Preparation method of 4-propyl-2, 6-piperidinedione compound

Abstract

The invention relates to a preparation method of a 4-propyl-2, 6-piperidinedione compound, and belongs to the field of pharmaceutical chemicals. Specifically, a compound represented by a formula III or a salt thereof reacts with a compound represented by a formula V or a salt thereof in the presence of a reaction accelerator to generate a compound represented by a formula IV or a salt thereof, the invention provides a new preparation method of the 4-propyl-2, 6-piperidinedione compound, and the preparation method is high in yield and high in product purity, in the formula, R1 and R2 are independently selected from hydrogen or C1-C4 alkyl, and R2 is selected from hydrogen or C1-C4 alkyl. And R4 is selected from hydrogen or C1-C4 alkyl.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing a 4-propyl-2,6-piperidinedione compound. Background Technology

[0002] Brivaceratam, chemical name: (2S)-2-[(4R)-2-oxo-4-propyl-1-pyrrolidine]butyramide, trade name Briviact, is a third-generation antiepileptic drug developed by UCB (UCB) of Belgium. It is used to treat partial seizures in adults and adolescents aged 16 years and older, with or without secondary generalized seizures, as adjunctive therapy. Brivaceratam was approved for marketing by the European Medicines Agency (EMA) on January 14, 2016, and subsequently received marketing approval from the U.S. Food and Drug Administration (FDA) on February 18, 2016.

[0003] 4-propyl-2,6-piperidinedione compounds are important intermediates in the synthesis of buvasitial and have the structure shown in Formula IV:

[0004]

[0005] R 4 The compounds are selected from hydrogen or C1-C4 alkyl groups, and there is still an urgent need to develop synthetic methods for these compounds. Summary of the Invention

[0006] This invention provides a method for preparing a compound of formula IV or a salt thereof, the method comprising reacting a compound of formula III or a salt thereof with a compound of formula V or a salt thereof in the presence of a reaction promoter to generate a compound of formula IV or a salt thereof.

[0007]

[0008] R 1 R 2 Each is independently selected from hydrogen or C1-C4 alkyl groups;

[0009] R 4 Selected from hydrogen or C1-C4 alkyl;

[0010] The reaction promoter is selected from one or a mixture of two or more of acids, alumina, silica gel, or molecular sieves.

[0011] This invention provides a method for preparing a compound of formula IV or a salt thereof, the method comprising reacting a compound of formula III or a salt thereof with a compound of formula V or a salt thereof in the presence of a reaction promoter to generate a compound of formula IV or a salt thereof.

[0012]

[0013] R 1 R 2 Each is independently selected from hydrogen or C1-C4 alkyl groups;

[0014] R 4 Selected from hydrogen or C1-C4 alkyl;

[0015] The reaction promoter is selected from one or a mixture of two or more of acids, silica gel, or molecular sieves.

[0016] In some embodiments of the present invention, the R 1 R 2 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; in some typical embodiments of the invention, the R... 1 R 2 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, or isopropyl; in some more typical embodiments of the invention, the R... 1 R 2 Each is independently selected from hydrogen, methyl, or ethyl; in some more typical embodiments of the invention, the R... 1 R 2 Selected from hydrogen, methyl, or ethyl, and R 1 R 2 They are the same functional groups; in some of the most typical embodiments of the invention, R 1 R 2 Both are hydrogen.

[0017] In some embodiments of the present invention, the R 4 Selected from hydrogen or C1-C3 alkyl; in some typical embodiments of the invention, the R... 4 Selected from hydrogen, methyl, ethyl, n-propyl, or isopropyl; in some more typical embodiments of the invention, the R... 4 Selected from hydrogen, methyl, or ethyl; in some of the most typical embodiments of the invention, the R... 4 It is hydrogen.

[0018] In some embodiments of the present invention, a method for preparing a compound of formula IV-1 or a salt thereof includes reacting a compound of formula III-1 or a salt thereof with a compound of formula V-1 or a salt thereof in the presence of a reaction promoter to generate a compound of formula IV-1 or a salt thereof.

[0019]

[0020] The reaction promoter is selected from one or a mixture of two or more of acids, alumina, silica gel, or molecular sieves.

[0021] In some embodiments of the present invention, a method for preparing a compound of formula IV-1 or a salt thereof includes reacting a compound of formula III-1 or a salt thereof with a compound of formula V-1 or a salt thereof in the presence of a reaction promoter to generate a compound of formula IV-1 or a salt thereof.

[0022]

[0023] The reaction promoter is selected from one or a mixture of two or more of acids, silica gel, or molecular sieves.

[0024] In some embodiments of the present invention, the compound of formula III or its salt participates in the reaction in the form of compound of formula III; in some typical embodiments of the present invention, the compound of formula III-1 or its salt participates in the reaction in the form of free acid of compound III-1.

[0025] In some embodiments of the present invention, the compound of formula V or its salt participates in the reaction as a free base of the compound of formula V; in some typical embodiments of the present invention, the compound of formula V-1 or its salt participates in the reaction as a free base of the compound of formula V-1.

[0026] In some embodiments of the present invention, the compound of formula IV or its salt is in the form of a free base of the compound of formula IV; in some embodiments of the present invention, the compound of formula IV-1 or its salt is in the form of a free base of the compound of formula IV-1.

[0027] In some embodiments of the present invention, the reaction promoter is one or a mixture of two or more of alumina, silica gel, or molecular sieve; in some embodiments of the present invention, the reaction promoter is an acid and silica gel; in some embodiments of the present invention, the reaction promoter is an acid and molecular sieve; in some embodiments of the present invention, the reaction promoter is an acid; in some embodiments of the present invention, the reaction promoter is silica gel; in some embodiments of the present invention, the reaction promoter is a molecular sieve; in some embodiments of the present invention, the reaction promoter is alumina.

[0028] In some embodiments of the present invention, the acid is one or a mixture of two or more selected from organic acids, inorganic acids, or their hydrates; in some typical embodiments of the present invention, the acid is one or a mixture of two or more selected from sulfuric acid, phosphoric acid, oxalic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, p-nitrobenzenesulfonic acid, acetic acid, trifluoroacetic acid, or their hydrates; in some more typical embodiments of the present invention, the acid is one or a mixture of two or more selected from p-toluenesulfonic acid, benzenesulfonic acid, p-nitrobenzenesulfonic acid, or their hydrates; in some more typical embodiments, the acid is p-toluenesulfonic acid, benzenesulfonic acid, or their hydrates; in some most typical embodiments, the acid is p-toluenesulfonic acid or its hydrate; in some most typical embodiments, the acid is p-toluenesulfonic acid; in some most typical embodiments, the acid is p-toluenesulfonic acid hydrate; in some most typical embodiments, the acid is p-toluenesulfonic acid monohydrate.

