Methods for producing lysine-specific demethylase 1 (LSD1) inhibitors

Abstract

To provide a production method of lysine-specific demethylase (LSD1) inhibitors that is easier to implement and has higher yields.SOLUTION: A method for producing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof comprises the step of converting a compound C to a compound D in a solvent under the action of an oxidizing agent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the technical field of drug synthesis, and specifically to a method for producing a lysine-specific demethylase (LSD1) inhibitor. [Background technology]

[0002] Histone post-translational modifications are an important area of ​​epigenetics research, and abnormal histone translation is closely linked to tumor initiation and development. LSD1 (also known as BHC110, p110b, and NPAO), identified by Shi's research group in 2004, is the first histone demethylase to be discovered. Its structure is highly conserved from yeast to humans. In normal blood cells, LSD1 binds to hematopoietic-related transcription factors (e.g., GFI1B and TAL1) to transcribe and repress the expression of downstream target genes, thereby suppressing hematopoietic cell differentiation. LSD1 plays an important role in the dynamic regulation of normal hematopoietic cell differentiation. However, imbalance in this dynamic regulation can disrupt the hematopoietic cell differentiation process and lead to leukemia. Studies have shown that high levels of LSD1 are detected in the bone marrow of 90% of acute myeloid leukemia (AML) and 78% of acute T-cell leukemia (T-ALL). LSD1 expression levels are significantly higher in less differentiated AML cells than in more differentiated AML cells. In a mouse model of MLL-AF9 fusion leukemia, LSD1 was found to be important for maintaining the stemness of leukemic stem cells, suppressing hematopoietic cell differentiation, and promoting excessive cell proliferation. When the LSD1 gene is knocked out, AML stem cells lose their stemness through induced differentiation and apoptosis, resulting in the inability to achieve clonal formation in vitro and tumor transplantation in vivo. Furthermore, abnormal expression of LSD1 is observed in cells and tissues of many solid tumors and is closely associated with poor prognosis. Therefore, LSD1 has become an effective epigenetic antitumor target, and the development and synthesis of small molecule LSD1 inhibitors with novel structures will be of great significance in research into the treatment of diseases such as malignant tumors and leukemia. Summary of the Invention [Problem to be solved by the invention]

[0003] It is an object of the present invention to provide a method for producing LSD1 inhibitors that is easier to carry out and has higher yields. [Means for solving the problem]

[0004] In a first aspect of the present invention, there is provided a method for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] (however, Ring A is a substituted or unsubstituted C6-C 10 It is selected from the group consisting of an aryl ring and a substituted or unsubstituted 5- to 12-membered heteroaryl ring. R1 is selected from the group consisting of -CH2-R, wherein said R is H, a C1-C4 alkyl group, a substituted or unsubstituted C6-C 10 The heteroaryl group or heterocyclic group is selected from the group consisting of an aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-10 membered heteroaryl group, and a substituted or unsubstituted 4-10 membered heterocyclic group, wherein the substitution means that one or more hydrogen atoms in the group are replaced with a group selected from the group consisting of halogen, a C1-C4 alkyl group, a hydroxy group, a carboxy group, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, or an amino protecting group, and the heteroaryl group or heterocyclic group contains 1, 2, or 3 heteroatoms selected from the group consisting of N, O, or S, and the amino protecting group is selected from the group consisting of Boc, SEM, Cbz, Fmoc, Alloc, Teoc, Tos, Tfa, PMB, and Bn. Each R2 is independently selected from the group consisting of methyl groups. n is 0, 1, or 2.) [ka] (1) Converting compound C to compound D in a solvent under the action of an oxidizing agent; wherein the oxidizing agent is selected from the group consisting of potassium dichromate-sulfuric acid, pyridinium dichromate / pyridine, pyridinium dichromate, pyridinium chlorochromate, oxalyl chloride / dimethyl sulfoxide, pyridine-sulfur trioxide / dimethyl sulfoxide / triethylamine, Dess-Martin hypervalent iodine oxidizing agent, and iodophenyldiacetic acid / TEMPO; The solvent is selected from the group consisting of C1-C4 halogenated hydrocarbon solvents, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, toluene, dioxane, or a combination thereof; [ka] (2) Compound D is subjected to reductive amination with compound E to produce compound G.

[0005] In another preferred embodiment, the step (2) is carried out under the action of a reducing agent and an additive. In another preferred embodiment, the reducing agent is selected from the group consisting of sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, or a combination thereof.

[0006] In another preferred embodiment, the additive is selected from the group consisting of formic acid, acetic acid, or a combination thereof. In another preferred embodiment, the step (2) is carried out in a solvent selected from the group consisting of a C1-C4 halogenated hydrocarbon solvent, a C1-C6 alcohol solvent, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, or a combination thereof.

[0007] In another preferred embodiment, R is selected from the group consisting of a substituted or unsubstituted phenyl group, a substituted or unsubstituted C5-C6 cycloalkyl group, a substituted or unsubstituted 5-7 membered heteroaryl group, and a substituted or unsubstituted 5-6 membered heterocyclic group, wherein the substitution means that one or more hydrogen atoms in the group are replaced with a group selected from the group consisting of halogen, a C1-C4 alkyl group, a hydroxy group, a carboxy group, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, or an amino protecting group, wherein the heteroaryl group or heterocyclic group contains 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S, and the amino protecting group is selected from the group consisting of Boc, SEM, Cbz, Fmoc, Alloc, Teoc, Tos, Tfa, PMB, and Bn.

