Substituted azabicyclooctane compounds, their intermediates, and preparation methods.

Abstract

This invention relates to an intermediate of a substituted azabicyclic [3.2.1]octane compound and a method for preparing the same. Specifically, this invention discloses an intermediate compound of formula (I), its preparation method, and a method for preparing an azabicyclic [3.2.1]octane compound from it, wherein the definitions of each group are detailed in the specification and claims.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, specifically to a substituted azabicyclic [3.2.1]octane compound, its intermediates, and a method for their preparation. Background Technology

[0002] Orexin is a hunger-regulating signal secreted by the hypothalamus, named for its strong appetite-stimulating effect. Orexin A and Orexin B are neuropeptides that act on G protein-coupled receptors, the orexin receptor OX1R and OX2R. OX1R binds to orexin A more strongly than orexin B, while OX2R binds to both orexin A and OX2R with similar binding affinity. Subsequent research found that dogs with narcolepsy had mutations in the gene expressing OX2R, leading to OX2R dysfunction. This research indicates that orexin not only affects feeding behavior but also participates in the regulation of the sleep-wake cycle. This has led to new insights into the etiology of insomnia, suggesting that insomnia may also be caused by inappropriate awakening. Considering the role of orexin in the sleep-wake cycle, Merck has been researching orexin receptor antagonists.

[0003] Several patents have reported various types of orexin receptor antagonists, including WO2017028732, which discloses a method for preparing the intermediate trans-chiral pure 13.

[0004]

[0005] However, the preparation of starting material 1 in this reaction route requires three steps: adding a benzyl protecting group, deprotecting, and then adding a protecting group again, which is cumbersome. The preparation of compound 3 requires sodium hydride, making scale-up operations quite dangerous. Furthermore, two intermediates in the synthetic route (compound 6 and a mixture of 10-a and 10-b) are difficult to purify, generally requiring column chromatography, resulting in poor reproducibility and the use of large amounts of organic solvents, causing significant environmental pollution. Additionally, because this method can only perform separation and purification in the final step, the overall atom economy of the reaction is poor, with numerous byproducts (isomers) generated during synthesis and low yields.

[0006] Therefore, developing a high-efficiency, low-cost, easily scalable, and reproducible synthetic process for trans-chiral pure substituted azabicyclic [3.2.1]octane compounds is of great significance for industrial production. Summary of the Invention

[0007] The purpose of this invention is to provide a substituted azabicyclo[3.2.1]octane compound and its preparation method, including the preparation method of the intermediate, which can be used to prepare orexin receptor antagonists.

[0008] The first aspect of the present invention provides a compound of formula (I) or a salt thereof:

[0009]

[0010] Where ring A is a benzene ring, a pyridine ring, or a naphthalene ring; (R) a ) n This indicates that the hydrogen on ring A is separated by n R. a Replace, each R a Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy;

[0011] R1 and R2 are each independently C 1-3 alkyl;

[0012] n is 0, 1, or 2.

[0013] In another preferred example, n is 0 or 1.

[0014] In another preferred embodiment, R a It can be hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0015] In another preferred embodiment, R a It is hydrogen.

[0016] In another preferred embodiment, R1 and R2 are each independently methyl, ethyl, propyl or isopropyl.

[0017] In another preferred embodiment, R1 is isopropyl.

[0018] In another preferred embodiment, R2 is a methyl group.

[0019] In another preferred embodiment, ring A is a benzene ring. In another preferred embodiment, the compound of formula (I) has the following structure:

[0020]

[0021] In another preferred embodiment, the salt is a salt formed by the compound of formula (I) and an acid.

[0022] In another preferred embodiment, the acid is an inorganic acid.

[0023] In another preferred embodiment, the inorganic acid is hydrochloric acid.

[0024] A second aspect of the present invention provides a method for preparing a compound of formula (I), comprising the steps of:

[0025] (1) In an inert solvent, compounds of formula a, b and c are subjected to a cyclization reaction to obtain a mixture containing compound (I);

[0026]

[0027] Where ring A is a benzene ring, a pyridine ring, or a naphthalene ring;

[0028] (R a ) n This indicates that the hydrogen on ring A is separated by n R. a Replace, each R a Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy;

[0029] R1 and R2 are each independently C 1-3 alkyl;

[0030] n is 0, 1, or 2;

[0031] (2) The mixture containing the compound of formula (I) was treated with acid to obtain a salt of the compound of formula (I);

[0032] (3) Treat (or “free”) the salt of the obtained compound (I) to obtain compound (I).

[0033] In another preferred example, n is 0 or 1.

[0034] In another preferred embodiment, R a It can be hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0035] In another preferred embodiment, R1 and R2 are each independently methyl, ethyl, propyl or isopropyl.

[0036] In another preferred embodiment, R1 is isopropyl.

[0037] In another preferred embodiment, R2 is a methyl group.

[0038] In another preferred embodiment, ring A is a benzene ring. In another preferred embodiment, the molar ratio of compounds of formulas a, b, and c is (1-2):1:1.

[0039] In another preferred embodiment, the mixture comprising the compound of formula (I) further comprises the isomer shown in formula (II).

[0040]

[0041] Among them, rings A and R a , n, R1 and R2 are as defined in the above specification.

[0042] In another preferred embodiment, the isomer shown in formula (II) has the following structure:

[0043]

[0044] In another preferred embodiment, the compound of formula a is prepared by a method comprising the following steps:

[0045] The 2H-pyran-2,4,6-(3H,5H)trione was reacted with an alkyl alcohol R1OH to obtain compound a;

[0046]

[0047] Where R1 is C 1-3 alkyl.

[0048] In another preferred embodiment, R1 is methyl, ethyl, propyl or isopropyl.

[0049] In another preferred embodiment, in step (1), the temperature of the reaction is -20°C to 50°C, preferably 0°C to 30°C, and more preferably 5°C to 25°C.

[0050] In another preferred embodiment, in step (1), the reaction time is greater than 0.5 hours.

[0051] In another preferred embodiment, in step (1), the molar ratio of compound (I) to compound (II) in the mixture containing compound (I) is greater than 1:1, preferably (1.5 to 2):1.

[0052] In another preferred embodiment, in step (1), compound a participates in the reaction in the form of an unpurified reaction solution.

[0053] In another preferred embodiment, in step (1), compound b participates in the reaction in the form of a reaction solution after reacting with hydrochloric acid.

[0054] In another preferred embodiment, in step (1), compound c participates in the reaction in the form of a mixture with hydrochloric acid.

[0055] In another preferred embodiment, in step (1), the reaction is carried out in a system with a pH of 1 to 5, preferably in a system with a pH of 3 to 4.

[0056] In another preferred embodiment, the reaction in step (1) is carried out in a system containing a pH adjuster.

[0057] In another preferred embodiment, the pH adjuster is selected from sodium acetate, sodium hydroxide, and a combination of sodium acetate and sodium hydroxide.

[0058] In another preferred embodiment, in step (2), the acid treatment is performed using a solution containing acid.

[0059] In another preferred embodiment, the acid-containing solution is a solution containing an acid and a solvent selected from the group consisting of: C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or combinations thereof.

[0060] In another preferred embodiment, the acid is selected from organic acids and inorganic acids, wherein the inorganic acids are selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid; and the organic acids are selected from: acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid.

[0061] In another preferred embodiment, the concentration of the acid in the acid-containing solution is from 0.1 mol / L to 10 mol / L, preferably from 0.5 mol / L to 5 mol / L.

[0062] In another preferred embodiment, the acid is hydrochloric acid.

[0063] In another preferred embodiment, the acid-containing solution is a solution composed of hydrochloric acid and ethyl acetate.

[0064] In another preferred embodiment, the treatment (or “freeing”) in step (3) refers to treating the salt of the compound of formula (I) obtained in step (2) with a solution containing an alkali selected from: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine, or combinations thereof.

[0065] In another preferred embodiment, the treatment (or “freeing”) in step (3) refers to treating the salt of the compound of formula (I) obtained in step (2) with a solution containing sodium hydroxide.

[0066] In another preferred embodiment, a method for preparing a mixture comprising the compound of formula (I) includes the steps of:

[0067] (1a) 2H-pyran-2,4,6-(3H,5H)trione was reacted with C 1-3The alkyl alcohol reacts to obtain a reaction solution 1a containing the compound of formula a;

[0068] (1b) Treat the mixture of compound b and the first solvent with acid to obtain mixture 1b;

[0069]

[0070] The first solvent is selected from water, C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof;

[0071] (1c) Treat the mixture of compound c and the second solvent with acid to obtain mixture 1c;

[0072]

[0073] The second solvent is selected from water, C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof;

[0074] (1d) In the presence of a pH adjuster system, reaction solution 1a, mixture 1b and mixture 1c are mixed to carry out a cyclization reaction, thereby obtaining a mixture containing compound (I).

[0075] The order of steps (1a), (1b) and (1c) can be arbitrarily changed.

[0076] In another preferred embodiment, the acid described in step (1b) is an inorganic acid, preferably hydrochloric acid.

[0077] In another preferred embodiment, the acid described in step (1c) is an inorganic acid, preferably hydrochloric acid.

[0078] In another preferred embodiment, the pH adjuster in step (1d) is selected from sodium acetate, sodium hydroxide, and a combination of sodium acetate and sodium hydroxide.

[0079] In another preferred embodiment, in step (1d), the reaction is carried out at a pH of 1 to 5, preferably at a pH of 3 to 4.

[0080] In another preferred embodiment, in step (1d), the reaction temperature is -20°C to 50°C, preferably 0°C to 30°C, and more preferably 5°C to 25°C.

[0081] In another preferred embodiment, C in step (1a)1-3 Alkyl alcohols are methanol, ethanol, or isopropanol.

[0082] In another preferred embodiment, n is 0 or 1 in compound c.

[0083] In another preferred embodiment, in compound c, R a It can be hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0084] In another preferred embodiment, in compound c, R2 is methyl, ethyl, propyl or isopropyl.

[0085] In another preferred embodiment, in compound c, ring A is a benzene ring, a pyridine ring, or a naphthalene ring.

