Oxaspiro substituted pyrrolopyrazole derivatives and intermediates and processes for their preparation

Abstract

This invention relates to an oxaspirocyclic substituted pyrrolopyrazole derivative, its intermediates, and a method for their preparation.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, specifically to oxaspirocyclic substituted pyrrolopyrazole derivatives, their intermediates, and methods for their preparation. Background Technology

[0002] Opioid receptors are an important class of G protein-coupled receptors (GPCRs) and are targets for the binding of endogenous opioid peptides and opioid drugs. Endogenous opioid peptides are naturally occurring opioid-like active substances in mammals, and are currently known to be broadly classified into enkephalins, endorphins, dynorphins, and neophorphins. Corresponding opioid receptors, namely μ(MOR), δ(DOR), and κ(KOR) receptors, exist in the central nervous system. Studies have found that the strength of the analgesic effect of endogenous opioid peptides mainly depends on the expression level of opioid receptors, which are the targets of opioid drugs and the analgesic effects of endogenous opioid peptides.

[0003] Numerous publications have reported on MOR agonists with different structures and disclosed their preparation methods, including WO2017106547, WO2017063509, WO2012129495, and WO2017106306. Developing efficient, low-cost, easily scalable, and reproducible synthetic processes for novel MOR agonists with better activity and selectivity is of great significance for the pharmaceutical industry and industrial production. Summary of the Invention

[0004] The purpose of this invention is to further develop intermediates and their preparation methods suitable for industrial production based on the already developed novel MOR agonists. The preparation method has the characteristics of high efficiency, low cost, easy scale-up, and good reproducibility.

[0005] The first aspect of this invention provides a compound of formula C, or a stereoisomer thereof:

[0006]

[0007] in,

[0008] R is C 1-8 Alkyl (preferably C) 1-4 Alkyl), -C 1-4 Alkyl-C 6-10 Aryl (preferably -CH2-aryl, more preferably benzyl), C 6-10 Aryl (preferably phenyl);

[0009] Ring A is C 6-10 Aromatic ring (preferably benzene ring) or 5- to 6-membered monocyclic heteroaryl ring (preferably pyridine ring);

[0010] (R0) n The hydrogen atom on ring A is replaced by n R0 groups, where n is 0, 1, 2, 3, or 4; each R0 group may be the same or different, and each is independently a hydrogen, cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, or halogenated C group. 1-8 Alkyl (preferably halogenated C) 1-4 Alkyl groups, halogens (preferably F or Cl), nitro groups, C 6-10 Aryl (preferably phenyl), 5- to 6-membered monocyclic heteroaryl, C 1-8 Alkyl (preferably C) 1-4 Alkyl), C 1-8 Alkoxy (preferably C) 1-4 alkoxy), C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 2-4 alkenyl, C 2-4 acetylenic, NR 11 R 12 -CONR 11 R 12 -C(O)OC 1-8 Alkyl (preferably -C(O)OC) 1-4 Alkyl), -OC(O)C 1-8 Alkyl groups (preferably -OC(O)C) 1-4 alkyl), -SO2C 1-8 Alkyl groups (preferably -SO2C) 1-4 alkyl), -SO2C 6-10 Aryl (preferably -SO2C6 aryl, such as -SO2-phenyl), -COC 6-10 Aryl (preferably -COC6 aryl, such as -CO-phenyl), 4- to 6-membered saturated monoheterocyclic rings, or 3- to 6-membered saturated monocyclic rings, wherein the C 6-10 The aryl, 5- to 6-membered monocyclic heteroaryl, 4- to 6-membered saturated monoheterocyclic, and 3- to 6-membered saturated monocyclic groups are unsubstituted or replaced by 1, 2, or 3 groups selected from acetyl, hydroxyl, cyano, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, NR 11 R 12 Substituents of the substituents;

[0011] R 11 R 12 Each independently is hydrogen, C 1-8 Alkyl (preferably C) 1-4 Alkyl), halogenated C 1-8 Alkyl (preferably halogenated C) 1-4 Alkyl), C 3-6 cycloalkyl or 4- to 6-membered saturated monoheterocycles; or R 11R 12 Together with the attached nitrogen atom, it forms a 4- to 6-membered saturated monoheterocycle; wherein the 4- to 6-membered saturated monoheterocycle is unsubstituted or surrounded by 1, 2, or 3 carbon atoms. 1-4 Alkyl substitution.

[0012] In some embodiments, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, phenyl, or benzyl, preferably methyl.

[0013] In some embodiments, A is a benzene ring, a pyridine ring, a pyrimidine ring, or a triazine ring.

[0014] In some embodiments, n is 0.

[0015] In some embodiments, the compound represented by formula C is a compound of formula C2:

[0016]

[0017] Wherein, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, or benzyl (preferably methyl).

[0018] In some embodiments, the compound represented by formula C is a compound of formula C3:

[0019]

[0020] Wherein, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, or benzyl (preferably methyl).

[0021] The second aspect of this invention provides a method for preparing the compound of formula C or its stereoisomers as described in the first aspect, comprising the following steps:

[0022]

[0023] S200: The compound shown in Formula E or its stereoisomer is subjected to one or more steps of reaction to prepare the compound shown in Formula C or its stereoisomer; further, in step S200, the compound shown in Formula E or its stereoisomer is subjected to alcoholysis reaction to prepare the compound shown in Formula C or its stereoisomer.

[0024] In some embodiments, in step S200, the compound of formula E or its stereoisomer is subjected to a one-step reaction to prepare the compound of formula C or its stereoisomer. Specifically, step S200 includes the following steps:

[0025] S211: The compound shown in Formula E or its stereoisomer is reacted with alcohol ROH under acid catalysis. After the reaction is completed, it is separated and purified to obtain the compound shown in Formula C or its stereoisomer.

[0026] In some embodiments, in step S211, the alcohol ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, phenol, or benzyl alcohol; further, the alcohol is methanol or ethanol.

[0027] In some embodiments, in step S211, the acid is an inorganic acid or an organic acid; further, the acid is hydrochloric acid or p-toluenesulfonic acid.

[0028] In some embodiments, step S211, the separation and purification step includes the following steps:

[0029] Water is added to the reaction solution after the reaction is complete to obtain a mixture. The mixture is then extracted with an organic solvent, and the extract is evaporated to dryness to obtain the compound shown in formula C or its stereoisomer. Further, the organic solvent is methyl tert-butyl ether.

[0030] In some embodiments, in step S200, the compound of formula E or its stereoisomer is subjected to a two-step reaction to prepare the compound of formula C or its stereoisomer:

[0031]

[0032] Specifically: Step S200 includes the following steps:

[0033] S221: React the compound of formula E or its stereoisomer to obtain the compound of formula D or its stereoisomer; and

[0034] S222: The compound shown in Formula D or its stereoisomer is reacted with ROH to obtain the compound shown in Formula C or its stereoisomer.

[0035] In some embodiments, step S221 includes the following steps:

[0036] The compound shown in Formula E or its stereoisomer, water, and acid are mixed and reacted at a temperature of 30°C-60°C (preferably 45°C-50°C). After the reaction is completed, the mixture is separated and purified to obtain the compound shown in Formula D or its stereoisomer.

[0037] In some embodiments, in step S221, the acid is an inorganic acid; further, the acid is sulfuric acid.

[0038] In some embodiments, in step S221, the concentration of acid is 30 g / mL to 60 g / mL.

[0039] In some embodiments, in step S221, the compound of formula E or its stereoisomer is mixed with water, cooled to 10°C-15°C, and then sulfuric acid is slowly added dropwise. After the addition is complete, the reaction is carried out at a temperature of 30°C-60°C (preferably 45°C-50°C) for 40-80 minutes. After the reaction is complete, the temperature is cooled to 5°C-10°C, and an organic solvent (preferably toluene) and an alkaline solution (preferably a sodium hydroxide or potassium hydroxide solution with a mass percentage of 10%-30%) are added. The mixture is stirred for a predetermined time (preferably 40-80 minutes). After standing, extraction, washing, and drying, the compound of formula D or its stereoisomer is obtained.

[0040] In some embodiments, step S222 includes the following steps:

[0041] The compound shown in Formula D or its stereoisomer is reacted with an alcohol (e.g., methanol, ethanol) under acid (e.g., thionyl chloride) catalysis. After the reaction is complete, the mixture is post-treated and dried to obtain the compound shown in Formula C or its stereoisomer.

[0042] In some embodiments, the stereoisomer of the compound shown in Formula C is the compound shown in Formula C1, and the stereoisomer of the compound shown in Formula E is the compound shown in Formula E1. The reaction route is as follows:

[0043]

[0044] The compound shown in formula E1 is prepared by undergoing one or two or more reactions to obtain the compound shown in formula C1.

[0045] In some embodiments, the compound represented by formula C is the same as the compound represented by formula C2, and the compound represented by formula E is the same as the compound represented by formula E2. The reaction route is as follows:

[0046]

[0047] The stereoisomer of the compound shown in formula E2 or its stereoisomers is prepared by one or two or more steps of reaction.

[0048] In some embodiments, the stereoisomer of the compound represented by formula C is the compound represented by formula C3, and the stereoisomer of the compound represented by formula E is the compound represented by formula E3. The reaction route is as follows:

[0049]

[0050] The compound shown in formula E3 is prepared by undergoing one or two or more reactions to obtain the compound shown in formula C3.