[0029] In some embodiments of the present invention, the molar ratio of the acid to the compound of formula III or its salt is 0.005-0.5:1; in some typical embodiments, the molar ratio of the acid to the compound of formula III or its salt is 0.008-0.5:1; in some more typical embodiments, the molar ratio of the acid to the compound of formula III or its salt is 0.009-0.2:1; in some most typical embodiments, the molar ratio of the acid to the compound of formula III or its salt is 0.005:1, 0.008:1, 0.009:1, 0.01:1, 0.035:1, 0.05:1, 0.1:1, 0.15:1, 0.2:1, 0.25:1, 0.3:1, or 0.4:1.

[0030] In some embodiments of the present invention, the silica gel is organic silica gel, inorganic silica gel, or a mixture thereof; in some typical embodiments of the present invention, the silica gel is inorganic silica gel; in some more typical embodiments of the present invention, the silica gel is column chromatography silica gel powder; in some most typical embodiments of the present invention, the silica gel is 200-400 mesh column chromatography silica gel powder; in some most typical embodiments of the present invention, the silica gel is 200-350 mesh column chromatography silica gel powder; in some most typical embodiments of the present invention, the silica gel is 300-400 mesh column chromatography silica gel powder.

[0031] In some typical embodiments, the mass ratio of the alumina, silica gel, or molecular sieve to the compound of formula III or its salt, based on the mass of the compound of formula III, is 0.05-1.5:1; in some typical embodiments, the mass ratio of the alumina, silica gel, or molecular sieve to the compound of formula III or its salt, based on the mass of the compound of formula III, is 0.1-1:1; in some more typical embodiments, the mass ratio of the alumina, silica gel, or molecular sieve to the compound of formula III or its salt, based on the mass of the compound of formula III, is 0.2-0.8:1; in some even more typical embodiments, the mass ratio of the alumina, silica gel, or molecular sieve to the compound of formula III or its salt, based on the mass of the compound of formula III, is 0.3-0.6:1; in some even more typical embodiments... In some embodiments, the mass ratio of the alumina, silica gel, or molecular sieve to the compound of formula III or its salt is 0.4-0.6:1, based on the mass of the compound of formula III; in some more typical embodiments, the mass ratio of the alumina, silica gel, or molecular sieve to the compound of formula III or its salt is 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, or 0.9:1, based on the mass of the compound of formula III; in some most typical embodiments, the reaction promoter is silica gel, and the mass ratio of the silica gel to the compound of formula III or its salt is 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, or 0.9:1, based on the mass of the compound of formula III.

[0032] In some embodiments of the present invention, the molar ratio of compound III or its salt to compound V or its salt in the method is 1:1-10; in some more typical embodiments, the molar ratio of compound III or its salt to compound V or its salt in the method is 1:1-5; in some even more typical embodiments, the molar ratio of compound III or its salt to compound V or its salt in the method is 1:1.1-3.5; in some even more typical embodiments, the molar ratio of compound III or its salt to compound V or its salt in the method is 1:1.2-3; in some even more typical embodiments, the molar ratio of compound III or its salt to compound V or its salt in the method is 1:1.2-3; The molar ratio of compound III or its salt to compound V or its salt is 1:1.5-2.7; in some of the most typical embodiments, the molar ratio of compound III or its salt to compound V or its salt in the method is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.5 or 1:4.

[0033] In some embodiments of the present invention, the method includes, optionally, carrying out the reaction in the presence of a reaction solvent; in some typical embodiments of the present invention, the reaction is carried out in the absence of a reaction solvent; in some typical embodiments of the present invention, the reaction is carried out in the presence of a reaction solvent; in some more typical embodiments, the reaction solvent is selected from toluene, chlorobenzene, xylene, nitrobenzene, N,N-dimethylformamide, dimethyl sulfoxide, 2-methyltetrahydrofuran, ethylene glycol, or a mixture of two or more solvents; in some more typical embodiments, the reaction solvent is selected from toluene, chlorobenzene, xylene, nitrobenzene, or a mixture of two or more solvents; in some even more typical embodiments, the reaction solvent is selected from toluene or xylene; in some most typical embodiments, the reaction solvent is xylene.

[0034] In some embodiments of the present invention, the reaction solvent is present and its mass is within 50 times that of the compound of formula III or a salt thereof; in some typical embodiments, the mass of the reaction solvent is 1-40 times that of the compound of formula III or a salt thereof; in some more typical embodiments, the mass of the reaction solvent is 1-30 times that of the compound of formula III or a salt thereof; in some even more typical embodiments, the mass of the reaction solvent is 2-15 times that of the compound of formula III or a salt thereof; in some even more typical embodiments, the mass of the reaction solvent is 2-6 times that of the compound of formula III or a salt thereof; in some most typical embodiments, the mass of the reaction solvent is 2-3 times that of the compound of formula III or a salt thereof; in some most typical embodiments, the mass of the reaction solvent is 10-12 times that of the compound of formula III or a salt thereof.

[0035] In some embodiments of the present invention, the reaction time of the method is 0.5 hours to 24 hours; in some typical embodiments, the reaction time is 1 hour to 20 hours; in some more typical embodiments, the reaction time is 2 hours to 10 hours; in some even more typical embodiments, the reaction time is 1 hour to 5 hours; and in some most typical embodiments, the reaction time is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours.

[0036] In some embodiments of the present invention, the reaction temperature of the method is 80℃-200℃; in some typical embodiments, the reaction temperature is 90℃-180℃; in some more typical embodiments, the reaction temperature is 120℃-160℃; in some even more typical embodiments, the reaction temperature is 140℃-150℃; in some most typical embodiments, the reaction temperature is 120℃, 125℃, 130℃, 135℃, 140℃, 145℃, 150℃, 155℃, or 160℃.

[0037] In some embodiments of the present invention, a reaction promoter is added simultaneously with the addition of a compound of formula III or a salt thereof and a compound of formula V or a salt thereof; in some embodiments of the present invention, the reaction promoter is added after the compound of formula III or a salt thereof and a compound of formula V or a salt thereof have reacted for a period of time. In some typical embodiments, the reaction promoter is added after the compound of formula III or a salt thereof and a compound of formula V or a salt thereof have reacted for 1 to 10 hours; in some more typical embodiments, the reaction promoter is added after the compound of formula III or a salt thereof and a compound of formula V or a salt thereof have reacted for 1 to 5 hours; in some even more typical embodiments, the reaction promoter is added after the compound of formula III or a salt thereof and a compound of formula V or a salt thereof have reacted for 1 to 3 hours; or after the compound of formula III or a salt thereof and a compound of formula V or a salt thereof have reacted for 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, or 6 hours.

