An intermediate of MK-8876 and a process for preparing the same

Abstract

This invention relates to an intermediate compound of MK-8876 and its preparation method, providing a highly efficient synthetic method for preparing MK-8876. It boasts advantages such as high efficiency, low cost, stable and safe process, controllable process quality, and the potential for industrial-scale production, thus holding significant potential in this field.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to an intermediate for chemically synthesized drugs and its preparation method, and particularly to an intermediate compound and method for preparing MK-8876. Background Technology

[0002] Chronic liver disease caused by hepatitis C virus (HCV) results in a large number of infections each year, and the disease exhibits high genetic heterogeneity. MK-8876, an oral small-molecule non-nucleoside inhibitor developed by Merck, demonstrates potential applications in this therapeutic field, as shown in structural formula 11.

[0003]

[0004] Compound with structural formula 10 is one of the key intermediates of this drug, and its synthesis methods currently mainly include the following routes:

[0005]

[0006] Patent WO 2011106986 uses ortho-hydroxyphenylacetic acid (structure 12) as a starting material to obtain compound 13 via tetrabutylammonium tribromide. After TBS protection of the hydroxyl group, it undergoes condensation with p-fluorobenzoyl chloride, followed by acid-catalyzed ring closure to form compound 17. The amino group is introduced by nitrosylation of the benzene ring with nitric acid, followed by reduction with iron powder to obtain compound 19. This route suffers from selectivity issues in the preparation of compound 13, leading to impurity formation and difficulties in separation and purification. Furthermore, the strategy of introducing the amino group with nitric acid and reducing with iron powder undoubtedly poses a significant challenge to the production process, necessitating further optimization of the route from a safety and environmental perspective.

[0007] Therefore, it is essential to design and develop a synthesis process that is highly safe, stable, low in raw material costs, efficient, and in line with green chemistry. Summary of the Invention

[0008] To overcome some shortcomings of the prior art, the present invention provides an intermediate compound of MK-8876 and a method for its preparation:

[0009] This invention provides an intermediate compound of formula 1 (MK-8876) and its salt, with the following specific structure:

[0010] ,

[0011] Wherein, R1 can be a chlorine atom, bromine atom, iodine atom, borate group, borate ester group, -O-methanesulfonyloxy, -O-trifluoromethanesulfonyloxy, -O-p-toluenesulfonyloxy, -O-p-nitrobenzenesulfonyloxy, -O-m-nitrobenzenesulfonyloxy, -O-acetoxy; R2 can be a substituted alkyl or alkenyl group; preferably, the substituted alkyl or alkenyl group can be a hydroxyl, carbonyl, or aldehyde group. Most preferably, R1 is a bromine atom; R2 is... or .

[0012] The salt may be an ammonium salt, an alkali metal salt, or an alkaline earth metal salt.

[0013] More preferably, the alkali metal salt can be a lithium salt, sodium salt, or potassium salt.

[0014] The MK-8876 intermediate compound of formula 1 provided by this invention has a structure of formula 1a or 1b.

[0015] or .

[0016] Wherein, R1 can be a chlorine atom, a bromine atom, an iodine atom, a borate group, a borate ester group, -O-methanesulfonyloxy, -O-trifluoromethanesulfonyloxy, -O-p-toluenesulfonyloxy, -O-p-nitrobenzenesulfonyloxy, -O-m-nitrobenzenesulfonyloxy, or -O-acetoxy. Most preferably, R1 is a bromine atom.

[0017] Intermediate compound 2 has the following specific structural formula:

[0018] ,

[0019] Wherein, R1 can be a chlorine atom, bromine atom, iodine atom, borate group, borate ester group, -O-methanesulfonyloxy, -O-trifluoromethanesulfonyloxy, -O-p-toluenesulfonyloxy, -O-p-nitrobenzenesulfonyloxy, -O-m-nitrobenzenesulfonyloxy, or -O-acetoxy; R3 can be CR4R5R6, where R4, R5, and R6 are the same or different and can be hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, substituted aryl, alkoxy, alkylthio, or alkylamino. More preferably, R1 is a bromine atom, and R3 is an alkyl or substituted alkyl group.

[0020] Intermediate compound 3 has the following specific structural formula:

[0021] ,

[0022] Wherein, R1 can be a chlorine atom, bromine atom, iodine atom, borate group, borate ester group, -O-methanesulfonyloxy, -O-trifluoromethanesulfonyloxy, -O-p-toluenesulfonyloxy, -O-p-nitrobenzenesulfonyloxy, -O-m-nitrobenzenesulfonyloxy, or -O-acetoxy; R3 can be CR4R5R6, where R4, R5, and R6 are the same or different and can be hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, substituted aryl, alkoxy, alkylthio, or alkylamino. More preferably, R1 is a bromine atom, and R3 is an alkyl or substituted alkyl group.

