Process for the preparation of pyrimido[6,1-a]isoquinolin-4-ones

Abstract

The present invention provides a facile process for the preparation of a pyrimido[6,1-a]isoquinolin-4-one of formula I or a pharmaceutically acceptable acid addition salt thereof, preferably encainide, which process involves the reaction of a precursor with a higher alkylating agent.

Description

[0001] This application claims the right to European patent application EP24382199.8, filed on February 23, 2024. Technical Field

[0002] The present invention provides a simple method for preparing pyrimido[6,1-a]isoquinoline-4-one of formula I or a pharmaceutically acceptable acid addition salt thereof (preferably ensifentrine), the method involving the reaction of the precursor with an advanced alkylating agent. Background Technology

[0003] Some pyrimido[6,1-a]isoquinoline-4-ones have been documented for use in respiratory diseases as bronchodilators with anti-inflammatory properties, such as trequinsin in GB1597717 A. 9,10-Dimethoxy-2-[(2,4,6-trimethylphenyl)imino]-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinoline-4-one, also known as encefentraline, as shown below as compound (Ia), is a dual inhibitor of phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4), possessing combined anti-inflammatory and bronchodilatory properties. Encefentraline is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic obstructive pulmonary disease (COPD) and is marketed under the brand name OHTUVAYRE as an inhaled suspension.

[0004] .

[0005] WO00 / 58308 A1 discloses encefentraline, its preparation method, and its use in the treatment of asthma or COPD. Specifically, encefentraline is prepared in Example 1 (Scheme 1), which involves the alkylation of intermediate (IIa) (where Ar is 2,4,6-trimethylphenyl) with N-(2-bromoethyl)phthalimide, followed by deprotection with hydrazine, and finally, the resulting amino intermediate (VI) is reacted with sodium cyanate in the presence of hydrochloric acid. This method has several disadvantages, such as a low yield of only 13.5% for the alkylation reaction with the phthalimide derivative, and the use of genotoxic hydrazine in the deprotection step.

[0006] Option 1 WO2016128742 A1 discloses a pharmaceutically acceptable acid addition salt of compound (Ia) with ethane-1,2-disulfonic acid, ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid, said acid addition salt having an improved intrinsic dissolution rate and suitable for use in pressurized dosage forms and dry powder formulations.

[0007] WO2018 / 020249 A1 discloses an alternative method for preparing encefentraline, the method involving the N-alkylation of the intermediate (IIa) (wherein Ar is 2,4,6-trimethylphenyl) with bromoacetonitrile to obtain intermediate (VII), which is further hydrogenated to obtain the aforementioned amino intermediate (VI), which is further converted into the final encefentraline (Ia) as described above. This method also has the disadvantage of using multiple steps, which increases the cost of the final encefentraline, thereby increasing the cost of pharmaceutical products containing the encefentraline.

[0008] Option 2 Therefore, based on what is known in the art, there is still a need to develop an efficient method for the industrial-scale preparation of encefentraline that is energy-efficient, cost-effective, and avoids the problems of known methods. Summary of the Invention

[0009] The aforementioned prior art methods provide enthalpyridine in very low yields and are accompanied by several associated impurities. Surprisingly, the inventors have discovered that the precursor amino intermediate of formula (II) can react directly with the advanced alkylating agent of formula (III) (Scheme 3) in moderate yields and with high purity, thereby providing enthalpyridine in a shorter sequence of steps. Therefore, advantageously, this method allows for the acquisition of enthalpyridine with a reduced number of steps while avoiding the use of toxic reagents.

[0010] Option 3 Therefore, the present invention relates to a method for preparing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. ; Where R 1 and R 2 They may be the same or different, and each is independently a C1-C6 alkyl or C2-C7 acyl group; or, R 1 and R 2 Together they form C1-C6 alkylene groups; R 3 and R 4 They may be the same or different, and each is independently selected from hydrogen, halogens, and C1-C6 alkyl groups; R5 and R 6 They may be the same or different, and each is independently selected from hydrogen, halogens, and C1-C6 alkyl groups; X is selected from CHR. 7 O and NR 7 ;R 7 It is hydrogen or C1-C6 alkyl; and Ar is 2,4,6-trimethylphenyl; the method includes the step of reacting a compound of formula (II) with a compound of formula (III). ; Where R 1 R 2 R 3 R 4 R 5 R 6 X and Ar are as defined for compounds of formula (I). ; Wherein Y is a leaving group, the leaving group being selected from halogens, methanesulfonate groups (OMs), p-toluenesulfonate groups (OTs), p-nitrobenzenesulfonate groups (ONs), acetate groups (OAc) and trifluoromethanesulfonate groups (OTf), preferably Y is a halogen, such as Cl, Br and I, more preferably Y is Cl.

[0011] In particular, the method of the present invention provides a compound of formula I in an efficient manner, wherein R 1 and R 2 Methyl; R 3 and R 4 It is hydrogen; R 5 and R 6 The substance is hydrogen; and X is CH2, i.e., a compound of formula (Ia) (i.e., encefentrane), the method involving making a compound of formula (II) (where R is hydrogen) 1 and R 2 Methyl; R 3 and R 4 It is hydrogen; R 5 and R 6 The compound (i.e., a compound of formula (IIa)) is hydrogen; and X is CH2. The compound of formula (III) is reacted with a higher alkylating agent in moderate yield and high purity.

[0012] The present invention also relates to a method in which the compound of formula I thus obtained is combined with a pharmaceutically acceptable acid, such as ethane-1,2-disulfonic acid, ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, to obtain the corresponding pharmaceutically acceptable acid addition salt of the compound of formula I.

[0013] definition When describing the compounds and methods of this invention, unless otherwise stated, the following terms have the following meanings.

[0014] As used herein, C1-C6 alkyl or alkyl moiety is a straight-chain or branched alkyl or alkyl moiety containing 1 to 6 carbon atoms. Typically, C1-C6 alkyl or alkyl moiety is a C1-C4 alkyl or alkyl moiety. C1-C4 alkyl or alkyl moiety is a straight-chain or branched alkyl or alkyl moiety containing 1 to 4 carbon atoms. Examples of C1-C6 alkyl and alkyl moiety include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and 3-methylbutyl. Examples of C1-C4 alkyl and alkyl moiety include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. For the avoidance of doubt, when two alkyl moiety are present in a group, the alkyl moiety may be the same or different.

[0015] As used herein, C1-C6 alkylene or alkylene moieties are straight-chain or branched alkylene or alkylene moieties. Examples include methylene, ethylene, and n-propylene, as well as some of them. As used herein, halogens are typically chlorine, fluorine, bromine, or iodine.

[0016] As used herein, the C2-C7 acyl group is typically the C1-C6 alkyl group attached to the -C(O)- group.

[0017] As used herein, the terms "conventional separation techniques" or "purification" refer to the process of removing foreign elements from a product to obtain a purified product. The term "industrial purification" refers to purification that can be carried out on an industrial scale, such as solvent extraction, filtration, pulping, washing, phase separation, distillation, centrifugation, or crystallization.

[0018] The term "crystallization" refers to any method known to those skilled in the art, such as crystallizing from a single solvent or a combination of solvents by optionally dissolving the compound at a high temperature and by cooling the solution or removing the solvent from the solution, or both. It also includes methods such as dissolving the compound in a solvent and precipitating the compound by adding an "antisolvent" (i.e., a solvent in which the target compound has low solubility or is insoluble, and which can be used to precipitate the compound by adding the solvent to the solution in which the compound is dissolved).

[0019] As used herein, the term "solvent" refers to water or an organic molecule capable of at least partially dissolving another substance (i.e., the solute). A solvent may be a liquid at room temperature. Suitable solvents may be, but are not limited to, (C1-C1) 12 Hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene; (C6-C 14 Aromatic solvents, such as toluene, o-xylene, m-xylene, and p-xylene; halogenated (C1-C2) solvents. 12Hydrocarbon solvents, such as 1,2-dichloroethane, dichloromethane, chloroform; (C1-C2) 12 Ether solvents, such as diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane; ester solvents, such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, diethyl malonate; ketone solvents, such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone; (C1-C 12 Alcohol solvents, such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol; nitrile solvents, such as acetonitrile; nitrobenzene; N,N-dimethylformamide; N,N-dimethylacetamide; N-methyl-2-pyrrolidone; or dimethyl carbonate. In some embodiments, the solvent may be formed from a combination of two or more solvents.

[0020] In the context of this invention, the term "room temperature" refers to a temperature of 15°C to 30°C, preferably 20°C to 25°C.

[0021] As used herein, the term "solvent extraction" refers to the process of separating components in a mixture using a solvent that has a greater affinity for a component, thereby separating the component from at least one second component that is less miscible with the solvent compared to the first component.

[0022] The term "filtration" refers to the operation of removing solid particles larger than a predetermined size from a mixture containing solid particles and liquid. The term "filtrate" refers to the mixture after the solid particles have been removed by the filtration process. It should be understood that the mixture may contain solid particles smaller than the predetermined particle size. The term "filter cake" refers to the residual solid matter remaining on the feed side of the filter element.

[0023] The term "evaporation" refers to the process of changing a solvent from a liquid state to a gaseous state and removing that gas from a reactor. Various solvents can be evaporated in the methods disclosed herein. As those skilled in the art will know, each solvent may have different evaporation times and / or temperatures.

[0024] The term "distillation" refers to the process of separating component substances from a liquid mixture through selective evaporation and condensation. This process can achieve near-complete separation (approximately pure components) or partial separation, thereby increasing the concentration of selected components in the mixture. In either case, the process utilizes the differences in volatility of the components in the mixture.

