Preparation method of GLP-1R receptor agonist and preparation method of intermediates and intermediates

Abstract

This invention discloses a method for preparing a GLP-1R receptor agonist and a method for preparing its intermediates. The method for preparing the GLP-1R receptor agonist and its intermediates comprises a method for preparing a compound of formula I-1, which includes the following steps: in the presence of an inorganic base, a compound of formula I-1-6 and a compound of formula I-1-7 are subjected to a substitution reaction in a solvent to obtain a compound of formula I-1; wherein the inorganic base includes one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate. This method has the advantages of high yield and low cost in the preparation of GLP-1R receptor agonists and their intermediates, and shows good application prospects.

Description

Technical Field

[0001] This invention relates to a method for preparing a GLP-1R receptor agonist and a method for preparing its intermediates, specifically to 2-amino-2-(hydroxymethyl)-1,3-propanediol, (S)-2-((4-(2-(((4-chloro-2-fluorophenylmethyl)oxy)phenyl)piperidin-1-yl)methyl)-1-(oxetane-2-aminomethyl)-1H-benzo[d]imidazolium-6-carboxylate and its intermediates. Background Technology

[0002] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-1-(oxacyclobut-2-aminomethyl)-1H-benzis[d]imidazole-6-carboxylic acid is a GLP-1R agonist used to treat metabolic-related diseases such as diabetes, obesity, non-alcoholic fatty liver disease, and hypertension.

[0003] Glucagon-like peptide-1 (GLP-1) is an endogenous incretin that stimulates insulin release. It binds to and is activated by the GLP-1 receptor (GLP-1R), a member of the G protein-coupled receptor (GPCR) class B family, to exert its regulatory function. GLP-1 receptor agonists (GLP-1RAs) are synthetic drugs designed to mimic the physiological functions of GLP-1. After binding to GLP-1R in pancreatic cells, they glucose-dependently stimulate insulin synthesis and secretion; reduce glucagon release; act on GLP-1R in the central nervous system, thereby reducing food intake; increase energy expenditure by promoting thermogenesis in brown adipose tissue and breakdown in white adipose tissue; and delay gastric emptying. GLP-1RAs are clinically indicated for adult patients with type 2 diabetes mellitus (T2DM), exhibiting significant hypoglycemic effects while also reducing weight, systolic blood pressure, and improving dyslipidemia. GLP-1RAs can be used alone or in combination with other hypoglycemic agents. Multiple clinical studies have shown that adding GLP-1RAs is effective after treatment with an oral hypoglycemic agent (metformin, sulfonylureas) has failed.

[0004] Chinese patent CN202110334388 provides the following general formula for GLP agonist compounds, with the following structure:

[0005]

[0006] Among them, Example 1 of patent CN202110334388 discloses the following preparation method (Route 1):

[0007] .

[0008] In this route, 2-hydroxyphenylboronic acid and trifluoromethanesulfonate are used as starting materials. The precious metal palladium catalyst is used in multiple steps, and column chromatography is required in multiple steps. It is not easy to scale up production, and the raw materials are quite expensive.

[0009] The literature (Chem. Pharm. Bull. 48(12)1978-1985(2000)) discloses the synthetic route (Route 2) for the intermediate 2-(piperidin-4-yl)phenol:

[0010] .

[0011] Route 2 uses 2-bromo-anisole as the starting material, and proceeds through Grignard reaction, palladium-on-carbon debenzylation, and hydrobromic acid demethoxylation to obtain the intermediate 2-(piperidin-4-yl)phenol. This route suffers from harsh demethoxylation conditions at the end, which is difficult to complete, resulting in a low yield.

[0012] The literature (Chem. Pharm. Bull. 50(2)292-297(2002)) discloses the synthetic route (Route 3) for the intermediate 2-(piperidin-4-yl-4-hydroxy)phenol:

[0013]

[0014] Unlike Route 2, Route 3 uses 2-bromophenylbenzyl ether as the starting material to synthesize the intermediate 4-(2-hydroxyphenyl)piperidin-4-ol; the deprotection is performed by removing two benzyl groups in one step using palladium hydroxide, which is relatively simple. However, palladium hydroxide is expensive, the reaction is difficult to control, the reaction is incomplete, and purification is difficult.

[0015] The literature (J. Org. Chem. 2014, 79, 328−338) discloses the synthetic route (Route 4) for the intermediate 2-(piperidin-4-yl-4-hydroxy)phenol analog:

[0016] .

[0017] Although Route 4 only has one step, the reaction yield is very low and it is not easy to scale up.

[0018] Analysis of current technological approaches reveals that the four routes for preparing the aforementioned GLP-1R receptor agonists all result in low yields, expensive reagents, and unsuitable process scale-up. Therefore, there is an urgent need to develop processes that offer good yields, low costs, and are suitable for scale-up. Summary of the Invention

[0019] This invention provides a method for preparing a GLP-1R receptor agonist, different from existing technologies, as well as a method for preparing its intermediates and the intermediates themselves. The GLP-1R receptor agonist prepared by the method of this invention exhibits excellent pharmacokinetics. Furthermore, the method for preparing the GLP-1R receptor agonist and its intermediates has advantages such as high yield, low cost, simple post-processing, and suitability for industrial production.

[0020] The present invention solves the above-mentioned technical problems through the following solution.

[0021] The present invention provides a method for preparing a compound as shown in Formula I-1-5, comprising the following steps: in the presence of Pd and hydrogen, a compound as shown in Formula I-1-4 is reduced in a solvent to obtain a compound as shown in Formula I-1-5.

[0022] .

[0023] The conditions and operations for the reduction reaction are conventional in the art, but the present invention particularly prefers the following conditions and operations:

[0024] The Pd is preferably Pd / C. The weight content of Pd in ​​the Pd / C is preferably 5-10%, where the weight content refers to the percentage of Pd by the total weight of the Pd / C.

[0025] The preferred weight ratio of Pd to the compound shown in Formula I-1-4 is (0.05%-10%):1, more preferably (0.08%-1%):1.

[0026] The reduction reaction is preferably carried out at atmospheric pressure to 5 MPa, and more preferably at 1.5 MPa to 5 MPa.

[0027] The solvent is preferably one or more (e.g., two or three) selected from alcohol solvents (e.g., methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, pentanol, trifluoroethanol), ether solvents (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, isopropyl ether), aromatic hydrocarbon solvents (e.g., toluene, chlorobenzene, xylene), amide solvents (N,N-dimethylformamide), sulfoxide solvents (dimethyl sulfoxide), pyrrolidone solvents (e.g., N-methylpyrrolidone), and carboxylic acid solvents (e.g., acetic acid, trifluoroacetic acid, trifluoroethanol), more preferably alcohol solvents and / or carboxylic acid solvents, and even more preferably a mixed solvent of acetic acid and isopropanol (e.g., a volume ratio of 1:2), or methanol.

[0028] The temperature of the reduction reaction is preferably 10~100℃, more preferably 40~60℃.

[0029] Preferably, when the reduction reaction is carried out at 1.5 MPa, the temperature of the reduction reaction is 55-65°C (e.g., 60°C).

[0030] The reduction reaction time is monitored using methods commonly used in the art (e.g., TLC, HPLC), and the reaction endpoint is generally defined as the disappearance of reactants or the cessation of reaction. The preferred reaction time for the reduction reaction is 15-25 hours.

[0031] The post-processing after the reduction reaction is completed preferably includes the following steps: filtration and concentration.

[0032] The method for preparing the compound shown in Formula I-1-5 may further include the method for preparing the compound shown in Formula I-1-4;

[0033] The method for preparing the compound shown in Formula I-1-4 includes the following steps: in the presence of an acid, the compound shown in Formula I-1-3 undergoes a dehydration reaction to obtain the compound shown in Formula I-1-4;

[0034] .

[0035] The acid is preferably one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid, more preferably acetic acid or hydrochloric acid (e.g. concentrated hydrochloric acid).

[0036] The compound represented by Formula I-1-3 is preferably an acid salt of the compound represented by Formula I-1-3, and more preferably a p-toluenesulfonate of the compound represented by Formula I-1-3.

[0037] The preferred volume-to-mass ratio of the acid to the compound shown in Formula I-1-3 is (3-2) mL / g.

[0038] The dehydration reaction is preferably carried out in the presence or absence of a solvent. When the dehydration reaction is carried out in the presence of a solvent, the solvent is preferably an ether solvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dioxane), an aromatic hydrocarbon solvent (e.g., toluene, chlorobenzene, xylene), a ketone solvent (e.g., butanone, isobutanone), a nitrile solvent (e.g., acetonitrile), an amide solvent (e.g., N,N-dimethylformamide), or a sulfoxide solvent (e.g., dimethyl sulfoxide), more preferably an aromatic hydrocarbon solvent.

[0039] The temperature of the dehydration reaction is preferably 10-150℃, more preferably 90-110℃.

[0040] The dehydration reaction time is monitored using methods commonly used in the art (e.g., TLC, HPLC), and the reaction endpoint is generally defined as the disappearance of the reactants or the cessation of the reaction (e.g., in this invention, the content of the compound shown in Formula I-1-3 is less than 1%). The preferred reaction time for the reduction reaction is 20-26 hours.

[0041] The post-treatment after the dehydration reaction preferably includes the following steps: adjusting the pH to 12, allowing the mixture to stand and separate, and collecting and concentrating the organic phase.

[0042] The method for preparing the compound shown in Formula I-1-5 may further include the method for preparing the compound shown in Formula I-1-3;

[0043] The preparation method of the compound shown in Formula I-1-3 includes the following steps: Step a, in the presence of an initiator, reacting the compound shown in Formula I-1-1 with magnesium in a solvent to obtain a Grignard reagent;

[0044] Step b: The Grignard reagent is reacted with the compound shown in Formula I-1-2 to obtain the compound shown in Formula I-1-3;

[0045] .

