Preparation method of oxaspiro derivative

Abstract

The invention relates to a preparation method of oxaspiro derivatives. In particular, the present invention relates to a method for preparing a compound represented by formula (II) or a salt thereof, comprising a step of chiral resolution of a compound represented by formula (IIA). The method is mild in condition, simple to operate, low in cost, more economical, stable in process, easy to reproduce, large in preparation amount and more suitable for industrial production, and the prepared compound shown in the formula (II) is high in optical purity and high in yield. # imgabs0 #

Description

[0001] This application claims the priority of Chinese Patent Application No. 202410103618.4 with a filing date of January 25, 2024. This application incorporates the entire text of the above-mentioned Chinese patent application by reference. Technical Field

[0002] The present invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of oxaspirocyclic derivatives. Background Art

[0003] Opioid receptors belong to one of the members of the G protein-coupled receptor (GPCR) family. Currently, nine opioid receptors such as μ, δ, κ, and ORL1 have been discovered, which are widely expressed in the central and peripheral nerves, as well as in neuroendocrine cells, immune cells, and endothelial cells. The μ (MOR), δ (DOR), and κ (KOR) opioid receptors regulate a series of behaviors of the body through the central nervous system, including pain sensation, emotion, stress response, and addictive behavior. Among them, the μ, δ, and κ opioid receptors are classical opioid receptors, and the basic structures of these three types of receptors are the same, that is, they simultaneously have an extracellular amino-terminal region and an intracellular carboxyl-terminal region. The agonists of these three subtypes of opioid receptors are mainly coupled to Gi-type G proteins, causing the dissociation of the β and γ subunits of the G protein from the α subunit. The β and γ subunits and the α subunit respectively mediate the activation of multiple intracellular signaling pathways, such as the inhibition of adenylate cyclase activity, the activation of G protein-coupled receptor kinase (GRK), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK).

[0004] Regarding the analgesic mechanism of opioid drugs, it has been clarified: during the conduction of pain sensation to the central nervous system, pain stimuli stimulate the sensory nerve endings and release glutamate (Glu), which acts on the corresponding receptors to complete the transmission of pain impulses to the central nervous system and cause pain. Exogenous opioid substances or endogenous opioid peptides activate opioid receptors on the presynaptic and postsynaptic membranes of sensory nerves. Through the G-protein coupling mechanism, they inhibit the degradation of ATP by adenylate cyclase to generate cAMP, thereby inhibiting the release of neurotransmitters such as substance P and acetylcholine from the presynaptic membrane. At the same time, they promote K + efflux and reduce Ca 2+ influx, and finally weaken the pain signal and produce an analgesic effect.

[0005] After years of research, various agonists and antagonists of opioid receptors have been discovered. Currently, the agonists of opioid receptors that have been discovered are: morphine, DAMGO, endomorphin, fentanyl and its derivatives, etc. Naloxone, CTOP, CTAP, naltrexone, etc. are antagonists of opioid receptors.

[0006] Long-term use of opioids can lead to tolerance and side effects such as respiratory depression and constipation, and these side effects have been proven to be closely related to the function of β-arrestin. In order to reduce the side effects of opioids, drugs can be designed based on the negative β-arrestin-biased ligands of MOR to reduce β-arrestin-mediated side effects and enhance the therapeutic effect. International Patent Application WO2023011422A1 discloses a MOR compound with a single configuration, chemically named (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine, and its structural formula is shown in Formula (I-1). This patent application discloses its preparation method as follows:

[0007]

[0008] This method has problems such as complex procedures, low yield and high cost caused by separation and purification using a chiral chromatographic column, and more impurities will be generated during the reaction process, which is not conducive to industrial scale-up production. It is necessary to improve its preparation method. Summary of the Invention

[0009] In order to overcome the defects existing in the prior art, the present invention provides a new preparation method: obtaining the target configuration enantiomer by chiral acid chemical resolution method. This method has mild conditions, simple operation, low cost, more economical, stable and easy-to-reproduce process, and higher yield and purity of the target configuration enantiomer, and is more suitable for industrial production.

[0010] To achieve the above object, the present invention provides a preparation method of a compound of formula (II) or a salt thereof, and the method includes the step of chiral resolution of a compound of formula (IIA),

[0011]

[0012] wherein, ring A is C 6-10 aryl or C 3-10 cycloalkyl and C 6-10 aryl, R1 is hydrogen or halogen, and each R2, when present, is independently hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, X1 is a chemical bond or CH2, and n is 0, 1, 2 or 3. Among them, the carbon atom with "*" is a chiral carbon atom, indicating that the compound exists in the form of (R) or (S) single enantiomer or in the form rich in a pair of enantiomers.

[0013] In a preferred embodiment of the present invention, ring A in the compound of formula (IIA) and formula (II) is phenyl, R1 is hydrogen or fluorine, each R2 is independently hydrogen, halogen, C 1-3 alkoxy or C 1-3 alkyl, X1 is a bond or CH2, and n is 2.

[0014] In a preferred embodiment of the present invention, the compound of formula (IIA) further has a structure represented by formula (IIA-1), formula (IIA-2) or formula (IIA-3):

[0015]

[0016] Wherein, the carbon atoms with "*" and "#" are chiral carbon atoms, indicating that the compound exists in the form of (R) or (S) single enantiomer or in a form rich in a pair of enantiomers.

[0017] In a further preferred embodiment of the present invention, it includes the step of chiral resolution of the compound of formula (IA).

[0018]

[0019] Wherein, R1 is hydrogen, fluorine, chlorine or bromine, preferably fluorine.

[0020] In a further preferred embodiment of the present invention, it relates to a method for preparing a compound represented by formula (I-1) or a salt thereof, including the step of chiral resolution of the compound represented by formula (IA-1).

[0021]

[0022] In a further preferred embodiment of the present invention, the chiral resolution method is mechanical resolution, simulated moving bed resolution, chemical resolution, chromatographic resolution, membrane resolution, capillary electrophoresis resolution or biological resolution, preferably chemical resolution or chromatographic resolution, more preferably chemical resolution.

[0023] In a further preferred embodiment of the present invention, the chemical resolution method includes a salt formation step: reacting the compound represented by formula (IIA) or formula (IA) with a chiral acid to obtain a chiral acid salt of the compound represented by formula (II) or formula (I).