[0025] As used herein, the term “pulping” refers to any process that uses a solvent to wash, suspend, or disperse a coarse solid product.

[0026] The term "phase separation" refers to a solution or mixture having at least two physically distinct regions.

[0027] The term "solvent" refers to a molecular crystalline form that further comprises solvent molecules bound into a crystal structure. When the solvent bound into the crystal is water, it is called a hydrate. The solvent molecules in the solvate can exist in a regular and / or irregular arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of the solvent molecules. Solvates can exhibit polymorphism.

[0028] Brief description of the attached figures Embodiments of the present invention are illustrated in the following figures: Figure 1 Representative X-ray powder diffraction (XRPD) patterns of crystal form 1 of the 1:1 stoichiometric ratio of ensefenate benzenesulfonate acid addition salt are provided.

[0029] Figure 2 Representative crystal form 1 of the 1:1 stoichiometric ratio of the ensefenitol benzenesulfonate acid addition salt is provided. 1 H-RMN spectrum.

[0030] Figure 3 Representative X-ray powder diffraction (XRPD) patterns of crystal form 1 of the 1:1 stoichiometric ratio of ensefenitol p-toluenesulfonate acid addition salt are provided.

[0031] Figure 4 Representative crystal form 1 of the 1:1 stoichiometric ratio of the ensefenitary acetonitrile p-toluenesulfonate acid addition salt is provided. 1 H-RMN spectrum. Detailed Implementation

[0032] The method for preparing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof according to the present invention includes the step of reacting a compound of formula (II) with a compound of formula (III), each of which is as defined above.

[0033] In the compound of formula (III), Y is a leaving group selected from halogens, methanesulfonate groups (OMs), p-toluenesulfonate groups (OTs), p-nitrobenzenesulfonate groups (ONs), acetate groups (OAc), and trifluoromethanesulfonate groups (OTf). In another specific embodiment, Y is a halogen, such as Cl, Br, and I, because this reduces impurities.

[0034] In another specific embodiment of the method, the amount of the compound of formula (III) is in the range of 0.5 to 10 equivalents relative to the compound of formula (II). In one specific embodiment, the amount of the compound of formula (III) is in the range of 1.0 to 8.0 equivalents relative to the compound of formula (II). In one specific embodiment, the amount of the compound of formula (III) is in the range of 1.0 to 5.0 equivalents relative to the compound of formula (II).

[0035] In another specific embodiment, the method is carried out in the presence of an alkali. In one specific embodiment, the alkali is selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium acetate, and potassium acetate. In a more specific embodiment, the alkali is lithium carbonate because it can improve the yield.

[0036] In another specific embodiment of the method, the amount of base used is 1.0 to 8.0 equivalents relative to the compound of formula (II). In another specific embodiment of the method, the amount of base used is 1.0 to 5.0 equivalents relative to the compound of formula (II). In one specific embodiment, the amount of base is 1.5 to 3.0 equivalents of the compound of formula (II) because it reduces impurities.

[0037] In another specific embodiment of the method, the compound of formula (III) and the base may be added sequentially at 24 hours, 48 ​​hours and 72 hours after the start of the reaction, wherein each addition is made in an amount of 1 to 3 equivalents relative to the equivalent of the compound of formula (II), so as to improve the yield of the reaction.

[0038] In another specific embodiment, the method of the present invention is carried out in the presence of a solvent. In one embodiment, a suitable solvent is selected from (C1-C2). 12 Hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene; (C6-C 14 Aromatic solvents, such as toluene, o-xylene, m-xylene, and p-xylene; halogenated (C1-C2) solvents. 12 Hydrocarbon solvents, such as 1,2-dichloroethane, dichloromethane, chloroform; ester solvents, such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, diethyl malonate; (C1-C 12 Ether solvents, such as diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane; ketone solvents, such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone; (C1-C 12Alcohol solvents, such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol; nitrile solvents, such as acetonitrile; nitrobenzene; N,N-dimethylformamide (DMF); N,N-dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); N-methyl-2-pyrrolidone; dimethyl carbonate; and combinations thereof.

[0039] In another specific embodiment, the method is carried out in the presence of a solvent selected from: nitrile solvents, such as acetonitrile; (C1-C2) 12 The solvent can be an ether solvent, such as diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane; and a ketone solvent, such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, and 3-methyl-2-pentanone. In one particular embodiment, the solvent is a nitrile solvent, such as acetonitrile.

[0040] In another specific embodiment of the method, the reaction is carried out at a temperature ranging from 50°C to 100°C. In one embodiment, the reaction is carried out at a temperature ranging from 60°C to 95°C. In another embodiment, the reaction is carried out at a temperature ranging from 70°C to 90°C. In a specific embodiment, the reaction is carried out at the reflux temperature of the solvent. In a more preferred embodiment, the reaction is carried out at a temperature ranging from 70°C to 80°C, because this reduces the degradation of the compound of formula (III) over a long period of time.

[0041] In another specific embodiment of the method, the reaction is maintained for at least 6 hours. In another specific embodiment of the method, the reaction is maintained for at least 12 hours. In one embodiment, the reaction is maintained for at least 24 hours, preferably at least 48 hours, and more preferably at least 120 hours.

[0042] In another specific embodiment of the method, the reaction is maintained for at least 72 hours, preferably at least 120 hours, and the compound of formula (III) and the base may be added continuously at 24 hours, 48 ​​hours and 72 hours after the start of the reaction, wherein each addition is made in an amount of 1 to 3 equivalents relative to the equivalent of the compound of formula (II), so as to improve the yield of the reaction.

[0043] In another specific embodiment of the method, the reaction is maintained for at least 120 hours, preferably at least 168 hours, and the compound of formula (III) and the base may be added continuously at 24 hours, 48 ​​hours and 72 hours after the start of the reaction, wherein each addition is made in an amount of 1 to 3 equivalents relative to the equivalent of the compound of formula (II), so as to improve the yield of the reaction.

[0044] In another specific embodiment of the method, the reaction is carried out in the presence of an iodide or bromide source, preferably in the form of an inorganic salt, such as sodium iodide, potassium iodide, and cesium iodide, or sodium bromide, potassium bromide, and cesium bromide. In yet another specific embodiment, the reaction is carried out in the presence of sodium iodide, potassium iodide, cesium iodide, or a combination thereof. In yet another specific embodiment, the reaction is carried out in the presence of sodium bromide, potassium bromide, or a combination thereof.

[0045] In another specific embodiment of the method, the compound of formula (I) is selected from R. 1 and R 2 Methyl; R 3 and R 4 It is hydrogen; R 5 and R 6 Compounds containing hydrogen and where X is CH2 are called compounds (Ia).

[0046] In another specific embodiment, the method for preparing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof according to the present invention, wherein R in the compound of formula (I) 1 and R 2 Methyl; R 3 and R 4 It is hydrogen; R 5 and R 6 Where X is hydrogen; and Ar is CH2, and Ar is 2,4,6-trimethylphenyl (i.e., the compound of formula Ia), the method comprising the step of reacting the compound of formula (IIa) with the compound of formula (III). (IIa) Where Ar is defined above, (III) Wherein Y is a leaving group, which is selected from halogens, methanesulfonate groups (OMs), p-toluenesulfonate groups (OTs), p-nitrobenzenesulfonate groups (ONs), acetate groups (OAc), and trifluoromethanesulfonate groups (OTf), preferably Y is a halogen, such as Cl, Br, and I.

[0047] In another specific embodiment, the compound of formula (Ia) (wherein R) 1 and R 2 Methyl; R 3 and R 4 It is hydrogen; R 5 and R 6 The method of adding a salt of a compound of formula (IIa) to a compound of formula (III) in the presence of a base and a solvent includes the step of reacting a compound of formula (IIa) with a compound of formula (III) in the presence of a base and a solvent. (IIa); Where Ar is defined above, (III) Wherein Y is a leaving group, which is selected from halogens, methanesulfonate groups (OMs), p-toluenesulfonate groups (OTs), p-nitrobenzenesulfonate groups (ONs), acetate groups (OAc), and trifluoromethanesulfonate groups (OTf), preferably Y is a halogen, such as Cl, Br, and I.

[0048] In another specific embodiment of the method, the alkali used is selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium acetate, and potassium acetate.

[0049] In another specific embodiment of the method, the solvent is selected from nitrile solvents, such as acetonitrile; (C1-C 12 Ether solvents, such as diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane; and ketone solvents, such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone.

[0050] In another specific embodiment, the compound of formula (Ia) (wherein R) 1 and R 2 Methyl; R 3 and R 4 It is hydrogen; R 5 and R 6 The method of adding a salt of a compound of formula (IIa) to a compound of formula (III) in the presence of a base and a solvent includes the step of reacting a compound of formula (IIa) with a compound of formula (III) in the presence of a base and a solvent. (IIa) Where Ar is defined above, (III) Wherein Y is a leaving group, the leaving group being selected from halogens (e.g., Cl, Br, and I), the base being selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium acetate, and potassium acetate, and the solvent being selected from nitrile solvents (e.g., acetonitrile), (Cl-C... 12 Ether solvents (e.g., diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane) and ketone solvents (e.g., acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone).

[0051] In another specific embodiment of the method, the amount of the compound of formula (III) is in the range of 0.5 to 10 equivalents relative to the equivalent of the compound of formula (II), preferably 1.0 to 5.0 equivalents.

