WO2022111683A1

WO2022111683A1 - Substituted azabicyclooctane compound and preparation method therefor, and intermediate and preparation method therefor

Info

Publication number: WO2022111683A1
Application number: PCT/CN2021/133949
Authority: WO
Inventors: 曾振亚; 张江波; 贾淼; 吴波; 蔡训志; 张兴松; 李雪健; 冯一骁; 马有红; 高清富
Original assignee: 上海海雁医药科技有限公司; 扬子江药业集团有限公司
Priority date: 2020-11-30
Filing date: 2021-11-29
Publication date: 2022-06-02
Also published as: CN116635392A; CN112480107B; CN112480107A

Abstract

The present invention relates to an intermediate of a substituted azabicyclo[3.2.1]octane compound, and a preparation method therefor. Specifically, disclosed in the present invention are an intermediate (the compound of formula (I)), a preparation method therefor, and a method for preparing an azabicyclo[3.2.1]octane compound by means of the intermediate. The definitions of groups in the formula are detailed in the description and the claims.

Description

Substituted azabicyclooctane compounds and their intermediates and preparation methods

technical field

The invention relates to the field of organic chemical synthesis, in particular to a substituted azabicyclo[3.2.1]octane compound, an intermediate thereof and a preparation method thereof.

Background technique

Orexin is a hunger-regulating signal secreted by the hypothalamus, named for its strong orexinic effect. Orexin A (Orexin A) and orexin B (Orexin B) are a kind of neuropeptides, both act on G protein-coupled receptors orexin receptor OX1R and orexin receptor OX2R. Among them, the binding ability of OX1R to orexin A was stronger than that of orexin B, while the binding ability of OX2R to orexin A and orexin B was comparable. Subsequently, studies have found that dogs with narcolepsy are due to mutations in the gene that expresses OX2R, which leads to OX2R dysfunction. This study shows that orexin not only affects the body's feeding behavior, but also participates in the regulation of the sleep-wake cycle. Since then, researchers have gained a new understanding of the etiology of insomnia, which may also be caused by inappropriate arousal. Considering the role of orexin in the sleep-wake cycle, Merck conducted research on orexin receptor antagonists.

At present, many patents have reported a variety of orexin receptor antagonists, and WO2017028732 discloses the preparation method of the intermediate trans-chiral pure 13:

However, the preparation process of the starting material 1 of this reaction route needs to be completed through three steps of adding a benzyl protecting group, deprotecting and adding a protecting group, and the steps are complicated. Sodium hydride is needed in the preparation process of compound 3, and the scale-up operation is dangerous. In addition, there are two intermediates in the synthetic route (compound 6; a mixture of 10-a and 10-b) which are difficult to purify, and generally need to be purified by column chromatography, which has poor repeatability, and uses a large amount of organic solvents, causing serious environmental pollution. In addition, since this method can only be separated and purified in the final step, the atom economy of the overall reaction is poor, many by-products (isomers) are produced in the synthesis, and the yield is low.

Therefore, the development of a high-efficiency, low-cost, easy-to-scale, and reproducible synthetic process for trans-chiral pure substituted azabicyclo[3.2.1]octane compounds is of great significance for industrial production. .

SUMMARY OF THE INVENTION

The object of the present invention is to provide a substituted azabicyclo[3.2.1]octane compound, a preparation method thereof, an intermediate thereof and a preparation method of the intermediate, the azabicyclo[3.2.1]octane compound can be used for Preparation of orexin receptor antagonists.

A first aspect of the present invention provides a compound of formula (I) or a salt thereof:

in,

Ring A is a benzene ring, a pyridine ring or a naphthalene ring; (R _a ) _n represents that the hydrogen on the ring A is substituted by n R _a , and each R _a is the same or different, and is independently hydrogen, halogen, C _{1- 3} alkyl or C _1-3 alkoxy;

R ₁ , R ₂ are each independently C _1-3 alkyl; and

n is 0, 1 or 2.

In another preferred embodiment, n is 0 or 1.

In another preferred example, R _a is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In another preferred embodiment, R _a is hydrogen.

In another preferred example, R ₁ and R ₂ are each independently methyl, ethyl, propyl or isopropyl.

In another preferred embodiment, R ₁ is isopropyl.

In another preferred example, R ₂ is methyl.

In another preferred example, ring A is a benzene ring.

In another preferred embodiment, the compound of formula (I) has the following structure:

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

In another preferred example, the acid is an inorganic acid.

In another preferred example, the inorganic acid is hydrochloric acid.

A second aspect of the present invention provides a preparation method of a compound of formula (I), comprising the steps:

(1) in an inert solvent, the compound of formula a, formula b and formula c is subjected to cyclization reaction, thereby obtaining a mixture comprising the compound of formula (I);

wherein ring A is a benzene ring, a pyridine ring or a naphthalene ring;

(R _a ) _n represents that the hydrogen on ring A is substituted with _n R _a , each of which is the same or different, and each is independently hydrogen, halogen, C _1-3 alkyl or C _1-3 alkoxy;

R ₁ and R ₂ are each independently C _1-3 alkyl;

n is 0, 1 or 2;

(2) the obtained mixture comprising the compound of formula (I) is subjected to acid treatment to obtain a salt of the compound of formula (I);

(3) Treatment (or "free") of the resulting salt of the compound of formula (I) to give the compound of formula (I).

In another preferred embodiment, n is 0 or 1.

In another preferred embodiment, R ₁ is isopropyl.

In another preferred example, R ₂ is methyl.

In another preferred example, ring A is a benzene ring.

In another preferred example, the molar ratio of the compounds of formula a, formula b and formula c is (1-2):1:1.

In another preferred embodiment, the mixture comprising the compound of formula (I) further comprises the isomer represented by formula (II),

wherein Rings A, R _a , n, R ₁ and R ₂ are as defined in the above specification.

In another preferred example, the isomer represented by formula (II) is the following structure:

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

2H-pyran-2,4,6-(3H,5H)trione is reacted with an alkyl alcohol R ₁ OH to obtain a compound of formula a;

wherein, R ₁ is a C _1-3 alkyl group.

In another preferred example, R ₁ is methyl, ethyl, propyl or isopropyl.

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

In another preferred example, in step (1), the reaction time is greater than 0.5 hour.

In another preferred example, in step (1), in the mixture comprising the compound of formula (I), the molar ratio of the compound of formula (I) to the compound of formula (II) is greater than 1:1, preferably (1.5-2 ):1.

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

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

In another preferred example, in step (1), the compound of formula c participates in the reaction in the form of a mixed solution with hydrochloric acid.

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

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

In another preferred example, the pH adjusting agent is selected from: sodium acetate, sodium hydroxide, a combination of sodium acetate and sodium hydroxide.

In another preferred example, in step (2), the acid addition treatment is treatment with an acid-containing solution.

In another preferred example, the acid-containing solution is a solution containing an acid and a solvent selected from the group consisting of: C _1-4 alkyl alcohol, 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 a combination thereof .

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

In another preferred example, in the acid-containing solution, the acid concentration is 0.1 mol/L to 10 mol/L, preferably 0.5 mol/L to 5 mol/L.

In another preferred embodiment, the acid is hydrochloric acid.

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

In another preferred example, the treatment (or "free") in the step (3) refers to treating the salt of the compound of formula (I) obtained in the step (2) with a solution containing a base 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 a combination thereof.

In another preferred embodiment, the treatment (or "free") in the step (3) refers to treating the salt of the compound of formula (I) obtained in the step (2) with a solution containing sodium hydroxide.

In another preference, the preparation method of the mixture comprising the compound of formula (I) comprises the steps:

(1a) reacting 2H-pyran-2,4,6-(3H,5H)trione with C _1-3 alkyl alcohol to obtain a reaction solution 1a containing the compound of formula a;

(1b) treating the mixture of the compound of formula b and the first solvent with an acid to obtain the mixture 1b;

The first solvent is selected from water, C _1-4 alkyl alcohol, 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 a combination thereof;

(1c) treating a mixture of a compound of formula c and a second solvent with an acid to obtain mixture 1c;

The second solvent is selected from water, C _1-4 alkyl alcohol, 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 a combination thereof;

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

Wherein, the sequence of steps (1a), (1b) and (1c) can be arbitrarily exchanged.

In another preferred example, the acid described in step (1b) is an inorganic acid, preferably hydrochloric acid.

In another preferred example, the acid described in step (1c) is an inorganic acid, preferably hydrochloric acid.

In another preferred example, the pH regulator in step (1d) is selected from the group consisting of: sodium acetate, sodium hydroxide, a combination of sodium acetate and sodium hydroxide.

In another preferred example, in step (1d), the reaction is carried out under the condition of pH 1 to 5, preferably under the condition of pH 3 to 4.

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

In another preferred embodiment, the C _1-3 alkyl alcohol in step (1a) is methanol, ethanol or isopropanol.

In another preferred embodiment, in the compound of formula c, n is 0 or 1.

In another preferred embodiment, in the compound of formula c, R _a is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In another preferred example, in the compound of formula c, R ₂ is methyl, ethyl, propyl or isopropyl.

