Method for preparing azabicyclo[3.2.1]octane derivative

Abstract

The present disclosure relates to a method for preparing an azabicyclo[3.2.1]octane derivative. Specifically, the present disclosure relates to a method for preparing methyl 4-((1S,3S,5R)-3-ethoxy-8-azabicyclo[3.2.1]octan-1-yl)benzoate, which has a good yield.

Description

A method for preparing a azirmonobicyclic [3.2.1]octane derivative Technical Field

[0001] This disclosure belongs to the field of pharmaceutical technology and relates to a method for preparing a azirbicyclo[3.2.1]octane derivative. Background Technology

[0002] Complement is a serum protein found in the serum and tissue fluid of humans and vertebrates. It is heat-sensitive and, once activated, has enzymatic activity. It can mediate immune responses and inflammatory reactions and can be activated by antigen-antibody complexes or microorganisms, leading to the lysis or phagocytosis of pathogenic microorganisms.

[0003] WO2022143845A1 discloses a complement factor B inhibitor. The synthesis of this compound requires an intermediate. WO2022143845 discloses a method for preparing this intermediate that requires chiral column chromatography separation, which is not suitable for industrial-scale production. Summary of the Invention

[0004] This disclosure provides a method for preparing compound G or a pharmaceutically acceptable salt thereof:

[0005] The steps include the formation of compound B from compound A in the presence of a resolving agent. in,

[0006] R 1 Selected from C 1-6 Alkyl groups, wherein the alkyl group is optionally composed of one or more elements selected from deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or amino substitutions;

[0007] R 2 Selected from C 1-6 Alkyl group, wherein the alkyl group is optionally composed of one or more elements selected from C10. 1-6 Alkyl, C 1-6 Alkoxy, halogen, or amino substitutions;

[0008] X is selected from halogens;

[0009] PG is selected from benzyl or p-methoxybenzyl.

[0010] In some implementation schemes, X is selected from chlorine, bromine, and iodine.

[0011] In some implementations, X is selected from bromine.

[0012] In some implementations, PG is selected from p-methoxybenzyl.

[0013] In some implementation schemes, R 1 Selected from methyl, ethyl, propyl, and deuterated methyl.

[0014] In some implementation schemes, R 1 Selected from ethyl.

[0015] In some implementation schemes, R 2 Selected from methyl, ethyl, propyl, isopropyl, and tert-butyl.

[0016] In some implementation schemes, R 2 Selected from methyl.

[0017] In some embodiments, the resolving agent is selected from (+)-di-p-methoxybenzoyl-D-tartaric acid.

[0018] In some embodiments, the molar ratio of compound A to (+)-di-p-methoxybenzoyl-D-tartaric acid is 1:0.1 to 1:1, including but not limited to 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, or any value between any two numbers. In some embodiments, the molar ratio of compound A to (+)-di-p-methoxybenzoyl-D-tartaric acid is 1:0.4 to 1:0.6. In some embodiments, the molar ratio of compound A to (+)-di-p-methoxybenzoyl-D-tartaric acid is 1:0.5.

[0019] In some embodiments, the solvent used for the reaction of compound A is selected from ethyl acetate, ethanol, isopropanol, acetone, toluene, dichloromethane, tetrahydrofuran, acetonitrile, and methanol.

[0020] In some implementations, the solvent used for the reaction of compound A is selected from dichloromethane.

[0021] In some embodiments, compound G is compound G-1. The method for preparing compound G-1 includes the step of forming compound B-1 from compound A-1 in the presence of a resolving agent.

[0022] In some embodiments, the method for preparing compound G or a pharmaceutically acceptable salt thereof further includes the step of reducing compound B to compound C in a reducing agent.

[0023] PG and X are defined as described above.

[0024] In some embodiments, the reducing agent is selected from: (-)-diisopinepine chloroborane, (+)-diisopinepine chloroborane, lithium triisobutylborohydride, sodium borohydride, DIBAL-H, LiAlH[OC(CH3)3]3.

[0025] In some embodiments, the reducing agent is selected from (-)-diisopinepine chloroborane.