[0052] In another specific embodiment, the compound of formula (Ia) of the present invention (wherein R) 1 and R 2 Methyl; R 3 and R 4 It is hydrogen; R 5 and R 6 The method of adding a salt of a compound of formula (IIa) to a compound of formula (III) in the presence of a base and a solvent includes the step of reacting a compound of formula (IIa) with a compound of formula (III) in the presence of a base and a solvent. (IIa) Where Ar is defined above, (III) Wherein Y is a leaving group, and the leaving group is selected from halogens (e.g., Cl, Br, and I); the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium acetate, and potassium acetate; the solvent is selected from nitrile solvents (e.g., acetonitrile), (Cl-C... 12 The solvents used are ether solvents (e.g., diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane) and ketone solvents (e.g., acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone); the amount of the compound of formula (III) used is in the range of 0.5 to 10 equivalents relative to the equivalent of the compound of formula (II); and the amount of the base is in the range of 1.0 to 8.0 equivalents relative to the equivalent of the compound of formula (II), preferably in the range of 1.0 to 5.0 equivalents.

[0053] In another specific embodiment, the method for preparing a compound of formula (Ia) or a pharmaceutically acceptable acid addition salt thereof includes the step of reacting a compound of formula (IIa) with a compound of formula (III) in the presence of a base and a solvent. (IIa) Where Ar is 2,4,6-trimethylphenyl. (III) Wherein Y is a leaving group, the leaving group is selected from halogens (e.g., Cl, Br, and I), the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate, and the solvent is selected from nitrile solvents (e.g., acetonitrile), (Cl-C... 12 The reaction is carried out in an ether solvent (e.g., diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane) and a ketone solvent (e.g., acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone), wherein the amount of compound of formula (III) used is in the range of 0.5 to 10 equivalents relative to the equivalent of compound of formula (II), and wherein the amount of base used is in the range of 1.0 to 8.0 equivalents relative to the equivalent of compound of formula (II), and wherein the reaction is carried out at a temperature in the range of 50°C to 100°C.

[0054] In another specific embodiment, the method for preparing a compound of formula (Ia) or a pharmaceutically acceptable acid addition salt thereof includes the step of reacting a compound of formula (IIa) with a compound of formula (III) in the presence of a base and a solvent. (IIa) Where Ar is 2,4,6-trimethylphenyl, (III) Wherein Y is a leaving group, and the leaving group is selected from halogens (e.g., Cl, Br, and I); the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; the solvent is selected from nitrile solvents (e.g., acetonitrile), (Cl-C... 12The reaction is carried out at a temperature in the range of 50°C to 100°C, and the reaction is maintained for at least 6 hours, preferably at least 12 hours. The solvents used are ether solvents (e.g., diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane) and ketone solvents (e.g., acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone). The amount of compound (III) used is in the range of 0.5 to 10 equivalents relative to the equivalent of compound (II). The amount of base used is in the range of 1.0 to 8.0 equivalents relative to the equivalent of compound (II). The reaction is carried out at a temperature in the range of 50°C to 100°C. The reaction is maintained for at least 6 hours, preferably at least 12 hours.

[0055] In another specific embodiment, the method for preparing a compound of formula (Ia) or a pharmaceutically acceptable acid addition salt thereof includes the step of reacting a compound of formula (IIa) with a compound of formula (III) in the presence of a base and a solvent. (IIa) Where Ar is 2,4,6-trimethylphenyl, (III) Wherein Y is a leaving group, and the leaving group is selected from halogens (e.g., Cl, Br, and I); the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; the solvent is selected from nitrile solvents (e.g., acetonitrile), (Cl-C... 12 The reaction is carried out in the presence of an ether solvent (e.g., diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane) and a ketone solvent (e.g., acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone); wherein the amount of the compound of formula (III) is in the range of 0.5 to 10 equivalents relative to the equivalent of the compound of formula (II); wherein the amount of the base is in the range of 1.0 to 8.0 equivalents relative to the equivalent of the compound of formula (II); wherein the reaction is carried out at a temperature in the range of 50°C to 100°C and the reaction is maintained for at least 6 hours, preferably at least 12 hours, more preferably at least 24 hours; and wherein the reaction is carried out in the presence of an iodide or bromide source, wherein the iodide or bromide source is preferably in the form of an inorganic salt, i.e., sodium iodide, potassium iodide and cesium iodide, or sodium bromide and potassium bromide.

[0056] In another specific embodiment, the method for preparing a compound of formula (Ia) or a pharmaceutically acceptable acid addition salt thereof includes the step of reacting a compound of formula (IIa) with a compound of formula (III) in the presence of a base and a solvent; (IIa) Where Ar is 2,4,6-trimethylphenyl, (III) Wherein Y is a leaving group, the leaving group being selected from halogens (e.g., Cl, Br, and I); the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; and the solvent is selected from nitrile solvents (e.g., acetonitrile), (Cl-C... 12 The solvents used are ether solvents (e.g., diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane) and ketone solvents (e.g., acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone); wherein the amount of the compound of formula (III) used is in the range of 0.5 to 10 equivalents relative to the equivalent of the compound of formula (II); and the amount of the base used is in the range of 1.0 to 8.0 equivalents relative to the equivalent of the compound of formula (II). The reaction is carried out at a temperature in the range of 50°C to 100°C, and the reaction is maintained for at least 24 hours, preferably at least 48 hours. The reaction is carried out in the presence of an iodide or bromide source, preferably in the form of an inorganic salt, i.e., sodium iodide, potassium iodide and cesium iodide, or sodium bromide and potassium bromide. The compound of formula (III) and the base are added continuously, wherein each addition is made in an amount of 1 to 3 equivalents relative to the equivalent of the compound of formula (II). The addition may be carried out 24 hours after the start of the reaction.

[0057] In another specific embodiment, the method for preparing a compound of formula (Ia) or a pharmaceutically acceptable acid addition salt thereof includes the step of reacting a compound of formula (IIa) with a compound of formula (III) in the presence of a base and a solvent; (IIa) Where Ar is 2,4,6-trimethylphenyl, (III) Wherein Y is a leaving group, the leaving group being selected from halogens (e.g., Cl, Br, and I); the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; and the solvent is selected from nitrile solvents (e.g., acetonitrile), (Cl-C... 12The solvents used are ether solvents (e.g., diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane) and ketone solvents (e.g., acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone); wherein the amount of the compound of formula (III) used is in the range of 0.5 to 10 equivalents relative to the equivalent of the compound of formula (II); and the amount of the base used is in the range of 1.0 to 8.0 equivalents relative to the equivalent of the compound of formula (II). The reaction is carried out at a temperature in the range of 50°C to 100°C, and the reaction is maintained for at least 48 hours, preferably at least 72 hours. The reaction is carried out in the presence of an iodide or bromide source, preferably in the form of an inorganic salt, i.e., sodium iodide, potassium iodide, and cesium iodide, or sodium bromide and potassium bromide. The compound of formula (III) and the base are added sequentially, wherein each addition is made in an amount of 1 to 3 equivalents relative to the equivalent of the compound of formula (II). The addition may be carried out 24 hours and 48 hours after the start of the reaction.

[0058] In another specific embodiment, the method for preparing a compound of formula (Ia) or a pharmaceutically acceptable acid addition salt thereof includes the step of reacting a compound of formula (IIa) with a compound of formula (III) in the presence of a base and a solvent; (IIa) Where Ar is 2,4,6-trimethylphenyl, (III) Wherein Y is a leaving group, the leaving group being selected from halogens (e.g., Cl, Br, and I); the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; and the solvent is selected from nitrile solvents (e.g., acetonitrile), (Cl-C... 12The reaction may use ether solvents (e.g., diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane) and ketone solvents (e.g., acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone); wherein the amount of compound of formula (III) used is in the range of 0.5 to 10 equivalents relative to the equivalent of compound of formula (II); wherein the amount of base used is in the range of 1.0 to 8.0 equivalents relative to the equivalent of compound of formula (II), wherein the reaction is carried out in... The reaction is carried out at a temperature in the range of 50°C to 100°C, and is maintained for at least 72 hours, preferably at least 120 hours. The reaction is carried out in the presence of an iodide or bromide source, preferably in the form of an inorganic salt, i.e., sodium iodide, potassium iodide, and cesium iodide, or sodium bromide and potassium bromide. The compound of formula (III) and the base are added sequentially, with each addition being 1 to 3 equivalents relative to the equivalent of the compound of formula (II). The additions may be carried out at 24 hours, 48 ​​hours, and 72 hours after the start of the reaction.

[0059] In another specific embodiment, the method for preparing the compound of formula (IIa) further includes reacting the compound of formula (IVa) with 2,4,6-trimethylaniline beforehand to obtain the compound of formula (IIa).

[0060] (IVa).

[0061] In another specific embodiment of the method, the reaction of the compound of formula (IVa) with 2,4,6-trimethylaniline occurs at (C1-C2) 12 The reaction is carried out in the presence of an alcohol solvent (e.g., methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, or mixtures thereof). In one particular embodiment, the reaction of the compound of formula (IVa) with 2,4,6-trimethylaniline is carried out in the presence of isopropanol.

[0062] The compound of formula (II) used in the method described in this invention can be prepared in a manner similar to that of the compound of formula (IIa) above.

[0063] In another specific embodiment, the method of the present invention further includes reacting the compound of formula (Va) with a chlorinating agent (e.g., phosphorus oxychloride) beforehand to obtain the compound of formula (IVa).

[0064] (Va).