[0086] In another preferred embodiment, the compound of formula c has the following structure:

[0087]

[0088] A third aspect of the present invention provides a method for preparing a compound of formula (VII), comprising the steps of:

[0089] (a) The compound of formula (I) is reduced to obtain the compound of formula (III);

[0090]

[0091] (b) The compound of formula (III) is subjected to an elimination reaction to obtain the compound of formula (IV);

[0092]

[0093] (c) The compound of formula (IV) is reduced to obtain the compound of formula (V);

[0094]

[0095] (d) The compound of formula (V) is reduced to obtain the compound of formula (VI);

[0096]

[0097] (e) The compound of formula (VI) is subjected to a substitution reaction with the compound of formula (VIa) to obtain the compound of formula (VII-a);

[0098]

[0099] (f) The compound of formula (VII-a) is purified to obtain the compound of formula (VII);

[0100]

[0101] in,

[0102] Ring A can be a benzene ring, a pyridine ring, or a naphthalene ring;

[0103] (R a ) n This indicates that the hydrogen on ring A is separated by n R. a Replace, each R a Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkyl groups, and (R) b ) m This indicates that the hydrogen on the ring is divided by m R b Replace, each R b Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy;

[0104] R1 and R2 are each independently C 1-3 alkyl;

[0105] m and n are each independently 0, 1 or 2;

[0106] Z represents N or CR3; R3 represents hydrogen, halogen, or C. 1-3 alkyl;

[0107] R LG It can be halogen, amino, hydroxyl, (HO)2B-, borate ester, (NO2)2C6H3O-, CH3S(O)2O-, CF3S(O)2O-, p-CH3C6H4S(O)2O-, CH3S(O)2-, CH3S(O)-.

[0108] In another preferred embodiment, R a R b Each can be independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0109] In another preferred embodiment, R1 and R2 are each independently methyl, ethyl, propyl or isopropyl.

[0110] In another preferred embodiment, Z is N or CR3; R3 is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl or isopropyl.

[0111] In another preferred embodiment, the compound of formula (V) has the following structure:

[0112]

[0113] In another preferred embodiment, the compound of formula (Ⅶ-a) has the following structure:

[0114]

[0115] In another preferred embodiment, in step (f), the purification is to acidify the compound of formula (Ⅶ-a) or a solution thereof.

[0116] In another preferred embodiment, the acid treatment is performed using a solution containing acid.

[0117] In another preferred embodiment, the acid-containing solution is a solution containing an acid and a solvent selected from the group consisting of: C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or combinations thereof.

[0118] In another preferred embodiment, the acid is selected from organic acids and inorganic acids, wherein the inorganic acids are selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid; and the organic acids are selected from: acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid.

[0119] In another preferred embodiment, the acid is hydrochloric acid.

[0120] In another preferred embodiment, the acid-containing solution is a solution composed of hydrochloric acid and ethyl acetate.

[0121] This invention provides another method for preparing a compound of formula (VII), comprising the steps of:

[0122] (a) The compound of formula (I) is reduced to obtain the compound of formula (III);

[0123]

[0124] (b) The compound of formula (III) is subjected to an elimination reaction to obtain the compound of formula (IV);

[0125]

[0126] (c1) The compound of formula (IV) is reduced to obtain the compound of formula (V-1);

[0127]

[0128] (d1) The compound of formula (V-1) is reduced to obtain the compound of formula (VI-1);

[0129]

[0130] (e1) The compound of formula (VI-1) is subjected to a substitution reaction with the compound of formula (VIa) to obtain the compound of formula (VII);

[0131]

[0132] In another preferred embodiment, (R) a ) n This indicates that the hydrogen on ring A is separated by n R. a Replace, each R a They may be the same or different, each independently being hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; (R b ) m This indicates that the hydrogen on the ring is divided by m R b Replace, each R b They may be the same or different, and each independently can be hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0133] In another preferred embodiment, R1 and R2 are each independently methyl, ethyl, propyl or isopropyl.

[0134] In another preferred embodiment, R1 is isopropyl.

[0135] In another preferred embodiment, R2 is a methyl group.

[0136] In another preferred embodiment, ring A is a benzene ring.

[0137] In another preferred example, Z is N.

[0138] In another preferred embodiment, the compound of formula (V-1) has the following structure:

[0139]

[0140] In another preferred embodiment, the compound of formula (VII) has the following structure:

[0141]

[0142] In another preferred embodiment, the compound of formula (I) is prepared by the preparation method described in the second aspect of the present invention.

[0143] In another preferred embodiment, the reduction reaction in step (a) is carried out in a system containing a reducing agent and an inert solvent. The reducing agent is selected from:

[0144] (a) Tetrabutylamine borohydride, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, potassium borohydride, borane, isopropanol-triisopropoxyaluminum, lithium aluminum hydride, lithium tritert-butoxyaluminum hydride, samarium diiodide;

[0145] (b) Combinations of zinc and Lewis acids (e.g., antimony trichloride);

[0146] (c) A combination of a catalyst selected from palladium, nickel, platinum and lead and a hydrogen donor selected from hydrogen, formic acid and formate;

[0147] The inert solvent is selected from: water, C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof.

[0148] In another preferred embodiment, the reduction reaction in step (a) is carried out in a system containing a reducing agent and an inert solvent; the reducing agent is sodium borohydride; and the inert solvent is methanol.

[0149] In another preferred embodiment, the molar ratio of compound (I) to reducing agent in step (a) is 1:(1-3).

[0150] In another preferred embodiment, the elimination reaction in step (b) is carried out in a system containing a hydroxyl activator, a base, and an inert solvent.

[0151] In another preferred embodiment, the hydroxyl activator is a sulfonyl chloride, which is selected from: benzenesulfonyl chloride, p-toluenesulfonyl chloride, and methanesulfonyl chloride.

[0152] In another preferred embodiment, the base is selected from: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine, or combinations thereof.

[0153] In another preferred embodiment, the base is selected from: ammonia, triethylamine, diisopropylethylamine, N,N-dimethylaniline, tetramethylethylenediamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), pyrazole, imididine, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium acetate, sodium phenolate, sodium benzoate, sodium citrate, N-methylmorpholine, pyridine, or combinations thereof. In another preferred embodiment, the inert solvent is selected from: toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, or combinations thereof.

[0154] In another preferred embodiment, the molar ratio of compound (III) to hydroxyl activator in step (b) is 1:(1-2).

[0155] In another preferred embodiment, the molar ratio of compound (III) to base in step (b) is 1:(1-2).

[0156] In another preferred embodiment, the reduction reaction in step (c) is carried out in a system containing a reducing agent and an inert solvent, wherein the reducing agent is selected from:

[0157] (a) Metallic magnesium, alkylsilane hydrides, sodium borohydride, lithium borohydride, hydrides of tin, selenium or tellurium, borane, sodium dithionite, olefin reductase, yeast enzyme;

[0158] (b) A combination of zinc and a hydrogen donor selected from formic acid and formate;

[0159] (c) A combination of tin, carbon monoxide and water;

[0160] (d) A combination of a complex selected from palladium, rhodium (e.g., rhodium tri(triphenylphosphine)chloride), cobalt, nickel, ruthenium, iridium, and copper with a hydrogen donor selected from hydrogen, formic acid, and formate; and

[0161] (e) A combination of a catalyst selected from palladium or nickel and a hydrogen donor selected from hydrogen, formic acid or formate;

[0162] The inert solvent is selected from: C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof.

[0163] In another preferred embodiment, the molar ratio of compound (IV) to reducing agent in step (c) is 1:(1-10).

[0164] In another preferred embodiment, the reduction reaction in step (c) takes place in a mixture containing metallic magnesium and C. 1-4 The process is carried out in a system of alkyl alcohol combinations.

[0165] In another preferred embodiment, the reduction reaction in step (c) is carried out in a system containing a combination of metallic magnesium and methanol.

[0166] In another preferred embodiment, the molar ratio of compound (IV) to metallic magnesium in step (c) is 1:(1-10).

[0167] In another preferred embodiment, the reduction reaction in step (c) is carried out in a system containing a reducing agent, a Lewis acid, and an inert solvent, wherein the reducing agent is selected from potassium borohydride, sodium borohydride, and lithium borohydride; and the inert solvent is selected from C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof; the Lewis acid is selected from lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, copper chloride, aluminum chloride, ferrous chloride, nickel chloride, and gallium dichloride.

[0168] In another preferred embodiment, the reduction reaction in step (c) is carried out in a system containing sodium borohydride, tetrahydrofuran, and lithium chloride.

[0169] In another preferred embodiment, the molar ratio of the compound of formula (IV), the reducing agent and the Lewis acid in step (c) is 1:(1-8):(1-5).

[0170] In another preferred embodiment, the reduction reaction in step (c1) is carried out in a system containing a reducing agent and an inert solvent, wherein the reducing agent is selected from:

[0171] (a) Metallic magnesium, alkylsilanes, sodium borohydride, lithium borohydride, tin, selenium or tellurium hydride, borane, sodium hydrosulfite, olefin reductase, yeast enzyme;

[0172] (b) A combination of zinc and a hydrogen donor selected from formic acid and formate;

[0173] (c) A combination of tin, carbon monoxide and water;

[0174] (d) A combination of a complex selected from palladium, rhodium (e.g., rhodium tri(triphenylphosphine)chloride), cobalt, nickel, ruthenium, iridium, and copper with a hydrogen donor selected from hydrogen, formic acid, and formate; and

[0175] (e) A combination of a catalyst selected from palladium or nickel and a hydrogen donor selected from hydrogen, formic acid or formate;

[0176] The inert solvent is selected from: C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof.

[0177] In another preferred embodiment, the reduction reaction in step (c1) takes place in a mixture containing metallic magnesium and C. 1-4 The process is carried out in a system of alkyl alcohol combinations.

[0178] In another preferred embodiment, the reduction reaction in step (c1) is carried out in a system containing a combination of metallic magnesium and methanol.

[0179] In another preferred embodiment, the reduction reaction in step (c1) is carried out in a system containing a reducing agent, a Lewis acid, and an inert solvent, wherein the reducing agent is selected from potassium borohydride, sodium borohydride, and lithium borohydride; and the inert solvent is selected from C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof.

[0180] In another preferred embodiment, the Lewis acid is selected from: lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, copper chloride, aluminum chloride, ferrous chloride, nickel chloride, and gallium dichloride.

[0181] In another preferred embodiment, the molar ratio of the compound of formula (IV), the reducing agent and the Lewis acid in step (c1) is 1:(1-8):(1-5).

[0182] In another preferred embodiment, the reduction reaction in step (c1) is carried out in a system containing sodium borohydride, tetrahydrofuran, and lithium chloride.

[0183] In another preferred embodiment, the reduction reaction in step (d) or step (d1) is carried out in a system containing a reducing agent and an inert solvent, wherein the reducing agent is selected from:

[0184] (a) Red aluminum, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, lithium triethylborohydride, lithium trisec-butylborohydride, potassium borohydride, borane, aluminum diisobutylhydride, lithium tritert-butoxyaluminum hydride, lithium tetraaluminum hydride, potassium hydroxide-diethylene glycol, samarium diiodide;

[0185] (b) A combination of palladium catalyst and hydrogen;

[0186] (c) A combination of sodium borohydride, potassium borohydride, or lithium borohydride and a Lewis acid;

[0187] (d) A combination of [CpFe(CO)2(PCy3)][BF4] and phenylsilane;

[0188] The inert solvent is selected from: C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof.

[0189] In another preferred embodiment, the palladium catalyst is selected from: palladium on carbon, tris(dibenzylacetone)palladium (Pd2(dba)3), tetra(triphenylphosphine)palladium (Pd(PPh3)4), palladium acetate, dichlorodi(triphenylphosphine)palladium, trifluoropalladium acetate, triphenylphosphine acetate, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphine)ethanepalladium dichloride, or combinations thereof.