[0046] The conditions and procedures for steps a and b are the same as those conventional for such reactions in the art, but the following conditions and procedures are particularly preferred for steps a and b:

[0047] In step a, the initiator is preferably one or more of iodine, ethyl magnesium, isopropyl magnesium, n-butyl lithium and tert-butyl lithium (e.g., one or more of ethyl magnesium THF solution, isopropyl magnesium THF solution, n-butyl lithium THF solution and tert-butyl lithium THF solution), more preferably isopropyl magnesium or n-butyl lithium, for example, isopropyl magnesium THF solution (2M) or n-butyl lithium THF solution (1.6M).

[0048] In step a, the reaction is preferably carried out in the presence of an initiator or a base.

[0049] When the reaction is carried out in the presence of an initiator, the initiator is preferably one, two or three of iodine, ethyl magnesium and isopropyl magnesium, such as iodine or a 2M THF solution of isopropyl magnesium.

[0050] When the reaction is carried out in the presence of an initiator, the molar ratio of the initiator to the compound shown in Formula I-1-1 is (0.05-0.15):1, for example (0.05-0.1):1.

[0051] When the reaction is carried out in the presence of a base, the base is preferably n-butyllithium, for example, a 1.6 M THF solution of n-butyllithium.

[0052] In step a, the molar ratio of magnesium to the compound shown in Formula I-1-1 is (1.0-1.5):1, for example 1.1:1.

[0053] In step a, the solvent is preferably an ether solvent (e.g., tetrahydrofuran or methyltetrahydrofuran) and / or an aromatic solvent (e.g., toluene), and more preferably tetrahydrofuran or methyltetrahydrofuran.

[0054] In step a, the reaction temperature is preferably -80 to 85°C, more preferably -20 to -10°C or 15 to 35°C.

[0055] The Grignard reagent obtained in step a can be used directly in the reaction of step b without any post-treatment steps.

[0056] The preferred molar ratio of the compound shown in Formula I-1-2 to the compound shown in Formula I-1-1 is (0.8-1.0):1.

[0057] In step b, the preferred temperature for the Grignard reaction is 20-40°C.

[0058] The post-treatment after the Grignard reaction preferably includes the following steps: salt washing (e.g., ammonium chloride washing), separation and concentration of the organic phase, and salt formation (e.g., formation of p-toluenesulfonate).

[0059] In the post-processing, during the salt formation process, the molar ratio of the acid to the compound shown in Formula I-1-1 is preferably (0.8-1.5):1, for example, 0.9:1.

[0060] This invention provides a method for preparing a compound of formula I-3, comprising the following steps:

[0061] Step I: In the presence of Pd and hydrogen, the compound shown in Formula I-1-4 is reduced in a solvent to obtain the compound shown in Formula I-1-5.

[0062] ;

[0063] Step II: The method for preparing compound I-3 by means of compounds shown in formula I-1-5;

[0064] ;

[0065] In Equation I-3, R 2 C 1-4 alkyl.

[0066] R 2 It can also be C 3-6 Cycloalkyl.

[0067] In step I, the conditions and operations for preparing the compounds shown in formula I-1-5 are the same as described above.

[0068] In step II, the method for preparing compound I-3 from compounds shown in formula I-1-5 preferably includes the following steps:

[0069] Step i: React the compound shown in Formula I-1-5 with an amino protecting agent to obtain the compound shown in Formula I-1-6;

[0070] Step ii: The compound shown in Formula I-1-6 is subjected to a substitution reaction with the compound shown in Formula I-1-7 to obtain the compound shown in Formula I-1;

[0071] Step iii: The compound shown in Formula I-1 undergoes a deprotection reaction to give the compound shown in Formula I-2;

[0072] Step iv: The compound shown in Formula I-2 and the compound shown in Formula I-1-8 are subjected to a substitution reaction to obtain the compound shown in Formula I-3;

[0073] ;

[0074] Where X is a halogen or -OS(=O)2-C 1-4 Alkyl; R 1 Amino protecting group (e.g., -Boc); R 2 C 1-4 alkyl.

[0075] R 2 It can also be C 3-6 Cycloalkyl.

[0076] The conditions and operations in steps i to iv of the above route are all conventional conditions and operations in the art.

[0077] The present invention particularly favors the following reaction conditions and operations:

[0078] In step i, the amino protecting agent is preferably (Boc)₂O.

[0079] In step i, the molar ratio of the amino protecting agent to the compound shown in Formula I-1-5 is preferably (0.9-5.0):1, more preferably 1.5:1.

[0080] In step i, the base used in the reaction is preferably one or more of the following: inorganic bases (e.g., alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal acetates (e.g., sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium acetate, potassium phosphate, sodium phosphate)) and / or organic bases (e.g., triethylamine, diisopropylethylamine, dimethylisopropylamine, pyridine, 4-methylmorpholine, N,N-dimethylpyridine), and more preferably sodium bicarbonate and / or potassium carbonate.

[0081] In step i, the pH of the reaction system is preferably 7-8.

[0082] In step i, the solvent used in the reaction is preferably one, two, three, or four of the following: aromatic solvent, ester organic solvent, ketone solvent, and water. More preferably, it is a mixed solvent of aromatic solvent, ester organic solvent, and water, or a mixed solvent of ketone solvent, ester organic solvent, and water. Further preferably, it is a mixed solvent of toluene-isopropyl acetate-water (e.g., a volume ratio of 1:5:4), or a mixed solvent of butanone-ethyl acetate-water (e.g., a volume ratio of 1:2:2).

[0083] In step i, the reaction temperature is preferably 20-30℃.

[0084] In step i, the reaction time is monitored using methods commonly used in the art (e.g., TLC, HPLC), and the reaction endpoint is generally defined as the disappearance of reactants or the cessation of reaction (e.g., in this invention, the content of the compound shown in Formula I-1-5 is ≤0.3%). The preferred reaction time is 3-8 hours, for example, 3-5 hours.

[0085] In step i, the post-processing steps after the reaction is completed preferably include extraction and concentration.

[0086] In step ii, the compound of formula I-1-7 is preferably one or more of 4-chloro-2-fluorobenzyl chloride, 4-chloro-2-fluorobromobenzyl chloride, 4-chloro-2-fluoroiodobenzyl chloride, 4-chloro-2-fluorobenzyl methanesulfonate, 4-chloro-2-fluorobenzyl ethanesulfonate, 4-chloro-2-fluorobenzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl p-benzenesulfonate and 4-chloro-2-fluorobenzyl trifluoromethanesulfonate, more preferably 2-fluoro-4-chlorobenzyl chloride or 2-fluoro-4-chlorobromobenzyl chloride.

[0087] In step ii, the molar ratio of the compound of formula I-1-7 to the compound of formula I-1-6 is preferably (1-3):1, more preferably 1.1:1.

[0088] In step ii, the base used for the substitution reaction is preferably an inorganic base (e.g., alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal acetates, alkali metal hydroxides (e.g., sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate), sodium acetate, potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide) and / or an organic base (e.g., triethylamine, diisopropylethylamine, dimethylisopropylamine, pyridine, 4-methylmorpholine, N,N-dimethylpyridine, 1,4-diazabicyclo[2,2,2]neoane (DABCO), 1,8-diazabicyclo[5,4,0]undecyl-7-ene (DBU), 1,5-diazabicyclo[4,3,0]neoane (DBN), imidazole), more preferably sodium carbonate or potassium carbonate. The molar ratio of the base used for the substitution reaction to the compound shown in Formula I-1-6 is (1-3):1, preferably (2-2.5):1.

[0089] In step ii, the solvent used for the substitution reaction is preferably one or more of the following: alcohol solvents (e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol), ketone solvents (e.g., acetone, butanone, isobutyl ketone, cyclohexanone), ether solvents (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, isopropyl formate, tert-butyl formate), nitrile solvents (e.g., acetonitrile), amide solvents (e.g., N,N-dimethylformamide), and sulfoxide solvents (e.g., dimethyl sulfoxide), and more preferably acetonitrile or isopropyl acetate.

[0090] In step ii, the volume-to-mass ratio of the solvent used in the substitution reaction to the compound shown in Formula I-1-5 is preferably 1-100 ml / g, more preferably 10 ml / g.

[0091] In step ii, the temperature of the substitution reaction is preferably 10-30°C.

[0092] In step ii, the reaction time of the substitution reaction is monitored using methods commonly used in the art (e.g., TLC, HPLC), and the reaction endpoint is generally defined as the disappearance of the reactants or the cessation of the reaction. The preferred reaction time is 20-48 hours, for example, 24 hours.

[0093] In step ii, the post-processing steps after the reaction are completed preferably include filtration and crystallization (using n-heptane for crystallization).

[0094] In step iii, the deprotection reaction is preferably carried out in an acidic or neutral system.

[0095] When the deprotection reaction is carried out in an acidic system, the acidic system can be adjusted by inorganic or organic acids to obtain an acidic system.

[0096] The inorganic acid can be one, two, three, or four of the following: hydrogen chloride, sulfuric acid, phosphoric acid, and hydrobromic acid (e.g., hydrochloric acid aqueous solution, ethyl acetate hydrogen chloride solution, methanol hydrogen chloride solution, dioxane hydrogen chloride solution, isopropanol hydrogen chloride solution (e.g., 4M), ethanol hydrogen chloride solution, isopropyl acetate hydrogen chloride solution, tetrahydrofuran hydrogen chloride solution, sulfuric acid aqueous solution, phosphoric acid aqueous solution, and hydrobromic acid aqueous solution), and is more preferably hydrochloric acid aqueous solution (e.g., concentrated hydrochloric acid) or isopropanol hydrogen chloride solution (e.g., 4M).

[0097] The organic acid can be one or more of trifluoroacetic acid, formic acid, methanesulfonic acid, chlorosulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, trichloroacetic acid, and oxalic acid.

