Intermediate for synthesizing dronedarone and preparation method thereof

Abstract

The invention relates to an intermediate of a chemical synthetic drug and a preparation method of the intermediate, in particular to an intermediate compound for preparing dronedarone and a preparation method of the intermediate compound. The intermediate is a new compound 2-n-valeryl-5-methanesulfonamide benzofuranone, and the compound can be applied to synthesis of a dronedarone drug through butt joint with 1-phenoxy-3-di-n-butylamine propane. The new intermediate is used for synthesizing dronedarone, raw materials and auxiliary materials are rich in source, low in price and easy to obtain, the process steps are short, the cost is low, the reaction conditions are mild and environmentally friendly, the target product preparation efficiency is high, no reaction device with special requirements exists, and the industrial production requirement can be met.

Description

Technical Field

[0001] This invention relates to a novel compound intermediate structure for the synthesis of dronedarone and its preparation method, belonging to the field of inventions of new drug synthesis routes and their industrial production applications. Background Technology

[0002] Atrial fibrillation (AF) is the most common sustained arrhythmia, significantly increasing the risk of heart failure, cognitive impairment, and dementia, and is also an independent risk factor for stroke. Dronedarone hydrochloride, developed by Sanofi-Aventis and first marketed in the United States in 2009, is an antiarrhythmic drug, as shown in structural formula 11. It is primarily used to control heart rate, maintain sinus rhythm, and slow ventricular rhythm in patients with atrial fibrillation and atrial flutter. Compared to the earlier classic drug amiodarone, although both have similar physiological effects, dronedarone's lack of iodine atoms significantly reduces its lipophilicity, thus minimizing its effects on the thyroid gland and thyroid hormones. It also shows improvements in cardiotoxicity and extracardiac adverse reactions. (Kuzniatsova N., Pamukcu B., Lip GYH, Therapy, 2011, 8 (6), 681-689;Patel PB, Patel KC, Mehta HR, Int. Res. J. Pharm,2011, 2 (3), 59-65; Patel PD, Bhuriya R., Patel DD, Arora BL, Singh PP, Arora RR, Vasc. Health Risk Manage, 2009, 5 , 635-642; Dobromir D., Stanley N., Lancet, 2010, 375 , 1212-1223; Singh BN, CapucciA., Radzik D., Hohnloser SN, Engl. J. Med., 2007, 357 (987-999) .

[0003] Due to the growing interest in this class of drugs, several routes have been developed and applied to the preparation of dronedarone or its intermediates. One such route involves the condensation of p-methanesulfonamide benzoquinone (Structural Formula 12) and 3-oxyheptanoate (Structural Formula 13) to obtain a phenolic hydroxyl intermediate (Structural Formula 14), which then requires intramolecular dehydration condensation to form a benzofuran core structure (Structural Formula 15). (CN 102153531) In this route, compound 12 is not commercially available, and its preparation requires the highly toxic and irritating odor of p-benzoquinone, making it unsuitable for large-scale industrial production. In addition, researchers have developed other routes that avoid the use of 2-butyl-5-nitrobenzofuran intermediates, but these routes all suffer from problems such as excessively long routes and uncontrollable costs (CN01101296.X, CN200480038285.2, CN200910006741.X, WO2009044143, WO2010038029). .

[0004] The preparation was completed using 2-butyl-5-nitrobenzofuran (structural formula 16) as an intermediate (US5223510, WO2002048078, W2003040120, FR28777341, CN200610113471.7). Currently, there is a lack of stable, industrially available supplies of 2-butyl-5-nitrobenzofuran, and it is expensive. The preparation of the compound with structural formula 16 requires 5-6 reaction steps. Therefore, this route suffers from lengthy steps and high costs. Furthermore, the scale-up preparation of nitro compounds also poses a safety risk of explosion, and the reduction of nitro compounds requires a high-pressure hydrogenation unit, placing high demands on the equipment. .

[0005] The route for preparing 5-nitro-2-butyl-3-benzofuranic acid (Structure 20) from p-nitrophenol (Structure 17) via iodination (Structure 18) – palladium-catalyzed alkynylation (Structure 19) – ring closure and carbon dioxide insertion also carries the risk of the nitro compound being explosive (Bull. Korean Chem. Soc. 2014, Vol. 35, No. 7). Five out of the nine steps in this route involve nitro compound intermediates. Furthermore, due to issues such as carbon dioxide gas insertion and catalytic hydrogenation reduction of the nitro group, it still requires high-strength pressurized equipment. .

[0006] Similarly, the iodination (Structure 18) and propargyl etherification (Structure 21) of p-nitrophenol (Structure 17) also carries the risk of scale-up due to the explosive nature of nitro compounds. Subsequent preparation of the diboron-based intermediate (Structure 22) using a gold catalyst in a photocatalytic system is costly and lacks atom economy. Furthermore, the industrial application of photocatalysis systems currently faces significant limitations. . Summary of the Invention

[0007] In the industrial production of dronedarone, there is still much room for improvement in the current technology. It is essential to design and develop a safe, practical, inexpensive and readily available raw and excipient-efficient, cost-effective, and environmentally friendly synthesis process.

[0008] One objective of this invention is to provide a benzofuranone compound and its salt, chemically named 2-n-pentanoyl-5-methanesulfonamidobenzofuranone, which is an intermediate that can be used in the synthesis of dronedarone, and has the following structural formula: .

[0009] Another object of the present invention is to provide a compound of formula A2 having the chemical structure shown in structural formula A2-1 / A2-2, which can be used to prepare a benzofuranone compound by methanesulfonation via a coupling reaction: ,

[0010] Wherein X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group, or borate ester group; more preferably, X is a halogen; most preferably, X is a bromine atom.

[0011] Another object of the present invention is to provide a compound of formula A3 having the chemical structure shown in formula A3, which can be used to prepare a benzofuranone compound by a dehydration condensation-lactoneation reaction: ,

[0012] Where R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different components may be hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; ynyl, substituted ynyl; aryl, substituted aryl; alkoxy, alkylthio, alkylamino. More preferably, R 1 R 2 R 3The same or different ones are hydrogen or alkyl; most preferably, R is methyl or ethyl.

[0013] The present invention also provides a compound of formula A4, which has the chemical structure shown in formula A4, and can be used to prepare a benzofuranone compound by a dehydration condensation-lactoneation reaction.

[0014] ,

[0015] Where R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different components may be hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; ynyl, substituted ynyl; aryl, substituted aryl; alkoxy, alkylthio, alkylamino. More preferably, R 1 R 2 R 3 The same or different ones are hydrogen or alkyl; most preferably, R is methyl or ethyl.

[0016] This invention also provides a novel synthetic route for the preparation of dronedarone, characterized by comprising the following steps:

[0017] Step 1-1: Compound A9 is prepared from compound A10 via a coupling reaction in the presence of an inorganic base, a transition metal catalyst, and an acidic aqueous solution. ,

[0018] Wherein, X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group or borate ester group.

[0019] Steps 1-2: Compound A7 is prepared by selective esterification of compound A9 under acid catalyst and alcohol additive conditions. ,

[0020] Wherein, X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group or borate ester group; R is a CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio or alkylamino.

[0021] Steps 1-3: Compound A5 is prepared by condensation esterification reaction of compound A7 and n-valeryl chloride under organic base conditions. ,

[0022] Wherein, X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group or borate ester group; R is a CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio or alkylamino.