[0024] In a further preferred example of the present invention, the chiral acid is a chiral tartaric acid derivative, selected from one or more of L-(-)-dibenzoyl tartaric acid, D-di-p-toluoyl tartaric acid, L-di-p-methoxybenzoyl tartaric acid, di(p-toluoyl)-L-tartaric acid monohydrate and (-)-di-tert-pentanoyl-L-tartaric acid, preferably (-)-di-tert-pentanoyl-L-tartaric acid.

[0025] The inventors found through research that these preferred chiral acids exhibit better resolution effects compared to some conventional chiral acids, such as L-camphorsulfonic acid, D-malic acid, L-mandelic acid, D-tartaric acid, L-arginine, L-glutamic acid, or L-pyroglutamic acid, etc. Surprisingly, especially when using (-)-di-tert-pivaloyl-L-tartaric acid, chiral acid salts with high optical purity can be obtained. This is different from what is taught in the prior art when using chiral acids as resolving agents to resolve amine compounds. For chiral acids such as chiral tartaric acid derivatives, introducing polar groups such as benzene rings and formyl groups into the tartaric acid molecule can generate new hydrogen bonds, steric hindrance, and hydrophobic effects, making the function of the chiral recognition region more complex and the spatial recognition ability stronger, and thus the resolution effect is often better. However, in the present invention, the inventors found through the resolution of the compounds shown in formula (IIA) or formula (IA) that when using chiral tartaric acid derivatives with benzoyl groups introduced for resolution, excellent resolution effects were not obtained, while unexpectedly, it was found that the optical purity of the chiral acid salt obtained by the reaction under the resolution of (-)-di-tert-pivaloyl-L-tartaric acid was significantly improved.

[0026] In the salt formation step of the present invention, the free base of the compound shown in formula (IIA) or formula (IA) as one of the reactants can be prepared by referring to the method disclosed in International Patent Application WO2023011422A1. The present invention places no restrictions on the source of the chiral acid, which can be any one purchased from the market or prepared by any method known to those skilled in the art.

[0027] Theoretically speaking, the compound shown in formula (IIA) or formula (IA) is a racemate, which contains a pair of optical isomers with a content ratio of 1:1. According to the correspondence of the acid-base salt formation reaction, its theoretical molar ratio with the chiral acid is 1:0.5. The present invention found through research that a higher proportion of chiral acid is beneficial to obtaining a resolved product with high chiral purity at a relatively ideal yield, that is, an excess of chiral acid is somewhat helpful.

[0028] In a further preferred embodiment of the present invention, the molar ratio of the compound shown in formula (IIA) or formula (IA) to the chiral acid is 1:0.3 - 1.2, preferably 1:0.5 - 1.0, and more preferably 1:0.6 - 0.9.

[0029] From the perspective of obtaining high enantioselectivity, the acid enantiomeric salt formed by the reactants in this ratio is more conducive to finally obtaining chiral acid salts with a relatively high yield and high optical purity, and the ee value of the target configuration chiral acid salt can reach more than 99% at most.

[0030] Considering the differences in the solubility of the diastereomeric salt complexes, i.e., chiral acid salts, formed in different reaction solvents, in order to obtain a higher reaction yield and a chiral acid salt with high optical purity, the first solvent suitable for the salt formation step of the present invention is an organic solvent, which can be alcohols, hydrocarbons such as halogenated hydrocarbons, esters, or a mixed solvent of any several of them.

[0031] The alcohol solvents include, but are not limited to, monohydric alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, butanol, isopropanol, etc., and polyhydric alcohols such as 1,2-ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, etc. Preferably, the alcohol solvent is methanol, ethanol, or isopropanol.

[0032] The halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, etc.; preferably, the halogenated hydrocarbon solvent is dichloromethane.

[0033] The ester solvents include, but are not limited to, methyl acetate, methyl propionate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, etc. Preferably, the ester solvent is ethyl acetate.

[0034] In a further preferred embodiment of the present invention, the resolution reaction is carried out in the first solvent, and the first solvent is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, and dichloromethane, preferably methanol, ethyl acetate, dichloromethane / ethyl acetate mixed solvent, or methanol / ethyl acetate mixed solvent.

[0035] In a further preferred embodiment of the present invention, the dosage of the first solvent is 10 - 40 times, preferably 20 - 30 times, more preferably 20 - 25 times the mass of the compound shown in formula (IIA) or formula (IA). Here, the dosage can be volume (V) or mass (m). When it is volume, it is the V / m multiple, where the volume unit is milliliters or liters, and the corresponding mass unit is grams or kilograms, that is, the unit of V / m is L / kg or mL / g; when it is mass, it is the m / m multiple, and the mass units are the same.

[0036] In a further preferred embodiment of the present invention, when the first solvent is a mixed solvent, it is preferably a methanol / ethyl acetate mixed solvent, and methanol and ethyl acetate can be mixed in any ratio. Preferably, the dosage ratio of methanol to ethyl acetate is 1:1 - 20, preferably 1:1 - 15, more preferably 1:1 - 10, and further preferably 1:1 - 5. Here, the dosage can be volume (V) or mass (m), and the units are the same.

[0037] For the compounds represented by formula (IIA) or formula (IA) and the chiral acid, the present invention does not make any requirements on their respective addition methods. Generally, to make the resolution reaction more complete, the compounds represented by formula (IIA) or formula (IA) and the chiral acid can be dissolved clearly in a suitable reaction solvent first, and then mixed to start the reaction. The clear dissolution can be achieved by stirring at room temperature or by heating at a high temperature. The present invention does not make any restrictions on this, as long as the reactants are dissolved clearly in the solvent.

[0038] In a further preferred embodiment of the present invention, the reaction temperature range of the resolution reaction is between room temperature and 60 °C, preferably room temperature.

[0039] When the resolution reaction of the salt formation step proceeds until no more precipitate is formed, it indicates that the reaction is complete. Usually, the reaction time is 2 - 24 h, and the reaction can be carried out overnight. After the reaction is completed, the precipitate is filtered to obtain the chiral acid salt. The filtration method can be normal pressure filtration, reduced pressure filtration such as suction filtration, etc. The chiral acid salt obtained after filtration can be directly subjected to the next reaction or dried and then subjected to the next reaction. Drying is preferably carried out. Drying can be natural air drying, drying by baking, vacuum drying, etc. The present invention does not impose any restrictions on this. The drying temperature is usually 10 - 100 °C, preferably 20 - 80 °C.