[0098] When the deprotection reaction is carried out in a neutral system, the neutral system may be adjusted with one or more of the following reagents: trimethylsilicon iodide, trimethylsilyl trifluoromethanesulfonate, or a mixture of trimethylchlorosilane and sodium iodide.

[0099] In step iii, the solvent used for the deprotection reaction is preferably one or more of the following: alkane solvents (e.g., cycloheptane), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, isopropyl formate, tert-butyl formate), ketone solvents (e.g., acetone, butanone, isobutyl ketone, cyclohexanone), alcohol solvents (e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol), nitrile solvents (e.g., acetonitrile or propionitrile), ether solvents (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether), chlorinated hydrocarbon solvents (e.g., dichloromethane, chloroform), amide solvents (e.g., N,N-dimethylformamide), and sulfoxide solvents (e.g., dimethyl sulfoxide). It is preferably an alkane solvent and / or an alcohol solvent, and more preferably a mixed solvent of n-heptane and isopropanol, or isopropanol.

[0100] In step iii, the temperature of the deprotection reaction is preferably 10-30°C (e.g., 20-30°C).

[0101] In step iii, the deprotection reaction time is monitored using methods commonly used in the art (e.g., TLC, HPLC), and the reaction endpoint is generally defined as the disappearance of the reactants or the cessation of the reaction. The preferred reaction time is 2-8 hours, for example, 2-8 hours.

[0102] In step iii, the post-treatment after the reaction is completed preferably includes the following steps: adjusting the pH to 12-14, centrifuging, and pulping (e.g., pulping in water).

[0103] In step iv, R 2 In the context, C 1-4 Alkyl groups are preferably methyl groups.

[0104] In step iv, the molar ratio of the compound of formula I-1-8 to the compound of formula I-2 is preferably (1-1.5):1, more preferably (0.9-1.1):1.

[0105] In step iv, the base used for the substitution reaction is preferably an inorganic base (e.g., alkali metal carbonates, alkali metal bicarbonates, alkali metal acetates, alkali metal phosphates, alkali metal hydroxides (e.g., sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate), sodium acetate, potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide) and / or an organic base (e.g., triethylamine, diisopropylethylamine, dimethylisopropylamine, pyridine, 4-methylmorpholine, N,N-dimethylpyridine, 1,4-diazabicyclo[2,2,2]neoane (DABCO), 1,8-diazabicyclo[5,4,0]undecyl-7-ene (DBU), 1,5-diazabicyclo[4,3,0]neoane (DBN), imidazole), and more preferably sodium carbonate or potassium carbonate. The molar ratio of the base used in the substitution reaction to the compound shown in Formula I-2 is preferably (1-3):1, more preferably (1.5-2.5):1, for example 2.5:1.

[0106] In step iv, the solvent used for the substitution reaction is preferably one or more of the following: alcohol solvents (e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol), ketone solvents (e.g., acetone, butanone, isobutyl ketone, cyclohexanone), ether solvents (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, isopropyl formate, tert-butyl formate), nitrile solvents (e.g., acetonitrile, propionitrile, succinic anion, glutaronitrile), amide solvents (e.g., N,N-dimethylformamide), and sulfoxide solvents (e.g., dimethyl sulfoxide), and more preferably acetone or 2-methyltetrahydrofuran.

[0107] In step iv, the temperature of the substitution reaction is preferably 0-150°C, more preferably 40-50°C.

[0108] In step iv, the duration of the substitution reaction is monitored using methods commonly used in the art (e.g., TLC, HPLC), and the reaction endpoint is generally defined as the disappearance of the reactants or the cessation of the reaction. In this invention, the endpoint is defined as the content of the compound shown in Formula I-2 being ≤0.3%. The preferred reaction time is 2-6 hours, for example, 4-5 hours.

[0109] In step iv, the post-treatment after the completion of the substitution reaction preferably includes the following steps: cooling, precipitation of solids, filtration, and pulping (e.g., pulping in water).

[0110] This invention provides a method for preparing a compound of formula I-2, comprising the following steps:

[0111] ;

[0112] Step a: In the presence of Pd and hydrogen, the compound shown in Formula I-1-4 is reduced in a solvent to obtain the compound shown in Formula I-1-5.

[0113] ;

[0114] Step b: A method for preparing compound I-2 from compounds shown in formula I-1-5.

[0115] In step a, the conditions and operations for preparing the compound as shown in Formula I-1-5 are the same as described above.

[0116] In step b, the method for preparing compound I-2 from compounds shown in formula I-1-5 preferably includes the following steps:

[0117] Step i: React the compound shown in Formula I-1-5 with an amino protecting agent to obtain the compound shown in Formula I-1-6;

[0118] Step ii: The compound shown in Formula I-1-6 is subjected to a substitution reaction with the compound shown in Formula I-1-7 to obtain the compound shown in Formula I-1;

[0119] Step iii: The compound shown in Formula I-1 undergoes a deprotection reaction to give the compound shown in Formula I-2;

[0120] .

[0121] The conditions and operations for steps i to iii in the above route are the same as described above.

[0122] This invention provides a method for preparing a compound of formula I-1, comprising the following steps:

[0123] Step 1: In the presence of Pd and hydrogen, the compound shown in Formula I-1-4 is reduced in a solvent to obtain the compound shown in Formula I-1-5.

[0124] ;

[0125] Step 2: Preparation method of compound I-1 by means of compound I-1 as shown in formula I-1-5;

[0126] ;

[0127] In Equation I-1, R 1 It is an amino protecting group (e.g., -Boc).

[0128] In step 1, the conditions and operations for preparing the compound as shown in Formula I-1-5 are the same as described above.

[0129] In step 2, those skilled in the art design a route based on the raw materials and products, and then obtain the corresponding products.

[0130] In step 2, the method for preparing compound I-1 from compounds shown in formula I-1-5 includes the following steps:

[0131] Step i: React the compound shown in Formula I-1-5 with an amino protecting agent to obtain the compound shown in Formula I-1-6;

[0132] Step ii: The compound shown in Formula I-1-6 is subjected to a substitution reaction with the compound shown in Formula I-1-7 to obtain the compound shown in Formula I-1;

[0133] ;

[0134] Where X is a halogen or -OS(=O)2-C 1-4 Alkyl; R 1 It is an amino protecting group (e.g., -Boc).

[0135] The reaction conditions and procedures in steps i and ii are conventional in the art.

[0136] The present invention also provides a method for preparing a compound of formula II, comprising the following steps:

[0137] S1: In the presence of Pd and hydrogen, the compound shown in Formula I-1-4 is reduced in a solvent to obtain the compound shown in Formula I-1-5.

[0138] ;

[0139] S2: A method for preparing compounds of formula II from compounds shown in formula I-1-5;

[0140] .

[0141] The conditions and operations for the compounds shown in Formula I-1-5 in S1 are the same as described above.

[0142] In S2 of this invention, those skilled in the art design a route based on the raw materials and products, and then obtain the corresponding products.

[0143] In S2, the compound of formula I-1-5 is preferably prepared as the compound of formula II via the following route, which includes the following steps:

[0144] Step i: React the compound shown in Formula I-1-5 with an amino protecting agent to obtain the compound shown in Formula I-1-6;

[0145] Step ii: The compound shown in Formula I-1-6 is subjected to a substitution reaction with the compound shown in Formula I-1-7 to obtain the compound shown in Formula I-1;

[0146] Step iii: The compound shown in Formula I-1 undergoes a deprotection reaction to give the compound shown in Formula I-2;

[0147] Step iv: The compound shown in Formula I-2 and the compound shown in Formula I-1-8 are subjected to a substitution reaction to obtain the compound shown in Formula I-3;

[0148] Step v: Hydrolyze the compound shown in Formula I-3 to obtain the compound shown in Formula I;

[0149] Step vi: The compound shown in Formula I and the compound shown in Formula I-1-9 are subjected to a salt formation reaction to obtain the compound shown in Formula II;

[0150] ;

[0151] Where X is a halogen or -OS(=O)2-C 1-4 Alkyl; R 1 Amino protecting group (e.g., -Boc); R 2 C 1-4 alkyl.

[0152] R 2 It can also be C 3-6 Cycloalkyl.

[0153] The conditions and operations for steps i to iv in the above route are the same as described above.

[0154] The reaction conditions and operations in steps v to vi are conventional in the art, but the present invention particularly prefers the following reaction conditions and operations:

[0155] In step v, the base used in the hydrolysis reaction is preferably an alkali metal hydroxide, more preferably one, two, or three of sodium hydroxide, potassium hydroxide, and lithium hydroxide, such as sodium hydroxide or potassium hydroxide. The molar ratio of the base used in the hydrolysis reaction to the compound shown in Formula I-3 is preferably (1-3):1, more preferably (1.5-2.5):1, for example 2.5:1.

[0156] In step v, the solvent used for the hydrolysis reaction is preferably one or more of the following: ketone solvents (e.g., acetone, butanone, isobutyl ketone, cyclohexanone), ether solvents (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether), alcohol solvents (e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, isopropyl formate, tert-butyl formate), nitrile solvents (e.g., acetonitrile, propionitrile, succinic anion, glutaronitrile), amide solvents (e.g., N,N-dimethylformamide), and sulfoxide solvents (e.g., dimethyl sulfoxide), and more preferably tetrahydrofuran.

[0157] In step v, the temperature of the hydrolysis reaction is preferably 0-150℃, more preferably 40-50℃.

[0158] In step v, the hydrolysis reaction time is monitored using methods commonly used in the art (e.g., TLC, HPLC), and the reaction endpoint is generally defined as the disappearance of reactants or the cessation of reaction. In this invention, the endpoint is defined as the content of the compound shown in Formula I-3 being ≤0.3%. The preferred reaction time is 4-5 hours.