[0023] Intermediate compound 4 has the following specific structural formula:

[0024] ,

[0025] Wherein, R1 can be a chlorine atom, a bromine atom, an iodine atom, a borate group, a borate ester group, -O-methanesulfonyloxy, -O-trifluoromethanesulfonyloxy, -O-p-toluenesulfonyloxy, -O-p-nitrobenzenesulfonyloxy, -O-m-nitrobenzenesulfonyloxy, or -O-acetoxy. Most preferably, R1 is a bromine atom.

[0026] Another aspect of the present invention provides a method for preparing the intermediate compound of formula 1, MK-8876, comprising the following steps:

[0027] The compound of formula 1 was subjected to transesterification and cyclization in the presence of an alkyl alcohol via an acid catalyst to yield benzofuran carboxylate compound of formula 10:

[0028]

[0029] Wherein, R1 is a chlorine atom, a bromine atom, an iodine atom, a borate group, a borate ester group, an O-methanesulfonyloxy group, an O-trifluoromethanesulfonyloxy group, an O-p-toluenesulfonyloxy group, an O-p-nitrobenzenesulfonyloxy group, an O-m-nitrobenzenesulfonyloxy group, an O-acetoxy group, preferably R1 is a bromine atom; R 11 For CR 12 R 13 R 14 R 12 R 13 R 14 The atoms that are the same or different are hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, substituted aryl, alkoxy, alkathiol, and alkamino. Preferably, R1 is a bromine atom, and R... 11 It is an alkyl or substituted alkyl group.

[0030] In some embodiments, the acid catalyst in the process steps of the present invention may be one of the following: formic acid, acetic acid, trifluoroacetic acid, benzoic acid, p-nitrobenzoic acid, p-toluenesulfonic acid, p-toluenesulfonic anhydride, methanesulfonic acid, methanesulfonic anhydride, trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, pyridine salt of 4-methylbenzenesulfonic acid, sulfonyl chloride, sulfonyl chloride, oxaloyl chloride, phosphorus oxychloride, trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, triethylchlorosilane, triisopropylchlorosilane, tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, concentrated hydrochloric acid, concentrated sulfuric acid, concentrated phosphoric acid, polyphosphoric acid, 1-propylphosphoric anhydride, Eaton reagent, zinc chloride, aluminum trichloride, titanium tetrachloride, boron trifluoride diethyl ether, boron trifluoride tetrahydrofuran, and boron tribromide.

[0031] The alkyl alcohol may be one of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, isopentanol, tert-pentanol, benzyl alcohol, allyl alcohol, cinnamyl alcohol, and propargyl alcohol. Preferably, the alkyl alcohol is methanol or ethanol.

[0032] The reaction temperature is 45~120℃, the preferred reaction temperature is 60~90℃, and the most preferred reaction temperature is 70~80℃.

[0033] Compound 2 undergoes cyclization via an alkaline catalyst to yield compound 1:

[0034] .

[0035] Wherein, R1 can be a chlorine atom, bromine atom, iodine atom, borate group, borate ester group, -O-methanesulfonyloxy, -O-trifluoromethanesulfonyloxy, -O-p-toluenesulfonyloxy, -O-p-nitrobenzenesulfonyloxy, -O-m-nitrobenzenesulfonyloxy, or -O-acetoxy; R3 can be CR4R5R6, where R4, R5, and R6 are the same or different and can be hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, substituted aryl, alkoxy, alkylthio, or alkylamino. More preferably, R1 is a bromine atom, and R3 is an alkyl or substituted alkyl group.

[0036] In some embodiments, the alkaline catalyst in the process steps of this invention can be one of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, diisopropylaminolithium, bis(trimethylsilylaminolithium), bis(trimethylsilylaminosodium), bis(trimethylsilylaminopotassium), lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, potassium trimethylsilanolate, sodium trimethylsilanolate, lithium trimethylsilanolate, magnesium methoxide, magnesium ethoxide, and magnesium tert-butoxide. Most preferably, the alkaline catalyst is lithium tert-butoxide.

[0037] The equivalent of the alkaline catalyst can be 0.5-3.0 equivalents.