In another preferred embodiment, in the compound of formula c, ring A is a benzene ring, a pyridine ring or a naphthalene ring.

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

A third aspect of the present invention provides a preparation method of a compound of formula (VII), comprising the steps:

(a) subjecting the compound of formula (I) to a reduction reaction to obtain the compound of formula (III);

(b) the compound of formula (III) is subjected to elimination reaction to obtain the compound of formula (IV);

(c) subjecting the compound of formula (IV) to a reduction reaction to obtain the compound of formula (V);

(d) subjecting the compound of formula (V) to a reduction reaction to obtain the compound of formula (VI);

(e) subjecting a compound of formula (VI) to a substitution reaction with a compound of formula (VIa) to obtain a compound of formula (VII-a);

(f) purifying the compound of formula (VII-a) to obtain the compound of formula (VII);

in,

Ring A is a benzene ring, a pyridine ring or a naphthalene ring;

(R _a ) _n represents that _a hydrogen on ring A is substituted with n R _a , each of which is the same or different, and each is independently hydrogen, halogen, C _1-3 alkyl or C _1-3 alkoxy, and (R _b ) _m represents that the hydrogen on the ring is substituted with m R _b s, each R _b being the same or different, and each independently hydrogen, halogen, C _1-3 alkyl or C _1-3 alkoxy;

R ₁ and R ₂ are each independently C _1-3 alkyl;

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

Z is N or CR ₃ ; R ₃ is hydrogen, halogen or C _1-3 alkyl;

R _LG is halogen, amino, hydroxyl, (HO) ₂ B-, boronate ester, (NO ₂ ) ₂ C ₆ H ₃ O-, CH ₃ S(O) ₂ O-, CF ₃ S(O) ₂ O -, p _- _CH3C6H4S (O)2O-, _CH3S (O) _2- , _CH3S ₍ O) _- .

In another preferred example, R _a and R _b are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In another preferred example, Z is N or CR ₃ ; R ₃ is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl or isopropyl.

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

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

In another preferred embodiment, in step (f), the purification is to add acid to the compound of formula (VII-a) or its solution.

In another preferred embodiment, the acid addition treatment is treatment with an acid-containing solution.

In another preferred embodiment, the acid is hydrochloric acid.

The present invention provides another preparation method of the compound of formula (VII), comprising the steps:

(c1) subjecting the compound of formula (IV) to a reduction reaction to obtain the compound of formula (V-1);

(d1) subjecting the compound of formula (V-1) to a reduction reaction to obtain the compound of formula (VI-1);

(e1) subjecting the compound of formula (VI-1) to a substitution reaction with the compound of formula (VIa) to obtain the compound of formula (VII);

In another preferred example, (R _a ) _n represents that the hydrogen on the ring A is replaced by n pieces of R _a , each R _a is the same or different, and each is independently hydrogen, fluorine, chlorine, bromine, iodine, methyl , ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; (R _b ) _m represents that the hydrogen on the ring is substituted by m R _b , and each R _b is the same or different, and each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In another preferred embodiment, R ₁ is isopropyl.

In another preferred example, R ₂ is methyl.

In another preferred example, ring A is a benzene ring.

In another preferred embodiment, Z is N.

In another preferred example, the compound of formula (V-1) has the following structure:

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

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

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

(a) Tetrabutylamine borohydride, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, potassium borohydride, borane, iso Propanol - aluminum triisopropoxide, lithium aluminum tetrahydrogen, lithium aluminum hydride tri-tert-butoxide, samarium diiodide;

(b) a combination of zinc and a Lewis acid (eg, antimony trichloride, etc.);

(c) a combination of a catalyst selected from the group consisting of metallic palladium, nickel, platinum and lead and a hydrogen donor selected from the group consisting of hydrogen, formic acid, formate;

The inert solvent is selected from: water, C _1-4 alkyl alcohol, 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 a combination thereof.

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

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

In another preferred embodiment, the elimination reaction of step (b) is carried out in a system containing the following reagents: a hydroxyl activator, a base and an inert solvent.

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

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

In another preferred example, the base is selected from: ammonia water, triethylamine, diisopropylethylamine, N,N-dimethylaniline, tetramethylethylenediamine, tributylamine, sodium methoxide, ethanol Sodium, 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 phenate, sodium benzoate, sodium citrate, N-methylmorpholine, pyridine, or a combination 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-dichloromethane Ethyl chloride, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, or combinations thereof.

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

In another preferred example, the molar ratio of the compound of formula (III) to the base in step (b) is 1:(1-2).

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

(a) Metal magnesium, alkyl silicon hydride, sodium borohydride, lithium borohydride, hydride of tin, selenium or tellurium, borane, hydrosulfite (sodium hydrosulfite), ethylenic reductase, yeast enzyme;

(b) a combination of zinc and a hydrogen donor selected from formic acid, formate;

(c) a combination of tin, carbon monoxide and water;

(d) a complex compound selected from the group consisting of palladium, rhodium (such as tris(triphenylphosphine) rhodium chloride), cobalt, nickel, ruthenium, iridium, copper and a hydrogen donor selected from hydrogen, formic acid and formate combination; and

(e) a combination of a catalyst selected from palladium and nickel and a hydrogen donor selected from hydrogen, formic acid and formate;

The inert solvent is selected from: C _1-4 alkyl alcohol, 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 a combination thereof.

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

In another preferred embodiment, the reduction reaction of step (c) is carried out in a system containing a combination of metal magnesium and C _1-4 alkyl alcohol.

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

In another preferred example, the molar ratio of the compound of formula (IV) to metal magnesium in step (c) is 1:(1-10).

In another preferred embodiment, the reduction reaction of step (c) is carried out in a system containing the following reagents: a reducing agent, a Lewis acid and an inert solvent, wherein the reducing agent is selected from: potassium borohydride, sodium borohydride and borohydride Lithium; the inert solvent is selected from: C _1-4 alkyl alcohol, 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 a combination thereof; the Lewis acid is selected from: lithium chloride, cobalt chloride, magnesium chloride, chloride Zinc, Cupric Chloride, Aluminum Chloride, Ferrous Chloride, Nickel Chloride and Gallium Dichloride.

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

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

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

(a) metal magnesium, alkyl silicon hydride, sodium borohydride, lithium borohydride, tin, selenium or tellurium hydride, borane, hydrosulfite, olefinic reductase, yeast enzyme;

(c) a combination of tin, carbon monoxide and water;

In another preferred embodiment, the reduction reaction of step (c1) is carried out in a system containing a combination of metal magnesium and C _1-4 alkyl alcohol.

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

In another preferred embodiment, the reduction reaction of step (c1) is carried out in a system containing the following reagents: a reducing agent, a Lewis acid and an inert solvent, wherein the reducing agent is selected from: potassium borohydride, sodium borohydride and borohydride Lithium; the inert solvent is selected from: C _1-4 alkyl alcohol, 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 a combination thereof.

In another preferred example, the Lewis acid is selected from lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, cupric chloride, aluminum chloride, ferrous chloride, nickel chloride and gallium dichloride.

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

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

In another preferred embodiment, the reduction reaction of step (d) or step (d1) is carried out in a system containing the following reagents: 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, tri-sec-butylborohydride Lithium, potassium borohydride, borane, diisobutylaluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium tetrahydroaluminum, potassium hydroxide-diglycol, samarium diiodide;

(b) a combination of a palladium catalyst and hydrogen;

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

(d) a combination of [CpFe(CO) ₂ (PCy ₃ )][BF ₄ ] and phenylsilane;

In another preferred embodiment, the palladium catalyst is selected from: palladium carbon, tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ), tetrakis(triphenylphosphine) palladium (Pd(PPh ₃ ) ₄ ), palladium acetate, bis(triphenylphosphine) palladium dichloro, palladium trifluoroacetate, palladium triphenylphosphine acetate, bis(tri-o-benzylphosphine) palladium dichloride, 1,2-bis(bis(di(triphenylphosphine) palladium) Phenylphosphino)ethane palladium dichloride or a combination thereof.

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

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).

In another preferred example, the substitution reaction of step (e) or step (e1) is carried out in a system containing the following reagents: a base and an inert solvent, 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.

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 a combination thereof.

In another preferred embodiment, the substitution reaction of step (e) or step (e1) is carried out in a system containing the following reagents: a base and an inert solvent, and the base is sodium tert-butoxide, potassium tert-butoxide or tert-butanol Lithium; the inert solvent is toluene.

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

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

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

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

The fourth aspect of the present invention provides a compound of formula (VII-a) or a salt thereof:

in,

Ring A is a benzene ring, a pyridine ring or a naphthalene ring;

R ₂ is C _1-3 alkyl;

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

Z is N or CR ₃ ; R ₃ is hydrogen, halogen or C _1-3 alkyl;

Said salt is a salt formed by the compound of formula (VII-a) and an acid.

In another preferred embodiment, n is 0 or 1.

In another preferred example, m is 1 or 2.

In another preferred embodiment, R _a is hydrogen.

In another preferred example, R _b is fluorine.

In another preferred example, R ₂ is methyl, ethyl, propyl or isopropyl.

In another preferred example, R ₂ is methyl.

