Intermediate of bicyclic system inhibitor and method for producing the same

Abstract

The present invention provides an intermediate of a bicyclic inhibitor and a method for producing the same. Specifically, it relates to the intermediate represented by formula (VI) and a method for producing the same. In this method, the starting materials used in the reaction are inexpensive and easily available, the synthesis process is mature, the quality of the product is stable, the yield and purity are high, important reagents can be recovered and reused, the production cost is reduced, and it is suitable for application in large-scale industrial production. 【Chemical 1】 TIFF2025525199000072.tif28161

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and specifically relates to an intermediate of a bicyclic inhibitor and a method for producing the same.

Background Art

[0002] The RET (rearranged during transfection) protein is encoded by the proto-oncogene RET on chromosome 10 and is a receptor tyrosine kinase, which consists of an extracellular region, a transmembrane region, and an intracellular kinase region. RET ligands are glial cell-derived neurotrophic factor (GDNF) family ligands (GFLs) such as GDN, neurturin (NRTN), artemin (ARTN), and persephin (PSPN), and the co-action of the co-receptor GFRa family is also required to activate the receptor. GFLs form a dimer with GFRa, bind to RET, and are mobilized to the cholesterol-rich membrane region. The RET protein dimerizes and autophosphorylates, thereby activating downstream signaling pathways such as RAS-MAPK, PI3K-AKT, and PKC. RET plays an important role in the development of the nervous system of the kidney and intestine during embryonic development and is also important for the homeostasis of tissues such as neuroendocrine, hematopoiesis, and male germ cells.

[0003] Dysfunction of the RET protein leads to the occurrence of various diseases. Loss of function of the RET protein during development causes a series of congenital diseases such as Hirschsprung disease (HSCR) and congenital anomalies of the kidney and urinary tract (CAKUT). Activating mutations of the RET protein including point mutations and RET protein fusions due to chromosomal rearrangements are also involved in the onset of various diseases. RET fusions mainly occur in 1-2% of non-small cell lung cancer (NSCLC) patients and 5-10% of papillary thyroid carcinomas, while RET mutations mainly occur in 60% of medullary thyroid carcinomas. In addition, activating mutations of the RET protein are also found in many other tumors such as breast cancer, gastric cancer, intestinal cancer, and chronic myelomonocytic leukemia.

[0004] Although there is a great clinical need, there are still significant limitations in current RET-targeted therapies. Different from targeted drugs such as ALK and EGFR that have achieved excellent clinical effects, there are still no approved targeted drugs for the RET target. Currently, in clinical dosing, multi-kinase inhibitors (MKIs) such as vandetanib and cabozantinib are widely used. These multi-kinase inhibitors have drawbacks such as low selectivity, high side effects, and low drug efficacy, and they cannot overcome the drug resistance problems that occur during treatment.

[0005] Currently, there are no specific targeted drugs for the RET target, and the clinical need is great. RET inhibitors with higher selectivity, better activity, better safety, and the ability to overcome drug-resistant mutations may have the potential to treat various cancers and have broad market prospects. In 2015, Jiangsu Hansoh Pharmaceutical Group Co., Ltd. disclosed a series of bicyclic derivatives in Patent Document 1. They exhibit excellent pharmacological properties and have a strong inhibitory effect on RET kinase activity, but a poor inhibitory effect on KDR kinase activity. The inhibitory effect on KDR / RET kinase activity is highly selective. Currently, it has entered Phase II clinical trials, and the following intermediates are used in the production of this compound.

Chemical formula

[0006] Patent Document 2 disclosed a series of RET inhibitors and the important intermediates and production methods shown above for manufacturing RET inhibitors. However, the production method of the intermediate in the patent is complex, the reaction steps are long, totaling 10 steps, the total yield of the product is low, and it is not suitable for industrial production. Therefore, the present invention is working on researching a production method of bicyclic compounds suitable for industrial production.

Prior art documents

Patent documents

[0007]

Patent Document 1

Patent Document 2

SUMMARY OF THE INVENTION

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

[0009] In a first aspect, an object of the present invention is to provide a compound represented by general formula (VI), stereoisomers and salts thereof,

CHEMICAL FORMULA

[0010] In a preferred embodiment of the present invention, R2 is selected from hydrogen, deuterium, amino group, hydroxy group, cyano group, nitro group, fluorine, chlorine, bromine, methyl group, ethyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, dimethoxymethyl group, dimethoxyethyl group, fluoromethyl group, fluoroethyl group, difluoromethyl group, difluoroethyl group, trifluoromethyl group or trifluoroethyl group, R3 is selected from methyl group, ethyl group, propyl group, vinyl group, allyl group, propenyl group, ethynyl group, propynyl group or propargyl group, R4 is -C(O)(CR aa R bb ) n R a or -(CR aa R bb ) m R b selected from R aa or R bb is each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxy group, amino group, methyl group, ethyl group, propyl group or isopropyl group, R a is selected from phenyl group, naphthyl group, pyridine, pyrimidine or a 6,6-membered heteroaryl group containing 1 to 3 N, O or S atoms, wherein the phenyl group, naphthyl group, pyridine, pyrimidine or 6,6-membered heteroaryl group containing 1 to 3 N, O or S atoms is optionally substituted with one or more substituents selected from deuterium, amino group, hydroxy group, cyano group, nitro group, fluorine, chlorine, bromine, methyl group, ethyl group, isopropyl group, methoxy group, ethoxy group, fluoromethyl group, fluoroethyl group, difluoromethyl group, difluoroethyl group, trifluoromethyl group or trifluoroethyl group, R bis selected from a benzenesulfonyl group, p-toluenesulfonyl group, p-nitrobenzenesulfonyl group, p-methoxybenzenesulfonyl group, p-trifluoromethylbenzenesulfonyl group, p-chlorobenzenesulfonyl group or 2-naphthalenesulfonyl group, preferably a p-nitrobenzenesulfonyl group or 2-naphthalenesulfonyl group, m is 0, 1 or 2, and n is 0, 1 or 2.

[0011] In a more preferred embodiment of the present invention, R4 is selected from a benzenesulfonyl group, p-toluenesulfonyl group, p-nitrobenzenesulfonyl group, p-methoxybenzenesulfonyl group, p-trifluoromethylbenzenesulfonyl group, p-chlorobenzenesulfonyl group or 2-naphthalenesulfonyl group, preferably a p-nitrobenzenesulfonyl group or 2-naphthalenesulfonyl group.

[0012] In a more preferred embodiment of the present invention, the compound of formula (VI) further has the general formula (XVII):

Chemical formula

[0013] R2 and R3 are as shown in formula (VI).

[0014] In another aspect, the object of the present invention is to provide a compound of formula (IX), stereoisomers and salts thereof,

Chemical formula

[0015] In a more preferred embodiment of the present invention, the following structure:

Chemical formula

[0016] The intermediate of the compound of formula (IX), stereoisomer and salt thereof is as shown in general formula (X),

Chemical formula

Chemical formula

[0017] The intermediate of the compound of formula (IX), stereoisomer and salt thereof is as shown in general formula (XI),

Chemical formula

Chemical formula

[0018] Another object of the present invention is to provide a method for producing the compound represented by formula (X), which includes the following steps,

Chemical formula

[0019] In a more preferred embodiment of the present invention, the method for producing the compound represented by formula (X) is as follows.

Chemical formula

[0020] In a more preferred embodiment of the present invention, formula (XII) reacts to obtain formula (XI),

Chemical formula

[0021] In a more preferred embodiment of the present invention, the method for producing the compound of formula (XI) is as follows.