[0040] In a further preferred embodiment of the present invention, the salt formation step is: carrying out a resolution reaction of the compound represented by formula (IIA) or formula (IA) with a chiral tartaric acid derivative in a first solvent to obtain the chiral acid salt of the compound represented by formula (II) or formula (I).

[0041] In a further preferred embodiment of the present invention, the salt formation step is: carrying out a resolution reaction of the free base of the compound represented by formula (IIA) or formula (IA) with (-)-di-tert-pivaloyl-L-tartaric acid in a mixed solvent of methanol / ethyl acetate at room temperature to obtain the chiral acid salt of the compound represented by formula (II) or formula (I), wherein the molar ratio of the compound represented by formula (IIA) or formula (IA) to the chiral acid is 1:0.6 - 0.9, the amount of the mixed solvent of methanol / ethyl acetate is 20 - 25 times the mass of the compound represented by formula (IIA) or formula (IA) (calculated in L / kg or mL / g), and the dosage ratio of methanol to ethyl acetate is 1:1 - 10.

[0042] Crystallization step

[0043] In a further preferred embodiment of the present invention, the method further includes a crystallization step: mixing the chiral acid salt with a second solvent and pulping to obtain a crystalline salt solid.

[0044] The chiral acid salt obtained after the salt formation step is a complex of diastereomeric salts. At this time, the optical purity ee value of the chiral acid salt can reach up to 80%. The inventors unexpectedly found that by further slurrying the chiral acid salt in a suitable second solvent, the optical purity of the target configuration product can be effectively improved, and a crystalline salt solid with higher enantioselectivity can be obtained. After crystallization, the optical purity ee value of the chiral acid salt can reach more than 99%. This may be because the presence of the second solvent is more conducive to the crystallization and precipitation of the compound shown in formula (II) or formula (I).

[0045] For the second solvent in the crystallization step, it is preferably an aqueous system, alcohols, hydrocarbons such as halogenated hydrocarbons, esters, or a mixed solvent of any several of them.

[0046] Alcohol solvents include but are not limited to monohydric alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, butanol, isopropanol, etc., and polyhydric alcohols such as 1,2-ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, etc. Preferably, the alcohol solvent is methanol, ethanol, or isopropanol.

[0047] Halogenated hydrocarbon solvents include but are not limited to dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, etc.; preferably, the halogenated hydrocarbon solvent is dichloromethane.

[0048] Ester solvents include but are not limited to methyl acetate, methyl propionate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, etc. Preferably, the ester solvent is ethyl acetate.

[0049] In a further preferred embodiment of the present invention, the second solvent in the crystallization step is one or more of water, methanol, ethanol, isopropanol, ethyl acetate, and dichloromethane, preferably one or more of water, methanol, and ethyl acetate, and more preferably an ethyl acetate / methanol mixed solvent or a water / methanol / ethyl acetate mixed solvent.

[0050] In a further preferred embodiment of the present invention, the amount of the second solvent used is 10 - 60 times the mass of the chiral acid salt, preferably 20 - 40 times, and more preferably 20 - 25 times. The amount used here can be volume (V) or mass (m). When it is volume, it is the V / m multiple, where the volume unit is milliliters or liters, and the corresponding mass unit is grams or kilograms, that is, the unit of V / m is L / kg or mL / g; when it is mass, it is the m / m multiple, where the mass units are the same.

[0051] In a further preferred embodiment of the present invention, when the second solvent is a mixed solvent, it is preferably an ethyl acetate / methanol / water mixed solvent, wherein ethyl acetate, methanol and water can be mixed in any ratio, and preferably the dosage ratio of ethyl acetate, methanol and water is 1-100:1-20:0.1-5, more preferably 10-70:1-10:0.1-1. The dosage here can be volume (V) or mass (m), as long as the units are consistent.

[0052] In a further preferred embodiment of the present invention, the pulping temperature range is between room temperature and 80 °C, preferably room temperature or 45-65 °C.

[0053] In a further preferred embodiment of the present invention, the crystallization step can be optionally repeated according to requirements until the ee value of the crystalline salt solid meets the requirements, that is, reaches more than 99%.

[0054] After the reaction is completed, the crystalline salt solid obtained by filtering through the pulping system, and the filtering method can be atmospheric pressure filtration, reduced pressure filtration such as suction filtration, etc. The crystalline salt solid obtained after filtration can be directly subjected to the next reaction or dried and then subjected to the next reaction, preferably dried. Drying can be natural air drying, drying, vacuum drying, etc., and the present invention has no limitation in this regard. The drying temperature is usually 10-100 °C, preferably 20-80 °C.

[0055] In a specific embodiment of the present invention, the method further includes a first crystallization step: mixing a chiral acid salt, ethyl acetate, methanol and water, and performing the first pulping at room temperature to obtain a first crystalline salt solid; and further includes a second crystallization step: mixing the first crystalline salt solid, ethyl acetate, methanol and water, and performing the second pulping at 60 °C to obtain a second crystalline salt solid. During the first crystallization, the dosage of the ethyl acetate / methanol / water mixed solvent is 20-25 times the mass of the chiral acid salt (calculated as L / kg or mL / g), and the dosage ratio of ethyl acetate, methanol and water is 10-70:1-10:1. During the second crystallization, the dosage of the ethyl acetate / methanol / water mixed solvent is 20-25 times the mass of the first crystalline salt solid (calculated as L / kg or mL / g), and the dosage ratio of ethyl acetate, methanol and water is 10-70:1-10:0.1-1.

[0056] Free step

[0057] In a further preferred embodiment of the present invention, the method further includes a free step: subjecting the crystalline salt solid to a free reaction under alkaline conditions to obtain the compound shown in formula (II) or formula (I), and optionally further reacting with an acidic reagent to prepare the corresponding salt.

[0058] By redissociating the crystalline salt solid obtained in the crystallization step under alkaline conditions, a compound or its salt represented by formula (II) or formula (I) with high optical purity can be obtained.