[0038] The above reaction is carried out in the presence of an organic solvent, which may be one of toluene, xylene, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, acetonitrile, acetone, water, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, 1,3-dimethylimidazolinone, hexamethylphosphoramide, dimethyl sulfoxide, sulfolane, dichloromethane, trichloromethane, and carbon tetrachloride. Preferably, the organic solvent is tetrahydrofuran or 2-methyltetrahydrofuran.

[0039] Compound 3 is condensed with 4-fluorobenzoyl chloride in the presence of a base additive to give compound 2:

[0040]

[0041] Wherein, R1 can be a chlorine atom, bromine atom, iodine atom, borate group, borate ester group, -O-methanesulfonyloxy, -O-trifluoromethanesulfonyloxy, -O-p-toluenesulfonyloxy, -O-p-nitrobenzenesulfonyloxy, -O-m-nitrobenzenesulfonyloxy, or -O-acetoxy; R3 can be CR4R5R6, where R4, R5, and R6 are the same or different and can be hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, substituted aryl, alkoxy, alkylthio, or alkylamino. More preferably, R1 is a bromine atom, and R3 is an alkyl or substituted alkyl group.

[0042] The above reaction is carried out in the presence of a base additive, which may be triethylamine, N,N-diisopropylethylamine (DIPEA), pyridine, 2,6-dimethylpyridine, 1,8-diazacyclo[5,4,0]-undec-7-ene (DBU), triethylenediamine (DABCO), N-methylmorpholine (NMM), 4-dimethylaminopyridine (DMAP), imidazole, N-methyltetrahydropyrrole, N-methylpiperidine, lithium diisopropylamino (LDA), lithium bis(trimethylsilylamino)amino (Li-HMDS), sodium bis(trimethylsilylamino)amino (Na-HMDS), potassium bis(trimethylsilylamino)amino (K-HMDS), lithium methoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, potassium trimethylsilanolate, sodium trimethylsilanolate, or lithium trimethylsilanolate. Preferably, it may be triethylamine or pyridine.

[0043] The reaction temperature is -20~25℃, and the preferred reaction temperature is 0-15℃.

[0044] Compound of Formula 4 undergoes dehydration condensation with an alkyl alcohol under acid-catalyzed conditions to yield compound of Formula 3.

[0045]

[0046] Wherein, R1 can be a chlorine atom, bromine atom, iodine atom, borate group, borate ester group, -O-methanesulfonyloxy, -O-trifluoromethanesulfonyloxy, -O-p-toluenesulfonyloxy, -O-p-nitrobenzenesulfonyloxy, -O-m-nitrobenzenesulfonyloxy, or -O-acetoxy; R3 can be CR4R5R6, where R4, R5, and R6 are the same or different and can be hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, substituted aryl, alkoxy, alkylthio, or alkylamino. More preferably, R1 is a bromine atom, and R3 is an alkyl or substituted alkyl group.

[0047] The acidic catalyst may be one of the following: p-toluenesulfonic acid, p-toluenesulfonic anhydride, methanesulfonic acid, methanesulfonic anhydride, trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, pyridine salt of 4-methylbenzenesulfonic acid, sulfonyl chloride, sulfonyl chloride, oxaloyl chloride, phosphorus oxychloride, trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, triethylchlorosilane, triisopropylchlorosilane, tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, concentrated hydrochloric acid, concentrated sulfuric acid, concentrated phosphoric acid, polyphosphoric acid, 1-propylphosphoric anhydride, Eaton reagent, zinc chloride, aluminum trichloride, titanium tetrachloride, boron trifluoride diethyl ether, boron trifluoride tetrahydrofuran, and boron tribromide.

[0048] The alkyl alcohol may be one of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, isopentanol, tert-pentanol, benzyl alcohol, allyl alcohol, cinnamyl alcohol, and propargyl alcohol. Preferably, the alkyl alcohol is methanol or ethanol.

[0049] The reaction temperature is -20~25℃, preferably 0-15℃.

[0050] Compound of Formula 5 undergoes a carbon-hydrogen bond hydroxylation reaction under transition metal catalysis to yield compound of Formula 4.

[0051]

[0052] The definition of R1 is consistent with the definition described in the above reaction.