[0008] In another preferred embodiment, R1 is selected from the group consisting of an ethyl group, a benzyl group, a phenyl group, a cyclohexylmethyl group, a 4-pyridylmethyl group, a phenylethyl group, a 1H-indol-5-ylmethyl group, a 2-thienylmethyl group, a 2-furylmethyl group, a 4-fluorophenylmethyl group, a 4-chlorophenylmethyl group, a 4-bromophenylmethyl group, a 4-methoxyphenyl group, a 4-trifluoromethylphenylmethyl group, a 3,5-dimethoxyphenylmethyl group, a 4-carbonylphenylmethyl group, a cyclopentylmethyl group, a cyclobutylmethyl group, a 4-piperidylmethyl group, a 3-chlorophenylmethyl group, a 2-chlorophenylmethyl group, and a 4-t-butylphenylmethyl group.

[0009] In another preferred embodiment, the compound of formula G is selected from the group consisting of: [ka]

[0010] In some embodiments, in step (1), the oxidizing agent is selected from the group consisting of oxalyl chloride / dimethyl sulfoxide, pyridine-sulfur trioxide / dimethyl sulfoxide / triethylamine, Dess-Martin oxidizing agent, or iodophenyldiacetic acid / TEMPO.

[0011] In some embodiments, in step (1), the solvent is a halogenated hydrocarbon solvent. In some embodiments, in step (1), the solvent is dichloromethane. In some embodiments, in step (1), the molar ratio of the compound of Formula C to the oxidizing agent is 1:1.0 to 1:6.0.

[0012] In another preferred embodiment, the reaction temperature is -80 to 40°C. In another preferred embodiment, the reaction time is 4 to 48 hours. In another preferred embodiment, the ratio V / W of the volume of the reaction solvent used to the mass of the substrate is 5 to 20 mL / g.

[0013] In some embodiments, the molar ratio of the compound of Formula C to the oxidizing agent is 1:2.0 to 1:4.0. In another preferred embodiment, the reaction temperature is -78 to 20°C. In another preferred embodiment, the reaction time is 2 to 24 hours.

[0014] In some embodiments, in step (2), the reducing agent is selected from the group consisting of sodium cyanoborohydride or sodium triacetoxyborohydride. In some embodiments, in step (2), the solvent is selected from the group consisting of C1-C6 alcohol solvents and C1-C4 halogenated alkane solvents.

[0015] In some embodiments, in step (2), the molar ratio of the compound of Formula D to the reducing agent is 1:0.8 to 1:2.0; and / or the molar ratio of the compound of formula D to the compound of formula E is 1:0.5 to 1:2.0; and / or The molar ratio of the compound of formula D to the additive is 1:0.5 to 1:2.0.

[0016] In another preferred embodiment, the reaction temperature is -10 to 50°C. In another preferred embodiment, the reaction time is 1 to 48 hours. In another preferred embodiment, the ratio V / W of the volume of the reaction solvent used to the mass of the substrate is 5 mL / g to 30 mL / g.

[0017] In some embodiments, the method further comprises the steps of: [ka] (3) Compound G is reacted with an organic or inorganic acid to obtain compound H.

[0018] In another preferred embodiment, in step (3), the organic acid or inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propanoic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetyloxybenzoic acid, and hydroxyethanesulfonic acid.

[0019] In another preferred embodiment, in step (3), the solvent is selected from the group consisting of methanol, ethanol, dimethyl sulfoxide, methyl t-butyl ether, dioxane, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, or a combination thereof.

[0020] In another preferred embodiment, in step (3), the solvent is selected from the group consisting of a C1-C6 alcohol solvent / water mixed solvent, an acetonitrile / water mixed solvent, and an acetone / water mixed solvent.

[0021] In some embodiments, in step (3), the molar ratio of the compound of formula G to the salt-forming reagent is 1:1.0-5.0. In another preferred embodiment, in step (3), the reaction temperature is 20 to 100°C.

[0022] In another preferred embodiment, in the step (3), the reaction time is 2 to 48 hours. In another preferred example, in the step (3), the ratio V / W of the volume of the reaction solvent used to the mass of the substrate is 5 mL / g to 30 mL / g.

[0023] In a second aspect of the present invention, there is provided a method for preparing an intermediate compound of formula D, comprising the steps of: [ka] (however, R1 is selected from the group consisting of an ethyl group, a benzyl group, a phenyl group, a cyclohexylmethyl group, a 4-pyridylmethyl group, a phenylethyl group, a 1H-indol-5-ylmethyl group, a 2-thienylmethyl group, a 2-furylmethyl group, a 4-fluorophenylmethyl group, a 4-chlorophenylmethyl group, a 4-bromophenylmethyl group, a 4-methoxyphenyl group, a 4-trifluoromethylphenylmethyl group, a 3,5-dimethoxyphenylmethyl group, a 4-carbonylphenylmethyl group, a cyclopentylmethyl group, a cyclobutylmethyl group, a 4-piperidylmethyl group, a 3-chlorophenylmethyl group, a 2-chlorophenylmethyl group, and a 4-t-butylphenylmethyl group. Each R2 is independently selected from the group consisting of methyl groups. n is 0, 1, or 2.) [ka] (1) Converting compound C to compound D in a solvent under the action of an oxidizing agent; wherein the oxidizing agent is selected from the group consisting of potassium dichromate-sulfuric acid, pyridinium dichromate / pyridine, pyridinium dichromate, pyridinium chlorochromate, oxalyl chloride / dimethyl sulfoxide, pyridine-sulfur trioxide / dimethyl sulfoxide / triethylamine, Dess-Martin hypervalent iodine oxidizing agent, and iodophenyldiacetic acid / TEMPO; The solvent is selected from the group consisting of C1-C4 halogenated hydrocarbon solvents, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, toluene, dioxane, or a combination thereof.