[0065] In another specific embodiment of the method, the reaction between the compound of formula (Va) and a chlorinating agent (e.g., phosphorus oxychloride) is carried out in the presence of a polar aprotic solvent (e.g., sulfolane).

[0066] In another specific embodiment of the method, the compound of formula (Va) can be obtained by reacting N-[2-(3,4-dimethoxyphenyl)ethyl]urea with dimethyl malonate in the presence of sodium methoxide.

[0067] The compounds of formula (V) used in this invention can be prepared in a similar manner to those of formula (Va).

[0068] In another specific embodiment, N-[2-(3,4-dimethoxyphenyl)ethyl]urea can be obtained by reacting 2-(3,4-dimethoxyphenyl)ethyl-1-amine or a salt thereof (e.g., commercially available hydrochloride) with sodium cyanate or potassium cyanate.

[0069] In another specific embodiment of the method, after the reaction of the compound of formula (II) with the compound of formula (III) is complete, the resulting compound of formula (I) is separated by conventional separation techniques. It can then be further purified by acid addition salt formation to provide compound (I) with even lower impurity content. Optionally, the formed salt can be purified before recovering compound (I).

[0070] In another specific embodiment of the method, the compound of formula (I) may be recovered after the method for preparing the compound of formula (I) by cooling the reaction mixture and filtering, optionally at a high temperature, followed by evaporation of the resulting solution to recover the compound of formula (I), preferably yielding an amorphous compound of formula (I). In another specific embodiment, the method for preparing the compound of formula (I) further includes crystallizing the compound of formula (I) from a solvent to obtain a crystal form of the compound of formula (I). For example, known crystal forms of the compound of formula (Ia), such as crystal form I, crystal form II, crystal form III, crystal form IV, and crystal form V, are disclosed in WO2012 / 020016 A1.

[0071] In another specific embodiment, the method of the present invention includes separating the compound of formula (I), preferably by evaporation. In one specific embodiment, the method includes separating the compound of formula (Ia) in an amorphous form, preferably by evaporation. In another specific embodiment, the method includes separating the compound of formula (Ia) in an amorphous form, preferably by evaporation.

[0072] In another particular embodiment, the method of the present invention comprises dissolving the obtained amorphous form of the compound of formula (I) (preferably the compound of formula (Ia)) in a solvent selected from: (C1-C1) 12 Hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane; (C6-C 14 Aromatic solvents, such as toluene, o-xylene, m-xylene, and p-xylene; halogenated (C1-C2) solvents. 12 Hydrocarbon solvents, such as 1,2-dichloroethane, dichloromethane, chloroform; ester solvents, such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, diethyl malonate; ketone solvents, such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone; (C1-C 12 An alcohol solvent, such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol; water and combinations thereof; and crystallization from said solvent or said solvent mixture to obtain a crystal form of the compound of formula (I), preferably crystal form I of the compound of formula (Ia).

[0073] In another specific embodiment, the method of the present invention includes (C1-C) 12 The compound of formula (Ia) is crystallized or slurried in an alcohol solvent (e.g., methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, and combinations thereof), preferably in methanol. In another specific embodiment, the method of the present invention includes (C1-C2)... 12 The compound of formula (Ia) is crystallized in a mixture of alcohol solvent and water in amounts ranging from 1:1 v / v to 6:1 v / v, wherein (C1-C 12 The alcohol is selected from methanol, ethanol, isopropanol, and 1-propanol.

[0074] In another specific embodiment of the method, the compound of formula (I) can be separated from the reaction medium by adding an antisolvent to precipitate it. A suitable antisolvent may be an organic solvent, water, or an aqueous or organic acid solution to precipitate the compound of formula (I) as a free base or acid addition salt.

[0075] In another specific embodiment, the method of the present invention comprises reacting a compound of formula I (preferably a compound of formula (Ia)) with an acid selected from ethane-1,2-disulfonic acid, ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid to obtain a corresponding pharmaceutically acceptable acid addition salt of the compound of formula I. In one specific embodiment, the pharmaceutically acceptable acid addition salt is an ethane-1,2-disulfonic acid addition salt.

[0076] In another specific embodiment, the method further includes a purification method for the compound (I) (preferably compound (Ia)), the purification method comprising the following steps: a) Converting the compound (I) (preferably compound (Ia)) into (i) a pharmaceutically acceptable acid addition salt of the compound (I) (preferably Ia) and (ii) an aryl sulfonic acid selected from benzenesulfonic acid and p-toluenesulfonic acid, wherein the stoichiometry of the compound (I) (preferably Ia) with the counterion is determined by... 1 The H-NMR measurement was 1:1; b) Optionally, purify the acid addition salt obtained in step a); and c) Convert the pharmaceutically acceptable acid addition salt obtained in step a) or b) into the compound (I) (preferably (Ia)).

[0077] The inventors have discovered that using specific aryl sulfonates (specifically benzenesulfonates or p-toluenesulfonates) in the purification of compound (Ia) significantly improves the achievable purity level compared to other acids tested (such as phosphoric acid, HBr, HCl, methanesulfonic acid, maleic acid, L-aspartic acid, and sulfuric acid). Aryl sulfonates (e.g., addition salts of benzenesulfonic acid and p-toluenesulfonic acid) are particularly effective due to their unique chemical properties, which facilitate the removal of impurities during purification. The purity of the resulting compound (I) (preferably compound (Ia)) is equal to or greater than 99.0% a / a by HPLC determination, preferably equal to or greater than 99.5% a / a by HPLC determination, more preferably equal to or greater than 99.7% a / a by HPLC determination, and even more preferably equal to or greater than 99.9% a / a by HPLC determination.

[0078] In another specific embodiment of the method, the amount of the arylsulfonic acid used in steps (a) and (ii) is 1.0 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, relative to the equivalent of the compound of formula (I) (preferably compound (Ia)).

[0079] In another specific embodiment, method step (a) may be carried out in the presence of a solvent selected from: ester solvents, such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, diethyl malonate; (C1-C 12 Alcohol solvents, such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol; (C1-C 12 Ether solvents, such as diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and 1,4-dioxane; ketone solvents, such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone; nitrile solvents, such as acetonitrile; and combinations thereof.

[0080] In another specific embodiment of the method, the amount of solvent used in step a) is 5 V to 25 V (i.e., 1 V = 1 mL / g), preferably 10 V to 20 V, relative to the compound of formula (I) (preferably (Ia)).

[0081] In another specific embodiment of the method, step a) is carried out at a temperature in the range of 50°C to 100°C, preferably in the range of 50°C to 95°C, and more preferably in the range of 75°C to 95°C. In one specific embodiment, the reaction method is carried out at the reflux temperature of the solvent or solvent mixture.

[0082] In one particular embodiment of the method, step a) is carried out by heating the compound (Ia) and the benzenesulfonic acid at a temperature in the range of 50°C to 95°C until completely dissolved, and then cooling the solution to crystallize the benzenesulfonate of the compound (Ia).

[0083] In a particular embodiment of the method, step a) is carried out by heating the compound (Ia) and the benzenesulfonic acid at a temperature in the range of 50°C to 95°C until completely dissolved, and cooling the solution to allow the benzenesulfonate of the compound (Ia) to crystallize, wherein the amount of the benzenesulfonic acid used is 1.0 to 1.5 equivalents relative to the compound (I) (preferably (Ia)).

[0084] In a particular embodiment of the method, step a) is performed by heating the compound (Ia) and the benzenesulfonic acid at a temperature in the range of 50°C to 95°C until completely dissolved, and cooling the solution to crystallize the benzenesulfonate of the compound (Ia), wherein the amount of benzenesulfonic acid used is 1.0 to 1.5 equivalents relative to the compound (I) (preferably (Ia)), and wherein the solvent is n-propanol (1-propanol).

[0085] In a particular embodiment of the method, step a) is performed by heating the compound (Ia) and the benzenesulfonic acid at a temperature in the range of 50°C to 95°C until completely dissolved, and cooling the solution to crystallize the benzenesulfonate of the compound (Ia), wherein the amount of the benzenesulfonic acid is 1.0 to 1.5 equivalents relative to the compound (I) (preferably (Ia)), and wherein the solvent is n-propanol, the amount of which is 10 V to 20 V relative to the compound (Ia).

[0086] In one embodiment of the method, the molar ratio of the compound (Ia) to the benzenesulfonic acid is determined by... 1 The H-NMR ratio was approximately 1:1.

[0087] In one embodiment of the method, the present invention relates to an acid addition salt of the compound (Ia) and benzenesulfonic acid, wherein the stoichiometry of the compound (Ia) and the counterion is determined by... 1 H-NMR measurements showed a 1:1 ratio, designated as crystal form 1, which has an X-ray powder diffraction pattern containing peaks at 5.2°±0.2°, 13.1°±0.2°, 21.6°±0.2°, and 24.3°±0.2°, measured at room temperature using Kα radiation of copper at an X-ray wavelength of 1.5406 Å.

[0088] In one embodiment of the method, the crystal form 1 of the encefentherlin benzenesulfonate acid addition salt is characterized by its XRPD pattern being similar to... Figure 1 The spectra shown are consistent. In one embodiment, the crystal form 1 is characterized in that its XRPD spectrum has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 peaks that match the peaks in the representative crystal form 1 spectra provided in Table 1.

[0089] Table 1. List of major XRPD peaks for benzenesulfonates.

[0090] In one particular embodiment of the method, step a) is performed by heating the compound (Ia) and the p-toluenesulfonic acid (p-TSA) at a temperature in the range of 50°C to 95°C until completely dissolved, and then cooling the solution to allow the compound (Ia) p-toluenesulfonate to crystallize.