In another preferred example, ring A is a benzene ring.

In another preferred example, the acid is an inorganic acid.

In another preferred example, the inorganic acid is hydrochloric acid.

In another preferred embodiment, Z is N.

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

wherein each group is as defined above; the salt is a salt of a compound of formula (VII) with an acid.

In another preferred example, the acid is an inorganic acid.

In another preferred example, the inorganic acid is hydrochloric acid.

In another preferred embodiment, n is 0 or 1.

In another preferred example, m is 1 or 2.

In another preferred embodiment, R _a is hydrogen.

In another preferred example, R _b is fluorine.

In another preferred example, R ₂ is methyl, ethyl, propyl or isopropyl.

In another preferred example, R ₂ is methyl.

In another preferred example, ring A is a benzene ring.

In another preferred embodiment, Z is N.

A fifth aspect of the present invention provides a method for preparing a compound of formula (VII-a), the method comprising the steps of: substituting the compound of formula (VI) with the compound of formula (VIa) in an inert solvent in the presence of a base reaction, thereby obtaining the compound of formula (VII-a);

wherein ring A is a benzene ring, a pyridine ring or a naphthalene ring;

R ₂ is C _1-3 alkyl;

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

Z is N or CR ₃ ; R ₃ is hydrogen, halogen or C _1-3 alkyl;

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

wherein each group is as defined above.

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

In another preferred embodiment, the purification is to add acid to the compound of formula (VII-a) or its solution.

In another preferred example, R ₂ is methyl, ethyl, propyl or isopropyl.

In another preferred example, R ₂ is methyl.

In another preferred example, ring A is a benzene ring.

In another preferred embodiment, Z is N.

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

In another preferred embodiment, the preparation method further comprises the step of forming a salt of the compound of formula (VII) with an acid to obtain a salt of the compound of formula (VII).

In another preferred example, the acid is an inorganic acid.

In another preferred example, the inorganic acid is hydrochloric acid.

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

Wherein in the above formulas, ring A is a benzene ring, a pyridine ring or a naphthalene ring;

n is 0, 1 or 2;

R ₁ and R ₂ are each independently C _1-3 alkyl.

In another preferred embodiment, n is 0.

In another preferred embodiment, R ₁ is isopropyl.

In another preferred example, R ₂ is methyl.

In another preferred example, ring A is a benzene ring.

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

wherein ring A is a benzene ring, a pyridine ring or a naphthalene ring;

R ₁ and R ₂ are each independently C _1-3 alkyl;

n is 0, 1 or 2;

In another preferred example, the acid is an inorganic acid.

In another preferred example, the inorganic acid is hydrochloric acid.

wherein, R ₁ is a C _1-3 alkyl group.

In another preferred embodiment, the mixture containing the compound of formula (I) further comprises the isomer represented by formula (II),

The sixth aspect of the present invention provides a preparation method of a compound of formula (IX), the method comprising the steps of: in a solvent, the compound of formula (VII) or its salt is removed from the substituent on the nitrogen atom, thereby obtaining the formula ( IX) compounds;

in,

Ring A is a benzene ring, a pyridine ring or a naphthalene ring;

(R _b ) _m represents that the hydrogen on the ring is replaced by m R _b , each R _b is the same or different, and each R b is independently hydrogen, halogen, C _1-3 alkyl or C _1-3 alkoxy;

R ₂ is C _1-3 alkyl;

m is 0, 1 or 2;

n is 0, 1 or 2;

Z is N or CR ₃ ; R ₃ is hydrogen, halogen or C _1-3 alkyl.

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

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

In another preferred example, the inorganic acid is hydrochloric acid.

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.

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

In another preferred example, R _b is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In another preferred embodiment, n is 0.

In another preferred example, m is 1.

In another preferred example, R ₂ is methyl, ethyl, propyl or isopropyl.

In another preferred example, R ₂ is methyl.

In another preferred embodiment, Z is N.

In another preferred example, ring A is a benzene ring.

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

A seventh aspect of the present invention provides a method for preparing a compound of formula (X), comprising the steps of: in an inert solvent, mixing the compound of formula (IX) or its salt with compound 5-methyl-2-(pyrimidin-2-yl) ) benzoic acid carries out condensation reaction, thereby obtains the compound of formula (X);

in,

m is 0, 1 or 2;

Z is N or CR ₃ ; R ₃ is hydrogen, halogen or C _1-3 alkyl.

In another preferred example, m is 1 or 2.

In another preferred embodiment, Z is N.

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

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

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

Description of drawings

FIG. 1 is an ellipsoid diagram of the three-dimensional structure of a compound 12 single crystal.

Detailed ways

Definition of Terms

As used herein, "alkyl" refers to straight and branched chain saturated aliphatic hydrocarbon groups, C _1-10 alkyl is an alkyl group containing 1 to 10 carbon atoms, preferably C _1-6 alkyl, more preferably _C1-3 alkyl, similarly defined; non-limiting examples of alkyl 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-dimethyl Butyl, 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-methylhexyl, 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 Alkyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl , and various branched chain isomers thereof are more preferred.

As used herein, "alkoxy" refers to -O-alkyl, wherein alkyl is as defined above. A C _1-6 alkoxy group is preferable, and a C _1-3 alkoxy group is more preferable. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like. As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.

As used herein, non-limiting examples of "boronic esters" include (CH3O) _2B- , ₍ _CH3CH2O ₎ _2B- ,

Wait.

In the present invention, "treating" the salt of the compound of formula (I) to obtain the compound of formula (I) is a free process, specifically, for example, after treating the salt of the compound of formula (I) with a suitable base or a solution of the base The compound of formula (I) is obtained in free base form.

After extensive and in-depth research, the inventors found an intermediate for preparing substituted azabicyclo[3.2.1]octane compounds and a preparation method for substituted azabicyclo[3.2.1]octane compounds The method has the advantages of simple and easy-to-obtain starting materials, good reaction selectivity, significantly improved atom economy of the reaction, simple operation, environmental friendliness, easy to scale up production, significantly reduced production cost, saved time, high product purity, direct Obtain high-purity clinical APIs. On this basis, the inventors have completed the present invention.

The present invention provides a method for preparing a compound of formula (VII), using compounds of formula a, formula b and formula c as starting materials, through cyclization reaction, reduction reaction, elimination reaction, two-step reduction reaction, and substitution reaction to obtain formula (VII) compound, the method comprises the steps of: in an inert solvent (such as water, ethyl acetate, etc.), at a certain temperature (such as -10 ° C to 25 ° C), the reaction solution containing the compound of formula a is treated with acid. The obtained mixture of the compound of formula b and the solvent, and the mixture of the compound of formula c obtained by acid treatment and the solvent are mixed, and the pH of the reaction solution is controlled to be 1-5, and the reaction is carried out for a period of time (such as 0.5 hours to 24 hours), thereby obtaining a mixture comprising: A mixture of compounds of formula (I), the resulting mixture is treated with an acid to give a salt of a compound of formula (I), and the resulting salt is treated (or "free") to give a compound of formula (I). Described inert solvent refers to the solvent that does not participate in or influence above-mentioned ring-forming reaction, including but not limited to water, ethyl acetate.

wherein Ring A is a benzene ring, a pyridine ring or a naphthalene ring; (R _a ) _n represents that the hydrogen on the ring A is substituted by n R _a , and each R _a is the same or different, and is independently hydrogen, halogen, C _{1 -3} alkyl or C _1-3 alkoxy; R ₁ and R ₂ are each independently C _1-3 alkyl; n is 0, 1 or 2; the acid is an inorganic acid, most preferably hydrochloric acid.

The compound of formula (I) is reacted with a reducing agent in an inert solvent at a temperature (eg -20°C to 50°C, preferably -10°C to 5°C) for a period of time (eg 0.5 hours to 6 hours, preferably 2 hours to 4 hours), thereby obtaining the compound of formula (III);

Wherein the inert solvent and the reducing agent may be known in the art, suitable for various combinations of reducing agents and inert solvents for the selective reduction of carbonyl groups when both ester groups and carbonyl groups are present, wherein the reducing agent may be selected from, for example, tetrabutyl borohydride Amine salts, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, potassium borohydride, borane, isopropanol-triisopropoxide aluminum , a combination of lithium aluminum tetrahydride, lithium aluminum tri-tert-butoxide, samarium diiodide, zinc and a Lewis acid (such as antimony trichloride, etc.), a catalyst selected from the group consisting of metal palladium, nickel, platinum and lead and a catalyst selected from Combination of hydrogen donors of hydrogen, formic acid, formate, etc. The inert solvent can be selected from, for example, water, C _1-4 alkyl alcohol, 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 a combination thereof. Preferably, the reaction is carried out in the presence of a reducing agent selected from the group consisting of sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride and potassium borohydride and C _1- The reaction is carried out in a system containing ₄ alkyl alcohols, more preferably in a system containing sodium borohydride and methanol.