[0024] Of course, it is understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be described here one by one due to space limitations. DETAILED DESCRIPTION OF THE INVENTION

[0025] After extensive research, the inventors have discovered a new method for producing tranylcypromine compounds. This synthetic method has the advantages of high yield, high product purity, and suitability for industrial production, making it highly suitable for producing tranylcypromine compounds. Based on this finding, the inventors have completed the present invention.

[0026] definition As used herein, the term "alkyl group" includes straight or branched chain alkyl groups. For example, a C1-C6 alkyl group is a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and the like.

[0027] As used herein, the term "alkenyl group" includes straight-chain and branched-chain alkenyl groups. For example, a C2-C6 alkenyl group is a straight-chain or branched-chain alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, and the like.

[0028] As used herein, the term "alkynyl group" includes straight-chain and branched-chain alkynyl groups. For example, a C2-C6 alkynyl group is a straight-chain or branched-chain alkynyl group having from 2 to 6 carbon atoms, such as ethynyl, propargyl, butynyl, and the like.

[0029] As used herein, the term "cycloalkyl group" refers to a cyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms, e.g., C3-C 10 A cycloalkyl group is a cyclic saturated aliphatic hydrocarbon group having 3-10 carbon atoms. It may be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, or bicyclic, such as bridged or spirocyclic.

[0030] As used herein, the term "alkylamino group" refers to an amino group substituted with an alkyl group. For example, a "C1-C6 alkylamino group" refers to an amino group substituted with a C1-C6 alkyl group, which may be mono- or di-substituted, such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, t-butylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di-t-butylamino group, etc.

[0031] As used herein, the term "alkoxy group" refers to a group having an alkyl-oxy structure. For example, a "C1-C8 alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 8 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and t-butoxy groups.

[0032] As used herein, the term "haloalkyl group" refers to an alkyl group in which one or more hydrogen atoms are replaced with halogen, where alkyl is as defined above.

[0033] As used herein, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced with halogen, where alkoxy is as defined above.

[0034] As used herein, the term "heterocyclic group" or "heterocycloalkyl group" refers to a saturated or partially saturated cyclic group having a specified number of ring atoms (e.g., 3-10 ring atoms), of which 1-3 atoms are heteroatoms selected from N, S, and O. It may be monocyclic, bicyclic, or polycyclic, including bridged and spirocyclic rings. Specific examples include oxetanyl, azetidyl, tetrahydro-2H-pyranyl, piperidyl, tetrahydrofuryl, morpholyl, and pyrrolidyl.

[0035] As used herein, the term "C6-C 10 An "aryl group" is an aryl group having 6-10 carbon atoms, such as phenyl, naphthyl, and the like.

[0036] As used herein, the term "5-12 membered heteroaryl group" refers to a cyclic aromatic group having 5-12 atoms, of which 1-3 atoms are heteroatoms selected from the group consisting of N, S, and O. It may be monocyclic or in the form of a fused ring. Specific examples include pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, triazyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like.

[0037] Unless specifically described as "substituted or unsubstituted," the groups described in the present invention include halogen, cyano, nitro, hydroxy, amino, C1-C6 alkyl-amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, allyl, benzyl, C6-C6 alkyl, C6-C6 haloalkoxy, C6-C6 haloalkyl, C6-C6 haloalkenyl, C6-C6 haloalkynyl, C1-C6 haloalkoxy, C6 ... 10 It may be substituted with a substituent selected from the group consisting of an aryl group, a C1-C6 alkoxy-C1-C6 alkyl group, a C1-C6 alkoxy-carbonyl group, a phenoxycarbonyl group, a C2-C6 alkynyl-carbonyl group, a C2-C6 alkenyl-carbonyl group, a C3-C6 cycloalkyl-carbonyl group, a C1-C6 alkyl-sulfonyl group, and the like.

[0038] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. Preferably, the halogen or halogen atom is selected from F, Cl, and Br. "Halogen-substituted" means substituted with an atom selected from F, Cl, Br, and I.

[0039] Unless otherwise specified, the structural formulae depicted in the present invention are intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric (or conformational) isomers), such as R, S configurations with asymmetric centers, (Z), (E) isomers of double bonds, etc. Therefore, any single stereoisomer or mixture of enantiomers, diastereomers, or geometric (or conformational) isomers of the compounds of the present invention are within the scope of the present invention.

[0040] As used herein, the term "tautomer" refers to structural isomers with different energies that can be converted to each other across a low energy barrier. For example, proton tautomers (i.e., prototropies) include tautomers that undergo proton migration, such as 1H-indazole and 2H-indazole. Valence tautomers include tautomers that undergo reorganization of some of the bonding electrons.

[0041] As used herein, the term "solvate" refers to a complex formed by coordination of a compound of the present invention with solvent molecules in a specific ratio. As used herein, the term "hydrate" refers to a complex formed by coordinating a compound of the present invention with water.

[0042] The main advantages of the present invention are as follows: (1) The synthesis method of the present invention is simple, requires mild conditions, causes little environmental pollution, and requires readily available raw materials. (2) The synthesis method of the present invention is stable and has a high yield, and is suitable for industrial production.