[0059] In a further preferred embodiment of the present invention, the base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, triethylamine, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and sodium acetate, preferably potassium hydroxide or sodium hydroxide. When used, the base needs to be formulated into an aqueous solution of the base, and it can be added in a quite wide concentration range. For example, the molar ratio of the crystalline salt solid to potassium hydroxide or sodium hydroxide is added at 1:1 - 20, and further examples can be 1:1, 1:2, 1:5, 1:8, 1:10, 1:12, 1:15, 1:20, preferably 1:2 - 10, more preferably 1:5.

[0060] In a further preferred embodiment of the present invention, the dissociation reaction is carried out in a third solvent, and the third solvent is dichloromethane or ethyl acetate, preferably dichloromethane.

[0061] In a further preferred embodiment of the present invention, the temperature range of the dissociation reaction is between room temperature and 60 °C, preferably room temperature. Too high a temperature will reduce the product yield, while too low a temperature is likely to cause aggregation of the salt and is not conducive to resolution.

[0062] In a further preferred embodiment of the present invention, the acidic reagent is hydrochloric acid, fumaric acid, maleic acid, malonic acid, ethanedisulfonic acid, L - malic acid, D - malic acid, citric acid, hippuric acid, p - hydroxybenzoic acid, pyruvic acid, pamolic acid, nicotinic acid, benzoic acid, succinic acid, oxalic acid, L - tartaric acid, D - tartaric acid, p - toluenesulfonic acid, L - pyroglutamic acid, or mandelic acid, preferably fumaric acid.

[0063] In a further preferred embodiment of the present invention, the molar ratio of the free base of the compound represented by formula (II) or formula (I) to the acidic reagent is 1:0.8 - 1.2, preferably 1:1.

[0064] In a further preferred embodiment of the present invention, the dissociation step is specifically: adding dichloromethane and an aqueous sodium hydroxide solution to the crystalline salt solid, stirring, extracting, and concentrating to obtain the free base of the compound represented by formula (II) or formula (I). Optionally, further reacting with fumaric acid to prepare the fumarate salt of the compound represented by formula (II) or formula (I).

[0065] In a further preferred embodiment of the present invention, the ee value of the compound or its salt represented by formula (II) or formula (I) is ≥60%, preferably ≥70%, preferably ≥80%, preferably ≥90%, preferably ≥95%, preferably ≥96%, preferably ≥97%, preferably ≥98%, preferably ≥99%.

[0066] Detailed description of the invention

[0067] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the definitions provided in this application shall prevail. When trade names appear in this text, they are intended to refer to the corresponding goods or their active ingredients. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0068] The term "aryl" refers to a fully carbon monocyclic group having a conjugated π - electron system (i.e., monocyclic aryl), which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms (i.e., C 6-14 aryl). The aryl preferably has 6 to 12 carbon atoms (i.e., C 6-12 aryl), more preferably has 6 to 10 (e.g., 6, 7, 8, 9, 10) carbon atoms (i.e., C 6-10 aryl). The aryl is preferably phenyl.

[0069] The term "alkyl" refers to a saturated straight - chain or branched - chain aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, i.e., "C 1-20 alkyl". The alkyl preferably has 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably has 1 to 8 carbon atoms (i.e., C 1-8 alkyl), further preferably has 1 to 6 carbon atoms (i.e., C 1-6 alkyl), and most preferably has 1 to 3 carbon atoms (i.e., C 1-3alkyl). Non-limiting examples 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, 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, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and their various branched isomers, etc.

[0070] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, i.e., C 3-20 cycloalkyl. The cycloalkyl preferably has a cycloalkyl having 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably having 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) carbon atoms, i.e., C 3-8 cycloalkyl. The cycloalkyl preferably has a cycloalkyl having 3 to 6 carbon atoms (i.e., C 3-6 cycloalkyl), most preferably having a cycloalkyl having 3 to 5 carbon atoms (i.e., C 3-5 cycloalkyl), or, having a cycloalkyl having 5 to 6 carbon atoms (i.e., C 5-6 cycloalkyl). Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, etc.; preferably cyclopentyl.

[0071] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), where alkyl and cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., C1-10 alkoxy group). The alkoxy group preferably has 1 to 8 carbon atoms (i.e., C 1-8 alkoxy group), more preferably has 1 to 6 carbon atoms (i.e., C 1-6 alkoxy group), and most preferably has 1 to 3 carbon atoms (i.e., C 1-3 alkoxy group). Non-limiting examples include: methoxy, ethoxy, propoxy, etc.; preferably methoxy or ethoxy.

[0072] The term "halo" or "halogen" or "halo-substituted" should be understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom; more preferably a fluorine atom.

[0073] The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, where the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc.

[0074] The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, where the alkoxy group is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, fluoroethoxy, chloroethoxy, bromoethoxy, iodoethoxy, difluoroethoxy, chlorofluoroethoxy, dichloroethoxy, bromofluoroethoxy, trifluoroethoxy, chlorodifluoroethoxy, dichlorofluoroethoxy, trichloroethoxy, bromodifluoroethoxy, bromochlorofluoroethoxy, dibromofluoroethoxy, etc.

[0075] The term "amino" refers to -NH2.

[0076] The term "cyano" refers to -CN.

[0077] The terms "comprising", "including", "having", "containing", or "involving" and other variant forms thereof herein are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art should understand that the above terms such as "comprising" cover the meaning of "consisting of".

[0078] The term "one or more" or a similar expression "at least one" can represent, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0079] When the lower and upper limits of a numerical range are disclosed, any numerical value and any included range falling within that range are specifically disclosed. In particular, each range of values disclosed herein should be understood to represent every numerical value and range subsumed within the broader range.

[0080] As used herein, the expression m - n refers to the range from m to n, as well as sub-ranges and individual point values composed of the respective point values therein.

[0081] The different expressions used herein, such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", "X is A, B, and C", etc., all convey the same meaning, that is, X can be any one or more of A, B, and C.

[0082] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and the description includes the occurrence and non-occurrence of the described event or situation. For example, "optionally alkyl-substituted cycloalkyl" means that the alkyl may or may not be present, and this description includes the case where the cycloalkyl is substituted by alkyl and the case where the cycloalkyl is not substituted by alkyl.

