Intermediate of bicyclic inhibitor and preparation method thereof

Abstract

The invention provides an intermediate of a bicyclic inhibitor and a preparation method of the intermediate. The invention particularly relates to an intermediate shown in the formula (VI) and a preparation method thereof. The method has the advantages of cheap and easily available initial raw materials, mature synthesis process, stable product quality, high yield and purity, recyclable and reusable key reagents and reduced production cost, and is suitable for large-scale industrial production and application. # imgabs0 #

Description

An intermediate of a dicyclopentadiene inhibitor and a preparation method thereof Technical Field

[0001] The present invention belongs to the field of drug synthesis, and particularly relates to an intermediate of a dicyclopentadiene inhibitor and a preparation method thereof. Background Art

[0002] The RET (rearranged during transfection) protein, encoded by the proto-oncogene RET located on chromosome 10, is a receptor tyrosine kinase composed of an extracellular domain, a transmembrane domain, and an intracellular kinase domain. RET ligands are glial cell-derived neurotrophic factor (GDNF) family ligands (GFLs), such as GDN, neurturin (NRTN), artemin (ARTN), and persephin (PSPN). Activation of the receptor requires the co-receptor GFRα. GFLs dimerize with GFRα, binding to and recruiting RET to cholesterol-rich membrane regions. RET dimerizes and undergoes autophosphorylation, activating downstream signaling pathways such as RAS-MAPK, PI3K-AKT, and PKC. RET plays a crucial role in the development of the kidney and enteric nervous system during embryonic development and is also crucial for the homeostasis of neuroendocrine, hematopoietic, and male germ cell tissues.

[0003] Disorders in the function of RET protein lead to the occurrence of many diseases. Loss of RET protein function during development can lead to a series of congenital diseases such as Hirschsprung disease (HSCR), congenital kidney and urinary tract malformations (CAKUT), etc. Activating mutations of RET protein, including point mutations and RET protein fusions caused by chromosomal rearrangements, are also related to the occurrence of many diseases. RET fusion mainly occurs in Non-small cell lung cancer (NSCLC) patients and RET mutations occur mainly in 60% of papillary thyroid cancer, while RET mutations occur mainly in 60% of medullary thyroid cancer. In addition, activating mutations of RET protein are found in many other tumors such as breast cancer, gastric cancer, intestinal cancer, chronic myelomonocytic leukemia, etc.

[0004] Despite significant clinical unmet need, current treatments targeting RET remain extremely limited. Unlike targeted drugs such as ALK and EGFR, which have demonstrated excellent clinical efficacy, there are currently no approved targeted drugs targeting RET. Currently, multikinase inhibitors (MKIs) such as vandetinib and cabozantinib are often used in clinical practice. These MKIs have poor selectivity, high side effects, and poor efficacy, and are unable to overcome drug resistance that can arise during treatment.

[0005] Currently, there is no specific targeted drug for the RET target, and there is a great clinical demand. RET inhibitors with higher selectivity, better activity, better safety, and the ability to overcome drug-resistant mutations have the potential to treat a variety of cancers and have broad market prospects. In 2015, Jiangsu Hausen Pharmaceuticals Group Co., Ltd. disclosed a series of dicyclic derivatives in patent WO2020228756A1, which exhibited outstanding pharmacological properties, had a strong inhibitory effect on RET kinase activity, and had a poor inhibitory effect on KDR kinase activity. The inhibitory effect on KDR / RET kinase activity is highly selective. It has entered the clinical phase II research stage, but the following intermediates are used in the preparation of this compound:

[0006] Patent WO2018071454A discloses a series of RET inhibitors and discloses key intermediates and preparation methods for preparing the RET inhibitors shown above. However, the preparation method of the intermediates described in the patent is complex, with a long reaction process of 10 steps, and the overall product yield is low, making it unsuitable for industrial production. Therefore, the present invention is dedicated to developing a preparation method for dicyclic ring compounds suitable for industrial production.

[0007] Summary of the Invention

[0008] In order to solve the problems existing in the prior art, the inventors developed a novel method for preparing RET inhibitors during a long-term research and development process. The present invention can improve the yield and purity of RET inhibitor compounds through specific intermediates of formula (V) and formula (VI) and their preparation methods, and is more conducive to industrial production.

[0009] In a first aspect, the present invention aims to provide a compound represented by general formula (VI), a stereoisomer and a salt thereof,

[0010] R2 is selected from hydrogen, deuterium, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy or C 1-3 Hydroxyalkyl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Base, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 The hydroxyalkyl group is substituted with one or more substituents;

[0011] R3 is selected from C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Base, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 The hydroxyalkyl group is substituted with one or more substituents;

[0012] R4 is selected from -C(O)(CR aa R bb ) n R a or -(CR aa R bb ) m R b ;

[0013] R aa or R bb are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino or C 1-3 Alkyl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Base, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 The hydroxyalkyl group is substituted with one or more substituents;

[0014] R a Selected from C 6-10 Aryl or 6-10 membered heteroaryl containing 1-3 N, O or S atoms, wherein the C 6-10 Aryl or 6-10 membered heteroaryl containing 1-3 N, O or S atoms, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Base, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 The hydroxyalkyl group is substituted with one or more substituents;

[0015] R b is selected from hydroxyl protecting groups, preferably substituted or unsubstituted sulfonyl;

[0016] m is 0, 1, or 2; and

[0017] n is 0, 1 or 2.

[0018] In a preferred embodiment of the present invention, R2 is selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, dimethoxymethyl, dimethoxyethyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl or trifluoroethyl;

[0019] R3 is selected from methyl, ethyl, propyl, vinyl, allyl, propenyl, ethynyl, propynyl or propargyl;

[0020] R4 is selected from -C(O)(CR aa R bb ) n R a or -(CR aa R bb ) m R b ;

[0021] R aa or R bb are each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, amino, methyl, ethyl, propyl or isopropyl;

[0022] R a is selected from phenyl, naphthyl, pyridine, pyrimidine or a six-membered heteroaryl containing 1-3 N, O or S atoms, wherein the phenyl, naphthyl, pyridine, pyrimidine or a six-membered heteroaryl containing 1-3 N, O or S atoms is optionally substituted with one or more substituents selected from deuterium, amino, hydroxyl, cyano, nitro, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl or trifluoroethyl;

[0023] R b is selected from benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, p-methoxybenzenesulfonyl, p-trifluoromethylbenzenesulfonyl, p-chlorobenzenesulfonyl or 2-naphthalenesulfonyl, preferably p-nitrobenzenesulfonyl or 2-naphthalenesulfonyl;

[0024] m is 0, 1, or 2; and

[0025] n is 0, 1 or 2.

[0026] In a further preferred embodiment of the present invention,

[0027] R4 is selected from benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, p-methoxybenzenesulfonyl, p-trifluoromethylbenzenesulfonyl, p-chlorobenzenesulfonyl or 2-naphthalenesulfonyl, preferably p-nitrobenzenesulfonyl or 2-naphthalenesulfonyl.

[0028] In a further preferred embodiment of the present invention, the compound of formula (VI) is further represented by general formula (XVII):

[0029] R2 and R3 are as shown in the general formula (VI).

[0030] On the other hand, the present invention aims to provide a compound represented by general formula (IX), stereoisomers and salts thereof,

[0031] R x Selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 Hydroxyalkyl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Base, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 One or more substituents in the hydroxyalkyl group are substituted; preferably, R4 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine;

[0032] R5 is selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 Hydroxyalkyl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Base, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3One or more substituents in the hydroxyalkyl group are substituted; preferably, R5 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine;

[0033] R6 is selected from hydrogen, deuterium, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynylhalogen, cyano, amino or hydroxy, preferably hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, cyano, vinyl, ethynyl, amino or hydroxy.