[0053] The transition metal catalyst may be 1,1'-bis(diphenylphosphine)-ferrocene palladium dichloride (Pd(dppf)Cl2), tetra(triphenylphosphine)palladium, palladium dichloride, bis(acetonitrile)palladium chloride, palladium acetate, bis(dibenzylacetone)palladium, tri(dibenzylacetone)dipalladium, diacetylacetone palladium, bis(triphenylphosphine)palladium chloride, allyl palladium(II) chloride dimer, methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (Ruphos PdG3), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'biphenyl)(2-amino-1,1'-biphenyl-3-yl)palladium(II) (SPhos Pd G3), Methanesulfonic acid (9,9-dimethyl-4,5-bis-diphenylphosphineoxanthracene) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (XantPhos Pd G3), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (t-BuXPhos Pd G3), methanesulfonic acid [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphino-2-amino-1,1'-biphenyl-2-yl)palladium(II) (APhos Pd G3), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Pd (G4), Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Pd G4), (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)methanesulfonic acid palladium(II) (BrettPhos Pd G4), Methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (t-BuXPhos Pd G4), Methanesulfonic acid (4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene) (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (XantPhos Pd G4), Methanesulfonic acid (tri-tert-butylphosphine) (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (P(t-Bu)3 Pd G4), Methanesulfonate 2-dicyclohexylphosphine-2-(N,One of N-dimethylamino)biphenyl(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (DavePhos Pd G4), most preferably, the transition metal catalyst is palladium acetate.

[0054] The reaction is carried out in the presence of an inorganic base, which is one of cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate, potassium acetate, sodium acetate, sodium cyanate, potassium cyanate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. Most preferably, the inorganic base is dipotassium hydrogen phosphate.

[0055] The compound of formula 6 was hydrolyzed in an alkaline aqueous solution to obtain the compound of formula 5.

[0056]

[0057] Wherein, the definition of R1 is consistent with the definition in the above reaction; R7 is an alkyl or substituted alkyl; more preferably, R7 is a C1-C4 alkyl or substituted alkyl, and most preferably, R7 is an ethyl.

[0058] The alkaline aqueous solution may be one of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, diisopropylaminolithium, bis(trimethylsilylaminolithium), bis(trimethylsilylaminosodium), bis(trimethylsilylaminopotassium), lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, potassium trimethylsilanolate, sodium trimethylsilanolate, lithium trimethylsilanolate, magnesium methoxide, magnesium ethoxide, and magnesium tert-butoxide.

[0059] Compound of Formula 7 was alkylated with a methylating agent under alkaline additive conditions to yield compound of Formula 6. ,

[0060] The definitions of R1 and R7 are consistent with those in the above reaction.

[0061] The methylating agent may be one of iodomethane, trimethyl orthoformate, dimethyl sulfate, dimethyl carbonate, TMS diazomethane, or trimethyloxonium tetrafluoroboronic acid.

[0062] The alkaline additive may be one of cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate, potassium acetate, sodium acetate, sodium cyanate, potassium cyanate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.

[0063] The above reaction is carried out in the presence of an organic solvent, which is one of the following: tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, methyl cyclopentyl ether, dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, 1,3-dimethylimidazolinone, hexamethylphosphoramide, dimethyl sulfoxide, sulfolane, toluene, and xylene.

[0064] The reaction temperature is 25~120℃, preferably 50~90℃.

[0065] Compound of Formula 8 was condensed with a methanesulfonating agent under alkaline additive conditions to give compound of Formula 7.

[0066] ,

[0067] The definitions of R1 and R7 are consistent with those described in the above reaction. The methanesulfonating agent can be one of methanesulfonyl chloride or methanesulfonic anhydride.

[0068] The alkaline additive may be triethylamine, N,N-diisopropylethylamine (DIPEA), pyridine, 2,6-dimethylpyridine, 1,8-diazacyclo[5,4,0]-undec-7-ene (DBU), triethylenediamine (DABCO), N-methylmorpholine (NMM), 4-dimethylaminopyridine (DMAP), imidazole, N-methyltetrahydropyrrole, N-methylpiperidine, lithium diisopropylamino (LDA), lithium bis(trimethylsilylamino)amino (Li-HMDS), sodium bis(trimethylsilylamino)amino (Na-HMDS), potassium bis(trimethylsilylamino)amino (K-HMDS), lithium methoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, potassium trimethylsilanolate, sodium trimethylsilanolate, or lithium trimethylsilanolate. Preferably, it may be triethylamine or pyridine.

[0069] The reaction temperature is -25~50℃, preferably -5~20℃.

[0070] Compared with existing technologies, the starting materials and raw and auxiliary materials of this invention are widely available, inexpensive, chemically stable, and have high process safety. The compound of Formula 1 and its salt are solids with good properties, which are conducive to crystallization and purification in a variety of physicochemical environments, and have significant advantages in quality control during the process. At the same time, their physicochemical properties are very different from those of impurities, which is conducive to pulping or crystallization, and can avoid the use of column chromatography to perform purification processes, which is beneficial for large-scale industrial production.