[0051] The preparation method of the second aspect of the present invention uses the compound shown in Formula E or its stereoisomer as the reaction raw material, and generates the compound shown in Formula C or its stereoisomer through the selection of a reasonable reaction route. The operation is simple and the post-processing is simple. Only simple purification is required to obtain a product with high purity. The target purity can be obtained without column separation or other processes. This can greatly reduce the difficulty of production, reduce the production cost, and is more conducive to industrial production.

[0052] A third aspect of the present invention provides a compound of formula B or a stereoisomer thereof:

[0053]

[0054] Among them, ring A and (R0) n As stated in the first aspect.

[0055] In some embodiments, the compound represented by formula B is a compound of formula B2:

[0056]

[0057] In some embodiments, the compound represented by formula B is a compound of formula B3:

[0058]

[0059] A fourth aspect of the present invention provides a method for preparing the compound of formula B or its stereoisomer as described in the third aspect, comprising the following steps:

[0060]

[0061] S400: React the compound shown in Formula C or its stereoisomer to prepare the compound shown in Formula B or its stereoisomer;

[0062] In some embodiments, a reduction reaction is carried out in step S400. Further, a red aluminum toluene solution is used for the reduction reaction in step S400.

[0063] In some embodiments, step S400 includes the following steps:

[0064] S410: Mix the compound shown in Formula C or its stereoisomer with toluene, cool to 0℃-10℃, slowly add red aluminum toluene solution and react, then post-process to obtain the compound shown in Formula B or its stereoisomer.

[0065] In some embodiments, after obtaining the compound shown in Formula B, step S410 further includes a step of chiral resolution to obtain the compound shown in Formula B1.

[0066]

[0067] In some embodiments, the chiral separation method is instrumental separation or chemical separation.

[0068] In some embodiments, the resolving agent for chiral resolution is D-tartaric acid, D-dibenzoyltartaric acid, D-malic acid, D-mandelic acid, D-camphorsulfonic acid, or R-binaphthol phosphate; preferably, the resolving agent is R-binaphthol phosphate.

[0069] In some embodiments, the chemical resolution method includes the following steps: mixing the compound of formula B, the resolving reagent, and a first solvent to react; after the reaction is complete, removing the first solvent, slurrying with a second solvent, filtering, and drying to obtain a solid; dissolving the solid in the first solvent, treating under reflux conditions for a predetermined time (preferably 40-80 min, more preferably 50-70 min), cooling, precipitating a solid, filtering, and drying to obtain the compound of formula B1. Further, the first solvent is tetrahydrofuran; further, the second solvent is ethyl acetate. Further, the molar ratio of the compound of formula B to the resolving reagent is 1:0.9-1:1.1.

[0070] By using the racemic compound E as the starting material, and then obtaining the compound C through a simple reaction, followed by a reduction reaction to obtain the compound B, and then performing chiral resolution, the difficulty of chiral resolution can be reduced, thereby improving production efficiency and reducing production costs.

[0071] In some embodiments, in step S410, the compound shown in formula C1 is used to carry out the reaction to obtain the compound shown in formula B1.

[0072]

[0073] In some embodiments, before step S400, the method of the second aspect is further included to prepare the compound of formula C or its stereoisomer.

[0074] The fifth aspect of this invention provides another method for preparing the compound of formula B or its stereoisomer as described in the third aspect, comprising the following steps:

[0075]

[0076] S500: React the compound shown in Formula D or its stereoisomer to prepare the compound shown in Formula B or its stereoisomer.

[0077] In some embodiments, a reduction reaction is carried out in step S500. Further, a red aluminum toluene solution is used for the reduction reaction in step S500.

[0078] In some embodiments, the stereoisomers of the compound shown in Formula D are shown in Formula D2, and the stereoisomers of the compound shown in Formula B are shown in Formula B3. The reaction route is as follows:

[0079]

[0080] Furthermore, step S500 includes the following steps:

[0081] S510: Mix the compound shown in Formula D or its stereoisomer with toluene, cool to 0℃-10℃, add red aluminum toluene solution, heat to 20℃-45℃ to react, quench the reaction after the reaction is complete, and then post-process to obtain the compound shown in Formula B or its stereoisomer.

[0082] In some embodiments, after obtaining the compound shown in Formula B, step S510 further includes a step of chiral resolution to obtain the compound shown in Formula B1.

[0083]

[0084] In some embodiments, the chiral separation method is instrumental separation or chemical separation.

[0085] In some embodiments, the resolving agent for chiral resolution is D-tartaric acid, D-dibenzoyltartaric acid, D-malic acid, D-mandelic acid, D-camphorsulfonic acid, or R-binaphthol phosphate; preferably, the resolving agent is R-binaphthol phosphate.

[0086] In some embodiments, the chemical resolution method includes the following steps: mixing the compound of formula B, the resolving reagent, and a first solvent to react; after the reaction is complete, removing the first solvent, pulping with a second solvent, filtering, and drying to obtain a solid; dissolving the solid in the first solvent, treating under reflux conditions for a predetermined time (preferably 40-80 min, more preferably 50-70 min), cooling, precipitating a solid, filtering, and drying to obtain the compound of formula B1. Further, the first solvent is tetrahydrofuran; even further, the second solvent is ethyl acetate. Further, the molar ratio of the compound of formula B to the resolving reagent is 1:0.9-1:1.1.

[0087] By using the racemic compound of formula D as a raw material, and then reducing it to obtain the compound of formula B, followed by chiral resolution, the difficulty of chiral resolution can be reduced, thereby improving production efficiency and reducing production costs. In some embodiments, before step S500, a step of preparing the compound of formula D or its stereoisomer is included. Specifically, the step of preparing the compound of formula D or its stereoisomer includes the following steps:

[0088]

[0089] S520: Mix the compound shown in Formula E or its stereoisomer, water and acid, and react them at a temperature of 30℃-60℃ (preferably 45℃-50℃). After the reaction is completed, separate and purify to obtain the compound shown in Formula D or its stereoisomer.

[0090] In some embodiments, in step S520, the acid is an inorganic acid; further, the acid is sulfuric acid; and further still, the concentration of the acid is 30 g / mL to 60 g / mL.

[0091] In some embodiments, in step S520, the compound of formula E or its stereoisomer is mixed with water, cooled to 10°C-15°C, and then sulfuric acid is slowly added dropwise. After the addition is complete, the reaction is carried out at a temperature of 30°C-60°C (preferably 45°C-50°C) for 40-80 minutes. After the reaction is complete, the temperature is cooled to 5°C-10°C, and an organic solvent (preferably toluene) and an alkaline solution (preferably a sodium hydroxide or potassium hydroxide solution with a mass percentage of 10%-30%) are added. The mixture is stirred for a predetermined time (preferably 40-80 minutes). After standing, extraction, washing, and drying, the compound of formula D or its stereoisomer is obtained.

[0092] In some embodiments, the stereoisomers of the compound represented by Formula E are shown as shown in Formula E3, and the stereoisomers of the compound represented by Formula D are shown as shown in Formula D2. The reaction route is as follows:

[0093]

[0094] The sixth aspect of this invention provides compounds with structures represented by formula X or formula Y:

[0095]

[0096] R a R b Each is independently hydrogen, halogen (preferably F or Cl), C 1-6 Alkyl (preferably C) 1-3 Alkyl), halogenated C 1-6 Alkyl (preferably halogenated C) 1-3 Alkyl), halogenated C 1-6 Alkoxy (preferably halogenated C) 1-3 alkoxy); or R a R b Together with the attached carbon atom, it forms a 4- to 6-membered saturated monocyclic heterocycle or a 3- to 6-membered saturated monocyclic ring; wherein the 4- to 6-membered saturated monocyclic heterocycle and the 3- to 6-membered saturated monocyclic ring are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of: cyano, hydroxy, hydroxymethyl, cyanomethyl, halogen, C 1-3 Alkoxy, C 1-3 Alkyl, -COC1-3 Alkyl, -CONR a1 R b1 NR a1 R b1 -NHCOC 1-3 Alkyl, -NHCONR a1 R b1 -NHSO2C 1-3 Alkyl group, -NHSO2NR a1 R b1 -NHSO2C 3-6 cycloalkyl;

[0097] R c Hydrogen, halogen (preferably F or Cl), C 1-6 Alkyl (preferably C) 1-3 Alkyl), C 2-6 alkenyl (preferably C) 2-4 alkenyl), C 2-6 alkynyl group (preferably C) 2-4 alkynyl group), C 1-6 Alkoxy (preferably C) 1-3 alkoxy), halogenated C 1-6 Alkyl (preferably halogenated C) 1-3 Alkyl), halogenated C 1-6 Alkoxy (preferably halogenated C) 1-3 Alkoxy, -COC 1-6 Alkyl groups (preferably -COC) 1-3 Alkyl), -CONR a1 R b1 NR a1 R b1 -NHCOC 1-6 Alkyl groups (preferably -NHCOC) 1-3 Alkyl), -NHCONR a1 R b1 -NHSO2C 1-3 Alkyl group, -NHSO2N R a1 R b1 -NHSO2C 3-6 cycloalkyl, -SO2C 1-3 Alkyl, -SO2NR a1 R b1 4 to 6-membered saturated monoheterocyclic rings, C 6-10 Aryl or 5- or 6-membered monocyclic heteroaryl; wherein the 4- to 6-membered saturated monoheterocyclic, C 6-10 The aryl group and the 5- or 6-membered monocyclic heteroaryl group are unsubstituted or substituted by 1, 2, or 3 substituents selected from the group consisting of: cyano, hydroxy, hydroxymethyl, cyanomethyl, halogen, C 1-3 Alkoxy, C 1-3 Alkyl, -COC1-3 Alkyl, -CONR a1 R b1 NR a1 R b1 -NHCOC 1-3 Alkyl, -NHCONR a1 R b1 -NHSO2C 1-3 Alkyl group, -NHSO2NR a1 R b1 -NHSO2C 3-6 cycloalkyl;

[0098] R a1 R b1 Each independently is hydrogen, C 1-6 Alkyl (preferably C) 1-3 Alkyl), halogenated C 1-6 Alkyl (preferably halogenated C) 1-3 Alkyl), C 3-6 cycloalkyl or 4- to 6-membered saturated monoheterocycles; or R a1 R b1 Together with the attached nitrogen atom, it forms a 4- to 6-membered saturated monoheterocycle; wherein the 4- to 6-membered saturated monoheterocycle is unsubstituted or surrounded by 1, 2, or 3 carbon atoms. 1-3 Alkyl substitution.