Chemical formula

[0022] In a more preferred embodiment of the present invention, formula (XIII) and formula (XIV) react to obtain formula (XII).

Chemical formula

[0023] Preferably, the reaction is carried out in the presence of an acid, where 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, 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 t-butyl ether, methanol, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, and preferably, it is dichloromethane.

[0024] In a more preferred embodiment of the present invention, the method for producing the compound represented by formula (XII) is as follows.

Chemical formula

[0025] In a more preferred embodiment of the present invention, formula (XV) reacts with N,N-dimethylformamide dimethyl acetal under the action of an acid to obtain formula (XIII).

Chemical formula

[0026] In a more preferred embodiment of the present invention, the method for producing the compound of formula (XIII) is as follows.

Chemical formula

[0027] In a more preferred embodiment of the present invention, formula (X) reacts to obtain formula (IX),

Chemical formula

[0028] Preferably, the reaction is carried out in the presence of an oxidizing agent, where the oxidizing agent is selected from one or more of sodium hypochlorite, calcium hypochlorite, Dess-Martin oxidant, 2-iodoxybenzoic acid, iodobenzene diacetate, oxalyl chloride-dimethyl sulfoxide combination reagent, pyridine-sulfur trioxide, 2,2,6,6-tetramethylpiperidine N-oxide, pyridine-N-oxide or trichloroisocyanuric acid, preferably a mixed oxidizing agent of 2,2,6,6-tetramethylpiperidine N-oxide and trichloroisocyanuric acid, more preferably, the molar ratio of 2,2,6,6-tetramethylpiperidine N-oxide to trichloroisocyanuric acid is 1:4 to 1:40, and even more preferably, the molar ratio of 2,2,6,6-tetramethylpiperidine N-oxide to trichloroisocyanuric acid is 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 t-butyl ether, methanol, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably dichloromethane.

[0029] In a more preferred embodiment of the present invention, the method for producing the compound represented by formula (IX) is as follows.

Chemical formula

[0030] In a more preferred embodiment of the present invention, formula (IX) reacts to obtain formula (V). [Chemical formula]

[0031] Preferably, the reaction is carried out under alkaline conditions, where the alkali is selected from one or more of sodium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium t-butoxide, sodium hydride, potassium carbonate, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium t-butoxide, cesium carbonate, lithium carbonate, lithium hydroxide, lithium chloride, lithium methoxide, lithium ethoxide, lithium isopropoxide or lithium t-butoxide, preferably a mixture of lithium hydroxide and lithium chloride, more preferably the molar ratio of lithium hydroxide to lithium chloride is 1:4 to 4:1, and even more preferably the molar ratio of lithium hydroxide to lithium chloride is 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 t-butyl ether, methanol, ethanol, t-butanol, water, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably a mixed solvent of ethylene glycol dimethyl ether, methyl t-butyl ether and water, preferably the volume ratio of ethylene glycol dimethyl ether, methyl t-butyl ether and water is 5 to 10:30 to 50:1, and more preferably the volume ratio of ethylene glycol dimethyl ether, methyl t-butyl ether and water is 8:40:1.

[0032] In a more preferred embodiment of the present invention, the method for producing the compound of formula (V) is as follows. [Chemical formula]

[0033] In a more preferred embodiment of the present invention, the method for producing the compound of formula (V) is as follows.

Chemical formula

[0034] In a more preferred embodiment of the present invention, formula (XVI) and R4X react in the presence of a base to obtain formula (VI).

Chemical formula

[0035] In a more preferred embodiment of the present invention, the method for producing the compound represented by formula (VI-1) is as follows.

Chemical formula

[0036] In a more preferred embodiment of the present invention, the method for producing the compound represented by formula (VI-3) is as follows.

Chemical formula

[0037] In a more preferred embodiment of the present invention, formula (XVII) reacts under the action of an alkali to obtain formula (XVI).

Chemical formula

[0038] Preferably, the reaction is carried out in the presence of an alkali, where the alkali is selected from sodium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium t-butoxide, sodium hydride, potassium carbonate, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium t-butoxide, cesium carbonate, lithium carbonate, lithium hydroxide, lithium methoxide, lithium ethoxide, lithium isopropoxide or lithium t-butoxide, and preferably, it is 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 t-butyl ether, methanol, ethanol, isopropanol, t-butanol, ethylene glycol, or water, and preferably, it is 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.

[0039] In a more preferred embodiment of the present invention, the method for producing the compound represented by formula (XVI) is as follows.

Chemical formula

[0040] In a more preferred embodiment of the present invention, formula (XVII-RAC) is resolved to obtain formula (XVII).

Chemical formula

[0041] Preferably, the dividing 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 t-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 the toluene solvent to the acetonitrile solvent used is selected from 20:1 to 3:1 or the volume ratio of the toluene solvent to the acetic acid solvent is selected from 20:1 to 5:1, still more preferably, the volume ratio of the toluene solvent to the acetonitrile solvent is selected from 10:1 to 4:1 or the volume ratio of the toluene solvent to the acetic acid solvent is selected from 15:1 to 10:1, and most preferably, the volume ratio of the toluene solvent to the acetonitrile solvent is 4:1 or the volume ratio of the toluene solvent to the acetic acid solvent is 12:1 or 12.5:1.

[0042] In a more preferred embodiment of the present invention, the method for producing the compound represented by the formula (XVII) is as follows.

Chemical formula

[0043] In a more preferred embodiment of the present invention, the formula (XVI-RAC) reacts to obtain the formula (XVII-RAC),

Chemical formula

[0044] Preferably, the reaction is carried out in the presence of a naproxen chlorination reagent, where the chlorination reagent is selected from oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or triphosgene, preferably oxalyl chloride and triphosgene. Preferably, the alkali is selected from pyridine, 2-methylpyridine, 4-methylpyridine, 2,6-dimethylpyridine, 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, and preferably, it is 2,6-dimethylpyridine. 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 t-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, and preferably, it is dichloromethane.

[0045] In a more preferred embodiment of the present invention, the method for producing the compound represented by formula (XVII-RAC) is as follows.

Chemical formula

[0046] In a more preferred embodiment of the present invention, formula (XVIII) reacts under the action of a reducing agent to obtain formula (XVI).

Chemical formula

[0047] Preferably, the reducing agent is selected from sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, borane tetrahydrofuran complex, sodium trimethoxyborohydride or lithium aluminum hydride, and preferably, it is sodium triacetoxyborohydride.

[0048] 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, t-butanol or ethylene glycol, and preferably is a mixed solvent of dichloromethane and methanol, and a more preferable ratio of dichloromethane to methanol is 5 to 20:1.

[0049] In a more preferable embodiment of the present invention, the method for producing the compound represented by formula (XVI) is as follows.

Chemical formula

[0050] In a more preferable embodiment of the present invention, formula (XIX) reacts in the presence of an acid to obtain formula (XVIII).

Chemical formula

[0051] In a more preferred embodiment of the present invention, the method for producing the compound represented by formula (XVIII) is as follows.

Chemical formula

[0052] In a more preferred embodiment of the present invention, formula (XX) reacts in the presence of an alkali to obtain formula (XIX).