[0071] This invention provides an intermediate compound for MK-8876 and its preparation method, which facilitates the efficient preparation of MK-8876 drug molecules. It offers advantages such as low cost, high process safety, controllable process quality, and suitability for large-scale industrial production, demonstrating significant potential in this field. Detailed Implementation

[0072] To further understand the present invention, a method for preparing the MK-8876 intermediate compound provided by the present invention will be described in detail below with reference to embodiments. It should be understood that these embodiments are described only to further illustrate the features of the present invention, and are not intended to limit the scope of the present invention or the scope of the claims.

[0073] Example 1: Preparation of compound of formula 8 (R1 is bromine atom, R7 is ethyl)

[0074] 50.00 g (278.9 mmol) of ethyl 4-aminophenylacetate was added to 250.0 mL of N,N-dimethylacetamide under nitrogen protection, and the internal temperature was lowered to 0 °C. 49.64 g (278.9 mmol) of N-bromosuccinimide was added in portions to the reaction mixture at 0 °C. After the addition was complete, the reaction mixture was slowly heated to 25 °C and stirred for 4 hours until the reaction was complete. A 5 wt% sodium sulfite aqueous solution (1000.0 mL) was added, and the reaction was quenched by stirring at 25 °C for 30 minutes. 500 mL of methyl tert-butyl ether was added to extract the product. The organic phase was then washed with 500 mL of saturated brine and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated to dryness to give 68.39 g of the target product, a pale yellow oil, with a yield of 95%. Characterization data for compound 8 (R1 is bromine, R7 is ethyl): 1 HNMR (400 MHz, DMSO-d6) δ: 7.27-7.21 (d, J = 1.96 Hz, 1H), 6.98-6.90 (dd, J =8.24, 1.96 Hz, 1H), 6.76-6.69 (d, J = 8.12 Hz, 1H), 5.28-5.15 (s, 1H), 4.13-3.98 (q, J = 7.04 Hz, 2H), 3.51-3.42 (s, 2H), 1.22-1.12 (t, J = 7.12 Hz). 13 CNMR (100 MHz, DMSO-d6) δ: 171.5, 144.5, 132.7, 129.3, 123.2, 115.2, 107.1, 60.1, 38.8, 14.1.

[0075] Example 2: Preparation of compound of formula 7 (R1 is bromine atom, R7 is ethyl)

[0076] 20.00 g (77.5 mmol) of compound 8 (R1 is bromine, R7 is ethyl) and 12.26 g (155.0 mmol) of pyridine were added to 200 mL of dichloromethane under nitrogen protection. The mixture was cooled to -5 °C, and 10.65 g (93.0 mmol) of methanesulfonyl chloride was added dropwise. After the addition was complete, the temperature was raised to 25 °C and the reaction was stirred for 2 hours. The mixture was concentrated, and 200.0 mL of ethyl acetate was added to dissolve the product. The organic phase was washed with 200.0 mL of saturated brine. The organic phase was collected in layers, dried over sodium sulfate, filtered, and the filtrate was concentrated and then slurried through n-heptane to give 22.67 g of the target product, an off-white solid, in 87% yield. Characterization data of compound 7 (R1 is bromine, R7 is ethyl): 1 H NMR (400 MHz, DMSO-d6) δ: 9.41-9.30 (s, 1H), 7.66-7.56 (s, 1H), 7.42-7.35 (d, J = 8.2 Hz, 1H), 7.32-7.25 (d, J = 7.28 Hz, 1H), 4.16-4.00 (q, J = 7.08 Hz, 2H), 3.77-3.65 (s, 2H), 3.11-2.96 (s, 3H), 1.26-1.12 (t, J = 7.08 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ: 170.8, 134.6, 134.0,133.9, 129.6, 128.0, 119.9, 60.5, 41.2, 14.1.

[0077] Example 3: Preparation of compound of formula 6 (R1 is bromine atom, R7 is ethyl)

[0078] 20.00 g (59.5 mmol) of compound 7 (R1 is bromine, R7 is ethyl), 16.44 g (119.0 mmol) of potassium carbonate, and 16.89 g (119.0 mmol) of iodomethane were added to 100 mL of N,N-dimethylformamide. The mixture was heated to 50 °C and stirred for 4 hours. After the reaction was completed, the reaction was quenched by adding 10 wt% citric acid aqueous solution. The product was extracted with 200 mL of methyl tert-butyl ether, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 18.96 g of the target product, a yellow slurry, with a yield of 91%. Characterization data of compound 6 (R1 is bromine, R7 is ethyl): 1HNMR (400 MHz, CDCl3) δ: 7.69-7.63 (d, J = 1.92 Hz, 1H), 7.57-7.51 (d, J =8.12 Hz, 1H), 7.37-7.31 (d, J = 8.20, 1.96 Hz, 1H), 4.17-4.03 (q, J = 7.04Hz, 2H), 3.78-3.67 (s, 2H), 3.19-3.09 (s, 3H), 1.25-1.16 (t, J = 7.08 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 170.6, 138.8, 136.7, 134.3, 130.1, 130.0,124.1, 60.5, 38.9, 38.2, 37.9, 14.1.