[0099] In one embodiment, R a R b Each is independently hydrogen, fluorine, or methyl; or R a R b Together with the attached carbon atom, it forms a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring; R c It can be hydrogen, fluorine, methyl, ethyl, methoxy, or trifluoromethyl.

[0100] In one embodiment, R a R b Each can be independently hydrogen, fluorine, or methyl; R c It can be hydrogen, fluorine, methyl, ethyl, methoxy, or trifluoromethyl.

[0101] In one embodiment, R a For methyl, R b For H, R c It is a methyl group.

[0102] In one embodiment, the compound represented by formula X is the compound represented by formula X-1, and the compound represented by formula Y is the compound represented by formula Y-1:

[0103]

[0104] In one embodiment, the compound represented by formula X is the compound represented by formula X1:

[0105]

[0106] The seventh aspect of this invention provides a method for preparing the compound of formula X or its stereoisomer as described in the sixth aspect, comprising the following steps:

[0107]

[0108] S710: React the compound shown in Formula Z or its stereoisomer to obtain the compound shown in Formula Y or its stereoisomer.

[0109] S720: React the compound shown in Formula Y or its stereoisomer to prepare the compound shown in Formula X or its stereoisomer.

[0110] In some embodiments, step S710 includes the following steps: mixing the compound shown in formula Z, hydroxylamine hydrochloride, a base (preferably pyridine), and an alcohol solvent (preferably anhydrous methanol), and reacting them at a temperature of 50°C-70°C (preferably 65°C) to obtain the compound shown in formula Y.

[0111] In some embodiments, the molar ratio of the compound represented by Formula Z to hydroxylamine hydrochloride is 1:1.1-1:1.5; further, the molar ratio of the compound represented by Formula Z to the base is 1:1.1-1:1.5; further, the molar ratio of the compound represented by Formula Z to the base is 1:1.2.

[0112] In some embodiments, step S720 uses a reduction method to obtain the compound of formula X or its stereoisomer; further, step S720 includes the following steps: mixing the compound of formula Y or its stereoisomer with a solvent (preferably anhydrous methanol), adding Pd / C, and reacting under a hydrogen atmosphere at a pressure of 15 atm to 20 atm (preferably 50°C to 75°C). After the reaction is complete (preferably 1 h to 3 h), the compound of formula X or its stereoisomer is obtained.

[0113] In some embodiments, in step S720, the stereoisomer of the compound shown in formula X is the compound shown in formula X1, and the preparation of the compound shown in formula X1 includes the following steps:

[0114] The compound shown in formula X was chirally resolved to obtain the compound shown in formula X1.

[0115]

[0116] In some embodiments, the chiral separation method is instrumental separation or chemical separation.

[0117] In some embodiments, a chemical resolution method is used for resolution, and further, the resolution reagent is L-tartaric acid, L-dibenzoyltartaric acid, L-malic acid, L-mandelic acid, L-camphorsulfonic acid or S-binaphthol phosphate, preferably L-tartaric acid.

[0118] In some embodiments, the above-described chemical resolution method includes the following steps: mixing the compound shown in Formula X with a solvent (preferably ethanol) to obtain a first solution; mixing the resolving reagent (preferably L-tartaric acid) with a solvent (preferably ethanol) to obtain a second solution; slowly adding the second solution to the first solution, resulting in the precipitation of a large amount of solid; filtering, washing, and drying to obtain a crude salt of the compound shown in Formula X1; and further, purifying the crude salt of the compound shown in Formula X1.

[0119] In some embodiments, the crude salt of the compound represented by formula X1 further includes the following steps:

[0120] S721: Repeated recrystallization of the crude salt of the compound shown in Formula X1 yields the refined salt of the compound shown in Formula X1.

[0121] S722: The purified salt of the compound shown in Formula X1 is dissolved in water, and the pH is adjusted to 10.5-11.5. Extraction is then performed to obtain the stereoisomer of the compound shown in Formula X1; and

[0122] S723: Dissolve the refined salt of the compound shown in Formula X1 in water, filter to remove insoluble matter, collect the filtrate, add methanol to the filtrate, let stand overnight until crystals precipitate, and obtain a single crystal of the salt of the compound shown in Formula X1.

[0123] In some embodiments, in step S721, two recrystallization processes are performed: the crude salt of the compound shown in Formula X1 is subjected to a first recrystallization process, and the collected crystals are subjected to a second recrystallization process.

[0124] The first recrystallization step is as follows: the crude salt of the compound shown in formula X1 is added to an alcohol-water solvent (preferably a mixed solvent of methanol and water in a volume ratio of 1:0.8-1:1.2), and the temperature is raised to an internal temperature of 65-70°C until the system is clear; an alcohol solvent (preferably methanol) is slowly added dropwise to the system, the internal temperature is controlled to be no lower than 55°C, the internal temperature is lowered to 46-47°C and stirring is continued for 30-90 minutes, the temperature is gradually lowered to room temperature, and stirring is continued until a solid precipitates out. The solid is collected to obtain the primary refined product.

[0125] The second recrystallization process is as follows: dissolve the primary concentrate obtained from the first recrystallization process in water, add an alcohol solvent (preferably anhydrous methanol), and heat to reflux to dissolve; lower the internal temperature to about 40℃-55℃ (preferably 50℃) and stir for 30-90 minutes, gradually lower to room temperature, stir, and a solid precipitates out. Collect the solid and wash it (preferably with isopropanol) to obtain the refined salt of the compound shown in Formula X1.

[0126] In some embodiments, during the first recrystallization process, 2-5 mL of alcohol-water solvent is added to every 1 g of crude salt of the compound shown in Formula X1, and after heating to an internal temperature of 65-70°C, 8-12 mL of alcohol solvent is added.

[0127] In some embodiments, during the second recrystallization step, 1-3 mL of water and 7-1 mL of alcohol solvent are added per 1 g of primary concentrate.

[0128] In some embodiments, in step S722, 4-6 mL of water is added to every 1 g of the refined salt of the compound shown in Formula X1.

[0129] In some embodiments, in step S723, 0.2-0.5 mL of water and 0.2-0.5 mL of methanol are added to every 100 mg of the purified salt of the compound shown in Formula X1.

[0130] The eighth aspect of the present invention provides a method for preparing the compound of formula I, comprising the following steps:

[0131] S810: React the compound shown in Formula B or its stereoisomer to obtain the compound shown in Formula A or its stereoisomer:

[0132]

[0133] S820: Reacting the compound or its stereoisomer shown in Formula A with the compound or its stereoisomer shown in Formula X yields the compound or its stereoisomer shown in Formula I:

[0134]

[0135] Among them, ring A and (R0) n As stated in the first aspect; R a R b and R c As described in the sixth aspect.

[0136] In some embodiments, in step S810, the method for preparing the compound represented by formula B is as described in the fourth and fifth aspects.

[0137] In some embodiments, in S810, 2-iodobenzoic acid (IBX) is used to oxidize the alcohol hydroxyl group to an aldehyde; further, in step S810, the molar ratio of the compound shown in Formula B to IBX is 1:2-1:3.

[0138] In some embodiments, the compound shown in formula B is the compound shown in formula B3, and the compound shown in formula B3 is oxidized to obtain the compound shown in formula A1:

[0139]

[0140] In some embodiments, the compound shown in formula B3 is prepared using the following method:

[0141]

[0142] (1) React the compound shown in formula E2 to obtain the compound shown in formula D1.

[0143] (2) The compound shown in formula D1 is reacted to prepare the compound shown in formula B2; and

[0144] (3) The compound shown in formula B2 was chirally resolved to obtain the compound shown in formula B3.

[0145] In some embodiments, the compound shown in formula B3 is prepared using the following method:

[0146]

[0147] (1) React the compound shown in formula E2 to obtain the compound shown in formula D1.