[0038] In some embodiments of the present invention, the method further includes cooling after the reaction is completed; in some typical embodiments, the method further includes cooling to -20°C to -20°C after the reaction is completed; in some more typical embodiments, the method further includes cooling to -10°C to -10°C after the reaction is completed; in some even more typical embodiments, the method further includes cooling to -8°C to -8°C after the reaction is completed; in some of the most typical embodiments, the method further includes cooling to -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, or 7°C after the reaction is completed.

[0039] In some embodiments of the present invention, the method further includes filtering.

[0040] In some embodiments of the present invention, the method optionally further includes pulping or recrystallization; in some typical embodiments, the method uses water for pulping or recrystallization; in some more typical embodiments, the mass of water used is 5 to 30 times the mass of the compound of formula III or its salt, based on the mass of the compound of formula III; in some even more typical embodiments, the mass of water used is 10 to 20 times the mass of the compound of formula III or its salt, based on the mass of the compound of formula III; in some even more typical embodiments, the mass of water used is 10, 11, 12, 13, 15, or 18 times the mass of the compound of formula III or its salt, based on the mass of the compound of formula III; in some even more typical embodiments, the method optionally further includes pulping with water, and the mass of water used is 10, 11, 12, 13, 15, or 18 times the mass of the compound of formula III or its salt.

[0041] In some embodiments of the present invention, the method further includes drying; in some embodiments of the present invention, the method further includes drying under vacuum conditions.

[0042] In some embodiments of the present invention, the method further includes sequentially performing filtration, pulping, and drying; in some embodiments of the present invention, the method further includes sequentially performing filtration, recrystallization, and drying.

[0043] On the other hand, the present invention provides a method for preparing a compound of formula III-1 or a salt thereof, the method comprising:

[0044] (i) The compound of formula I and the compound of formula II or their salts react in the presence of a base and a reaction solvent;

[0045] (ii) In the presence of an acid, further reaction produces a compound of formula III-1 or its salt.

[0046]

[0047] In some embodiments of the present invention, the compound of formula II or its salt participates in the reaction in the form of a free acid.

[0048] In some embodiments of the present invention, the compound of formula III-1 or its salt is in the form of a free acid of the compound of formula III-1.

[0049] In some embodiments of the present invention, the base is an inorganic base; in some typical embodiments, the inorganic base is selected from one or a mixture of two or more of alkali metal hydroxides, alkali metals, alkali metal alkoxides, and alkali metal hydrides; in some more typical embodiments, the inorganic base is selected from one or a mixture of two or more of alkali metal hydroxides, alkali metals, and alkali metal hydrides; in some more typical embodiments, the inorganic base is an alkali metal hydroxide; in some even more typical embodiments, the alkali metal hydroxide is selected from one or a mixture of two or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide; in some even more typical embodiments, the alkali metal hydride is selected from one or a mixture of two or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide; The oxide is selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide; in some of the most typical embodiments, the alkali metal hydroxide is sodium hydroxide; in some more typical embodiments, the inorganic base is an alkali metal; in some even more typical embodiments, the alkali metal is selected from one or more of sodium, potassium, and lithium; in some of the most typical embodiments, the alkali metal is sodium; in some more typical embodiments, the inorganic base is selected from alkali metal hydrides; in some even more typical embodiments, the alkali metal is selected from one or more of sodium hydride, potassium hydride, and lithium hydride; in some of the most typical embodiments, the alkali metal is sodium hydride.

[0050] In some embodiments of the present invention, the reaction solvent is selected from one or more mixed solvents selected from water, alcohol solvents, ether solvents, and ester solvents; in some embodiments of the present invention, the reaction solvent is selected from one or more mixed solvents selected from water and alcohol solvents; in some of the most typical embodiments, the reaction solvent is water.

[0051] In some embodiments of the present invention, the mass of the solvent, based on the mass of the compound of formula II, is 0.5 to 50 times the mass of the compound of formula II or its salt; in some typical embodiments, the mass of the solvent, based on the mass of the compound of formula II, is 0.8 to 40 times the mass of the compound of formula II or its salt; in some more typical embodiments, the mass of the solvent, based on the mass of the compound of formula II, is 1 to 20 times the mass of the compound of formula II or its salt; in some even more typical embodiments, the mass of the solvent, based on the mass of the compound of formula II, is 1 to 10 times the mass of the compound of formula II or its salt; in some even more typical embodiments, the mass of the solvent, based on the mass of the compound of formula II, is 2 to 4 times the mass of the compound of formula II or its salt; in some of the most typical embodiments, the mass of the solvent, based on the mass of the compound of formula II, is 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, or 7 times the mass of the compound of formula II or its salt.

[0052] In some embodiments of the present invention, the molar ratio of compound I to compound II or its salt in step (i) of the method is 1:1-10; in some typical embodiments, the molar ratio of compound I to compound II or its salt in step (i) of the method is 1:1.5-4; in some more typical embodiments, the molar ratio of compound I to compound II or its salt in step (i) of the method is 1:1.8-4; in some even more typical embodiments, the molar ratio of compound I to compound II or its salt in step (i) of the method is 1:2-4; in some most typical embodiments, the molar ratio of compound I to compound II or its salt in step (i) of the method is selected from 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4.

[0053] In some embodiments of the present invention, the molar ratio of the base to the compound of formula I in step (i) of the method, based on a monobasic base, is 1-5:1; in some typical embodiments, the molar ratio of the base to the compound of formula I in step (i) of the method, based on a monobasic base, is 1-4:1; in some more typical embodiments, the molar ratio of the base to the compound of formula I in step (i) of the method, based on a monobasic base, is 2-4:1; in some even more typical embodiments, the molar ratio of the base to the compound of formula I in step (i) of the method, based on a monobasic base, is 2-4:1; and in some even more typical embodiments, the molar ratio of the base to the compound of formula I in step (i) of the method, based on a monobasic base, is 1-5:1. Based on the alkali, the molar ratio of the alkali to the compound of formula I in step (i) of the method is 2-3:1; in some of the most typical embodiments, based on a monobasic alkali, the molar ratio of the alkali to the compound of formula I in step (i) of the method is 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3:1, 3.1:1, 3.3:1, 3.5:1, 3.8:1 or 4:1.

[0054] In some embodiments of the present invention, the alkali is added in the form of an aqueous solution of alkali, wherein the mass fraction of alkali is 20%-50%; in some typical embodiments, the alkali is added in the form of an aqueous solution of alkali, wherein the mass fraction of alkali is 20%-40%; in some more typical embodiments, the alkali is added in the form of an aqueous solution of alkali, wherein the mass fraction of alkali is 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34% or 35%.

