted with one or more halogens, and C1-C4 alkoxy optionally substituted with one or more halogens; R is as defined in claim 1.

14. The method for preparing the compound of formula (VI) according to claim 13, wherein Y is selected from H or F.

15. The method for preparing the compound of formula (VI) according to claim 14, wherein Y is selected from F.

16. The method for preparing the compound of formula (VI) according to claim 13, wherein Z is selected from CF3 or CH3O.

17. The method for preparing the compound of formula (VI) according to claim 16, wherein Z is selected from CF3.

18. A method for preparing a compound of formula (VI), comprising: The compound of formula (III) or its pharmaceutically acceptable salt is reacted with chlorobutanol or its hydrate to give the compound of formula (II); The compound of formula (II) or its pharmaceutically acceptable salt is esterified with ROH to obtain the compound of formula (I); The compound of formula (I) or its pharmaceutically acceptable salt undergoes a ring-closure reaction with the compound of formula (V) to give the compound of formula (VI); in: Y is selected from hydrogen, halogen, C1-C3 alkoxy, hydroxyl, CF3O and cyano; Z is selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl optionally substituted with one or more halogens, and C1-C4 alkoxy optionally substituted with one or more halogens; R is selected from C1-C6 alkyl groups.

19. The preparation method according to claim 18, characterized in that: Y is H or F; Z is CF3 or CH3O; R is selected from C1-C4 alkyl groups.

20. The preparation method according to claim 19, characterized in that: Y represents F; Z represents CF3; R represents methyl.

21. Use of the compound of formula (I) according to claim 1, for the preparation of the compound of formula (VI); in: Y is selected from hydrogen, halogen, C1-C3 alkoxy, hydroxyl, CF3O and cyano; Z is selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl optionally substituted with one or more halogens, and C1-C4 alkoxy optionally substituted with one or more halogens.

22. The use according to claim 21, characterized in that: Y is H or F; Z is CF3 or CH3O.

23. The use according to claim 22, characterized in that: Y is F; Z is CF3.

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