[0026] In some embodiments, the molar ratio of compound B to the reducing agent is 1:1 to 1:2, including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, or any value between any two numbers. In some embodiments, the molar ratio of compound B to the reducing agent is 1:1.1 to 1:1.5. In some embodiments, the molar ratio of compound B to the reducing agent is 1:1.5.

[0027] In some embodiments, the molar ratio of compound B to sodium triacetoxyborohydride is 1:1.5.

[0028] In some embodiments, the molar ratio of compound B to (-)-diisopinepine chloroborane is 1:1.5.

[0029] In some embodiments, the solvent used for the reaction of compound B is selected from acetonitrile, dichloromethane, tetrahydrofuran, toluene, methyltetrahydrofuran, and ethylene glycol dimethyl ether.

[0030] In some embodiments, the solvent used for the reaction of compound B is selected from tetrahydrofuran.

[0031] In some embodiments, the method for preparing compound G-1 or its pharmaceutically acceptable salt further includes the step of reducing compound B-1 to compound C-1 in the presence of (-)-diisopinepinechloroborane.

[0032] In some embodiments, the method for preparing compound G or a pharmaceutically acceptable salt thereof further includes the step of reacting compound C with an alkylating agent in the presence of base I to generate compound D.

[0033] Where R 1 X and PG are as defined above.

[0034] In some embodiments, the alkylating agent is selected from iodomethane, iodoethane, iodopropane, deuterated iodomethane, bromomethane, bromoethane, dimethyl sulfate, diethyl sulfate, and ethyl p-toluenesulfonate.

[0035] In some embodiments, the alkylating agent is selected from iodoethane.

[0036] In some embodiments, the alkylating agent is selected from deuterated iodomethane.

[0037] In some embodiments, the base I is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, and sodium hydride.

[0038] In some embodiments, the base I is selected from sodium tert-butoxide.

[0039] In some embodiments, the molar ratio of compound C to base I is 1:1 to 1:2, including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, or any value between any two numbers. In some embodiments, the molar ratio of compound C to base I is 1:1 to 1:1.5. In some embodiments, the molar ratio of compound C to base I is 1:1.3.

[0040] In some embodiments, the molar ratio of compound C to sodium tert-butoxide is 1:1.3.

[0041] In some embodiments, the molar ratio of compound C to the alkylating agent is 1:1 to 1:2, including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, or any value between any two numbers. In some embodiments, the molar ratio of compound C to the alkylating agent is 1:1 to 1:1.5. In some embodiments, the molar ratio of compound C to the alkylating agent is 1:1.

[0042] In some embodiments, the molar ratio of compound C to iodoethane is 1:1.

[0043] In some embodiments, the solvent used for the reaction of compound C is selected from acetonitrile, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and sulfolane.

[0044] In some embodiments, the solvent used for the reaction of compound C is selected from N,N-dimethylformamide.

[0045] In some embodiments, the method for preparing compound G-1 or its pharmaceutically acceptable salt further includes the step of reacting compound C-1 with iodoethane in the presence of sodium tert-butoxide to generate compound D-1.

[0046] In some embodiments, the method for preparing compound G or a pharmaceutically acceptable salt thereof further includes the step of reacting compound D with carbon dioxide in the presence of base II and a Grignard reagent to generate compound E.

[0047] R 1 PG and X are as defined above.

[0048] In some embodiments, the base II is selected from n-butyllithium and sec-butyllithium.

[0049] In some embodiments, the base II is selected from n-butyllithium.

[0050] In some embodiments, the molar ratio of compound D to base II is 1:1 to 1:2, including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, or any value between any two numbers. In some embodiments, the molar ratio of compound D to base II is 1:1 to 1:1.5. In some embodiments, the molar ratio of compound D to base II is 1:1.4.

[0051] In some embodiments, the molar ratio of compound D to n-butyllithium is 1:1.4.

[0052] In some embodiments, the Grignard reagent is selected from isopropyl magnesium chloride, butyl magnesium chloride, and dibutyl magnesium.

[0053] In some embodiments, the Grignard reagent is selected from isopropyl magnesium chloride.