[0034] In a further preferred embodiment of the present invention, there are provided compounds, stereoisomers and salts thereof with the following structures:

[0035] An intermediate of a compound of formula (IX), a stereoisomer and a salt thereof is represented by the general formula (X):

[0036] Preferred

[0037] An intermediate of a compound of formula (IX), a stereoisomer and a salt thereof is represented by the general formula (XI):

[0038] Preferred

[0039] Another object of the present invention is to provide a method for preparing a compound as shown in formula (X), comprising the following steps:

[0040] Formula (XI) reacts with formula (XI') to prepare formula (X);

[0041] R x is selected from hydrogen, deuterium, C1-3 alkyl or halogen, preferably hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine;

[0042] R5 is selected from hydrogen, deuterium, C1-3 alkyl or halogen, preferably hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine;

[0043] R6 is selected from hydrogen, deuterium, C1-3 alkyl, halogen, cyano, amino or hydroxy, preferably hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, cyano, amino or hydroxy;

[0044] R7 is selected from halogen, preferably fluorine, chlorine or bromine;

[0045] Preferably, the reaction is carried out in the presence of an organometallic reagent, wherein the organometallic reagent is selected from an organolithium or organomagnesium reagent, preferably n-butyllithium, sec-butyllithium, isobutyllithium, tert-butyllithium, isopropylmagnesium chloride, isopropylmagnesium bromide or isopropylmagnesium chloride-lithium chloride, more preferably n-butyllithium;

[0046] Preferably, the solvent used in the reaction is selected from one or more of toluene, xylene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether or methyl tert-butyl ether, preferably a mixed solvent of tetrahydrofuran and toluene or ethylene glycol dimethyl ether and methyl tert-butyl ether, more preferably the volume ratio of tetrahydrofuran to toluene is 4:1 to 1:4 or the volume ratio of ethylene glycol dimethyl ether to methyl tert-butyl ether is 1:5 to 1:1, further preferably the volume ratio of ethylene glycol dimethyl ether to methyl tert-butyl ether is 1:2 or the volume ratio of tetrahydrofuran to toluene is 1.5:1.

[0047] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (X) is as follows:

[0048] In a further preferred embodiment of the present invention, formula (XII) is reacted to give formula (XI),

[0049] Wherein, R8 is selected from C 1-3 Alkyl, preferably methyl, ethyl, n-propyl or isopropyl;

[0050] Preferably, the reaction is carried out in the presence of an acid, wherein the acid is selected from formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, citric acid, malic acid or tartaric acid, preferably p-toluenesulfonic acid;

[0051] Preferably, the solvent used in the reaction is selected from dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, methanol, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably toluene.

[0052] In a further preferred embodiment of the present invention, the preparation method of the compound of formula (XI) is as follows:

[0053] In a further preferred embodiment of the present invention, the reaction of formula (XIII) with formula (XIV) yields formula (XII),

[0054] Preferably, the reaction is carried out in the presence of an acid, wherein the acid is selected from formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, citric acid, malic acid or tartaric acid, preferably acetic acid;

[0055] Preferably, the solvent used in the reaction is selected from dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, methanol, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably dichloromethane.

[0056] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (XII) is as follows:

[0057] In a further preferred embodiment of the present invention, the compound of formula (XV) reacts with N,N-dimethylformamide dimethyl acetal in the presence of an acid to obtain the compound of formula (XIII),

[0058] wherein R9 is selected from Na, K or H;

[0059] Preferably, the acid is selected from formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, citric acid, malic acid or tartaric acid, preferably acetic acid;

[0060] Preferably, the solvent used in the reaction is selected from dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, methanol, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably dichloromethane.

[0061] In a further preferred embodiment of the present invention, the preparation method of the compound of formula (XIII) is as follows:

[0062] In a further preferred embodiment of the present invention, formula (X) is reacted to give formula (IX),

[0063] Preferably, the reaction is carried out in the presence of an oxidant, wherein the oxidant is selected from one or more of sodium hypochlorite, calcium hypochlorite, Dess-Martin periodinane, 2-iodoacylbenzoic acid, iodobenzene diacetate, oxalyl chloride-dimethyl sulfoxide combination reagent, pyridine-sulfur trioxide, 2,2,6,6-tetramethylpiperidinyl oxide, pyridine-N-oxide or trichloroisocyanuric acid, preferably a mixed oxidant of 2,2,6,6-tetramethylpiperidinyl oxide and trichloroisocyanuric acid, more preferably a molar ratio of 2,2,6,6-tetramethylpiperidinyl oxide to trichloroisocyanuric acid of 1:4 to 1:40, further preferably a molar ratio of 2,2,6,6-tetramethylpiperidinyl oxide to trichloroisocyanuric acid of 1:10;

[0064] Preferably, the solvent used in the reaction is selected from dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, methanol, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably dichloromethane.

[0065] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (IX) is as follows:

[0066] In a further preferred embodiment of the present invention, formula (IX) is reacted to give formula (V),

[0067] Preferably, the reaction is carried out under alkaline conditions, wherein the base is selected from one or more of sodium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, sodium hydride, potassium carbonate, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, cesium carbonate, lithium carbonate, lithium hydroxide, lithium chloride, lithium methoxide, lithium ethoxide, lithium isopropoxide or lithium tert-butoxide, preferably a mixture of lithium hydroxide and lithium chloride, more preferably a molar ratio of lithium hydroxide to lithium chloride of 1:4 to 4:1, further preferably a molar ratio of lithium hydroxide to lithium chloride of 1:1;

[0068] Preferably, the solvent used in the reaction is selected from one or more of toluene, xylene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, methanol, ethanol, tert-butanol, water, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably a mixed solvent of ethylene glycol dimethyl ether, methyl tert-butyl ether and water, preferably a volume ratio of ethylene glycol dimethyl ether to methyl tert-butyl ether to water of 5 to 10:30 to 50:1, more preferably a volume ratio of ethylene glycol dimethyl ether to methyl tert-butyl ether to water of 8:40:1.

[0069] In a further preferred embodiment of the present invention, the preparation method of the compound of formula (V) is as follows:

[0070] In a further preferred embodiment of the present invention, the preparation method of the compound of formula (V) is as follows:

[0071] In a further preferred embodiment of the present invention, formula (XVI) reacts with R4X in the presence of a base to obtain formula (VI);

[0072] Wherein, R2 is selected from hydrogen, deuterium, hydroxyl, amino or C 1-3 Alkyl, preferably hydrogen, deuterium, amino, methyl, ethyl, propyl or isopropyl;

[0073] R3 is selected from C 1-3 Alkyl, C 1-3 Alkenyl or C 1-3 Alkynyl, preferably methyl, ethyl, propyl, vinyl, allyl, propenyl, ethynyl, propynyl or propargyl;

[0074] R4 is selected from benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, p-methoxybenzenesulfonyl, p-trifluoromethylbenzenesulfonyl, p-chlorobenzenesulfonyl, 2-naphthalenesulfonyl, preferably p-nitrobenzenesulfonyl or 2-naphthalenesulfonyl;

[0075] X is selected from halogen, preferably fluorine, chlorine or bromine;

[0076] Preferably, the base is selected from pyridine, 2-methylpyridine, 4-methylpyridine, 2,6-lutidine, 4-dimethylaminopyridine, imidazole, 1-methylimidazole, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, cesium carbonate, lithium carbonate or lithium hydroxide, preferably 2,6-lutidine or triethylamine;

[0077] Preferably, the solvent used in the reaction is selected from dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably dichloromethane.