[0023] Steps 1-4: Benzofuranone compounds of formula A2-1 / A2-2 are prepared from compound A5 by dehydration condensation-lactoneation reaction in the presence of a base catalyst. ,

[0024] Wherein, X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group or borate ester group; R is a CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio or alkylamino.

[0025] Steps 1-5: Benzofuranone compounds were prepared from compounds of formula A2-1 / A2-2 via a coupling reaction in the presence of a transition metal catalyst and ligands. ,

[0026] Wherein, X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group or borate ester group.

[0027] Steps 1-6: Compound A1 is added to an organic solvent, followed by the addition of 1-phenoxy-3-di-n-butylaminopropane and an acid catalyst, and then reacted to prepare dronedarone A11. ,

[0028] More preferably, X is a halogen; most preferably, X is a bromine atom.

[0029] More preferably, R 1 R 2 R 3 The same or different ones are hydrogen or alkyl; most preferably, R is methyl or ethyl.

[0030] The organic solvent is at least 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.

[0031] In step 1-1, the inorganic base is at least one selected from 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. More preferably, the inorganic base is dipotassium hydrogen phosphate.

[0032] In step 1-1, the transition metal catalyst is at least one of Pd(dppf)Cl2, tetrakis(triphenylphosphine)palladium, palladium dichloride, bis(acetonitrile)palladium chloride, palladium acetate, bis(dibenzylacetone)palladium, tri(dibenzylacetone)dipalladium, diacetylacetonepalladium, bis(triphenylphosphine)palladium chloride, allylpalladium(II) chloride dimer, Ruphos Pd G3, SPhos Pd G3, XantPhosPd G3, t-BuXPhos Pd G3, APhos Pd G3, RuPhos Pd G4, XPhos Pd G4, BrettPhos Pd G4, t-BuXPhos Pd G4, XantPhos Pd G4, P(t-Bu)3 Pd G4, and DavePhos Pd G4. More preferably, the transition metal catalyst is palladium acetate.

[0033] In step 1-1, the reaction temperature can be one of 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, or 70℃.

[0034] In step 1-1, the acidic aqueous solution may be an aqueous solution prepared from at least one of the following: citric acid, citric acid monohydrate, tartaric acid, citric acid, fumaric acid, glacial acetic acid, oxalic acid, malonic acid, succinic acid, lactic acid, ammonium chloride, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, sodium bisulfate, potassium bisulfate, sodium bisulfite, potassium bisulfite, potassium dihydrogen phosphate, and sodium dihydrogen phosphate.

[0035] In steps 1-2, the acid catalyst is at least one of 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.

[0036] In steps 1-2, the equivalent of the acid catalyst can be one of 0.5 equivalent, 1.0 equivalent, 1.5 equivalent, 2.0 equivalent, 2.5 equivalent, 3.0 equivalent, 3.5 equivalent, 4.0 equivalent, 5.0 equivalent, 10.0 equivalent, 15.0 equivalent, or 20.0 equivalent.

[0037] In steps 1-2, the organic solvent is at least one of toluene, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, n-hexane, and n-heptane.

[0038] In steps 1-2, the alcohol additive is at least 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.

[0039] In steps 1-2, the equivalent amount of the alcohol additive can be one of 0.8 equivalents, 1.0 equivalents, 1.2 equivalents, 1.5 equivalents, 2.0 equivalents, 2.5 equivalents, 3.0 equivalents, 4.0 equivalents, 5.0 equivalents, 10.0 equivalents, 20.0 equivalents, and 50.0 equivalents.

[0040] In steps 1-2, the reaction temperature can be one of -10℃, 5℃, 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, or 75℃.

[0041] In steps 1-3, the organic base is at least one of 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, and lithium trimethylsilanolate.

[0042] In steps 1-3, the equivalent of the organic base can be one of 0.5 equivalent, 1.0 equivalent, 1.5 equivalent, 2.0 equivalent, 2.5 equivalent, 3.0 equivalent, 4.0 equivalent, 5.0 equivalent, 6.0 equivalent, 7.0 equivalent, 8.0 equivalent, 9.0 equivalent, and 10.0 equivalent.

[0043] In steps 1-3, the equivalent of n-valeryl chloride can be one of 0.5 equivalent, 0.6 equivalent, 0.7 equivalent, 0.8 equivalent, 0.9 equivalent, 1.0 equivalent, 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent, 1.5 equivalent, 2.0 equivalent, 2.5 equivalent, 3.0 equivalent, 3.5 equivalent, 4.0 equivalent, 4.5 equivalent, and 5.0 equivalent.

[0044] In steps 1-3, the reaction temperature can be one of -10℃, 5℃, 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, or 40℃.

[0045] In steps 1-4, 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.

[0046] In steps 1-4, the equivalent amount of the alkaline catalyst additive can be one of 0.5 equivalent, 0.6 equivalent, 0.7 equivalent, 0.8 equivalent, 0.9 equivalent, 1.0 equivalent, 1.2 equivalent, 1.5 equivalent, 2.0 equivalent, 2.5 equivalent, 3.0 equivalent, 3.5 equivalent, and 4.0 equivalent.

[0047] In steps 1-4 and 2-6, the amount of water added during the reaction is one of the following: 1.0 V, 2.0 V, 3.0 V, 4.0 V, 5.0 V, 6.0 V, 7.0 V, 8.0 V, 9.0 V, 10.0 V, 11.0 V, 12.0 V, 13.0 V, 14.0 V, 15.0 V, 16.0 V, 17.0 V, 18.0 V, 19.0 V, and 20.0 V.

[0048] In steps 1-5, the transition metal catalyst is at least one of copper acetate, copper trifluoroacetate, basic copper carbonate, copper trifluoromethanesulfonate, copper tetraacetonitrile hexafluorophosphate, cuprous bromide, cuprous iodide, cuprous chloride, cuprous oxide, copper bromide, copper chloride, copper sulfate, copper nitrate, copper phosphate, copper acetylacetonate, and cuprous thiocyanate.

[0049] In steps 1-5, the equivalent of the transition metal catalyst is 0.2 mol%, 0.4 mol%, 0.6 mol%, 0.8 mol%, 1.0 mol%, 1.2 mol%, 1.5 mol%, 2.0 mol%, 2.5 mol%, 3.0 mol%, 3.5 mol%, 4.0 mol%, 4.5 mol%, 5.0 mol%, 5.5 mol%, 6.0 mol%, 6.5 mol%, 7.0 mol%, 7.5 mol%, 8.0 mol%, 8.5 mol%, 9.0 mol%, 9.5 mol%, 10.0 mol%, 11.0 mol%, 12.0 mol%, 13.0 mol%, 14.0 mol%, 15.0 mol%, 16.0 mol%, 17.0 mol%, 18.0 mol%, 19.0 mol%, 20.0 mol%, 25.0 mol%, 30.0 mol%, 35.0 mol%. One of the following: mol%, 40.0 mol%, 45.0 mol%, 50.0 mol%, 55.0 mol%, 60.0 mol%, 65.0 mol%, 70.0 mol%, 75.0 mol%, 80.0 mol%, 85.0 mol%, 90.0 mol%, 95.0 mol%, 1.0 equivalent, 1.5 equivalent, 2.0 equivalent, 2.5 equivalent, 3.0 equivalent.