[0083] The terms "substituted" and "substitued" mean that one or more (e.g., one, two, three, or four) hydrogens on the specified atom are replaced by a selection from the indicated groups, provided that the normal atomic valence of the specified atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are only permitted when such combinations form stable compounds. When it is described that a certain substituent is absent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure enables the compound to reach a stable state. When it is described that each carbon atom in a group can optionally be replaced by a heteroatom, the condition is that the normal atomic valence of all atoms in the group in the current situation is not exceeded, and a stable compound is formed.

[0084] If a substituent is described as "optionally... substituted", the substituent can be unsubstituted or can be substituted. If an atom or group is described as optionally substituted by one or more of a list of substituents, one or more hydrogens on that atom or group can be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. When the substituent is hydrogen, this can also mean that the corresponding group is "unsubstituted" or "not substituted". Unless otherwise indicated, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

[0085] When the bond of a substituent is shown as passing through a bond connecting two atoms in a ring, such a substituent can be bonded to any ring-forming atom in the ring that can be substituted.

[0086] Any hydrogen atom described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the exemplified compounds of the present invention can also be replaced by a deuterium atom.

[0087] When any variable (e.g., R), and a variable with a label (e.g., R1, R2, etc.) appear more than once in the composition or structure of a compound, its definition is independent in each case at each occurrence. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group can optionally be substituted by up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0088] The term "pharmaceutically acceptable" substance refers to a substance that, within the scope of normal medical judgment, is suitable for contact with the tissues of a patient without undue toxicity, irritation, allergic response, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0089] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which has safety and effectiveness when used in mammals and has the appropriate biological activity.

[0090] The term "THF" refers to tetrahydrofuran.

[0091] The term "MeCN" or "ACN" refers to acetonitrile.

[0092] The term "DCM" refers to dichloromethane.

[0093] The term "EA" refers to ethyl acetate.

[0094] The term "IPA" refers to isopropyl alcohol.

[0095] The term "IPAc" refers to isopropyl acetate.

[0096] The term "MIBK" refers to 4-methyl-2-pentanone.

[0097] The term "MEK" refers to methyl ethyl ketone.

[0098] The term "room temperature" refers to a temperature ranging from 10°C to 30°C. In some embodiments, "room temperature" refers to a temperature ranging from 18°C to 25°C.

[0099] The terms "high enantioselectivity" and "high optical purity" are terms well known in the art.

[0100] The terms "ee value", "enantiomeric excess" or "e.e. %" can be used to describe the enantiomeric composition of a compound sample, which represents the excess of one enantiomer over the other, usually expressed as a percentage. Specifically in the present invention, the "ee value of the target configuration product" is calculated by the following formula: (content of the target configuration product - content of the other configuration product) / (content of the target configuration product + content of the other configuration product) × 100%, where the product content is detected and calculated by HPLC method.

[0101] In some embodiments, the high optical purity corresponds to an enantiomeric excess value of at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%.

[0102] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the basic raw material used in each step (1 equivalent) according to the equivalent relationship of chemical reactions.

[0103] In the context of the present invention, when the words "about" or "approximately" are used or whether or not they are used, it means within 10% of the given value or range, suitably within 5%, especially within 1%. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within the acceptable standard error range of the average value. Whenever a number with an N value is disclosed, any number within the range of N + / – 1%, N + / – 2%, N + / – 3%, N + / – 5%, N + / – 7%, N + / – 8% or N + / – 10% will be explicitly disclosed, where "+ / –" means plus or minus.

[0104] As used herein, the term "treatment" includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, improving or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, e.g., arresting the development of a disease or symptom, alleviating a disease or symptom, promoting remission of a disease or symptom, or causing the manifestations of a disease or symptom to cease, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to eradicating or ameliorating the treated condition. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological manifestations associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease is observable. A prophylactic benefit refers to a patient using a composition to prevent the risk of a certain disease, or taking the composition when the patient presents with one or more physiological manifestations of a disease, although the disease has not yet been diagnosed.

[0105] The following detailed description of the invention is intended to illustrate non-limiting embodiments and enable other technicians in the art to more fully understand the technical solutions of the invention, its principles and its practical applications, so that other technicians in the art can modify and implement the invention in many forms to best meet the requirements of a particular use.

[0106] Beneficial effects

[0107] The preparation method of the compound of formula (II) or its salt of the present invention overcomes the defects existing in the preparation process by chromatographic resolution method in the prior art, such as cumbersome operation, low resolution efficiency, high cost, small scale and difficulty in large-scale production.

[0108] The preparation method of the present invention has mild conditions, simple operation, high resolution efficiency, low cost, significantly improves the production efficiency (ordinary chromatographic resolution takes 200 g / 7 days, cost: about 20,000 yuan; while the resolution process of the present invention takes 2 - 5 kg / 2 days, cost: about 2,000 yuan), is more economical, the process is stable and easy to reproduce, and the preparation amount is large, more suitable for industrial production. The optically pure compound of formula (II) or formula (I) prepared has a high optical purity (the ee value can reach up to more than 99%) and a high yield (up to about 30%). In addition, the present invention further studies the influencing factors of the conditions for chiral acid resolution, such as acid reagent, pulping temperature, solvent system, etc., which can be regarded as a further preferred embodiment of the present invention. Detailed Embodiments

[0109] The following will describe the embodiments of the present invention in detail in conjunction with the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the examples, the conventional conditions or the conditions recommended by the manufacturer are followed. Those reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0110] Taking the preparation of the compound shown by formula (I-1) or its salt as an example, it includes the step of chiral resolution of the compound shown by formula (IA-1).

[0111]

[0112] Among them, the method of chiral resolution preferably adopts the chemical resolution method, and the chemical resolution method includes a salt formation step: reacting the compound shown by formula (IA-1) with a chiral acid to prepare a chiral acid salt of the compound shown by formula (I-1).

[0113] The chemical resolution method further includes a crystallization step: mixing the chiral acid salt with a second solvent and pulping to obtain a crystalline salt solid.

[0114] The chemical resolution method also further includes a liberation step: subjecting the crystalline salt solid to a liberation reaction under alkaline conditions to obtain the compound shown by formula (I-1), and optionally, further reacting with an acidic reagent to prepare the corresponding salt.