[0091] In a particular embodiment of the method, step a) is performed by heating the compound (Ia) and the p-toluenesulfonic acid (p-TSA) at a temperature in the range of 50°C to 95°C until completely dissolved, and then cooling the solution to allow the compound (Ia) p-toluenesulfonate to crystallize, wherein the amount of p-toluenesulfonic acid used is 1.0 to 1.5 equivalents relative to the compound (Ia).

[0092] In a particular embodiment of the method, step a) is performed by heating the compound (Ia) and the p-toluenesulfonic acid (p-TSA) at a temperature in the range of 50°C to 95°C until completely dissolved, and cooling the solution to allow the compound (Ia) p-toluenesulfonate to crystallize, wherein the amount of p-toluenesulfonic acid used is 1.0 to 1.5 equivalents relative to the compound (Ia), and wherein the solvent is methyl ethyl ketone (MEK).

[0093] In a particular embodiment of the method, step a) is performed by heating the compound (Ia) and the p-toluenesulfonic acid (p-TSA) at a temperature in the range of 50°C to 95°C until completely dissolved, and then cooling the solution to crystallize the p-toluenesulfonate of the compound (Ia), wherein the amount of p-toluenesulfonic acid used is 1.0 to 1.5 equivalents relative to the compound (Ia), and wherein the solvent is methyl ethyl ketone (MEK) used in an amount of 10 V to 20 V relative to the compound (Ia).

[0094] In one embodiment of the method, the molar ratio of the compound (Ia) to the p-toluenesulfonic acid is determined by... 1 The H-NMR ratio was approximately 1:1.

[0095] In one embodiment of the method, the present invention relates to an acid addition salt of the compound (Ia) and p-toluenesulfonic acid, wherein the stoichiometry of the compound (Ia) and the counterion is determined by... 1 H-NMR measurements showed a 1:1 ratio, designated as crystal form 1, which has an X-ray powder diffraction pattern containing peaks at 2θ values ​​of 5.0°±0.2°, 8.8°±0.2°, 17.0°±0.2°, and 24.2°±0.2°, as measured at room temperature using Kα radiation of copper at an X-ray wavelength of 1.5406 Å.

[0096] In one embodiment of the method, the crystal form 1 of the encefentralin p-toluenesulfonate acid addition salt is characterized by its XRPD pattern being similar to... Figure 3The spectra shown are consistent. In one embodiment, the crystal form 1 is characterized in that its XRPD spectrum has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 peaks that match the peaks in the representative crystal form 1 spectra provided in Table 2.

[0097] Table 2. List of major XRPD peaks for p-toluenesulfonate.

[0098] In another embodiment of the method, the compound (Ia) is an acid addition salt of an aryl sulfonic acid selected from benzenesulfonic acid and p-toluenesulfonic acid, which contains water in the crystal lattice, or contains water mixed with other organic solvents in the crystal lattice.

[0099] In another embodiment of the method, the compound (Ia) and an acid addition salt of an aryl sulfonic acid selected from benzenesulfonic acid and p-toluenesulfonic acid contain an organic solvent, such as n-propanol or MEK, in the crystal lattice.

[0100] In one particular embodiment of the method, step b) is carried out by reacting the pharmaceutically acceptable acid addition salt with ammonia in methanol as a solvent.

[0101] Typically, step b) is carried out at a temperature in the range of 30°C to 45°C. In a particular embodiment, step b) is carried out at a temperature in the range of 35°C to 40°C. Typically, the salt is separated at room temperature (20°C–25°C). A pharmaceutically acceptable acid addition salt is (i) a salt of compound (Ia) and (ii) an aryl sulfonic acid selected from benzenesulfonic acid and p-toluenesulfonic acid, wherein the stoichiometry of compound (Ia) with the counterion is determined by... 1 The H-NMR measurement was 1:1, which constitutes part of this invention.

[0102] The compound (Ia) and benzenesulfonic acid crystal form 1 can be detected by proton nuclear magnetic resonance (NMR). 1 Characterization by H-NMR, such as Figure 2 As shown. The stoichiometric ratio of the compound (Ia) to benzenesulfonic acid is determined by... 1 H-NMR measurements showed a ratio of approximately 1:1. It can also be characterized by X-ray powder diffraction patterns containing peaks at 2θ values ​​of 5.2°±0.2°, 13.1°±0.2°, 21.6°±0.2°, and 24.3°±0.2°, as measured at room temperature using Kα radiation of copper at an X-ray wavelength of 1.5406 Å. More specifically, it is characterized by X-ray powder diffraction patterns containing peaks with 2θ values ​​as shown in Table 1 above.

[0103] The compound (Ia) and p-toluenesulfonic acid crystal form 1 can be detected by proton nuclear magnetic resonance (NMR). 1 Characterization by H-NMR, such as Figure 4 As shown. The stoichiometric ratio of the compound (Ia) to the counterion is determined by... 1 The H-NMR determination is 1:1. It can also be characterized by X-ray powder diffraction patterns containing peaks at 2θ values ​​of 5.0°±0.2°, 8.8°±0.2°, 17.0°±0.2°, and 24.2°±0.2°, as measured at room temperature using Kα radiation of copper with an X-ray wavelength of 1.5406 Å. More particularly, it is characterized by X-ray powder diffraction patterns containing peaks with 2θ values ​​as shown in Table 2 above.

[0104] In another specific embodiment, the method for preparing a compound of formula (Ia) or a pharmaceutically acceptable acid addition salt thereof includes the step of reacting a compound of formula (IIa) with a compound of formula (III) in the presence of a base and a solvent; (IIa) Where Ar is 2,4,6-trimethylphenyl, (III) Wherein Y is a leaving group, the leaving group being selected from halogens (e.g., Cl, Br, and I); the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; and the solvent is selected from nitrile solvents (e.g., acetonitrile), (Cl-C... 12 The solvents used are ether solvents (e.g., diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane) and ketone solvents (e.g., acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone); wherein the amount of the compound of formula (III) used is in the range of 0.5 to 10 equivalents relative to the equivalent of the compound of formula (II); and the amount of the base used is 1 equivalent relative to the equivalent of the compound of formula (II). The reaction is carried out in the range of 0 to 8.0 equivalents, wherein the reaction is carried out at a temperature in the range of 50°C to 100°C, the reaction is maintained for at least 6 hours, preferably at least 12 hours, more preferably at least 24 hours, and even more preferably at least 72 hours, wherein the reaction is carried out in the presence of an iodide or bromide source, wherein the iodide or bromide source is preferably in the form of an inorganic salt, i.e., sodium iodide, potassium iodide and cesium iodide, or sodium bromide and potassium bromide, and wherein the method further includes a purification method for the compound (Ia), the purification method comprising the following steps: a) Converting the compound (I) (preferably compound (Ia)) into (i) a pharmaceutically acceptable acid addition salt of the compound (I) (preferably Ia) and (ii) an aryl sulfonic acid selected from benzenesulfonic acid and p-toluenesulfonic acid, wherein the stoichiometry of the compound (I) (preferably Ia) with the counterion is determined by... 1 The H-NMR measurement was 1:1; b) Optionally, purify the acid addition salt obtained in step a); and c) Convert the pharmaceutically acceptable acid addition salt obtained in step a) or b) into the compound (Ia).

[0105] In another specific embodiment, the method for preparing a compound of formula (Ia) or a pharmaceutically acceptable acid addition salt thereof includes the step of reacting a compound of formula (IIa) with a compound of formula (III) in the presence of a base and a solvent; (IIa) Where Ar is 2,4,6-trimethylphenyl, (III) Wherein Y is a leaving group, the leaving group being selected from halogens (e.g., Cl, Br, and I); the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; and the solvent is selected from nitrile solvents (e.g., acetonitrile), (Cl-C... 12 The reaction is carried out in an ether solvent (e.g., diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane) and a ketone solvent (e.g., acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone); wherein the amount of the compound of formula (III) is in the range of 0.5 to 10 equivalents relative to the equivalent of the compound of formula (II); wherein the amount of the base is in the range of 1.0 to 8.0 equivalents relative to the equivalent of the compound of formula (II), wherein the reaction is carried out at a temperature in the range of 50°C to 100°C, wherein the reaction... The reaction should be maintained for at least 72 hours, preferably at least 120 hours, and more preferably at least 168 hours, wherein the reaction is carried out in the presence of an iodide or bromide source, preferably in the form of an inorganic salt, i.e., sodium iodide, potassium iodide, and cesium iodide, or sodium bromide and potassium bromide, wherein the compound of formula (III) and the base are added sequentially, wherein each addition is 1 to 3 equivalents of the compound of formula (II), and the addition may be carried out at 24 hours, 48 ​​hours, and 72 hours after the start of the reaction, and wherein the method further includes a purification method for the compound (Ia), the purification method comprising the following steps: d) Converting the compound (I) (preferably compound (Ia)) into (i) a pharmaceutically acceptable acid addition salt of the compound (I) (preferably Ia) and (ii) an aryl sulfonic acid selected from benzenesulfonic acid and p-toluenesulfonic acid, wherein the stoichiometry of the compound (I) (preferably Ia) with the counterion is determined by... 1 The H-NMR measurement was 1:1; e) Optionally, purify the acid addition salt obtained in step a); and f) Convert the pharmaceutically acceptable acid addition salt obtained in step a) or b) into the compound (Ia).