[0190] In another preferred embodiment, the reduction reaction in step (d) or step (d1) is carried out in a system containing aluminum red and toluene.

[0191] In another preferred embodiment, the molar ratio of the compound of formula (V) or formula (V-1) to the reducing agent in step (d) or step (d1) is 1:(1-5).

[0192] In another preferred embodiment, the substitution reaction in step (e) or step (e1) is carried out in a system containing a base and an inert solvent, said base being selected from: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine, or combinations thereof.

[0193] The inert solvent is selected from: toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, or combinations thereof.

[0194] In another preferred embodiment, the substitution reaction in step (e) or step (e1) is carried out in a system containing a base and an inert solvent, wherein the base is sodium tert-butoxide, potassium tert-butoxide or lithium tert-butoxide, and the inert solvent is toluene.

[0195] In another preferred embodiment, the substitution reaction in step (e) or step (e1) is carried out in a system containing sodium tert-butoxide and toluene.

[0196] In another preferred embodiment, the molar ratio of compound (VI) or (VI-1) to base in the substitution reaction is 1:(1-5).

[0197] In another preferred embodiment, the molar ratio of compound (VI) or (VI-1) to compound (VIa) in the substitution reaction is 1:(1-2).

[0198] In another preferred embodiment, the compound of formula (VIa) is selected from:

[0199]

[0200]

[0201] A fourth aspect of the present invention provides a compound of formula (Ⅶ-a) or a salt thereof:

[0202]

[0203] in,

[0204] Ring A can be a benzene ring, a pyridine ring, or a naphthalene ring;

[0205] (R a ) n This indicates that the hydrogen on ring A is separated by n R. a Replace, each R a Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkyl groups, and (R) b ) m This indicates that the hydrogen on the ring is divided by m R b Replace, each R b Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy;

[0206] R2 is C 1-3 alkyl;

[0207] m and n are each independently 0, 1 or 2;

[0208] Z represents N or CR3; R3 represents hydrogen, halogen, or C. 1-3 alkyl;

[0209] The salt is a salt formed by a compound of formula (Ⅶ-a) and an acid.

[0210] In another preferred example, n is 0 or 1.

[0211] In another preferred embodiment, m is 1 or 2.

[0212] In another preferred embodiment, R a Rb Each can be independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0213] In another preferred embodiment, R a It is hydrogen.

[0214] In another preferred embodiment, R b It is fluorine.

[0215] In another preferred embodiment, R2 is methyl, ethyl, propyl or isopropyl.

[0216] In another preferred embodiment, R2 is a methyl group.

[0217] In another preferred embodiment, ring A is a benzene ring.

[0218] In another preferred embodiment, the acid is an inorganic acid.

[0219] In another preferred embodiment, the inorganic acid is hydrochloric acid.

[0220] In another preferred embodiment, Z is N or CR3; R3 is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl or isopropyl.

[0221] In another preferred example, Z is N.

[0222] In another preferred embodiment, the compound of formula (Ⅶ-a) has the following structure:

[0223]

[0224] The present invention also provides a compound of formula (VII) or a salt thereof:

[0225]

[0226] The groups are as defined above; the salt is a salt formed by the compound of formula (VII) and an acid.

[0227] In another preferred embodiment, the acid is an inorganic acid.

[0228] In another preferred embodiment, the inorganic acid is hydrochloric acid.

[0229] In another preferred example, n is 0 or 1.

[0230] In another preferred embodiment, m is 1 or 2. In another preferred embodiment, R a R b Each can be independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0231] In another preferred embodiment, Ra It is hydrogen.

[0232] In another preferred embodiment, R b It is fluorine.

[0233] In another preferred embodiment, R2 is methyl, ethyl, propyl or isopropyl.

[0234] In another preferred embodiment, R2 is a methyl group.

[0235] In another preferred embodiment, ring A is a benzene ring.

[0236] In another preferred example, Z is N.

[0237] In another preferred embodiment, the compound of formula (VII) has the following structure:

[0238]

[0239] The fifth aspect of the present invention provides a method for preparing a compound of formula (VII-a), the method comprising the steps of: in an inert solvent and in the presence of a base, subjecting a compound of formula (VI) and a compound of formula (VIa) to a substitution reaction to obtain a compound of formula (VII-a);

[0240]

[0241] Where ring A is a benzene ring, a pyridine ring, or a naphthalene ring;

[0242] (R a ) n This indicates that the hydrogen on ring A is separated by n R. a Replace, each R a Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkyl groups, and (R) b ) m This indicates that the hydrogen on the ring is divided by m R b Replace, each R b Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy;

[0243] R2 is C 1-3 alkyl;

[0244] m and n are each independently 0, 1 or 2;

[0245] Z represents N or CR3; R3 represents hydrogen, halogen, or C. 1-3 alkyl;

[0246] R LGIt can be halogen, amino, hydroxyl, (HO)2B-, borate ester, (NO2)2C6H3O-, CH3S(O)2O-, CF3S(O)2O-, p-CH3C6H4S(O)2O-, CH3S(O)2-, CH3S(O)-.

[0247] The present invention also provides a method for preparing a compound of formula (VII), the method comprising the steps of: purifying a compound of formula (VII-a) to obtain a compound of formula (VII);

[0248]

[0249] The groups are defined as above.

[0250] In another preferred embodiment, the compound of formula (Ⅶ-a) is prepared by the above-described preparation method.

[0251] In another preferred embodiment, the purification is performed by acid treatment of the compound of formula (Ⅶ-a) or a solution thereof.

[0252] In another preferred embodiment, the acid treatment is performed using a solution containing acid.

[0253] In another preferred embodiment, the acid is selected from organic acids and inorganic acids, wherein the inorganic acids are selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid; and the organic acids are selected from: acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid.

[0254] In another preferred embodiment, R a R b Each can be independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0255] In another preferred embodiment, R2 is methyl, ethyl, propyl or isopropyl.

[0256] In another preferred embodiment, R2 is a methyl group.

[0257] In another preferred embodiment, ring A is a benzene ring.

[0258] In another preferred example, Z is N.

[0259] In another preferred embodiment, the compound of formula (VIa) is selected from:

[0260]

[0261] In another preferred embodiment, the substitution reaction is carried out in a system containing a base and an inert solvent, wherein the base is selected from: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine, or combinations thereof;

[0262] The inert solvent is selected from: toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, or combinations thereof.

[0263] In another preferred embodiment, the preparation method further includes the step of reacting the compound of formula (VII) with an acid to obtain a salt of the compound of formula (VII).

[0264] In another preferred embodiment, the acid is an inorganic acid.

[0265] In another preferred embodiment, the inorganic acid is hydrochloric acid.

[0266] In another preferred embodiment, the compound of formula (VI) is prepared by a method comprising the following steps:

[0267] (a) The compound of formula (I) is reduced to obtain the compound of formula (III);

[0268]

[0269] (b) The compound of formula (III) is subjected to an elimination reaction to obtain the compound of formula (IV);

[0270]

[0271] (c) The compound of formula (IV) is reduced to obtain the compound of formula (V);

[0272]

[0273] (d) The compound of formula (V) is reduced to obtain the compound of formula (VI);

[0274]

[0275] In the above formulas, ring A is a benzene ring, a pyridine ring, or a naphthalene ring;

[0276] (R a ) n This indicates that the hydrogen on ring A is separated by n R. aReplace, each R a Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy;

[0277] n is 0, 1, or 2;

[0278] R1 and R2 are each independently C 1-3 alkyl.

[0279] In another preferred example, n is 0.

[0280] In another preferred embodiment, R a It can be hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0281] In another preferred embodiment, R1 and R2 are each independently methyl, ethyl, propyl or isopropyl.

[0282] In another preferred embodiment, R1 is isopropyl.

[0283] In another preferred embodiment, R2 is a methyl group.

[0284] In another preferred embodiment, ring A is a benzene ring.

[0285] In another preferred embodiment, the compound of formula (I) is prepared by a method comprising the following steps:

[0286] (1) In an inert solvent, compounds of formula a, b and c are subjected to a cyclization reaction to obtain a mixture containing compound (I);

[0287]

[0288] Where ring A is a benzene ring, a pyridine ring, or a naphthalene ring;

[0289] (R a ) n This indicates that the hydrogen on ring A is separated by n R. a Replace, each R a Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy;

[0290] R1 and R2 are each independently C 1-3 alkyl;

[0291] n is 0, 1, or 2;

[0292] (2) The mixture containing the compound of formula (I) was treated with acid to obtain a salt of the compound of formula (I);

[0293] (3) Treat (or “free”) the salt of the obtained compound (I) to obtain compound (I).

[0294] In another preferred embodiment, the acid is an inorganic acid.

[0295] In another preferred embodiment, the inorganic acid is hydrochloric acid.

[0296] In another preferred embodiment, the compound of formula a is prepared by a method comprising the following steps:

[0297] The 2H-pyran-2,4,6-(3H,5H)trione was reacted with an alkyl alcohol R1OH to obtain compound a;

[0298]

[0299] Where R1 is C 1-3 alkyl.

[0300] In another preferred embodiment, the mixture containing formula (I) further comprises the isomer shown in formula (II).

[0301]

[0302] Among them, rings A and R a , n, R1 and R2 are as defined in the above specification.

[0303] The sixth aspect of the present invention provides a method for preparing a compound of formula (IX), the method comprising the steps of: removing a substituent on a nitrogen atom from a compound of formula (VII) or a salt thereof in a solvent, thereby obtaining a compound of formula (IX);

[0304]

[0305] in,

[0306] Ring A can be a benzene ring, a pyridine ring, or a naphthalene ring;

[0307] (R a ) n This indicates that the hydrogen on ring A is separated by n R. a Replace, each R a Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy;

[0308] (R b ) m This indicates that the hydrogen on the ring is divided by m R b Replace, each R b Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3Alkoxy;

[0309] R2 is C 1-3 alkyl;

[0310] m is 0, 1, or 2;

[0311] n is 0, 1, or 2;

[0312] Z represents N or CR3; R3 represents hydrogen, halogen, or C. 1-3 alkyl.

[0313] In another preferred embodiment, the compound of formula (VII) is prepared by the preparation method described in the fifth aspect of the present invention.

[0314] In another preferred embodiment, the salt is a salt formed by a compound of formula (VII) and an inorganic acid.

[0315] In another preferred embodiment, the inorganic acid is hydrochloric acid.

[0316] In another preferred embodiment, the reaction is carried out in a system containing a palladium catalyst and selected from hydrogen, formic acid, and ammonium formate.