[0159] In step v, the post-treatment after the hydrolysis reaction preferably includes the following steps: adjusting the pH value to 5.0-6.0 (e.g., adjusting with citric acid aqueous solution), filtration, and pulping (e.g., pulping in water).

[0160] In step vi, the molar ratio of the compound shown in Formula I-1-9 to the compound shown in Formula I is preferably (0.9-1.5):1.

[0161] In step vi, the solvent used for the salt formation reaction is preferably one, two, or three of the following: water, ketone solvents (e.g., acetone, butanone, isobutyl ketone, cyclohexanone) and ether solvents (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether), and more preferably a mixed solvent of water, 2-methyltetrahydrofuran, and acetone.

[0162] In step vi, the temperature of the salt formation reaction is preferably 40-50℃, more preferably 20-30℃.

[0163] In step vi, the salt-forming reaction time is monitored using methods commonly used in the art (e.g., TLC, HPLC), and the reaction endpoint is generally defined as the disappearance of reactants or the cessation of reaction. The preferred reaction time is 2-3 hours.

[0164] In step vi, the post-treatment after the salt formation reaction is completed is preferably as follows: filtration, washing the filter cake, and drying (e.g., pulping in water).

[0165] The present invention also provides a method for preparing a compound of formula I-1, comprising the following steps: in the presence of an inorganic base, a compound of formula I-1-6 and a compound of formula I-1-7 are subjected to a substitution reaction in a solvent to obtain a compound of formula I-1.

[0166] The inorganic bases mentioned include one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate (e.g., two, such as sodium bicarbonate and potassium carbonate).

[0167] ;

[0168] Where X is a halogen or -OS(=O)2-C 1-4 Alkyl; R 1 It is an amino protecting group (e.g., -Boc).

[0169] The conditions and procedures for the substitution reaction are conventional in the art, but the present invention particularly prefers the following conditions and procedures:

[0170] The inorganic base may also include one or more of cesium carbonate, cesium bicarbonate, alkali metal phosphates and alkali metal acetates, and may also include potassium carbonate, for example.

[0171] The inorganic base is preferably sodium carbonate, sodium bicarbonate, or a mixture of sodium bicarbonate and potassium carbonate (e.g., a molar ratio of (0.5-2):1, for example, 1:1).

[0172] The molar ratio of the alkali to the compound shown in Formula I-1-6 can be (1-4):1 or (2.5-4):1.

[0173] The compound of formula I-1-7 may be one or more of 4-chloro-2-fluorobenzyl chloride, 4-chloro-2-fluorobromobenzyl chloride, 4-chloro-2-fluoroiodobenzyl chloride, 4-chloro-2-fluorobenzyl methanesulfonate, 4-chloro-2-fluorobenzyl ethanesulfonate, 4-chloro-2-fluorobenzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl p-benzenesulfonate and 4-chloro-2-fluorobenzyl trifluoromethanesulfonate, and may also be 2-fluoro-4-chlorobenzyl chloride or 2-fluoro-4-chlorobromobenzyl chloride.

[0174] The molar ratio of the compound of formula I-1-7 to the compound of formula I-1-6 is preferably (1-3):1, more preferably (1-1.5):1, for example 1.1:1.

[0175] The solvent is preferably one or more of the following: alcohol solvents (e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol), ketone solvents (e.g., acetone, butanone, isobutyl ketone, cyclohexanone), ether solvents (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, isopropyl formate, tert-butyl formate), nitrile solvents (e.g., acetonitrile), amide solvents (e.g., N,N-dimethylformamide), and sulfoxide solvents (e.g., dimethyl sulfoxide). Preferably, it is a nitrile solvent or a mixture of an ester solvent and a ketone solvent (the volume ratio of the two can be (4-6):1, for example 5:1). More preferably, it is a mixture of acetonitrile or acetone and isopropyl acetate.

[0176] The preferred temperature for the substitution reaction is 10-30°C.

[0177] The reaction time of the substitution reaction is monitored using methods commonly used in the art (e.g., TLC, HPLC), and the reaction endpoint is generally defined as the disappearance of the reactants or the cessation of the reaction. The preferred reaction time is 20-48 hours, for example, 24 hours.

[0178] The post-processing steps following the completion of the reaction preferably include filtration and crystallization. The crystallization step includes dissolving the compound shown in Formula I-1 in n-heptane (e.g., at 7-80°C) and crystallizing (e.g., at 0-5°C).

[0179] The method for preparing the compound of formula I-1 may further include the method for preparing the compound of formula I-1-6, which includes the following steps: reacting the compound of formula I-1-5 with an amino protecting agent to obtain the compound of formula I-1-6.

[0180] .

[0181] The conditions and procedures for preparing the compound of formula I-1-6 are the same as those described above.

[0182] The method for preparing compound I-1 may further include the method for preparing compound I-1-5, wherein the conditions and operations for preparing compound I-1-5 are the same as described above.

[0183] The present invention also provides a method for preparing a compound of formula I-3, comprising the following steps: in the presence of an inorganic base, a compound of formula I-2 and a compound of formula I-1-8 are subjected to a substitution reaction to obtain a compound of formula I-3;

[0184] ;

[0185] R 2 C 1-4 alkyl.

[0186] R 2 It can also be C 3-6 Cycloalkyl.

[0187] R 2 In the context, C 1-4 Alkyl groups are preferably methyl groups.

[0188] The molar ratio of the compound of formula I-1-8 to the compound of formula I-2 is preferably (1-1.5):1, more preferably (0.9-1.1):1.

[0189] The inorganic base is preferably one or more of alkali metal carbonates, alkali metal bicarbonates, alkali metal acetates, alkali metal phosphates, and alkali metal hydroxides (e.g., sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium acetate, potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide), more preferably alkali metal carbonates, and even more preferably sodium carbonate and / or potassium carbonate.

[0190] The preferred molar ratio of the inorganic base to the compound shown in Formula I-2 is (1-3):1, more preferably (1.5-2.5):1, for example 2.0:1.

[0191] The solvent used in the substitution reaction is preferably one or more of the following: alcohol solvents (e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol), ketone solvents (e.g., acetone, butanone, isobutyl ketone, cyclohexanone), ether solvents (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, isopropyl formate, tert-butyl formate), nitrile solvents (e.g., acetonitrile, propionitrile, succinic anion, glutaronitrile), amide solvents (e.g., N,N-dimethylformamide), and sulfoxide solvents (e.g., dimethyl sulfoxide), and more preferably acetone and / or 2-methyltetrahydrofuran.

[0192] Preferably, when the base is potassium carbonate, the solvent is a ketone solvent (e.g., acetone); or, when the base is sodium carbonate, the solvent is an ether solvent (e.g., 2-methyltetrahydrofuran).

[0193] The temperature of the substitution reaction is preferably 0-150℃, more preferably 40-50℃.

[0194] The substitution reaction time is monitored using methods commonly used in the art (e.g., TLC, HPLC), and the reaction endpoint is generally defined as the disappearance of the reactants or the cessation of the reaction. In this invention, the endpoint is defined as the content of the compound shown in Formula I-2 being ≤0.3%. The preferred reaction time is 2-6 hours, for example, 4-5 hours.

[0195] The post-treatment after the substitution reaction preferably includes the following steps: cooling, precipitation of solids, filtration, and pulping (e.g., pulping in water).

[0196] The method for preparing the compound of formula I-3 may further include a method for preparing the compound of formula I-2, wherein the method for preparing the compound of formula I-2 includes the following steps: the compound of formula I-1 undergoes a deprotection reaction to obtain the compound of formula I-2;

[0197] .

[0198] The conditions and procedures for the deprotection reaction are the same as described above.

[0199] The preparation method of compound I-3 may also include the preparation method of compound I-1, wherein the conditions and operations of the preparation method of compound I-1 are the same as those described above.

[0200] This invention provides a method for preparing a compound of formula I, which is scheme 1 and / or scheme 2:

[0201] Option 1: It includes the following steps:

[0202] Step 1: In the presence of an inorganic base, the compounds shown in Formula I-1-6 and Formula I-1-7 are subjected to a substitution reaction in a solvent to obtain the compound shown in Formula I-1.

[0203] The inorganic base includes one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate.

[0204] ;

[0205] Where X is a halogen or -OS(=O)2-C 1-4 Alkyl; R 1 It is an amino protecting group (e.g., -Boc);

[0206] Step 2: Preparation method of compound I by means of compound shown in Formula I-1;

[0207] ;

[0208] Option 2: It includes the following steps:

[0209] Step a: In the presence of an inorganic base, the compound shown in Formula I-2 and the compound shown in Formula I-1-8 are subjected to a substitution reaction to obtain the compound shown in Formula I-3;

[0210] Step b: Hydrolyze the compound shown in Formula I-3 to obtain the compound shown in Formula I;

[0211] ;

[0212] R 2 C 1-4 alkyl.

[0213] R 2 It can also be C 3-6 Cycloalkyl.

[0214] The conditions and operations in the preparation methods of Schemes 1 and 2 above are the same as those in any of the previous schemes.

[0215] This invention provides a method for preparing a compound of formula II, which is scheme I and / or scheme II:

[0216] Option I includes the following steps:

[0217] Step 1: In the presence of an inorganic base, the compounds shown in Formula I-1-6 and Formula I-1-7 are subjected to a substitution reaction in a solvent to obtain the compound shown in Formula I-1.

[0218] The inorganic base includes one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate.

[0219] ;

[0220] Where X is a halogen or -OS(=O)2-C 1-4 Alkyl; R 1 It is an amino protecting group (e.g., -Boc);

[0221] Step 2: Preparation method of compound II by means of compound shown in formula I-1;

[0222] ;

[0223] Option II includes the following steps:

[0224] Step a: In the presence of an inorganic base, the compound shown in Formula I-2 and the compound shown in Formula I-1-8 are subjected to a substitution reaction to obtain the compound shown in Formula I-3;

[0225] ;

[0226] Step b: Hydrolyze the compound shown in Formula I-3 to obtain the compound shown in Formula II;

[0227] ;

[0228] R 2 C 1-4 alkyl.