Chemical formula

[0053] Preferably, the alkali is selected from sodium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium t-butoxide, sodium hydride, potassium carbonate, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium t-butoxide, cesium carbonate, lithium carbonate, lithium hydroxide, lithium methoxide, lithium ethoxide, lithium isopropoxide or lithium t-butoxide, and preferably, it is 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 t-butyl ether, methanol, ethanol, isopropanol, t-butanol, ethylene glycol or water, and preferably, it is a mixed solvent of tetrahydrofuran and water. More preferably, the volume ratio of tetrahydrofuran to water is 20:1 to 5:1, and even more preferably, the volume ratio of tetrahydrofuran to water is 10:1.

[0054] In a more preferred embodiment of the present invention, the method for producing the compound represented by formula (XIX) is as follows.

Chemical formula

[0055] In a more preferred embodiment of the present invention, formula (XX-RAC) is split to obtain formula (XX).

Chemical formula

[0056] Preferably, the splitting solvent is selected from one or more of dichloromethane, chloroform, toluene, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, acetone, ethylene glycol dimethyl ether, methyl t-butyl ether, ethyl acetate, isopropyl acetate, n-heptane, methanol, ethanol, isopropanol, n-butanol, and water, and preferably is isopropanol.

[0057] In a more preferred embodiment of the present invention, the method for producing the compound represented by formula (XX) is as follows.

Chemical formula

[0058] In a more preferred embodiment of the present invention, formula (XIX-RAC) reacts with a naproxen chlorination reagent under the action of an alkali to obtain formula (XX-RAC).

Chemical formula

[0059] Preferably, the chlorination reagent is selected from oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or triphosgene, and preferably is oxalyl chloride and triphosgene. Preferably, the alkali is selected from pyridine, 2-methylpyridine, 4-methylpyridine, 2,6-dimethylpyridine, 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, and preferably, it is pyridine. 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 t-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, and preferably, it is dichloromethane.

[0060] In a more preferred embodiment of the present invention, the method for producing the compound represented by formula (XX-RAC) is as follows.

Chemical formula

[0061] In a more preferred embodiment of the present invention, the method for producing the compound of formula (VI) is as follows.

Chemical formula

[0062] In a more preferred embodiment of the present invention, the method for producing the compound of formula (VI) is as follows.

Chemical formula

[0063] In a more preferred embodiment of the present invention, the method for producing the compound of formula (VI) is as follows.

Chemical formula

[0064] In a more preferred embodiment of the present invention, the method for producing the compound of formula (VI) is as follows.

Chemical formula

[0065] The present invention provides a method for producing the compound represented by formula (VI). In this method, the starting materials used in the reaction are inexpensive and easily available, the synthesis process is mature, the quality of the product is stable, important reagents can be recovered and reused, the production cost is reduced, and it is suitable for application in large-scale industrial production.

[0066] For the compound of formula (V) in the present invention, a new production method is used. In this method, the starting materials used in the reaction are inexpensive and easily available, the synthesis process is mature, a continuous dosing reaction can be carried out during the reaction, the reaction steps are shortened, the operation is simple, the purification process by column chromatography is avoided, the quality of the product is stable, the production cost is low, the yield and purity are improved, and it is very suitable for application in large-scale industrial production.

[0067] The present invention can improve the yield and purity of the RET inhibitor compound through a specific intermediate formula (V), formula (VI) and their production methods, which is more advantageous for industrial production.

Embodiments for Carrying out the Invention

[0068] Detailed Description of the Invention: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0069] "Alkyl group" refers to a straight-chain alkyl group and a branched-chain alkyl group containing 1 to 4 carbon atoms. The alkyl group refers to a saturated aliphatic hydrocarbon group, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, s-butyl group.

[0070] The present invention will be described in more detail and completely below in conjunction with examples, but it does not limit the present invention, nor is the present invention limited only to the content of the examples.

[0071] The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift is given in units of parts per million (ppm). The NMR measurement is carried out using a Bruker AVANCE-400 nuclear magnetic meter, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-D6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0072] The measurement of liquid chromatography-mass spectrometry LC-MS was carried out using an Agilent 1200 Infinity Series mass spectrometer. For the HPLC measurement, an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 X 4.6mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gi minute i C18 150 X 4.6mm chromatography column) were used.

[0073] For the thin layer chromatography silica gel plate, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used. For TLC, a specification of 0.15mm - 0.20mm was used, and for the separation and purification of products by thin layer chromatography, a specification of 0.4mm - 0.5mm was used. For column chromatography, generally, silica gel of 200 - 300 mesh from Yantai Huanghai was used as the carrier.

[0074] Unless otherwise specified, all reactions of the present invention were carried out while continuously magnetically stirring.

[0075] Example 1 Preparation of the compound shown in formula (XIII)

Chemical formula

[0076] The compound shown in formula (XV) (140 g, 0.942 mol), N,N-dimethylformamide dimethylacetal (337 g, 2.83 mol), and dichloromethane (700 mL) were sequentially added to a three-necked flask. The mixture was cooled to 0 - 2 °C and stirred uniformly. While stirring at 0 - 2 °C, a dichloromethane (140 mL) solution of acetic acid (170 g, 2.83 mol) was added, and the temperature was raised to 20 - 25 °C, and stirring was continued for 3 hours to allow the reaction to proceed. The completion of the reaction was judged by HPLC. A saturated aqueous sodium hydrogen carbonate solution (700 mL) was slowly added to the reaction mixture to quench the reaction, and the mixture was allowed to stand for liquid separation. The aqueous phase was extracted 3 times with dichloromethane (700 mL × 3). After combining the organic phases, the organic phase was washed with water, the organic phases were combined, concentrated to dryness under vacuum, and a yellow-green solid product was obtained, which was dried under vacuum to obtain 150 g of the compound shown in formula (XIII) of the product, with a yield of 87.4%.

[0077] The above product was directly charged into the next step. MS, m / z (ESI): 183.1 [M+H] + . 1 H NMR, (400 MHz, CDCl3) δ 7.93 (s, 1H), 3.87 (s, 3H), 3.48 (s, 3H), 3.33 (s, 3H).

[0078] Example 2 Preparation of the compound shown in formula (XI)

Chemical formula

[0079] The compound shown by the formula (XIII) of the raw material (90.0 g, 494 mmol) was put into a reactor, toluene (360 mL) was added at room temperature of 20 - 25 °C, then acetic acid (270 mL) was added, and the mixture was stirred until the solution became clear. The mixture was cooled to 0 - 2 °C, and a dichloromethane solution (45 mL) of the compound shown by the formula (XIV) (53.5 g, 593 mmol) was slowly added while stirring. The reaction was heated to 40 - 45 °C and stirred for 4 - 6 hours. The completion of the reaction was judged by HPLC analysis. The reaction solution was cooled to room temperature, added to water (900 mL) and washed thoroughly, then left to stand for liquid separation. The aqueous phase was extracted twice with dichloromethane (900 mL x 2). The organic phases were combined, concentrated, and replaced with toluene (900 mL x 2) solvent to obtain a toluene solution / mixture of the compound shown by the formula (XII) of the intermediate product, which was directly charged into the reaction of the next step.