[0317] In another preferred embodiment, the palladium catalyst is selected from: palladium on carbon, tris(dibenzylacetone)palladium (Pd2(dba)3), tetra(triphenylphosphine)palladium (Pd(PPh3)4), palladium acetate, dichlorodi(triphenylphosphine)palladium, trifluoropalladium acetate, triphenylphosphine acetate, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphine)ethanepalladium dichloride, or combinations thereof.

[0318] In another preferred embodiment, the reaction is carried out in a system containing palladium on carbon and ammonium formate.

[0319] In another preferred embodiment, R a It can be hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0320] In another preferred embodiment, R b It can be hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0321] In another preferred example, n is 0.

[0322] In another preferred example, m is 1.

[0323] In another preferred embodiment, R2 is methyl, ethyl, propyl or isopropyl.

[0324] In another preferred embodiment, R2 is a methyl group.

[0325] In another preferred example, Z is N.

[0326] In another preferred embodiment, ring A is a benzene ring.

[0327] In another preferred embodiment, the compound of formula (IX) has the following structure:

[0328]

[0329] The seventh aspect of the present invention provides a method for preparing a compound of formula (X), comprising the steps of: in an inert solvent, reacting a compound of formula (IX) or a salt thereof with compound 5-methyl-2-(pyrimidin-2-yl)benzoic acid to obtain a compound of formula (X);

[0330]

[0331] in,

[0332] (R b ) m This indicates that the hydrogen on the ring is divided by m R b Replace, each R b Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy;

[0333] m is 0, 1, or 2;

[0334] Z represents N or CR3; R3 represents hydrogen, halogen, or C. 1-3 alkyl.

[0335] In another preferred embodiment, R b It can be hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0336] In another preferred embodiment, m is 1 or 2.

[0337] In another preferred example, Z is N.

[0338] In another preferred embodiment, the compound of formula (X) has the following structure:

[0339]

[0340] In another preferred embodiment, the compound of formula (IX) is prepared by the method described in the sixth aspect of the present invention.

[0341] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0342] Figure 1 This is an ellipsoidal diagram of the single-crystal stereostructure of compound 12.

[0343] Terminology Definition

[0344] As used in this article, "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, C 1-10 The alkyl group is an alkyl group containing 1 to 10 carbon atoms, preferably C14. 1-6 Alkyl, more preferably C 1-3 Alkyl groups, as defined similarly; non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methyl Hexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and their various branched isomers are preferred.

[0345] As used herein, "alkoxy" refers to -O-alkyl, where alkyl is defined as described above. Preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, etc. As used herein, "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0346] As used herein, non-limiting examples of "boronic acid esters" include (CH3O)2B-, (CH3CH2O)2B-, wait.

[0347] In this invention, “treating” the salt of compound (I) to obtain compound (I) is a process of freeing it. Specifically, for example, the salt of compound (I) is treated with a suitable base or a solution of base to obtain the free base form of compound (I). Detailed Implementation

[0348] Through extensive and in-depth research, the inventors discovered an intermediate for preparing substituted azabicyclo[3.2.1]octane compounds and a method for preparing substituted azabicyclo[3.2.1]octane compounds. This method uses readily available and simple starting materials, exhibits good reaction selectivity, significantly improves atom economy, and is easy to operate, environmentally friendly, and readily scaled up for production. It significantly reduces production costs, saves time, and produces high-purity products, directly yielding high-purity clinical-grade active pharmaceutical ingredients. Based on these findings, the inventors completed this invention.

[0349] This invention provides a method for preparing a compound of formula (VII), using compounds of formulas a, b, and c as starting materials, and obtaining the compound of formula (VII) through a cyclization reaction, a reduction reaction, an elimination reaction, a two-step reduction reaction, and a substitution reaction. The method includes the following steps:

[0350] In an inert solvent (such as water, ethyl acetate, etc.), at a certain temperature (e.g., -10°C to 25°C), a mixture containing a compound of formula a, a compound of formula b obtained by acid treatment, and a solvent, and a mixture containing a compound of formula c obtained by acid treatment and a solvent are mixed. The pH of the reaction solution is controlled at 1-5, and the reaction is carried out for a period of time (e.g., 0.5 hours to 24 hours) to obtain a mixture containing a compound of formula (I). The resulting mixture is then treated with acid to obtain a salt of compound (I). The salt is then treated (or "freed") to obtain compound (I). The inert solvent refers to a solvent that does not participate in or affect the above cyclization reaction, including but not limited to water and ethyl acetate.

[0351]

[0352] Where ring A is a benzene ring, a pyridine ring, or a naphthalene ring; (R) a ) n This indicates that the hydrogen on ring A is separated by n R. a Replace, each R a Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkyl group; R1 and R2 are each independently C 1-3 Alkyl group; n is 0, 1, or 2;

[0353] The acid is an inorganic acid, with hydrochloric acid being the most preferred.

[0354] In an inert solvent, at a certain temperature (e.g. -20°C to 50°C, preferably -10°C to 5°C), the compound of formula (I) is reacted with a reducing agent for a period of time (e.g. 0.5 hours to 6 hours, preferably 2 hours to 4 hours) to obtain the compound of formula (III).

[0355]

[0356] The inert solvent and reducing agent can be any combination of various reducing agents and inert solvents known in the art, suitable for the selective reduction of carbonyl groups when ester and carbonyl groups are present simultaneously. The reducing agent can be selected from combinations such as tetrabutylamine borohydride, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, potassium borohydride, borane, isopropanol-triisopropoxyaluminum, lithium aluminum hydride, lithium tritert-butoxyaluminum hydride, samarium diiodide, zinc, and Lewis acids (e.g., antimony trichloride), and combinations of catalysts selected from palladium, nickel, platinum, and lead with hydrogen donors selected from hydrogen, formic acid, and formate. The inert solvent can be selected from water, C... 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or combinations thereof. Preferably, the reaction is carried out in a reducing agent containing sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, and potassium borohydride, and C2O2. 1-4 The reaction can be carried out in a system of alkyl alcohols, and more preferably in a system containing sodium borohydride and methanol.

[0357] In an inert solvent, at a certain temperature (e.g. -20°C to 25°C, preferably -10°C to 10°C), the compound of formula (III) is subjected to an elimination reaction for a period of time (e.g. 0.5 hours to 24 hours) to obtain the compound of formula (IV).

[0358]

[0359] The elimination reaction can be carried out in any system known in the art suitable for β-elimination, such as a reaction system containing a hydroxyl activator and a base. The hydroxyl activator can be a sulfonyl chloride, such as benzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, etc. The base can be ammonia, triethylamine, diisopropylethylamine, N,N-dimethylaniline, tetramethylethylenediamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), pyrazole, imididine, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium acetate, sodium phenolate, sodium benzoate, sodium citrate, N-methylmorpholine, pyridine, etc., or combinations thereof. The inert solvent may be selected from toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, or combinations thereof. The hydroxyl activator is preferably p-toluenesulfonyl chloride or methanesulfonyl chloride. The base is preferably triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), sodium hydroxide, or potassium hydroxide. The inert solvent is preferably toluene, tetrahydrofuran, 1,4-dioxane, or dichloromethane.

[0360] In an inert solvent, at a certain temperature (e.g., -20°C to 25°C, preferably -10°C to 10°C), the compound of formula (IV) is reacted with a reducing agent for a period of time (e.g., 0.5 hours to 48 hours) to obtain the compound of formula (V).

[0361]

[0362] The inert solvent and reducing agent can be any combination of various reducing agents and inert solvents known in the art, suitable for the selective reduction of unsaturated double or triple bonds in α,β-unsaturated esters. The reducing agent can be selected from, for example, metallic magnesium, alkyl silane hydrides, hydrides of tin, selenium, or tellurium, combinations of zinc and hydrogen donors selected from formic acid and formate, combinations of tin, carbon monoxide, and water, combinations of complexes selected from palladium, rhodium (such as tris(triphenylphosphine)rhodium chloride), cobalt, nickel, ruthenium, iridium, and copper with hydrogen donors selected from hydrogen, formic acid, and formate, combinations of catalysts selected from palladium and nickel with hydrogen donors selected from hydrogen, formic acid, and formate, borane, sodium hydrosulfite, olefin reductases, yeast enzymes, etc. The inert solvent can be selected from, for example, C 1-4Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or combinations thereof. Preferably, the reaction is carried out in a reaction containing metallic magnesium and C. 1-4 The process can be carried out in alkyl alcohol systems, or in systems containing palladium catalyst / hydrogen and C. 1-4 The reaction is carried out in a system containing alkyl alcohols, wherein the palladium catalyst can be palladium on carbon, tris(dibenzylacetone)palladium (Pd2(dba)3), tetra(triphenylphosphine)palladium (Pd(PPh3)4), palladium acetate, dichlorodi(triphenylphosphine)palladium, trifluoropalladium acetate, triphenylphosphine acetate, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphine)ethanepalladium dichloride, or combinations thereof. The reaction is more preferably carried out in a system containing metallic magnesium and methanol.

[0363] The reducing agent can also be potassium borohydride, sodium borohydride, or a combination of lithium borohydride and a Lewis acid; the Lewis acid is selected from: lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, copper chloride, aluminum chloride, ferrous chloride, nickel chloride, and gallium dichloride. The inert solvent is selected from: C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof. Preferably, the reaction is carried out in a system containing sodium borohydride and lithium chloride.

[0364] In an inert solvent, at a certain temperature (e.g., -20°C to 25°C, preferably -10°C to 10°C), the compound of formula (IV) is reacted with a reducing agent for a period of time (e.g., 0.5 hours to 48 hours) to obtain the compound of formula (V-1).

[0365]

[0366] The reducing agent is a combination of potassium borohydride, sodium borohydride, or lithium borohydride with a Lewis acid; the Lewis acid is selected from: lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, copper chloride, aluminum chloride, ferrous chloride, nickel chloride, and gallium dichloride. The inert solvent is selected from: C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof. Preferably, the reaction is carried out in a system containing sodium borohydride and lithium chloride.

[0367] The reducing agent can also be a combination of metallic magnesium and methanol.

[0368] In an inert solvent, at a certain temperature (e.g., -20°C to 25°C, preferably -10°C to 10°C), the compound of formula (V) is reacted with a reducing agent for a period of time (e.g., 0.5 hours to 24 hours) to obtain the compound of formula (VI).

[0369]

[0370] Alternatively, in an inert solvent, at a certain temperature (e.g., -20°C to 25°C, preferably -10°C to 10°C), the compound of formula (V-1) is reacted with a reducing agent for a period of time (e.g., 0.5 hours to 24 hours) to obtain the compound of formula (VI-1).

[0371]

[0372] The inert solvent and reducing agent can be any combination of reducing agents and inert solvents known in the art, suitable for reducing ester groups to hydroxyl groups. The reducing agent can be selected from combinations such as red aluminum, palladium catalysts and hydrogen, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, triethyllithium borohydride, trisec-butyllithium borohydride, sodium borohydride, potassium borohydride, or combinations of lithium borohydride and Lewis acids, borane, diisobutylaluminum hydride, lithium tritert-butoxyaluminum hydride, lithium aluminum hydride, potassium hydroxide-diethylene glycol, samarium diiodide, [CpFe(CO)2(PCy3)][BF4] and phenylsilanes, etc. The inert solvent can be selected from C... 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof. Preferably, the reaction is carried out in a system containing aluminum hydroxide and an inert solvent selected from toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, and acetonitrile.