[0055] In some embodiments of the present invention, step (i) of the method includes adding an alkali or an aqueous solution thereof and a compound of formula II or a salt thereof into water, and then adding a compound of formula I dropwise to react; in some typical embodiments, step (i) of the method further includes adding an alkali or an aqueous solution thereof and a compound of formula II or a salt thereof into water, and then adding a compound of formula I dropwise to react under conditions of -20°C to 40°C; in some more typical embodiments, step (i) of the method further includes adding an alkali or an aqueous solution thereof and a compound of formula II or a salt thereof into water, and then adding a compound of formula I dropwise to react under conditions of 0°C to 15°C; in some even more typical embodiments, adding an alkali or an aqueous solution thereof and a compound of formula II or a salt thereof into water, and then adding a compound of formula I dropwise to react under conditions of 0°C to 15°C.

[0056] In some embodiments of the present invention, the reaction temperature of step (i) in the method is -20°C to 40°C; in some typical embodiments, the reaction temperature of step (i) in the method is -10°C to 15°C; in some more typical embodiments, the reaction temperature of step (i) in the method is 0°C to 15°C.

[0057] In some embodiments of the present invention, the reaction time of step (i) in the method is 5 minutes to 500 minutes; in some typical embodiments, the reaction time of step (i) in the method is 15 minutes to 150 minutes; in some more typical embodiments, the reaction time of step (i) in the method is 30 minutes to 120 minutes; in some most typical embodiments, the reaction time of step (i) in the method is 30 minutes, 45 minutes, 60 minutes or 75 minutes.

[0058] In some embodiments of the present invention, the acid is selected from one or a mixture of two or more of hydrogen chloride, sulfuric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid; in some typical embodiments, the acid is selected from one or a mixture of hydrogen chloride, sulfuric acid, and phosphoric acid; in some more typical embodiments, the acid is selected from one or a mixture of hydrogen chloride and sulfuric acid; in some most typical embodiments, the acid is hydrogen chloride; in some most typical embodiments, the acid is sulfuric acid.

[0059] In some embodiments of the present invention, the acid in step (ii) participates in the reaction in the form of an acid solution, and one or more of water, alcohol solvents, ester solvents, and dioxane form a solution with the acid; in some typical embodiments, the acid in step (ii) participates in the reaction in the form of an acid solution, and one of water, ethanol, ethyl acetate, and dioxane forms a mixed solution with the acid; in some typical embodiments, the acid in step (ii) participates in the reaction in the form of an ethanol solution of the acid; in some typical embodiments, the acid in step (ii) participates in the reaction in the form of an aqueous solution of the acid.

[0060] In some typical embodiments, the acid in step (ii) is hydrogen chloride, and it participates in the reaction in solution form, wherein the mass fraction of hydrogen chloride in the hydrogen chloride solution is 5%-50%; in some more typical embodiments, the acid in step (ii) is hydrogen chloride, and it participates in the reaction in solution form, wherein the mass fraction of hydrogen chloride in the hydrogen chloride solution is 10%-38%; in some even more typical embodiments, the acid in step (ii) is hydrogen chloride, and it participates in the reaction in solution form, wherein the mass fraction of hydrogen chloride in the hydrogen chloride solution is 35%-38%; in some of the most typical embodiments, the acid in step (ii) is hydrogen chloride. The acid in step (ii) is sulfuric acid, which participates in the reaction in solution form, wherein the mass fraction of hydrogen chloride in the hydrogen chloride solution is 35%, 36%, 37%, or 38%. In some more typical embodiments, the acid in step (ii) is sulfuric acid, which participates in the reaction in solution form, and the mass fraction of sulfuric acid in the sulfuric acid solution is 10%-98%. In some even more typical embodiments, the acid in step (ii) is sulfuric acid, which participates in the reaction in solution form, and the mass fraction of sulfuric acid in the sulfuric acid solution is 50%-70%. In some of the most typical embodiments, the acid in step (ii) is sulfuric acid, which participates in the reaction in solution form, and the mass fraction of sulfuric acid in the sulfuric acid solution is 98%.

[0061] In some embodiments of the present invention, the molar ratio of the acid to the compound of formula I in step (ii) is 1-20:1, based on a monocarboxylic acid; in some typical embodiments, the molar ratio of the acid to the compound of formula I in step (ii) is 4-12:1, based on a monocarboxylic acid; in some more typical embodiments, the molar ratio of the acid to the compound of formula I in step (ii) is 5-10:1, based on a monocarboxylic acid; and in some even more typical embodiments, the molar ratio of the acid to the compound of formula I in step (ii) is 2:1, 3:1, 4:1, 5:1, 5.5:1, 6:1, 7:1, 8:1, 9:1, or 10:1, based on a monocarboxylic acid.

[0062] In some embodiments of the present invention, the reaction temperature in step (ii) is 60°C-140°C; in some typical embodiments, the reaction temperature in step (ii) is 80°C-140°C; in some more typical embodiments, the reaction temperature in step (ii) is 100°C-140°C; in some even more typical embodiments, the reaction temperature in step (ii) is 100°C-125°C; in some even more typical embodiments, the reaction temperature in step (ii) is 100°C-115°C; in some most typical embodiments, the reaction temperature in step (ii) is 70°C, 75°C, 80°C, 85°C, 90°C, 100°C, 105°C, 110°C, 115°C, 120°C, or 125°C.

[0063] In some embodiments of the present invention, the reaction time in step (ii) is 5 hours to 90 hours; in some typical embodiments, the reaction time in step (ii) is 8 hours to 72 hours; in some more typical embodiments, the reaction time in step (ii) is 12 hours to 48 hours; in some even more typical embodiments, the reaction time in step (ii) is 18 hours to 36 hours; in some even more typical embodiments, the reaction time in step (ii) is 22 hours to 25 hours; in some of the most typical embodiments, the reaction time in step (ii) is 18 hours, 24 hours, 30 hours, or 36 hours.

[0064] In some embodiments of the present invention, the method further includes extracting the compound of formula III-1 or its salt; in some typical embodiments, the method further includes extracting and concentrating the compound of formula III-1 or its salt; in some more typical embodiments, the method further includes extracting the compound of formula III-1 using one or more solvents selected from dichloromethane, chloroform, ester solvents, ether solvents, toluene, xylene, and chlorobenzene; in some even more typical embodiments, the method further includes extracting the compound of formula III-1 using one or more solvents selected from dichloromethane, chloroform, xylene, and chlorobenzene; in some even more typical embodiments, the method further includes extracting the compound of formula III-1 using one or more solvents selected from dichloromethane, chloroform, xylene, and toluene; in some most typical embodiments, the method further includes extracting the compound of formula III-1 using xylene or toluene; in some most typical embodiments, the method further includes extracting the compound of formula III-1 using xylene; in some most typical embodiments, the method further includes extracting the compound of formula III-1 using toluene.

[0065] This invention provides a method for preparing a compound of formula IV or a salt thereof, the method comprising:

[0066] (i) The compound of formula I and the compound of formula II or their salts react in the presence of a base and a reaction solvent;

[0067] (ii) In the presence of an acid, the reaction further produces a compound of formula III-1 or a salt thereof;

[0068] (iii) A compound of formula III-1 or a salt thereof reacts with a compound of formula V or a salt thereof in the presence of a reaction promoter to produce a compound of formula IV or a salt thereof.