[0078] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (VI-1) is as follows:

[0079] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (VI-3) is as follows:

[0080] In a further preferred embodiment of the present invention, the compound of formula (XVII) is reacted with a base to obtain the compound of formula (XVI),

[0081] Preferably, the reaction is carried out in the presence of a base, wherein the base is selected from sodium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, sodium hydride, potassium carbonate, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, cesium carbonate, lithium carbonate, lithium hydroxide, lithium methoxide, lithium ethoxide, lithium isopropoxide or lithium tert-butoxide, preferably sodium hydroxide;

[0082] Preferably, the solvent used in the reaction is selected from one or more of acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, methanol, ethanol, isopropanol, tert-butyl alcohol, ethylene glycol, or water, preferably a mixed solvent of tetrahydrofuran and water. More preferably, the volume ratio of tetrahydrofuran to water is 40:1 to 30:1, and even more preferably, the volume ratio of tetrahydrofuran to water is 33:1.

[0083] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (XVI) is as follows:

[0084] In a further preferred embodiment of the present invention, formula (XVII-RAC) is resolved to obtain formula (XVII),

[0085] Preferably, the resolution solvent is selected from one or more of dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, acetic acid, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, methanol, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably a combination of toluene and acetonitrile or a combination of toluene and acetic acid, more preferably the volume ratio of toluene to acetonitrile solvent is selected from 20:1 to 3:1 or the volume ratio of toluene to acetic acid solvent is selected from 20:1 to 5:1, further preferably the volume ratio of toluene to acetonitrile solvent is selected from 10:1 to 4:1 or the volume ratio of toluene to acetic acid solvent is selected from 15:1 to 10:1, most preferably the volume ratio of toluene to acetonitrile solvent is 4:1 or the volume ratio of toluene to acetic acid solvent is 12:1 or 12.5:1.

[0086] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (XVII) is as follows:

[0087] In a further preferred embodiment of the present invention, formula (XVI-RAC) is reacted to give formula (XVII-RAC),

[0088] Preferably, the reaction is carried out in the presence of a naproxen chlorination agent, wherein the chlorination agent is selected from oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or triphosgene, preferably oxalyl chloride and triphosgene;

[0089] Preferably, the base is selected from pyridine, 2-methylpyridine, 4-methylpyridine, 2,6-lutidine, 4-dimethylaminopyridine, imidazole, 1-methylimidazole, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, cesium carbonate, lithium carbonate or lithium hydroxide, preferably 2,6-lutidine;

[0090] Preferably, the solvent used in the reaction is selected from dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably dichloromethane.

[0091] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (XVII-RAC) is as follows:

[0092] In a further preferred embodiment of the present invention, the compound of formula (XVIII) is reacted with a reducing agent to obtain the compound of formula (XVI),

[0093] Preferably, the reducing agent is selected from sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, borane tetrahydrofuran complex, sodium trimethoxyborohydride or lithium aluminum hydride, preferably sodium triacetoxyborohydride.

[0094] Preferably, the reaction solvent is selected from dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, tert-butanol or ethylene glycol, preferably a mixed solvent of dichloromethane and methanol, and more preferably the ratio of dichloromethane to methanol is 5 to 20:1.

[0095] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (XVI) is as follows:

[0096] In a further preferred embodiment of the present invention, the compound of formula (XIX) is reacted in the presence of an acid to give the compound of formula (XVIII),

[0097] Among them, R9 and R 10 Each independently selected from C 1-3 Alkyl, preferably methyl, ethyl, n-propyl or isopropyl;

[0098] Preferably, the acid is selected from concentrated hydrochloric acid, concentrated sulfuric acid, concentrated phosphoric acid, a 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, methanesulfonic acid or p-toluenesulfonic acid, preferably trifluoroacetic acid;

[0099] Preferably, the solvent used in the reaction is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, tert-butanol, ethylene glycol or water, preferably dichloromethane.

[0100] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (XVIII) is as follows:

[0101] In a further preferred embodiment of the present invention, formula (XX) is reacted in the presence of a base to give formula (XIX),

[0102] Preferably, the base is selected from sodium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, sodium hydride, potassium carbonate, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, cesium carbonate, lithium carbonate, lithium hydroxide, lithium methoxide, lithium ethoxide, lithium isopropoxide or lithium tert-butoxide, preferably sodium hydroxide;

[0103] Preferably, the solvent used in the reaction is selected from one or more of acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, methanol, ethanol, isopropanol, tert-butanol, ethylene glycol or water, preferably a mixed solvent of tetrahydrofuran and water, more preferably a volume ratio of tetrahydrofuran to water of 20:1 to 5:1, further preferably a volume ratio of tetrahydrofuran to water of 10:1.

[0104] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (XIX) is as follows:

[0105] In a further preferred embodiment of the present invention, formula (XX-RAC) is resolved to obtain formula (XX),

[0106] Preferably, the resolution solvent is selected from one or more of dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, acetone, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, n-heptane, methanol, ethanol, isopropanol, n-butanol, and water, preferably isopropanol.

[0107] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (XX) is as follows:

[0108] In a further preferred embodiment of the present invention, the compound of formula (XIX-RAC) reacts with a naproxen chlorination reagent in the presence of a base to obtain the compound of formula (XX-RAC),

[0109] Preferably, the chlorination agent is selected from oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or triphosgene, preferably oxalyl chloride and triphosgene;

[0110] Preferably, the base is selected from pyridine, 2-methylpyridine, 4-methylpyridine, 2,6-lutidine, 4-dimethylaminopyridine, imidazole, 1-methylimidazole, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, cesium carbonate, lithium carbonate or lithium hydroxide, preferably pyridine;

[0111] Preferably, the solvent used in the reaction is selected from dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably dichloromethane.

[0112] In a further preferred embodiment of the present invention, the preparation method of the compound represented by formula (XX-RAC) is as follows:

[0113] In a further preferred embodiment of the present invention, the preparation method of the compound of formula (VI) is as follows:

[0114] In a further preferred embodiment of the present invention, the preparation method of the compound of formula (VI) is as follows:

[0115] In a further preferred embodiment of the present invention, the preparation method of the compound of formula (VI) is as follows:

[0116] In a further preferred embodiment of the present invention, the preparation method of the compound of formula (VI) is as follows:

[0117] The method for preparing the compound represented by formula (VI) of the present invention uses cheap and readily available starting materials, has a mature synthesis process, stable product quality, and key reagents that can be recycled and reused, thereby reducing production costs and being suitable for large-scale industrial production applications.

[0118] The formula (V) of the present invention adopts a brand-new preparation method. The starting raw materials used in the reaction are cheap and readily available, the synthesis process is mature, and continuous reaction can be carried out during the reaction, shortening the reaction steps. The operation is simple and avoids the column chromatography purification process. The product quality is stable, the production cost is reduced, and the yield and purity are improved. The method is very suitable for large-scale industrial production applications.

[0119] The present invention can improve the yield and purity of RET inhibitor compounds through specific intermediates of formula (V) and formula (VI) and their preparation methods, and is more conducive to industrial production. DETAILED DESCRIPTION

[0120] DETAILED DESCRIPTION: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0121] "Alkyl" refers to straight-chain and branched alkyl groups containing 1 to 4 carbon atoms, and alkyl refers to saturated aliphatic hydrocarbon groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc.