[0050] In steps 1-5, the ligand is N1,N2-bis(4-methoxybenzyl)oxalyldiamine, N1,N2-bis(4-trifluoromethylbenzyl)oxalyldiamine, N1-(2-methyl-1-naphthyl)-N2-(2-pyrazinylmethyl)oxalyldiamine, N1-(2,6-dimethylphenyl)-N2-(2-pyridinemethyl)oxalyldiamine, N1-(2,6-dimethylphenyl)-N2-(2-phenylmethyl)oxalyldiamine, or N-(2,6-dimethylphenyl) At least one of -1,6-dihydro-6-oxo-2-pyridinecarboxamide, N-(2,6-dimethylphenyl)-2-pyridinecarboxamide, N-(2,6-dimethylphenyl)-5-hydroxy-2-pyridinecarboxamide, N-(2,6-dimethylphenyl)-4-hydroxy-2-pyridinecarboxamide, 4-hydroxy-N-(2-methyl-1-naphthyl)-2-pyridinecarboxamide, and 1,6-dihydro-N-(2-methyl-1-naphthyl)-6-oxo-2-pyridinecarboxamide.

[0051] In steps 1-5, the equivalent amounts of the ligands are 0.4 mol%, 0.8 mol%, 1.2 mol%, 1.6 mol%, 2.0 mol%, 2.4 mol%, 3.0 mol%, 4.0 mol%, 5.0 mol%, 6.0 mol%, 7.0 mol%, 8.0 mol%, 9.0 mol%, 10.0 mol%, 11.0 mol%, 12.0 mol%, 13.0 mol%, 14.0 mol%, 15.0 mol%, 16.0 mol%, 17.0 mol%, 18.0 mol%, 19.0 mol%, 20.0 mol%, 22.0 mol%, 24.0 mol%, 26.0 mol%, 28.0 mol%, 30.0 mol%, 32.0 mol%, 34.0 mol%, 36.0 mol%, 38.0 mol%, 40.0 mol%, and 50.0 mol%. One of the following: mol%, 60.0 mol%, 70.0 mol%, 80.0 mol%, 90.0 mol%, 1.0 equivalent, 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent, 1.5 equivalent, 1.6 equivalent, 1.7 equivalent, 1.8 equivalent, 1.9 equivalent, 2.0 equivalent, 3.0 equivalent, 4.0 equivalent, 5.0 equivalent, and 6.0 equivalent.

[0052] In steps 1-5, the inorganic base is at least one selected from 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. More preferably, the inorganic base is dipotassium hydrogen phosphate.

[0053] In steps 1-5, the equivalent of the inorganic base is one of 1.0 equivalent, 1.5 equivalent, 2.0 equivalent, 2.5 equivalent, 3.0 equivalent, 3.5 equivalent, 4.0 equivalent, 4.5 equivalent, 5.0 equivalent, 5.5 equivalent, 6.0 equivalent, 6.5 equivalent, 7.0 equivalent, 7.5 equivalent, and 8.0 equivalent.

[0054] In steps 1-5, the reaction temperature can be one of 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, or 120℃.

[0055] In steps 1-6, the acid catalyst is at least one of 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, 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.

[0056] In steps 1-6, the equivalent of the acid catalyst can be one of the following: 0.5 equivalent, 1.0 equivalent, 1.5 equivalent, 2.0 equivalent, 2.5 equivalent, 3.0 equivalent, 3.5 equivalent, 4.0 equivalent, 4.5 equivalent, 5.0 equivalent, 5.5 equivalent, 6.0 equivalent, 6.5 equivalent, 7.0 equivalent, 7.5 equivalent, 8.0 equivalent, 8.5 equivalent, 9.0 equivalent, 9.5 equivalent, and 10.0 equivalent.

[0057] In steps 1-6, the reaction temperature can be one of the following: -20℃, -15℃, -10℃, -5℃, 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, and 120℃.

[0058] Based on the compound of structural formula 1, this invention provides another novel synthetic route for the preparation of dronedarone, characterized by comprising the following steps:

[0059] Step 2-1: Compound A8 is prepared from compound A9 via a coupling reaction under the conditions of an organic solvent, a transition metal catalyst, a ligand, and an inorganic base. ,

[0060] X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group, or borate ester group.

[0061] Step 2-2: Compound A6 is prepared from compound A8 by selective esterification in the presence of an organic solvent, an alcohol, and an acid catalyst. ,

[0062] R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio or alkylamino.

[0063] Steps 2-3: Compound A3 is prepared by condensation reaction of compound A6 in the presence of n-valeryl chloride, an organic solvent, and an organic base. ,

[0064] R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio or alkylamino.

[0065] Steps 2-4: Compound A4 is prepared by condensation reaction of compound A6 in the presence of n-valeryl chloride, an organic solvent, and an organic base. ,

[0066] R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio or alkylamino.

[0067] Steps 2-5: Benzofuranone products of formula A1-1 / A1-2 are prepared from compound A3 via dehydration condensation-lactoneation reaction in the presence of an organic solvent and a base catalyst. ,

[0068] R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio or alkylamino.

[0069] Steps 2-6: Benzofuranone products of formula A1-1 / A1-2 were prepared from compound A4 via dehydration condensation-lactoneation reaction in the presence of an organic solvent and a base catalyst. ,

[0070] R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio or alkylamino.

[0071] More preferably, X is a halogen; most preferably, X is a bromine atom. More preferably, R 1 R 2 R 3 The same or different ones are hydrogen or alkyl; most preferably, R is methyl or ethyl.

[0072] Finally, the dronedarone A11 compound was prepared from formula A1-1 / A1-2 via steps 1-6 described above.

[0073] The organic solvent is at least 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.

[0074] In step 2-1, the transition metal catalyst is at least one of copper acetate, copper trifluoroacetate, basic copper carbonate, copper trifluoromethanesulfonate, copper tetraacetonitrile hexafluorophosphate, cuprous bromide, cuprous iodide, cuprous chloride, cuprous oxide, copper bromide, copper chloride, copper sulfate, copper nitrate, copper phosphate, copper acetylacetonate, and cuprous thiocyanate.

[0075] In step 2-1, the equivalent of the transition metal catalyst is 0.2 mol%, 0.4 mol%, 0.6 mol%, 0.8 mol%, 1.0 mol%, 1.2 mol%, 1.5 mol%, 2.0 mol%, 2.5 mol%, 3.0 mol%, 3.5 mol%, 4.0 mol%, 4.5 mol%, 5.0 mol%, 5.5 mol%, 6.0 mol%, 6.5 mol%, 7.0 mol%, 7.5 mol%, 8.0 mol%, 8.5 mol%, 9.0 mol%, 9.5 mol%, 10.0 mol%, 11.0 mol%, 12.0 mol%, 13.0 mol%, 14.0 mol%, 15.0 mol%, 16.0 mol%, 17.0 mol%, 18.0 mol%, 19.0 mol%, 20.0 mol%, 25.0 mol%, 30.0 mol%, 35.0 mol%. One of the following: mol%, 40.0 mol%, 45.0 mol%, 50.0 mol%, 55.0 mol%, 60.0 mol%, 65.0 mol%, 70.0 mol%, 75.0 mol%, 80.0 mol%, 85.0 mol%, 90.0 mol%, 95.0 mol%, 1.0 equivalent, 1.5 equivalent, 2.0 equivalent, 2.5 equivalent, 3.0 equivalent.