[0080] p - Toluene sulfonic acid monohydrate (14.1 g, 74.1 mmol) was added to the mixture obtained in the previous step, and the temperature was raised to 120 °C under the outside air temperature and heated. The completion of the reaction was judged by HPLC analysis. The reacted mixture was cooled to room temperature of 20 - 25 °C, and the reaction solution was slowly added to a mixture of ice and water (about 900 mL), and a large amount of yellow solid precipitated. Ethyl acetate (900 mL x 3) was added and extracted three times. The obtained organic phases were combined and concentrated. Methyl t - butyl ether (450 mL) was added, the temperature was raised to 50 - 55 °C and stirred for 2 - 3 hours, n - heptane (270 mL) was slowly added dropwise, stirred at 50 - 55 °C for 1 - 2 hours, slowly cooled to room temperature, filtered, the filter cake was rinsed thoroughly with a methyl t - butyl ether / n - heptane mixture (methyl t - butyl ether / n - heptane = 2 / 3, 90 mL), and the filter cake was dried in a vacuum drying oven to obtain 42.4 g of the crude product of the compound shown by the formula (XI) as a pale yellow powder solid, and the continuous input yield was 48.6%. MS, m / z (ESI): 178.1[M + H] + . 11H NMR, (400 MHz, CDCl3) δ 7.93 (s, 1H), 5.05 - 4.96 (m, 1H), 4.58 - 4.53 (m, 1H), 4.27 - 4.21 (m, 1H), 1.49 (d, J = 8.0 Hz, 3H).

[0081] Example 3 Preparation of the compound represented by formula (X)

Chemical formula

[0082] The compound (9.30 g, 52 mmol) represented by formula (XI) as the raw material and 2-fluoro-5-bromopyridine (10.75 g, 60 mmol) were added to a three-necked flask at room temperature of 20 - 25 °C. Under the protection of a N2 gas stream, THF (60 mL) and toluene (40 mL) were added to the three-necked flask and stirred uniformly. The reaction was cooled to -60 - 70 °C, and n-butyllithium solution (52.8 mL, 2.5 M in hexane) was added. After the addition, the temperature was maintained at -60 - 70 °C for 3 h for reaction, then slowly warmed to -30 - 25 °C and maintained at -30 - 20 °C for 3 h for reaction. An aqueous trifluoroacetic acid solution (40 mL, 50%, V / V) was added at -30 - 25 °C to quench the reaction. After the addition, the temperature was raised to room temperature of 20 - 25 °C, stirred for 3 - 4 h, water (80 mL) was added to the reaction, stirred uniformly, and then allowed to stand for liquid separation. The upper organic phase was retained. Ethyl acetate (60 mL in total) was added to the aqueous phase for extraction twice. The organic phases were combined, washed once with a saturated aqueous sodium bicarbonate solution (60 mL), allowed to stand for liquid separation, and the organic phase was retained. The aqueous phase was back-extracted once with ethyl acetate (30 mL), and the organic phases were combined. The solvent was replaced, dichloromethane (100 mL in total) was added to obtain the crude product of the compound represented by formula (X), which was directly charged into the next step. MS, m / z (ESI): 275.1 [M + H] + .

[0083] Example 4 Preparation of the compound represented by formula (IX)

Chemical formula

[0084] At room temperature of 20 - 25 °C, a solution of the compound shown by formula (X) (32.9 g, 120 mmol) in dichloromethane (about 200 mL) was added to a reactor. Sodium bicarbonate (15.2 g, 180 mmol) and potassium bromide (1.43 g, 12.0 mmol) were added at room temperature of 20 - 25 °C, and the mixture was stirred uniformly. While stirring at 20 - 25 °C, the first batch of 2,2,6,6 - tetramethylpiperidine N - oxide (375 mg, 2.40 mmol) was added, and then the first batch of trichloroisocyanuric acid (5.58 g, 24.0 mmol) was slowly added. After the addition was completed, the reaction was carried out at 20 - 25 °C for 2 hours. While stirring at 20 - 25 °C, the second batch of 2,2,6,6 - tetramethylpiperidine N - oxide (375 mg, 2.40 mmol) was added, and then trichloroisocyanuric acid (5.58 g, 24.0 mmol) was slowly added. Then, while stirring at 20 - 25 °C, the third batch, the fourth batch, and the fifth batch of 2,2,6,6 - tetramethylpiperidine N - oxide (375 mg, 2.40 mmol) and trichloroisocyanuric acid (5.58 g, 24.0 mmol) were continuously added. The reaction completion was judged by HPLC analysis. The solid was rinsed with dichloromethane (40 mL), and the organic phases were combined. Isopropanol (7.2 g, 120 mmol) was added to the organic phase to quench the reaction. The organic phase was washed with saturated aqueous sodium bicarbonate solution and water, methyl t - butyl ether was added, and the mixture was concentrated and dried to obtain the compound shown by formula (IX) of the product as a white powdery solid of 24.2 g, and the total yield of the two - step process was 74.0%. MS, m / z (ESI): 273.1[M + H] + . 1 H NMR (400 MHz, DMSO) δ 8.72 (dd, J = 2.1, 1.2 Hz, 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).

[0085] Example 5 Preparation of the compound shown by formula (V) [Chemistry]

[0086] At room temperature of 20 - 25 °C, the compound shown in formula (IX) (544 g, 2.0 mol) and lithium chloride (168 g, 4.0 mol) were added to a three-necked flask. Methyl t-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, stirred uniformly, and stirred at 25 - 30 °C overnight for 16 - 20 hours to react. It was analyzed by HPLC to judge the completion of the reaction. At room temperature, aqueous ammonia (20%, 10 L) and ethyl acetate (2 L) were added to the reaction mixture and stirred well. The liquid was separated, the organic phase was discarded, and an aqueous citric acid solution (10 - 12%, w / w) was slowly added to the aqueous phase while stirring at room temperature. After adjusting the pH value to 2 - 3, a large amount of solid precipitated. It was filtered, the solid crude product was collected, added to a mixed solvent of dimethyl sulfoxide (1.6 L) and water (800 mL), stirred overnight at room temperature, filtered, and the solid was collected to obtain 381 g of a purified product of the target product with a yield of 75%, which was an off-white solid powder. It was measured that the purity was 98.1% by HPLC method. MS, m / z (ESI): 255.1 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.54 (s, 1H), 8.47 (d, J = 2.5 Hz, 1H), 8.41 (d, J = 1.9 Hz, 1H), 8.24 (td, J = 8.1, 2.6 Hz, 1H), 7.37 (dd, J = 8.4, 2.7 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H).

[0087] Example 6 Purification Step of Naproxen Acid Chloride Naproxen (500 g, 2.17 mol) and dichloromethane (2.0 L) were added to the reactor, followed by N,N-dimethylformamide (12 mL, 7 mol%). The reactor was placed in a water bath at 0 °C, and a solution of oxalyl chloride (305 g, 2.40 mol) in dichloromethane (1.0 L) was added dropwise to the reaction flask and stirred at 0 °C for 6 - 8 hours. Analysis by HPLC was used to determine the completion of the reaction. It was concentrated to obtain 540 g of solid naproxen acid chloride product, with a yield of 99%. It was directly charged into the next step for use. MS, m / z (ESI): 249.1 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 7.75 - 7.66 (m, 3H), 7.32 - 7.35 (m, 1H), 7.18 - 7.12 (m, 2H), 4.23 (q, J = 8.0 Hz, 1H), 3.90 (s, 3H), 1.65 (d, J = 8.0 Hz, 3H).