[0122] The present invention will be further described in detail and completely below with reference to the embodiments, but the present invention is by no means limited thereto, and the present invention is not limited to the contents of the embodiments.

[0123] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts are given in parts per million (ppm). NMR measurements are performed using a Bruker AVANCE-400 nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-Cl6), deuterated methanol (CD3⑽), and deuterated chloroform (CDCl3) as the internal standard, with tetramethylsilane (TMS).

[0124] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gi min i C18 150 x 4.6 mm column).

[0125] Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are The specifications used for thin layer chromatography separation and purification products are Column chromatography generally uses Yantai Huanghai silica gel Silica gel is used as the carrier.

[0126] Unless otherwise specified, all reactions in the present invention were carried out under continuous magnetic stirring.

[0127] Example 1

[0128] Preparation of the compound represented by formula (XIII)

[0129] The compound represented by formula (XV) (140 g, 0.942 mol), N,N-dimethylformamide dimethyl acetal (337 g, 2.83 mol), and dichloromethane (700 mL) were added sequentially to a three-necked flask, and the mixture was cooled to 0-2°C and stirred evenly. A solution of acetic acid (170 g, 2.83 mol) in dichloromethane (140 mL) was slowly added with stirring at 0-2°C, and the temperature was raised to 20-25°C and the reaction was continued with stirring for 3 hours. HPLC analysis determined the reaction was complete. Saturated aqueous sodium bicarbonate solution (700 mL) was slowly added to the reaction mixture to quench the reaction, and the mixture was allowed to stand for separation. The aqueous phase was extracted three times with dichloromethane (700 mL x 3). The organic phases were combined, washed with water, combined, and concentrated to dryness under vacuum to obtain a yellow-green solid product. The product was vacuum-dried to obtain 150 g of the compound represented by formula (XIII) in a yield of 87.4%.

[0130] The above product was directly used in the next step.

[0131] MS,m / z(ESI):183.1[M+H] + .

[0132] 1 H NMR, (400MHz, CDCl3) δ7.93(s,1H),3.87(s,3H),3.48(s,3H),3.33(s,3H).

[0133] Example 2

[0134] Preparation of the compound represented by formula (XI)

[0135] The raw material compound represented by formula (XIII) (90.0 g, 494 mmol) was added to a reactor, toluene (360 mL) was added at room temperature of 20-25°C, and then acetic acid (270 mL) was added and stirred to dissolve. The mixture was cooled to 0-2°C and stirred, and a dichloromethane solution (45 mL) of the compound represented by formula (XIV) (53.5 g, 593 mmol) was slowly added. The reaction temperature was raised to 40-45°C and stirred for 4-6 hours. The reaction was determined to be complete by HPLC analysis. The reaction solution was cooled to room temperature, added to water (900 mL), washed thoroughly, and allowed to stand for separation. The aqueous phase was extracted twice with dichloromethane (900 mL x 2), the organic phases were combined, concentrated, and solvent replaced with toluene (900 mL x 2) to obtain a toluene solution / mixture of the intermediate product represented by formula (XII), which was directly used for the next reaction.

[0136] Toluenesulfonic acid monohydrate (14.1 g, 74.1 mmol) was added to the mixture obtained in the previous step, heated to an external temperature of 120°C, and the reaction was determined to be complete by HPLC analysis. The reaction mixture was cooled to room temperature (20-25°C), and the reaction solution was slowly added to an ice-water mixture (about 900 mL), and a large amount of yellow solid precipitated. Ethyl acetate (900 mL x 3) was added and extracted three times. The resulting organic phases were combined and concentrated. Methyl tert-butyl ether (450 mL) was added, and the temperature was raised to 50-55°C and beaten for 2-3 hours. N-heptane (270 mL) was slowly added dropwise, beaten at 50-55°C for 1-2 hours, and then slowly cooled to room temperature. The filter cake was thoroughly rinsed with a mixture of methyl tert-butyl ether / n-heptane (methyl tert-butyl ether / n-heptane = 2 / 3, 90 mL). The filter cake was dried in a vacuum drying oven to obtain 42.4 g of a crude compound represented by formula (XI) as a light yellow powder solid with a continuous yield of 48.6%.

[0137] MS,m / z(ESI):178.1[M+H] + .

[0138] 1 H NMR, (400MHz, CDCl3) δ7.93 (s, 1H), 5.05-4.96 (m, 1H), 4.58-4.53 (m, 1H), 4.27-4.21 (m, 1H), 1.49 (d, J = 8.0Hz, 3H).

[0139] Example 3

[0140] Preparation of the compound represented by formula (X)

[0141] The compound represented by formula (XI) (9.30 g, 52 mmol) and 2-fluoro-5-bromopyridine (10.75 g, 60 mmol) were added to a three-necked flask at room temperature (20-25°C). THF (60 mL) and toluene (40 mL) were added to the flask under N2 protection and stirred evenly. The reaction mixture was cooled to -60-70°C and n-butyllithium solution (52.8 mL, 2.5 M in hexane) was added. After the addition, the reaction was maintained at -60-70°C for 3 hours. The temperature was then slowly raised to -30-25°C and the reaction was maintained at -30-20°C for 3 hours. The reaction was quenched by adding trifluoroacetic acid aqueous solution (40 mL, 50%, V / V) at -30 to -25°C. After addition, the temperature was raised to room temperature (20 to 25°C) and stirred for 3 to 4 hours. Water (80 mL) was added to the reaction mixture, stirred evenly, and allowed to stand for separation, retaining the upper organic phase. The aqueous phase was extracted twice with ethyl acetate (60 mL in total), and the organic phases were combined. The combined organic phases were washed once with saturated sodium bicarbonate aqueous solution (60 mL), allowed to stand for separation, and the organic phase was retained. The aqueous phase was back-extracted once with ethyl acetate (30 mL). The organic phases were combined. The solvent was replaced by adding dichloromethane (100 mL in total) to obtain the crude product of the compound represented by formula (X), which was directly used in the next step.

[0142] MS,m / z(ESI):275.1[M+H] + .

[0143] Example 4

[0144] Preparation of the compound represented by formula (IX)

[0145] A solution of the compound represented by formula (X) (32.9 g, 120 mmol) in dichloromethane (approximately 200 mL) was added to a reactor at room temperature (20-25°C). Sodium bicarbonate (15.2 g, 180 mmol) and potassium bromide (1.43 g, 12.0 mmol) were added at room temperature (20-25°C) and stirred uniformly. The first batch of 2,2,6,6-tetramethylpiperidinyl oxide (375 mg, 2.40 mmol) was added under stirring at 20-25°C, followed by the slow addition of trichloroisocyanuric acid (5.58 g, 24.0 mmol). After the addition was complete, the mixture was reacted at 20-25°C for 2 hours. The second batch of 2,2,6,6-tetramethylpiperidinyl oxide (375 mg, 2.40 mmol) was added under stirring at 20-25°C, followed by the slow addition of trichloroisocyanuric acid (5.58 g, 24.0 mmol). Then, the third, fourth and fifth batches of 2,2,6,6-tetramethylpiperidinyl oxide (375 mg, 2.40 mmol) and trichloroisocyanuric acid (5.58 g, 24.0 mmol) were slowly added under stirring at 20-25 ° C. The reaction was determined to be complete by HPLC analysis. The solid was rinsed with dichloromethane (40 mL) and the organic phase was combined. Isopropyl alcohol (7.2 g, 120 mmol) was added to the organic phase to quench the reaction, and the organic phase was washed with saturated sodium bicarbonate aqueous solution and water, methyl tert-butyl ether was added, and the mixture was concentrated to dryness to give the compound shown in the product formula (IX), which was a white powdery solid 24.2 g with a two-step total yield of 74.0%.