[0373] In an inert solvent, at a certain temperature (e.g., -20°C to 100°C, preferably -10°C to 50°C), the compound of formula (VI) and the compound of formula (VIa) are reacted in the presence of a base for a period of time (e.g., 0.5 hours to 24 hours) to obtain the compound of formula (VII-a), and then the compound of formula (VII-a) is purified to obtain the compound of formula (VII).

[0374]

[0375] Alternatively, in an inert solvent, at a certain temperature (e.g., -20°C to 100°C, preferably -10°C to 50°C), the compound of formula (VI-1) is reacted with the compound of formula (VIa) in the presence of a base for a period of time (e.g., 0.5 hours to 24 hours) to obtain the compound of formula (VII).

[0376]

[0377] Among them, rings A and R a R2 and n are defined as above, R b For hydrogen, halogen, C 1-3 Alkyl or C 1-3 alkoxy group; Z is N or CR3; R3 is hydrogen, halogen, or C. 1-3 Alkyl; m is 0, 1, or 2; R LG This indicates a leaving group, which can be, for example, halogen, amino, hydroxyl, (HO)2B-, borate ester, (NO2)2C6H3O-, CH3S(O)2O-, CF3S(O)2O-, p-CH3C6H4S(O)2O-, CH3S(O)2-, CH3S(O)-, etc.

[0378] The base in this reaction can be, for example, triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine, etc., or combinations thereof. The inert solvent can be, for example, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, etc., or combinations thereof.

[0379] The purification of compound (VII-a) to compound (VII) can be performed using various purification methods known in the art, including, for example, column chromatography. A preferred purification method is to treat compound (VII-a) or its solution with acid. The acid treatment involves treating the compound with a solution containing acid. The acid is selected from organic and inorganic acids, wherein the inorganic acids are selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid; and the organic acids are selected from: acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. The acid-containing solution is a solution containing the acid and a solvent selected from the following group: C 1-4Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or combinations thereof.

[0380] This invention provides a method for preparing a compound of formula (X), using a compound of formula (VII) as a starting material, and obtaining the compound of formula (X) through a deprotection reaction and a condensation reaction. The method includes the following steps:

[0381] In an inert solvent, at a certain temperature (e.g., -20°C to 100°C, preferably -10°C to 50°C), the compound of formula (VII) is subjected to a deprotection reaction for a period of time (e.g., 0.5 hours to 48 hours) to obtain the compound of formula (IX).

[0382]

[0383] Where ring A is a benzene ring, a pyridine ring, or a naphthalene ring;

[0384] (R a ) n This indicates that the hydrogen on ring A is separated by n R. a Replace, each R a Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkyl groups, and (R) b ) m This indicates that the hydrogen on the ring is divided by m R b Replace, each R b Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy;

[0385] R2 is C 1-3 alkyl;

[0386] m and n are each independently 0, 1 or 2;

[0387] Z represents N or CR3; R3 represents hydrogen, halogen, or C. 1-3 alkyl;

[0388] Those skilled in the art can select various known suitable reaction systems to carry out deprotection reactions based on the substrate structure, preferably in a system containing a palladium catalyst and selected from hydrogen and ammonium formate.

[0389] In an inert solvent, at a certain temperature (e.g., -10°C to 100°C, preferably 0°C to 80°C), the compound of formula (IX) is subjected to a condensation reaction with the compound 5-methyl-2-(pyrimidin-2-yl)benzoic acid, and after a reaction time (e.g., 0.5 hours to 24 hours), the compound of formula (X) is obtained.

[0390]

[0391] Among them (R) b ) m This indicates that the hydrogen on the ring is divided by m R b Replace, each R b Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 alkoxy group; m is 0, 1, or 2; Z is N or CR3; R3 is hydrogen, halogen, or C. 1-3 Alkyl groups. Those skilled in the art can select various known suitable condensing agents and inert solvents to carry out this reaction. For example, condensing agents can be selected from T3P, CDI, EDCI, HOBt, HATU, etc. Inert solvents can be selected from toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, etc., or combinations thereof.

[0392] This invention provides a method for preparing compound (IX) using novel intermediate compounds of formula (I) and formula (VII). Compared with the prior art, this synthetic method has the following advantages:

[0393] 1. The preparation process of the starting materials is simpler and easier to purify to obtain the required isomer intermediate product. It overcomes the shortcomings of the existing technology that cannot separate and purify the required configuration intermediate in the early synthesis steps, and avoids the large consumption of organic solvents and long purification process caused by the column chromatography purification of the existing technology, which is more conducive to scale-up production.

[0394] 2. The intermediates obtained from the starting materials of this invention are easier to separate and purify in the early stages of the reaction to obtain the desired isomer intermediate products, which greatly reduces the difficulty of separating and purifying the by-products (isomers) generated in the later stages, improves the atom economy of the reaction, and reduces the generation of waste.

[0395] 3. The preparation of starting materials avoids the use of dangerous reagents such as sodium hydroxide, while improving the selectivity of the reaction and greatly reducing the operational risks of process scale-up.

[0396] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise defined. Unless otherwise defined, the terms used herein have the same meaning as those familiar with the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the present invention.

[0397] Reagents and Instruments

[0398] 1 HNMR: Bruker AVANCE-400 NMR spectrometer, internal standard: tetramethylsilane (TMS).

[0399] LC-MS: Agilent 1290 HPLC System / 6130 / 6150 MS liquid chromatography-mass spectrometry (manufacturer: Agilent), Waters BEH / CHS column, 50×2.1mm, 1.7μm.

[0400] HPLC analysis was performed using an Agilent 1260 Infinity HPLC system, OpenLAB CDS Chemstationworkstation, XBridge C18 4.6*250mm column, ID 5μm column, and DAD detector.

[0401] An ISCO Combiflash-Rf75 or Rf200 automatic column chromatography system was used, with Agela disposable silicone columns in sizes of 4g, 12g, 20g, 40g, 80g, and 120g.

[0402] Specific rotation was measured using a Rudolf Autopol VI polarimeter at a temperature of 20°C.

[0403] The single-crystal structure was measured using a D8 Venture X-ray single-crystal diffractometer. Light source: Cu target, X-rays: Detector: CMOS surface detector, resolution Current and voltage: 50kV, 1.2mA, exposure time 10s, distance from surface detector to sample 40mm, test temperature 150(2)K.

[0404] The known starting materials can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCRGmbH & Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc., and Darui Chemicals.

[0405] Unless otherwise specified, the reactions in the examples are carried out under a nitrogen or argon atmosphere.

[0406] As used in this article, DMB is 2,4-dimethoxybenzyl, THF is tetrahydrofuran, EA is ethyl acetate, PE is petroleum ether, Ac2O is acetic anhydride, NBS is N-bromosuccinimide, DCM is dichloromethane, AIBN is azobisisobutyronitrile, Pd(dppf)Cl2 is 1,1'-bis(diphenylphosphine)ferrocene[1,1'-palladium dichloride], TFA is trifluoroacetic acid, TBSCl is tert-butyldimethylchlorosilane, NCS is N-chlorosuccinimide, D... HP stands for dihydrotetrahydropyran, LiAlH4 for lithium aluminum hydride, PMB for p-methoxybenzyl, LiHMDS for bis(trimethylsilyl)aminolithium, Pd2(dba)3 for tris(dibenzylacetone)dipalladium, RuPhos for 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl, DMAP for 4-dimethylaminopyridine, THP for tetrahydrotetrahydropyran, n-BuLi for n-butyllithium, and TMsOTf for trimethylsilyl trifluoromethanesulfonate. TEBAC is triethylbenzylammonium chloride, HATU is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, DMF is dimethylformamide, DMSO is dimethyl sulfoxide, DIEA is N,N-diisopropylethylamine, BINAP is (2R,3S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, LDA is diisopropylaminolithium; MsCl is methanesulfonyl chloride; rt is room temperature; TEA is triethylamine. DBU is 1,8-diazabicycloundec-7-ene; CDI is carbonyl diimidazole; MeOH is methanol; EtOH is ethanol; IPA is isopropanol; ACN is acetonitrile; MEK is butanone; MIBK is methyl isobutyl ketone; MTBE is methyl tert-butyl ether; T3P is propyl phosphoric anhydride; EDCI is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBt is 1-hydroxybenzotriazole; Ph is phenyl; and sodium dithionite is sodium dithionite.

[0407] As used in this article, room temperature refers to approximately 20-25°C.

[0408] Example 1: Preparation of Compound 1

[0409]

[0410] Step 1: Cool a mixture of 200g of 1,3-propanone dicarboxylic acid, 280mL of acetic acid, and 200mL of toluene to 5-10℃, and slowly add 220mL of acetic anhydride dropwise. After the addition is complete, continue stirring for 4-10 hours. Filter the mixture, and dry the filter cake under reduced pressure at 40-50℃ for 6 hours to obtain 224g of compound 1-a as a white solid, with a yield of 87%. MS m / z (ESI): 129 [M+H] + .

[0411] Step 2: Add 107g of compound 1-a to the reaction flask, add 215mL of isopropanol dropwise at 0-15℃, control the internal temperature at 5-20℃, stir until dissolved, add 300mL of ice water, store at 0-10℃, and use directly in the next reaction without purification.

[0412] Example 2: Preparation of Compound 2

[0413]

[0414] Add 25g of compound 1-a to a reaction flask, and add 50mL of ethanol dropwise at 0-15℃. After the addition is complete, raise the temperature to room temperature and continue stirring for 3 hours. Add 70mL of water and store at 0-10℃. It can be used directly in the next reaction without purification.

[0415] Example 3: Preparation of compound 4-1

[0416]

[0417] Step 1.1: Add 33.2 mL of concentrated hydrochloric acid and 177.3 mL of water to reaction flask ①, then add 86.3 g of compound b, heat to 50-55 °C, stir for 3 hours, then cool to about 25 °C, and add 430 mL of water for later use.

[0418] Step 1.2: Add 140 mL of concentrated hydrochloric acid and 740 mL of water to reaction flask ②, cool to 5-15 °C, and add 79.1 g of compound 3 dropwise with stirring for later use.