[0088] Example 7 Compound shown in formula (XVI)

Chemical formula

[0089] Step 1, Esterification step, Preparation of the compound shown in formula (XVII-RAC) To the reactor, add the compound shown in formula (XVI-RAC) (78.5 g, 785 mmol), dichloromethane (400 mL), and 2,6-dimethylpyridine (168 g, 1.57 mol). Place the reaction in a water bath at 0 °C, and dropwise add a solution of naproxen acid chloride (214.8 g, 864 mmol) in dichloromethane (800 mL) to the reaction flask. React at 0 °C for 4 hours. Analyze by GC to determine the completion of the reaction. Quench the reaction by adding aqueous acetic acid solution (240 mL, 5 M), then wash with saturated aqueous sodium bicarbonate solution (240 mL x 4), and concentrate the organic phase. Add toluene (240 mL) and n-heptane (880 mL), filter to obtain a large amount of off-white solid, and after drying, obtain 196 g of the compound shown in formula (XVII-RAC). The yield of this step was 80%, and it was a white or off-white solid powder. MS, m / z (ESI): 313.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.72 - 7.69 (m, 3H), 7.45 - 7.41 (m, 1H), 7.16 - 7.11 (m, 2H), 4.25 (dd, J = 16.0, 8.0 Hz, 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, 4.0 Hz, 3H), 1.40 (s, 3H).

[0090] Step 2, Crystallization and Resolution Step, Preparation of the Compound Shown in Formula (XVII) First split: Take a reaction flask, add the compound shown in formula (XVII-RAC) (196 g, 627 mmol), add toluene (1200 mL), heat to 55 - 60 °C, stir until the solution becomes clear, cool down to 30 - 35 °C, slowly add the compound shown in formula (XVII) (mg, 0.001 w / w, dr = 95%) into it, continue to cool down to 20 - 25 °C after adding, maintain at room temperature and stir for 12 - 16 hours, filter, collect the solid, rinse the filter cake with toluene (200 mL), and dry. 122 g of solid was obtained, and the yield of the first split was 62%. It was measured by chiral column HPLC that the dr value of the solid product was 72.0%.

[0091] Second split: Add toluene (850 mL) to the solid sample obtained from the first split, heat to 50 - 55 °C and stir for 1 hour, cool down to 20 - 25 °C, stir for 12 - 16 hours, filter, collect the solid, rinse the filter cake with toluene (200 mL), and dry to obtain 78.0 g of the solid compound shown in formula (XVII). The yield of the second split was 64%, and the total yield of the two-step split steps was 40%. It was measured by chiral column HPLC that the dr value of the solid product was 93.0%.

[0092] Or the following split step operation may be performed: First split: Take a reaction flask, add the compound shown in formula (XVII-RAC) (196 g, 627 mmol), add toluene (480 mL) and acetonitrile (120 mL), heat to 55 - 60 °C, stir until the solution becomes clear, cool down to 37 - 39 °C, slowly add the compound shown in formula (XVII) (1.0 g, 0.005 w / w, dr = 95%) as a seed crystal into it, after adding, maintain at 37 - 39 °C and stir for 1 hour, then cool down to 22 - 23 °C, stir for 11 - 12 hours, filter, collect the solid, 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, and the yield of the first split was 36.8%. It was measured by chiral column HPLC that the dr value of the solid product was 68.2%.

[0093] Second division: Toluene (265 mL) and acetic acid (22 mL) were added to the solid sample obtained in the first division, heated to 65 - 70 °C, stirred for 1 hour, cooled to 58 - 59 °C, and the compound shown in formula (XVII) (2.0 g, 0.01 w / w, dr = 99%) was slowly added thereto as a seed crystal. After the addition was complete, the temperature was maintained at 58 - 59 °C, stirred for 2 hours, then cooled to 24 - 25 °C, stirred for 10 - 11 hours, filtered, the solid was collected, the filter cake was rinsed with a mixed solvent of toluene (50 mL) and acetic acid (4 mL), dried, and 53.7 g of the solid compound shown in formula (XVII) was obtained. The yield of the second division was 74.5%, and the total yield of the two division steps was 27%. It was measured by chiral column HPLC that the dr value of the solid product was 95.2%.

[0094] Third division: Toluene (192 mL) and acetic acid (16 mL) were added to the solid sample obtained in the second division, heated to 65 - 70 °C, stirred for 1 hour, cooled to 63 - 64 °C, and the compound shown in formula (XVII) (2.0 g, 0.01 w / w, dr = 99%) was slowly added thereto as a seed crystal. After the addition was complete, the temperature was maintained at 63 - 64 °C, stirred for 2 hours, then cooled to 24 - 25 °C, stirred for 7 - 8 hours, filtered, the solid was collected, the filter cake was rinsed with a mixed solvent of toluene (25 mL) and acetic acid (2 mL), dried, and 48.1 g of the solid compound shown in formula (XVII) was obtained. The yield of the second division was 89.6%, and the total yield of the three division steps was 24.5%. It was measured by chiral column HPLC that the dr value of the solid product was 99.0%. MS, m / z (ESI): 313.1 [M + H] + . 11H NMR (400 MHz, CDCl3) δ 7.71 - 7.68 (m, 3H), 7.43 - 7.41 (m, 1H), 7.15 - 7.10 (m, 2H), 4.23 (d, J = 12.0 Hz, 1H), 4.04 (d, J = 8.0 Hz, 1H), 3.97 - 3.92 (m, 1H), 3.91 (s, 3H), 2.36 (s, 1H), 2.14 (br, 1H), 1.62 (d, J = 8.0 Hz, 3H), 1.40 (s, 3H).

[0095] Step 3, Hydrolysis Step, Production of the Compound Shown in Formula (XVI) Take the reaction flask, add the compound shown in formula (XVII) (50.0 g, 160 mmol) and a mixed solvent of tetrahydrofuran (500 mL) and water (15 mL), stir uniformly, add solid sodium hydroxide (12.8 g, 320 mL) little by little at 20 - 25 °C, stir at 20 - 25 °C for 3 hours for reaction. Analyze by HPLC to judge the completion of the reaction. Filter the mixture after the reaction to remove solid naproxen sodium salt, rinse the solid filtration cake with tetrahydrofuran (50 mL), and combine the filtrates. Add dichloromethane to replace the solvent, concentrate, and obtain 20.2 g of the compound shown in formula (XVI), with a content of 79.1% (w / w). In terms of conversion, the yield of this step was 99%. It was directly charged into the next step. MS, m / z (ESI): 101.1 [M + H] + .

[0096] 1 1H NMR was the same as the known reports.

[0097] Example 8 Production of the Compound Shown in Formula (VI - 1)

Chemical Structure

[0098] To the reactor, the compound shown in formula (XVI) (16.0 g, 160 mmol), dichloromethane (120 mL), and 2,6-dimethylpyridine (34.3 g, 320 mmol) were sequentially added. The reaction was placed in a water bath at 0 °C, stirred to dissolve uniformly, and p-nitrobenzenesulfonyl chloride (39.0 g, 176 mmol) was slowly added to the reaction flask at 0 °C. After the addition was complete, the reaction was slowly warmed to room temperature and left standing overnight for 14 - 16 hours. It was analyzed by GC to determine the completion of the reaction. At 20 - 25 °C, an aqueous acetic acid solution (100 mL, 5 M) was added to the reaction to quench the reaction, and the reaction was allowed to proceed. The liquid was separated, water (100 mL) and saturated aqueous sodium hydrogen carbonate solution (60 mL) were added to wash the organic phase, and it was concentrated. At 50 - 55 °C, dichloromethane (20 mL) and n-heptane (240 mL) were added, slowly warmed to 20 - 25 °C, and stirred at room temperature for 2 hours. It was filtered, rinsed with a mixed solvent of dichloromethane / n-heptane, and dried to obtain 39.2 g of the compound shown in formula (VI-1) as a solid product, and the total yield of the two steps was 86%. It was measured by chiral column HPLC that the ee value of the solid product was 95%. MS, m / z (ESI): 286.0[M+H] + . 1 H NMR, (400 MHz, CDCl3) δ 8.41 (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).