[0106] Finally, a pharmaceutical composition comprising a compound of formula I obtained therefrom or a pharmaceutically acceptable acid addition salt thereof (preferably a compound of formula (Ia), i.e., encefentraline) and one or more pharmaceutically acceptable carriers or excipients also constitutes part of the present invention.

[0107] Terms and Conditions Article 1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, (I) Where: R 1 and R 2 They may be the same or different, and each is independently a C1-C6 alkyl or C2-C7 acyl group; or, R 1 and R 2 Together they form C1-C6 alkylene groups; R 3 and R 4 They may be the same or different, and each is independently selected from hydrogen, halogens, and C1-C6 alkyl groups; R 5 and R 6 They may be the same or different, and each is independently selected from hydrogen, halogens, and C1-C6 alkyl groups; X is selected from CHR. 7 O and NR 7 ;R 7 It is hydrogen or C1-C6 alkyl; and Ar is 2,4,6-trimethylphenyl; the method includes the step of reacting a compound of formula (II) with a compound of formula (III). (II) Where R 1 R 2 R 3 R 4 R 5 R 6 X and Ar are as defined for compounds of formula (I). (III) Wherein Y is a leaving group, and the leaving group is selected from halogen, methanesulfonate (OMs), p-toluenesulfonate (OTs), p-nitrobenzenesulfonate (ONs), acetate (OAc) and trifluoromethanesulfonate (OTf).

[0108] Article 2. The method according to Article 1, wherein the amount of the compound of formula (III) is in the range of 0.5 to 10 equivalents relative to the equivalent of the compound of formula (II).

[0109] Article 3. The method according to any one of Articles 1 to 2, wherein the method is carried out in the presence of an alkali selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium acetate, and potassium acetate.

[0110] Article 4. The method according to Article 3, wherein the amount of the base used is in the range of 1.0 to 5.0 equivalents relative to the equivalent of the compound of formula (II).

[0111] Article 5. The method according to any one of Articles 1 to 4, wherein the method is carried out in the presence of a solvent selected from nitrile solvents (e.g., acetonitrile), (C1-C2) 12 Ether solvents (e.g., diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran and 1,4-dioxane) and combinations thereof.

[0112] Article 6. The method according to any one of Articles 1 to 5, wherein the reaction is carried out at a temperature in the range of 50°C to 100°C.

[0113] Article 7. The method according to any one of Articles 1 to 6, wherein the reaction is sustained for at least 6 hours.

[0114] Article 8. The method according to any one of Articles 1 to 7, wherein the reaction is carried out in the presence of an iodine source.

[0115] Article 9. The method according to any one of Articles 1 to 8, wherein R 1 and R 2 Methyl; R 3 and R 4 It is hydrogen; R 5 and R 6 If X is hydrogen and CH2, it is called a compound of formula (Ia) and a compound of formula (IIa).

[0116] Article 10. The method according to any one of Articles 1 to 9, wherein the method further comprises reacting the compound of formula (IVa) with 2,4,6-trimethylaniline beforehand to obtain the compound of formula (IIa).

[0117] (IVa).

[0118] Article 11. The method according to any one of Articles 1 to 10, wherein the method further comprises reacting the compound of formula (Va) with a chlorinating agent (e.g., phosphorus oxychloride) beforehand to obtain the compound of formula (IVa).

[0119] (Va).

[0120] Article 12. The method according to any one of Articles 1 to 11, wherein the method comprises separating the compound of formula (I) in an amorphous form, preferably by evaporation.

[0121] Article 13. The method according to Article 12, wherein the method comprises dissolving the amorphous form obtained in Article 12 in a solvent selected from: (C1-C1) 12 Hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane; (C6-C 14 Aromatic solvents, such as toluene, o-xylene, m-xylene, and p-xylene; halogenated (C1-C2) solvents. 12 Hydrocarbon solvents, such as 1,2-dichloroethane, dichloromethane, chloroform; ester solvents, such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, diethyl malonate; (C1-C 12 Alcohol solvents, such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, and combinations thereof; and crystallize from said solvent or mixtures of said solvents into crystalline form.

[0122] Article 14. The method according to any one of Articles 1 to 13, wherein the method comprises reacting the compound of Formula I with an acid selected from ethane-1,2-disulfonic acid, ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid to obtain a pharmaceutically acceptable acid addition salt of the corresponding compound of Formula I.

[0123] Article 15. The method according to any one of Articles 1 to 14, wherein the pharmaceutically acceptable acid addition salt is an ethane-1,2-disulfonate acid addition salt.

[0124] The invention is further illustrated below by way of examples. These examples should in no way be construed as limiting the scope of the invention as defined in the claims. Unless otherwise stated, all percentages are weight percentages, and temperatures are in degrees Celsius.

[0125] General Method Proton nuclear magnetic resonance (NMR) 1 H-NMR) Sample preparation: Dissolve approximately 2–5 mg of sample in 0.5–0.7 mL of deuterated solvent (CDCl3 or DMSO). Data acquisition: Proton NMR analysis was performed on a Bruker Avance III HD 400 NMR spectrometer equipped with a 5 mm z-gradient BBO (broadband observation) probe (with ATM) and an autosampler. Measurement conditions: The sample was analyzed at room temperature.

[0126] X-ray powder diffraction (XRPD) Diffraction data were acquired using a PANanalytical EMPYREAN vs. 8.2 20201404 diffractometer equipped with a Cu-Kα radiation source (λ = 1.541874 Å) and operated in transmission θ-θ configuration at 45 kV and 40 mA. Samples were scanned from 2 to 40 °2θ in steps of 0.013 °2θ for 78.795 seconds. Data acquisition was performed using DATA COLLECTOR vs. 7.1.

[0127] Differential scanning calorimetry (DSC) DSC analysis was performed using a Thermal Analysis (TA) Discovery instrument model DSC 25. The samples (typically weighed 1–3 mg) were heated in a sealed standard Tzero aluminum dish at a nitrogen flow rate of 50 mL / min at a heating rate of 5 °C / min. A sealed empty Tzero aluminum dish was used as a reference. Data acquisition was performed using TRIOS software.

[0128] Thermogravimetric analysis (TGA) TGA analysis was performed on a Thermal Analysis (TA) Discovery instrument model TGA 550 under a nitrogen atmosphere at a gas flow rate of 60 mL / min and a heating rate of 10 °C / min. Approximately 1 to 5 mg of sample was used. Data acquisition was performed using TRIOS software.

[0129] Balance The RAGWAG analytical balance model AS.220 R2 PLUS and TA microbalance were used with the TA Discovery TGA 550 instrument.

[0130] High-performance liquid chromatography (HPLC) HPLC analysis was performed on an Agilent 1220 Infinity II LC system equipped with a high-pressure binary pump, autosampler, temperature-controlled column oven, and variable wavelength detector. Data acquisition and processing were performed using OpenLab CDS software. Samples were prepared in glass vials, first dissolved in DCM:MeOH 1:1 v:v, then diluted 1 / 10 with MeCN to a target concentration of 0.1 mg / mL (for solid samples). Samples were filtered before injection into the HPLC system. Chromatographic separations were performed on a C18 column (Xbridge Shield RP18 3.5 μm 4.6 x 100 mm; 30 °C) using ammonium formate buffer (pH=5.0) and acetonitrile (ACN) as the mobile phase. The gradients shown in Table 24 were used. The run time was 60.1 min, plus a 5-minute equilibration step between injections. The detection wavelength was 360 nm.

[0131] HPLC parameters Column: Xbridge Shield RP18 3.5 μm 4.6 x 100 mm; Column temperature: 30 ℃ Flow rate: 0.8 mL / min Mobile phase A: Ammonium formate buffer, pH = 5.0 Mobile phase B: MeCN Injection volume: 5 μL (clean the injection needle with ACN) Detection wavelength: 360 nm Diluent: MeCN Sample preparation: 0.1 mg / mL Table 3. HPLC gradient Example Example 1. Preparation of 1-(3,4-dimethoxyphenethyl)barbituric acid (a compound of formula Va) A mixture of N-[2-(3,4-dimethoxyphenyl)ethyl]urea (195.0 g, 869.6 mmol, 1.0 equivalent) and dimethyl malonate (149.4 g, 1130.5 mmol, 1.30 equivalent) in methanol (780 mL) was stirred at 20–25 °C. Then, 25% sodium methoxide (259 mL, 1130.5 mmol, 1.30 equivalent) was slowly added. The resulting yellow suspension was stirred at reflux for 30 hours, then at 20–25 °C for 1 hour. A mixture of 1N HCl (1257 mL) and water (878 mL) was slowly added, and the resulting suspension was stirred at 20–25 °C for 1 hour. The solid was filtered and washed twice with water (200 mL). The resulting wet solid was dried at 40–45 °C, recrystallized from acetonitrile (1544 mL), and dried. A grayish-white solid was obtained (202.7 g, 693.5 mmol, yield: 80%).

[0132] Example 2. Preparation of 2-chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimidino[6,1-a]isoquinoline-4-one (a compound of formula IVa) The 1-(3,4-dimethoxyphenethyl)barbituric acid (46.2 mg, 158 mmol, 1.0 equivalent) obtained in Example 1 and sulfolane (92 mL) were stirred at 20-25°C. Then, phosphorus oxychloride (44.2 mL, 474 mmol, 3.0 equivalent) was added at 20-25°C. The resulting suspension was stirred at 120-125°C for 2 hours. Afterward, the reaction was cooled to 5-10°C, and dichloromethane (462 mL) and water (277 mL) were slowly added, maintaining the temperature below 10°C. Next, a 20% aqueous sodium hydroxide solution was added at a temperature below 10°C until neutralization. The reaction was heated to 35-40°C, and the phases were separated. The organic phase was extracted twice with dichloromethane (120 mL) at 35-40°C. The combined organic phases were washed twice with water (120 mL) at 35-40°C. The solvent in the organic phase was removed by distillation. The resulting residue was stirred with water (924 mL) at 40-45°C for 1 hour. The resulting suspension was cooled to 20-25°C and filtered at this temperature. The resulting solid was stirred with acetone (176 mL) at 40-45°C for 1 hour, cooled to 20-25°C, and filtered. A yellow solid was given (32.8 g, 112 mmol, yield: 71%; HPLC: 97.2%).