In an inert solvent, at a certain temperature (eg -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 (eg 0.5 hours to 24 hours), thereby to obtain the compound of formula (IV);

The elimination reaction can be carried out in any system known in the art that is suitable for the β-elimination reaction, such as in a reaction system containing a hydroxyl activator and a base, wherein the hydroxyl activator can be sulfonyl chloride, etc., and the sulfonyl chloride can be selected Such as benzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride and the like. The base can be selected from: ammonia water, triethylamine, diisopropylethylamine, N,N-dimethylaniline, tetramethylethylenediamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, tert-butanol Sodium, 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 phenate, sodium benzoate, sodium citrate, N-methylmorpholine, pyridine, etc., or a combination thereof. The inert solvent may be selected from, 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 a combination 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-diazabicycle [5,4,0]-7-undecene (DBU), sodium hydroxide or potassium hydroxide. The inert solvent is preferably toluene, tetrahydrofuran, 1,4-dioxane or dichloromethane.

The compound of formula (IV) is reacted with a reducing agent in an inert solvent at a temperature (eg -20°C to 25°C, preferably -10°C to 10°C) for a period of time (eg 0.5 hours to 48 hours), thereby to obtain the compound of formula (V);

The inert solvent and reducing agent can be known in the art, and are suitable for the combination of various reducing agents and inert solvents that can selectively reduce unsaturated double bonds or triple bonds in α,β-unsaturated esters, wherein the reducing agent is optional Metals such as magnesium, alkyl silicon hydrides, hydrides of tin, selenium or tellurium, zinc and a combination of a hydrogen donor selected from formic acid, formate, a combination of tin, carbon monoxide and water, selected from palladium, rhodium (such as A combination of a complex of tris(triphenylphosphine) rhodium chloride), cobalt, nickel, ruthenium, iridium, copper and a hydrogen donor selected from hydrogen, formic acid and formate, a catalyst selected from palladium, nickel and The combination of hydrogen donors selected from hydrogen, formic acid, formate, borane, hydrosulfite, ethylenic reductase, yeast enzyme, etc. The inert solvent can be selected from, for example, C _1-4 alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloromethane Ethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or a combination thereof. Preferably, the reaction is carried out in a system containing metal magnesium and C _1-4 alkyl alcohol, or in a system containing palladium catalyst/hydrogen and C _1-4 alkyl alcohol, wherein the palladium catalyst can be palladium carbon, Tris(dibenzylideneacetone)dipalladium(Pd2(dba)3), tetrakis(triphenylphosphine)palladium(Pd(PPh3)4), palladium acetate, dichlorobis(triphenylphosphine)palladium, trifluoro Palladium acetate, triphenylphosphine palladium acetate, bis(tri-o-benzylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethane palladium dichloride, etc., or a combination thereof. The reaction is more preferably carried out in a system containing metallic magnesium and methanol.

Wherein the reducing agent can also be potassium borohydride, sodium borohydride or a combination of lithium borohydride and Lewis acid; the Lewis acid is selected from: lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, copper chloride, chloride Aluminum, ferrous chloride, nickel chloride and gallium dichloride. The inert solvent is selected from: C _1-4 alkyl alcohol, 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 a combination thereof. Preferably, the reaction is carried out in a system containing sodium borohydride and lithium chloride.

The compound of formula (IV) is reacted with a reducing agent in an inert solvent at a temperature (eg -20°C to 25°C, preferably -10°C to 10°C) for a period of time (eg 0.5 hours to 48 hours), thereby to obtain the compound of formula (V-1);

Wherein the reducing agent is potassium borohydride, sodium borohydride or a combination of lithium borohydride and Lewis acid; the Lewis acid is selected from: lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, copper chloride, aluminum chloride, Ferric chloride, nickel chloride and gallium dichloride. The inert solvent is selected from: C _1-4 alkyl alcohol, 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 a combination thereof. Preferably, the reaction is carried out in a system containing sodium borohydride and lithium chloride.

The reducing agent can also be a combination of metal magnesium and methanol.

The compound of formula (V) is reacted with a reducing agent in an inert solvent at a temperature (eg -20°C to 25°C, preferably -10°C to 10°C) for a period of time (eg 0.5 hours to 24 hours), thereby to obtain the compound of formula (VI);

Alternatively, in an inert solvent, at a certain temperature (such as -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 (such as 0.5 hours to 24 hours). ), thereby obtaining the compound of formula (VI-1);

Wherein the inert solvent and the reducing agent can be known in the art, suitable for reducing the ester group to a combination of various reducing agents and inert solvents, wherein the reducing agent can be selected from the combination of red aluminum, palladium catalyst and hydrogen, propylene Sodium diacyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, lithium triethylborohydride, lithium trisec-butylborohydride, sodium borohydride, boron A combination of potassium hydride or lithium borohydride and a Lewis acid, borane, diisobutylaluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium aluminum tetrahydride, potassium hydroxide-diglycol, samarium diiodide, [ A combination of CpFe(CO) ₂ (PCy ₃ )][BF ₄ ] and phenylsilane, and the like. The inert solvent can be selected from, for example, C _1-4 alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloromethane Ethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or a combination thereof. Preferably, the reaction is carried out in a reaction containing red aluminum and selected from the group consisting of toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane alkane and acetonitrile in an inert solvent system.

In an inert solvent, at a certain temperature (such as -20°C to 100°C, preferably at -10°C to 50°C), the compound of formula (VI) is reacted with the compound of formula (VIa) in the presence of a base for a period of time (such as 0.5 hours to 24 hours), thereby obtaining the compound of formula (VII-a), and then purifying the compound of formula (VII-a) to obtain the compound of formula (VII);

Or in an inert solvent, at a certain temperature (such as -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 (eg 0.5 hours to 24 hours), thereby obtaining the compound of formula (VII);

wherein ring A, R _a , R ₂ , and n are as defined above, R _b is hydrogen, halogen, C _1-3 alkyl or C _1-3 alkoxy; Z is N or CR ₃ ; R ₃ is hydrogen, halogen or C _1-3 alkyl; m is 0, 1 or 2; R _LG represents a leaving group, such as halogen, amino, hydroxyl, (HO) ₂ B-, boronate, (NO ₂ ) ₂ C ₆ H ₃ O-, CH ₃ S(O) ₂ O-, CF ₃ S(O) ₂ O-, p-CH ₃ C ₆ H ₄ S(O) ₂ O-, CH ₃ S(O) ₂ - , CH ₃ S(O)-, etc.

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 its combination. The inert solvent may 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 a combination thereof.

The compound of formula (VII-a) can be purified to the compound of formula (VII) by various purification methods known in the art, including, for example, chromatographic column separation and purification. The preferred purification method is to purify the compound of formula (VII-a) The compound or its solution is subjected to acid treatment. The acid addition treatment is treatment with an acid-containing solution. Described acid is selected from organic acid and inorganic acid, wherein inorganic acid is selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid; Organic acid is selected from: acetic acid, propionic acid, isobutyric acid, maleic acid, propionic acid Diacid, benzoic acid, succinic acid, suberic 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 an acid and a solvent selected from the group consisting of C _1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane , ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or a combination thereof.

The present invention provides a preparation method of the compound of formula (X), which takes the compound of formula (VII) as a starting material, and obtains the compound of formula (X) through deprotection reaction and condensation reaction, and the method comprises the steps:

In an inert solvent, at a certain temperature (such as -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 (such as 0.5 hours to 48 hours), Thereby the compound of formula (IX) is obtained;

wherein ring A is a benzene ring, a pyridine ring or a naphthalene ring;

R ₂ is C _1-3 alkyl;

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

Z is N or CR ₃ ; R ₃ is hydrogen, halogen or C _1-3 alkyl;

Those skilled in the art can select various known appropriate reaction systems to carry out the deprotection reaction according to the structure of the substrate, preferably the reaction is carried out in a system comprising a palladium catalyst and a system selected from hydrogen and ammonium formate.

The compound of formula (IX) is combined with compound 5-methyl-2-(pyrimidin-2-yl)benzene in an inert solvent at a certain temperature (eg -10°C to 100°C, preferably 0°C to 80°C) Formic acid is subjected to condensation reaction, and the compound of formula (X) is obtained after the reaction for a period of time (such as 0.5 hours to 24 hours);

wherein (R _b ) _m represents that hydrogen on the ring is substituted with m R _b s, each R _b being the same or different, and each independently being hydrogen, halogen, C _1-3 alkyl or C _1-3 alkoxy; m is 0, 1 or 2; Z is N or CR ₃ ; R ₃ is hydrogen, halogen or C _1-3 alkyl. Those skilled in the art can select various types of condensing agents and inert solvents known to be suitable for carrying out the reaction. For example, the condensing agent may be selected from _T3P , CDI, EDCI, HOBt, HATU and the like. The inert solvent can be selected such as 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 a combination thereof.

The present invention provides a method for preparing the compound of formula (IX) by adopting novel intermediate compounds of formula (I) and formula (VII). Compared with the prior art, this synthetic method has the following advantages:

1. The preparation process of the starting material is simpler, and it is easier to purify to obtain the desired isomer intermediate product, which overcomes the disadvantage that the prior art cannot separate and purify the desired configuration intermediate in the previous synthesis step and avoids the The prior art requires a large amount of organic solvent consumption and a long purification process caused by column chromatography purification, which is more conducive to scale-up production.