[0099] The compound shown in formula (VI-2)

Chemical Structure

[0100] A solution of the compound shown in formula (XVI) (15.0 g, 150 mmol) in dichloromethane (90 mL) was added to the reactor, triethylamine (30.3 g, 300 mmol) was added, the reaction was placed in an ice bath at 0 - 5 °C, and stirred until uniformly dissolved. At 0 - 5 °C, p-toluenesulfonyl chloride (31.4 g, 165 mmol) was added little by little to the reaction flask, reacted at 0 - 5 °C for 1 hour, then slowly warmed to room temperature at 20 - 25 °C, and stirred for 14 - 16 hours. The reaction was analyzed by GC to determine its completion. An aqueous acetic acid solution was added to quench the reaction, concentrated, placed at 0 - 4 °C, a solid precipitated, filtered, and dried to obtain 24.5 g of the compound shown in formula (VI-2) as the product, with a yield of 64.3%. It was measured by chiral column HPLC that the ee value of the solid product was 97.4%. MS, m / z (ESI): 255.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.83 - 7.79 (m, 2H), 7.38 - 7.31 (m, 2H), 3.98 (q, J = 9.7 Hz, 2H), 2.45 (s, 4H), 2.44 (s, 1H), 1.47 (s, 3H).

[0101] The compound shown in formula (VI-3)

Chemical Structure

[0102] A solution of the compound shown in formula (XVI) (25.0 g, 250 mmol) in dichloromethane (150 mL) was added to the reactor, and then 2,6-dimethylpyridine (53.5 g, 500 mmol) was added. The reaction was placed in an ice-water bath at 0 - 5 °C and stirred until uniformly dissolved. 2-Naphthalenesulfonyl chloride (62.3 g, 275 mmol) was added little by little to the reaction flask at 0 - 5 °C, and then the temperature was slowly raised to room temperature at 20 - 25 °C and stirred for 14 - 16 hours for the reaction. The completion of the reaction was judged by GC. At 20 - 25 °C, an aqueous acetic acid solution (150 mL, 5 M) was added to the reaction to quench the reaction, extracted, the liquids were separated, the organic phase was washed with aqueous acetic acid solution and water, concentrated, n-heptane was added, a solid precipitated, and after drying, 62.3 g of the compound shown in formula (VI-3) of the solid product was obtained, and the yield was 85.9%. It was measured by chiral column HPLC that the ee value of the solid product was 97.8%, meeting the quality requirements. MS, m / z (ESI): 291.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 1.9 Hz, 1H), 8.01 (dd, J = 8.2, 4.7 Hz, 2H), 7.94 (dd, J = 8.2, 1.3 Hz, 1H), 7.89 (dd, J = 8.7, 1.9 Hz, 1H), 7.68 (dddd, J = 19.3, 8.2, 6.9, 1.4 Hz, 2H), 4.05 (q, J = 9.8 Hz, 2H), 2.41 (s, 1H), 2.39 (s, 1H), 1.48 (s, 3H).

[0103] Example 9

Chemical formula

[0104] Step 1, Esterification step, production of the compound shown in formula (XX-RAC) To the reactor, add the compound shown in formula (XIX-RAC) (72.1 g, 500 mmol), dichloromethane (360 mL), and pyridine (79.1 g, 1.0 mol). Place the reaction in a water bath at 0 °C, and dropwise add a solution of naproxen acid chloride (136.8 g, 550 mmol) in dichloromethane (550 mL) to the reaction flask. React at 0 °C for 4 hours. Analyze by GC to determine the completion of the reaction. Quench the reaction by adding aqueous acetic acid, wash with water and saturated aqueous sodium bicarbonate solution, concentrate, then add toluene and n-heptane. A white solid precipitates. After drying, 147.0 g of the compound shown in formula (XX-RAC) is obtained. The yield of this step is 82.5%, and it is a white or off-white solid powder. MS, m / z (ESI): 357.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.71 - 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 = 7.2 Hz, 3H).

[0105] Step 2, crystallization separation step, preparation of the compound shown in formula (XX) Take the reaction flask, add the compound shown in formula (XX-RAC) (60.0 g, 168 mmol), add isopropanol (100 mL), heat to 55 - 60 °C, stir until the solution becomes clear, slowly raise the temperature to 0 - 5 °C, maintain at 0 - 5 °C, stir for 12 - 16 hours, filter at 0 - 5 °C, collect the solid, rinse the filter cake with n-heptane (50 mL), and after drying, 22.5 g of solid is obtained, with a yield of 37.5%. It was measured by chiral column HPLC that the dr value of the solid product is 88.5%. MS, m / z (ESI): 357.2 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 7.71 - 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 = 7.2 Hz, 3H).

[0106] Step 3, Hydrolysis step of the ester, preparation of the compound shown in formula (XIX) Take the reaction flask, add the compound shown in formula (XX) (20.0 g, 56.1 mmol) and a mixed solvent of tetrahydrofuran (100 mL) and water (10 mL), stir uniformly, add solid sodium hydroxide (4.5 g, 112.3 mmol) little by little at 20 - 25 °C, stir at 20 - 25 °C and react for 3 hours. Analyze by HPLC to judge the completion of the reaction. Filter the reaction mixture, remove the solid sodium naproxen salt, rinse the solid filtration cake with tetrahydrofuran (50 mL), and combine the filtrates. Add dichloromethane (100 mL x 2) to replace the solvent, concentrate to obtain a dichloromethane solution of the compound shown in formula (XIX), and directly charge it into the next step. MS, m / z (ESI): 143.1 [M - H] - .

[0107] Step 4, Hydrolysis - reduction step of the acetal, preparation of the compound shown in formula (XVI) At room temperature of 20 - 25 °C, add trifluoroacetic acid (50 mL) to the dichloromethane solution of the compound shown in formula (XIX) obtained in the previous step, stir uniformly, heat to 43 - 45 °C, stir and react for 4 - 5 hours. Raise the temperature of the reaction mixture to room temperature, add water (200 mL) and dichloromethane (200 mL) to the mixture, separate the liquids, add dichloromethane (100 mL x 2) for extraction, wash with saturated aqueous sodium bicarbonate solution (200 mL), concentrate to obtain a dichloromethane solution of the compound shown in formula (XVIII), and directly charge it into the next step. MS, m / z (ESI): 97.1 [M - H]- .

[0108] At room temperature of 20 - 25 °C, methanol (10 mL) was added to a dichloromethane solution of the compound shown in formula (XVIII) obtained in the previous step, stirred uniformly, and while stirring at 20 - 25 °C, sodium triacetoxyborohydride (23.7 g, 112 mmol) was slowly added. After the addition was complete, stirring was continued for 3 - 4 hours. Analysis by HPLC was performed to determine the completion of the reaction. An aqueous sodium chloride solution (100 mL) was added at room temperature, the liquid was separated, extracted with dichloromethane (50 mL × 5), concentrated, and 4.6 g of the compound shown in formula (XVI) was obtained, and the yield of the three-step continuous input was 82.0%. MS, m / z (ESI): 101.1 [M + H] + .

[0109] 1 1H NMR is the same as the previously reported one.