[0133] Example 3. Preparation of (E)-2-(trimethylmethylimino)-9,10-dimethoxy-2,3,6,7-tetrahydro-4H-pyrimidino[6,1-a]isoquinoline-4-one (a compound of formula IIa) A mixture of 2-chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimidino[6,1-a]isoquinoline-4-one (60 g, 205 mmol, 1.0 equivalent), 2,4,6-trimethylaniline (58.2 g, 430 mmol, 2.1 equivalent), and isopropanol (180 mL) obtained in Example 2 was stirred at reflux for 3 hours. The resulting reaction mixture was cooled to 0-5°C and stirred further at this temperature for 1 hour. The resulting solid was filtered and washed twice with ice-cooled isopropanol. The resulting solid was recrystallized from isopropanol to give a yellow solid (78.6 g, 201 mmol, yield: 98%).

[0134] Example 4. Preparation of Encefentraline (a compound of formula Ia) A mixture of (E)-2-(trimethylmethylimino)-9,10-dimethoxy-2,3,6,7-tetrahydro-4H-pyrimidino[6,1-a]isoquinoline-4-one (398 mg, 1.0 mmol, 1.0 equivalent), N-(2-chloroethyl)urea (compound of formula III, where Y is Cl) (623 mg, 5.1 mmol, 5.0 equivalent), Li₂CO₃ (225 mg, 3.1 mmol, 3.0 equivalent), and potassium iodide (84 mg, 0.5 mmol, 0.5 equivalent) in acetonitrile (2 mL) was stirred at reflux for 4 days. The resulting reaction mixture was cooled to 20-25°C, and dichloromethane (10 mL) and a saturated aqueous solution of ammonium chloride (10 mL) were added. The phases were separated, and the aqueous phase was extracted with dichloromethane (5 mL). The organic phases were combined and washed with a saturated aqueous solution of ammonium chloride (5 mL). The solvent in the organic phase was removed by vacuum distillation, and the resulting residue was purified by column chromatography. A fraction of 200 mg enthalpyrin was obtained (yield: 40%).

[0135] 1 H-NMR (400 MHz, CDCl3): δ (ppm): 2.06 (6H, s), 2.28 (3H, s), 2.91 (2H, t, J=4 Hz), 3.54 (2H, m), 3.76 (3H, s), 3.90 (3H, s), 4.04 (2H, t, J=4Hz), 4.40 (2H, t, J=4 Hz), 5.35 (2H, br. s), 5.45 (1H, s), 6.67 (1H, s), 6.70(1H, s), 6.88 (2H, s).

[0136] Example 5. Preparation of Encerfentrane Crystal Form I by Slurry Preparation in Ethanol The solid fraction (2.8 g) obtained in Example 4 above was suspended in ethanol (28 mL) and stirred at 50 °C for 16 hours. The resulting suspension was cooled to 20-25 °C, filtered, washed with ethanol, and dried under reduced pressure at 20-25 °C (yield: 90%; XRPD: crystal form I).

[0137] Example 6. Large-scale preparation of Encerfentrine crystal form I A mixture of (E)-2-(trimethylimino)-9,10-dimethoxy-2,3,6,7-tetrahydro-4H-pyrimidino[6,1-a]isoquinoline-4-one (125 g, 319 mmol, 1.0 equivalent), N-(2-chloroethyl)urea (78.3 g, 639 mmol, 2.0 equivalent), Li₂CO₃ (70.8 g, 958 mmol, 3.0 equivalent) and potassium bromide (22.8 g, 192 mmol, 0.6 equivalent) in acetonitrile (1000 mL) was stirred at reflux for 6 days. Three consecutive additions of N-(2-chloroethyl)urea (78.3 g, 639 mmol, 2.0 equivalent) and Li₂CO₃ (23.6 g, 319 mmol, 1.0 equivalent) were made on days 1, 2, and 3 after the start of the reaction. The resulting reaction mixture was cooled to 20-25°C, and the solvent was removed by vacuum distillation. A mixture of 1250 mL of 2-MeTHF and 1250 mL of water was added to the resulting yellow residue. The mixture was stirred at 40°C for 15 minutes, filtered, and the phases were separated at 40°C. The aqueous phase was extracted twice with 500 mL of 2-MeTHF. The organic phases were combined, washed twice with 500 mL of water, and twice with 500 mL of brine. The solvent in the organic phase was removed by vacuum distillation, and the resulting brown residue was dissolved in 500 mL of MeOH at 60°C. Seed crystals were added to the brown solution and the mixture was cooled to 20-25°C and maintained for 16 hours. The yellow solid was filtered, washed twice with 125 mL of MeOH, and purified by column chromatography. 63 g of encefentraline fraction was obtained (yield: 41%, purity: 97.40% HPLC; XRPD: crystal form I).

[0138] Example 7. Purification of Encefentraline using conventional separation methods 7.1. Encefentraline (78.1 g; HPLC: 89.89%) was suspended in a mixture of dichloromethane (150 mL) and MeOH (1.5 mL) and stirred at 20-25 °C for 18 hours. The resulting yellow solid was filtered off, washed with dichloromethane (2 × 75 mL), and dried at 40-45 °C (yield: 54.6 g; 70%; HPLC: 96.37%).

[0139] 7.2. The encefentraline (54.6 g) obtained in (7.1) was mixed with 1-propanol (550 mL) and heated to reflux temperature (93 °C). Water (130 mL) was added to the yellow suspension. The resulting yellow solution was cooled to 73 °C and seeded. The resulting suspension was cooled to 20 °C–25 °C and held at this temperature for 3 hours, while stirring for 16 hours. The yellow solid was filtered and washed twice with 1-propanol:water (4:1) (50 mL) (yield: 26.6 g; 49%; HPLC: 97.13%).

[0140] 7.3. The encefentraline (4.0 g) obtained in (7.2) was recrystallized from 50 mL of 1-propanol:water (4:1) (yield: 3.37 g; 84%; HPLC: 97.42%).

[0141] 7.4. The encefentraline (3.24 g) obtained in (7.3) was recrystallized from 40 mL of 1-propanol:water (4:1) (yield: 2.87 g; 89%; HPLC: 97.49%).

[0142] 7.5. The encefentraline (2.69 g) obtained in (7.4) was recrystallized from 34 mL of 1-propanol:water (4:1) (yield: 2.36 g; 88%; HPLC: 97.72%).

[0143] Example 8. Purification of encefentherlin by salt formation with aryl sulfonic acid Compound Ia (100 mg; HPLC purity 93.67%) was mixed with 1.1 equivalents of arylsulfonic acid and solvents (10, 15, and 20V), as shown in Table 4. The resulting suspension was heated to 75°C and stirred at this temperature for 30 min. Then, the sample was cooled to 25°C at 0.5°C / min and stirred at this temperature for 16 h. The sample was vacuum filtered and washed twice with crystallization solvent (2V). The solids were dried at 40°C for 5–16 h and analyzed by HPLC and XRPD.

[0144] Table 4 Characterization of aryl sulfonic acid addition salts: The acid addition salt of compound (Ia) and benzenesulfonic acid XRPD ( Figure 1 ): Crystal form spectrum.

[0145] 1 H-NMR ( Figure 2; 400 MHz, DMSO): δ 11.53 (bs, 1H), 7.59 (dd, J = 7.3, 2.2 Hz,2H), 7.38 – 7.22 (m, 3H), 7.10 (s, 2H), 7.08 (s, 1H), 6.80 (s, 1H), 6.54 (t,J = 4.5 Hz, 1H), 6.03 (bs, 2H), 5.61 (s, 1H), 4.26 (t, J = 6.8 Hz, 2H), 4.08(t, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.65 (s, 3H), 3.41 – 3.24 (m, 4H), 3.00(t, J = 6.2 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 6H), 1.54 – 1.32 (m, 2H), 0.83(t, J = 7.4 Hz, 3H).

[0146] DSC: Sharp endothermic peak, with an initial temperature of 131℃ (-96 J / g).

[0147] TGA: Loses 8.65% weight between 105 °C and 150 °C (possibly losing 1 equivalent of n-propanol). Decomposition begins at approximately 250 °C.

[0148] Compound (Ia) and the acid addition salt of p-toluenesulfonic acid XRPD ( Figure 3 ): Crystal form spectrum.

[0149] 1 H-NMR ( Figure 4; 400 MHz, DMSO): δ 11.52 (bs, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.19 – 6.99 (m, J = 6.4 Hz, 5H), 6.80 (s, 1H), 6.55 (t, J = 5.0 Hz, 1H), 6.03(bs, 2H), 5.61 (s, 1H), 4.26 (t, J = 6.9 Hz, 2H), 4.08 (t, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.65 (s, 3H), 3.48 – 3.37 (m, 2H), 3.00 (t, J = 6.2 Hz, 2H),2.43 (q, J = 7.3 Hz, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 2.20 (s, 6H), 2.07 (s,2H), 0.90 (t, J = 7.3 Hz, 2H).