[0079] Example 4: Preparation of compound of formula 5 (R1 is a bromine atom)

[0080] 16.50 g (41.7 mmol) of compound 6 (R1 is bromine, R7 is ethyl) was added to a mixture of 150 mL tetrahydrofuran and 150 mL water, followed by the addition of 3.95 g (94.2 mmol) lithium hydroxide. The reaction mixture was heated to 25 °C and stirred for 6 hours. After the reaction was complete, 10 wt% citric acid aqueous solution was added to quench the reaction, and the pH was adjusted to 5.0-6.0. The product was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 12.76 g of the target product as a white solid, with a yield of 95%. Characterization data of compound 5 (R1 is bromine): 1 H NMR (400 MHz, CDCl3) δ: 12.67-12.40 (brs, 1H) 7.67-7.61 (d, J = 1.92 Hz, 1H), 7.56-7.48(d, J = 8.12 Hz, 1H), 7.37-7.29 (dd, J = 8.16, 1.96 Hz, 1H), 3.68-3.59 (s, 2H), 3.19-3.08 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ: 172.1, 138.7, 137.4,134.3, 130.1, 129.9, 124.0, 39.4, 38.2, 37.9.

[0081] Example 5: Preparation of compound of formula 4 (R1 is a bromine atom)

[0082] 5.80 g (18.0 mmol) of compound 5 (R1 being bromine), 4.70 g (27.0 mmol) of dipotassium hydrogen phosphate, 0.33 g (1.8 mmol) of 1,6-dihydro-α,α-dimethyl-6-oxo-2-pyridineacetic acid (CAS: 1785560-03-3), and 202.1 mg (0.9 mmol) of palladium acetate were added to 50 mL of acetonitrile under nitrogen protection. 7.14 g (63.0 mmol) of 30% hydrogen peroxide aqueous solution was added dropwise at room temperature. The reaction mixture was stirred at 35 °C for 12 hours until the reaction was complete. The pH was adjusted to 5.0-6.0 with 10 wt% citric acid aqueous solution, and 100 mL of isopropyl acetate was added to extract the product. The organic phase was washed with 50 mL of saturated brine and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated to dryness to give 5.05 g of the target product, an off-white solid, with a yield of 83%. Characterization data for compound of formula 4 (R1 is a bromine atom): 1 H NMR (400 MHz, DMSO-d6) δ: 7.37-7.33 (s, 1H), 7.00-6.95 (s, 1H), 3.63-3.54 (s, 2H), 3.24-3.16 (s, 3H), 3.09-3.02 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ: 176.3, 154.9, 139.2, 135.5, 123.8, 119.3, 113.2,39.9, 38.1, 35.7.

[0083] Example 6: Preparation of compound of formula 3 (R1 is bromine atom, R3 is methyl)

[0084] 5.00 g (14.8 mmol) of the compound shown in Formula 4 (R1 being a bromine atom) and 10.8 mg (0.148 mmol) of N,N-dimethylformamide were added to 60 mL of dichloromethane. After purging with nitrogen, the mixture was cooled to -10 °C. 3.76 g (29.6 mmol) of oxaloyl chloride was added dropwise to the reaction mixture at low temperature, and the mixture was stirred for 1 hour. Then, 5 mL of methanol was added dropwise to the reaction mixture, and the temperature was raised to 20 °C, with stirring continued for 2 hours. After the reaction was complete, the organic solvent was removed by concentration under reduced pressure. 50 mL of isopropyl acetate was added, followed by washing the organic phase with 80 mL of saturated brine. The organic phase was dried over sodium sulfate, the solid was removed by filtration, and the product was concentrated under reduced pressure to obtain 4.48 g of the target product as a yellow solid, with a yield of 86%. Characterization data of compound 3: 1H NMR (400 MHz, CDCl3) δ: 7.39–7.35 (s, 1H), 7.05–7.01 (s, 1H), 3.78–3.72 (s, 3H), 3.66–3.58 (s, 2H), 3.26–3.20 (s, 3H), 3.10–3.03 (3H). 13 C NMR (100 MHz, CDCl3) δ: 173.0, 155.3, 139.5, 135.3, 123.7, 120.0, 113.4, 52.9, 39.8, 38.1, 36.3.