Claims

1. A compound of formula (VI), stereoisomers thereof, and salts thereof, wherein 【Chemical 1】 R ２ is selected from hydrogen, deuterium, a hydroxy group, an amino group, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ haloalkyl group, C １－３ alkoxy group, halogenated C １－３ alkoxy group or C １－３ hydroxyalkyl group, and is optionally substituted with one or more substituents selected from deuterium, halogen, an amino group, a hydroxy group, a cyano group, a nitro group, C １－３ alkyl group, C ２－４ group, C ２－４ alkynyl group, C １－３ deuterated alkyl group, C １－３ haloalkyl group, C １－３ alkoxy group, halogenated C １－３ alkoxy group or C １－３ hydroxyalkyl group, R ３ is selected from a C １－３ alkyl group, a C ２－３ alkenyl group or a C ２－３ alkynyl group, and optionally is substituted with one or more substituents selected from deuterium, halogen, an amino group, a hydroxy group, a cyano group, a nitro group, a C １－３ alkyl group, a C ２－４ group, a C ２－４ alkynyl group, a C １－３ deuterated alkyl group, a C １－３ haloalkyl group, a C １－３ alkoxy group, a halogenated C １－３ alkoxy group or a C １－３ hydroxyalkyl group, R ４ is selected from -C(O)(CR ａａ R ｂｂ ) ｎ R ａ or -(CR ａａ R ｂｂ ) ｍ R ｂ and is selected from R ａａ or R ｂｂ is, independently, hydrogen, deuterium, halogen, hydroxy group, amino group or C １－３ alkyl group, and is optionally substituted with one or more substituents selected from deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ alkyl group, C ２－４ group, C ２－４ alkynyl group, C １－３ deuterated alkyl group, C １－３ haloalkyl group, C １－３ alkoxy group, halogenated C １－３ alkoxy group or C １－３ hydroxyalkyl group R ａ is selected from an aryl group or a 6- to 10-membered heteroaryl group containing 1 to 3 N, O, or S atoms, where the ６－１０ aryl group or 6- to 10-membered heteroaryl group containing 1 to 3 N, O, or S atoms is optionally deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C ６－１０ alkyl group, C １－３ group, C ２－４ group, C ２－４ alkynyl group, C １－３ deuterated alkyl group, C １－３ haloalkyl group, C １－３ alkoxy group, halogenated C １－３ alkoxy group or C １－３ hydroxyalkyl group, and is substituted with one or more substituents selected therefrom. R ｂ is selected from hydroxy group protecting groups and is preferably a substituted or unsubstituted sulfonyl group, m is 0, 1, or 2, and n is 0, 1, or 2, a compound of formula (VI), stereoisomers thereof, and salts thereof.

2. R ２ is selected from hydrogen, deuterium, amino group, hydroxy group, cyano group, nitro group, fluorine, chlorine, bromine, methyl group, ethyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, dimethoxymethyl group, dimethoxyethyl group, fluoromethyl group, fluoroethyl group, difluoromethyl group, difluoroethyl group, trifluoromethyl group or trifluoroethyl group, R ３ is selected from a methyl group, an ethyl group, a propyl group, a vinyl group, an allyl group, a propenyl group, an ethynyl group, a propynyl group or a propargyl group, R ４ is selected from -C(O)(CR ａａ R ｂｂ ) ｎ R ａ or -(CR ａａ R ｂｂ ) ｍ R ｂ and is selected from R ａａ or R ｂｂ is independently selected from hydrogen, deuterium, fluorine, chlorine, a hydroxy group, an amino group, a methyl group, an ethyl group, a propyl group or an isopropyl group, R ａ is selected from a phenyl group, a naphthyl group, pyridine, pyrimidine or a 6,6-membered heteroaryl group containing 1 to 3 N, O or S atoms, wherein the phenyl group, naphthyl group, pyridine, pyrimidine or 6,6-membered heteroaryl group containing 1 to 3 N, O or S atoms is optionally substituted with one or more substituents selected from hydrogen, deuterium, an amino group, a hydroxy group, a cyano group, a nitro group, fluorine, chlorine, bromine, a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a fluoromethyl group, a fluoroethyl group, a difluoromethyl group, a difluoroethyl group, a trifluoromethyl group or a trifluoroethyl group, R ｂ is selected from a benzenesulfonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a p-methoxybenzenesulfonyl group, a p-trifluoromethylbenzenesulfonyl group, a p-chlorobenzenesulfonyl group or a 2-naphthalenesulfonyl group, preferably a p-nitrobenzenesulfonyl group or a 2-naphthalenesulfonyl group, m is 0, 1, or 2, and n is 0, 1, or 2, a compound of formula (VI), stereoisomers thereof, and salts thereof according to claim 1, characterized in that.

3. The compound further has the general formula (XVII): 【Chemical 2】 as shown, a compound of formula (VI), stereoisomers thereof, and salts thereof according to claim 1 or 2, characterized in that.

4. A compound of formula (IX), stereoisomers thereof, and salts thereof, wherein 【Chemical Formula 3】 R ｘ is selected from hydrogen, deuterium, C １－３ alkyl group, halogen, C １－３ deuterated alkyl group, C １－３ haloalkyl group, C １－３ alkoxy group, halogenated C １－３ alkoxy group or C １－３ hydroxyalkyl group, and is optionally substituted with one or more substituents selected from deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ alkyl group, C ２－４ group, C ２－４ alkynyl group, C １－３ deuterated alkyl group, C １－３ haloalkyl group, C １－３ alkoxy group, halogenated C １－３ alkoxy group or C １－３ hydroxyalkyl group, and preferably, R ｘ is selected from hydrogen, deuterium, methyl group, ethyl group, n-propyl group, isopropyl group, fluorine, chlorine or bromine, R ５ is selected from hydrogen, deuterium, C １－３ alkyl group, halogen, C １－３ deuterated alkyl group, C １－３ haloalkyl group, C １－３ alkoxy group, halogenated C １－３ alkoxy group or C １－３ hydroxyalkyl group, and is optionally substituted with one or more substituents selected from deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ alkyl group, C ２－４ group, C ２－４ alkynyl group, C １－３ deuterated alkyl group, C １－３ haloalkyl group, C １－３ alkoxy group, halogenated C １－３ alkoxy group or C １－３ hydroxyalkyl group, and preferably, R ５ is selected from hydrogen, deuterium, methyl group, ethyl group, n-propyl group, isopropyl group, fluorine, chlorine or bromine, R ６ is selected from hydrogen, deuterium, C １－３ alkyl group, C ２－３ alkenyl group, C ２－３ alkynyl halogen, cyano group, amino group or hydroxy group, preferably hydrogen, deuterium, methyl group, ethyl group, n-propyl group, isopropyl group, fluorine, chlorine, bromine, cyano group, vinyl group, ethynyl group, amino group or hydroxy group, a compound of formula (IX), stereoisomers and salts thereof.

5. The structure of the compound is [Chemical Formula 4] as shown, a compound of formula (IX), stereoisomers thereof, and salts thereof according to any one of claims 1 to 4, characterized in that.

6. The intermediate of general formula (IX) is as shown in general formula (X), 【Chemical Formula 5】 preferably, [Chemical Formula 6] a compound of formula (IX), stereoisomers thereof, and salts thereof according to claim 4.

7. The intermediate of the general formula (IX) is as shown in the general formula (XI), 【Chemical Formula 7】 preferably, 【Chemical 8】 a compound of formula (IX), stereoisomers thereof, and salts thereof according to claim 4.