[0229] R 2 It can also be C 3-6 Cycloalkyl.

[0230] The conditions and operations in the preparation methods of Schemes I and II above are the same as those in any of the previous schemes.

[0231] Those skilled in the art can design routes based on raw materials and products to obtain the corresponding products.

[0232] For example, Scheme I prepares compound II via the following route:

[0233] ;

[0234] Where X is a halogen or -OS(=O)2-C 1-4 Alkyl; R 1 Amino protecting group (e.g., -Boc); R 2 C 1-4 alkyl.

[0235] R 2It can be C 3-6 Cycloalkyl.

[0236] The conditions and operations for each step in the above route are the same as described above.

[0237] For example, Scheme II prepares compound II via the following route:

[0238] ;

[0239] R 2 C 1-4 alkyl.

[0240] R 2 It can also be C 3-6 Cycloalkyl.

[0241] The conditions and operations for each step in the above route are the same as described above.

[0242] The present invention also provides a compound of formula I-1, formula I-2, formula I-3, formula I-1-1, or formula I-3-1:

[0243] , , ,

[0244] or ;

[0245] In Equation I-1, R 1 It is an amino protecting group (e.g., -Boc); in formula I-3, R 2 C 1-4 alkyl.

[0246] R 2 It can also be C 3-6 Cycloalkyl.

[0247] In this invention, C 1-4 Alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0248] In this invention, C 3-6 Cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0249] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0250] The reagents and raw materials used in this invention are all commercially available.

[0251] The positive and progressive effects of this invention are as follows: the GLP-1R receptor agonist prepared by the method of this invention has excellent pharmacokinetics. Furthermore, the preparation method of the GLP-1R receptor agonist and the preparation method of its intermediates have the advantages of high yield, low cost, simple post-processing and suitability for industrial production. Attached Figure Description

[0252] Figure 1 The XRPD map is shown in Example 17.

[0253] Figure 2 This is the single crystal spectrum of Example 17. Detailed Implementation

[0254] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 10-30 °C.

[0255] The present invention will be further described in detail below with reference to specific embodiments. However, the present invention is not limited to the following embodiments. The embodiments are provided to better illustrate certain specific manifestations of the present invention and should not be construed as limiting the scope of the present invention in any way. Conditions not specified in the embodiments are conventional conditions. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0256] The structures of the compounds in the following examples were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (8) were measured at 10⁻⁶ ppm. -6 Units (ppm) are given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. MS measurements were performed using a Finnigan LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantageMAX).

[0257] Reaction route:

[0258] ;

[0259] Example 1: Preparation of I-1-3

[0260] I-1-1 (1000 g, 1.0 eq) was added to a reaction vessel, followed by tetrahydrofuran (5 L) and toluene (5 L). The mixture was stirred, and the temperature was maintained at 25-35°C. Magnesium strips (100.3 g, 1.1 eq, with the amount added adjusted according to the temperature) were added in portions. Isopropylmagnesium chloride (250 ml, 2 M) was added, and the reaction was initiated by stirring. After 0.5 h, the temperature was lowered to 0-10°C, and N-benzylpiperidin-4-one I-1-2 (647.3 g, 0.9 eq) was added dropwise. The reaction was stirred for 0.5 h, and then the reaction was stopped. Ammonium chloride solution was added dropwise, and the mixture was stirred. Ethyl acetate (9 L) was added, and the mixture was separated to obtain the organic phase. P-toluenesulfonic acid (589 g, 0.9 eq) was added, and the mixture was stirred to form a salt. The mixture was filtered, and the solid was washed and dried under reduced pressure to obtain 1206 g of solid with a purity of 98.34%. The yield was 85%.

[0261] 1 H NMR (CDCl3, ppm) δ7.19-7.48 (12H, m), 6.92-6.96 (2H, m), 5.12 (2H, s), 3.96 (1H, s) 3. 50 (2H, s), 2.68-2.76 (2m, m) 2.44-2.58 (2m, m), 2.06-2.18 (2H, m), 1.96-2.06 (2H, m)

[0262] Example 2: Preparation of p-toluenesulfonic acid from I-1-3

[0263] I-1-1 (200 g, 1.0 eq) was added to a 5 L reactor, followed by 1.5 L of 2-methyltetrahydrofuran. The mixture was stirred and the temperature was maintained at 15-25 °C. Magnesium strip (20.3 g, 1.1 eq) and iodine (9.65 g, 0.05 eq) were added in portions, and the reaction was initiated by stirring. After 0.5 h, the temperature was lowered to 0-10 °C, and N-benzylpiperidine-4-one I-1-2 (129.5 g, 0.9 eq) was added dropwise. The reaction was stirred for 0.5 h, and then the reaction was stopped. Ammonium chloride solution was added dropwise, and the mixture was stirred and separated to obtain the organic phase. The organic phase was evaporated to dryness, dissolved in 1.9 L of ethyl acetate, and p-toluenesulfonic acid (117 g, 0.9 eq) was added. After stirring, the mixture formed a salt. The mixture was filtered, the solid was washed, and then dried under reduced pressure to obtain 212.8 g of solid with a purity of 97.4%. The yield was 75%.

[0264] Example 3: Preparation of p-toluenesulfonic acid from I-1-3

[0265] I-1-1 (200 g, 1.0 eq) was added to a 5 L reactor, followed by 1.5 L of tetrahydrofuran. The mixture was stirred and the temperature was maintained below -20 °C. A 499 mL, 1.6 M solution of n-butyllithium was added dropwise, and the reaction was initiated by stirring. After 0.5–1 h, 129.5 g, 0.9 eq of N-benzylpiperidin-4-one I-1-2 was added dropwise. The temperature was raised to 15–25 °C and the reaction was stirred for 0.5 h. The reaction was then stopped, and an ammonium chloride solution was added dropwise while stirring. Ethyl acetate (2 L) was added for extraction to obtain the organic phase. 117 g, 0.9 eq of p-toluenesulfonic acid was added, and the mixture was stirred to form a salt. The mixture was filtered, and after rinsing the solid, it was dried under reduced pressure to obtain 227 g of solid with a purity of 96.8%. The yield was 80.1%.

[0266] Example 4: Preparation of I-1-4

[0267] 1000 g (1.0 eq) of p-toluenesulfonic acid from I-1-3 was added to a reaction vessel, followed by 3.0 L of acetic acid. The mixture was stirred and heated to 110°C. The reaction was allowed to proceed for 24 h. When the reactant concentration was less than 1%, the reaction was stopped. 12 L of dichloromethane was added and stirred. Sodium hydroxide solution was added to adjust the pH to approximately 12. After separation, the organic phase was concentrated, and dichloromethane was removed by distillation with isopropanol to obtain an oily substance with a purity of 97.39%. The yield was 100%. The excess weight was used directly for the next step. [M+1]: 356.2.

[0268] Example 5: Preparation of I-1-4

[0269] 1000 g (1.0 eq) of p-toluenesulfonic acid from I-1-3 was added to a reaction vessel, followed by 2.0 L of concentrated hydrochloric acid. The mixture was stirred and heated to 90°C. The reaction was allowed to proceed for 24 hours. When the reactant concentration was less than 1%, the reaction was stopped. 5 L of dichloromethane was added and stirred. Sodium hydroxide solution was added to adjust the pH to approximately 12. After separation, the organic phase was concentrated, and dichloromethane was removed by distillation with isopropanol to obtain an oily substance with a purity of 95.89%. The yield was 100%. The excess weight was used directly for the next step. [M+1]: 356.2.

[0270] Example 6: Preparation of I-1-5

[0271] I-1-4 (1248 g, 1.0 eq) was added to a reaction vessel, along with acetic acid (1.2 L) and isopropanol (2.4 L). The mixture was stirred, and Pd / C (10% w, 10 g) was added. Hydrogen gas was introduced, and the reaction solution was heated to 60°C. The pressure was adjusted to 1.5 MPa, and the reaction was carried out for 16 h. After the reaction was complete, the mixture was cooled, filtered, washed with methanol, and the organic phase was concentrated to obtain an oily substance with a purity of 98.7%. The yield was 100%. The excess weight was used directly in the next step; [M+1]: 178.1.

[0272] Example 7: Preparation of I-1-5

[0273] I-1-4 (100 g, 1.0 eq) was added to a reaction vessel, followed by methanol (1 L). The mixture was stirred, and Pd / C (10 g, 5% w) was added. Hydrogen gas was introduced, and the reaction solution was heated to 40°C. The pressure was adjusted to 5 MPa, and the reaction was carried out for 24 h. After the reaction was complete, the mixture was cooled, filtered, washed with methanol, and the organic phase was concentrated to obtain an oily substance with a purity of 97.8%. The yield was 100%. The excess weight was used directly in the next step; [M+1]: 178.1.

[0274] Example 8: Preparation of I-1-6a

[0275] ;

[0276] Under nitrogen atmosphere, add I-1-5 (1000g, 1.0 eq), toluene (1L), and drinking water (5.0L) to the reactor and stir until dissolved. Maintain the internal temperature at 20-30℃, add isopropyl acetate (4.0L) and sodium bicarbonate (2.0 eq), adjust the pH to 7-8, and stir at 20-30℃ for 0.5-1 hour. Maintain the internal temperature at 20-30℃, add (Boc)₂O (1.85kg, 1.5 eq) dropwise. After the addition is complete, maintain the internal temperature at 20-30℃ and stir for 3-5 hours.