[0043] The present invention will be further described below with reference to specific examples. It is understood that these examples are only used to explain the present invention and do not limit the scope of the present invention. In the following examples, experimental methods for which specific conditions are not described were generally carried out under conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are for illustrative purposes only. Unless otherwise specified, all experimental materials and reagents used in the following examples are commercially available products.

[0045] Example Example 1 Preparation of benzyl 4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate hydrochloride (H1) Synthetic Route: [ka]

[0046] Preparation of D1: Oxalyl chloride (57.5 mL, 680.2 mmol, 2 eq) was dissolved in anhydrous dichloromethane solution (1.03 L) and cooled to -78°C. Anhydrous dimethyl sulfoxide (72.4 mL, 1.022 mol, 3 eq) was added at a temperature of less than -60°C, and the mixture was allowed to react for 0.5 hours at -78°C. A dichloromethane solution (250 mL) of compound C1 (91.1 g, 340.7 mmol, 1 eq) was then added and the mixture was allowed to react for 1.5 hours at -78°C. Triethylamine (235 mL, 1.703 mol, 5 eq) was then added and the mixture was allowed to react for 10 minutes at -78°C. The mixture was then warmed to room temperature and allowed to react for 0.5 hours. The reaction mixture was poured into 2.5 L of water for extraction, and the aqueous phase was extracted with dichloromethane (300 mL x 2). The organic phase was collected and washed with saturated brine (0.5 L x 2), dried over anhydrous sodium sulfate, rotary dried, and loaded onto a column with PE:EA = 2:1 to obtain 77.7 g of the target compound D1 as a yellow oil. Yield: 86%. LC-MS (ESI): m / z [M+H] + = 266.

[0047] Preparation of G1: Compound D1 (77 g, 290.3 mmol, 1 eq), (1S,2R)-2-phenylcyclopropylamine (38.7 g, 290.3 mmol, 1 eq), and formic acid (16.6 mL, 290.3 mmol, 1 eq) were dissolved in 500 mL of dichloromethane, evacuated and replaced with nitrogen gas three times, and heated to reflux for 15 min. The mixture was cooled to room temperature, and sodium cyanoborohydride (36.5 g, 580.6 mmol, 2 eq) was added in portions. The mixture was stirred at room temperature for 12 hours, quenched by slowly adding 300 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (300 mL x 2), and the combined organic phases were washed with saturated brine (0.5 L x 2), dried over anhydrous sodium sulfate, rotary evaporated, and loaded onto a column with DCM:MeOH = 20:1 to obtain 99 g of the target compound G1 as a colorless oil. Yield: 89%. LC-MS (ESI): m / z [M+H] + = 383.

[0048] Preparation of H1: Compound G1 (95 g, 248 mmol, 1 eq) was dissolved in 1,4-dioxane (0.5 L) and a 4 N solution of hydrochloric acid in dioxane (63.2 mL, 253 mmol, 1.02 eq) was added dropwise with stirring. The mixture was stirred overnight at room temperature. After rotary drying, the mixture was redissolved in 100 mL of methanol and 2 L of ethyl acetate was added with stirring. A white solid precipitated, which was suction filtered, washed with ethyl acetate, and dried to obtain 96 g of the target compound H1 as a white solid. Yield: 92%. LC-MS (ESI): m / z [M+H] + = 383.

[0049] Example 2 3-chlorobenzyl-4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester hydrochloride (H2) [ka] Compound H2 was prepared by following the synthesis method for H1 and replacing the benzyl group in the starting material with a 3-chlorobenzyl group. Total yield: 72%. LC-MS (ESI): m / z [M+H] + = 417.

[0050] Example 3 Furan-2-ylmethyl-4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester hydrochloride (H3) [ka] Compound H3 was prepared by following the method for synthesizing H1, but replacing the benzyl group in the starting material with furan-2-ylmethyl. Total yield: 58%. LC-MS (ESI): m / z [M+H] + = 373.

[0051] Example 4 Preparation of 4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl p-toluenesulfonate (H4) Preparation of H4: [ka] The synthesis route of G1 is based on the preparation route of H1 above.

[0052] Preparation of H4: Compound G1 (50 g, 131 mmol, 1 eq) was dissolved in 1,4-dioxane (0.5 L) and a solution of p-toluenesulfonic acid (23 g, 131 mmol, 1 eq) in dioxane (100 mL) was added dropwise with stirring. The mixture was stirred overnight at room temperature. After rotary evaporation, the mixture was redissolved in 300 mL of water / acetone (1 / 2, V / V), heated to 55 °C, and stirred until complete dissolution. Upon cooling, a white solid precipitated. This was filtered with suction, washed with 50 mL of water / acetone (1 / 2, V / V), and dried to give 60 g of the target compound H4 as a white solid. Yield: 82%. LC-MS (ESI): m / z [M+H] + =383.

[0053] Example 5 Preparation of cyclohexylmethyl-4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester p-toluenesulfonate (H5) [ka] Compound H5 was prepared by following the synthesis method for H4, but replacing the benzyl group in the starting material with cyclohexylmethyl. Total yield: 67%. LC-MS (ESI): m / z [M+H] + = 389.

[0054] Example 6 Preparation of pyridin-4-ylmethyl-4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester p-toluenesulfonate (H6) [ka] Compound H6 was prepared by following the method for synthesizing H4, but replacing the benzyl group in the starting material with pyridin-4-ylmethyl. Total yield: 45%. LC-MS (ESI): m / z [M+H] + = 384.