[0069]

[0070] R 4 Selected from hydrogen or C1-C4 alkyl;

[0071] The reaction promoter is selected from one or a mixture of two or more of acids, alumina, silica gel, or molecular sieves.

[0072] This invention provides a method for preparing a compound of formula IV or a salt thereof, the method comprising:

[0073] (i) The compound of formula I and the compound of formula II or their salts react in the presence of a base and a reaction solvent;

[0074] (ii) In the presence of an acid, the reaction further produces a compound of formula III-1 or a salt thereof;

[0075] (iii) A compound of formula III-1 or a salt thereof reacts with a compound of formula V or a salt thereof in the presence of a reaction promoter to produce a compound of formula IV or a salt thereof.

[0076]

[0077] R 4 Selected from hydrogen or C1-C4 alkyl;

[0078] The reaction promoter is selected from one or a mixture of two or more of acids, silica gel, or molecular sieves.

[0079] This invention provides a method for preparing a compound of formula IV-1 or a salt thereof, the method comprising:

[0080] (i) The compound of formula I and the compound of formula II or their salts react in the presence of a base and a reaction solvent;

[0081] (ii) In the presence of an acid, the reaction further produces a compound of formula III-1 or a salt thereof;

[0082] (iii) A compound of formula III-1 or a salt thereof reacts with a compound of formula V-1 or a salt thereof in the presence of a reaction promoter to produce a compound of formula IV-1 or a salt thereof.

[0083]

[0084] The reaction promoter is selected from one or a mixture of two or more of acids, alumina, silica gel, or molecular sieves.

[0085] This invention provides a method for preparing a compound of formula IV-1 or a salt thereof, the method comprising:

[0086] (i) The compound of formula I and the compound of formula II or their salts react in the presence of a base and a reaction solvent;

[0087] (ii) In the presence of an acid, the reaction further produces a compound of formula III-1 or a salt thereof;

[0088] (iii) A compound of formula III-1 or a salt thereof reacts with a compound of formula V-1 or a salt thereof in the presence of a reaction promoter to produce a compound of formula IV-1 or a salt thereof.

[0089]

[0090] The reaction promoter is selected from one or a mixture of two or more of acids, silica gel, or molecular sieves.

[0091] In some embodiments of the present invention, the compound of formula III-1 or its salt obtained in step (ii) is used directly in step (iii) to prepare compound IV-1 without separation and purification; in some embodiments of the present invention, after the reaction in step (ii) is completed, it is extracted with an extraction solvent and then directly used in step (iii) to prepare compound IV-1; in some embodiments of the present invention, after the reaction in step (ii) is completed, it is extracted and concentrated with an extraction solvent and then directly used in step (iii) to prepare compound IV-1. In some typical embodiments of the present invention, the mass of compound III-1 or its salt in step (iii) is determined by detection or calculation; in some embodiments of the present invention, the mass of compound III-1 or its salt in step (iii) is calculated by combining the amount of compound I in step (i) and the yield of compound III-1 or its salt in steps (i) and (ii). In some embodiments of the present invention, the yield of the compound of formula III-1 or its salt in steps (i) and (ii) is 60%-80%; in some typical embodiments of the present invention, the yield of the compound of formula III-1 or its salt in steps (i) and (ii) is 65%-80%; in some more typical embodiments of the present invention, the yield of the compound of formula III-1 or its salt in steps (i) and (ii) is 70%-78%; and in some of the most typical embodiments of the present invention, the yield of the compound of formula III-1 or its salt in steps (i) and (ii) is 75%-77%.

[0092] In some embodiments of the present invention, the amount of material fed in step (iii) is based on the amount of compound I fed in step (i). In some typical embodiments of the present invention, the molar ratio of compound I to compound V or its salt is 1:0.8-2.6; in some more typical embodiments, the molar ratio of compound I to compound V or its salt is 1:0.9-2.3. In some embodiments of the present invention, the reaction promoter in step (iii) is an acid, and the molar ratio of acid to compound I is 0.006-0.375:1; in some more typical embodiments, the reaction promoter in step (iii) is an acid, and the molar ratio of acid to compound I is 0.0067-0.15:1.

[0093] In some embodiments of the invention, step (ii) further comprises extracting the compound of formula III-1 or a salt thereof; in some typical embodiments, step (ii) further comprises extracting the compound of formula III-1 or a salt thereof and optionally concentrating it; in some more typical embodiments, it further comprises extracting and concentrating the compound of formula III-1 or a salt thereof, directly for use in step (iii) to prepare the compound of formula IV-1, and step (iii) does not add any solvent.

[0094] This invention provides a method for preparing buvacertane, the method comprising reacting a compound of formula III or a salt thereof with a compound of formula V or a salt thereof in the presence of a reaction promoter to generate a compound of formula IV or a salt thereof.

[0095]

[0096] R 1 R 2 Each is independently selected from hydrogen or C1-C4 alkyl groups;

[0097] R 4 Selected from hydrogen or C1-C4 alkyl;

[0098] The catalyst reaction promoter is selected from one or a mixture of two or more of acids, alumina, silica gel or molecular sieves.

[0099] This invention provides a method for preparing buvacertane, the method comprising reacting a compound of formula III or a salt thereof with a compound of formula V or a salt thereof in the presence of a reaction promoter to generate a compound of formula IV or a salt thereof.

[0100]

[0101] R 1 R 2 Each is independently selected from hydrogen or C1-C4 alkyl groups;

[0102] R 4 Selected from hydrogen or C1-C4 alkyl;

[0103] The catalyst reaction promoter is selected from one or a mixture of two or more of acids, silica gel, or molecular sieves.

[0104] This invention provides a method for preparing buvacertane, the method comprising reacting a compound of formula III-1 or a salt thereof with a compound of formula V-1 or a salt thereof in the presence of a reaction promoter to generate a compound of formula IV-1 or a salt thereof.

[0105]

[0106] The reaction promoter is selected from one or a mixture of two or more of acids, alumina, silica gel, or molecular sieves.

[0107] This invention provides a method for preparing buvacertane, the method comprising reacting a compound of formula III-1 or a salt thereof with a compound of formula V-1 or a salt thereof in the presence of a reaction promoter to generate a compound of formula IV-1 or a salt thereof.

[0108]

[0109] The reaction promoter is selected from one or a mixture of two or more of acids, silica gel, or molecular sieves.

[0110] This invention provides a method for preparing buvacertane, the method comprising:

[0111] (i) The compound of formula I and the compound of formula II or their salts react in the presence of a base and a reaction solvent;

[0112] (ii) In the presence of an acid, further reaction produces a compound of formula III-1 or its salt.