[0419] Step 1.3: Slowly add the solution from reaction flask ① to reaction flask ②, stir for 0.5 hours, add the solution prepared and preserved in Example 1 to reaction flask ②, then add 250 mL of aqueous solution containing 53.5 g of sodium acetate, and then add 40% sodium hydroxide solution to adjust the pH value to about 3-4. Maintain the internal temperature at 5-15℃ and stir for 12 hours. Add 20% sodium hydroxide solution dropwise until the pH reaches approximately 12, extract with 1L of ethyl acetate, separate the layers, add anhydrous sodium sulfate to dry the ethyl acetate layer, filter, concentrate the filtrate to obtain 203.5g of red oily substance (containing a mixture of compounds 4-1 and 4-2; HPLC (column: XBridge C18 4.6*250mm, ID 5μm column; mobile phase: A: water [0.1% trifluoroacetic acid] B: acetonitrile [0.1% trifluoroacetic acid]; gradient: 5%-95% B within 19.5 min; flow rate: 1.2ml / min; detection wavelengths: 220nm, 254nm, column temperature: 30℃) showed that the molar ratio of compound 4-1 (retention time 8.587min) to 4-2 (retention time 8.510min) was 1.74:1), with a yield of 98.8%, which was directly used in the next step.

[0420] Step 2: Add 203.5 g of the obtained mixture and 500 mL of ethyl acetate to a reaction flask. Slowly add 330 mL of HCl / ethyl acetate (concentration 2.0 mol / L) dropwise at 0–5 °C. After the addition is complete, continue stirring at 0–5 °C for 3–4 hours. Filter, wash the filter cake with EA, and dry the filter cake under vacuum at 50 °C to obtain 79.5 g of the hydrochloride of compound 4-1, a pale yellow solid with a purity of 97.5%. MS m / z (ESI): 316.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)=11.63(br s,1H),7.98(d,J=6.4,1H),7.76(d,J=6.5,1H),7.48(m,3H),4.86(m,1H),4.56(m,1H),4.24(m,1H),3.70(m,1H) ,3.38(m,1H),2.57(m,1H),2.19~1.91(m,5H),1.74(d,J=6.6,3H),1.30(dd,J=1.4,6.2,3H),1.06(d,J=6.2,3H).

[0421] Step 3: Mix 60.0 g of the hydrochloride of compound 4-1 with 300 mL of ethyl acetate and stir. At 0–10 °C, add 20% sodium hydroxide solution dropwise until the pH is alkaline. Stir for 0.5 hours, allow to stand and separate into layers. Extract the aqueous phase with ethyl acetate 300 mL × 2 times. Combine the organic phases, dry with anhydrous sodium sulfate, filter, wash the filter cake with ethyl acetate, and concentrate the filtrate to obtain 52 g of compound 4-1 as a red oily substance with a yield of 96.6% and a purity of 97.3%.

[0422] Comparative Example 1

[0423] The molar ratios of compounds 4-1 and 4-2 in the resulting mixtures at different reaction temperatures and pH values ​​are shown in Tables 1 and 2 below:

[0424] Table 1 shows the effect of reaction temperature on the content of product isomers at a reaction solution pH of 3.4.

[0425] compound Reaction temperature 5℃ Reaction temperature 20℃ Reaction temperature 45℃ 4-1 40.04％ 39.58％ 33.15％ 4-2 29.27％ 25.54％ 21.51％

[0426] Table 2 shows the effect of reaction solution pH on the content of product isomers at reaction temperatures of 5–15 °C.

[0427] compound pH = 1.1 pH = 2.89 pH = 3.42 pH = 4.01 pH = 5.2 4-1 38.59％ 44.75％ 43.81％ 44.68％ 24.44％ 4-2 19.53％ 27.22％ 29.27％ 34.1％ 22.37％

[0428] As shown in Tables 1 and 2, the reaction temperature and pH value of the reaction solution in step 1.3 of Example 3 have a significant impact on the molar ratio of compound 4-1 and compound 4-2 in the resulting mixture. At a reaction temperature of around 45°C, the content of target product 4-1 decreases significantly, while the content of target product 4-1 is higher at reaction temperatures of 5°C and 20°C. The content of target product 4-1 is higher at reaction solution pH values ​​of 2.89, 3.42, and 4.01. When the reaction solution pH value is 5.2, the overall product content decreases significantly, as does the content of target product 4-1, and the impurity content in the reaction solution increases significantly. At a reaction solution pH value of 1.1, both the overall product content and the content of target product 4-1 decrease.

[0429] Example 4:

[0430]

[0431] Step 1.1: Add 7.5 mL of concentrated hydrochloric acid and 40 mL of water to reaction flask ③, then add 20.2 g of compound b, heat to 50-55 °C, stir for 3 hours, then cool to about 25 °C, and add 100 mL of water for later use.

[0432] Step 1.2: Add 32 mL of concentrated hydrochloric acid and 168 mL of water to reaction flask ④, cool to 5-15 °C, and add 18.5 g of compound 3 dropwise with stirring for later use.

[0433] Step 1.3: Slowly add the solution from reaction flask ③ to reaction flask ④, stir for 0.5 hours, add the solution prepared and preserved in Example 2 to reaction flask ④, then add 65 mL of aqueous solution containing 12.5 g of sodium acetate, and then add 40% sodium hydroxide solution to adjust the pH value to about 3-4. Stir overnight at room temperature. Add 20% sodium hydroxide solution dropwise until the pH reaches approximately 12, extract with 200 mL of ethyl acetate, separate the layers, dry the ethyl acetate layer with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 45.2 g of a red oily substance (containing a mixture of compounds 4-3 and 4-4; HPLC (column: XBridge C18 4.6*250 mm, ID 5 μm column; mobile phase: A: water [0.1% trifluoroacetic acid] B: acetonitrile [0.1% trifluoroacetic acid]; gradient: 5%-95% B within 19.5 min; flow rate: 1.2 mL / min; column temperature: 30 °C) showed that the molar ratio of compound 4-3 (retention time 8.057 min) to 4-4 (retention time 7.987 min) was 1.65:1), yield 98.3%. MS m / z (ESI): 302.1 [M+H] + .

[0434] Comparative Example 2

[0435]

[0436] Step 1.1: Add 20 mL of concentrated hydrochloric acid and 100 mL of water to reaction flask ⑤, then add 50 g of compound b, heat to 50-55 °C, stir for 3 hours, then cool to about 25 °C, and add 250 mL of water for later use.

[0437] Step 1.2: Add 80 mL of concentrated hydrochloric acid and 420 mL of water to reaction flask ⑥, cool to 5-15 °C, and add 45.8 g of compound 3 dropwise with stirring for later use.

[0438] Step 1.3: Slowly add the solution from reaction flask ⑤ to reaction flask ⑥. After stirring for 0.5 hours, add 250 mL of an aqueous solution containing 70.8 g of 1,3-acetone dicarboxylic acid to reaction flask ⑥, followed by 150 mL of an aqueous solution containing 31 g of sodium acetate. Adjust the pH to approximately 3-4 by adding 40% sodium hydroxide solution dropwise. Stir overnight at room temperature. Add 20% sodium hydroxide solution dropwise until the pH reaches approximately 12. Extract with 500 mL of ethyl acetate, separate the layers, dry the ethyl acetate layer with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 81.2 g of crude product with a purity of 60.1%. Column chromatography purification yields 3.6 g of compound 13 as a yellow solid with a purity of 89.3%. MS m / z (ESI): 230.2 [M+H] + .

[0439] Step 2: Add 20 ml of anhydrous toluene to a 100 ml three-necked flask. Under nitrogen protection, add 0.5 g of NaH in portions, while simultaneously adding 0.8 g of diethyl carbonate dropwise. After the addition is complete, stir until no more bubbles are released. Raise the temperature to 85-95℃, and add dropwise a solution of 1.0 g of compound 13 dissolved in 5 mL of toluene, controlling the temperature at approximately 95℃. After the addition is complete, continue stirring at this temperature for 1 hour, and take a sample for testing; the reaction is complete. Cool the reaction solution to approximately 60℃, and quench it by pouring it into a mixture of 60 mL of ice water, 30 mL of ethyl acetate, and 5 mL of hydrochloric acid, stirring continuously and controlling the temperature below 10℃ during the process. After complete quenching, the mixture was allowed to stand and separate into layers. The aqueous phase was then extracted with 30 mL of ethyl acetate. The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at 55 °C to give 1.0 g of a red oily substance (a mixture of compounds 4-3 and 4-4; HPLC (column: XBridge C18 4.6*250 mm, ID 5 μm column; mobile phase: A: water [0.1% trifluoroacetic acid] B: acetonitrile [0.1% trifluoroacetic acid]; gradient: 5%-95% B over 19.5 min; flow rate: 1.2 mL / min; column temperature: 30 °C) showed that the molar ratio of compounds 4-3 to 4-4 was 0.4:1), yielding 75.2%. MS m / z (ESI): 302.1 [M+H] + .

[0440] Comparative Example 3

[0441]

[0442] Equal amounts of the mixture containing compounds 4-1 and 4-2 were weighed and added to ethyl acetate, respectively. Then, HCl and D-tartaric acid were slowly added at room temperature, and the mixture was stirred for 3-4 hours at room temperature. The reaction state was observed, and the amount of each reactant added and the reaction phenomena are shown in Table 3 below:

[0443] Table 3

[0444]

[0445] Example 5-1: Preparation of Compound 8

[0446]

[0447] Step 1: Add 52g of compound 4-1 and 250mL of methanol to a three-necked flask. Under nitrogen protection, add 12.5g of sodium borohydride in portions while stirring at -10℃. Stir for 2 hours, monitoring the reaction until complete using LCMS. Control the internal temperature to -10~0℃, and quench the reaction by adding 80mL of water and 40mL of saturated ammonium chloride solution dropwise. Concentrate the reaction solution, extract with 300mL of ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, filter, wash the filter cake with ethyl acetate, and concentrate under reduced pressure to obtain 52.2g of a reddish-brown oil (compound 5), purity: 86.6%, yield: 100%. MS m / z (ESI): 318.2 [M+H] + .

[0448] Step 2: 47.3 g of compound 5 and 250 mL of toluene were added to a reaction flask and stirred. 18.6 g of sodium tert-butoxide was added at 0–10 °C, followed by slow dropwise addition of 120 mL of a toluene solution containing 34.1 g of p-toluenesulfonyl chloride. After the addition was complete, the mixture was stirred at 0–10 °C for 1 hour. 20.0 g of sodium tert-butoxide was then added, and the mixture was stirred overnight. The reaction was monitored for completeness by LC-MS. The reaction was quenched with 300 mL of water, stirred for 30 minutes, and allowed to stand to separate the phases. The organic layer was washed with 150 mL of saturated sodium chloride solution and 300 mL of 2 mol / L hydrochloric acid. The aqueous phases were combined, and 20% sodium hydroxide solution was added dropwise until the pH was alkaline. The mixture was extracted with 500 mL × 2 of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 34.2 g of a reddish-brown oil (compound 6), with a yield of 76.7% and a purity of 89.2%. MS m / z (ESI): 300.2 [M+H] + .