[0146] MS,m / z(ESI):273.1[M+H] + .

[0147] 1 H NMR (400MHz, DMSO) δ8.72 (dd, J = 2.1, 1.2Hz, 1H), 8.50-8.39 (m, 1H), 8.37 (s, 1H), 7.49-7.46 (m, 1H), 5.51 (s, 2H), 2.22 (s, 3H).

[0148] Example 5

[0149] Preparation of the compound represented by formula (V)

[0150] The compound represented by formula (IX) (544 g, 2.0 mol) and lithium chloride (168 g, 4.0 mol) were added to a three-necked flask at room temperature of 20-25°C. Methyl tert-butyl ether (10 L), ethylene glycol dimethyl ether (2.0 L) and water (250 mL) were added. Lithium hydroxide monohydrate (168 g, 4.0 mol) was added to the reaction flask at room temperature of 20-25°C and stirred evenly. The reaction was stirred at 25-30°C overnight for 16-20 hours. HPLC analysis determined that the reaction was complete. Ammonia water (20%, 10 L) and ethyl acetate (2 L) were added to the reaction mixture at room temperature and stirred thoroughly. The organic phase was separated and discarded. A citric acid aqueous solution (10-12%, w / w) was slowly added to the aqueous phase under stirring at room temperature to adjust the pH to 2-3, after which a large amount of solid precipitated. The crude solid was collected by filtration and added to a mixture of dimethyl sulfoxide (1.6 L) and water (800 mL). The mixture was stirred overnight at room temperature and the solid was collected by filtration to obtain 381 g of the purified target product (75% yield) as an off-white solid powder. The purity was 98.1% as determined by HPLC.

[0151] MS,m / z(ESI):255.1[M+H] + .

[0152] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.54(s,1H),8.47(d,J=2.5Hz,1H),8.41(d,J=1.9 Hz,1H),8.24(td,J=8.1,2.6Hz,1H),7.37(dd,J=8.4,2.7Hz,1H),7.31(d,J=2.0Hz,1H).

[0153] Example 6 Preparation steps of naproxen acyl chloride

[0154] Naproxen (500 g, 2.17 mol) and dichloromethane (2.0 L) were added to a reactor, followed by N,N-dimethylformamide (12 mL, 7 mol%). The reactor was placed in a 0°C water bath. A solution of oxalyl chloride (305 g, 2.40 mol) in dichloromethane (1.0 L) was added dropwise to the reaction flask, and the mixture was stirred at 0°C for 6-8 hours. HPLC analysis determined the reaction was complete. Concentration afforded 540 g of naproxen chloride as a solid, a 99% yield. This was used directly in the next step.

[0155] MS,m / z(ESI):249.1[M+H] + .

[0156] 1H NMR (400MHz, CDCl3) δ7.75-7.66(m,3H),7.32-7.35(m,1H),7.18-7.12(m,2H),4.23(q,J=8.0Hz,1H),3.90(s,3H),1.65(d,J=8.0Hz,3H).

[0157] Example 7

[0158] Compound represented by formula (XVI)

[0159] The first step, esterification step, preparation of the compound represented by formula (XVII-RAC)

[0160] The compound represented by Formula (XVI-RAC) (78.5 g, 785 mmol), dichloromethane (400 mL), and 2,6-lutidine (168 g, 1.57 mol) were added to a reactor and placed in a 0°C water bath. A solution of naproxen acyl chloride (214.8 g, 864 mmol) in dichloromethane (800 mL) was added dropwise to the reaction flask and allowed to react at 0°C for 4 hours. GC analysis determined the reaction was complete. Aqueous acetic acid (240 mL, 5 M) was added to quench the reaction, followed by washing with saturated aqueous sodium bicarbonate (240 mL x 4). The organic phase was concentrated. Toluene (240 mL) and n-heptane (880 mL) were added, and the resulting mixture was filtered to obtain a large amount of off-white solid, which was dried to yield 196 g of the compound represented by Formula (XVII-RAC). The yield for this step was 80%, resulting in a white or off-white solid powder.

[0161] MS,m / z(ESI):313.1[M+H] + .

[0162] 1 H NMR (400MHz, CDCl3) δ7.72-7.69(m,3H),7.45-7.41(m,1H),7.16-7.11(m,2H),4.25(dd,J=16.0,8.0Hz,1H) ,4.06-3.94(m,2H),3.91(s,3H),2.36-2.28(m,1H),2.22(s,1H),1.63(dd,J=8.0,4.0Hz,3H),1.40(s,3H).

[0163] The second step is the crystallization and resolution step, the preparation of the compound represented by formula (XVII)

[0164] First resolution: Add the compound represented by formula (XVII-RAC) (196 g, 627 mmol) to a reaction flask, add toluene (1200 mL), heat to 55-60°C and stir until dissolved. Cool to 30-35°C, and slowly add the compound represented by formula (XVII) (200 mg, 0.001 w / w, dr = 95%). After addition, continue cooling to 20-25°C. Stir at room temperature for 12-16 hours, collect the solid by filtration, rinse the filter cake with toluene (200 mL), and dry. 122 g of solid was obtained, with a first resolution yield of 62%. The dr value of the solid product was 72.0% as determined by chiral column HPLC.

[0165] Second resolution: The solid sample obtained in the first resolution was added toluene (850 mL), heated to 50-55°C with stirring for 1 hour, cooled to 20-25°C, and stirred for 12-16 hours. The solid was collected by filtration, and the filter cake was rinsed with toluene (200 mL) and dried to obtain 78.0 g of the compound represented by Formula (XVII). The second resolution yield was 64%, and the total yield of the two resolution steps was 40%. The dr value of the solid product was 93.0% as determined by chiral column HPLC.

[0166] Or take the following split steps:

[0167] First resolution: Add the compound represented by formula (XVII-RAC) (196 g, 627 mmol) to a reaction flask, add toluene (480 mL) and acetonitrile (120 mL), heat to 55-60°C and stir until dissolved. Cool to 37-39°C, and slowly add the compound represented by formula (XVII) (1.0 g, 0.005 w / w, dr = 95%) as a seed crystal. Maintain stirring at 37-39°C for 1 hour, then cool to 22-23°C and stir for 11-12 hours. Collect the solid by filtration, rinse the filter cake with a mixed solvent of toluene (200 mL) and acetonitrile (20 mL), and dry. 72.1 g of solid was obtained, with a first resolution yield of 36.8%. The dr value of the solid product was 68.2% as determined by chiral column HPLC.

[0168] Second resolution: The solid sample obtained in the first resolution was added toluene (265 mL) and acetic acid (22 mL), heated to 65-70° C. with stirring for 1 hour, cooled to 58-59° C., and slowly added the compound represented by formula (XVII) (2.0 g, 0.01 w / w, dr=99%) as a seed crystal. After addition, the mixture was stirred at 58-59° C. for 2 hours, then cooled to 24-25° C. with stirring for 10-11 hours. The solid was collected by filtration, and the filter cake was rinsed with a mixed solvent of toluene (50 mL) and acetic acid (4 mL) and dried to obtain 53.7 g of the compound represented by formula (XVII). The second resolution yield was 74.5%, and the total yield of the two resolution steps was 27%. The dr value of the solid product was measured by chiral column HPLC and was 95.2%.