[0277] Samples were sent to HPLC with a concentration of I-1-5 ≤ 0.3%, and the reaction was carried out under controlled internal temperature of 20-30℃ with stirring. After the reaction was completed, the mixture was allowed to stand for 30 minutes, then separated, with the intermediate layer placed on top. Isopropyl acetate (2 L) was added to the aqueous phase under controlled internal temperature of 20-30℃, stirred, and allowed to stand for 30 minutes with stirring. The mixture was then separated, and the organic phases were combined and concentrated to 2-3 L. Toluene (3.0 L) was added, and the mixture was further concentrated to 2-3 L. After cooling, the mixture was filtered, and the filter cake was washed with toluene. The filter cake was then dried under vacuum at 50±5℃ for 16-24 hours to obtain a white solid (1455 g), yield: 93%. Purity: 98.2%.

[0278] [M+1]:278.2.

[0279] Example 9: Preparation of I-1-6a

[0280] Under nitrogen atmosphere, add I-1-5 (500g, 1.0 eq), methyl ethyl ketone (1L), and drinking water (2.0L) to the reactor and stir until dissolved. Maintain the internal temperature at 20-30℃, add ethyl acetate (2.0L) and potassium carbonate (2.5 eq), adjust the pH to 7-8, maintain the internal temperature at 20-30℃, and dropwise add (Boc)₂O (1.24kg, 2 eq). After the addition is complete, maintain the temperature at 20-30℃ and stir for 5 hours. Take a sample to test for I-1-5 ≤ 0.3%, and maintain the internal temperature at 20-30℃ while stirring. After the reaction is complete, let stand for 30 minutes, separate the layers, and transfer the middle layer to the bottom layer. The internal temperature was controlled at 20-30℃. Ethyl acetate (1 L) was added to the aqueous phase, stirred, and allowed to stand for 30 minutes with stirring. The liquid and liquid phases were separated, and the organic phases were combined and concentrated to 1-2 L. Toluene (2.0 L) was added, and the concentration was further reduced to 0.5 L. After cooling, the mixture was filtered, and the filter cake was washed with toluene. The filter cake was then dried under vacuum at 50±5℃ for 24 hours to obtain a white solid (665 g). Yield: 85%. Purity: 98.5%.

[0281] [M+1]:278.2.

[0282] Example 10: Preparation of I-1a

[0283] ;

[0284] Nitrogen gas was introduced, and I-1-6a (1000 g, 1.0 eq), potassium carbonate (997 g, 2.0 eq), and acetone (9 L) were added to the reactor. The internal temperature was maintained at 10-30℃. A solution of 2-fluoro-4-chlorobenzyl bromide (886 g, 1.1 eq) and acetone (1 L) was added dropwise, followed by isopropyl acetate (5.0 L) and sodium bicarbonate (600 g, 2.0 eq). The pH was adjusted to 7-8, and the internal temperature was maintained at 25℃. The mixture was stirred for 24 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with acetone. The filtrate was concentrated until almost no droplets remained. Heptane (10 L) was added, and the external temperature was maintained below 50℃. The mixture was concentrated to 6-7 L; the temperature was then raised to 70-80℃, and the mixture was stirred until dissolved. The temperature was lowered to 0-5℃, and the mixture was stirred for 1-2 hours. The mixture was filtered, and the filter cake was dried under vacuum at 45℃ for 24 hours to obtain a white solid. Yield: 95%, Purity: 99.9%.

[0285] [M+1]:420.2.

[0286] Example 11: Preparation of I-1a

[0287] Nitrogen gas was introduced into the reactor, and I-1-6a (1000 g, 1.0 eq), sodium carbonate (957 g, 2.5 eq), and acetonitrile (9 L) were added. The internal temperature was maintained at 10-30 °C, and a solution of 2-fluoro-4-chlorobenzyl chloride (710 g, 1.1 eq) and acetonitrile (1 L) was added dropwise. The internal temperature was maintained at 25 °C, and the mixture was stirred for 24 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated until almost no droplets remained. Heptane (10 L) was added, and the external temperature was maintained at no more than 50 °C. The mixture was concentrated to 5-6 L; the temperature was raised to 80 °C, and the mixture was stirred until dissolved. The temperature was lowered to 0-5 °C, and the mixture was stirred for 1-2 hours. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C for 24 hours to obtain a white solid. Yield: 95%, Purity: 99.5%.

[0288] [M+1]:420.2.

[0289] Example 12: Preparation of I-2

[0290] Under nitrogen atmosphere, I-1a (1450 g, 1.0 eq) and n-heptane (5.5 L) were added to the reactor, and the reaction solution temperature was controlled at 20-30 °C. A 4 mol / L hydrogen chloride / isopropanol solution (3800 g) was added dropwise to the reactor, maintaining the temperature at 20-30 °C. After the addition was complete, the temperature was raised, and the reactor was stirred at 45-55 °C for 2-4 h. Central control monitoring showed that I-1-6 was less than 2.0%. After the reaction was complete, the temperature was lowered to 20-30 °C, and the mixture was washed with n-heptane to obtain a wet product. Purified water (12 L) was added to the reactor, and the mixture was stirred. The wet product was transferred to the reactor, and the pH was adjusted to 12-14 with sodium hydroxide solution. The reactor temperature was controlled below 25 °C, and after stirring for 30 min, the pH reached 13. The solution in the reactor was centrifuged, and the water was stirred and slurried twice, then centrifuged again to collect the wet product. The wet product was dried under reduced pressure at 45-55 °C to obtain a white solid (1047 g). Yield: 95%. Liquid phase purity: 99.9%; content: 100%.

[0291] [M+1]:320.2.

[0292] Example 13: Preparation of I-2

[0293] Under nitrogen atmosphere, I-1a (1000g, 1.0eq) and isopropanol (2.5L) were added to the reactor. The reaction solution temperature was controlled at 20-30 °C. Concentrated hydrochloric acid (710g) was added dropwise to the reactor. After the addition was complete, the temperature was raised, and the reactor was stirred at 40-55 °C for 4 hours. Central control monitoring showed that I-1 was less than 2.0%. After the reaction was complete, the temperature was lowered to 20-30 °C, and water (2.5L) was added. The mixture was stirred, and the pH was adjusted to 12-14 with sodium hydroxide solution. The reactor temperature was controlled below 25 °C. After stirring for 30 minutes, the pH reached 13. The solution in the reactor was centrifuged, and the water was stirred and slurried twice. The mixture was then centrifuged again, and the wet product was collected. The wet product was dried under reduced pressure at 45-55 °C to obtain a white solid (1070g). Yield: 97%. Liquid phase purity: 99.9%; content: 99%.

[0294] [M+1]:320.2.

[0295] Example 14: Preparation of I-3a

[0296] ;

[0297] Under nitrogen atmosphere, acetone (4 L), I-2 (1000 g, 1.0 eq), and potassium carbonate (864 g) were added to the reactor in batches. The reactor temperature was adjusted to 20-30 °C, and the mixture was stirred for 1 h. Methyl (S)-2-(chloromethyl)-3-(oxacyclobut-2-ylmethyl)-3-hydro-benzo[d]imidazolium-5-carboxylate (916 g) was added to the reactor in batches, and the reactor temperature was adjusted to 40-50 °C. The mixture was stirred for 4.0-5.0 h, and the I-2 concentration was monitored to be ≤0.3%. The mixture was cooled, and water (15 L) was added to the reactor. The mixture was stirred for 1.0-2.0 h, centrifuged, filtered, and the filter cake was washed with purified water to obtain a wet product. The wet product was then stirred and slurried again with water, centrifuged, and filtered to obtain a filter cake. The filter cake was mixed with methanol / water (10L / 15L) and stirred for 2.0-3.0 h. The mixture was then centrifuged, filtered, washed with water, and dried to obtain a wet product. 1802 g of a white solid was obtained. Yield: 97%. Purity: 99.9%. Content: 99.3%.

[0298] [M+1]:578.2.

[0299] Example 15: Preparation of I-3a

[0300] Under nitrogen atmosphere, 2-methyltetrahydrofuran (4 L), I-2 (1000 g, 1.0 eq), and sodium carbonate (664 g) were added in portions to the reactor. The reactor temperature was adjusted to 20-30 °C, and the mixture was stirred for 1 h. Methyl (S)-2-(chloromethyl)-3-(oxacyclobut-2-ylmethyl)-3-hydro-benzo[d]imidazolium-5-carboxylate (916 g) was added in portions to the reactor. The reactor temperature was adjusted to 40-50 °C, and the mixture was stirred for 4.0-5.0 h, with I-2 ≤ 0.3% monitored. The mixture was cooled, and water (15 L) was added to the reactor. The mixture was stirred for 1.0-2.0 h, separated, and the organic phase was washed again with water, concentrated, and then concentrated again after the addition of n-heptane. After the addition of n-heptane, the mixture was stirred (10 L) for 8 h, centrifuged, filtered, and dried to obtain 1579 g of white solid, yield: 85%. Purity: 99.9%, Content: 99.0%.

[0301] [M+1]:578.2.

[0302] Example 16: Preparation of Compound I

[0303] Under nitrogen atmosphere, tetrahydrofuran (10 L), I-3 (1515 g, 1.0 eq), methanol (8 L), and 3% lithium hydroxide aqueous solution were added to a reactor. The reactor temperature was adjusted to 40-50 °C, and the mixture was stirred for 4.0-5.0 h. I-3 ≤ 0.5%. The temperature was lowered to 20-30 °C, and 1 mol / L citric acid aqueous solution was slowly added dropwise to adjust the pH to 5.0-6.0. The mixture was stirred at 20-30 °C for 0.5-2.0 h. Purified water (8 L) was added to the reactor, and the mixture was stirred at 20-30 °C for 1.0-4.0 h. After centrifugation and filtration, a wet product was obtained. This product was slurried with purified water (15 L), washed with water, and filtered dry to obtain the wet product of compound -I, with a purity of 100% and a content of 71.6%. The wet product was used directly in the next step.