[0076] In step 2-1, the ligand is N1,N2-bis(4-methoxybenzyl)oxalyldiamine, N1,N2-bis(4-trifluoromethylbenzyl)oxalyldiamine, N1-(2-methyl-1-naphthyl)-N2-(2-pyrazinylmethyl)oxalyldiamine, N1-(2,6-dimethylphenyl)-N2-(2-pyridinemethyl)oxalyldiamine, N1-(2,6-dimethylphenyl)-N2-(2-benzylmethyl)oxalyldiamine, or N-(2,6-dimethylphenyl) At least one of -1,6-dihydro-6-oxo-2-pyridinecarboxamide, N-(2,6-dimethylphenyl)-2-pyridinecarboxamide, N-(2,6-dimethylphenyl)-5-hydroxy-2-pyridinecarboxamide, N-(2,6-dimethylphenyl)-4-hydroxy-2-pyridinecarboxamide, 4-hydroxy-N-(2-methyl-1-naphthyl)-2-pyridinecarboxamide, and 1,6-dihydro-N-(2-methyl-1-naphthyl)-6-oxo-2-pyridinecarboxamide.

[0077] In step 2-1, the equivalent amounts of the ligands are 0.4 mol%, 0.8 mol%, 1.2 mol%, 1.6 mol%, 2.0 mol%, 2.4 mol%, 3.0 mol%, 4.0 mol%, 5.0 mol%, 6.0 mol%, 7.0 mol%, 8.0 mol%, 9.0 mol%, 10.0 mol%, 11.0 mol%, 12.0 mol%, 13.0 mol%, 14.0 mol%, 15.0 mol%, 16.0 mol%, 17.0 mol%, 18.0 mol%, 19.0 mol%, 20.0 mol%, 22.0 mol%, 24.0 mol%, 26.0 mol%, 28.0 mol%, 30.0 mol%, 32.0 mol%, 34.0 mol%, 36.0 mol%, 38.0 mol%, 40.0 mol%, and 50.0 mol%. One of the following: mol%, 60.0 mol%, 70.0 mol%, 80.0 mol%, 90.0 mol%, 1.0 equivalent, 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent, 1.5 equivalent, 1.6 equivalent, 1.7 equivalent, 1.8 equivalent, 1.9 equivalent, 2.0 equivalent, 3.0 equivalent, 4.0 equivalent, 5.0 equivalent, and 6.0 equivalent.

[0078] In step 2-1, the inorganic base is at least one selected from 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. More preferably, the inorganic base is dipotassium hydrogen phosphate.

[0079] In step 2-1, the equivalent of the inorganic base is one of 1.0 equivalent, 1.5 equivalent, 2.0 equivalent, 2.5 equivalent, 3.0 equivalent, 3.5 equivalent, 4.0 equivalent, 4.5 equivalent, 5.0 equivalent, 5.5 equivalent, 6.0 equivalent, 6.5 equivalent, 7.0 equivalent, 7.5 equivalent, and 8.0 equivalent.

[0080] In step 2-1, the reaction temperature can be one of 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, or 120℃.

[0081] In step 2-2, the acid catalyst is at least one of 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.

[0082] In step 2-2, the equivalent of the acid catalyst can be one of 0.5 equivalent, 1.0 equivalent, 1.5 equivalent, 2.0 equivalent, 2.5 equivalent, 3.0 equivalent, 3.5 equivalent, 4.0 equivalent, 5.0 equivalent, 10.0 equivalent, 15.0 equivalent, or 20.0 equivalent.

[0083] In step 2-2, the organic solvent is at least one of toluene, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, n-hexane, and n-heptane.

[0084] In step 2-2, the alcohol additive is at least 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.

[0085] In step 2-2, the equivalent amount of the alcohol additive can be one of 0.8 equivalents, 1.0 equivalents, 1.2 equivalents, 1.5 equivalents, 2.0 equivalents, 2.5 equivalents, 3.0 equivalents, 4.0 equivalents, 5.0 equivalents, 10.0 equivalents, 20.0 equivalents, and 50.0 equivalents.

[0086] In step 2-2, the reaction temperature can be one of -10℃, 5℃, 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, or 75℃.

[0087] In steps 2-3 and 2-4, the organic base is at least one of triethylamine, N,N-diisopropylethylamine (DIPEA), pyridine, 2,6-dimethylpyridine, 1,8-diazacyclic[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, and lithium trimethylsilanolate.

[0088] In steps 2-3 and 2-4, the equivalent of the organic base can be one of 0.5 equivalent, 1.0 equivalent, 1.5 equivalent, 2.0 equivalent, 2.5 equivalent, 3.0 equivalent, 4.0 equivalent, 5.0 equivalent, 6.0 equivalent, 7.0 equivalent, 8.0 equivalent, 9.0 equivalent, and 10.0 equivalent.

[0089] In steps 2-3 and 2-4, the reaction temperature can be one of -10℃, 5℃, 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, or 40℃.

[0090] In steps 2-3, the equivalent of n-valeryl chloride can be one of 0.5 equivalent, 0.6 equivalent, 0.7 equivalent, 0.8 equivalent, 0.9 equivalent, 1.0 equivalent, 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent, or 1.5 equivalent.

[0091] In steps 2-4, the equivalent of n-valeryl chloride can be one of 2.0 equivalent, 2.2 equivalent, 2.4 equivalent, 2.6 equivalent, 2.8 equivalent, 3.0 equivalent, 3.2 equivalent, 3.4 equivalent, 3.6 equivalent, 3.8 equivalent, 4.0 equivalent, 4.2 equivalent, 4.4 equivalent, 4.6 equivalent, 4.8 equivalent, and 5.0 equivalent.

[0092] In steps 2-5 and 2-6, 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.

[0093] In steps 2-5 and 2-6, the equivalent amount of the alkaline catalyst additive is 0.5 equivalent, 0.6 equivalent, 0.7 equivalent, 0.8 equivalent, 0.9 equivalent, 1.0 equivalent, 1.2 equivalent, 1.5 equivalent, 2.0 equivalent, 2.5 equivalent, 3.0 equivalent, 3.5 equivalent, or 4.0 equivalent.

[0094] In steps 2-5 and 2-6, the amount of water added during the reaction is one of the following: 1.0 V, 2.0 V, 3.0 V, 4.0 V, 5.0 V, 6.0 V, 7.0 V, 8.0 V, 9.0 V, 10.0 V, 11.0 V, 12.0 V, 13.0 V, 14.0 V, 15.0 V, 16.0 V, 17.0 V, 18.0 V, 19.0 V, or 20.0 V.

[0095] The 2-n-pentanoyl-5-methanesulfonamide benzofuranone and its preparation method provided by this invention can efficiently prepare dronedarone. Compared with the prior art, the starting materials and raw and auxiliary materials used in each step of this invention are widely available and inexpensive; the raw and auxiliary materials used in each step are chemically stable, and the process safety is high; the 2-n-pentanoyl-5-methanesulfonamide benzofuranone and its salts provided by this invention are solids with good properties, which are conducive to crystallization and purification in various physicochemical environments, and have advantages in quality control during the process; the 2-n-pentanoyl-5-methanesulfonamide benzofuranone and its salts provided by this invention are solids with good properties, and their physicochemical properties are very different from those of impurities, which is conducive to pulping or crystallization. Therefore, column chromatography can be avoided in the process route, which is conducive to the industrialization of the process. Attached Figure Description

[0096] Figure 1It is the [M+H] of 2-n-pentanoyl-5-methanesulfonamide benzofuranone (compound of formula A1) in Examples 7, 15 and 16 of this invention. + Mass spectrometry information.

[0097] Figure 2 [MH] refers to 2-n-pentanoyl-5-methanesulfonamide benzofuranone (compound of formula A1) in Examples 7, 15, and 16 of this invention. - Mass spectrometry information. Detailed Implementation

[0098] To further understand the present invention, the following detailed description, in conjunction with embodiments, provides an intermediate for the synthesis of dronedarone and a method for its preparation. It should be understood that these embodiments are merely for further detailing the features of the present invention and are not intended to limit the scope of the invention or the scope of the claims.