2. The intermediates prepared from the starting materials of the present invention are easier to separate and purify in the early steps of the reaction to obtain the desired isomer intermediate products, which greatly reduces the amount of by-products (isomers) produced in the later steps. The separation and purification are difficult, the atom economy of the reaction is improved, and the generation of three wastes is reduced.

3. The preparation of starting materials avoids the use of dangerous reagents sodium and hydrogen, and at the same time improves the selectivity of the reaction and greatly reduces the operational risk of process amplification.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated. Unless otherwise defined, terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the present invention.

Reagents and Instruments

¹ HNMR: Bruker AVANCE-400 nuclear magnetic instrument, the internal standard is tetramethylsilane (TMS).

LC-MS: Agilent 1290 HPLC System/6130/6150MS Liquid Mass Spectrometer (manufacturer: Agilent), column Waters BEH/CHS, 50×2.1 mm, 1.7 μm.

HPLC analysis adopts Agilent 1260 Infinity HPLC, OpenLAB CDS Chemstation workstation, chromatographic column XBridge C18 4.6*250mm, ID 5μm column, detector DAD.

Use ISCO Combiflash-Rf75 or Rf200 automatic column passing instrument, Agela 4g, 12g, 20g, 40g, 80g, 120g disposable silica gel column.

The specific rotation was measured by a Rudolf Autopol VI polarimeter at a detection temperature of 20 °C.

The single crystal structure was tested using a D8 Venture X-ray single crystal diffractometer. Light source: Cu target, X-ray:

Detector: CMOS area detector, resolution

Current and voltage: 50kV, 1.2mA, exposure time 10s, distance from surface detector to sample 40mm, test temperature 150(2)K.

Known starting materials can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc) and Darui Chemicals, etc. company.

Unless otherwise specified, the reactions in the examples are all carried out under nitrogen atmosphere or argon atmosphere.

As used herein, 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)Cl is 1,1' _- bis(diphenylphosphonium)ferrocene]palladium dichloride, TFA is trifluoroacetic acid, TBSCl is tert-butyldimethylsilyl chloride, NCS is N _- chlorosuccinimide, DHP is dihydrotetrahydropyran, LiAlH is lithium aluminum hydride, PMB is p-methoxybenzyl, and LiHMDS is two (trimethylsilyl) lithium amide, Pd ₂ (dba) ₃ is tris(dibenzylideneacetone)dipalladium, RuPhos is 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1 ,1'-biphenyl, DMAP is 4-dimethylaminopyridine, THP is tetrahydrotetrahydropyran, n-BuLi is n-butyl lithium, TMsOTf is trimethylsilyl trifluoromethanesulfonate, TEBAC is trimethylsilyl trifluoromethanesulfonate Ethylbenzylammonium 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'-binaphthalene, LDA is lithium diisopropylamide; MsCl is methylsulfonyl chloride; rt is room temperature; TEA is triethylamine; DBU is 1,8-diazabicycloundec-7-ene; CDI is carbonyldiimidazole; 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; T ₃ P is propyl phosphoric anhydride; EDCI It is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride; HOBt is 1-hydroxybenzotriazole, Ph is phenyl, and sodium hydrosulfite is sodium hydrosulfite.

As used herein, room temperature refers to about 20-25°C.

Example 1: Preparation of Compound 1

Step 1: Cool the mixture of 200 g of 1,3-propanedicarboxylic acid, 280 mL of acetic acid and 200 mL of toluene to 5-10 °C, slowly add 220 mL of acetic anhydride dropwise, and continue stirring for 4 to 10 h after the dropwise addition; The filter cake was dried under reduced pressure at 40-50° C. for 6 hours to obtain 224 g of compound 1-a as a white solid with a yield of 87%. MS m/z (ESI): 129 [M+H] ⁺ .

Step 2: Add 107 g of compound 1-a into the reaction flask, drop 215 mL of isopropanol at 0-15 °C, control the internal temperature to 5-20 °C, stir until dissolved, add 300 mL of ice water, store at 0-10 °C, no need Purification was used directly in the next reaction.

Example 2: Preparation of Compound 2

25 g of compound 1-a was added to the reaction flask, 50 mL of ethanol was added dropwise at 0 to 15° C., and after the dropping was completed, the mixture was raised to room temperature and stirred for 3 hours, and 70 mL of water was added for later use. Store at 0-10°C and use it in the next step without purification.

Example 3: Preparation of compound 4-1

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

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

Step 1.3: Slowly drop the solution of the reaction flask ① prepared in step 1.1 into the solution of the reaction flask ② prepared in step 1.2, stir for 0.5 hours, add the solution prepared in Example 1 to the reaction flask ②, and then add the solution to the reaction flask ②. 250 mL of an aqueous solution containing 53.5 g of sodium acetate was added, and then 40% sodium hydroxide solution was added dropwise to adjust the pH to about 3-4, and the internal temperature was maintained at 5 to 15° C. and stirred for 12 hours. Add 20% sodium hydroxide solution dropwise until the pH value is about 12, add 1 L of ethyl acetate for extraction, separate the layers, add anhydrous sodium sulfate to dry the ethyl acetate layer, filter, and concentrate the filtrate to obtain 203.5 g of red oil (containing compound Mixture of 4-1 and 4-2, 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 19.5min; flow rate: 1.2ml/min; detection wavelength 220nm, column temperature: 30°C) shows that compounds 4-1 (retention time 8.587min) and 4-2 (retention time 8.510min) have The molar ratio was 1.74:1), and the yield was 98.8%, which was directly used in the next step.

Step 2: Add 203.5 g of the obtained mixture and 500 mL of ethyl acetate into the reaction flask, and slowly add 330 mL of HCl/ethyl acetate (concentration 2.0 mol/L) dropwise at 0 to 5 °C; ℃ continue to stir for 3-4 hours, filter, wash the filter cake with EA, and vacuum dry the filter cake at 50 ℃ to obtain 79.5 g of the hydrochloride salt of compound 4-1 as a pale yellow solid with a purity of 97.5%. MS m/z (ESI): 316.1 [M+H] ⁺ . ¹ H NMR (400 MHz, 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).

Step 3: Mix and stir 60.0 g of the hydrochloride of compound 4-1 and 300 mL of ethyl acetate, add dropwise 20% sodium hydroxide solution at 0 to 10 ° C until the pH value is alkaline, stir for 0.5 hours, and let stand The layers were separated, the aqueous phase was extracted with ethyl acetate 300 mL×2, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to obtain 52 g of compound 4-1, which was a red oil, yield 96.6%, purity 97.3%.

Comparative Example 1

Under different reaction temperatures and pH values of the reaction solution, the molar ratios of compound 4-1 and compound 4-2 in the obtained mixture are shown in Tables 2 and 3 below:

Table 2 When the pH value of the reaction solution is 3.4, the effect of reaction temperature on the content of product isomers

化合物compound	反应温度5℃Reaction temperature 5℃	反应温度20℃Reaction temperature 20℃	反应温度45℃Reaction temperature 45℃
4-14-1	40.04％40.04%	39.58％39.58%	33.15％33.15%
4-24-2	29.27％29.27%	25.54％25.54%	21.51％21.51%

Table 3 Influence of pH value of reaction solution on product isomer content at reaction temperature of 5 to 15 °C

compound

pH=1.1

pH=2.89

pH=3.42

pH=4.01

pH=5.2

4-14-1	38.59％38.59%	44.75％44.75%	43.81％43.81%	44.68％44.68%	24.44％24.44%
4-24-2	19.53％19.53%	27.22％27.22%	29.27％29.27%	34.1％34.1%	22.37％22.37%

It can be seen from Tables 2 and 3 that the reaction temperature and pH value of the reaction solution in step 1.3 of Example 3 have a great influence on the molar ratio of compound 4-1 and compound 4-2 in the mixture obtained by the reaction. When the reaction temperature is about 45°C, the content of the target product 4-1 is significantly reduced, while the content of the target product 4-1 is higher when the reaction temperature is 5°C and 20°C. When the pH value of the reaction solution is 2.89, 3.42 and 4.01, the content of the target product 4-1 is relatively high. When the pH value of the reaction solution is 5.2, the overall content of the product is significantly reduced, and the content of the target product 4-1 is also significantly reduced. The content of impurities in the reaction solution Significantly increased; when the pH value of the reaction solution was 1.1, the overall product content and the target product 4-1 content decreased.

Example 4:

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

Step 1.2: 32 mL of concentrated hydrochloric acid and 168 mL of water were added to the reaction flask ④, cooled to 5-15° C., and 18.5 g of compound 3 was added dropwise with stirring for later use.