[0304] [M+1]:564.2

[0305] Example 17: Preparation of Compound II

[0306] Under nitrogen atmosphere, 12 L of 2-methyltetrahydrofuran, 0.8 L of purified water, and 4.2 L of acetone were added to the reactor. Stirring was started, and the wet product of compound -I was continuously added. The reactor temperature was adjusted to 20-30 °C, and stirring was continued for 0.5-2.0 h until the solution was clear. The reactor temperature was then adjusted to 20-30 °C, and 332 g of tromethorphanol and approximately 1.4 L of purified water were added. Stirring was started, and the temperature was adjusted to 20-30 °C, and stirring was continued for 10-30 min until the solution was clear. The solution was added dropwise to the reactor, maintaining the temperature at 20-30 °C. Stirring was continued at 20-30 °C for 2.0-3.0 h. The material in the reactor was filtered, and the reactor and filter cake were washed with acetone. The filter cake was dried under reduced pressure at 45-55 °C to obtain 1420 g of a white solid. Yield: 94%, Purity: 99.9%.

[0307] [M+1]: 564.2 (free acid);

[0308] 1 H NMR (400MHz CD3OD) 8.21 (1H, d), 7.96-7.97 (1H, dd), 7.94-7.95 (1H, d), 7.50-7.61 (1H, td), 7.25-7.29 (2H, m ), 7.20-7.22 (2H, m), 6.96-7.02 (1H, dd), 6.94-6.96 (1H, t), 5.12 (1H, m), 4.95 (2H, s), 4.85-4.8 9 (2H, m), 4.73-4.74 (1H, m), 4.63-4.70 (1H, m), 4.47-4.48 (1H, m), 3.67-4.46 (2H, ABq), 3.67 (6H, s), 2.96-3.02 (3H, m), 2.78-2.88 (1H, m), 2.48-2.58 (1H, m), 2.20-2.28 (2H, m), 1.75-1.80 (4H, m). HPLC purity: 99.95%.

[0309] X-ray powder single-crystal diffraction was performed on the white solid, and it was determined to be crystal form A of the monohydrate of compound II. Its XRPD pattern is shown below. Figure 1 As shown in Table 1, the analytical data is presented.

[0310] Table 1

[0311] .

[0312] Its single crystal structure is as follows Figure 1 As shown, its main crystal parameters are as follows:

[0313] .

[0314] Test Example: Rat Pharmacokinetic Evaluation

[0315] Using rats as test animals, the plasma drug concentration at different time points after gavage administration of the test substance was tested. The pharmacokinetic behavior of the compound of this invention in rats was studied, and its metabolic characteristics were evaluated. Three rats of similar weight were used in each example group, and the oral dose was 10 mg / kg, administered once. Blood samples were collected from the animals at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. The concentration of the compound in plasma was detected by LC-MS / MS analysis, with a limit of quantitation of 20 ng / mL. The plasma concentration data were statistically analyzed using WinNonlin 7.0 software, and pharmacokinetic parameters were calculated using the non-compartmental model (NCA).

[0316] Experimental reagents: Crystal form A of the monohydrate of compound II obtained in Example 17 and compound I (free acid) in Example 16.

[0317] Drug preparation:

[0318] Take the test sample with a final concentration (calculated as the content of compound I) of 1.0 mg / mL for oral administration. The solvent is 0.5% CMC Na aqueous solution. After preparation, it is a milky white homogeneous suspension.

[0319] Administration: After fasting overnight (12 hours), rats were administered the drug by gavage at a dose of 10 mg / kg.

[0320] Procedure: Rats were administered the drug by gavage. Blood was collected from the tail vein before administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. The blood samples were placed in heparinized sample tubes and centrifuged at 3500 rpm for 10 minutes at 4°C to separate the plasma. The plasma was stored at -20°C and fed 2 hours after administration.

[0321] Determination of the content of the target compound in rat plasma after oral administration of the drug: After thawing the plasma sample at room temperature, add 300 µL of internal standard (terfenadine 200 ng / mL, acetonitrile), vortex for 1 min, and centrifuge at 15400 rpm for 10 min at 4 °C. Dilute the supernatant 20 times with 80% acetonitrile-water and analyze by LC / MS / MS.

[0322] ;

[0323] As shown in the table above, the monohydrate crystal form A of compound II in this invention has significantly better oral absorption than compound I (free acid).

Claims

1. A process for the preparation of a compound of formula I-1 ###0001### I-1 characterized in that It includes the following steps: in the presence of an inorganic base, a compound as shown in Formula I-1-6 and a compound as shown in Formula I-1-7 are subjected to a substitution reaction in a solvent to obtain a compound as shown in Formula I-1. The inorganic bases mentioned include one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate. ； wherein X is halogen or -OS(=0)2-C 1-4 alkyl; R 1 is an amino protecting group.

2. The process according to claim 1 for the preparation of a compound of formula 1-1, wherein It meets one or more of the following conditions: (1) The inorganic base also includes one or more of cesium carbonate, cesium bicarbonate, alkali metal phosphate and alkali metal acetate; the inorganic base is preferably sodium carbonate, sodium bicarbonate, or a mixture of sodium bicarbonate and potassium carbonate; (2) The molar ratio of the inorganic base to the compound shown in Formula I-1-6 is (1-4):1, or it can be (2.5-4):1; (3) The compound of formula I-1-7 is one or more of 4-chloro-2-fluorobenzyl chloride, 4-chloro-2-fluorobromobenzyl chloride, 4-chloro-2-fluoroiodobenzyl chloride, 4-chloro-2-fluorobenzyl methanesulfonate, 4-chloro-2-fluorobenzyl ethanesulfonate, 4-chloro-2-fluorobenzyl benz ... (4) The molar ratio of the compound of formula I-1-7 to the compound of formula I-1-6 is (1-3):1, preferably (1-1.5):1; (5) The solvent is one or more of alcohol solvents, ketone solvents, ether solvents, ester solvents, nitrile solvents, amide solvents and sulfoxide solvents, and is more preferably acetone or acetonitrile; (6) The temperature of the substitution reaction is 10-30℃; (7) The post-processing steps after the reaction include filtration and crystallization; the crystallization step includes dissolving and crystallizing the compound as shown in Formula I-1 in n-heptane; The method for preparing the compound of formula I-1 as described in (8) further includes the method for preparing the compound of formula I-1-6 as described in (8). The method for preparing the compound of formula I-1-6 includes the following steps: reacting the compound of formula I-1-5 with an amino protecting agent to obtain the compound of formula I-1-6; 。 3. The process according to claim 1 for the preparation of a compound of formula 1-1, wherein It meets one or more of the following conditions: (1) In the preparation method of the compound of formula I-1-6, the amino protecting agent is (Boc)2O; (2) In the preparation method of the compound of formula I-1-6, the molar ratio of the amino protecting agent to the compound of formula I-1-5 is (0.9-5.0):1, preferably (1.0-2.0):1; (3) In the preparation method of the compound of formula I-1-6, the base used in the reaction is an inorganic base and / or an organic base, more preferably an alkali metal carbonate and / or an alkali metal bicarbonate, and more preferably sodium bicarbonate and / or potassium carbonate. (4) In the preparation method of the compound of formula I-1-6, the solvent used in the reaction is one, two, three or four kinds of aromatic solvent, ester organic solvent, ketone solvent and water, preferably a mixed solvent of aromatic solvent, ester organic solvent and water, or a mixed solvent of ketone solvent, ester organic solvent and water, more preferably a mixed solvent of toluene-isopropyl acetate-water, or a mixed solvent of butanone-ethyl acetate-water; (5) In the method for preparing the compound of formula I-1-6, the reaction temperature is 20-30℃; (6) In the method for preparing the compound of formula I-1-6, the post-processing steps after the reaction include extraction and concentration. The method for preparing the compound of formula I-1 as described in (7) further includes the method for preparing the compound of formula I-1-5 as described in (7). The preparation method of the compound of formula I-1-5 includes the following steps: in the presence of Pd and hydrogen, the compound of formula I-1-4 is reduced in a solvent to obtain the compound of formula I-1-5. 。 4. The process according to claim 3 for the preparation of a compound of formula 1-1, wherein It also includes methods for preparing compounds as shown in Formula I-1-4; The method for preparing the compound shown in Formula I-1-4 includes the following steps: in the presence of an acid, the compound shown in Formula I-1-3 undergoes a dehydration reaction to obtain the compound shown in Formula I-1-4; 。 5. The process according to claim 4 for the preparation of a compound of formula 1-1, wherein It meets one or more of the following conditions: (1) In the method for preparing the compound as shown in Formula I-1-4, the acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid, preferably acetic acid or concentrated hydrochloric acid. (2) In the method for preparing the compound shown in Formula I-1-4, the compound shown in Formula I-1-3 is an acid salt of the compound shown in Formula I-1-3, preferably a p-toluenesulfonate of the compound shown in Formula I-1-3. (3) In the method for preparing the compound shown in Formula I-1-4, the volume-to-mass ratio of the acid to the compound shown in Formula I-1-3 is preferably (3-2) mL / g; (4) In the method for preparing the compound as shown in Formula I-1-4, the dehydration reaction is carried out in the presence or absence of a solvent; When the dehydration reaction is carried out in the presence of a solvent, the solvent is preferably an ether solvent, an aromatic hydrocarbon solvent, a ketone solvent, a nitrile solvent, an amide solvent, or a sulfoxide solvent, and more preferably an aromatic hydrocarbon solvent. (5) In the method for preparing the compound as shown in Formula I-1-4, the temperature of the dehydration reaction is 10-150℃, preferably 90-110℃; (6) In the method for preparing the compound as shown in Formula I-1-4, the post-treatment after the dehydration reaction includes the following steps: adjusting the pH to 12, allowing the mixture to stand and separate, collecting and concentrating the organic phase; And, (7) the method for preparing the compound of formula I-1 also includes the method for preparing the compound of formula I-1-3; The method for preparing the compound as shown in Formula I-1-3 includes the following steps: Step a: React the compound shown in Formula I-1-1 with magnesium in a solvent to obtain a Grignard reagent; Step b: The Grignard reagent is reacted with the compound shown in Formula I-1-2 to obtain the compound shown in Formula I-1-3; ； Preferably, the preparation method of the compound shown in Formula I-1-3 satisfies one or more of the following conditions: (1) In step a of the method for preparing the compound as shown in Formula I-1-3, the reaction is carried out in the presence of an initiator or a base; When the reaction is carried out in the presence of an initiator, the initiator is preferably one, two or three of iodine, ethyl magnesium and isopropyl magnesium, such as iodine or a 2M THF solution of isopropyl magnesium. When the reaction is carried out in the presence of an initiator, the molar ratio of the initiator to the compound shown in Formula I-1-1 is (0.05-0.15):1, for example (0.05-0.1):1; When the reaction is carried out in the presence of a base, the base is preferably n-butyllithium, for example, a 1.6 M THF solution of n-butyllithium; (2) In step a of the preparation method of the compound shown in Formula I-1-3, the molar ratio of magnesium to the compound shown in Formula I-1-1 is (1.0-1.5):1, for example 1.1:1; (3) In step a of the method for preparing the compound as shown in Formula I-1-3, the solvent is an ether solvent and / or an aromatic solvent, more preferably tetrahydrofuran or methyltetrahydrofuran; (4) In step a of the method for preparing the compound as shown in Formula I-1-3, the reaction temperature is -80 to 85°C, preferably -20 to -10°C or 15 to 35°C; (5) The Grignard reagent obtained in step a of the preparation method of the compound shown in Formula I-1-3 is used directly in the reaction of step b without any post-treatment steps. (6) In the method for preparing the compound shown in Formula I-1-3, the molar ratio of the compound shown in Formula I-1-2 to the compound shown in Formula I-1-1 is (0.8-1.0):1; (7) In step b of the method for preparing the compound as shown in Formula I-1-3, the temperature of the Grignard reaction is 20-40℃; The post-processing of the Grignard reaction described in (8) includes the following steps: salt washing, separation and concentration of the organic phase and salt formation.