[0054] In some embodiments, the molar ratio of compound D to Grignard reagent is 1:0.1 to 1:1, including but not limited to 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, or any value between any two numbers. In some embodiments, the molar ratio of compound D to Grignard reagent is 1:0.5 to 1:1. In some embodiments, the molar ratio of compound D to Grignard reagent is 1:0.7.

[0055] In some embodiments, the molar ratio of compound D to isopropyl magnesium chloride is 1:0.7.

[0056] In some embodiments, the solvent used for the reaction of compound D is selected from dichloromethane, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, and toluene.

[0057] In some embodiments, the solvent used for the reaction of compound D is selected from tetrahydrofuran.

[0058] In some embodiments, the method for preparing compound G-1 or its pharmaceutically acceptable salt further includes the step of reacting compound D-1 with carbon dioxide in the presence of n-butyllithium / isopropylmagnesium chloride to generate compound E-1.

[0059] In some embodiments, the method for preparing compound G or its pharmaceutically acceptable salt further includes the step of reacting compound E with an alcohol to generate compound F.

[0060] R 1 R 2 PG and X are as defined above.

[0061] In some embodiments, the alcohol is selected from methanol, ethanol, propanol, isopropanol, and tert-butanol.

[0062] In some embodiments, the alcohol is selected from methanol.

[0063] In some embodiments, the step of reacting compound E with an alcohol to generate compound F further includes the step of reacting compound E with an alcohol in the presence of thionyl chloride.

[0064] In some embodiments, the molar ratio of compound E to thionyl chloride is 1:1 to 1:2, including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, or any value between any two numbers. In some embodiments, the molar ratio of compound E to thionyl chloride is 1:1 to 1:1.5. In some embodiments, the molar ratio of compound E to thionyl chloride is 1:1.1.

[0065] In some embodiments, the solvent used for the reaction of compound E is selected from acetonitrile, methanol, ethanol, dichloromethane, tetrahydrofuran, and N,N-dimethylformamide.

[0066] In some embodiments, the solvent used for the reaction of compound E is selected from methanol.

[0067] In some embodiments, the method for preparing compound G-1 or its pharmaceutically acceptable salt further includes the step of reacting compound E-1 with methanol in the presence of thionyl chloride to generate compound F-1.

[0068] In some embodiments, the method for preparing compound G or a pharmaceutically acceptable salt thereof further includes a step of deprotecting compound F in the presence of an oxidizing agent.

[0069] R 1 R 2PG is defined as described above.

[0070] In some embodiments, the oxidant is selected from cerium ammonium nitrate (CAN), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), diisopropyl azodicarbonate (DIAD), tert-butyl peroxyphthalate (PIFA), and hydrogen peroxide.

[0071] In some embodiments, the oxidant is selected from cerium ammonium nitrate.

[0072] In some embodiments, the molar ratio of compound F to oxidant is 1:1 to 1:3, including but not limited to 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3, or any value between any two numbers. In some embodiments, the molar ratio of compound F to oxidant is 1:2 to 1:3. In some embodiments, the molar ratio of compound F to oxidant is 1:3.

[0073] In some embodiments, the molar ratio of compound F to cerium ammonium nitrate is 1:3.

[0074] In some embodiments, the solvent used for the reaction of compound F is selected from acetonitrile, dichloromethane, tetrahydrofuran, and N,N-dimethylformamide.

[0075] In some embodiments, the solvent used for the reaction of compound F is selected from acetonitrile.

[0076] In some embodiments, the method for preparing compound G-1 or its pharmaceutically acceptable salt further includes the step of reacting compound F-1 in the presence of cerium ammonium nitrate.

[0077] In some embodiments, the method for preparing compound G or a pharmaceutically acceptable salt thereof further includes a step of deprotecting compound F in the presence of a reducing agent / catalyst.

[0078] In some embodiments, the reducing agent is selected from hydrogen, formic acid, acetic acid, ammonium formate, triethylsilane, cyclohexene, etc.

[0079] In some embodiments, the reducing agent is selected from formic acid.