Step 1.3: Slowly drop the solution of the reaction flask ③ prepared in step 1.1 into the solution of the reaction flask ④ prepared in step 1.2, stir for 0.5 hours, add the solution prepared in Example 2 to the reaction flask ④, and then add the solution to the reaction flask ④. 65 mL of an aqueous solution containing 12.5 g of sodium acetate was added, and then 40% sodium hydroxide solution was added dropwise to adjust the pH to about 3-4, and the mixture was stirred at room temperature overnight. Add 20% sodium hydroxide solution dropwise until the pH value is about 12, add 200 mL of ethyl acetate to extract, separate the layers, add anhydrous sodium sulfate to dry the ethyl acetate layer, filter, and concentrate the filtrate to obtain 45.2 g of red oil (containing compound Mixture of 4-3 and 4-4, 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 19.5min; flow rate: 1.2ml/min; column temperature: 30°C; detection wavelength 220nm) shows that the compound 4-3 (retention time 8.057min) and 4-4 (retention time 7.987min) have The molar ratio was 1.65:1), and the yield was 98.3%. MS m/z (ESI): 302.1 [M+H] ⁺ .

Comparative Example 2

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

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

Step 1.3: Slowly drop the solution of the reaction flask ⑤ prepared in step 1.1 into the solution of the reaction flask ⑥ prepared in step 1.2, stir for 0.5 hours, and add 250 mL of an aqueous solution containing 70.8 g of 1,3-propanedicarboxylic acid. Add it to the reaction flask ⑥, then add 150 mL of an aqueous solution containing 31 g of sodium acetate, and then add dropwise 40% sodium hydroxide solution to adjust the pH to about 3-4, and stir at room temperature overnight. Add 20% sodium hydroxide solution dropwise until the pH value is about 12, add 500 mL of ethyl acetate to extract, separate the layers, add anhydrous sodium sulfate to dry the ethyl acetate layer, filter, and concentrate the filtrate to obtain 81.2 g of crude product with a purity of 60.1%. Column chromatography gave 3.6 g of compound 13 as a yellow solid with a purity of 89.3%. MS m/z (ESI): 230.2 [M+H] ⁺ .

Step 2: Add 20ml of anhydrous toluene into a 100ml three-necked flask, add 0.5g of NaH in batches under nitrogen protection, and dropwise add 0.8g of diethyl carbonate at the same time. After the addition, stir until no more bubbles are released. The temperature was raised to 85-95°C, and a solution prepared by dissolving 1.0 g of compound 13 in 5 mL of toluene was added dropwise, and the temperature was controlled to be about 95°C. After the addition was completed, stirring was continued for 1 hour at this temperature, and sampling was carried out for detection, and the reaction was complete. The reaction solution was cooled to about 60 °C, poured into a mixture of 60 mL of ice water, 30 mL of ethyl acetate and 5 mL of hydrochloric acid for quenching, and the temperature was kept below 10 °C with constant stirring. After the quenching was completed, it was left to stand for separation, and the aqueous phase was 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 obtain 1.0 g of red oil. (A mixture containing 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 in 19.5 min; flow rate: 1.2 ml/min; column temperature: 30° C.) showed that the molar ratio of compound 4-3 to 4-4 was 0.4:1), and the yield was 75.2%. MS m/z (ESI): 302.1 [M+H] ⁺ .

Comparative Example 3

Weigh equal amounts of mixtures containing compounds 4-1 and 4-2 and add them to ethyl acetate respectively, then slowly add HCl and D-tartaric acid at room temperature, continue stirring at room temperature for 3 to 4 hours, observe the reaction state, The charging amount and reaction phenomenon of each reactant are shown in the following table:

Example 5-1: Preparation of Compound 8

Step 1: Add 52 g of compound 4-1 and 250 mL of methanol into a three-necked flask, under nitrogen protection, add 12.5 g of sodium borohydride in batches while stirring at -10°C, stir for 2 hours, and LCMS monitors the completion of the reaction. The internal temperature was controlled at -10 to 0°C, and 80 mL of water and 40 mL of saturated ammonium chloride solution were added dropwise to quench the reaction. The reaction solution was concentrated, 300 mL of ethyl acetate was added for extraction, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filter cake was washed with ethyl acetate, and concentrated under reduced pressure to obtain 52.2 g of a reddish-brown oil (compound 5), purity: 86.6% , the yield is 100%. MS m/z (ESI): 318.2 [M+H] ⁺ .

Step 2: Add 47.3 g of compound 5 and 250 mL of toluene into the reaction flask and stir, add 18.6 g of sodium tert-butoxide at 0 to 10 °C, and slowly dropwise add 120 mL of a toluene solution containing 34.1 g of p-toluenesulfonyl chloride, and the dropwise addition is completed. , stirred for 1 hour at 0-10° C., added 20.0 g of sodium tert-butoxide, stirred overnight, and monitored the reaction by LCMS. 300 mL of water was added dropwise to quench the reaction, stirred for 30 minutes, left to stand for stratification, 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 to pH value. Alkaline, extracted with ethyl acetate 500 mL×2, combined organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 34.2 g of 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] ⁺ .

Step 3: Dissolve 21.4 g of compound 6 in 160 mL of methanol, add 15.4 g of magnesium chips in batches at 0 to 10° C., and continue stirring 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 dropwise add 20% potassium carbonate solution to pH 6-7. The layers were left to stand, 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 obtain 18.1 g of a red oil (compound 7). The yield was 84.2%, and the purity was 82.5%. MS m/z (ESI): 302.2 [M+H] ⁺ .

Step 4: Under nitrogen protection, 18.1g of compound 7 (1.0eq) and 180mL of toluene were added to the reaction flask, and 52g of toluene solution containing 70% red aluminum (3.0eq) was added dropwise at 0 to 5°C, and the reaction solution was at room temperature. under stirring for 18 hours. 20% sodium hydroxide solution was added dropwise at 0 to 10° C. to adjust the pH value to be greater than 12. Filtration, the filtrate was left to stand for layers, the aqueous phase was extracted with 100 mL of ethyl acetate, the organic layers were combined, 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] ⁺ . used directly in the next reaction.

Example 5-2: Preparation of Compound 11

Step 1: Under nitrogen protection, add 14.7 g of compound 8 and 300 mL of toluene into the reaction flask and stir, and add 11.0 g of 2,5-difluoropyridine (compound 9) and 23.1 g of sodium tert-butoxide at 0-10 °C, Stir at room temperature until the reaction is complete. 88 mL of water was added dropwise to the reaction solution, left to stand for separation, the aqueous layer was extracted with ethyl acetate 2×60 mL, the organic layers were combined, filtered, dried over anhydrous sodium sulfate, filtered, and concentrated 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 NH ₄ HCO ₃ ] B: acetonitrile; gradient: 50%-90%-90% in 21 min- 50%-50%B; flow rate: 1.0ml/min; detection wavelength 210nm, column temperature: 30℃) shows that the molar ratio of compound 10-1 (retention time 13.628min) to compound 10-2 (retention time 10.188min) is 82.3:6.9, yield of compound 10 89.7%, purity 80.8%.

Step 2: Add 18.3 g of compound 10 and 180 mL of ethyl acetate into a 500 mL three-necked flask and stir, add dropwise 2mol/L HCl/40 mL of ethyl acetate under an ice bath, a large amount of solids are precipitated, and continue to stir under an ice water bath for 3 to 4 hours , filtered with suction, 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%. To the obtained 19.0 g of compound 10-1 hydrochloride, 380 mL of isopropanol was added, heated to 80°C and stirred for 3 hours, and stirred at room temperature overnight, filtered, and the filter cake was dried under reduced pressure to obtain 13.4 g of white solid with a yield of 70.5% and a purity of 96.3 %, ee value 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).

The chirality detection method is as follows:

Step 3: Add 5.0 g of compound 10-1 hydrochloride, 100 mL of methanol, and 0.5 g of palladium carbon into a 250 mL three-necked flask, stir at room temperature, add 4.2 g of ammonium formate, and stir overnight. Suction filtration, adding 50 mL of water, rotary evaporation to remove most of the methanol, dropwise addition of NaOH solution (2M) until the pH is basic, extraction with ethyl acetate (100 mL, 50 x 2), and the organic phase is washed with saturated NaCl solution (50 mL). , dried over anhydrous sodium sulfate, and rotary-evaporated to obtain 3.13 g of compound 11, which is a colorless transparent liquid, yield: 100%, purity: 95.1%.

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

Example 5-3: Preparation of Compound 7

21.4 g of compound 6 was dissolved in 160 mL of methanol, 15.4 g of magnesium turnings were added in batches at 5-25° C., and the stirring was continued until the reaction was 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 dropwise add 20% potassium carbonate solution to pH 6-7. The layers were left to stand, 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 obtain 19.8 g of a red oil (compound 7). HPLC (column: XBridge C18 4.6*250 mm, ID 5 μm column; mobile phase: A: water [10 mmol/L NH ₄ HCO ₃ ] B: acetonitrile; gradient: 50%-90%-90%-50%-50 in 21 min %B; flow rate: 1.0ml/min; column temperature: 30°C; detection wavelength 254nm) shows that the molar ratio of compound 7-1 (retention time 11.072min) to compound 7-2 (retention time 10.354min) is 81:7, The yield of compound 7 was 91.9% and the purity was 83%. MS m/z (ESI): 302.2 [M+H] ⁺ .