[0113]

[0114] This invention provides a method for preparing buvacertane, the method comprising:

[0115] (i) The compound of formula I and the compound of formula II or their salts react in the presence of a base and a reaction solvent;

[0116] (ii) In the presence of an acid, the reaction further produces a compound of formula III-1 or a salt thereof;

[0117] (iii) A compound of formula III-1 or a salt thereof reacts with a compound of formula V or a salt thereof in the presence of a reaction promoter to produce a compound of formula IV or a salt thereof.

[0118]

[0119] R 4 Selected from hydrogen or C1-C4 alkyl;

[0120] The catalyst reaction promoter is selected from one or a mixture of two or more of acids, alumina, silica gel or molecular sieves.

[0121] This invention provides a method for preparing buvacertane, the method comprising:

[0122] (i) The compound of formula I and the compound of formula II or their salts react in the presence of a base and a reaction solvent;

[0123] (ii) In the presence of an acid, the reaction further produces a compound of formula III-1 or a salt thereof;

[0124] (iii) A compound of formula III-1 or a salt thereof reacts with a compound of formula V or a salt thereof in the presence of a reaction promoter to produce a compound of formula IV or a salt thereof.

[0125]

[0126] R 4 Selected from hydrogen or C1-C4 alkyl;

[0127] The catalyst reaction promoter is selected from one or a mixture of two or more of acids, silica gel, or molecular sieves.

[0128] This invention provides a method for preparing buvacertane, the method comprising:

[0129] (i) The compound of formula I and the compound of formula II or their salts react in the presence of a base and a reaction solvent;

[0130] (ii) In the presence of an acid, it further generates a compound of formula III-1 or a salt thereof;

[0131] (iii) A compound of formula III-1 or a salt thereof reacts with a compound of formula V-1 or a salt thereof to produce a compound of formula IV-1 or a salt thereof.

[0132]

[0133] The catalyst reaction promoter is selected from one or a mixture of two or more of acids, alumina, silica gel or molecular sieves.

[0134] This invention provides a method for preparing buvacertane, the method comprising:

[0135] (i) The compound of formula I and the compound of formula II or their salts react in the presence of a base and a reaction solvent;

[0136] (ii) In the presence of an acid, it further generates a compound of formula III-1 or a salt thereof;

[0137] (iii) A compound of formula III-1 or a salt thereof reacts with a compound of formula V-1 or a salt thereof to produce a compound of formula IV-1 or a salt thereof.

[0138]

[0139] The catalyst reaction promoter is selected from one or a mixture of two or more of acids, silica gel, or molecular sieves.

[0140] The compounds of formula I and formula II in this invention can be obtained by purchase or prepared according to existing technology.

[0141] The purity of compounds of formula III and formula IV in this invention can be determined by liquid chromatography, and the specific detection conditions are as follows:

[0142] Instrumentation: High-performance liquid chromatograph equipped with a UV detector and a ghost peak collection column;

[0143] Column: Agilent Zobax Eclipse XDB C18 150×4.6mm, 5μm;

[0144] Column temperature: 30℃; Wavelength: 205nm;

[0145] Flow rate: 1.0 ml / min; Injection volume: 20 μl; Run time: 33 min;

[0146] Mobile phase A: 0.01 mol / L ammonium dihydrogen phosphate aqueous solution, with pH adjusted to 2.7 using phosphoric acid;

[0147] Mobile phase B: Acetonitrile;

[0148] The gradient table is shown in Table 1:

[0149] Table 1

[0150] Time (min) Mobile phase A (%V / V) Mobile phase B (% V / V) 0 95 5 10 88 12 18 40 60 24 40 60 26 95 5 33 95 5

[0151] The mass spectra of compounds of formula III and formula IV in this invention can be obtained by liquid chromatography-mass spectrometry, and the specific detection conditions are as follows:

[0152] Instrumentation: High-performance liquid chromatograph equipped with a single-stage quadrupole mass spectrometer detector;

[0153] Chromatographic column: ACE Excel 3C18-PFP 150*4.6mm, 3.0μm;

[0154] Mobile phase A: 0.05% (V / V) aqueous formic acid;

[0155] Mobile phase B: Acetonitrile;

[0156] Column temperature: 40℃; Injection volume: 5.0 μL; Run time: 15 min;

[0157] The gradient table is shown in Table 2:

[0158] Table 2

[0159] Time (min) Mobile phase A (%V / V) Mobile phase B (% V / V) Flow rate (mL / min) 0 90 10 1.0 2 90 10 1.0 8 30 70 1.0 9 30 70 1.0 9.5 90 10 1.0 15 90 10 1.0

[0160] Mass spectrometry parameters are shown in Table 3:

[0161] Table 3

[0162]

[0163] This invention provides a method for preparing a compound of formula IV, which yields a high-yield product with high purity. This compound of formula IV is a key intermediate in the synthesis of buvasidan.

[0164] This invention provides a method for preparing a compound of formula III, which yields a high-yield product with high purity. The compound of formula III is a key intermediate in the synthesis of buvasidan.

[0165] Definitions and Explanations

[0166] Unless otherwise specified, the following terms in this invention have the following meanings:

[0167] "Salts of compounds" include acid addition salts formed by compounds with inorganic or organic acids, including but not limited to hydrochlorides, hydrobroms, sulfates, phosphates, methanesulfonates, ethanesulfonates, toluenesulfonates, benzenesulfonates, naphthalene disulfonates, formates, acetates, trifluoroacetates, propionates, lactates, tartrates, malates, citrates, fumarates, maleates, and benzoates; or base addition salts formed by compounds with conventional bases, including but not limited to alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines having 1-16 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyl diisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, or N-methylpiperidine.

[0168] "Xylene" refers to one or more of the following reagents: o-xylene, m-xylene, and para-xylene, such as commercially available xylene.

[0169] "Water" refers to purified water.

[0170] "Alkali metal alkoxides" include, but are not limited to, one or more of lithium methoxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide.

[0171] "Alcohol solvents" include, but are not limited to, one or more of the following solvents: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, propylene glycol, and glycerol.

[0172] "Ether solvents" include, but are not limited to, one or more of the following solvents: diethyl ether, isopropyl ether, n-butyl ether, n-hexyl ether, 2-ethylhexyl ether, dimethyl dioxane, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol mono-n-butyl ether, ethylene glycol mono-n-hexyl ether, ethylene glycol monophenyl ether, ethylene glycol mono-2-ethylbutyl ether, ethylene glycol dibutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol mono-n-butyl ether, diethylene glycol mono-n-hexyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, propylene glycol monobutyl ether, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether, dipropylene glycol monobutyl ether, tripropylene glycol monomethyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0173] "Ester solvents" include, but are not limited to, one or more of the following solvents: diethyl carbonate, methyl acetate, ethyl acetate, γ-butyrolactone, γ-valerolactone, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-butyl propionate, methyl lactate, ethyl lactate, γ-butyrolactone, n-butyl lactate, n-pentyl lactate, diethyl malonate, dimethyl phthalate, and diethyl phthalate.