[0148] (2) React the compound shown in formula D1 to obtain the compound shown in formula C2;

[0149] (3) The compound of formula C2 is reacted to prepare the compound of formula B2; the R group in the compound of formula C2 is as described in the first aspect; and

[0150] (4) The compound shown in formula B2 was chirally resolved to obtain the compound shown in formula B3.

[0151] In some embodiments, the compound shown in formula B3 is prepared using the following method:

[0152]

[0153] (1) The compound shown in formula E3 is reacted to obtain the compound shown in formula C3; and

[0154] (2) The compound shown in formula C3 was reacted to obtain the compound shown in formula B3.

[0155] In some embodiments, the compound shown in formula B3 is prepared using the following method:

[0156]

[0157] (1) The compound shown in formula E3 is reacted to obtain the compound shown in formula D2; and

[0158] (2) The compound shown in formula D2 was reacted to obtain the compound shown in formula B3.

[0159] In some embodiments, in step S820, the method for preparing the compound of formula X or its stereoisomer is as described in the seventh aspect.

[0160] In some embodiments, in step S820, the molar ratio of the compound shown in formula A to the compound shown in formula X is 1:0.8-1:1.2.

[0161] In some embodiments, step S820 includes the following steps: mixing the compound of formula A or its stereoisomer, the compound of formula X or its stereoisomer, sodium cyanoborohydride and a solvent, reacting them, and then separating and purifying them to obtain the compound of formula I or its stereoisomer.

[0162] In some embodiments, the compound represented by formula A is the compound represented by formula A1, and the compound represented by formula X is the compound represented by formula X1-1. In step S820, the compound represented by formula A1 and the compound represented by formula X1-1 are reacted to obtain the compound represented by formula I-1.

[0163]

[0164] In some embodiments, the compound of formula X1-1 is selected from the free base of formula X1-1 or its L-tartrate, L-dibenzoyltartrate, L-malate, L-mandelate, L-camphorsulfonate or S-binaphthol phosphate salt, preferably L-tartrate.

[0165] This invention optimizes the reaction route to obtain novel MOR agonist compounds of formula I with high ee values ​​in high yield. Furthermore, the reaction conditions of each step of the above method are relatively mild, the post-processing is simple and convenient, and it is easy to scale up production, thus having high industrial application value.

[0166] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0167] Figure 1This is a single-crystal structure diagram of the L-tartrate salt of compound X1-1. Detailed Implementation

[0168] Terminology Definition

[0169] As used in this article, "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, C 1-8 The alkyl group is an alkyl group containing 1 to 8 carbon atoms, preferably C14. 1-4 Alkyl, more preferably C 1-3 Alkyl groups, as defined similarly; non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl More preferably, 2-methylhexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, and their various branched isomers.

[0170] As used herein, "alkenyl" refers to a straight-chain or branched carbon chain containing at least one carbon-carbon double bond, C 1-4 The alkenyl group is an alkenyl group containing 1 to 4 carbon atoms; non-limiting examples of alkenyl groups include: vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl.

[0171] As used herein, "alkynyl" refers to a straight-chain or branched carbon chain containing at least one carbon-carbon triple bond, C 1-4 The alkynyl group is an alkynyl group containing 1 to 4 carbon atoms; examples of alkynyl groups include ethynyl and propynyl.

[0172] As used in this article, "C" 6-10 "Aryl" and "C" 6-10The term "aromatic ring" is used interchangeably and refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, and specifically to an aryl group containing 6 to 10 carbon atoms; phenyl and naphthyl are preferred, with phenyl being more preferred.

[0173] As used herein, "5- to 6-membered monocyclic heteroaryl ring" and "5- to 6-membered monocyclic heteroaryl" are used interchangeably, both referring to monocyclic heteroaryl rings containing 5 to 6 ring atoms, including (but not limited to): thiophene ring, N-alkyl ring, pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetraazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, etc.; preferably, pyridine ring.

[0174] As used in this article, "halogenated C" 1-8 "Alkyl" refers to an alkyl group that has been substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, as defined above. The halogenated C is chosen. 1-4 Alkyl group. Halogenated C 1-8 Examples of alkyl groups include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.

[0175] As used in this article, "C" 1-8 "Alkoxy" refers to -O-(C 1-8 Alkyl group), wherein the definition of alkyl group is as described above. Preferably C 1-4 Alkoxy, more preferably C 1-3 Alkoxy groups. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, etc.

[0176] As used herein, "cycloalkyl" and "cycloalkyl ring" are used interchangeably, both referring to saturated or partially unsaturated monocyclic cyclic hydrocarbon groups. 3-6 "Cycloalkyl" refers to a cyclic hydrocarbon group containing 3 to 6 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc., with cyclopropyl, cyclopentyl, and cyclohexenyl being preferred.

[0177] As used in this article, "C" 3-6 "Cycloalkoxy" refers to -O-(C 3-6 (Cycloalkyl), wherein the definition of cycloalkyl is as described above. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.

[0178] As used in this article, "3- to 6-membered saturated monocyclic ring" refers to a saturated all-carbon monocyclic ring containing 3 to 6 ring atoms. Examples of 3- to 6-membered saturated monocyclic rings include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, etc.

[0179] As used in this article, "4- to 6-membered saturated monoheterocycles" refers to monocycles in which one, two, or three carbon atoms are selected from nitrogen, oxygen, or S(O). t The heteroatom is replaced by (where t is an integer from 0 to 2), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon; preferably 5 to 6 members. Examples of 4 to 6-membered saturated monoheterocycles include (but are not limited to) azacyclic butane, oxacyclic butane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxopentane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, etc.

[0180] As used in this article, "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0181] The term "stereoisomer" as used in this invention refers to compounds of this invention that may contain one or more chiral centers and exist in different optically active forms. When a compound of this invention contains one chiral center, each of these chiral centers independently produces two optical isomers. When a compound of this invention contains more than one chiral center, diastereomers may exist. The scope of this invention includes all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds.

[0182] In this invention, the compound represented by formula E can be made from commercially available raw materials (e.g., CAS NO. 1401031-37-5; CAS NO.). 1401031-38-6 ).

[0183] In this invention, there is no particular limitation on the timing of the introduction of the chiral center. It can be chiralized after the corresponding compound is obtained, or it can be prepared directly using chiral raw materials. It should be understood that both are within the protection scope of this invention.

[0184] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise defined. Unless otherwise defined, the terms used herein have the same meaning as those familiar with the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the present invention.

[0185] As used in this article, THF is tetrahydrofuran, EA is ethyl acetate, PE is petroleum ether, DMF is dimethylformamide, DMSO is dimethyl sulfoxide, rt is room temperature, DCM is dichloromethane, DBU is 1,8-diazabicycloundec-7-ene, TEMPO is 2,2,6,6-tetramethylpiperidine oxide, Oxone is potassium peroxymonosulfonate, IBX is 2-iodobenzoic acid, MeOH is methanol, EtOH is ethanol, IPA isopropanol, and ACN is acetonitrile.

[0186] As used in this article, room temperature refers to approximately 20-25°C.

[0187] Example 1: Preparation of intermediate X1-1a

[0188]

[0189] Step 1: Add triethylphosphonoacetate (476 mL, 2.4 mol), DBU (365 g, 2.4 mol), lithium chloride (127 g, 3 mol), and acetonitrile (1.2 L) to a 3 L single-necked flask, and stir at room temperature for 20 minutes under argon protection. Cool to 0 °C (internal temperature), and slowly add isobutyraldehyde (144 g, 2 mol). Stir at room temperature for 12 hours. Filter, and wash the filter cake with EA (100 mL x 2). Add water (1 L), extract with EA (1.5 L x 2), wash with saturated sodium chloride, dry to anhydrous sodium sulfate, and evaporate to dryness to obtain compound v1 (175 g).

[0190] Step 2: Add 1L of DMF to a 3L single-necked flask containing compound v1 (300g, 2.1mol). While stirring, add potassium carbonate (579g, 4.2mol) and pyrazole (287g, 4.2mol). Stir at 65℃ for 18 hours, then evaporate to dryness. Pulverize the remaining solid with acetonitrile (150ml) and filter to obtain a white solid. Filter, and wash the filter cake with EA (500mL x 2). Wash with saturated brine (300mL x 3), dry to anhydrous sodium sulfate, evaporate to dryness, and purify by column chromatography (using PE containing 5% EA as the mobile phase) to obtain compound v2 (258g). MS m / z (ESI): 211.1 [M+1] + .

[0191] Step 3: Dissolve 200 mL of water in potassium hydroxide (133 g, 3.32 mol) and pre-cool to 5 °C. Add compound v2 (465 g, 2.21 mol), methanol (0.5 L), and THF (0.5 L) to a 3 L flask, then add the pre-cooled potassium hydroxide aqueous solution and stir for 2 hours. Adjust the pH to approximately 3 with concentrated hydrochloric acid, extract with DCM (800 mL x 2), combine all organic phases, wash with saturated brine, dry, and concentrate to obtain compound v3 (410.5 g). MS m / z (ESI): 183.1 [M+1] + .