Example 5-4: Preparation of Compound 7

To a 250ml there-necked flask, add 3g of compound 6, 30ml of tetrahydrofuran, 1g of NaBH ₄ and 0.3g of LiCl, and the reaction solution was stirred at room temperature overnight, LCMS showed that the reaction was incomplete, and 1.9g of NaBH ₄ , 1g of LiCl and 5ml of methanol were added and then continued to stir at room temperature for 72 The reaction was complete after hours. 100 ml of water was added to the reaction solution, a large amount of air bubbles were released, the reaction solution was extracted three times with 50 ml of ethyl acetate, the extracts were combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain 2.8 g of an oil (compound 7). HPLC (column: ACQUITY UPLC CSH C18, 2.1*50 mm, ID 1.7 μm; mobile phase: A: water [0.01% trifluoroacetic acid] B: acetonitrile [0.01% trifluoroacetic acid]; gradient: 5%-95% in 15 min B; flow rate: 0.8ml/min; column temperature: 50°C; detection wavelength 254nm) shows that the molar ratio of compound 7-1 (retention time 0.96min) to compound 7-2 (retention time 0.93min) is 94.5:5.5, the compound The yield of 7 was 93% and the purity was 87%. MS m/z (ESI): 302.2 [M+H] ⁺ .

Example 6: Preparation of Compound 12

2.4g of compound 11, 2.6g of 5-methyl-2-(pyrimidin-2-yl)benzoic acid and 27g of ethyl acetate were added to the reaction flask, stirred at a temperature below 25°C, 7.0g of T ₃ P solution was added dropwise, and After completion, continue stirring for 0.5h. The temperature was raised to 50-60°C, and the reaction was stirred for 2 h, and the reaction was completed by sampling and testing. Cool to 10℃～30℃, slowly add 30.0g water, after the addition, stir for 16h, let stand for layers, extract the aqueous layer once with 27g ethyl acetate, combine the organic layers, add 30.0g water to the organic layer, use 4% The NaOH solution was adjusted to pH 9-10, the layers were left to stand, the organic layer was washed once with 30 g of water, concentrated under reduced pressure, added 15.0 g of ethyl acetate, stirred for 16 h, filtered with suction, and the filter cake was washed with 2.0 g x 2 of ethyl acetate, and rotary evaporated. After drying for 1 h, 3.0 g of crude compound 12 was obtained as a khaki solid with a yield of 68.2% and a purity of 98.7%.

In a 50mL three-necked flask, add 3.0g of compound 12 crude product, 7.8g of ethyl acetate, and 0.234g of isopropanol, stir and heat up to 65-80°C, and slowly cool down to 50°C～60°C after dissolving (takes 1.5h～ 2.0h), a solid was precipitated; continue to cool down to 40°C to 50°C, keep stirring for 24h; continue to slowly cool to 10°C to 20°C, keep stirring for 24h; suction filtration, and the filter cake is rinsed with 1 mL*2 ethyl acetate. The filter cake was dried by vacuum rotary evaporation at 40-50° C. for 1 hour to obtain 2.17 g of light 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 H 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). About 300 mg of the purified compound 12 was weighed and dissolved in 2 mL of ethyl acetate at room temperature, and the insoluble matter was removed by filtration. About 1 mL of methyl tert-butyl ether was added to the filtrate and allowed to stand. After about 24 hours, light yellow fine crystals were precipitated, and the single crystal structure was shown in Figure 1.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

A compound of formula (I) or a salt thereof:

in,

Ring A is a benzene ring, a pyridine ring or a naphthalene ring;

(R a ) n represents that the hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;

R 1 , R 2 are each independently C 1-3 alkyl; and

n is 0, 1 or 2.
The compound or salt thereof according to claim 1, wherein the salt is a salt formed by the compound of formula (I) and an acid.
The compound or its salt according to claim 2, wherein the acid is an inorganic acid.
A preparation method of a compound of formula (I), comprising the steps:

(1) in an inert solvent, the compound of formula a, formula b and formula c is subjected to cyclization reaction, thereby obtaining a mixture comprising the compound of formula (I);

in,

Ring A is a benzene ring, a pyridine ring or a naphthalene ring;

(R a ) n represents that the hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;

R 1 , R 2 are each independently C 1-3 alkyl; and

n is 0, 1 or 2;

(2) subjecting the resulting mixture comprising the compound of formula (I) to acid treatment to obtain a salt of the compound of formula (I); and

(3) The resulting salt of the compound of formula (I) is treated to obtain the compound of formula (I).
The preparation method according to claim 4, wherein the compound of formula a is prepared by reacting 2H-pyran-2,4,6-(3H,5H)trione with an alkyl alcohol R 1 OH:

wherein, R 1 is a C 1-3 alkyl group.
The preparation method according to claim 4, wherein in step (1), the temperature of the reaction is -20°C to 50°C, preferably 0°C to 30°C, more preferably 5°C to 25°C.
The preparation method according to claim 4, characterized in that, in step (1), the reaction is carried out in a system with a pH value of 1 to 5, preferably in a system with a pH value of 3 to 4.
The preparation method according to claim 4, wherein the reaction of step (1) is carried out in a system containing a pH adjuster.
The preparation method according to claim 4, characterized in that, in step (2), adding acid to the obtained mixture containing the compound of formula (I) comprises using an acid-containing solution to treat the obtained mixture containing the compound of formula (I) with an acid. The mixture of compounds is processed.
The preparation method of claim 9, wherein the acid is selected from an organic acid and an inorganic acid, wherein the inorganic acid is selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid; the organic acid is selected from: Acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid acid, citric acid, tartaric acid and methanesulfonic acid.
The preparation method of claim 9, wherein in the acid-containing solution, the acid concentration is 0.1 mol/L to 10 mol/L, preferably 0.5 mol/L to 5 mol/L.
The preparation method of claim 4, wherein the step (1) comprises the steps:

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

(1b) treating the mixture of the compound of formula b and the first solvent with an acid to obtain the mixture 1b;

The first solvent is selected from: water, C 1-4 alkyl alcohol, 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 a combination thereof;

(1c) treating a mixture of a compound of formula c and a second solvent with an acid to obtain mixture 1c;

The second solvent is selected from: water, C 1-4 alkyl alcohol, 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 a combination thereof; and

(1d) in the presence of a pH adjusting agent, the reaction solution 1a, the mixture 1b and the mixture 1c are mixed to carry out a cyclization reaction, thereby obtaining a mixture comprising the compound of formula (I);

Wherein, the sequence of steps (1a), (1b) and (1c) can be arbitrarily exchanged.
The preparation method according to claim 12, wherein the pH adjusting agent described in step (1d) is selected from: (i) sodium acetate, (ii) sodium hydroxide, and (iii) sodium acetate and hydroxide A combination of sodium.
The preparation method according to claim 12, wherein in step (1d), the reaction is carried out under the condition of pH 1 to 5, preferably under the condition of pH 3 to 4.
The preparation method according to claim 12, wherein in step (1d), the reaction temperature is -20°C to 50°C, preferably 0°C to 30°C, more preferably 5°C to 25°C.
A compound of formula (VII-a) or a salt thereof:

in,

Ring A is a benzene ring, a pyridine ring or a naphthalene ring;

(R a ) n represents that a hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy, and (R b ) m represents that the hydrogen on the ring is substituted with m R b s, each R b being the same or different, and each independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;

R 2 is C 1-3 alkyl;

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

Z is N or CR 3 ; R 3 is hydrogen, halogen or C 1-3 alkyl;

Wherein, the salt is the salt formed by the compound of formula (VII-a) and an acid.
A preparation method of a compound of formula (VII-a), comprising the steps of: in an inert solvent, in the presence of a base, the compound of formula (VI) is subjected to a substitution reaction with a compound of formula (VIa), thereby obtaining formula (VII-a) compound;

in,

Ring A is a benzene ring, a pyridine ring or a naphthalene ring;

(R a ) n represents that a hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy, and (R b ) m represents that the hydrogen on the ring is substituted with m R b s, each R b being the same or different, and each independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;

R 2 is C 1-3 alkyl;

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

Z is N or CR 3 ; R 3 is hydrogen, halogen or C 1-3 alkyl; and

R LG is selected from: halogen, amino, hydroxyl, (HO) 2 B-, boronate ester, (NO 2 ) 2 C 6 H 3 O-, CH 3 S(O) 2 O-, CF 3 S(O) 2 O-, p-CH 3 C 6 H 4 S(O) 2 O-, CH 3 S(O) 2 -, CH 3 S(O)-.
A compound of formula (VII) or a salt thereof:

in,

Ring A is a benzene ring, a pyridine ring or a naphthalene ring;

(R a ) n represents that a hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy, and (R b ) m represents that the hydrogen on the ring is substituted with m R b s, each R b being the same or different, and each independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;

R 2 is C 1-3 alkyl;

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

Z is N or CR 3 ; R 3 is hydrogen, halogen or C 1-3 alkyl;

Wherein, the said salt is a salt formed by the compound of formula (VII) and an acid.
The compound or its salt according to claim 16 or 18, wherein the acid is an inorganic acid.
The compound or its salt according to claim 18, wherein the compound of formula (VII) has the following structure:
A preparation method of the compound of formula (VII), comprising the steps of: purifying the compound of formula (VII-a) to obtain the compound of formula (VII);

in,

Ring A is a benzene ring, a pyridine ring or a naphthalene ring;