[0055] Example 7 Preparation of thiophen-2-yl-4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester p-toluenesulfonate (H7) [ka] Compound H6 was prepared by following the method for synthesizing H4, but replacing the benzyl group in the starting material with thiophen-2-ylmethyl. Overall yield: 46%. LC-MS (ESI): m / z [M+H] + = 389.

[0056] Example 8 Preparation of benzyl 4-fluoro-4-(((1R,2S-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate hydrochloride (H8) [ka] Following the method for synthesizing H1, compound H8 was prepared by replacing E1 with its enantiomer E2.

[0057] Preparation of G2: Compound D1 (50 g, 188.5 mmol, 1 eq), (1R,2S)-2-phenylcyclopropylamine (25.1 g, 188.5 mmol, 1 eq), and formic acid (10.8 mL, 188.5 mmol, 1 eq) were dissolved in 300 mL of dichloromethane, evacuated and replaced with nitrogen gas three times, and heated to reflux for 15 min. The mixture was cooled to room temperature, and sodium cyanoborohydride (23.7 g, 580.6 mmol, 2 eq) was added in portions. The mixture was stirred at room temperature for 12 hours, quenched by slowly adding 150 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (150 mL x 2), and the combined organic phases were washed with saturated brine (0.5 L x 2), dried over anhydrous sodium sulfate, rotary evaporated, and loaded onto a column with DCM:MeOH = 20:1 to obtain 60.5 g of the target compound G1 as a colorless oil. Yield: 84%. LC-MS (ESI): m / z [M+H] + = 383.

[0058] Preparation of H8: Compound G2 (55 g, 144 mmol, 1 eq) was dissolved in 1,4-dioxane (0.4 L) and a 4 N solution of hydrochloric acid in dioxane (36.7 mL, 147 mmol, 1.02 eq) was added dropwise with stirring. The mixture was stirred overnight at room temperature. After rotary evaporation, the mixture was redissolved in 80 mL of methanol and 1.6 L of ethyl acetate was added with stirring. A white solid precipitated, which was suction filtered, washed with ethyl acetate, and dried to give 54 g of the target compound H8 as a white solid. Yield: 90%. LC-MS (ESI): m / z [M+H] + = 383.

[0059] Example 9 Preparation of 4-fluorobenzyl-4-fluoro-4-(((1R,2S-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester hydrochloride (H9) [ka] Compound H9 was prepared by following the method for synthesizing H8, except that the benzyl group in the starting material was replaced with a 4-fluorobenzyl group. Total yield: 52%. LC-MS (ESI): m / z [M+H] + = 401.

[0060] Example 10 Preparation of 4-methoxybenzyl-4-fluoro-4-(((1R,2S-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester hydrochloride (H10) [ka] Compound H9 was prepared by following the method for synthesizing H8, except that the benzyl group in the starting material was replaced with a 4-methoxybenzyl group. Total yield: 57%. LC-MS (ESI): m / z [M+H] + = 413.

[0061] Example 11 Preparation of piperidine-4-methyl-4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester hydrochloride (H11) [ka]

[0062] Preparation of D3: Oxalyl chloride (45.1 mL, 534 mmol, 2 eq) was dissolved in anhydrous dichloromethane solution (1 L) and cooled to -78°C. Anhydrous dimethyl sulfoxide (56.7 mL, 0.801 mol, 3 eq) was added at a temperature of less than -60°C, and the mixture was allowed to react for 0.5 hours at -78°C. A dichloromethane solution (250 mL) of compound C3 (100 g, 267 mmol, 1 eq) was then added and the mixture was allowed to react for 1.5 hours at -78°C. Triethylamine (184 mL, 1.335 mol, 5 eq) was then added and the mixture was allowed to react for 10 minutes at -78°C. The mixture was then warmed to room temperature and allowed to react for 0.5 hours. The reaction mixture was poured into 2.5 L of water for extraction. The aqueous phase was extracted with dichloromethane (300 mL x 2). The organic phase was collected and washed with saturated brine (0.5 L x 2), dried over anhydrous sodium sulfate, and rotary evaporated. The residue was then loaded onto a column with PE:EA = 2:1 to obtain 87.6 g of the target compound D3 as a yellow oil. Yield: 88%. LC-MS (ESI): m / z [M+H] + = 373.

[0063] Preparation of G3: Compound D3 (80 g, 301.6 mmol, 1 eq), (1S,2R)-2-phenylcyclopropylamine (40.2 g, 301.6 mmol, 1 eq), and formic acid (17.2 mL, 301.6 mmol, 1 eq) were dissolved in 500 mL of dichloromethane, evacuated and replaced with nitrogen gas three times, and heated to reflux for 15 minutes. The mixture was cooled to room temperature, and sodium cyanoborohydride (37.9 g, 603.2 mmol, 2 eq) was added in portions. The mixture was stirred at room temperature for 12 hours, quenched by slowly adding 310 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (300 mL x 2), and the combined organic phases were washed with saturated brine (0.5 L x 2), dried over anhydrous sodium sulfate, rotary evaporated, and loaded onto a column with DCM:MeOH = 20:1 to give 123 g of the target compound G3 as a colorless oil. Yield: 83%. LC-MS (ESI): m / z [M+H] + = 490.