[0192] Step 4: Under nitrogen protection, compound v3 (10.2 g, 0.055 mol) and THF (200 mL) were added to a three-necked flask (500 mL), and the temperature was lowered to -75 °C. A 2.5 M solution of n-butyllithium in THF (55 mL, 0.137 mol) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to -10 °C, and stirring was continued for 3 hours. The mixture was quenched with saturated ammonium chloride, and water (100 mL) was added. Extraction was performed with EA (400 mL x 2). The organic phases were combined, washed with saturated brine, dried, and concentrated to obtain a brown liquid. Purification by column chromatography (PE containing 30% EA as the mobile phase) yielded compound X1-1a (4 g), MS m / z (ESI): 165.1 [M+1]. + .

[0193] Example 2: Preparation of Amine X1-1

[0194]

[0195] Step 1: Compound X1-1a (16.0 g, 97.4 mmol, 1.0 equiv) was added to a 250 mL three-necked flask, along with anhydrous methanol (128 mL, 8.0 v / w), hydroxylamine hydrochloride (6.85 g, 98.6 mmol, 1.2 equiv), and pyridine (7.80 g, 98.6 mmol, 1.2 equiv). The mixture was heated to 65 °C and reacted for 1 hour. The reaction solution was evaporated to dryness, 160 mL of water was added and stirred, and the mixture was extracted with dichloromethane (80 mL * 2). The organic phases were combined. The organic phase was washed once with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound X1-1b (16.5 g). 1 HNMR: cis-trans isomer ratio 1:0.4).

[0196] Step 2: Dissolve compound X1-1b (4.0 g, 22.3 mmol, 1.0 equiv) in 80 mL of anhydrous methanol, add Pd / C (0.4 g); purge three times with hydrogen, maintaining the autoclave temperature at 65 °C. Maintain the pressure inside the autoclave at 15–20 atm, react for 1.5 h, then stop hydrogen absorption, continue the reaction for another 0.5 h, filter, and evaporate to dryness to obtain compound X1-1c. MS m / z (ESI): 166.1 [M+1] + .

[0197] Step 3: Dissolve compound X1-1c (10.1 g, 61.1 mmol, 1.0 equiv) in anhydrous ethanol (20 mL) and stir at room temperature to obtain an ethanol solution of compound X1-1c. Dissolve L-tartaric acid (11.0 g, 73.4 mmol, 1.2 equiv) in anhydrous ethanol (175 mL) and then slowly add it dropwise to the ethanol solution of X1-1c, precipitating a large amount of solid. Filter, wash the filter cake with a small amount of ethanol, and dry to obtain 21.0 g of solid. Take 20g of the solid and add it to a 500mL three-necked flask. Add 20mL of water and 20mL of anhydrous methanol, and heat to an internal temperature of 65-70℃ until the system is clear. Slowly add 200mL of anhydrous methanol to the system, controlling the internal temperature to not be lower than 55℃. Lower the internal temperature to 46-47℃ and continue stirring for 1 hour. After about 2 hours, lower the temperature to room temperature and stir overnight. Filter, and wash the filter cake with 20mL of isopropanol. Dry the filter cake to constant weight to obtain 10.3g of white solid. Add 15mL of water to the 10.3g white solid, then add 80mL of anhydrous methanol, and heat to reflux to dissolve. Lower the internal temperature to about 50℃ and stir for 1 hour. After about 2 hours, lower the temperature to room temperature and stir overnight. Filter, and wash the filter cake with 10mL of isopropanol. Dry the filter cake to constant weight to obtain L-tartrate of compound X1-1 (5.02g).

[0198] Preparation of L-tartrate single crystals of compound X1-1: 300 mg of L-tartrate of compound X1-1 was dissolved in 1 mL of water, and the insoluble matter was removed by filtration. 1 mL of anhydrous methanol was added, and the mixture was left to stand overnight. A small amount of colorless, transparent crystals precipitated from the solution. Single-crystal X-ray analysis of the colorless, transparent crystals obtained in this example was performed using a Bruker D8 Venture X single-crystal diffractometer. The crystal structure diagram of the obtained product is shown below. Figure 1 As shown. Therefore, the absolute configuration of compound X1-1 can be deduced from the single crystal structure of its L-tartrate salt as (4S, 6S) configuration.

[0199] Instrument parameters:

[0200]

[0201] Step 4: Dissolve the L-tartrate of X1-1 (39g) in water (200mL), adjust the pH to about 11 with saturated sodium carbonate aqueous solution, extract six times with 40mL of dichloromethane, dry the organic phase with anhydrous sodium sulfate, remove the solvent under reduced pressure, and obtain compound X1-1 (18.0g).

[0202] Example 3-1: Preparation of racemic alcohol

[0203]

[0204] Step 1: Add E2 (20g, CAS NO. 1401031-37-5) and 80mL of water to a 250mL three-necked flask. Cool to 10-15℃, stir, and add sulfuric acid solution dropwise (prepared by adding 11.5g of concentrated sulfuric acid to 20mL of water). After the addition is complete, raise the temperature to 45-50℃ and maintain this temperature with stirring for 1 hour. Cool to 5-10℃, add 100mL of toluene, and add 30g of 20% sodium hydroxide solution dropwise. After the addition is complete, stir at room temperature for 1 hour. Allow to stand and separate the layers, separating the organic phase. Extract the aqueous phase twice with 2 x 100mL toluene. Combine the organic phases, wash once with 100mL of saturated saline solution, dry with anhydrous sodium sulfate, filter, and add toluene solution to the next step.

[0205] Step 2: Take the above toluene solution (containing approximately 5.1 g D1), under nitrogen protection, cool to 0-10℃, and add 16.9 g of 70% red aluminum toluene solution dropwise while maintaining the temperature. After the addition is complete, raise the temperature to 40-45℃ and stir for 1 hour. Cool to 0-10℃, add 25 mL of water to quench the reaction, then add 10 mL of 20% sodium hydroxide solution, raise to room temperature and stir for 1 hour. Filter, wash the filter cake with 100 mL of methyl tert-butyl ether, allow the mother liquor to stand and separate into layers, separate the organic phase, and extract the aqueous phase again with 50 mL of methyl tert-butyl ether. Combine the organic phases, wash once with 25 mL of saturated brine, dry with anhydrous sodium sulfate, filter, wash the filter cake with a small amount of methyl tert-butyl ether, and concentrate the filtrate under reduced pressure to obtain B2 (4.66 g of yellow oily product, yield 91.4%, purity 92.6%). 1 HNMR(400MHz, CDCl3): δ8.55-8.53(m,1H),7.64(td, 3 J = 7.6 Hz 4 J = 2.0 Hz, 1H), 7.32 (d, 3 J = 8.0 Hz, 1H), 7.12 (ddd, 3 J = 7.6 Hz 3 J = 4.8 Hz 4J=1.2Hz,1H),3.74-3.71(m,2H),3.53-3.47(m,1H),3.27-3.21(m,1H),2.43-2.40(m,2H),2.27(br,1H),2.01-1.91(m,2 H),1.82-1.72(m,3H),1.67-1.58(m,1H),1.55-1.44(m,3H),1.43-1.33(m,1H),1.12-1.06(m,1H),0.74-0.66(m,1H).MS m / z(ESI):262.1[M+1] + .

[0206] Example 3-2: Preparation of racemic alcohol

[0207]

[0208] Step 1: Dissolve compound D1 (2.0 g, 7.26 mmol, 1.0 equiv) in methanol (10.0 mL, 5.0 v / w) and add it to a 50 mL three-necked flask; under N2 protection, cool to 5–10 °C; add SOCl2 (1.08 g, 9.08 mmol, 1.25 equiv) dropwise to the three-necked flask, completing the addition over approximately 10 min, while maintaining the internal temperature at 10–15 °C; raise the temperature to 50–55 °C and react for 3 h; evaporate the reaction solution to dryness, add 15 mL of methyl tert-ethyl ether; add 25% sodium carbonate aqueous solution to the system until the pH of the aqueous phase reaches approximately 9, while maintaining the internal temperature at 10–15 °C; separate the liquid and extract the aqueous phase twice with 10 mL of methyl tert-ethyl ether; combine the organic phases and evaporate to dryness to obtain C2-1 (2.0 g, purity 98.0%, yield 94.7%). 1 HNMR(400MHz, CDCl3): δ8.57-8.56(m,1H),7.63(td, 3 J = 7.6 Hz 4 J = 1.6 Hz, 1H), 7.32 (d, 3 J = 8.0 Hz, 1H), 7.11(ddd, 3 J = 7.6 Hz 3 J = 4.8 Hz 4 J=0.8Hz,1H),3.79-3.77(m,2H),3.42(s,3H),2.83(d, 2J=14.0Hz,1H),2.57-2.43(m,3H),2.00-1.88(m,2H),1.82-1.78(m,1H),1.71-1.61( m,1H),1.57-1.47(m,3H),1.44-1.35(m,1H),1.22-1.16(m,1H),0.82-0.74(m,1H).MS m / z(ESI):290.1[M+1] + .