[0080] In some embodiments, the molar ratio of compound F to reducing agent is 1:1 to 1:10, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, or any value between any two numbers. In some embodiments, the molar ratio of compound F to reducing agent is 1:1 to 1:5. In some embodiments, the molar ratio of compound F to reducing agent is 1:4.

[0081] In some embodiments, the molar ratio of compound F to formic acid is 1:4.

[0082] In some embodiments, the catalyst is selected from Pd / C, Pt / C, Ru / C, Pd(OH)2 / C, Pd(OH)2 / Al2O3, Pd / Al2O3, Pt / Al2O3, Pd / Al2O3, and Pd / CaCO3.

[0083] In some embodiments, the catalyst is selected from Pd / C.

[0084] In some embodiments, the mass ratio of compound F to catalyst is 1:1% to 1:15%, including but not limited to 1:1%, 1:2%, 1:3%, 1:4%, 1:5%, 1:6%, 1:7%, 1:8%, 1:9%, 1:10%, 1:11%, 1:12%, 1:13%, 1:14%, 1:15%, or any two values ​​between these numbers. In some embodiments, the mass ratio of compound F to catalyst is 1:5% to 1:15%. In some embodiments, the mass ratio of compound F to catalyst is 1:10%.

[0085] In some embodiments, the mass ratio of compound F to Pd / C is 1:10%.

[0086] In some embodiments, the solvent used for the reaction of compound F is selected from methanol, ethanol, ethyl acetate, dichloromethane, tetrahydrofuran, and N,N-dimethylformamide.

[0087] In some embodiments, the solvent used for the reaction of compound F is selected from ethanol.

[0088] In some embodiments, the method for preparing compound G-1 or its pharmaceutically acceptable salt further includes the step of reacting compound F-1 in the presence of Pd / C and formic acid.

[0089] Some implementations provide methods for preparing compound G or pharmaceutically acceptable salts thereof, including:

[0090] Step 1: Compound A is reacted with a resolving agent to form compound B;

[0091] Step 2: Compound B is reduced to compound C in the presence of a reducing agent;

[0092] Step 3: Compound C reacts with an alkylating agent in the presence of base I to generate compound D;

[0093] Step 4: Compound D reacts with carbon dioxide in the presence of base II and Grignard reagent to produce compound E;

[0094] Step 5: Compound E reacts with an alcohol under thionyl chloride to produce compound F;

[0095] Step 6: Compound F undergoes deprotection in the presence of an oxidizing agent;

[0096] Where R 1 R 2 PG and X are as defined above.

[0097] Some implementations provide methods for preparing compound G or pharmaceutically acceptable salts thereof, including:

[0098] Step 1: Compound A is reacted with a resolving agent to form compound B;

[0099] Step 2: Compound B is reduced to compound C in the presence of a reducing agent;

[0100] Step 3: Compound C reacts with an alkylating agent in the presence of base I to generate compound D;

[0101] Step 4: Compound D reacts with carbon dioxide in the presence of base II and Grignard reagent to produce compound E;

[0102] Step 5: Compound E reacts with an alcohol under thionyl chloride to produce compound F;

[0103] Step 6: Deprotecting compound F in the presence of a catalyst / reducing agent.

[0104] Some embodiments provide methods for preparing G-1 compounds or pharmaceutically acceptable salts thereof, including:

[0105] Step 1: Compound A-1 is converted into compound B-1 in the presence of (+)-di-p-methoxybenzoyl-D-tartaric acid;

[0106] Step 2: Compound B-1 is reduced to compound C-1 in (-)-diisopinepine chloroborane;

[0107] Step 3: Compound C-1 reacts with iodoethane in the presence of sodium tert-butoxide to generate compound D-1;

[0108] Step 4: Compound D-1 reacts with carbon dioxide in the presence of n-butyllithium / isopropylmagnesium chloride to generate compound E-1;

[0109] Step 5: Compound E-1 reacts with methanol under thionyl chloride to generate compound F-1;

[0110] Step 6: Compound F-1 is deprotected in the presence of cerium ammonium nitrate;

[0111] Some embodiments provide methods for preparing G-1 compounds or pharmaceutically acceptable salts thereof, including:

[0112] Step 1: Compound A-1 is converted into compound B-1 in the presence of (+)-di-p-methoxybenzoyl-D-tartaric acid;

[0113] Step 2: Compound B-1 is reduced to compound C-1 in (-)-diisopinepine chloroborane;

[0114] Step 3: Compound C-1 reacts with iodoethane in the presence of sodium tert-butoxide to generate compound D-1;

[0115] Step 4: Compound D-1 reacts with carbon dioxide in the presence of n-butyllithium / isopropylmagnesium chloride to generate compound E-1;

[0116] Step 5: Compound E-1 reacts with methanol under thionyl chloride to generate compound F-1;

[0117] Step 6: Compound F-1 is deprotected in the presence of Pd / C and formic acid;

[0118] This disclosure provides the use of the aforementioned method for preparing compound G in the preparation of Factor B inhibitors.

[0119] In some implementations, the Factor B inhibitor is selected from, but not limited to:

[0120] On the other hand, this disclosure also provides a method for preparing compound AA or a salt thereof, the method comprising the steps of the aforementioned method for preparing compound G.

[0121] In some embodiments, the method for preparing compound AA includes the steps of the aforementioned method for preparing compound G-1.

[0122] In some embodiments, the method for preparing compound AA or a salt thereof includes the step of reacting compound G-1 with compound H to form compound AA. The reaction conditions and procedures are based on WO2022143845, and the relevant content is incorporated herein for illustrative purposes.

[0123] The preparation method described in this disclosure further includes one or more steps of filtration, washing, drying, concentration or recrystallization.

[0124] Salts of the compounds / intermediates disclosed herein, including but not limited to addition salts of the compounds / intermediates in their free state with acids or bases, wherein the acids used to form the salts include but are not limited to hydrochloric acid, DL-camphorsulfonic acid, and (+)-di-p-methoxybenzoyl-D-tartaric acid, and the bases used to form the salts include but are not limited to 4-dimethylaminopyridine.

[0125] Terminology Definition

[0126] The terms "to form" and "to transform" do not specifically refer to a single-step transformation reaction between two substrates; they can be single-step or multi-step reactions between two substrates. If the intermediate contains a protecting group, the intermediate undergoes a step of deprotection before reacting with the corresponding substrate to obtain the target product.

[0127] The values ​​in this disclosure are instrument measurements and are subject to a certain degree of error. Generally, ±10% is within the reasonable error range. Of course, the context in which the value is used must be considered. For example, in the case of particle size of the active ingredient, where the measurement error variation does not exceed ±10%, the value can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0128] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0129] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0130] Unless otherwise stated, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The natural abundance of deuterium in the compounds in the examples can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or higher. Commercially available deuterated starting materials can be used to prepare compounds in their deuterated form, or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0131] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations.

[0132] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms are also included. 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, and their various branched isomers. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable link, preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, oxo groups, cyano groups, amino groups, C1-6 alkyl groups, C1-6 alkoxy groups, 3- to 6-membered cycloalkyl groups, or 3- to 6-membered heterocycloalkyl groups, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl group is optionally substituted with a halogen, hydroxyl, nitro, cyano, or amino group.

[0133] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxyl, oxo, cyano, amino, C1-6 alkyl, C1-6 alkoxy, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally substituted by halogen, hydroxyl, nitro, cyano, or amino.

[0134] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0135] "Substitution" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms that are independently substituted by the corresponding number of substituents.

[0136] DCM: Dichloromethane

[0137] EA: Ethyl acetate

[0138] DIP-Cl: Diisopinepine chloroborane

[0139] LiAlH[OC(CH3)3]3: Lithium tritert-butoxyaluminum hydride

[0140] DIBAL-H: Diisobutylaluminum hydride

[0141] NaBH4: Sodium borohydride. Detailed Implementation

[0142] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure and are not intended to limit the substance and scope of the present disclosure.

[0143] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0144] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), or a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0145] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0146] Chromatographic conditions: The analysis was performed using an Agilent 1200 chromatographic column, a CHIRALPAK AD-H column (5µm*4.6mm*250mm), an elution gradient of hexane solution containing 20% ​​ethanol (containing 0.1% diethylamine), a flow rate of 1.0 mL / min, a detection temperature of 30℃, and a detection wavelength of 230 nm.