[0064] Preparation of H11: Compound G3 (110 g, 287.2 mmol, 1 eq) was dissolved in 1,4-dioxane (0.5 L) and a 4 N solution of hydrochloric acid in dioxane (287 mL, 1148.8 mmol, 4.0 eq) was added dropwise with stirring. The mixture was stirred overnight at room temperature. After rotary drying, the mixture was redissolved in 100 mL of methanol and 2 L of ethyl acetate was added with stirring. A white solid precipitated, which was suction filtered, washed with ethyl acetate, and dried to give 123 g of the target compound H11 as a white solid. Yield: 93%. LC-MS (ESI): m / z [M+H] + = 390.

[0065] Example 12 Preparation of piperidin-4-ylmethyl-4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester p-toluenesulfonate (H12) [ka]

[0066] Preparation of H12: Compound G3 (100 g, 261.1 mmol, 1 eq) was dissolved in 1,4-dioxane (1 L). A solution of p-toluenesulfonic acid (180 g, 1044.4 mmol, 4 eq) in dioxane (200 mL) was added dropwise with stirring, and the mixture was stirred overnight at room temperature. After rotary evaporation, the mixture was redissolved in 600 mL of water / acetone (1 / 2, V / V), heated to 55 °C, and stirred until complete dissolution. Upon cooling, a white solid precipitated. This was suction filtered, washed with 100 mL of water / acetone (1 / 2, V / V), and dried to obtain 153 g of the target compound H12 as a white solid. Yield: 80%. LC-MS (ESI): m / z [M+H] + = 390.

[0067] Example 13 Preparation of piperidine-4-methyl-4-fluoro-4-(((1R,2S-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester hydrochloride (H13) [ka] Following the method for synthesizing H1, compound H13 was prepared by replacing E1 with its enantiomer E2.

[0068] Preparation of G4: Compound D3 (50 g, 188.5 mmol, 1 eq), (1R,2S)-2-phenylcyclopropylamine (25.1 g, 301.6 mmol, 1 eq), and formic acid (10.8 mL, 188.5 mmol, 1 eq) were dissolved in 300 mL of dichloromethane, evacuated and replaced with nitrogen gas three times, and heated to reflux for 15 min. The mixture was cooled to room temperature, and sodium cyanoborohydride (23.7 g, 377 mmol, 2 eq) was added in portions. The mixture was stirred at room temperature for 12 hours, quenched by slowly adding 180 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (180 mL x 2), and the organic phases were combined. The organic phase was further washed with saturated brine (0.3 L x 2), dried over anhydrous sodium sulfate, rotary evaporated, and column-coated with DCM:MeOH = 20:1 to give 78 g of the target compound G4 as a colorless oil. Yield: 85%. LC-MS (ESI): m / z [M+H] + = 490.

[0069] Preparation of H13: Compound G4 (50 g, 130.5 mmol, 1 eq) was dissolved in 1,4-dioxane (0.25 L) and a 4 N solution of hydrochloric acid in dioxane (131 mL, 522 mmol, 4.0 eq) was added dropwise with stirring. The mixture was stirred overnight at room temperature. After rotary evaporation, the mixture was redissolved in 60 mL of methanol and 1 L of ethyl acetate was added with stirring. A white solid precipitated, which was suction filtered, washed with ethyl acetate, and dried to give 52 g of the target compound H13 as a white solid. Yield: 87%. LC-MS (ESI): m / z [M+H] + = 390.

[0070] Example 14 Preparation of piperidin-4-ylmethyl-4-fluoro-4-(((1R,2S-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester p-toluenesulfonate (H14) [ka] Preparation of H14: Compound G4 (50 g, 130 mmol, 1 eq) was dissolved in 1,4-dioxane (0.5 L) and a solution of p-toluenesulfonic acid (90 g, 522 mmol, 4 eq) in dioxane (100 mL) was added dropwise with stirring. The mixture was stirred overnight at room temperature. After rotary evaporation, the mixture was redissolved in 300 mL of water / acetone (1 / 2, V / V), heated to 55 °C, and stirred until complete dissolution. Upon cooling, a white solid precipitated. This was filtered with suction, washed with 50 mL of water / acetone (1 / 2, V / V), and dried to give 80 g of the target compound H14 as a white solid. Yield: 84%. LC-MS (ESI): m / z [M+H] + = 390.

[0071] Example 15 Preparation of piperidin-4-ylmethyl-4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester p-toluenesulfonate (K1) [ka]

[0072] Preparation of J1: Compound H11 (50 g, 108 mmol) was dissolved in saturated aqueous sodium hydroxide (100 mL) and stirred for 30 minutes. The mixture was then extracted with dichloromethane (3 x 1000 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 30.5 g of crude product, which was used directly in the next step. Yield: 72.4%. LC-MS (ESI): m / z [M+H] + = 390.

[0073] Preparation of K1: Compound J1 (30 g, 77.0 mmol) was placed in a reactor and a predetermined amount of acetonitrile was added to prepare a 0.12 M solution (approximately 321 mL of acetonitrile solvent). A 0.12 M solution of p-toluenesulfonic acid (6.63 g, 38.51 mmol, 321 mL) was then added. The reaction mixture was stirred at 60 °C for 1 hour, then cooled to room temperature and allowed to stand overnight. The precipitated solid was filtered and washed three times with a small amount of acetonitrile. The resulting solid was then dissolved in 100 mL of ethyl acetate and suction filtered to obtain 26.8 g of the target compound K1 as a white solid. Yield: 62%. LC-MS (ESI): m / z [M+H] + = 390.