8. A method for producing a compound of formula (IX), stereoisomers thereof, and salts thereof according to claim 4, comprising the following steps: 【Chemical Formula 9】 Formula (XI) and formula (XI') react to produce formula (X), R ｘ is selected from hydrogen, deuterium, C １－３ alkyl group or halogen, preferably hydrogen, deuterium, methyl group, ethyl group, n-propyl group, isopropyl group, fluorine, chlorine or bromine, and R ５ is selected from hydrogen, deuterium, C １－３ alkyl group or halogen, preferably hydrogen, deuterium, methyl group, ethyl group, n-propyl group, isopropyl group, fluorine, chlorine or bromine, and R ６ is selected from hydrogen, deuterium, C １－３ alkyl group, halogen, cyano group, amino group or hydroxy group, preferably hydrogen, deuterium, methyl group, ethyl group, n-propyl group, isopropyl group, fluorine, chlorine, bromine, cyano group, amino group or hydroxy group, R ７ is selected from halogen, preferably fluorine, chlorine or bromine, preferably, the reaction is carried out with an organometallic reagent, where the organometallic reagent is selected from organolithium or organomagnesium reagents, preferably n-butyllithium, s-butyllithium, isobutyllithium, t-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 t-butyl ether, preferably a mixed solvent of tetrahydrofuran and toluene or a mixed solvent of ethylene glycol dimethyl ether and methyl t-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 t-butyl ether is 1:5 to 1:1, even more preferably, the volume ratio of ethylene glycol dimethyl ether to methyl t-butyl ether is 1:2 or the volume ratio of tetrahydrofuran to toluene is 1.5:1, A process for producing a compound of formula (IX), a stereoisomer and a salt thereof, characterized by the above.

9. A process for producing a compound of formula (IX), a stereoisomer and a salt thereof according to claim 4 or 8, comprising the following steps: 【Chemical Formula 10】 Preferably, the reaction is carried out in the presence of an oxidizing agent, where the oxidizing agent is selected from one or more of sodium hypochlorite, calcium hypochlorite, Dess-Martin oxidizing agent, 2-iodoxybenzoic acid, iodobenzene diacetate, oxalyl chloride-dimethyl sulfoxide combination reagent, pyridine-sulfur trioxide, 2,2,6,6-tetramethylpiperidine N-oxide, pyridine-N-oxide or trichloroisocyanuric acid, preferably a mixed oxidizing agent of 2,2,6,6-tetramethylpiperidine N-oxide and trichloroisocyanuric acid, more preferably, the molar ratio of 2,2,6,6-tetramethylpiperidine N-oxide to trichloroisocyanuric acid is 1:4 to 1:40, even more preferably, the molar ratio of 2,2,6,6-tetramethylpiperidine N-oxide to trichloroisocyanuric acid is 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 t-butyl ether, methanol, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, and preferably, it is dichloromethane. A method for producing a compound of formula (IX), a stereoisomer and a salt thereof, characterized by this.

10. A method for producing the compound of formula (IX), a stereoisomer and a salt thereof according to claim 4, wherein the production of the general formula (V) includes the following steps: 【Chemical Formula 11】 Preferably, the reaction is carried out under alkaline conditions, where the alkali is selected from one or more of sodium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium t-butoxide, sodium hydride, potassium carbonate, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium t-butoxide, cesium carbonate, lithium carbonate, lithium hydroxide, lithium chloride, lithium methoxide, lithium ethoxide, lithium isopropoxide or lithium t-butoxide, preferably, it is a mixture of lithium hydroxide and lithium chloride, more preferably, the molar ratio of lithium hydroxide to lithium chloride is 1:4 to 4:1, and even more preferably, the molar ratio of lithium hydroxide to lithium chloride is 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 t-butyl ether, methanol, ethanol, t-butanol, water, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably a mixed solvent of ethylene glycol dimethyl ether, methyl t-butyl ether and water, more preferably, the volume ratio of ethylene glycol dimethyl ether, methyl t-butyl ether and water is 5 to 10:30 to 50:1, still more preferably, the volume ratio of ethylene glycol dimethyl ether, methyl t-butyl ether and water is 8:40:1, a method for producing a compound of formula (IX), a stereoisomer and a salt thereof, characterized in that.

11. A method for producing a compound of formula (VI), a stereoisomer and a salt thereof according to claim 1, comprising the following steps: 【Chemical Formula 12】 Formula (XVI) and R ４ X reacts to obtain formula (VI), Here, R ２ is selected from hydrogen, deuterium, a hydroxy group, an amino group or a C １－３ alkyl group, preferably hydrogen, deuterium, a hydroxy group, an amino group, a methyl group, an ethyl group, a propyl group or an isopropyl group, R ３ is selected from a C １－３ alkyl group, a C １－３ alkenyl group or a C １－３ alkynyl group, preferably a methyl group, an ethyl group, a propyl group, a vinyl group, an allyl group, a propenyl group, an ethynyl group, a propynyl group or a propargyl group, R ４ is selected from a benzenesulfonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a p-methoxybenzenesulfonyl group, a p-trifluoromethylbenzenesulfonyl group, a p-chlorobenzenesulfonyl group or a 2-naphthalenesulfonyl group, preferably a p-nitrobenzenesulfonyl group or a 2-naphthalenesulfonyl group, X is selected from halogens, preferably fluorine, chlorine or bromine; Preferably, the base is selected from pyridine, 2-methylpyridine, 4-methylpyridine, 2,6-dimethylpyridine, 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-dimethylpyridine 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 t-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably dichloromethane, a method for producing a compound of formula (VI), a stereoisomer and a salt thereof, characterized in that.

12. The production of general formula (XVI) includes the following steps: 【Chemical 13】 Preferably, the reaction is carried out in the presence of an alkali, where the alkali is selected from sodium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium t-butoxide, sodium hydride, potassium carbonate, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium t-butoxide, cesium carbonate, lithium carbonate, lithium hydroxide, lithium methoxide, lithium ethoxide, lithium isopropoxide or lithium t-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 t-butyl ether, methanol, ethanol, isopropanol, t-butanol, 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, still more preferably the volume ratio of tetrahydrofuran to water is 33:1, a method for producing a compound, stereoisomer and salt thereof of formula (VI) according to claim 11, characterized in that. [

13. ] The production of general formula (XVII) includes the following steps, 【Chemical 14】 Preferably, the dividing 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 t-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 the toluene solvent to the acetonitrile solvent used is selected from 20:1 to 3:1 or the volume ratio of the toluene solvent to the acetic acid solvent is selected from 20:1 to 5:1, still more preferably, the volume ratio of the toluene solvent to the acetonitrile solvent is selected from 10:1 to 4:1 or the volume ratio of the toluene solvent to the acetic acid solvent is selected from 15:1 to 10:1, most preferably, the volume ratio of the toluene solvent to the acetonitrile solvent is 4:1 or the volume ratio of the toluene solvent to the acetic acid solvent is 12:1, a method for producing the compound, stereoisomer and salt thereof of formula (VI) according to claim 12, characterized in that.

14. The production of the general formula (XVII-RAC) includes the following steps, 【Chemical Formula 15】 Preferably, the reaction is carried out in a naproxen chlorination reagent, where 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, where the base is selected from pyridine, 2-methylpyridine, 4-methylpyridine, 2,6-dimethylpyridine, 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-dimethylpyridine. 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 t-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, and preferably dichloromethane, and a method for producing a compound of formula (VI), a stereoisomer and a salt thereof according to claim 13, characterized in that.

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