[0085] Example 7: Preparation of compound of formula 2 (R1 is bromine atom, R3 is methyl)

[0086] 4.2 g (11.9 mmol) of compound 3 (R1 is bromine, R3 is methyl) and 3.08 g (23.8 mmol) of N,N-diisopropylethylamine were added to 40 mL of dichloroethane solvent, and the mixture was cooled to -10 °C. 2.07 g (13.1 mmol) of 4-fluorobenzoyl chloride was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was heated to 25 °C and stirred for 6 hours. After the conversion was complete, saturated brine was added and stirred for 30 minutes. The organic phase was collected separately, and the aqueous phase was extracted with 40 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, and the filtrate was collected and concentrated under reduced pressure to give 4.97 g of the target compound as a yellow oil, with a yield of 88%. Characterization data of compound 2 (R1 is bromine, R3 is methyl): 1H NMR (400 MHz, CDCl3) δ: 8.16-8.06 (dd,J = 8.64, 5.84 Hz, 2H), 7.63-7.56 (s, 1H), 7.40-7.33 (s, 1H), 7.18-7.08 (t, J= 8.52 Hz, 2H), 3.59-3.46 (s, 5H), 3.27-3.19 (s, 3H), 3.03-2.92 (s, 3H). 13 CNMR (100 MHz, CDCl3) δ: 170.1, 166.5 (d, J C-F = 254.6 Hz), 163.1, 148.7,139.6, 135.8, 133.0 (d, J C-F =9.5 Hz), 129.3, 126.3, 124.8 (d, J C-F =2.9 Hz), 120.8, 116.2 (d, J C-F =22.0 Hz), 52.4, 39.8, 38.2, 35.8. 19 F NMR (376 MHz, CDCl3): δ 103.1.

[0087] Example 8: Preparation of compound of formula 1 (R1 is a bromine atom)

[0088] 4.10 g (8.6 mmol) of compound 2 (R1 is bromine, R3 is methyl) was added to 40 mL of anhydrous tetrahydrofuran, followed by 1.38 g (17.2 mmol) of lithium tert-butoxide. After nitrogen purging, the mixture was stirred at 25 °C for 12 hours. After the reaction was complete, 20.0 mL of 10 wt% citric acid aqueous solution was added to the reaction solution, and the organic solvent was removed by vacuum concentration. The aqueous solution was slurryed for 30 min and then filtered under vacuum. The filter cake was washed with 20 mL of water. The wet product was dried in a vacuum drying oven at 50 °C for 12 hours to obtain 2.97 g of the target product as a white solid, with a yield of 78%. Characterization data of compound 1 (R1 is bromine): 1 H NMR(400 MHz, DMSO-d6) δ: 7.99-7.92 (s, 1H), 7.74-7.66 (dd, J = 8.64, 5.60 Hz, 2H), 7.41-7.37 (s, 1H), 7.37-7.27 (t, J = 8.92 Hz, 2H), 3.16 (s, 3H), 3.15 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 175.7, 167.3, 163.5 (d, J C-F =246.6 Hz),148.7, 135.8, 131.6 (d, J C-F = 8.92 Hz), 131.4, 128.9, 124.0, 118.0, 114.9 (d,J C-F =21.7 Hz), 110.7, 94.2, 38.2, 38.0. 19 F NMR (376 MHz, DMSO-d6): δ 109.6.

[0089] Example 9: Compound of Formula 10 (R1 is a bromine atom, R...) 11 Preparation of methyl

[0090] 1.20 g (2.71 mmol) of compound 1 (R1 being a bromine atom) was added to 20 mL of anhydrous methanol, followed by 2 mL of concentrated sulfuric acid. After purging with nitrogen, the mixture was heated to 80 °C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to 25 °C and added dropwise to a 5 wt% sodium bicarbonate aqueous solution. The mixture was concentrated under reduced pressure until a solid precipitated. The mixture was filtered under reduced pressure, the filter cake was washed with 10 mL of water, and dried under vacuum at 40 °C for 12 hours to obtain 0.93 g of the target product, an off-white solid, with a yield of 75%. The compound shown in Formula 10 (R1 being a bromine atom, R...) 11 Characterization data for (methyl group): 1 H NMR (400 MHz, DMSO-d6) δ: 8.32 (s, 1H), 8.19 (s, 1H), 8.18-8.11 (dd, J = 8.96, 5.48 Hz, 2H), 7.53-7.46 (t, J = 8.96 Hz, 2H), 3.95 (s, 3H), 3.28 (s, 3H), 3.27 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ:163.6 (d, J C-F =248.5Hz), 162.8, 161.3, 152.1, 137.3, 132.1(d, J C-F =8.9 Hz),127.9, 125.5, 124.7, 120.7, 115.6 (d, J C-F =21.9 Hz), 113.7, 107.7, 52.1,38.2, 38.1. 19F NMR (376 MHz, DMSO-d6): δ 108.4。