[0099] Example 1: Preparation of compound with structural formula A9 (X is a bromine atom) 2.15 g (10.0 mmol) of 3-bromophenylacetic acid, 2.62 g (15.0 mmol) of dipotassium hydrogen phosphate, 36.2 mg (0.2 mmol) of 1,6-dihydro-α,α-dimethyl-6-oxo-2-pyridineacetic acid, and 22.5 mg (0.1 mmol) of palladium acetate were added to 30 mL of acetonitrile. Under nitrogen protection, 4.02 g (35.0 mmol) of 30% hydrogen peroxide aqueous solution was added dropwise at room temperature. The reaction solution was stirred at 35 °C for 12 hours until the reaction was complete. The pH was adjusted to 5.0-6.0 with 10% citric acid aqueous solution, and 30 mL of isopropyl acetate was added to extract the product. The organic phase was washed with 30 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 obtain 2.01 g of the target product, a pale yellow solid, with a yield of 87%.

[0100] Characterization data for compound A9 (where X is a bromine atom): 1 H NMR (400 MHz, DMSO-d6) δ:12.19 (brs, 1H), 9.78 (brs, 1H), 731-7.26 (d, J = 2.60 Hz, 1H), 7.25-7.18(dd, J = 8.60, 2.40 Hz, 1H), 6.79-6.70 (d, J = 8.60 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ: 172.3, 154.9, 133.5, 130.4, 124.7, 116.8, 109.6, 34.9.

[0101] Example 2: Preparation of compound with structural formula A7 (X is bromine atom, R is methyl group) 2.01 g (8.7 mmol) of compound A9 (X being bromine) was added to 30 mL of methanol under nitrogen protection. The mixture was cooled to -5 °C, and 4.72 g (43.5 mmol) of trimethylchlorosilane 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 30 mL of ethyl acetate was added to dissolve the product. The organic phase was washed with 20 mL of saturated brine. The organic phase was collected after separation, dried over sodium sulfate, filtered, and the filtrate was concentrated and then slurried through n-heptane to give 1.81 g of the target product, a pale yellow solid, in 85% yield.

[0102] Characterization data for compound A7 (X is bromine, R is methyl): 1 H NMR (400 MHz, DMSO-d6)δ: 9.88-9.80 (s, 1H), 7.34-7.28 (d, J = 2.52 Hz, 1H), 7.26-7.20 (dd, J =8.52, 2.48 Hz, 1H), 6.78-6.72 (d, J = 8.56 Hz, 1H), 3.64-3.57 (s, 3H), 3.58-3.53 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ: 171.3, 154.9, 133.4, 130.6, 124.0,116.8, 109.6, 51.6, 34.6.

[0103] Example 3: Preparation of compound with structural formula A7 (X is bromine atom, R is ethyl) 3.50 g (15.1 mmol) of compound A9 (X being bromine) was added to 30 mL of ethanol under nitrogen protection. The mixture was cooled to -5 °C, and 2.21 g (17.4 mmol) of oxaloyl 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 30 mL of ethyl acetate was added to dissolve the product. The organic phase was washed with 20 mL of saturated brine. The organic phase was collected as separates, dried over sodium sulfate, filtered, and the filtrate was concentrated to give 3.72 g of the target product, a pale yellow oil, with a yield of 95%.

[0104] Characterization data for compound A7 (X is bromine, R is ethyl): 1H NMR (400 MHz, CDCl3) δ:7.29-7.24 (dd, J = 8.52, 2.48 Hz, 1H), 7.23-7.20 (d, J = 2.48 Hz, 1H), 6.83-6.77 (d, J = 8.52 Hz, 1H), 4.25-4.16 (q, J = 7.12 Hz, 2H), 3.65-3.60 (s, 2H), 1.35-1.26 (t, J = 7.12 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 173.7, 154.6, 133.4, 131.9, 122.8, 119.4, 112.6, 62.2, 37.7, 14.0.

[0105] Example 4: Preparation of compound with structural formula A5 (X is bromine atom, R is methyl group) 10.00 g (40.8 mmol) of compound A7 (X is bromine, R is methyl) was added to 100 mL of dichloromethane, followed by 10.61 g (81.6 mmol) of N,N-diisopropylethylamine. The mixture was cooled to -5 °C, and 5.90 g (49.0 mmol) of n-valeryl chloride was slowly added dropwise. The reaction mixture was heated to 5 °C and stirred for 4 hours. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 12.36 g of the target product, a yellow oil, with a yield of 92%.

[0106] Characterization data for compound A5 (where X is a bromine atom and R is a methyl group): 1 H NMR (400 MHz, CDCl3) δ:7.47-7.44 (d, J = 2.36 Hz, 1H), 7.44-7.38 (dd, J = 8.56, 2.44 Hz, 1H), 7.02-6.95 (d, J = 8.52 Hz, 1H), 3.73-3.61 (s, 3H), 3.56-3.47 (s, 2H), 2.62-2.50(t, J = 7.56 Hz, 2H), 1.78-1.66 (tt, J = 7.56, 7.4 Hz, 2H), 1.50-1.38 (tq, J= 7.52, 7.44 Hz, 2H), 1.01-0.93 (t, J = 7.32 Hz, 3H). 13C NMR (100 MHz, CDCl3)δ: 171.6, 170.5, 148.3, 134.1, 131.5, 128.7, 124.3, 118.9, 52.3, 35.9, 33.8,26.8, 22.3, 13.7.

[0107] Example 5: Preparation of compound with structural formula A5 (X is bromine atom, R is ethyl) 8.00 g (30.8 mmol) of compound A7 (X is bromine, R is ethyl) was added to 90 mL of dichloromethane, followed by 6.25 g (61.7 mmol) of triethylamine. The mixture was cooled to -5 °C, and 4.82 g (40.0 mmol) of n-valeryl chloride was slowly added dropwise. The reaction mixture was heated to 25 °C and stirred for 2 hours. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 9.94 g of the target product, a yellow oil, with a yield of 94%.

[0108] Characterization data for compound A5 (where X is a bromine atom and R is an ethyl group): 1 H NMR (400 MHz, CDCl3) δ:7.47-7.44 (d, J = 2.44 Hz, 1H), 7.43-7.37 (dd, J = 8.52, 2.36 Hz, 1H), 7.01-6.95 (d, J = 8.56 Hz, 1H), 4.18-4.09 (q, J = 7.16 Hz, 2H), 3.53-3.47 (s, 2H), 2.61-2.51 (t, J = 7.56 Hz, 2H), 1.80-1.68 (tt, J = 7.60, 7.44 Hz, 2H), 1.50-1.38 (tq, J = 7.52, 7.48 Hz, 2H), 1.27-1.20 (t, J = 7.24 Hz, 3H), 1.01-0.93 (t, J = 7.36 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 171.5, 170.0, 148.3, 134.0,131.4, 128.8, 124.2, 118.8, 61.2, 36.2, 33.9, 26.8, 22.3, 14.1, 13.7.

[0109] Example 6: Preparation of compound with structural formula A2 (X is a bromine atom) 5.50 g (15.2 mmol) of compound A5 (X is bromine, R is methyl) was added to 50 mL of tetrahydrofuran, followed by 2.43 g (31.0 mmol) of lithium tert-butoxide. The mixture was stirred at room temperature for 2 hours, and then 20 mL of water was added. Stirring continued at room temperature for another 2 hours. After the reaction was complete, 5.95 g (31.0 mmol) of citric acid monohydrate was added and the mixture was stirred for 30 minutes. The mixture was concentrated to remove the organic solvent, stirred at room temperature for 30 minutes, filtered, and the filter cake was washed with 20 mL of water. The filter cake was collected and dried in a vacuum drying oven at 45 °C for 12 hours to obtain 3.43 g of the target product, a white solid, with a yield of 76%.