[0074] Example 16 Preparation of piperidin-4-ylmethyl-4-fluoro-4-(((1R,2S-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester p-toluenesulfonate (K2) [ka]

[0075] Preparation of J2: Compound H13 (50 g, 108 mmol) was dissolved in saturated aqueous sodium hydroxide (100 mL) and stirred for 30 minutes. The mixture was then extracted with dichloromethane (3 x 1000 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 32 g of crude product, which was used directly in the next step. Yield: 76%. LC-MS (ESI): m / z [M+H] + = 390.

[0076] Preparation of K2: Compound J2 (30 g, 77.0 mmol) was placed in a reactor and a predetermined amount of acetonitrile was added to prepare a 0.12 M solution (approximately 321 mL of acetonitrile solvent). A 0.12 M solution of p-toluenesulfonic acid (6.63 g, 38.51 mmol, 321 mL) was then added. The reaction mixture was stirred at 60 °C for 1 hour, then cooled to room temperature and allowed to stand overnight. The precipitated solid was filtered and washed three times with a small amount of acetonitrile. The resulting solid was then dissolved in 100 mL of ethyl acetate and suction filtered to obtain 28 g of the target compound K2 as a white solid. Yield: 65%. LC-MS (ESI): m / z [M+H] + = 390.

[0077] Example 17 Preparation of 4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid benzyl sulfate (K3) [ka] Compound G1 (30 g, 78.44 mmol, 1 eq) was dissolved in acetonitrile (0.65 L) and a 0.12 M sulfuric acid solution in acetonitrile (0.33 L) was added. The reaction mixture was stirred at 60°C for 1 hour, then cooled to room temperature and allowed to stand overnight. The precipitated solid was filtered, and after suction filtration, the cake was washed three times with a small amount of acetonitrile. 33 g of the target compound K3 was obtained as a white solid. Yield: 88%. LC-MS (ESI): m / z [M+H] + = 383.

[0078] Example 18 Preparation of 4-fluoro-4-(((1R,2S-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid benzyl sulfate (K4) [ka] Compound K4 was prepared by following the method for synthesizing K3 and replacing G1 with its enantiomer G2. Yield: 79%. LC-MS (ESI): m / z [M+H] + = 383.

[0079] Example 19 Preparation of 3-chlorobenzyl-4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester sulfate (K5) [ka] Compound K5 was prepared by following the method for synthesizing K3, except that the benzyl group in the starting material was replaced with a 3-chlorobenzyl group. Overall yield: 70%. LC-MS (ESI): m / z [M+H] + = 417.

[0080] Example 20 Preparation of 4-methoxybenzyl-4-fluoro-4-(((1R,2S-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester sulfate (K6) [ka] Following the synthesis of K3, the free base of H10 was prepared as starting material to give compound K6. Total yield: 85%. LC-MS (ESI): m / z [M+H] + = 413.

[0081] Example 21 Preparation of piperidine-4-methyl-4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester sulfate (K7) [ka] Following the synthesis of K3, compound K7 was obtained from J1. Total yield: 83%. LC-MS (ESI): m / z [M+H] + = 390.

[0082] Example 22 Preparation of piperidine-4-methyl-4-fluoro-4-(((1R,2S-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester sulfate (K8) [ka] Following the synthesis of K3, compound K8 was obtained from J2. Total yield: 90%. LC-MS (ESI): m / z [M+H] + = 390.

[0083] Example 23 Preparation of 4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid benzyl oxalate (K9) [ka] Compound G1 (50 g, 130.73 mmol, 1 eq) was dissolved in acetonitrile (1.1 L) and a 0.12 M oxalic acid solution in acetonitrile (11.8 g, 130.73 mmol, 1.1 L) was added. The reaction mixture was stirred at 60°C for 1 hour, then cooled to room temperature and allowed to stand overnight. The precipitated solid was filtered, and after suction filtration, the cake was washed three times with a small amount of acetonitrile. 55 g of the target compound K9 was obtained as a white solid. Yield: 89%. LC-MS (ESI): m / z [M+H] + = 383.

[0084] Example 24 Preparation of 4-fluoro-4-(((1R,2S-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid benzyl oxalate (K10) [ka] Following the method for synthesizing K9, compound K10 was prepared by replacing G1 with its enantiomer G2. Yield: 84%. LC-MS (ESI): m / z [M+H] + = 383.

[0085] Example 25 Preparation of thiophen-2-yl-4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid oxalate (K11) [ka] Compound K11 was prepared by following the method for synthesizing K9, but replacing the benzyl group in the starting compound with thiophen-2-ylmethyl. Yield: 72%. LC-MS (ESI): m / z [M+H] + = 389.

[0086] Example 26 Preparation of piperidine-4-methyl-4-fluoro-4-(((1S,2R-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester oxalate (K12) [ka] Following the synthesis of K9, compound K12 was obtained from J1. Total yield: 81%. LC-MS (ESI): m / z [M+H] + = 390.

[0087] Example 27 Preparation of piperidine-4-methyl-4-fluoro-4-(((1R,2S-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylic acid ester oxalate (K13) [ka] Following the synthesis of K9, compound K13 was obtained from J2. Total yield: 87%. LC-MS (ESI): m / z [M+H] + = 390.

[0088] All documents related to the present invention are incorporated herein by reference as if each document were individually incorporated by reference. After reading the above content of the present invention, it should be understood that those skilled in the art can make various changes and modifications to the present invention, and that equivalents thereof are within the scope of the claims of the present invention.