Claims

1. An intermediate compound of Formula 1 of MK-8876 and salts thereof, characterized by, The specific structural formula is as follows: ， wherein R1is a bromine atom; R2is or .

2. The compound and its salt according to claim 1, wherein the salt is an ammonium salt, an alkali metal salt, or an alkaline earth metal salt.

3. The compound and its salt according to claim 2, wherein the alkali metal salt is a lithium salt, sodium salt, or potassium salt.

4. The compound and its salt according to claim 1, characterized in that, Specific structural formulas include 1a or 1b: or , In this case, R1 is a bromine atom.

5. An intermediate compound of formula 2, characterized in that, The specific structural formula is as follows: ， In this context, R1 represents a bromine atom, and R3 represents an alkyl group.

6. An intermediate compound of formula 3, characterized in that, The specific structural formula is as follows: ， In this context, R1 represents a bromine atom, and R3 represents an alkyl group.

7. An intermediate compound of formula 4, characterized in that, The specific structural formula is as follows: ， In this case, R1 is a bromine atom.

8. A method for preparing an intermediate compound of formula 10, MK-8876, characterized in that, The following compounds of Formula 1 are subjected to transesterification and cyclization in the presence of alkyl alcohols via an acid catalyst to form benzofuran carboxylate compounds of Formula 10: ， wherein R1is a bromine atom; R 11 is an alkyl group; The compound of formula 1 shown is prepared by cyclization of the compound of formula 2 using an alkaline catalyst: ， Wherein, R1 is a bromine atom; R3 is an alkyl group; The compound of formula 2 is prepared in the following manner: Compound of Formula 8 was condensed with a methanesulfonating agent under alkaline additive conditions to give compound of Formula 7. ， And the compound of formula 7 was alkylated with a methylating agent under alkaline additive conditions to obtain the compound of formula 6. ， The compound of formula 6 was hydrolyzed in an alkaline aqueous solution to obtain the compound of formula 5. ， Compound of Formula 5 undergoes a carbon-hydrogen bond hydroxylation reaction under transition metal catalysis to yield compound of Formula 4. ， Compound of Formula 4 undergoes dehydration condensation with an alkyl alcohol under acid-catalyzed conditions to yield compound of Formula 3. ， Compound of Formula 3 was condensed with 4-fluorobenzoyl chloride in the presence of a base additive to give compound of Formula 2. ， Where R1 is a bromine atom; R3 is an alkyl group; and R7 is a C1-C4 alkyl group.

9. The preparation method according to claim 8, characterized in that, The alkaline catalyst is at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, diisopropylaminolithium, bis(trimethylsilylaminolithium), bis(trimethylsilylaminosodium), bis(trimethylsilylaminopotassium), lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, potassium trimethylsilanolate, sodium trimethylsilanolate, lithium trimethylsilanolate, magnesium methoxide, magnesium ethoxide, and magnesium tert-butoxide.

10. The preparation method according to claim 8, characterized in that, The transition metal catalysts are 1,1'-bis(diphenylphosphine)-ferrocene palladium dichloride, tetra(triphenylphosphine)palladium, palladium dichloride, bis(acetonitrile)-palladium chloride, palladium acetate, bis(dibenzylacetone)palladium, tri(dibenzylacetone)dipalladium, diacetylacetone palladium, bis(triphenylphosphine)-palladium chloride, allyl palladium(II) chloride dimer, methanesulfonic acid (2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonic acid (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'biphenyl)(2-amino-1,1'-biphenyl-3-yl)palladium(II), methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphineoxanthracene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II). Methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonic acid [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphino-2-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), Palladium(II) methanesulfonate (2-dicyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)methanesulfonate, Palladium(II) methanesulfonate (2-di-tert-butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)methanesulfonate, Palladium(II) methanesulfonate (4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene)(2'-methylamino-1,1'-biphenyl-2-yl)methanesulfonate, Palladium(II) methanesulfonate (tri-tert-butylphosphine)(2'-methylamino-1,1'-biphenyl-2-yl)methanesulfonate, One of the methanesulfonate 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II).

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