[0209] Step 2: Add C2-1 (1.86 g) and 15 mL of toluene to a 100 mL three-necked flask. Purge with nitrogen three times, cool to an internal temperature of 0-10 °C, and add red aluminum solution (6.5 g) dropwise, keeping the internal temperature below 10 °C. The addition should be completed over approximately 30 minutes. Raise the temperature to 40-45 °C and stir for 1 hour. Cool the reaction solution to 0-10 °C, add water (9.3 mL) dropwise to extinguish the reaction, and then add 20% NaOH solution (3.7 mL) dropwise. After the addition is complete, raise the temperature to room temperature (20-25 °C) and stir for 1 hour. Filter the solution, and wash the filter cake with methyl tert-butyl ether (37 mL). The aqueous phase was extracted with methyl tert-butyl ether (19 mL), separated, and the organic phases were combined and washed with saturated NaCl (9.3 mL). The mixture was stirred for 15 minutes, separated, and the organic phase was dried over 3.7 g of anhydrous Na2SO4. The mixture was concentrated under reduced pressure until no solvent was distilled off to give B2 (1.66 g, purity: 98.49%, yield: 98.8%).

[0210] Example 3-3: Resolution of alcohols

[0211]

[0212] Compound B2 (2.50 g, 9.56 mmol, 1.0 equiv) and R-binaphthol phosphate (3.33 g, 9.56 mmol, 1.0 equiv) were added to 25 mL of tetrahydrofuran and stirred at room temperature for 1 h. The solvent was removed by vacuum distillation, and 20 mL of ethyl acetate was added and the mixture was stirred. The mixture was filtered and dried to obtain a solid (5.0 g). The solid was then refluxed in 50 mL of tetrahydrofuran and stirred for 1.5 h. After cooling to room temperature, the mixture was stirred for another 1.5 h. After filtration and drying, a pale yellow solid (1.83 g, ee%: 84.58%) was obtained. 18 mL of tetrahydrofuran was added to the obtained solid and the mixture was refluxed for another 1 h. After cooling to room temperature, the mixture was stirred for another 1 h. After filtration, the filter cake was dried to obtain a pale yellow solid (1.03 g, ee%: 91.64%). Add 1.03 g of filter cake to 10 mL of tetrahydrofuran and reflux for 1 h. Cool to room temperature and pulverize for 1 h. Filter and dry the filter cake to obtain a pale yellow solid (0.53 g, ee%: 97.34%). Dissolve the filter cake in 10 mL of water, adjust the pH to 9-10 using saturated sodium carbonate solution, extract with dichloromethane (10 mL * 3), dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain a colorless oily substance (0.23 g, yield 9.1%). 1 HNMR(400MHz, CDCl3): δ8.55-8.54(m,1H),7.65(td, 3 J = 7.6 Hz 4 J = 2.0 Hz, 1H), 7.32 (d, 3 J = 8.0 Hz, 1H), 7.12 (ddd, 3 J = 7.6 Hz 3 J = 4.8 Hz 4 J=1.2Hz,1H),3.75-3.72(m,2H),3.54-3.48(m,1H),3.28-3.22(m,1H),2.44-2.40(m,2H),2.03-1.91(m,2H),1.8 2-1.72(m,3H),1.67-1.59(m,1H),1.55-1.44(m,3H),1.42-1.34(m,1H),1.12-1.06(m,1H),0.74-0.66(m,1H).MS m / z(ESI):262.2[M+1] + The obtained colorless oily substance and compound B3 synthesized in Example 4 were analyzed and compared by HPLC, and their retention times were consistent. Combined with mass spectrometry data, it can be determined that the colorless oily substance obtained in this example is compound B3.

[0213] Example 4: Preparation of chiral alcohols

[0214]

[0215] Step 1: Under nitrogen protection, compound E3 (CAS NO.1401031-38-6) (1.03g), hydrochloric acid methanol solution (4mol / L, 7mL) and anhydrous methanol (10mL) were added to a 50mL single-necked flask and stirred at room temperature for 7h. Then, hydrochloric acid methanol solution (4mol / L, 3mL) was added and stirred at room temperature for another 2h. Add 10 mL of water to the above reaction mixture, stir at room temperature for 1.0 h, concentrate the reaction mixture under reduced pressure to dryness, add 20 mL of methyl tert-butyl ether and 10 mL of water, then add saturated sodium carbonate solution to adjust the pH to 8, and control the temperature at 10-30℃; separate the liquid and extract the aqueous phase twice with 2*20 mL of methyl tert-butyl ether; separate the liquid and extract the organic phase, combine the organic phases, wash with 20 mL of saturated sodium chloride solution, and dry the organic phase with 5 g of anhydrous sodium sulfate; filter, wash the filter cake with 10 mL of methyl tert-butyl ether, concentrate the filtrate to dryness, and obtain C3-1 (1.08 g, yield: 93.1%, purity: 99.6%). 1 HNMR(400MHz, CDCl3): δ8.57-8.56(m,1H),7.63(td, 3 J = 7.6 Hz 4 J = 1.6 Hz, 1H), 7.32 (d, 3 J=8.0Hz,1H),7.13-7.10(m,1H),3.79-3.77(m,2H),3.42(s,3H),2.83(d, 2 J=14.4Hz,1H),2.57-2.43(m,3H),2.00-1.86(m,2H),1.82-1.75(m,1H),1.69-1.61( m,1H),1.57-1.47(m,3H),1.46-1.34(m,1H),1.22-1.16(m,1H),0.82-0.74(m,1H).MS m / z(ESI):290.1[M+1] + .

[0216] Step 2: Add C3-1 (0.58 g) and toluene (12 mL) to a three-necked flask and cool to 0-5 °C; slowly add 3.0 eq of red aluminum toluene solution, maintaining the temperature at 0-5 °C; after the addition is complete, keep warm and stir for 0.5 h; raise the temperature to room temperature (27 °C) and keep warm and stir for 1 h; post-processing yields B3 (0.33 g, yield: 63.2%, purity: 99.33%). MS m / z (ESI): 262.2 [M+1] + .

[0217] Example 5: Preparation of chiral alcohols

[0218]

[0219] Step 1: Compound E3 (0.78 g, 3.0 mmol, 1.0 equiv) and TsOH·H2O (628 mg, 3.3 mmol, 1.1 equiv) were added to a flask, along with anhydrous ethanol (7.8 mL, 10.0 v / w) and water (54 mg, 3.0 mmol, 1.0 equiv). The mixture was refluxed for 8 h. The reaction solution was evaporated to dryness under reduced pressure, and 10 mL of water was added. The aqueous phase was then adjusted to pH ~9 with saturated sodium carbonate. The aqueous phase was extracted with methyl tert-butyl ether (10 mL × 2). The organic phases were combined after rotary evaporation to give C3-2 (0.84 g, yield 91.3%, purity 91.2%). 1H NMR (400MHz, CDCl3): δ8.58-8.57(m,1H),7.63(td,3J=7.6Hz,4J=2.0Hz,1H),7.32(d,3J=8.0Hz,1 H),7.14-7.10(m,1H),3.87(q,3J=7.2Hz,2H),3.81-3.78(m,2H),2.83(d,2J=14.0Hz,1H),2.57-2 .50(m,2H),2.46(d,2J=14.0Hz,1H),2.01-1.90(m,2H),1.84-1.79(m,1H),1.72-1.60(m,1H),1.5 9-1.48(m,3H),1.46-1.34(m,1H),1.22-1.18(m,1H),1.01(t,3J=7.2Hz,3H)0.83-0.75(m,1H).MS m / z(ESI):304.2[M+1] + .

[0220] Step 2: Compound B3 was prepared by referring to the method in Step 2 of Example 4.

[0221] Example 5-1: Preparation of chiral alcohols

[0222]

[0223] Step 1: Add compound E3 (100g) and water (400mL) to a reaction flask and cool to 5-15℃. Dissolve 57.4g of concentrated sulfuric acid in 100mL of water and add it dropwise to the reaction flask. After the addition is complete, raise the temperature to 45-50℃ and maintain the temperature with stirring for 1.5h. Cool the system to an internal temperature of 0-10℃, add 500mL of toluene, and add 20% NaOH solution (150g) dropwise. Let stand, separate the layers, and extract the aqueous phase twice with toluene (500mL*2), stirring for 0.5h each time. Let stand, separate the layers, and combine the three organic phases. Wash the combined organic phase with saturated NaCl (500mL), dry the organic phase with anhydrous Na2SO4, and evaporate to dryness to obtain compound D2 (108g).

[0224] Step 2: Add a toluene solution (total 836 g) containing compound D2 (107.4 g) to the reaction flask, cool the internal temperature to 0-10℃, and purge with nitrogen three times; slowly add red aluminum solution (394.3 g), controlling the internal temperature at 0-10℃. After the addition is complete, raise the internal temperature to 43℃ and stir for 1 hour. Cool the reaction solution to 0-10℃, add 500 mL of water to quench the reaction, and then add 1500 mL of 20% NaOH solution. Extract the reaction solution with 1000 mL × 2 of methyl tert-butyl ether with stirring, and combine the two organic phases. Dry the mixture with anhydrous Na2SO4, filter, and concentrate the filtrate under reduced pressure to obtain compound B3 (91.5 g, yield 89.8%).