[0169] Third resolution: The solid sample obtained from the second resolution was added toluene (192 mL) and acetic acid (16 mL). The mixture was heated to 65-70°C and stirred for 1 hour. The temperature was then lowered to 63-64°C, and the compound represented by Formula (XVII) (2.0 g, 0.01 w / w, dr = 99%) was slowly added as a seed crystal. After addition, the mixture was stirred at 63-64°C for 2 hours. The mixture was then cooled to 24-25°C and stirred for 7-8 hours. The solid was collected by filtration, and the filter cake was rinsed with a mixed solvent of toluene (25 mL) and acetic acid (2 mL) and dried to obtain 48.1 g of the compound represented by Formula (XVII). The yield of the second resolution was 89.6%, and the total yield of the three resolution steps was 24.5%. The dr value of the solid product was determined by chiral column HPLC to be 99.0%.

[0170] MS,m / z(ESI):313.1[M+H] + .

[0171] 1 H NMR (400MHz, CDCl3) δ7.71-7.68(m,3H),7.43-7.41(m,1H),7.15-7.10(m,2H),4.23(d,J=12.0Hz,1H),4.04(d ,J=8.0Hz,1H),3.97-3.92(m,1H),3.91(s,3H),2.36(s,1H),2.14(br,1H),1.62(d,J=8.0Hz,3H),1.40(s,3H).

[0172] The third step, the hydrolysis step, is the preparation of the compound represented by formula (XVI)

[0173] To a reaction flask, add the compound represented by formula (XVII) (50.0 g, 160 mmol) and a mixture of tetrahydrofuran (500 mL) and water (15 mL) and stir until uniform. Solid sodium hydroxide (12.8 g, 320 mL) is added portionwise at 20-25°C and stirred for 3 hours at 20-25°C. The reaction is determined to be complete by HPLC analysis. The reaction mixture is filtered to remove solid naproxen sodium salt, and the solid filter cake is rinsed with tetrahydrofuran (50 mL). The filtrates are combined. Dichloromethane is added to replace the solvent, and the mixture is concentrated to yield 20.2 g of the compound represented by formula (XVI) with a content of 79.1% (w / w), resulting in a yield of 99%. This is directly carried out in the next step.

[0174] MS,m / z(ESI):101.1[M+H] + .

[0175] 1 H NMR, the same as known reports.

[0176] Example 8

[0177] Preparation of the compound represented by formula (VI-1)

[0178] The compound represented by formula (XVI) (16.0 g, 160 mmol), dichloromethane (120 mL), and 2,6-lutidine (34.3 g, 320 mmol) were added sequentially to the reactor and stirred in a 0°C water bath until uniformly dissolved. p-Nitrobenzenesulfonyl chloride (39.0 g, 176 mmol) was slowly added to the reaction flask at 0°C. After addition, the reaction was slowly warmed to room temperature and allowed to stand overnight for 14-16 hours. GC analysis determined the reaction was complete. The reaction was quenched by the addition of aqueous acetic acid (100 mL, 5 M) at 20-25°C, and the liquid phase was extracted. The organic phase was washed with water (100 mL) and saturated aqueous sodium bicarbonate (60 mL) and concentrated. Dichloromethane (20 mL) and n-heptane (240 mL) were added at 50-55°C, the temperature was slowly lowered to 20-25°C, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, washed with a mixed solvent of dichloromethane / n-heptane, and dried to obtain 39.2 g of a solid product represented by formula (VI-1), with a total yield of 86% for two steps. The ee value of the solid product was 95% as determined by chiral column HPLC.

[0179] MS,m / z(ESI):286.0[M+H] + .

[0180] 1H NMR, (400MHz, CDCl3) δ8.41 (d, J = 8.0 Hz, 2H), 8.15 (d, J = 8.0 Hz, 2H), 4.14-4.07 (m, 2H), 2.47 (s, 1H), 2.36 (br, 1H), 1.50 (s, 3H).

[0181] Compound represented by formula (VI-2)

[0182] A solution of the compound represented by formula (XVI) (15.0 g, 150 mmol) in dichloromethane (90 mL) was added to the reactor, followed by triethylamine (30.3 g, 300 mmol). The reaction was stirred in an ice-water bath at 0-5°C until uniformly dissolved. p-Toluenesulfonyl chloride (31.4 g, 165 mmol) was added to the reaction flask in batches at 0-5°C, and the reaction was continued at 0-5°C for 1 hour. The temperature was then slowly raised to room temperature (20-25°C) and stirred for 14-16 hours. The reaction was determined to be complete by GC analysis. Aqueous acetic acid was added to quench the reaction and the mixture was concentrated. The mixture was placed at 0-4°C to precipitate a solid, which was filtered and dried to obtain 24.5 g of the compound represented by formula (VI-2) with a yield of 64.3%. The ee value of the solid product was 97.4% as determined by chiral column HPLC.

[0183] MS,m / z(ESI):255.1[M+H] + .

[0184] 1 H NMR (400MHz, CDCl3) δ7.83-7.79(m,2H),7.38-7.31(m,2H),3.98(q,J=9.7Hz,2H),2.45(s,4H),2.44(s,1H),1.47(s,3H).

[0185] Compound represented by formula (VI-3)

[0186] A solution of the compound represented by Formula (XVI) (25.0 g, 250 mmol) in dichloromethane (150 mL) was added to a reaction flask, followed by 2,6-lutidine (53.5 g, 500 mmol). The reaction was stirred in an ice-water bath at 0-5°C until uniformly dissolved. 2-Naphthalenesulfonyl chloride (62.3 g, 275 mmol) was slowly added portionwise to the reaction flask at 0-5°C. The temperature was then slowly raised to 20-25°C and stirred for 14-16 hours. GC analysis determined the reaction was complete. Acetic acid aqueous solution (150 mL, 5 M) was added to quench the reaction at 20-25°C, and the liquid phases were separated by extraction. The organic phase was washed with acetic acid aqueous solution and water, concentrated, and then added with n-heptane to precipitate the solid. After drying, 62.3 g of the solid product represented by Formula (VI-3) was obtained in an 85.9% yield. The ee value of the solid product was 97.8% as determined by chiral HPLC, meeting quality requirements.

[0187] MS,m / z(ESI):291.1[M+H] + .

[0188] 1 H NMR (400MHz, CDCl3) δ8.52(d,J=1.9Hz,1H),8.01(dd,J=8.2,4.7Hz,2H),7.94(dd,J=8.2,1.3Hz,1H),7.89(dd,J=8.7 ,1.9Hz,1H),7.68(dddd,J=19.3,8.2,6.9,1.4Hz,2H),4.05(q,J=9.8Hz,2H),2.41(s,1H),2.39(s,1H),1.48(s,3H).

[0189] Example 9

[0190] The first step, esterification step, preparation of the compound represented by formula (XX-RAC)

[0191] The compound represented by Formula (XIX-RAC) (72.1 g, 500 mmol), dichloromethane (360 mL), and pyridine (79.1 g, 1.0 mol) were added to a reactor and placed in a 0°C water bath. A solution of naproxen chloride (136.8 g, 550 mmol) in dichloromethane (550 mL) was added dropwise to the reaction flask and allowed to react at 0°C for 4 hours. GC analysis determined the reaction was complete. Aqueous acetic acid was added to quench the reaction, and the mixture was washed with water and saturated sodium bicarbonate solution. After concentration, toluene and n-heptane were added to precipitate a white solid, which was dried to yield 147.0 g of the compound represented by Formula (XX-RAC). The yield for this step was 82.5%, resulting in a white or off-white solid powder.