[0449] Step 3: Dissolve 21.4 g of compound 6 in 160 mL of methanol. Add 15.4 g of magnesium shavings in portions at 0–10 °C, stirring continuously until the reaction is complete. Quench with 90 mL of acetic acid and 45 mL of water. Concentrate under reduced pressure to remove methanol. Add 215 mL of ethyl acetate to the residue, and add 20% potassium carbonate solution dropwise to adjust the pH to 6–7. Allow to stand and separate the layers. Wash the organic layer with 150 mL of saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 18.1 g of a red oil (compound 7). Yield 84.2%, purity 82.5%. MS m / z (ESI): 302.2 [M+H] + .

[0450] Step 4: Under nitrogen protection, 18.1 g of compound 7 (1.0 eq) and 180 mL of toluene were added to a reaction flask. 52 g of a toluene solution containing 70% red aluminum (3.0 eq) was added dropwise at 0–5 °C. The reaction mixture was stirred at room temperature for 18 hours. The pH was adjusted to greater than 12 by adding 20% ​​sodium hydroxide solution dropwise at 0–10 °C. The mixture was filtered, and the filtrate was allowed to separate into layers. The aqueous phase was extracted with 100 mL of ethyl acetate. The combined organic layers were washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 15.8 g of a red oil (compound 8), yield 98.5%, MS m / z (ESI): 246.2 [M+H]. + It can be used directly in the next reaction.

[0451] Example 5-2: Preparation of Compound 11

[0452]

[0453] Step 1: Under nitrogen protection, 14.7g of compound 8 and 300mL of toluene were added to a reaction flask and stirred. 11.0g of 2,5-difluoropyridine (compound 9) and 23.1g of sodium tert-butoxide were added at 0-10℃ and stirred at room temperature until the reaction was complete. Add 88 mL of water dropwise to the reaction solution, allow to stand and separate. Extract the aqueous layer with ethyl acetate 2 × 60 mL, combine the organic layers, filter, dry to anhydrous sodium sulfate, filter again, concentrate under reduced pressure to obtain 18.3 g of red oil (compound 10). HPLC (column: XBridge C18 4.6*250 mm, ID 5 μm column; mobile phase: A: water [10 mmol / L NH4HCO3] B: acetonitrile; gradient: 50%-90%-90%-50%-50%B within 21 min; flow rate: 1.0 mL / min; detection wavelength: 210 nm, column temperature: 30 °C) showed that the molar ratio of compound 10-1 (retention time 13.628 min) to compound 10-2 (retention time 10.188 min) was 82.3:6.9, the yield of compound 10 was 89.7%, and the purity was 80.8%.

[0454] Step 2: 18.3 g of compound 10 and 180 mL of ethyl acetate were added to a 500 mL three-necked flask and stirred. 40 mL of 2 mol / L HCl / ethyl acetate was added dropwise under ice bath conditions. A large amount of solid precipitated. Stirring was continued for 3–4 hours under ice-water bath conditions. The mixture was filtered, and the solid was dried under vacuum at 50 °C. 19.0 g of compound 10⁻¹ hydrochloride was obtained, with a yield of 93.8% and a purity of 82.9%. 380 mL of isopropanol was added to the obtained 19.0 g of compound 10⁻¹ hydrochloride. The mixture was heated to 80 °C and stirred for 3 hours. It was then stirred overnight at room temperature. The mixture was filtered, and the filter cake was dried under reduced pressure to obtain 13.4 g of a white solid, with a yield of 70.5%, a purity of 96.3%, and an ee value of 99.8%. MS m / z (ESI): 341.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)=9.36(s,1H),8.09(d,J=2.8,1H),7.73(d,J=3.3,2H),7.66(m,1H),7.40(m,1H),7.33(m,2H),6.33(dd,J =3.6,9.2,1H),4.70(m,1H),4.37(m,2H),4.27(m,1H),2.57(m,1H),2.14(m,7H),1.73(d,J=6.6,3H),1.64(m,1H),1.37(m,1H).

[0455] The chirality detection methods are shown in Table 4 below:

[0456] Table 4

[0457]

[0458]

[0459] Step 3: Add 5.0 g of compound 10-1 hydrochloride, 100 mL of methanol, and 0.5 g of palladium on carbon to a 250 mL three-necked flask. Stir at room temperature, then add 4.2 g of ammonium formate and stir overnight. Filter by suction, add 50 mL of water, and remove most of the methanol by rotary evaporation. Add NaOH solution (2 M) dropwise until the pH is alkaline. Extract with ethyl acetate (100 mL, 50 x 2). Wash the organic phase with saturated NaCl solution (50 mL), dry with anhydrous sodium sulfate, and rotary evaporate to obtain 3.13 g of compound 11 as a colorless and transparent liquid. Yield: 100%, purity: 95.1%.

[0460] 3.13 g of compound 11 and 23 mL of ethyl acetate were added to a 100 mL three-necked flask. A D-tartaric acid aqueous solution (2.1 g D-tartaric acid dissolved in 3 g water) was added dropwise while stirring at 50 °C. The mixture was cooled to 5-15 °C and stirred overnight. A white solid precipitated. The precipitate was filtered, and the filter cake was washed with 2.5 mL x 2 portions of water. The mixture was then dried under vacuum at 40-50 °C to obtain 4.5 g of white solid. 25 g of water was added to the solid, and the mixture was adjusted to pH > 9 with 10% sodium hydroxide solution under ice-water bath conditions. The solid was extracted with ethyl acetate, washed with saturated brine, and concentrated to obtain 2.4 g of a pale yellow oily compound 11. Yield: 77.7%, purity: 98.6%, ee value: 99.8%. The absolute configuration of compound 11 can be deduced through single-crystal X-ray structural analysis of compound 12. MS m / z (ESI): 237.2 [M+H] + .

[0461] Example 5-3: Preparation of Compound 7

[0462]

[0463] 21.4 g of compound 6 was dissolved in 160 mL of methanol. At 5–25 °C, 15.4 g of magnesium shavings were added in portions, and the reaction was continued with stirring until complete. The mixture was quenched with 90 mL of acetic acid and 45 mL of water. The methanol was removed by concentration under reduced pressure. 215 mL of ethyl acetate was added to the residue, and 20% potassium carbonate solution was added dropwise to adjust the pH to 6–7. The mixture was allowed to stand and separate into layers. The organic layer was washed with 150 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 19.8 g of a red oily substance (compound 7). HPLC analysis (column: XBridge C18 4.6*250mm, ID 5μm column; mobile phase: A: water [10mmol / L NH4HCO3], B: acetonitrile; gradient: 50%-90%-90%-50%-50%B over 21 min; flow rate: 1.0 mL / min; column temperature: 30℃) showed a molar ratio of compound 7-1 (retention time 11.072 min) to compound 7-2 (retention time 10.354 min) of 81:7, with a yield of 91.9% and a purity of 83%. MS m / z (ESI): 302.2 [M+H] + .

[0464] Examples 5-4: Preparation of Compound 7

[0465]

[0466] 3g of compound 6, 30ml of tetrahydrofuran, 1g of NaBH4, and 0.3g of LiCl were added to a 250ml three-necked flask. The reaction mixture was stirred overnight at room temperature. LC-MS showed that the reaction was incomplete. 1.9g of NaBH4, 1g of LiCl, and 5ml of methanol were added, and the mixture was stirred at room temperature for another 72 hours until the reaction was complete. 100ml of water was added to the reaction mixture, resulting in a large amount of bubbles. The reaction mixture was extracted three times with 50ml of ethyl acetate, and the extracts were combined. The extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 2.8g of an oily substance (compound 7). HPLC (column: ACQUITYUPLC CSH C18, 2.1*50mm, ID 1.7μm; mobile phase: A: water [0.01% trifluoroacetic acid], B: acetonitrile [0.01% trifluoroacetic acid]; gradient: 5%-95% B within 15 min; flow rate: 0.8 mL / min) showed a molar ratio of compound 7-1 (retention time 0.96 min) to compound 7-2 (retention time 0.93 min) of 94.5:5.5, with a yield of 93% and a purity of 87% for compound 7. MS m / z (ESI): 302.2 [M+H] + .

[0467] Example 6: Preparation of Compound 12

[0468]

[0469] Add 2.4 g of compound 11, 2.6 g of 5-methyl-2-(pyrimidin-2-yl)benzoic acid, and 27 g of ethyl acetate to a reaction flask. Stir at below 25°C, add 7.0 g of T3P solution dropwise, and continue stirring for 0.5 h after the addition is complete. Raise the temperature to 50-60°C and stir for 2 h. Take a sample to check if the reaction is complete. Cool to 10°C-30°C, slowly add 30.0 g of water, and stir for 16 h after the addition is complete. Allow to stand and separate the layers. Extract the aqueous layer once with 27 g of ethyl acetate. Combine the organic layers, add 30.0 g of water to the organic layer, adjust the pH to 9-10 with 4% NaOH solution, allow to stand and separate the layers. Wash the organic layer once with 30 g of water, concentrate under reduced pressure, add 15.0 g of ethyl acetate and stir for 16 h. Filter, wash the filter cake twice with 2.0 g of ethyl acetate, and dry by rotary evaporation for 1 h to obtain 3.0 g of crude compound 12, a light yellow solid, with a yield of 68.2% and a purity of 98.7%.

[0470] In a 50 mL three-necked flask, add 3.0 g of crude compound 12, 7.8 g of ethyl acetate, and 0.234 g of isopropanol. Stir and heat to 65-80 °C. After dissolving completely, slowly cool to 50-60 °C (1.5-2.0 h), precipitating a solid. Continue cooling to 40-50 °C and maintain this temperature with stirring for 24 h. Continue slowly cooling to 10-20 °C and maintain this temperature with stirring for 24 h. Filter under vacuum, and wash the filter cake with 1 mL x 2 ethyl acetate. Dry the filter cake under vacuum at 40-50 °C for 1 h to obtain 2.17 g of a pale yellow solid product. Yield: 70.0%, purity: 99.4%. [α] 589 20 = -48.0° (c = 1, methanol). MS m / z (ESI): 433.2 [M+H] + . 1 ¹H NMR (400MHz, DMSO-d6) = 8.83 (br.s., 2H), 8.17–8.01 (m, 2H), 7.49–7.33 (m, 3H), 6.86 (dd, J = 3.5, 9.0Hz, 1H), 6.86 (dd, J = 3.5, 9.0Hz, 1H), 4.63 (br.s., 1H), 4.43 (m, 1H), 4.11 (br.s., 1H), 3.79 (m, 1H), 2.52–2.48 (m, 2H), 2.35–1.95 (m, 8H), 1.29–1.20 (m, 2H). Weigh approximately 300 mg of the purified compound 12, dissolve it in 2 mL of ethyl acetate at room temperature, and filter to remove insoluble matter. Add approximately 1 mL of methyl tert-butyl ether to the filtrate and let it stand. Approximately 24 hours later, pale yellow fine crystals precipitated, with a single crystal structure as shown. Figure 1 As shown.