[0115] I. Condition screening of the chemical resolution method

[0116] 1. Chiral acid in the salt formation step

[0117] Example 1

[0118] Take the free base of the compound shown by formula (IA-1) (0.24 mmol, 100 mg) in a 20 mL single-necked flask, add 2 mL of EA solution and stir until dissolved clearly. Add 1 mL of IPA solution containing L-camphorsulfonic acid (0.17 mmol, 0.7 eq), and no solid precipitates. Add 10 mL of the solvent described in the following table, stir at room temperature overnight, observe whether a large amount of solid precipitates. If so, take out the resolved product and detect its ee value, and the target configuration enantiomer is P2. The specific results are shown in Table 1 below.

[0119] Table 1 Resolution experiment under the L-camphorsulfonic acid system

[0120]

[0121] Example 2

[0122] Take the free base of the compound shown by formula (IA-1) (0.24 mmol, 100 mg) in a 20 mL single-necked flask, add 2 mL of EA solution and stir until dissolved clearly. Add 1 mL of IPA solution containing D-di-p-toluoyl tartaric acid (0.17 mmol, 0.7 eq), and no solid precipitates. Add 10 mL of the solvent described in the following table, stir at room temperature overnight, observe whether a large amount of solid precipitates. If so, take out the resolved product and detect its ee value, and the target configuration enantiomer is P2. The specific results are shown in Table 2 below.

[0123] Table 2 Resolution experiments under the D-ditoluoyl tartaric acid system

[0124]

[0125] Example 3

[0126] Take the free base of the compound shown in formula (IA-1) (0.24 mmol, 100 mg) in a 20 mL single-necked flask, add 2 mL of EA solution and stir until clear. Add 1 mL of IPA solution containing L-dimethoxybenzoyl tartaric acid (0.17 mmol, 0.7 eq), and no solid precipitates. Then add 10 mL of the solvent described in the following table, stir at room temperature overnight, observe whether a large amount of solid precipitates. If so, take out the resolved product and detect its ee value. The target configuration enantiomer is P2. The specific results are shown in Table 3 below.

[0127] Table 3 Resolution experiments under the L-dimethoxybenzoyl tartaric acid system

[0128]

[0129] Example 4

[0130] Take the free base of the compound shown in formula (IA-1) (0.24 mmol, 100 mg) in a 20 mL single-necked flask, add 2 mL of EA solution and stir until clear. Add 1 mL of IPA solution containing R-2-phenylpropionic acid (0.17 mmol, 0.7 eq), and no solid precipitates. Then add 10 mL of the solvent described in the following table, stir at room temperature overnight, observe whether a large amount of solid precipitates. If so, take out the resolved product and detect its ee value. The target configuration enantiomer is P2. The specific results are shown in Table 4 below.

[0131] Table 4 Resolution experiments under the R-2-phenylpropionic acid system

[0132]

[0133] Example 5

[0134] Take the free base of the compound shown in formula (IA-1) (0.24 mmol, 100 mg) in a 20 mL single-necked flask, add 2 mL of EA solution and stir until clear. Add 1 mL of IPA solution containing bis(p-toluoyl)-L-tartaric acid monohydrate (0.17 mmol, 0.7 eq), and no solid precipitates. Then add 10 mL of the solvent described in the following table, stir at room temperature overnight, observe whether a large amount of solid precipitates. If so, take out the resolved product and detect its ee value. The target configuration enantiomer is P2. The specific results are shown in Table 5 below.

[0135] Table 5 Resolution experiments under the bis(p-toluoyl)-L-tartaric acid monohydrate system

[0136]

[0137] Example 6

[0138] Take the free base of the compound shown in formula (IA-1) (0.24 mmol, 100 mg) in a 20 mL single-necked flask, add 2 mL of EA solution and stir until clear. Add 1 mL of IPA solution containing (-)-di-tert-pivaloyl-L-tartaric acid (0.17 mmol, 0.7 eq), and no solid precipitates. Then add 10 mL of the solvent described in the following table, stir at room temperature overnight, observe whether a large amount of solid precipitates. If so, take out the resolved product and detect its ee value, and the target configuration enantiomer is P2. The specific results are shown in Table 6 below.

[0139] Table 6 Resolution experiments under the (-)-di-tert-pivaloyl-L-tartaric acid system

[0140]

[0141] It can be seen from the results of the above Examples 1-6 that: under the same conditions, after screening different chiral acids, in terms of the resolution effect, the chiral tartaric acid derivatives have a better resolution effect than the achiral tartaric acid derivatives. In particular, the ee value of the target configuration chiral acid salt obtained after the resolution with (-)-di-tert-pivaloyl-L-tartaric acid is significantly improved.

[0142] 2. Solvents and reaction temperatures in the salt formation step

[0143] Example 7

[0144] Take the free base of the compound shown in formula (IA-1) (4.9 mmol, 2.0 g) in a 100 mL single-necked flask, add the first solvent described in the following table, stir for 30 min, add 8 mL of EA solution of (-)-di-tert-pivaloyl-L-tartaric acid (3.7 mmol, 0.75 eq), and no solid precipitates. Continue to stir overnight, and a large amount of solid precipitates. Filter the sample and detect its ee value, and the target configuration enantiomer is P2. The specific results are shown in Table 7 below.

[0145] Table 7 Influence of solvents and reaction temperatures on the resolution effect in the salt formation step

[0146] Experimental grouping Second solvent (volume) Reaction temperature P1:P2 ee value (%) 7-1 EA (32 mL) Room temperature 3：7 40 7-2 EA (32 mL) + DCM (5 mL) Room temperature 2：8 60 7-3 EA (32 mL) + DCM (10 mL) Room temperature 2：8 60 7-4 EA (32 mL) + DCM (2 mL) 50℃ 2：8 60 7-5 EA (32 mL) + methanol (5 mL) Room temperature 2：8 60 7-6 EA (32 mL) + methanol (10 mL) Room temperature 1：9 80

[0147] It can be seen from the results of the above Example 7 that: in the salt formation step with (-)-di-tert-pivaloyl-L-tartaric acid as the chiral acid, in terms of the final resolution effect, when the mixed solvent system is used as the first solvent, the ee value of the target configuration chiral acid salt can reach more than 60%. In particular, in the mixed solvent system of methanol and ethyl acetate at room temperature, the ee value reaches 80%.