[0192] MS,m / z(ESI):357.2[M+H] + .

[0193] 1 H NMR (400MHz, CDCl3) δ7.71-7.67(m,3H),7.42-7.40(m,1H),7.15-7.10(m,2H),4.61(s,1H),3.91 (s,3H),3.70(m,1H),3.47(s,3H),3.27(s,3H),2.55(s,1H),1.63(s,3H),1.57(d,J=7.2Hz,3H).

[0194] The second step is the crystallization and resolution step, the preparation of the compound represented by formula (XX)

[0195] To a reaction flask, add the compound represented by formula (XX-RAC) (60.0 g, 168 mmol) and isopropanol (100 mL). Heat to 55-60°C and stir until dissolved. Slowly cool to 0-5°C and maintain stirring at 0-5°C for 12-16 hours. Collect the solid by filtration at 0-5°C. Rinse the filter cake with n-heptane (50 mL) and dry to obtain 22.5 g of a solid, with a yield of 37.5%. Chiral HPLC analysis of the solid product revealed a dr value of 88.5%.

[0196] MS,m / z(ESI):357.2[M+H] + .

[0197] 1 H NMR (400MHz, CDCl3) δ7.71-7.66(m,3H),7.41-7.38(m,1H),7.15-7.11(m,2H),4.63(s,1H),3.91 (s,3H),3.86(m,1H),3.51(s,3H),3.39(s,3H),2.55(s,1H),1.57(s,3H),1.56(d,J=7.2Hz,3H).

[0198] The third step, ester hydrolysis step, preparation of the compound represented by formula (XIX)

[0199] To a reaction flask, add the compound represented by formula (XX) (20.0 g, 56.1 mmol) and a mixture of tetrahydrofuran (100 mL) and water (10 mL) and stir until uniform. Solid sodium hydroxide (4.5 g, 112.3 mmol) is added portionwise at 20-25°C. Stir and react at 20-25°C for 3 hours. HPLC analysis confirms the reaction is complete. The reaction mixture is filtered to remove solid naproxen sodium salt. The solid filter cake is rinsed with tetrahydrofuran (50 mL), and the filtrates are combined. Dichloromethane (100 mL x 2) is added to replace the solvent. Concentrate the mixture to obtain a dichloromethane solution of the compound represented by formula (XIX), which is directly used in the next step.

[0200] MS,m / z(ESI):143.1[MH] - .

[0201] The fourth step is the acetal hydrolysis-reduction step, the preparation of the compound represented by formula (XVI)

[0202] At room temperature (20-25°C), add trifluoroacetic acid (50 mL) to the dichloromethane solution of the compound represented by Formula (XIX) obtained in the previous step and stir evenly. Heat to 43-45°C and stir for 4-5 hours. Cool the reaction mixture to room temperature, add water (200 mL) and dichloromethane (200 mL), separate the layers, extract with dichloromethane (100 mL x 2), wash with saturated aqueous sodium bicarbonate (200 mL), and concentrate to obtain a dichloromethane solution of the compound represented by Formula (XVIII), which is directly used in the next step.

[0203] MS,m / z(ESI):97.1[MH] - .

[0204] To the dichloromethane solution of the compound represented by Formula (XVIII) obtained in the previous step, methanol (10 mL) was added at room temperature (20-25°C) and stirred uniformly. Sodium triacetoxyborohydride (23.7 g, 112 mmol) was slowly added with stirring at 20-25°C and stirring was continued for 3-4 hours. HPLC analysis determined the reaction was complete. Sodium chloride aqueous solution (100 mL) was added at room temperature, the mixture was separated, and extraction with dichloromethane (50 mL x 5) was performed. The mixture was concentrated to obtain 4.6 g of the compound represented by Formula (XVI), with a three-step yield of 82.0%.

[0205] MS,m / z(ESI):101.1[M+H] + .

[0206] 1 H NMR, the same as known reports.

Claims

1. Compounds of formula (VI), stereoisomers and salts thereof, R2 is selected from hydrogen, deuterium, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy or C 1-3 Hydroxyalkyl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Base, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 The hydroxyalkyl group is substituted with one or more substituents; R3 is selected from C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Base, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 The hydroxyalkyl group is substituted with one or more substituents; R4 is selected from -C(O)(CR aa R bb ) n R a or -(CR aa R bb ) m R b ; R aa or R bb are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino or C 1-3 Alkyl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Base, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 The hydroxyalkyl group is substituted with one or more substituents; R a Selected from C 6-10 Aryl or 6-10 membered heteroaryl containing 1-3 N, O or S atoms, wherein the C 6-10 Aryl or 6-10 membered heteroaryl containing 1-3 N, O or S atoms, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Base, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 The hydroxyalkyl group is substituted with one or more substituents; R b is selected from hydroxyl protecting groups, preferably substituted or unsubstituted sulfonyl; m is 0, 1, or 2; and n is 0, 1 or 2.

2. The compound of formula (VI), stereoisomers and salts thereof according to claim 1, characterized in that: R2 is selected from hydrogen, deuterium, amino, hydroxy, cyano, nitro, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, dimethoxymethyl, dimethoxyethyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl or trifluoroethyl; R3 is selected from methyl, ethyl, propyl, vinyl, allyl, propenyl, ethynyl, propynyl or propargyl; R4 is selected from -C(O)(CR aa R bb ) n R a or -(CR aa R bb ) m R b ; R aa or R bb are each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, amino, methyl, ethyl, propyl or isopropyl; R a is selected from phenyl, naphthyl, pyridine, pyrimidine or a six-membered heteroaryl containing 1-3 N, O or S atoms, wherein the phenyl, naphthyl, pyridine, pyrimidine or a six-membered heteroaryl containing 1-3 N, O or S atoms is optionally substituted with one or more substituents selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl or trifluoroethyl; R b is selected from benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, p-methoxybenzenesulfonyl, p-trifluoromethylbenzenesulfonyl, p-chlorobenzenesulfonyl or 2-naphthalenesulfonyl, preferably p-nitrobenzenesulfonyl or 2-naphthalenesulfonyl; m is 0, 1, or 2; and n is 0, 1 or 2.

3. The compound of formula (VI), stereoisomer and salt thereof according to claim 1 or 2, characterized in that: The compound is further represented by the general formula (XVII):

4. Compounds of formula (IX), stereoisomers and salts thereof, R x Selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 Hydroxyalkyl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro Base, C 1-3 Alkyl, C 2-4 Base, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 One or more substituents in the hydroxyalkyl group are substituted; preferably, R x is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine; R5 is selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 Hydroxyalkyl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Base, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or C 1-3 One or more substituents in the hydroxyalkyl group are substituted; preferably, R5 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine; R6 is selected from hydrogen, deuterium, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynylhalogen, cyano, amino or hydroxy, preferably hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, cyano, vinyl, ethynyl, amino or hydroxy.