6. A process for the preparation of a compound of formula I-3, characterized by, It includes the following steps: in the presence of an inorganic base, a compound as shown in Formula I-2 and a compound as shown in Formula I-1-8 are subjected to a substitution reaction to obtain a compound as shown in Formula I-3; ； R 2 is C 1-4 alkyl or C 3-6 cycloalkyl.

7. The process for the preparation of a compound of formula 1-3 as claimed in claim 6, wherein, ###00013### 1-3 It meets one or more of the following conditions: (1) R 2 In particular, the C 1-4 alkyl is methyl; (2) The molar ratio of the compound of formula I-1-8 to the compound of formula I-2 is (1-1.5):1, preferably (0.9-1.1):1; (3) The inorganic base is one or more of alkali metal carbonates, alkali metal bicarbonates, alkali metal acetates, alkali metal phosphates and alkali metal hydroxides, preferably alkali metal carbonates, and more preferably sodium carbonate and / or potassium carbonate. (4) The molar ratio of the inorganic base to the compound shown in Formula I-2 is (1-3):1, preferably (1.5-2.5):1; (5) The solvent used in the substitution reaction is one or more of alcohol solvents, ether solvents, ester solvents, nitrile solvents, amide solvents and sulfoxide solvents, and is more preferably acetone and / or 2-methyltetrahydrofuran; (6) The temperature of the substitution reaction is 0-150℃, preferably 40-50℃; The method for preparing the compound of formula I-3 further includes the method for preparing the compound of formula I-2; The preparation method of the compound of formula I-2 includes the following steps: the compound of formula I-1 is subjected to a deprotection reaction to obtain the compound of formula I-2; 。 8. The method for preparing compounds of formula I-3 as described in claim 7, characterized in that, It meets one or more of the following conditions: (1) In the preparation method of the compound of formula I-2, the deprotection reaction is carried out in an acidic system and a neutral system; When the deprotection reaction is carried out in an acidic system, the acidic system is preferably obtained by adjusting the acidic system with an inorganic acid or an organic acid. The inorganic acid can be one, two, three or four of hydrogen chloride, sulfuric acid, phosphoric acid and hydrobromic acid, and is more preferably an aqueous solution of hydrochloric acid or an isopropanol solution of hydrogen chloride. The organic acid can be one or more of trifluoroacetic acid, formic acid, methanesulfonic acid, chlorosulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, trichloroacetic acid, and oxalic acid. When the deprotection reaction is carried out in a neutral system, the neutral system may be adjusted by one or more of the following reagents: trimethylsilicon iodide, trimethylsilyl trifluoromethanesulfonate, or a mixture of trimethylchlorosilane and sodium iodide. (2) In the preparation method of the compound of formula I-2, the solvent used in the deprotection reaction is one or more of alkane solvents, ester solvents, ketone solvents, alcohol solvents, nitrile solvents, ether solvents, chlorinated hydrocarbon solvents, amide solvents and sulfoxide solvents, preferably alkane solvents and / or alcohol solvents, and more preferably a mixed solvent of n-heptane and isopropanol, or isopropanol; (3) In the preparation method of the compound of formula I-2, the temperature of the deprotection reaction is 10-30℃, preferably 20-30℃; (4) In the preparation method of the compound of formula I-2, the post-treatment after the reaction includes the following steps: adjusting the pH to 12-14, centrifuging and slurrying; (5) The method for preparing the compound of formula I-3 further includes the method for preparing the compound of formula I-1 as described in any one of claims 1-6.

9. A method for preparing a compound of Formula I, characterized in that, These are Option 1 and / or Option 2: Option 1 includes the following steps: Step 1: In the presence of an inorganic base, the compounds shown in Formula I-1-6 and Formula I-1-7 are subjected to a substitution reaction in a solvent to obtain the compound shown in Formula I-1. The inorganic bases mentioned include one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate. ； wherein X is halogen or -OS(=0)2-C 1-4 alkyl; R 1 is an amino protecting group; Step 2: Preparation method of compound I by means of compound shown in Formula I-1; ； Option 2 includes the following steps: Step a: In the presence of an inorganic base, the compound shown in Formula I-2 and the compound shown in Formula I-1-8 are subjected to a substitution reaction to obtain the compound shown in Formula I-3; Step b: Hydrolyze the compound shown in Formula I-3 to obtain the compound shown in Formula I; ； R 2 is C 1-4 alkyl or C 3-6 cycloalkyl.

10. The method of claim 9, wherein the compound is of formula I: ###0002### I It meets one or more of the following conditions: (1) In step b of scheme 2, the base used in the hydrolysis reaction is an alkali metal hydroxide, preferably one, two or three of sodium hydroxide, potassium hydroxide and lithium hydroxide, such as sodium hydroxide or potassium hydroxide; (2) In step b of scheme 2, the molar ratio of the base used in the hydrolysis reaction to the compound shown in formula I-3 is preferably (1-3):1, more preferably (1.5-2.5):1, for example 2.5:1; (3) In step b of scheme 2, the solvent used for the hydrolysis reaction is one or more of ketone solvents, ether solvents, alcohol solvents, ester solvents, nitrile solvents, amide solvents and sulfoxide solvents, and is more preferably tetrahydrofuran or 2-methyltetrahydrofuran; (4) In step b of scheme 2, the temperature of the hydrolysis reaction is 0-150℃, preferably 40-50℃; And, (5) In step b of scheme 2, the post-treatment after the hydrolysis reaction is completed includes the following steps: adjusting the pH value to 5.0-6.0, filtering and pulping.

11. A process for the preparation of a compound of formula II, characterized by, These are Scheme I and / or Scheme II: Option I includes the following steps: Step 1: In the presence of an inorganic base, the compounds shown in Formula I-1-6 and Formula I-1-7 are subjected to a substitution reaction in a solvent to obtain the compound shown in Formula I-1. The inorganic bases mentioned include one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate. ； wherein X is halogen or -OS(=0)2-C 1-4 alkyl; R 1 is an amino protecting group; Step 2: Preparation method of compound II by means of compound shown in formula I-1; ； Option II includes the following steps: Step a: In the presence of an inorganic base, the compound shown in Formula I-2 and the compound shown in Formula I-1-8 are subjected to a substitution reaction to obtain the compound shown in Formula I-3; ; Step b: A method for preparing compounds of formula II from compounds of formula I-3; ； R 2 is C 1-4 alkyl or C 3-6 cycloalkyl.

12. The process of claim 11 for the preparation of a compound of formula II, wherein Scheme I involves preparing compound II via the following route: ： Scheme II involves preparing compound II via the following route: ； In Schemes I and II, the preparation method II involves preparing compounds from compounds shown in Formula I and Formula I-1-9: The preferred molar ratio of the compound shown in Formula I-1-9 to the compound shown in Formula I is (0.9-1.5):1; The solvent used is preferably one, two or three of water, ketone solvents and ether solvents, and more preferably a mixed solvent of water, 2-methyltetrahydrofuran and acetone; The reaction temperature is preferably 40-50℃, more preferably 20-30℃.

13. A method of preparing a compound of formula I-1-5, wherein ###0001### I-1-5 characterized in that It includes the following steps: in the presence of Pd and hydrogen, the compound shown in Formula I-1-4 is reduced in a solvent to obtain the compound shown in Formula I-1-5; 。 14. A compound of formula I-1, formula I-2, formula I-3, formula I-1-1, or formula I-3-1: 、 、 、 or ; wherein R 1 is an amino protecting group; in formula I-3, R 2 is C 1-4 alkyl or C 3-6 cycloalkyl.

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