[0148] 3. Solvent and reaction temperature in the crystallization step

[0149] Example 8

[0150] The chiral acid salt solid obtained in the salt formation step (P1:P2 = 1:9, 2.8 mmol, 2.0 g) was added to the second solvent described in the following table, slurried, filtered, and the resolved product was taken out and its ee value was detected. The target configuration enantiomer was P2, and the results are shown in the following table.

[0151] Table 8 Influence of solvent and slurrying temperature on the resolution effect in the crystallization step

[0152] Experimental grouping Second solvent (volume) Slurrying temperature P1:P2 ee value (%) 8-1 EA (40 mL) + methanol (5 mL) + water (1 mL) Room temperature 3:97 94 8-2 EA (40 mL) + methanol (5 mL) + water (1 mL) 60℃ 3:97 94 8-3 EA (40 mL) + methanol (5 mL) + water (2 mL) Room temperature 2:98 96

[0153] It can be seen from the results of Example 8 that in the crystallization step, under the same solvent system, different slurrying temperatures have no significant influence on the resolution effect; and when using the ethyl acetate / methanol / water mixed solvent system as the second solvent, the ee values of the target configuration products are all above 90%.

[0154] Example 9

[0155] The crystalline salt solid obtained in the first crystallization step (P1:P2 = 1:99) was taken and subjected to a second crystallization in the solvents shown in the following table, slurried, filtered, and the ee value of the target configuration enantiomer P2 of the resolved product was detected. The results are shown in the following table.

[0156] Table 9 Resolution effects obtained by crystallization in different solvents and at different slurrying temperatures

[0157]

[0158] It can be seen from Example 9 that in the slurrying crystallization step after the chiral acid completes the resolution reaction, by increasing the slurrying crystallization step, the ee value of the target configuration product can be further increased, and an ee value of up to more than 99% can be obtained.

[0159] II. Preparation method of the compound represented by formula (I-1):

[0160] Synthesis route:

[0161]

[0162] Example 10

[0163] Salt formation step: In a 50 L reactor, add the free base of the compound shown in formula (IA-1) (570 g, 1.14 mol, 1 eq) and methanol (2 L, 3.5 V / m). Heat up to 90 °C until dissolved clearly, turn off the heating, cool down to 50 - 60 °C, and slowly add dropwise a solution of (-)-ditertiarybutyryl-L-tartaric acid (331 g, 0.86 mol, 0.75 eq) in ethyl acetate (1.7 L, 3 V / m). Cool down to room temperature, add additional ethyl acetate (9.7 L, 17 V / m), stir overnight at room temperature. By normal phase detection, P1:P2 = 13:87. Stop stirring, filter, and dry at 55 °C to obtain the (-)-ditertiarybutyryl-L-tartrate salt of the compound shown in formula (I-1) (300 g, white solid).

[0164] Crystallization step: Add the 300 g white solid obtained in the previous step to ethyl acetate (6 L, 20 V / m), and add methanol (750 mL, 2.5 V / m) and water (150 mL, 0.5 V / m). Pulp at room temperature overnight. By normal phase detection, P1:P2 = 3:97. Stop stirring, filter, and dry at 55 °C to obtain the (-)-ditertiarybutyryl-L-tartrate salt of the compound shown in formula (I-1) (228 g, white solid).

[0165] Add the dried solid to ethyl acetate (4.5 L, 19.7 V / m), and add methanol (228 mL, 1 V / m) and water (70 mL, 0.3 V / m). Stir at 60 °C for 7 h, cool down to room temperature and stir overnight. By normal phase detection, P1:P2 = 1.1:98.9; Add additional water (40 mL, 0.2 V / m), stir at 60 °C for 2 h. By normal phase detection, P1:P2 = 0.9:99.1. Stop stirring, filter, and dry at 55 °C to obtain the (-)-ditertiarybutyryl-L-tartrate salt of the compound shown in formula (I-1) (206 g, white solid, molar yield 25%).

[0166] Freeing step: In a 5 L three-necked flask, add the white solid obtained in the previous step (206 g, 0.28 mol, 1 eq) and DCM (2 L, 10 V / m), add an aqueous solution of NaOH (57 g, 1.4 mol, 5 eq) (2 L, 10 V / m), stir until dissolved clearly, separate the layers. Extract the aqueous layer once with DCM (1 L, 5 V / m), wash the organic layer twice with water (1 L). Separate the layers, concentrate the organic layer until no liquid drips out to obtain the free base of the compound shown in formula (I-1) (134 g, transparent oil).

[0167] To the concentrated oily substance, ethanol (3 L, 15 V / m) was added, and fumaric acid (28.8 g, 0.28 mol, 1 eq) was added. The mixture was stirred at room temperature for 40 h. After filtration and drying at 65 °C, the fumarate of the compound shown in formula (I-1) was obtained (155 g, white solid, normal phase detection P1:P2 = 0.6:99.4, LC-MS 99.7%, molar yield 87.5%).

[0168] Example 11

[0169] Salt formation step: In a 100 L reaction kettle, the free base of the compound shown in formula (IA-1) (3.22 kg, 7.84 mol, 1 eq), (-)-ditertiarybutyryl-L-tartaric acid (1.87 kg, 5.88 mol, 0.75 eq), methanol (8.93 kg, 2.77 m / m) and ethyl acetate (57.96 kg, 18 m / m) solution were added. After stirring for 60 min, the solution became clear. The mixture was stirred at room temperature overnight, and a large amount of solid precipitated. The normal phase detection showed P1:P2 = 14:86. Stirring was stopped, and the mixture was filtered and dried at 55 °C to obtain the (-)-ditertiarybutyryl-L-tartrate of the compound shown in formula (I-1) (2.25 kg, white solid).

[0170] Crystallization step: The solid obtained after drying in the previous step was added to ethyl acetate (40.5 kg, 18 m / m), and methanol (4.4 kg, 1.96 m / m) and water (1.12 g, 0.5 m / m) were added. The mixture was slurried at 60 °C for 6 h, cooled naturally with stirring overnight. The normal phase detection showed P1:P2 = 0.8:99.2. Stirring was stopped, and the mixture was filtered and dried at 55 °C to obtain the (-)-ditertiarybutyryl-L-tartrate of the compound shown in formula (I-1) (1.55 kg, white solid, molar yield 39.66%).