[0471] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing a compound of formula (I), characterized in that, Including the following steps: (1) In an inert solvent, compounds of formula a, b and c are subjected to a cyclization reaction to obtain a mixture containing compound (I); Where ring A is a benzene ring, a pyridine ring, or a naphthalene ring; R a For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkoxy; R1 and R2 are each independently C 1-3 alkyl; n is 0, 1, or 2; (2) The mixture containing the compound of formula (I) was treated with acid to obtain a salt of the compound of formula (I); and (3) Treat the salt of the obtained compound (I) to obtain compound (I); In step (1), the cyclization reaction is carried out in a system with a pH value of 1 to 5, and the temperature of the cyclization reaction is -20°C to 50°C. In step (2), the acid is hydrochloric acid.

2. The preparation method according to claim 1, characterized in that, The compound of formula a is prepared by reacting 2H-pyran-2,4,6-(3H,5H)trione with an alkyl alcohol R1OH: Where R1 is C 1-3 alkyl.

3. The preparation method according to claim 1, characterized in that, The reaction in step (1) is carried out in a system containing a pH adjuster.

4. The preparation method according to claim 1, characterized in that, In step (2), the acid treatment of the resulting mixture containing compound (I) is carried out with an acid-containing solution.

5. The preparation method according to claim 4, characterized in that, In the acid-containing solution, the concentration of the acid is from 0.1 mol / L to 10 mol / L.

6. The preparation method according to claim 1, characterized in that, Step (1) includes the following steps: (1a) 2H-pyran-2,4,6-(3H,5H)trione was reacted with C 1-3 The alkyl alcohol reacts to obtain a reaction solution 1a containing the compound of formula a; (1b) Treat the mixture of compound b and the first solvent with acid to obtain mixture 1b; The first solvent is selected from water, C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof; (1c) Treat the mixture of compound c and the second solvent with acid to obtain mixture 1c; The second solvent is selected from water, C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof; and (1d) In the presence of a pH adjuster system, reaction solution 1a, mixture 1b and mixture 1c are mixed to carry out a cyclization reaction, thereby obtaining a mixture containing compound (I); The order of steps (1a), (1b) and (1c) can be arbitrarily changed.

7. The preparation method according to claim 6, characterized in that, The pH adjuster mentioned in step (1d) is selected from sodium acetate, sodium hydroxide, and a combination of sodium acetate and sodium hydroxide.

8. The preparation method according to claim 6, characterized in that, In step (1d), the reaction is carried out under conditions with a pH of 1 to 5.

9. The preparation method according to claim 6, characterized in that, In step (1d), the reaction temperature is between -20°C and 50°C.

10. The compound of formula (I) or a salt thereof obtained by the preparation method according to claim 1: in, Ring A can be a benzene ring, a pyridine ring, or a naphthalene ring; R a For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkoxy; R1 and R2 are each independently C 1-3 alkyl; n is 0, 1, or 2.

11. The compound or a salt thereof as claimed in claim 10, characterized in that, The salt is a salt formed by the compound of formula (I) and an acid.

12. The compound or a salt thereof as claimed in claim 11, characterized in that, The acid is an inorganic acid.

13. A method for preparing a compound of formula (VII), characterized in that, The method includes the step of: purifying the compound of formula (VII-a) to obtain the compound of formula (VII); in, Ring A can be a benzene ring, a pyridine ring, or a naphthalene ring; R a For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkyl groups, and (R) b ) m This indicates that the hydrogen on the ring is divided by m R b Replace, each R b Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy; R2 is C 1-3 alkyl; m and n are each independently 0, 1 or 2; Z represents N or CR3; R3 represents hydrogen, halogen, or C. 1-3 alkyl; The method for preparing the compound of formula (VII-a) includes the steps of: in an inert solvent and in the presence of a base, reacting the compound of formula (VI) with the compound of formula (VIa) by a substitution reaction to obtain the compound of formula (VII-a); Among them, ring A is a benzene ring, a pyridine ring, or a naphthalene ring; R a Hydrogen, halogens, C 1-3 Alkyl or C 1-3 Alkyl groups, and (R) b ) m This indicates that the hydrogen on the ring is divided by m R b Replace, each R b Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy; R2 is C 1-3 alkyl; m and n are each independently 0, 1 or 2; Z represents N or CR3; R3 represents hydrogen, halogen, or C. 1-3 alkyl; R LG Selected from halogens, amino groups, hydroxyl groups, (HO)2B-, borate esters, (NO2)2C6H3O-, CH3S(O)2O-, CF3S(O)2O-, p-CH3C6H4S(O)2O-, CH3S(O)2-, CH3S(O)-; The compound of formula (VI) is prepared by a method comprising the following steps: (a) The compound of formula (I) is reduced to obtain the compound of formula (III); (b) The compound of formula (III) is subjected to an elimination reaction to obtain the compound of formula (IV); (c) Reduction of compound (IV) to obtain compound (V); and (d) The compound of formula (V) is reduced to obtain the compound of formula (VI); In the above formulas, ring A is a benzene ring, a pyridine ring, or a naphthalene ring; R a For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkoxy; n is 0, 1, or 2; R1 and R2 are each independently C 1-3 alkyl; The compound of formula (I) is prepared by the method of claim 1.

14. The preparation method according to claim 13, characterized in that, The reduction reaction in step (a) is carried out in a system containing a reducing agent and an inert solvent, wherein the reducing agent is selected from: (a) Tetrabutylamine borohydride, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, potassium borohydride, borane, isopropanol-triisopropoxyaluminum, lithium aluminum hydride, lithium tritert-butoxyaluminum hydride, samarium diiodide; (b) Combinations of zinc and Lewis acids; and (c) A combination of a catalyst selected from palladium, nickel, platinum and lead and a hydrogen donor selected from hydrogen, formic acid and formate; The inert solvent is selected from: water, C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof.

15. The preparation method according to claim 13, characterized in that, The elimination reaction in step (b) is carried out in a system containing the following reagents: hydroxyl activator, base and inert solvent.

16. The preparation method according to claim 15, characterized in that, The hydroxyl activator is a sulfonyl chloride, which is selected from: benzenesulfonyl chloride, p-toluenesulfonyl chloride, and methanesulfonyl chloride.

17. The preparation method according to claim 15, characterized in that, The base is selected from: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine, or combinations thereof.

18. The preparation method according to claim 15, characterized in that, The base is selected from: ammonia, triethylamine, diisopropylethylamine, N,N-dimethylaniline, tetramethylethylenediamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene, pyrazole, imididine, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium acetate, sodium phenolate, sodium benzoate, sodium citrate, N-methylmorpholine, pyridine, or combinations thereof.

19. The preparation method according to claim 15, characterized in that, The inert solvent is selected from: toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, or combinations thereof.

20. The preparation method according to claim 13, characterized in that, The reduction reaction in step (c) is carried out in a system containing a reducing agent and an inert solvent, wherein the reducing agent is selected from: (a) metallic magnesium, alkylsilane hydrides, sodium borohydride, lithium borohydride, potassium borohydride, hydrides of tin, selenium or tellurium, borane, sodium dithionite, olefin reductase, yeast enzyme; (b) A combination of zinc and a hydrogen donor selected from formic acid and formate; (c) A combination of tin, carbon monoxide and water; (d) Combinations of complexes selected from palladium, rhodium, cobalt, nickel, ruthenium, iridium, and copper with hydrogen donors selected from hydrogen, formic acid, and formate; and (e) A combination of a catalyst selected from palladium or nickel and a hydrogen donor selected from hydrogen, formic acid or formate; The inert solvent is selected from: C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof.

21. The preparation method according to claim 13, characterized in that, The reduction reaction in step (c) is carried out in a system containing a reducing agent, a Lewis acid, and an inert solvent, wherein the reducing agent is selected from potassium borohydride, sodium borohydride, and lithium borohydride. The inert solvent is selected from: C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof; The Lewis acid is selected from: lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, copper chloride, aluminum chloride, ferrous chloride, nickel chloride, and gallium dichloride.

22. The preparation method according to claim 13, characterized in that, The reduction reaction is carried out in a system containing a reducing agent and an inert solvent, wherein the reducing agent is selected from: (a) Red aluminum, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, lithium triethylborohydride, lithium trisec-butylborohydride, potassium borohydride, borane, aluminum diisobutylhydride, lithium tritert-butoxyaluminum hydride, lithium tetraaluminum hydride, potassium hydroxide-diethylene glycol, samarium diiodide; (b) A combination of palladium catalyst and hydrogen; (c) A combination of sodium borohydride, potassium borohydride, or lithium borohydride and a Lewis acid; and (d) A combination of [CpFe(CO)2(PCy3)][BF4] and phenylsilane; The inert solvent is selected from: C 1-4 Alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof.

23. The preparation method according to claim 13, characterized in that, The substitution reaction is carried out in a system containing a base and an inert solvent, wherein the base is selected from: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine, or combinations thereof; The inert solvent is selected from: toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, or combinations thereof.

24. The preparation method according to claim 13, characterized in that, Compounds of formula (VIa) are selected from:

25. The preparation method according to claim 13, characterized in that, The preparation method further includes the step of: reacting the compound of formula (VII) with an acid to form a salt of the compound of formula (VII).

26. The preparation method according to claim 13, characterized in that, The purification process involves acidifying the compound of formula (Ⅶ-a) or its solution.

27. The preparation method according to claim 26, characterized in that, The acid treatment is performed using a solution containing acid.

28. The preparation method according to claim 27, characterized in that, The acid is selected from organic acids and inorganic acids, wherein the inorganic acids are selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid; and the organic acids are selected from: acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid.

29. The compound of formula (VII-a) or a salt thereof obtained by the preparation method according to claim 13: in, Ring A can be a benzene ring, a pyridine ring, or a naphthalene ring; R a For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkyl groups, and (R) b ) m This indicates that the hydrogen on the ring is divided by m R b Replace, each R b Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy; R2 is C 1-3 alkyl; m and n are each independently 0, 1 or 2; Z represents N or CR3; R3 represents hydrogen, halogen, or C. 1-3 alkyl; The salt is a salt formed by a compound of formula (Ⅶ-a) and an acid.

30. The compound of formula (VII) or a salt thereof obtained by the preparation method according to claim 13: in, Ring A can be a benzene ring, a pyridine ring, or a naphthalene ring; R a For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkyl groups, and (R) b ) m This indicates that the hydrogen on the ring is divided by m R b Replace, each R b Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-3 Alkyl or C 1-3 Alkoxy; R2 is C 1-3 alkyl; m and n are each independently 0, 1 or 2; Z represents N or CR3; R3 represents hydrogen, halogen, or C. 1-3 alkyl; The salt is a salt formed by the compound of formula (VII) and an acid.

31. The compound or a salt thereof as claimed in claim 30, characterized in that, The acid is an inorganic acid.

32. The compound or a salt thereof as claimed in claim 30, characterized in that, The compound of formula (VII) has the following structure:

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