[0110] Characterization data for compound A2 (where X is a bromine atom): 1 H NMR (400 MHz, DMSO-d6) δ:7.78-7.70 (s, 1H), 7.35-7.28 (d, J = 8.32 Hz, 1H), 7.11-7.05 (d, J = 8.36 Hz,1H), 3.00-2.88 (t, J = 7.80 Hz, 2H), 1.66-1.53 ​​(tt, J = 7.64, 7.56 Hz, 2H), 1.44-1.30 (tq, J = 7.44, 7.40 Hz, 2H), 0.96-0.85 (t, J = 7.24 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ: 180.7, 168.0, 148.0, 127.8, 127.2, 123.8, 115.1, 111.1,95.4, 31.7, 29.3, 22.0, 13.6.

[0111] Example 7: Preparation of compound with structural formula A1 6.20 g (20.8 mmol) of compound A2 (X being bromine atom), 3.96 g (41.6 mmol) of methanesulfonamide, 10.16 g (31.2 mmol) of cesium carbonate, 0.40 g (2.1 mmol) of cuprous iodide, and 0.69 g (2.1 mmol) of N1,N2-bis(4-methoxybenzyl)oxalyldiamine were added to 80 mL of anhydrous ethanol. After purging with nitrogen, the mixture was heated to 80 °C and stirred for 12 hours. After the reaction was complete, the organic solvent was removed by concentration under reduced pressure. 80 mL of isopropyl acetate was added, and the organic phase was washed with 80 mL of 1.0 N dilute hydrochloric acid aqueous solution, followed by 80 mL of saturated brine. The organic phase was dried over sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure to give 4.40 g of the target product as a yellow solid, with a yield of 68%.

[0112] Characterization data of compound A1: 1 H NMR (400 MHz, DMSO-d6) δ: 9.52-9.40 (s,1H), 7.66-7.58 (s, 1H), 7.10-7.05 (d, J = 8.52 Hz, 1H), 7.05-6.99 (d, J =8.60 Hz, 1H), 3.01-2.92 (t, J = 7.84 Hz, 2H), 2.92-2.85 (s, 3H), 1.66-1.54(m, 2H), 1.44-1.31 (m, 2H), 0.95-0.87 (t, J = 7.40 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ: 178.9, 168.7, 146.3, 133.5, 125.4, 118.9, 115.7, 109.5, 96.5, 58.5, 31.5, 29.3, 22.0, 13.6.

[0113] Example 8: Preparation of compound with structural formula A11 1.10 g (3.3 mmol) of compound A1 was added to 30 mL of dichloroethane solvent. The mixture was cooled to -10 °C, stirred, and heated to reflux. 0.74 g (4.9 mmol) of aluminum trichloride was added in portions. The mixture was stirred at this temperature for 1 hour, and then 0.87 g (3.3 mmol) of 1-phenoxy-3-di-n-butylaminopropane was added to the reaction mixture. The reaction mixture was heated to 80 °C and stirred for 4 hours. After conversion, the reaction mixture was quenched dropwise in a 10% sodium carbonate aqueous solution and isopropanol mixture at 0 °C (1:1). The organic solvent was removed by vacuum concentration, and 30 mL of ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The mixture was cooled to -10 °C, and 30 mL of n-heptane was added and stirred for 30 minutes. The mixture was then filtered under vacuum, and the filter cake was washed with n-heptane. The filter cake was collected and dried under vacuum at 40°C for 3 hours to obtain 1.05 g of the target compound as an off-white solid, with a yield of 54%.

[0114] Characterization data of compound with structural formula A11: 1 H NMR (400 MHz, CDCl3) δ: 7.80-7.76 (d, J =8.86 Hz, 2H), 7.61-7.59 (s, 1H), 7.45-7.40 (d, J = 8.86, 1H), 7.34-7.30 (dd,J = 8.89, 2.44 Hz, 1H), 7.20-7.15 (d, J = 2.00 Hz, 1H), 7.02-6.90 (d, J =8.80 Hz, 2H), 4.50-4.25 (m, 2H), 3.26-3.21 (m, 2H), 3.12-3.03 (m, 2H), 2.99-2.96 (t, J = 7.82 Hz, 2H), 2.92-2.90 (s, 3H), 2.44-2.37 (m, 2H), 1.83-1.72(m, 6H), 1.45-1.30 (m, 8H), 0.99-0.96 (t, J = 7.84 Hz, 6H), 0.93-0.90 (t, J =7.28 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ:189.4, 167.0, 161.5, 150.4, 132.8,131.9, 131.5, 128.2, 118.7, 115.4, 115.2, 114.1, 110.9, 64.2, 52.0, 50.2,38.2, 30.0, 27.8, 24.9, 23.7, 22.1, 20.1, 13.8, 13.5.

[0115] Example 9: Preparation of compound with structural formula A6 (R is methyl) 8.40 g (36.3 mmol) of compound A9 (X being bromine atom), 6.92 g (72.7 mmol) of methanesulfonamide, 17.73 g (54.5 mmol) of cesium carbonate, 1.04 g (5.45 mmol) of cuprous iodide, and 3.58 g (10.89 mmol) of N1,N2-bis(4-methoxybenzyl)oxalyldiamine were added to 120 mL of anhydrous ethanol. After purging with nitrogen, the mixture was heated to 80 °C and stirred for 12 hours. After the reaction was complete, the organic solvent was removed by concentration under reduced pressure. 120 mL of isopropyl acetate was added, and the organic phase was washed with 120 mL of 1.0 N dilute hydrochloric acid aqueous solution, followed by 120 mL of saturated brine. The organic phase was dried over sodium sulfate, and the solid was removed by filtration. The filtrate was concentrated to dryness. 100 mL of methanol was added, and the mixture was protected with nitrogen. The mixture was cooled to -10°C, and 19.68 g (181.5 mmol) of trimethylchlorosilane was added dropwise. After the addition was complete, the temperature was raised to 35°C, and the reaction was stirred for 4 hours. The mixture was concentrated, and 100 mL of 2-methyltetrahydrofuran was added to dissolve the product. The organic phase was washed with 120 mL of saturated brine. The organic phase was collected after separation, dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness. The filtrate was then passed through 30 mL of n-heptane to give 6.59 g of the target product as a pale yellow solid, with a two-step yield of 70%.

[0116] Characterization data for compound A6 (R stands for methyl): 1 H NMR (400 MHz, DMSO-d6) δ: 9.55-9.48 (s, 1H), 9.22-9.14 (s, 1H), 7.01-6.98 (d, J = 2.72 Hz, 1H), 6.98-6.93(dd, J = 8.52, 2.64 Hz, 1H), 6.78-6.73 (dd, J = 8.48, 2.20 Hz, 1H), 3.62-3.56(s, 3H), 3.56-3.50 (s, 2H), 2.89-2.80 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ:171.5, 153.0, 129.0, 125.7, 122.8, 121.9, 115.2, 51.5, 38.5, 35.1.