[0174] "Compound of Formula X" refers to the compound represented by Formula X itself. "Compound of Formula X or its salt" means that when Compound X is a free acid, "Compound of Formula X or its salt" is Compound X or its base addition salt that conforms to the principle of valence bond; when Compound X is a free base, "Compound of Formula X or its salt" is Compound X or its acid addition salt that conforms to the principle of valence bond; when, based on common knowledge of those skilled in the art, Compound X cannot form a salt, "Compound of Formula X or its salt" refers only to the compound represented by Formula X itself.

[0175] "Extraction" refers to the process of extracting nutrients.

[0176] When the chemical formula of the compound of the present invention contains two Rs simultaneously 4 At that time, two R 4 For example, two R groups exist in compound V. 4 When R 4 When hydrogen is present, compound V is compound V-1.

[0177] "Yield" refers to the ratio of the actual quality of the product obtained to the quality of the product that can be obtained through theoretical calculations.

[0178] "Within" refers to a certain range, including the endpoints of that range; for example, "within 50 times" means less than or equal to 50 times.

[0179] "Hydrate" refers to a compound containing water, such as water that is linked to the compound by coordinate bonds or covalent bonds.

[0180] "Aluminum oxide" refers to aluminum oxide.

[0181] "Silicone" refers to a type of amorphous silicon dioxide.

[0182] "Molecular sieve" refers to a type of hydrated aluminosilicate.

[0183] "Calculated as a monobasic alkali" means that the equivalent ratio of substances is calculated based on a monobasic alkali. For example, "Calculated as a monobasic alkali, the molar ratio of the alkali to the compound of formula I in step (i) of the method is 1-5:1". When the alkali is sodium hydroxide, the molar ratio of the alkali to the compound of formula I in step (i) of the method is 1-5:1; when the alkali is magnesium hydroxide, the molar ratio of the alkali to the compound of formula I in step (i) of the method is 0.5-2.5:1.

[0184] "Calculated as a monocarboxylic acid" means that the equivalent ratio of substances is calculated based on monocarboxylic acids. For example, "Calculated as a monocarboxylic acid, the molar ratio of acid to compound I in the method of step (ii) is 1-20:1". When the acid is hydrogen chloride, the molar ratio of acid to compound I in the method of step (ii) is 1-20:1; when the acid is sulfuric acid, the molar ratio of acid to compound I in the method of step (ii) is 0.5-10:1.

[0185] "Independently" means that several groups present in a compound can each independently choose within the range of substituents without affecting each other; they can be the same substituent or different substituents. For example, "R" 1 R 2 "Each is independently selected from hydrogen or C1-C4 alkyl" includes "R" 1 R 2 Simultaneously hydrogen, "R" 1 R 2 Simultaneously C1-C4 alkyl, "R" 1 For hydrogen, R 2 "C1-C4 alkyl" and "R" 1 It is a C1-C4 alkyl group, R 2 The case of "for hydrogen".

[0186] "36% hydrochloric acid" refers to an aqueous solution of hydrogen chloride with a mass fraction of 36%.

[0187] "98% concentrated sulfuric acid" refers to an aqueous solution of sulfuric acid with a mass fraction of 98%.

[0188] Those skilled in the art will readily understand that the error range of the parameters listed in this invention also falls within the scope of protection of this invention. The error range includes, but is not limited to, the degree of expected experimental error, technical error, instrument error, and industrial operation error of the given technique for measuring the value. Detailed Implementation

[0189] For clarity, the present invention will be further described in detail below with reference to embodiments; however, it should be understood that the embodiments are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification.

[0190] Example 1: Preparation of Compound III-1

[0191] 58.0 g of sodium hydroxide and 100 g of the free acid of compound II were added to 300 g of water; the temperature was lowered to 0℃-15℃, and 42 g of compound I was added dropwise while maintaining the temperature at 0℃-15℃ during the addition process; after the addition was completed, the reaction was maintained at 0℃-15℃ for 45 minutes, then 353.3 g of 36% hydrochloric acid was added, and the temperature was raised to 105℃ for 24 hours. The mixture was extracted twice with 400 mL of toluene (400 mL / time, for a total of 2 times), and the toluene was concentrated to obtain 76 g of the free acid of compound III-1, with a yield of 75% and a purity of 99.2%, [M+H]. + :175.1.

[0192] Preparation of Compound III-1 in Examples 2-5

[0193] Following the operating steps of Example 1, only the type of base and / or its molar ratio with the compound of Formula I were changed to prepare the free acid of compound III-1. The specific conditions are shown in Table 4.

[0194] Table 4

[0195]

[0196] Preparation of Compound III-1 in Examples 6-8

[0197] Following the operating steps of Example 1, only the molar ratio of the free acids of Formula I and Formula II was changed to prepare the free acid of Formula III-1. The specific conditions are shown in Table 5.

[0198] Table 5

[0199]

[0200] Preparation of Compound III-1 in Examples 9-11

[0201] Following the operating steps of Example 1, only the type of acid and / or its molar ratio with the compound of Formula I (wherein the acid is a monocarboxylic acid) were changed to prepare the free acid of compound III-1. Specific conditions are shown in Table 6.

[0202] Table 6

[0203]

[0204] Preparation of Compound III-1 in Examples 12-13

[0205] Following the operating steps of Example 1, only the "heat to 105°C for reaction" was replaced with the following reaction temperatures to prepare the free acid of compound III-1. Specific conditions are shown in Table 7:

[0206] Table 7

[0207] Example reaction temperature yield purity 1 105℃ 75％ 99.2％ 12 115℃ 73％ 99.0％ 13 125℃ 69％ 98.5％

[0208] Example 14 Preparation of Compound IV-1

[0209] Take 17.4g of the free acid of compound III-1 obtained by the preparation method described in Example 1, add 7.2g of the free base of compound V-1, 200g of xylene, and then add 0.17g of p-toluenesulfonic acid. Heat the reaction system to 140℃ and react for 3 hours. After 3 hours of reaction, cool to -5℃ and filter after 0.5 hours. After filtration, pulp with 200g of drinking water for 0.5 hours, filter again, and dry to obtain 14g of the free base of compound IV-1, with a yield of 90.3% and a purity of 99.5%, [M+H]. + :156.2.

[0210] Preparation of Compound IV-1 in Examples 15-20

[0211] Following the operating steps of Example 14, only the type of reaction promoter and / or its ratio with the free acid of Formula III-1 were changed to prepare the free base of Formula IV-1. Specific conditions are shown in Tables 8 and 9.

[0212] Table 8

[0213]

[0214] "-" indicates that it has not been added.