[0225] Example 6: Preparation of Aldehydes

[0226]

[0227] Compound B3 (1.19 g, 4.55 mmol, 1.0 equiv) was added to a 25 mL single-necked flask, followed by DMSO (6.0 mL, 5.0 v / w), and dissolved until clear. IBX (3.10 g, 11.4 mmol, 2.5 equiv) was added, and the mixture was stirred at room temperature for 90 min. TLC confirmed the presence of a small amount of reactant remaining. IBX (0.65 g, 2.27 mmol, 0.5 equiv) was added, along with DMSO (3.6 mL, 3.0 v / w), and the mixture was stirred for 1 h. TLC showed almost no reactant remaining. The reaction solution was poured into 40 mL of water, and a large amount of solid precipitated. The precipitate was filtered, and the filter cake was washed with 5 mL of water twice. The aqueous phase was adjusted to pH using a 10% Na₂CO₃ aqueous solution. 8–9. The aqueous phase was extracted with DCM (15 mL × 3); the DCM phase was washed with saturated brine (6 mL × 2); after rotary evaporation of the DCM phase, a small amount of solid particles were present in the oily substance; 5 mL of ethyl acetate was added to the oily substance, and the supernatant was rotary evaporated to obtain compound A1 (0.76 g, yield 64.4%, purity >98.0%), MS m / z (ESI): 260.2 [M+1). + .

[0228] Example 7:

[0229]

[0230] Compound A1 (50 mg, 0.3 mmol) was dissolved in 5 mL of methanol. Compound X1-1 (78.3 mg, 0.3 mmol) and sodium cyanoborohydride (94 mg, 1.5 mmol) were added, and the mixture was stirred at 20 °C for 3 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted with DCM (30 mL × 2). The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative chromatography (21.2 × 250 mm C18 column, system: 10 mM NH4HCO3 H2O, wavelength: 254 / 214 nm, gradient: 30%–60% acetonitrile) to give a single-configuration compound I-1 (10.12 mg). MS m / z (ESI): 409.2 [M+1] + ; 1 H NMR (400MHz, CD3OD) δ8.51(ddd,J=4.9,1.8,0.8Hz,1H),7.79–7.71(m,1H),7.50(d,J=8.1Hz,1H),7.41(d,J=1. 9Hz,1H),7.22(ddd,J=7.5,4.9,1.0Hz,1H),5.87(dd,J=1.9,0.6Hz,1H),4.07(ddd,J=21.0,11.7,6.2Hz,2H),3 .81–3.69(m,2H),2.73–2.58(m,2H),2.52(dd,J=14.0,2.3Hz,1H),2.48–2.35(m,2H),2.12–1.97(m,2H),1.95– 1.82(m,2H),1.78–1.65(m,3H),1.64–1.36(m,5H),1.14–1.04(m,1H),0.99(d,J=7.0Hz,3H),0.79–0.65(m,4H).

[0231] Example 8:

[0232]

[0233] Add compound A1 (950 g), L-tartrate of compound X1-1 (1.16 kg), anhydrous ethanol (7.51 kg), and triethylamine (0.74 kg) to the reaction vessel. Cool the system to 10–15 °C, and add sodium triacetoxyborohydride (1.32 kg) in portions, continuing to stir the reaction for 2 hours. Add purified water (38.0 kg) to the reaction vessel and stir for 0.5 hours. Then, slowly add an appropriate amount of hydrochloric acid aqueous solution to the reaction vessel to adjust the pH to approximately 4.5. Add 7.04 kg of methyl tert-ethyl ether to the reaction vessel, stir for 15 minutes, allow to stand and separate the layers, and collect the aqueous phase. Add an appropriate amount of sodium carbonate aqueous solution to the aqueous phase to adjust the pH to 6.5. Add 7.04 kg × 2 kg of methyl tert-ethyl ether to the aqueous phase for extraction and separation, collecting the organic phase. Combine the organic phases, wash with 5.70 kg of purified water, and separate the layers. The filtrate was concentrated under reduced pressure to constant weight to give compound I-1 (823 g, yield 55%).

[0234] Test Example 1: HTRF-cAMP Cell Experiment

[0235] Experimental methods and procedures

[0236] I. Cell resuscitation

[0237] 1. Remove the resuscitation fluid from the 4°C refrigerator and preheat it in a 37°C water bath for 15 minutes.

[0238] 2. Remove the P6 generation cells from the liquid nitrogen tank, and quickly place the frozen cell cryovials into a 37°C water bath and gently shake for 30 seconds to 1 minute, until small ice crystals are visible or the cells are about to completely thaw.

[0239] 3. Thoroughly disinfect and dry with 70% alcohol.

[0240] 4. Centrifuge to remove the cryopreservation solution, and resuspend the cells in preheated fresh resuscitation solution.

[0241] a. Transfer 3 ml of preheated cell resuscitation solution into a 15 ml centrifuge tube.

[0242] b. Centrifuge at 1300 rpm for 3 minutes.

[0243] c. Remove the supernatant cryopreservation solution and resuspend the cells in 4 ml of preheated resuscitation solution.

[0244] 5. Transfer the cell suspension to a T25 cell culture flask and incubate for 24 hours at 37°C and 5% CO2.

[0245] 6. After culturing for 24 hours, replace the resuscitation solution in the cell culture flask with preheated cell culture medium.

[0246] II. Cell Passaging

[0247] 1. When the cell growth density in the T25 culture flask is >70%, digest and passage the cells using cell digestion solution.

[0248] a. Remove the culture medium from the culture flask, add 4 ml of preheated PBS, gently shake to rinse the cells, and then discard the PBS.

[0249] b. Add 1 ml of cell digestion solution to a T25 culture flask.

[0250] c. Shake the culture flask repeatedly to ensure the digestion solution completely covers the flask, and place it in a 37°C, 5% CO2 incubator for 5 minutes.

[0251] d. Remove the cell culture flask and observe the cells under a microscope to see if the cells have been separated.

[0252] e. Add 3ml of preheated cell culture medium to stop digestion.

[0253] f. Rinse the culture flask gently and repeatedly with cell culture medium, and collect the cell suspension into a 15ml centrifuge tube.

[0254] g. Centrifuge at 1300 rpm for 3 minutes and remove the supernatant.

[0255] h. Resuspend in 3 ml of cell culture medium.

[0256] 2. Passage cells at a ratio of 1:3 (add 1 ml of cell resuspension solution + 3 ml of cell culture medium to each flask and pass them to flask T25).

[0257] III. Cell Seeding Plate

[0258] 1. Repeat step 2.2.1(ah) until the cells are passaged to P8. Count the cells and then resuspend them in 2× / 1mM IBMX stimulation buffer to achieve a cell density of 1.2*10^6 / ml.

[0259] 2. Using a multichannel pipette, seed a cell solution of 1.2*10^6 / ml into a 384-well plate at a volume of 10μl per well (i.e., 12,000 cells per well).

[0260] IV. c-AMP Experiment

[0261] 1. Prepare the relevant reagents and prepare the compounds according to the drug dilution preparation table.

[0262] a. 1×Stimulation buffer solution: Add 1 ml of 5×Stimulation buffer solution to 4 ml of distilled water and mix well.

[0263] b. 5 ml of 2× / 1 mM IBMX stimulation buffer: Add 10 μl of 500 mM IBMX storage solution to 4990 μl of cell culture medium and gently pipette to mix.

[0264] c. Morphine gradient dilution preparation table:

[0265]

[0266]

[0267] d. Before diluting the compound, dissolve it in DMSO to achieve a storage concentration of 10 mM.

[0268] Dilution preparation table for compound I-1:

[0269]

[0270] e. 50 μM NK477 1 ml: Add 1 μl of 50 mM NKH477 storage solution to 999 μl of 1× Stimulation buffer solution and vortex to mix.

[0271] f. Test reagents

[0272] A. cAMP-Cryptate (donor, lyophilized) reaction solution: Add 1 ml of 5×cAMP-Cryptate storage solution to 4 ml of 1×Lysis & Detection Buffer solution and mix gently.

[0273] B. Anti-cAMP-d2 (acceptor, lyophilized) reaction solution: Add 1 ml of 5× Anti-cAMP-d2 storage solution to 4 ml of 1× Lysis & Detection Buffer solution and mix gently.

[0274] 2. cAMP experimental procedure

[0275] a. Seed cells at a density of 12,000 cells per well in 10 μl of 2x IBMX stimulation buffer.

[0276] b. Add 8 μl of compound sample diluent to each well of cells.

[0277] c. Add 2 μl of the prepared 10xNKH477 solution to each well.

[0278] d. Incubate at 37℃ for 45 mins.

[0279] e. Add 10 μl of cAMP-d2 and 10 μl of anti-cAMP Cryptate reaction solution.

[0280] f. Incubate at room temperature in the dark for 60 minutes.

[0281] g. HTRF reading board.

[0282] 3. RFU detection reader

[0283] After 60 minutes of incubation, all samples will be read using homogeneous time-resolved fluorescence.

[0284] Data Analysis

[0285] Data, including signal values ​​at 665nm and 620nm, was exported from the computer connected to the multi-functional plate reader. The ratio was calculated using the formula: Ratio = 665nm signal value / 620nm signal value × 10000. The data was analyzed using GraphPadPrism software. The best-fit curve was determined using log(agonist) vs. response. The EC50 value of the compound was determined using computer-aided dose-response nonlinear regression analysis; PEC50 = -logEC50 (EC50 is in moles); the maximum effect value of % morphine = (compound sample ratio - blank well ratio) / TOP × 100 (Note: the TOP value is the top value of the fitted curve obtained by analyzing the morphine sample ratio - blank well ratio using GraphPadPrism software). The results are shown in Table 1.