[0117] Example 10: Preparation of compound with structural formula A6 (R is ethyl) 2.80 g (12.1 mmol) of compound A9 (X being bromine atom), 2.30 g (24.2 mmol) of methanesulfonamide, 5.91 g (18.2 mmol) of cesium carbonate, 0.35 g (1.81 mmol) of cuprous iodide, and 1.19 g (3.63 mmol) of N1,N2-bis(4-methoxybenzyl)oxalyldiamine were added to 40 mL of anhydrous ethanol. After purging with nitrogen, the mixture was heated to 80 °C and stirred for 12 hours. After the reaction was complete, the organic solvent was removed by concentration under reduced pressure. 50 mL of isopropyl acetate was added, and the organic phase was washed with 50 mL of 1.0 N dilute hydrochloric acid aqueous solution, followed by 50 mL of saturated brine. The organic phase was dried over sodium sulfate, filtered to remove the solid, and the filtrate was concentrated to dryness. 30 mL of ethanol was added under nitrogen protection. The mixture was cooled to -5 °C, and 3.07 g (24.2 mmol) of oxalyl chloride was added dropwise. After the addition was complete, the temperature was raised to 35°C and the reaction was stirred for 2 hours. The mixture was concentrated, and 40 mL of isopropyl acetate was added to dissolve the product. The organic phase was washed with 40 mL of saturated brine. The organic phase was collected in layers, dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain 2.55 g of the target product, a light yellow oily substance, with a two-step yield of 77%.

[0118] Characterization data for compound A6 (R stands for ethyl): 1 H NMR (400 MHz, CDCl3) δ: 7.85-7.52(s, 1H), 7.12-6.97 (m, 2H), 6.92-6.81 (d, J = 8.34 Hz,1H), 6.66-6.54 (s, 1H),4.28-4.15 (q, J = 7.16 Hz, 2H), 3.72-3.57 (s, 2H), 3.06-3.84 (s, 3H), 1.37-1.25 (t, J = 7.16 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 173.8, 153.9, 129.0,126.3, 124.2, 121.9, 118.5, 62.2, 38.9, 37.7, 14.0.

[0119] Example 11: Preparation of compound with structural formula A3 (R is methyl) 7.60 g (29.3 mmol) of compound A6 (R being methyl) was added to 80 mL of dichloromethane, followed by 6.08 g (60.0 mmol) of triethylamine. The mixture was cooled to -5 °C, and 3.53 g (29.3 mmol) of n-valeryl chloride was slowly added dropwise. The reaction mixture was heated to 30 °C and stirred for 3 hours. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 9.06 g of the target product, a yellow oil, in 90% yield.

[0120] Characterization data for compound A3 (where R is methyl): 1 H NMR (400 MHz, CDCl3) δ: 7.49-7.42(s, 1H), 7.21-7.16 (d, J = 2.68 Hz, 1H), 7.14-7.08 (d, J = 8.80, 2.42 Hz,1H), 7.05-6.99 (dd, J = 8.68 Hz, 1H), 3.70-3.64 (s, 3H), 3.57-3.51 (s, 2H), 2.98-2.90 (s, 3H), 2.62-2.50 (t, J = 7.52 Hz, 2H), 1.79-1.65 (tt, J = 7.52,7.44 Hz, 2H), 1.50-1.37 (tq, J = 7.48, 7.48 Hz, 2H), 1.02-0.89 (t, J = 7.36Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 172.0, 171.0, 146.2, 134.7, 127.7, 123.7,123.4, 120.8, 52.1, 39.0, 35.9, 33.7, 26.7, 22.1, 13.6.

[0121] Example 12: Preparation of compound with structural formula A3 (R is ethyl) 6.80 g (24.9 mmol) of compound A6 (R being ethyl) was added to 100 mL of dichloromethane, followed by 6.50 g (50.0 mmol) of N,N-diisopropylethylamine. The mixture was cooled to -10 °C, and 3.00 g (24.9 mmol) of n-valeryl chloride was slowly added dropwise. The reaction mixture was heated to 10 °C and stirred for 4 hours. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 8.28 g of the target product, a yellow oil, with a yield of 93%.

[0122] Characterization data for compound A3 (R is ethyl): 1 H NMR (400 MHz, DMSO-d6) δ: 9.82-9.72 (S, 1H), 7.20-7.16 (m, 1H), 7.17-7.11 (d, J = 8.80 Hz, 1H), 7.11-7.05(d, J = 8.60 Hz, 1H), 4.11-3.98 (q, J = 7.08 Hz, 2H), 3.58-3.49 (s, 2H), 3.07-2.94 (s, 3H), 2.58-2.50 (t, J = 7.44 Hz, 2H), 1.67-1.55 (tt, J = 7.48,7.36 Hz, 2H), 1.43-1.31 (tq, J = 7.48, 7.44 Hz, 2H), 1.19-1.12 (t, J = 7.12Hz, 3H), 0.95-0.87 (t, J = 7.32 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ: 171.9,170.5, 146.2, 134.6, 127.8, 123.6, 123.3, 120.8, 61.1, 38.9, 36.1, 33.7,26.7, 22.1, 14.0, 13.9.

[0123] Example 13: Preparation of compound with structural formula A4 (R is methyl) 7.00 g (26.9 mmol) of compound A6 (R being methyl) was added to 75 mL of dichloromethane, followed by 6.08 g (60.0 mmol) of triethylamine. The mixture was cooled to -5 °C, and 8.12 g (67.5 mmol) of n-valeryl chloride was slowly added dropwise. The reaction mixture was heated to 30 °C and stirred for 3 hours. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 8.68 g of the target product, a yellow oil, with a yield of 94%.

[0124] Characterization data for compound A4 (where R is methyl): 1H NMR (400 MHz, CDCl3) δ: 7.29-7.24(m, 2H), 7.24-7.20 (m, 1H), 3.70-3.65 (s, 3H), 3.63-3.56 (s, 2H), 3.48-3.41(s, 3H), 2.63-2.55 (t, J = 7.44 Hz, 2H), 2.18-2.10 (t, J = 7.32 Hz, 2H), 1.79-1.68 (tt, J = 7.56, 7.40 Hz, 2H), 1.62-1.52 (tt, J = 7.48, 7.36 Hz, 2H),1.51-1.39 (tq, J = 7.48, 7.44 Hz, 2H), 1.31-1.19 (tq, J = 7.60, 7.48 Hz, 2H), 1.02-0.94 (t, J = 7.36 Hz, 3H), 0.87-0.79 (t, J = 7.28 Hz, 3H). 13 C NMR (100MHz, CDCl3) δ: 174.3, 171.2, 170.2, 150.2, 132.7, 132.6, 129.7, 128.4, 123.9,52.2, 42.1, 36.3, 35.7, 33.8, 26.8, 26.4, 22.2, 21.9, 13.6.

[0125] Example 14: Preparation of compound with structural formula A4 (R is ethyl) 6.20 g (22.7 mmol) of compound A6 (R being ethyl) was added to 70 mL of dichloromethane, followed by 6.50 g (50.0 mmol) of N,N-diisopropylethylamine. The mixture was cooled to -10 °C, and 6.02 g (50.0 mmol) of n-valeryl chloride was slowly added dropwise. The reaction mixture was heated to 20 °C and stirred for 4 hours. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 9.12 g of the target product, a yellow oil, with a yield of 91%.