[0171] In summary, the preparation method of the present invention has mild conditions, simple operation, high resolution efficiency, low cost, significantly improves production efficiency, is more economical, the process is stable and easy to reproduce, and the preparation amount is large, making it more suitable for industrial production. The compounds or their salts shown in formula (II) or formula (I) prepared have high optical purity (the ee value can reach up to more than 99%) and high yield (about 30%), and have great application prospects.

Claims

1. A method for preparing a compound represented by formula (II) or a salt thereof, characterized in that, A step including the compound shown in formula (IIA) for chiral resolution, Among them, ring A is C 6-10 aryl or C 3-10 cycloalkyl and C 6-10 aryl, R1 is hydrogen or halogen, and each R2, when present, is independently hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, X1 is a bond or CH2, and n is 0, 1, 2 or 3; Preferably, the compound shown in formula (IIA) further has the structure shown in formula (IIA-1), formula (IIA-2) or formula (IIA-3): wherein R1 is hydrogen or fluorine, each R2 is independently hydrogen, halogen, C 1-3 alkoxy or C 1-3 alkyl, and n is 2; More preferably, a method for preparing the compound shown in formula (I) or a salt thereof includes a step of chiral resolution of the compound shown in formula (IA), Wherein, R1 is hydrogen, fluorine, chlorine or bromine, preferably fluorine.

2. The preparation method according to claim 1, characterized in that, The method for chiral resolution is mechanical resolution, simulated moving bed resolution, chemical resolution, chromatographic resolution, membrane resolution, capillary electrophoresis resolution or biological resolution, preferably chemical resolution or chromatographic resolution, more preferably chemical resolution.

3. The preparation method according to claim 2, characterized in that, The chemical resolution method includes a salt formation step: reacting the compound shown in formula (IIA) or formula (IA) with a chiral acid to obtain the chiral acid salt of the compound shown in formula (II) or formula (I).

4. The preparation method according to claim 3, characterized in that, Satisfy one or more of the following: (1) The chiral acid is a chiral tartaric acid derivative, preferably selected from one or more of L-(-)-dibenzoyl tartaric acid, D-di-p-toluoyl tartaric acid, L-di-p-methoxybenzoyl tartaric acid, di(p-toluoyl)-L-tartaric acid monohydrate and (-)-di-tert-pentanoyl-L-tartaric acid, more preferably (-)-di-tert-pentanoyl-L-tartaric acid; (2) The molar ratio of the compound shown in formula (IIA) or formula (IA) to the chiral acid is 1:0.3 - 1.2, preferably 1:0.5 - 1.0, more preferably 1:0.6 - 0.9; (3) The resolution reaction is carried out in a first solvent, and the first solvent is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate and dichloromethane, preferably methanol, ethyl acetate, dichloromethane / ethyl acetate mixed solvent or methanol / ethyl acetate mixed solvent; (4) The reaction temperature range of the resolution reaction is between room temperature and 60 °C, preferably room temperature.

5. The preparation method according to claim 4, characterized in that, Satisfy one or more of the following: (1) The dosage of the first solvent is 10 - 40 times the mass of the compound shown in formula (IIA) or formula (IA), preferably 20 - 30 times, more preferably 20 - 25 times; (2) When the first solvent is a mixed solvent, preferably a methanol / ethyl acetate mixed solvent, and the dosage ratio of methanol to ethyl acetate is 1:1 - 20, preferably 1:1 - 15, more preferably 1:1 - 10.

6. The preparation method according to any one of claims 1-5, characterized in that, The method further includes a crystallization step: mixing the obtained chiral acid salt of the compound shown in formula (II) or formula (I) with a second solvent and pulping to obtain a crystalline salt solid.

7. The preparation method according to claim 6, characterized in that, Satisfy one or more of the following: (1) The second solvent is selected from one or more of water, methanol, ethanol, isopropanol, ethyl acetate and dichloromethane; preferably selected from one or more of water, methanol and ethyl acetate, more preferably ethyl acetate / methanol mixed solvent or ethyl acetate / methanol / water mixed solvent; (2) The dosage of the second solvent is 10 - 60 times the mass of the chiral acid salt, preferably 20 - 40 times, more preferably 20 - 25 times; (3) When the second solvent is a mixed solvent, it is preferably an ethyl acetate / methanol / water mixed solvent, wherein the usage ratio of ethyl acetate, methanol and water is 1 - 100:1 - 20:0.1 - 5, preferably 10 - 70:1 - 10:0.1 - 1; (4) The pulping temperature range is between room temperature and 80 °C, preferably room temperature or 45 - 65 °C.

8. The preparation method according to any one of claims 1-7, characterized in that, The method further includes a free step: reacting the crystalline salt solid under alkaline conditions to obtain the compound shown in formula (I), and optionally, further reacting with an acidic reagent to obtain the corresponding salt.

9. The preparation method according to claim 8, wherein Meet one or more of the following: (1) The base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, triethylamine, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium acetate, preferably potassium hydroxide or sodium hydroxide; (2) The free reaction is carried out in a third solvent, and the third solvent is dichloromethane or ethyl acetate, preferably dichloromethane; (3) The free reaction temperature range is between room temperature and 60 °C, preferably room temperature; (4) The acidic reagent is hydrochloric acid, fumaric acid, maleic acid, malonic acid, ethanedisulfonic acid, L - malic acid, D - malic acid, citric acid, hippuric acid, p - hydroxybenzoic acid, pyruvic acid, pamonic acid, nicotinic acid, benzoic acid, succinic acid, oxalic acid, L - tartaric acid, D - tartaric acid, p - toluenesulfonic acid, L - pyroglutamic acid or mandelic acid; preferably fumaric acid.

10. The preparation method according to any one of claims 1-9, characterized in that, The ee value of the compound or its salt shown in formula (II) or formula (I) prepared is ≥60%, preferably ≥70%, preferably ≥80%, preferably ≥90%, preferably ≥95%, preferably ≥96%, preferably ≥97%, preferably ≥98%, preferably ≥99%.

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