[0215] Table 9

[0216]

[0217] Preparation of Compounds of Formula IV-1 in Examples 21-23

[0218] Following the operating steps of Example 14, only the molar ratio of the free acid of compound III-1 to the free base of compound V-1 was changed to prepare the free base of compound IV-1. The specific conditions are shown in Table 10.

[0219] Table 10

[0220]

[0221] Preparation of Compounds of Formula IV-1 in Examples 24-27

[0222] Following the procedure of Example 14, only the reaction solvent and / or reaction temperature were changed to prepare the free base of compound IV-1. Specific conditions are shown in Table 11.

[0223] Table 11

[0224] Example reaction solvent reaction temperature yield purity 14 xylene 140℃ 90％ 99.5％ 24 Toluene 110℃ 78％ 99.7％ 25 Toluene 120℃ 80％ 99.5％ 26 xylene 120℃ 84％ 99.6％ 27 xylene 150℃ 89％ 99.3％

[0225] Example 28 Preparation of Compound IV-1

[0226] Take 65.0 g of sodium hydroxide and 110 g of the free acid of compound II, and add it to 350 g of water; cool to 0℃-15℃, and add 45 g of compound I dropwise, maintaining the temperature at 0℃-15℃ during the dropwise addition; after the dropwise addition, maintain the temperature at 0℃-15℃ for 30 minutes, add 360 g of 36% hydrochloric acid, and heat to 105℃ to react for 30 hours. Extract twice with 500 mL of xylene (i.e., 500 mL / time, for a total of 2 times), and add 35 g of the free base of compound V-1 and 0.75 g of p-toluenesulfonic acid to the xylene solution. Heat the reaction system to 140℃ and react for 2 hours. After reacting for 2 hours, cool to -5℃. After crystallization for 0.5 hours, filter. After filtration, pulp with 1000 g of drinking water. After pulping, filter again and dry to obtain 68 g of the free base of compound IV-1 with a purity of 99.6%.

[0227] The embodiments described above are merely examples of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. A process for preparing a compound of formula IV or a salt thereof, said process comprising reacting a compound of formula III or a salt thereof with a compound of formula V or a salt thereof in the presence of a reaction promoter to form a compound of formula IV or a salt thereof, ###0001### III IV V said reaction promoter being selected from the group consisting of an acid, alumina, silica gel or a mixture of two or more thereof. R 1 , R 2 are each independently selected from hydrogen or C1-C4alkyl; R 4 selected from hydrogen or C1-C4alkyl; 2. A process for preparing a compound of formula IV-1 or a salt thereof, said process comprising reacting a compound of formula III-1 or a salt thereof with a compound of formula V-1 or a salt thereof in the presence of a reaction promoter to form a compound of formula IV-1 or a salt thereof, ###0002### III-1 IV-1 V-1 said reaction promoter being selected from the group consisting of an acid, alumina, silica gel or a mixture of two or more thereof.

3. A process for preparing a compound of formula III-1 or a salt thereof, said process comprising: (i) reacting a compound of formula I and a compound of formula II or a salt thereof in the presence of a base and a reaction solvent; (ii) further reacting in the presence of an acid to form a compound of formula III-1 or a salt thereof, ###0003### III-1 4. A process for preparing a compound of formula IV or a salt thereof, said process comprising: (i) reacting a compound of formula I and a compound of formula II or a salt thereof in the presence of a base and a reaction solvent; (ii) further reacting in the presence of an acid to form a compound of formula III-1 or a salt thereof; (iii) reacting a compound of formula III-1 or a salt thereof with a compound of formula V or a salt thereof in the presence of a reaction promoter to form a compound of formula IV or a salt thereof, ###0004### III IV V said reaction promoter being selected from the group consisting of an acid, alumina, silica gel or a mixture of two or more thereof.

5. A process for preparing a compound of formula IV-1 or a salt thereof, said process comprising: (i) reacting a compound of formula I and a compound of formula II or a salt thereof in the presence of a base and a reaction solvent; (ii) further reacting in the presence of an acid to form a compound of formula III-1 or a salt thereof; (iii) reacting a compound of formula III-1 or a salt thereof with a compound of formula V-1 or a salt thereof in the presence of a reaction promoter to form a compound of formula IV-1 or a salt thereof, ###0005### III-1 IV-1 V-1 said reaction promoter being selected from the group consisting of an acid, alumina, silica gel or a mixture of two or more thereof.

6. A process for preparing brivaracetam, said process comprising reacting a compound of formula III or a salt thereof with a compound of formula V or a salt thereof in the presence of a reaction promoter to form a compound of formula IV or a salt thereof, ###0006### III IV V said reaction promoter being selected from the group consisting of an acid, alumina, silica gel or a mixture of two or more thereof.

7. A process for preparing brivaracetam, said process comprising reacting a compound of formula III-1 or a salt thereof with a compound of formula V-1 or a salt thereof in the presence of a reaction promoter to form a compound of formula IV-1 or a salt thereof, ###0007### III-1 IV-1 V-1 said reaction promoter being selected from the group consisting of an acid, alumina, silica gel or a mixture of two or more thereof.

8. A process for preparing brivaracetam, said process comprising: (i) reacting a compound of formula I and a compound of formula II or a salt thereof in the presence of a base and a reaction solvent; (ii) further reacting in the presence of an acid to form a compound of formula III-1 or a salt thereof, ###0008### III-1 9. A process for preparing brivaracetam, said process comprising: (i) reacting a compound of formula I and a compound of formula II or a salt thereof in the presence of a base and a reaction solvent; ​ ​ R 4 selected from hydrogen or C1-C4alkyl; ​ ​ ​ ​ ​ ​ ​ R 1 , R 2 are each independently selected from hydrogen or C1-C4alkyl; R 4 selected from hydrogen or C1-C4alkyl; ​ ​ ​ ​ ​ ​ ​ ​ (ii) further reacting in the presence of an acid to form a compound of formula III-1 or a salt thereof; (iii) reacting a compound of formula III-1 or a salt thereof with a compound of formula V or a salt thereof in the presence of a reaction promoter to form a compound of formula IV or a salt thereof, R 4 selected from hydrogen or C1-C4alkyl; the catalyst reaction promoter is selected from the group consisting of an acid, alumina, silica gel, or a mixture of two or more thereof.

10. A method of preparing Brivaracetam, the method comprising, (i) reacting a compound of formula I and a compound of formula II or a salt thereof in the presence of a base and a reaction solvent; (ii) further reacting in the presence of an acid to form a compound of formula III-1 or a salt thereof; (iii) reacting a compound of formula III-1 or a salt thereof with a compound of formula V-1 or a salt thereof to form a compound of formula IV-1 or a salt thereof, the catalyst reaction promoter is selected from the group consisting of an acid, alumina, silica gel, or a mixture of two or more thereof.

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