(R a ) n represents that a hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy, and (R b ) m represents that the hydrogen on the ring is substituted with m R b s, each R b being the same or different, and each independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;

R 2 is C 1-3 alkyl;

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

Z is N or CR 3 ; R 3 is hydrogen, halogen or C 1-3 alkyl.
The preparation method of claim 21, wherein the compound of formula (VII-a) is prepared by the preparation method of claim 17.
The preparation method according to claim 21, characterized in that, the purification is adding acid to the compound of formula (VII-a) or its solution.
The preparation method according to claim 23, wherein the acid addition treatment is treatment with an acid-containing solution.
The preparation method of claim 24, wherein the acid is selected from an organic acid and an inorganic acid, wherein the inorganic acid is selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid; the organic acid is selected from: Acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid acid, citric acid, tartaric acid and methanesulfonic acid.
The preparation method of claim 17, wherein the compound of formula (VI) is prepared by a method comprising the following steps:

(a) subjecting the compound of formula (I) to a reduction reaction to obtain the compound of formula (III);

(b) the compound of formula (III) is subjected to elimination reaction to obtain the compound of formula (IV);

(c) subjecting the compound of formula (IV) to a reduction reaction to obtain a compound of formula (V); and

(d) subjecting the compound of formula (V) to a reduction reaction to obtain the compound of formula (VI);

Wherein in the above formulas, ring A is a benzene ring, a pyridine ring or a naphthalene ring;

(R a ) n represents that the hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;

n is 0, 1, or 2; and

R 1 and R 2 are each independently C 1-3 alkyl.
A preparation method of a compound of formula (VII), comprising the steps:

(a) subjecting the compound of formula (I) to a reduction reaction to obtain the compound of formula (III);

(b) the compound of formula (III) is subjected to elimination reaction to obtain the compound of formula (IV);

(c1) subjecting the compound of formula (IV) to a reduction reaction to obtain the compound of formula (V-1);

(d1) subjecting the compound of formula (V-1) to a reduction reaction to obtain a compound of formula (VI-1); and

(e1) subjecting the compound of formula (VI-1) to a substitution reaction with the compound of formula (VIa) to obtain the compound of formula (VII);
The preparation method of claim 27, wherein the compound of formula (I) is prepared by the preparation method of claim 4.
The preparation method according to claim 26 or 27, wherein the reduction reaction of step (a) is carried out in a system containing a reducing agent and an inert solvent,

The reducing agent is selected from:

(a) Tetrabutylamine borohydride, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, potassium borohydride, borane, iso Propanol—one or more of aluminum triisopropoxide, lithium aluminum tetrahydrogen, lithium aluminum tri-tert-butoxide, and samarium diiodide;

(b) a combination of zinc and a Lewis acid; and

(c) a combination of a catalyst and a hydrogen donor, wherein the catalyst is selected from metal palladium, nickel, platinum and lead, and the hydrogen donor is selected from hydrogen, formic acid and formate;

The inert solvent is selected from: water, C 1-4 alkyl alcohol, 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, and combinations thereof.
The preparation method according to claim 26 or 27, wherein the elimination reaction of step (b) is carried out in a system containing the following reagents: a hydroxyl activator, a base and an inert solvent.
The preparation method of claim 30, wherein the hydroxyl activator is a sulfonyl chloride, and the sulfonyl chloride is selected from the group consisting of: benzenesulfonyl chloride, p-toluenesulfonyl chloride, and methanesulfonyl chloride.
The preparation method of claim 30, wherein the base is selected from the group consisting of: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, tertiary Potassium butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N- Methylmorpholine, pyridine, and combinations thereof.
The preparation method of claim 30, wherein the base is selected from the group consisting of: ammonia water, triethylamine, diisopropylethylamine, N,N-dimethylaniline, tetramethylethylenediamine, triethylamine Butylamine, 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 phenate, sodium benzoate, sodium citrate, N-methylmorpholine, Pyridine and combinations thereof.
The preparation method of claim 30, wherein the inert solvent is selected from the group consisting of: 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, and combinations thereof.
The preparation method of claim 26, wherein the reduction reaction of step (c) is carried out in a system containing a reducing agent and an inert solvent,

wherein the reducing agent is selected from:

(a) One or more of the following: magnesium metal, alkyl silicon hydride, sodium borohydride, lithium borohydride, potassium borohydride, hydride of tin, selenium or tellurium, borane, sodium hydrosulfite, olefinic bond Reductase, yeast enzyme;

(b) a combination of zinc and a hydrogen donor selected from formic acid and formate salts;

(c) a combination of tin, carbon monoxide and water;

(d) a combination of a complex and a hydrogen donor, the complex is selected from the complex of palladium, rhodium, cobalt, nickel, ruthenium, iridium, copper, and the hydrogen donor is selected from hydrogen, formic acid and methyl acid; and

(e) a combination of a catalyst and a hydrogen donor, the catalyst is selected from palladium and nickel, and the hydrogen donor is selected from hydrogen, formic acid and formate;

The inert solvent is selected from: C 1-4 alkyl alcohol, 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, and combinations thereof.
The preparation method of claim 26, wherein the reduction reaction of step (c) is carried out in a system containing the following reagents: 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 alcohol, 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, and combinations thereof; and

The Lewis acid is selected from the group consisting of: lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, cupric chloride, aluminum chloride, ferrous chloride, nickel chloride and gallium dichloride.
The preparation method of claim 27, wherein the reduction reaction of step (c1) is carried out in a system containing a reducing agent and an inert solvent,

wherein the reducing agent is selected from:

(a) One or more of the following: magnesium metal, alkyl silicon hydride, sodium borohydride, lithium borohydride, potassium borohydride, hydride of tin, selenium or tellurium, borane, sodium hydrosulfite, olefinic bond Reductase, yeast enzyme;

(b) a combination of zinc and a hydrogen donor selected from formic acid and formate salts;

(c) a combination of tin, carbon monoxide and water;

(d) a combination of a complex and a hydrogen donor, the complex is selected from the complex of palladium, rhodium, cobalt, nickel, ruthenium, iridium, copper, and the hydrogen donor is selected from hydrogen, formic acid and methyl acid; and

(e) a combination of a catalyst and a hydrogen donor, the catalyst is selected from palladium and nickel, and the hydrogen donor is selected from hydrogen, formic acid and formate;

The inert solvent is selected from: C 1-4 alkyl alcohol, 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, and combinations thereof.
The preparation method according to claim 27, wherein the reduction reaction of step (c1) is carried out in a system containing the following reagents: 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 alcohol, 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, and combinations thereof.
The preparation method of claim 38, wherein the Lewis acid is selected from the group consisting of: lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, copper chloride, aluminum chloride, ferrous chloride, chloride Nickel and Gallium Dichloride.
The preparation method according to claim 26 or 27, wherein 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, tri-sec-butylborohydride one or more of lithium, potassium borohydride, borane, diisobutylaluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium tetrahydroaluminum, potassium hydroxide-diglycol, and samarium diiodide;

(b) a combination of a 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 (PCy 3 )][BF 4 ] and phenylsilane;

The inert solvent is selected from: C 1-4 alkyl alcohol, 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, and combinations thereof.
The preparation method according to claim 17 or 27, wherein the substitution reaction is carried out in a system containing a base and an inert solvent,

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-dimethoxide azabicyclo[5,4,0]-7-undecene (DBU), lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine, and 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, and combinations thereof.
The preparation method according to claim 17 or 27, wherein the compound of formula (VIa) is selected from:
The preparation method according to claim 21 or 27, characterized in that, the preparation method further comprises the step of: salting the compound of formula (VII) with an acid to obtain a salt of the compound of formula (VII).
A preparation method of a compound of formula (IX), comprising the steps of: in a solvent, removing a substituent on a nitrogen atom from a compound of formula (VII) or a salt thereof to obtain a compound of formula (IX);

in,

Ring A is a benzene ring, a pyridine ring or a naphthalene ring;

(R a ) n represents that a hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;

(R b ) m represents that the hydrogen on the ring is replaced by m R b , each R b is the same or different, and each R b is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;

R 2 is C 1-3 alkyl;

m is 0, 1 or 2;

n is 0, 1, or 2; and

Z is N or CR 3 ; R 3 is hydrogen, halogen or C 1-3 alkyl.
The preparation method of claim 44, wherein the compound of formula (VII) is prepared by the preparation method of claim 21 or 27.
A preparation method of a compound of formula (X), comprising the steps of: in an inert solvent, a compound of formula (IX) or a salt thereof is subjected to a condensation reaction with 5-methyl-2-(pyrimidin-2-yl)benzoic acid, thereby to obtain the compound of formula (X);

in,

(R b ) m represents that the hydrogen on the ring is replaced by m R b , each R b is the same or different, and each R b is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;

m is 0, 1, or 2; and

Z is N or CR 3 ; R 3 is hydrogen, halogen or C 1-3 alkyl.
The preparation method of claim 46, wherein the compound of formula (IX) is prepared by the preparation method of claim 44.