[0286] Table 1. Activities of compounds with cAMP

[0287]

[0288] Test Example 2: β-Arrestin Cell Experiment

[0289] Experimental methods and procedures

[0290] I. Cell resuscitation

[0291] 1. Remove the resuscitation fluid from the 4°C refrigerator and preheat it in a 37°C water bath for 15 minutes.

[0292] 2. Remove the P6 generation cells from the liquid nitrogen tank, and quickly place the frozen cell culture tubes in a 37°C water bath and gently shake for 30 seconds to 1 minute, until you see small ice crystals or the cells are about to completely melt.

[0293] 3. Thoroughly disinfect and dry with 70% alcohol.

[0294] 4. Centrifuge to remove the cryopreservation solution, and resuspend the cells in preheated fresh resuscitation solution.

[0295] a. Transfer 3 ml of preheated cell resuscitation solution into a 15 ml centrifuge tube.

[0296] b. Centrifuge at 1300 rpm for 3 minutes.

[0297] c. Remove the supernatant and resuspend the cells in 4 ml of preheated resuscitation solution.

[0298] 5. Transfer the cell suspension to a T25 cell culture flask and incubate for 24 hours at 37°C and 5% CO2.

[0299] 6. After culturing for 24 hours, replace the resuscitation solution in the cell culture flask with preheated cell culture medium.

[0300] II. Cell Passaging

[0301] 1. When the cell growth density in the T25 culture flask is >70%, digest and passage the cells using cell digestion solution.

[0302] a. Aspirate the culture medium from the culture flask, add 4 ml of preheated PBS, gently shake to rinse the cells, and then discard the PBS.

[0303] b. Add 1 ml of cell digestion solution to a T25 culture flask.

[0304] c. Shake the culture flask repeatedly to ensure the digestion solution completely covers the flask, and place it in a 37°C, 5% CO2 incubator for 5 minutes.

[0305] d. Remove the cell culture flask and observe the cells under a microscope to see if the cells have been separated.

[0306] e. Add 3 ml of preheated cell culture medium to stop digestion.

[0307] f. Rinse the culture flask gently and repeatedly with cell culture medium, and finally transfer the cell suspension to a 15ml centrifuge tube.

[0308] Centrifuge at 1300 rpm for 3 minutes and remove the supernatant.

[0309] h. Resuspend in 3 ml of cell culture medium.

[0310] 2. Passage cells at a ratio of 1:3 (add 1 ml of cell resuspension solution + 3 ml of cell culture medium to each flask and pass them to flask T25).

[0311] 3. Repeat step 2.2.1(ah) until the cells are passaged to generation P8.

[0312] III. Cell Seeding Plate

[0313] 1. Use a pipette to take 20 μl of cell suspension and measure the cell count using a cell counter.

[0314] 2. Centrifuge at 1300 rpm for 3 minutes to precipitate the cells.

[0315] 3. Remove the supernatant and add the appropriate cell plating medium to make the cell concentration 2×10^5 / ml.

[0316] 4. Using a multichannel pipette, according to the experimental design, seed a cell solution of 2×10^5 / ml into a 384-well plate at a volume of 20μl per well (i.e., 4000 cells per well).

[0317] 5. Place the 384-well plate inoculated with cells in a 37°C, 5% CO2 incubator for 24 hours.

[0318] IV. β-arrestin test

[0319] 1. Prepare the compounds according to the following dilution table.

[0320] a. Morphine gradient dilution configuration table:

[0321]

[0322] b. Before diluting the compound, dissolve it in DMSO to achieve a storage concentration of 10 mM.

[0323] Dilution preparation table for compound I-1:

[0324]

[0325]

[0326] 2. Take 5 μl of the prepared diluent for each compound sample and add it to a 384-well plate.

[0327] 3. After adding the samples, place the 384-well plate back into the 37℃, 5% CO2 incubator and incubate for 90 minutes.

[0328] V. RLU Detection

[0329] 1. Before the end of compound incubation, prepare the Working Detection solution according to the following ratio (avoid light). Then add 12.5 μl to each well and incubate for 1 hour at room temperature in the dark on a shaker.

[0330]

[0331] 2. After the compound incubation is complete, add 12.5 μl of the above working solution to each well and incubate for 1 hour at room temperature and 80 rpm in the dark.

[0332] 3. After incubation, use a multi-functional plate reader to read the plates.

[0333] Data Analysis

[0334] Data was exported from the computer connected to the multi-functional plate reader and analyzed using GraphPad Prism software. The best-fit curve was determined using log(agonist) vs. response. The EC50 value of the compound was determined using computer-aided dose-response nonlinear regression analysis; PEC50 = -logEC50 (EC50 is in moles); the maximum effect value of % morphine = (RLU value of the compound sample - RLU value of the blank well) / TOP × 100 (Note: TOP value is the TOP value of the fitted curve obtained by analyzing the RLU value of the morphine sample - RLU value of the blank well using GraphPad Prism software). The results are shown in Table 2.

[0335] Table 2 shows the test results of the compounds on β-arrestin.

[0336]

[0337] As can be seen from Tables 1 and 2, compound I-1 has high inhibitory activity against cAMP and a high Emax value, while it has a low Emax value against β-arrestin, indicating good bias.

[0338] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing the compound shown in Formula I or its stereoisomers, comprising the steps (i) and (ii): (i) React the compound of formula B or its stereoisomer to obtain the compound of formula A or its stereoisomer: in, If ring A is a pyridine ring and n is 0, and the compound shown in formula B is the same as the compound shown in formula B3, then the compound shown in formula A is the same as the compound shown in formula A1; the compound shown in formula B3 is oxidized to obtain the compound shown in formula A1. (ii) Reacting the compound or its stereoisomer shown in Formula A with the compound or its stereoisomer shown in Formula X to prepare the compound or its stereoisomer shown in Formula I: in, The compound shown in formula X is the same as the compound shown in formula X1: R a R b Each is independently hydrogen or C 1-3 Alkyl; or R a R b Together with the attached carbon atoms, they form a 3- to 6-membered saturated monocyclic ring; wherein the 3- to 6-membered saturated monocyclic ring is unsubstituted; R c It is hydrogen or C 1-3 alkyl.

2. The preparation method according to claim 1, characterized in that, The compound represented by Formula I has the structure shown in Formula I-1:

3. The preparation method according to claim 2, characterized in that, The compound shown in Formula I-1 was prepared using the following synthetic route:

4. The preparation method according to claim 3, characterized in that, The compound of formula X1-1 is selected from the free base of formula X1-1 or its L-tartrate, L-dibenzoyltartrate, L-malate, L-mandelate, L-camphorsulfonate or S-binaphthol phosphate salt.

5. The preparation method according to claim 4, characterized in that, The compound of formula X1-1 is an L-tartrate.

6. The preparation method according to claim 1, characterized in that, The compound shown in formula B3 was prepared using the following synthetic route:

7. The preparation method according to claim 1, characterized in that, The compound shown in formula B3 was prepared using the following synthetic route: Wherein, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, phenyl or benzyl.

8. The preparation method according to claim 7, characterized in that, R stands for methyl.

9. The preparation method according to claim 1, characterized in that, The compound shown in formula B3 was prepared using the following synthetic route: Wherein, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, or benzyl.

10. The preparation method according to claim 9, characterized in that, R stands for methyl.

11. The preparation method according to claim 1, characterized in that, The compound shown in formula B3 was prepared using the following synthetic route:

12. The preparation method according to claim 1, characterized in that, The preparation method of the compound represented by formula X includes the following steps: The compound of formula Z or its stereoisomers is reacted to prepare the compound of formula Y or its stereoisomers; and The compound shown in Formula Y or its stereoisomers are reacted to prepare the compound shown in Formula X or its stereoisomers.

13. The preparation method according to claim 12, characterized in that, Compound X has the structure shown in Formula X1:

14. The preparation method according to claim 13, characterized in that, The preparation of the compound shown in formula X1 further includes the following steps: The compound shown in Formula X was chirally resolved to obtain the compound shown in Formula X1.

15. The preparation method according to any one of claims 1, 12 to 14, characterized in that, R a R b Each is independently hydrogen or C 1-3 alkyl.

16. The preparation method according to any one of claims 1, 12 to 14, characterized in that, R a R b Each is independently hydrogen or methyl, R c It can be hydrogen or methyl.

17. The preparation method according to any one of claims 1, 12 to 14, characterized in that, R a For methyl, R b For H, R c It is a methyl group.

18. The preparation method according to claim 14, characterized in that, In the chiral resolution step, the resolving agent used is L-tartaric acid, L-dibenzoyltartaric acid, L-malic acid, L-mandelic acid, L-camphorsulfonic acid, or S-binaphthol phosphate.

19. The preparation method according to claim 18, characterized in that, In the chiral resolution step, the resolving agent used is L-tartaric acid.

20. The preparation method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula A to the compound shown in Formula X is 1:0.8 to 1:1.

2.

21. The preparation method according to claim 20, characterized in that, The compound shown in Formula A or its stereoisomer, the compound shown in Formula X or its stereoisomer, sodium cyanoborohydride and solvent are mixed and reacted. After separation and purification, the compound shown in Formula I or its stereoisomer is obtained. Wherein, the compound represented by formula A is the compound represented by formula A1; The compound represented by formula X is the same as the compound represented by formula X1-1: The compound represented by Formula I has the structure shown in Formula I-1:

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