Claims

1. 1. A process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising the steps of: 【Chemistry 1】 (however, Ring A is a substituted or unsubstituted C ６ -C １０ It is selected from the group consisting of an aryl ring and a substituted or unsubstituted 5- to 12-membered heteroaryl ring. R １ is -CH ２ -R, wherein said R is selected from the group consisting of H, C １ -C ４ alkyl group, substituted or unsubstituted C ６ -C １０ aryl group, substituted or unsubstituted C ３ -C ８ a cycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, and a substituted or unsubstituted 4- to 10-membered heterocyclic group, wherein the substitution means that one or more hydrogen atoms in the group are replaced with halogen, C １ -C ４ Alkyl group, hydroxy group, carboxy group, C １ -C ４ Alkoxy group, C １ -C ４ The heteroaryl or heterocyclic group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O or S, by being substituted with a group selected from the group consisting of a haloalkyl group or an amino protecting group, and the amino protecting group is selected from the group consisting of Boc, SEM, Cbz, Fmoc, Alloc, Teoc, Tos, Tfa, PMB, Bn. Each R ２ are each independently selected from the group consisting of methyl groups. n is 0, 1 or 2. 【Chemistry 2】 (1) converting compound C to compound D in a solvent under the action of an oxidizing agent; wherein the oxidizing agent is selected from the group consisting of oxalyl chloride / dimethyl sulfoxide, pyridine-sulfur trioxide / dimethyl sulfoxide / triethylamine, and the reaction temperature is −78 to 20° C.; The solvent is C １ -C ４ selected from the group consisting of halogenated hydrocarbon solvents, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, toluene, dioxane, or combinations thereof; 【Transformation 3】 (2) Compound D is reductively aminated with compound E to form compound G, where R 3 is H.

2. The method described in claim 1, characterized in that the step (2) is carried out under the action of a reducing agent and an additive.

3. The method of claim 1, wherein the reducing agent is selected from the group consisting of sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, or a combination thereof.

4. The method of claim 1, wherein the additive is selected from the group consisting of formic acid, acetic acid, or a combination thereof.

5. The method according to claim 1, wherein the step (2) is carried out in a solvent selected from the group consisting of C1-C4 halogenated hydrocarbon solvents, C1-C6 alcohol solvents, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, or a combination thereof.

6. The method according to claim 1, wherein R 1 is selected from the group consisting of an ethyl group, a benzyl group, a phenyl group, a cyclohexylmethyl group, a 4-pyridylmethyl group, a phenylethyl group, a 1H-indol-5-ylmethyl group, a 2-thienylmethyl group, a 2-furylmethyl group, a 4-fluorophenylmethyl group, a 4-chlorophenylmethyl group, a 4-bromophenylmethyl group, a 4-methoxyphenyl group, a 4-trifluoromethylphenylmethyl group, a 3,5-dimethoxyphenylmethyl group, a 4-carbonylphenylmethyl group, a cyclopentylmethyl group, a cyclobutylmethyl group, a 4-piperidylmethyl group, a 3-chlorophenylmethyl group, a 2-chlorophenylmethyl group, and a 4-t-butylphenylmethyl group.

7. The compound of formula G, which is selected from the group consisting of: 【Chemistry 4】 The method according to claim 1, characterized in that it is selected from:

8. 2. The method according to claim 1, wherein in step (1), the oxidizing agent is selected from the group consisting of oxalyl chloride / dimethyl sulfoxide, pyridine-sulfur trioxide / dimethyl sulfoxide / triethylamine, Dess-Martin oxidizing agent, or iodophenyldiacetic acid / TEMPO.

9. 2. The method according to claim 1, wherein in step (1), the solvent is a halogenated hydrocarbon solvent.

10. 2. The method of claim 1, wherein in step (1), the solvent is dichloromethane.

11. 2. The method according to claim 1, wherein in step (1), the molar ratio of the compound of formula C to the oxidizing agent is 1:1.0 to 1:6.

0.

12. 2. The method according to claim 1, wherein in step (1), the molar ratio of the compound of formula C to the oxidizing agent is 1:2.0 to 1:4.

0.

13. 2. The method of claim 1, wherein in step (2), the reducing agent is selected from the group consisting of sodium cyanoborohydride or sodium triacetoxyborohydride.

14. In step (2), the solvent is C １ -C ６ Alcohol-based solvents, C １ -C ４ 2. The process of claim 1, wherein the solvent is selected from the group consisting of halogenated alkane solvents.

15. In step (2), the molar ratio of the compound of formula D to the reducing agent is 1:0.8 to 1:2.0; and / or the molar ratio of the compound of formula D to the compound of formula E is from 1:0.5 to 1:2.0; and / or 2. The method according to claim 1, wherein the molar ratio of the compound of formula D to the additive is 1:0.5 to 1:2.

0.

16. 10. The method of claim 1, further comprising the steps of: 【Transformation 5】 (3) Compound G is reacted with an organic or inorganic acid to obtain compound H.

17. The method of claim 16, wherein in step (3), the organic acid or inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propanoic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetyloxybenzoic acid, hydroxyethanesulfonic acid, or a combination thereof.

18. The method of claim 16, wherein in step (3), the solvent is selected from the group consisting of methanol, ethanol, dimethyl sulfoxide, methyl t-butyl ether, dioxane, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, or a combination thereof.

19. The method according to claim 16, wherein in step (3), the solvent is selected from the group consisting of a C 1 -C 6 alcohol solvent / water mixed solvent, an acetonitrile / water mixed solvent, and an acetone / water mixed solvent.

20. The method according to claim 16, wherein in step (3), the molar ratio of the compound of formula G to the salt-forming reagent is 1:1.0-5.0.

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