[0150] DSC: Sharp endothermic peak, with an initial temperature of 114℃ (-53 J / g).

[0151] TGA: 6.9% weight loss between 50°C and 170°C (possibly due to loss of MEK). Decomposition begins at approximately 250°C.

[0152] Example 9. Purification of encefentraline by forming benzenesulfonate in propanol Ensefentylene (2 g; HPLC purity 93.67%) was mixed with 1.1 equivalents (744.4 mg) of benzenesulfonic acid and 10 V of n-propanol (20 mL). The resulting suspension was heated to 90 °C and stirred at this temperature for 30 min (to obtain a solution). The sample was then cooled to 25 °C at 0.5 °C / min and stirred at this temperature for 16 h. The sample was vacuum filtered and washed twice with n-propanol (4 mL, 2 V). Yield: 2.17 g (75%). HPLC: 99.90%.

[0153] The resulting salt (50 mg) was suspended in 0.5 mL of n-propanol at 10°C and heated to 90°C, where it was stirred for 30 minutes. The resulting solution was then cooled to 25°C at 0.5°C / min and stirred for 4 hours. The sample was filtered under vacuum and washed twice with n-propanol (2°C). Yield: 45 mg (85%). HPLC: 100%.

[0154] Example 10. Purification of encefentraline by forming a p-toluenesulfonate acid addition salt in ethanol Encefentraline (5.05 g; HPLC purity 96.37%) was suspended in ethanol (30 mL) at 20-25°C. A solution of p-toluenesulfonic acid monohydrate (2.21 g, 11.6 mmol, 1.10 equivalents) in ethanol (20 mL) was added to the resulting pale yellow suspension at 20-25°C. The resulting solution was heated to 80°C. The resulting suspension was cooled to 20-25°C and stirred at this temperature for 18 hours. The white solid was filtered and washed twice with ethanol (5 mL). Yield: 4.84 g (71%; HPLC: 99.17%).

[0155] Example 11. Preparation of purified enthalpyridine Encefentraline benzenesulfonate (30 mg; 99.17%) was suspended in methanol (180 μL) at 25 °C. Ammonium hydroxide (12.6 μL, 2 equivalents) was added. The color changed from white to yellow. The suspension was heated to 35 °C and stirred at this temperature for 1 hour. The mixture was cooled to 25 °C at 0.5 °C / min and stirred at this temperature for 2 hours. The mixture was filtered under vacuum, and the wet filter cake was washed twice with MeOH:H₂O 3:5 (2 × 30 μL). Both the mother liquor and the solid were analyzed by HPLC. Yield: 75%. Purity: 99.58% (HPLC).

[0156] Example 12. Preparation of purified enthalpyridine The encefentraline p-toluenesulfonate acid addition salt obtained above (500 mg, 0.77 mmol, 1.00 equivalent, 99.58%) was mixed with methanol (3.00 mL) at 20-25°C. 25% ammonia (0.10 mL, 1.92 equivalent, 74.2 mmol) was added to the resulting white suspension. The mixture was heated to 35-40°C. The resulting pale yellow suspension was stirred at this temperature for 1 hour. Water (5 mL) was added at 35-40°C, and the mixture was stirred at this temperature for 1 hour. The mixture was cooled to 20-25°C, and stirred at this temperature for 1 hour. The yellow solid was filtered and washed twice with methanol (0.5 mL). Yield: 313 mg (85%). HPLC: 99.45%.

Claims

1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, ； in: R 1 and R 2 They may be the same or different, and each is independently a C1-C6 alkyl or C2-C7 acyl group; or, R 1 and R 2 Together they form C1-C6 alkylene groups; R 3 and R 4 They may be the same or different, and each is independently selected from hydrogen, halogens, and C1-C6 alkyl groups; R 5 and R 6 They may be the same or different, and each is independently selected from hydrogen, halogens, and C1-C6 alkyl groups; X is selected from CHR. 7 O and NR 7 ;R 7 It is hydrogen or C1-C6 alkyl; and Ar is 2,4,6-trimethylphenyl; the method includes the step of reacting a compound of formula (II) with a compound of formula (III). ； Where R 1 R 2 R 3 R 4 R 5 R 6 X and Ar are as defined for compounds of formula (I). ； Wherein Y is a leaving group, and the leaving group is selected from halogen, methanesulfonate (OMs), p-toluenesulfonate (OTs), p-nitrobenzenesulfonate (ONs), acetate (OAc) and trifluoromethanesulfonate (OTf).

2. The method according to claim 1, wherein the amount of the compound of formula (III) is in the range of 0.5 to 10 equivalents relative to the equivalent of the compound of formula (II).

3. The method according to any one of claims 1 to 2, wherein the method is carried out in the presence of an alkali selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium acetate, and potassium acetate.

4. The method according to claim 3, wherein the amount of the base is in the range of 1.0 to 8.0 equivalents relative to the equivalent of the compound of formula (II).

5. The method according to any one of claims 1 to 4, wherein the method is carried out in the presence of a solvent selected from nitrile solvents, such as acetonitrile; (C1-C 12 Ether solvents, such as diethyl ether, dipropyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane; ketone solvents, such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), ethyl isopropyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone; and combinations thereof.

6. The method according to any one of claims 1 to 5, wherein the reaction is carried out at a temperature in the range of 50°C to 100°C, preferably 60°C to 95°C.

7. The method according to any one of claims 1 to 6, wherein the reaction is maintained for at least 6 hours, preferably at least 12 hours, more preferably at least 24 hours, and even more preferably 72 hours.

8. The method according to any one of claims 1 to 7, wherein the reaction is carried out in the presence of an iodide or bromide source.

9. The method according to any one of claims 1 to 8, wherein the method comprises separating the compound of formula (I), preferably by evaporation.

10. The method according to any one of claims 1 to 9, wherein R 1 and R 2 Methyl; R 3 and R 4 It is hydrogen; R 5 and R 6 If X is hydrogen and CH2, it is called a compound of formula (Ia) and a compound of formula (IIa).

11. The method of claim 10, wherein the method further comprises reacting the compound of formula (IVa) with 2,4,6-trimethylaniline beforehand to obtain the compound of formula (IIa), 。 12. The method of claim 11, wherein the method further comprises pre-reacting the compound of formula (Va) with a chlorinating agent such as phosphorus oxychloride to obtain the compound of formula (IVa). 。 13. The method according to any one of claims 10 to 12, further comprising a method for purifying the compound (Ia), the purification method comprising the following steps: a) Converting the compound (Ia) into (i) a pharmaceutically acceptable acid addition salt of the compound (Ia) and (ii) an aryl sulfonic acid selected from benzenesulfonic acid and p-toluenesulfonic acid, wherein the stoichiometry of the compound (Ia) with the counterion is determined by... 1 The H-NMR measurement was 1:1; b) Optionally, purify the acid addition salt obtained in step a); as well as c) Convert the pharmaceutically acceptable acid addition salt obtained in step a) or b) into compound (Ia).

14. The method of claim 13, wherein the pharmaceutically acceptable addition salt is the compound (Ia) benzenesulfonate, and step a) is carried out in the presence of n-propanol as a solvent.

15. The method of claim 13, wherein the pharmaceutically acceptable addition salt is p-toluenesulfonate of compound (Ia), and step a) is carried out in the presence of methyl ethyl ketone (MEK) as a solvent.

16. The method according to any one of claims 13 to 15, wherein step c) is carried out by reacting the pharmaceutically acceptable acid addition salt with ammonia in methanol as a solvent to provide the purified compound (Ia).

17. The method according to any one of claims 9 to 16, wherein the method comprises dissolving the compound obtained from any one of claims 9 to 16 in a solution selected from (C1-C2). 12 It can be dissolved in an alcohol solvent, water, or a combination thereof, and crystallized from the solvent or a mixture of the solvents, such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, or tert-butanol.

18. The method according to any one of claims 9 to 16, wherein the method comprises reacting the compound of formula I, preferably (Ia), with an acid selected from ethane-1,2-disulfonic acid, ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid to obtain a pharmaceutically acceptable acid addition salt of the corresponding compound of formula I, preferably (Ia).

19. The method of claim 18, wherein the pharmaceutically acceptable acid addition salt is an ethane-1,2-disulfonate acid addition salt.

20. A pharmaceutically acceptable acid addition salt of (i) compound (Ia) and (ii) an aryl sulfonic acid selected from benzenesulfonic acid and p-toluenesulfonic acid, wherein the stoichiometry of said compound (Ia) with said counterion is determined by... 1 The H-NMR measurement was 1:

1.

21. The pharmaceutically acceptable acid addition salt according to claim 20, wherein the compound (Ia) benzenesulfonate is characterized in that... It has a powder X-ray diffraction pattern containing characteristic peaks at 2θ at approximately 5.2°±0.2°, 13.1°±0.2°, 21.6°±0.2° and 24.3°±0.2°, measured using Cu Kα1 radiation (λ = 1.54060 Å).

22. The pharmaceutically acceptable acid addition salt according to claim 20, wherein the compound (Ia) is p-toluenesulfonate, characterized in that... It has a powder X-ray diffraction pattern containing characteristic peaks at 2θ at approximately 5.0°±0.2°, 8.8°±0.2°, 17.0°±0.2° and 24.2°±0.2°, determined using Cu Kα1 radiation (λ = 1.54060 Å).

23. Use of a pharmaceutically acceptable acid addition salt according to any one of claims 20 to 22 for the purification of a compound of formula (Ia).

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