5. The compound, stereoisomer and salt thereof according to any one of claims 1 to 4, characterized in that: The compound structure is as follows:

6. A compound of formula (IX), stereoisomers and salts thereof according to claim 4, wherein the intermediate of general formula (IX) is represented by general formula (X): Preferred 7. A compound of formula (IX), stereoisomers and salts thereof according to claim 4, wherein the intermediate of general formula (IX) is represented by general formula (XI): Preferred 8. A method for preparing the compound of formula (IX), its stereoisomers and salts thereof according to claim 4, characterized in that: Contains the following steps, Formula (XI) reacts with formula (XI') to prepare formula (X); R x Selected from hydrogen, deuterium, C 1-3 Alkyl or halogen, preferably hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine; R5 is selected from hydrogen, deuterium, C 1-3 Alkyl or halogen, preferably hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine; R6 is selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, cyano, amino or hydroxy, preferably hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, cyano, amino or hydroxy; R7 is selected from halogen, preferably fluorine, chlorine or bromine; Preferably, the reaction is carried out in the presence of an organometallic reagent, wherein the organometallic reagent is selected from an organolithium or organomagnesium reagent, preferably n-butyllithium, sec-butyllithium, isobutyllithium, tert-butyllithium, isopropylmagnesium chloride, isopropylmagnesium bromide or isopropylmagnesium chloride-lithium chloride, more preferably n-butyllithium; Preferably, the solvent used in the reaction is selected from one or more of toluene, xylene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether or methyl tert-butyl ether, preferably a mixed solvent of tetrahydrofuran and toluene or ethylene glycol dimethyl ether and methyl tert-butyl ether, more preferably the volume ratio of tetrahydrofuran to toluene is 4:1 to 1:4 or the volume ratio of ethylene glycol dimethyl ether to methyl tert-butyl ether is 1:5 to 1:1, further preferably the volume ratio of ethylene glycol dimethyl ether to methyl tert-butyl ether is 1:2 or the volume ratio of tetrahydrofuran to toluene is 1.5:

1.

9. A method for preparing the compound of formula (IX), stereoisomers and salts thereof according to claim 4 or 8, characterized in that: Contains the following steps, Preferably, the reaction is carried out in the presence of an oxidant, wherein the oxidant is selected from one or more of sodium hypochlorite, calcium hypochlorite, Dess-Martin periodinane, 2-iodoacylbenzoic acid, iodobenzene diacetate, oxalyl chloride-dimethyl sulfoxide combination reagent, pyridine-sulfur trioxide, 2,2,6,6-tetramethylpiperidinyl oxide, pyridine-N-oxide or trichloroisocyanuric acid, preferably a mixed oxidant of 2,2,6,6-tetramethylpiperidinyl oxide and trichloroisocyanuric acid, more preferably a molar ratio of 2,2,6,6-tetramethylpiperidinyl oxide to trichloroisocyanuric acid of 1:4 to 1:40, further preferably a molar ratio of 2,2,6,6-tetramethylpiperidinyl oxide to trichloroisocyanuric acid of 1:10; Preferably, the solvent used in the reaction is selected from dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, methanol, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably dichloromethane.

10. A method for preparing the compound of formula (IX), its stereoisomers and salts thereof according to claim 4, characterized in that: The preparation of general formula (V) comprises the following steps, Preferably, the reaction is carried out under alkaline conditions, wherein the base is selected from one or more of sodium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, sodium hydride, potassium carbonate, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, cesium carbonate, lithium carbonate, lithium hydroxide, lithium chloride, lithium methoxide, lithium ethoxide, lithium isopropoxide or lithium tert-butoxide, preferably a mixture of lithium hydroxide and lithium chloride, more preferably a molar ratio of lithium hydroxide to lithium chloride of 1:4 to 4:1, further preferably a molar ratio of lithium hydroxide to lithium chloride of 1:1; Preferably, the solvent used in the reaction is selected from one or more of toluene, xylene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, methanol, ethanol, tert-butanol, water, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably a mixed solvent of ethylene glycol dimethyl ether, methyl tert-butyl ether and water, more preferably the volume ratio of ethylene glycol dimethyl ether, methyl tert-butyl ether and water is 5 to 10:30 to 50:1, and further preferably the volume ratio of ethylene glycol dimethyl ether, methyl tert-butyl ether and water is 8:40:

1.

11. A method for preparing the compound of formula (VI), its stereoisomers and salts thereof as claimed in claim 1, characterized in that: The following steps are included: Formula (XVI) reacts with R4X to obtain formula (VI); Wherein, R2 is selected from hydrogen, deuterium, hydroxyl, amino or C 1-3 Alkyl, preferably hydrogen, deuterium, hydroxy, amino, methyl, ethyl, propyl or isopropyl; R3 is selected from C 1-3 Alkyl, C 1-3 Alkenyl or C 1-3 Alkynyl, preferably methyl, ethyl, propyl, vinyl, allyl, propenyl, ethynyl, propynyl or propargyl; R4 is selected from benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, p-methoxybenzenesulfonyl, p-trifluoromethylbenzenesulfonyl, p-chlorobenzenesulfonyl or 2-naphthalenesulfonyl, preferably p-nitrobenzenesulfonyl or 2-naphthalenesulfonyl; X is selected from halogen, preferably fluorine, chlorine or bromine; Preferably, the base is selected from pyridine, 2-methylpyridine, 4-methylpyridine, 2,6-lutidine, 4-dimethylaminopyridine, imidazole, 1-methylimidazole, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, cesium carbonate, lithium carbonate or lithium hydroxide, preferably 2,6-lutidine or triethylamine; Preferably, the solvent used in the reaction is selected from dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably dichloromethane.

12. A method for preparing the compound of formula (VI), its stereoisomers and salts thereof according to claim 11, characterized in that: The preparation of general formula (XVI) comprises the following steps, Preferably, the reaction is carried out in the presence of a base, wherein the base is selected from sodium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, sodium hydride, potassium carbonate, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, cesium carbonate, lithium carbonate, lithium hydroxide, lithium methoxide, lithium ethoxide, lithium isopropoxide or lithium tert-butoxide, preferably sodium hydroxide; Preferably, the solvent used in the reaction is selected from one or more of acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, methanol, ethanol, isopropanol, tert-butanol, ethylene glycol or water, preferably a mixed solvent of tetrahydrofuran and water, more preferably a volume ratio of tetrahydrofuran to water of 40:1 to 30:1, further preferably a volume ratio of tetrahydrofuran to water of 33:

1.

13. A method for preparing the compound of formula (VI), its stereoisomers and salts thereof as claimed in claim 12, characterized in that: The preparation of general formula (XVII) comprises the following steps, Preferably, the resolution solvent is selected from one or more of dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, acetic acid, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, methanol, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably a combination of toluene and acetonitrile or a combination of toluene and acetic acid, more preferably the volume ratio of toluene to acetonitrile solvent is selected from 20:1 to 3:1 or the volume ratio of toluene to acetic acid solvent is selected from 20:1 to 5:1, further preferably the volume ratio of toluene to acetonitrile solvent is selected from 10:1 to 4:1 or the volume ratio of toluene to acetic acid solvent is selected from 15:1 to 10:1, most preferably the volume ratio of toluene to acetonitrile solvent is 4:1 or the volume ratio of toluene to acetic acid solvent is 12:

1.

14. A method for preparing the compound of formula (VI), its stereoisomers and salts thereof as claimed in claim 13, characterized in that: The preparation of general formula (XVII-RAC) comprises the following steps, Preferably, the reaction is carried out in a naproxen chlorination reagent, wherein the chlorination reagent is selected from oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or triphosgene, preferably oxalyl chloride and triphosgene; Preferably, the reaction is carried out in the presence of a base, wherein the base is selected from pyridine, 2-methylpyridine, 4-methylpyridine, 2,6-lutidine, 4-dimethylaminopyridine, imidazole, 1-methylimidazole, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, cesium carbonate, lithium carbonate or lithium hydroxide, preferably 2,6-lutidine; Preferably, the solvent used in the reaction is selected from dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably dichloromethane.

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