[0126] Characterization data for compound A4 (where R is ethyl): 1H NMR (400 MHz, CDCl3) δ: 7.31-7.27(s, 1H), 7.27-7.24 (d, J = 8.60 Hz, 1H), 7.24-7.19 (d, J = 9.04 Hz, 1H), 4.18-4.08 (q, J = 7.08 Hz, 2H), 3.63-3.54 (s, 2H), 3.48-3.40 (s, 3H), 2.64-2.55 (t, J = 7.48 Hz, 2H), 2.18-2.08 (t, J = 7.32 Hz, 2H), 1.79-1.68 (tt, J =7.48, 7.44 Hz, 2H), 1.61-1.51 (tt, J = 7.48, 7.44 Hz, 2H), 1.28-1.18 (m, 5H), 1.01-0.94 (t, J = 7.24 Hz, 3H), 0.86-0.78 (t, J = 7.36 Hz, 3H). 13 C NMR (100MHz, CDCl3) δ: 174.2, 171.2, 169.8, 150.1, 132.7, 132.6, 129.6, 128.6, 123.9, 61.1, 42.1, 36.3, 35.9, 33.9, 26.7, 26.3, 22.2, 21.9, 14.0, 13.7.

[0127] Example 15: Preparation of compound with structural formula A1 7.80 g (22.7 mmol) of compound A3 (R being methyl) was added to 80 mL of tetrahydrofuran, followed by 4.36 g (45.4 mmol) of sodium tert-butoxide. The mixture was stirred at room temperature for 2 hours, and then 60 mL of water was added. Stirring continued at room temperature for 1 hour. After the reaction was complete, 3.00 g (50.0 mmol) of acetic acid was added and the mixture was stirred for 30 minutes. The mixture was concentrated to remove the organic solvent, stirred at room temperature for 30 minutes, filtered, and the filter cake was washed with 50 mL of water. The filter cake was collected and dried in a vacuum drying oven at 45 °C for 12 hours to obtain 5.58 g of the target product, a white solid, with a yield of 79%.

[0128] Characterization data of compound with structural formula A1: 1H NMR (400 MHz, DMSO-d6) δ: 9.52-9.40 (s,1H), 7.66-7.58 (s, 1H), 7.10-7.05 (d, J = 8.52 Hz, 1H), 7.05-6.99 (d, J =8.60 Hz, 1H), 3.01-2.92 (t, J = 7.84 Hz, 2H), 2.92-2.85 (s, 3H), 1.66-1.54(m, 2H), 1.44-1.31 (m, 2H), 0.95-0.87 (t, J = 7.40 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ: 178.9, 168.7, 146.3, 133.5, 125.4, 118.9, 115.7, 109.5, 96.5, 58.5, 31.5, 29.3, 22.0, 13.6.

[0129] Example 16: Preparation of compound with structural formula A1 9.60 g (22.4 mmol) of compound A4 (R being methyl) was added to 100 mL of tetrahydrofuran, followed by 6.28 g (56.0 mmol) of potassium tert-butoxide. The mixture was stirred at room temperature for 4 hours, and then 80 mL of water was added. Stirring continued at room temperature for 1 hour. After the reaction was complete, 3.60 g (60.0 mmol) of acetic acid was added and the mixture was stirred for 30 minutes. The mixture was concentrated to remove the organic solvent, stirred at room temperature for 30 minutes, filtered, and the filter cake was washed with 60 mL of water. The filter cake was collected and dried in a vacuum drying oven at 45 °C for 12 hours to obtain 5.65 g of the target product, a white solid, with a yield of 81%.

[0130] Characterization data of compound with structural formula A1: 1 H NMR (400 MHz, DMSO-d6) δ: 9.52-9.40 (s,1H), 7.66-7.58 (s, 1H), 7.10-7.05 (d, J = 8.52 Hz, 1H), 7.05-6.99 (d, J =8.60 Hz, 1H), 3.01-2.92 (t, J = 7.84 Hz, 2H), 2.92-2.85 (s, 3H), 1.66-1.54(m, 2H), 1.44-1.31 (m, 2H), 0.95-0.87 (t, J = 7.40 Hz, 3H). 13C NMR (100 MHz,DMSO-d6) δ: 178.9, 168.7, 146.3, 133.5, 125.4, 118.9, 115.7, 109.5, 96.5,58.5, 31.5, 29.3, 22.0, 13.6。

Claims

1. A benzofuranone compound and its salt, characterized in that, The structural formula is: 。 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. A method for preparing a benzofuranone compound, characterized in that, The compound of formula A2-1 / A2-2 was prepared by coupling reaction in the presence of a transition metal catalyst and ligands: ， Where X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group or borate ester group.

5. A method for preparing a benzofuranone compound, characterized in that, The steps include preparing benzofuranone compounds of formula A1-1 / A1-2 from compounds of formula A3 via dehydration condensation-lactoneation in the presence of an organic solvent and a base catalyst: ， Where R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio, or alkylamino.

6. A method for preparing a benzofuranone compound, characterized in that, The steps include preparing benzofuranone compounds of formula A1-1 / A1-2 from compounds of formula A4 via dehydration condensation-lactoneation in the presence of an organic solvent and a base catalyst: ， Where R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio, or alkylamino.

7. The method for preparing the compound according to claim 4, characterized in that, This includes the steps of preparing compounds of formula A2-1 / A2-2 from compounds of formula A5 via dehydration condensation-lactoneation in the presence of a base catalyst: ， Where X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group, or borate ester group; R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio, or alkylamino.

8. The method for preparing the compound according to claim 7, characterized in that, The steps include preparing compound A5 by condensation esterification reaction of compound A7 and n-valeryl chloride under organic base conditions: , Where X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group, or borate ester group; R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio, or alkylamino.

9. The method for preparing the compound according to claim 8, characterized in that, The steps include selective esterification of compound A9 under acid catalyst and alcohol additive conditions to prepare compound A7: ， Where X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group, or borate ester group; R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio, or alkylamino.

10. The method for preparing the compound according to claim 5, characterized in that, The steps include preparing compound A3 from compound A6 by condensation reaction in the presence of n-valeryl chloride, an organic solvent, and an organic base: ， Where R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio, or alkylamino.

11. The method for preparing the compound according to claim 6, characterized in that, The steps include preparing compound A4 from compound A6 by condensation reaction in the presence of n-valeryl chloride, an organic solvent, and an organic base: ， Where R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio, or alkylamino.

12. The method for preparing the compound according to claim 10, characterized in that, The steps include the selective esterification reaction of compound A8 in an organic solvent, followed by the addition of an alcohol and an acid catalyst, to prepare compound A6: , Where R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio, or alkylamino.

13. The method for preparing the compound according to claim 12, characterized in that, The steps include preparing compound A8 from compound A9 via a coupling reaction under conditions of organic solvent, transition metal catalyst, ligand, and inorganic base: ， Where X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group or borate ester group.

14. The method for preparing the compound according to claim 13, characterized in that, The steps include preparing compound A9 by coupling reaction of compound A10 in the presence of an inorganic base, a transition metal catalyst, and an acidic aqueous solution: ， Where X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group or borate ester group.

15. A compound of formula A2, characterized in that, The structural formula of the compound is: , Where X is a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, m-nitrobenzenesulfonyloxy, acetoxy, borate group or borate ester group.

16. A compound of formula A3, characterized in that, The structural formula of the compound is: , Where R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio, or alkylamino.

17. A compound of formula A4, characterized in that, The structural formula of the compound is: , Where R is CR 1 R 2 R 3 , R 1 R 2 R 3 The same or different elements are hydrogen; alkyl, substituted alkyl; alkenyl, substituted alkenyl; alkynyl, substituted alkynyl; aryl, substituted aryl; alkoxy, alkylthio, or alkylamino.

18. A method for preparing dronedarone hydrochloride, characterized in that, The reaction formula is ， Where R is methyl or ethyl, and X is halogen.

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