[0147] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0148] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0149] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0150] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0151] In the examples, the reaction process was monitored using thin-layer chromatography (TLC). The volume ratio of the developing solvent used in the reaction, the eluent system used for column chromatography to purify the compound, and the developing solvent system for TLC were adjusted according to the different polarities of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0152] Example 1

[0153] Step 1: (1S,5R)-1-(4-bromophenyl)-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane-3-one D-(+)-di-p-methoxybenzoyl tartrate compound 1b-HA

[0154] Under nitrogen protection, dichloromethane (800 kg, 10-11 Vol) was added to a 1000 L reactor. 1-(4-bromophenyl)-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane-3-one (compound 1a, 60 kg, 1.0 eq) was added to the reactor and stirred until dissolved. (+)-di-p-methoxybenzoyl-D-tartaric acid (31.4 kg, 0.5 eq.) was added in batches. The mixture was heated to 40 °C and refluxed. After the solid dissolved, the mixture was slowly cooled to 35 °C. 0.05% seed crystals were added to induce solid precipitation. The mixture was stirred continuously until a large amount of solid precipitated. The mixture was then centrifuged. The filter cake was washed with dichloromethane (1-2 vol), and the solid was transferred to a 1000 L reactor. Dichloromethane (3.5-4 vol) was added, the mixture was heated to 35 °C and stirred for 6 h, then cooled to 25 °C and stirred for 3 h, then cooled to 10 °C and stirred for 3 h. The mixture was then centrifuged. The product was dried under vacuum at 45 °C to obtain compound 1b-HA, 36.8 kg, ee ≥ 99%, yield 30%.

[0155] 1 H NMR(400MHz,MeOH-d4)δ8.08–8.02(m,4H),7.53(s,4H),7.36–7.22(m,2H),7.05–6.98(m,4H),6.91–6.79(m,2H),5.91(s,2H),3. 87(s,6H),3.82–3.61(m,5H),3.47(d,J=13.4Hz,1H),3.15-2.93(m,1H),2.80–2.65(m,1H),2.33–1.92(m,4H),1.71–1.56(m,1H).

[0156] Step 2

[0157] (1S,3S,5R)-1-(4-bromophenyl)-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane-3-ol compound 1c

[0158] Under nitrogen protection, dichloromethane (600 kg, 16-18 vol) and compound 1b (33 kg, 1.0 eq.) were added to a 1000 L reactor. A 1 M sodium hydroxide aqueous solution was slowly added to adjust the pH to 10. The mixture was stirred, separated, and the organic phases were combined and concentrated. Under nitrogen protection, anhydrous tetrahydrofuran (110 kg, 3-4 vol) was added, and the mixture was cooled to -15 °C. Under nitrogen protection, anhydrous tetrahydrofuran was added to a heptane solution of (-)-diisopinepinechloroborane (33 kg, 1.5 eq., 1.7 M), and the mixture was stirred until homogeneous. The prepared (-)-diisopinepinechloroborane was slowly added dropwise to the reaction system, and the mixture was stirred continuously for 12 h. Purified water was slowly added dropwise, and the mixture was stirred for 1 h before being concentrated to 1-2 vol. Isopropyl acetate was added and the mixture was stirred and concentrated. Isopropyl acetate was added again and methyl tert-butyl ether was slowly added to the reaction vessel. The mixture was stirred for 6 hours, centrifuged, and dried under vacuum at 45°C to obtain compound 1c, 17.7 kg, with a yield of 100%.

[0159] 1 H NMR (400MHz, DMSO-d6) δ11.79(d,1H,J=8.0Hz),7.97(brs,1H),7.80-7.58(m,4H),6.93(d,2H,J=8.0Hz),5.13(brs,1H),4.0 5-3.85(m,2H),3.75(s,3H),3.65-3.30(m,2H),3.05-2.70(m,3H),2.69-2.33(m,2H),2.32-2.10(m,1H),1.92-1.82(m,2H).

[0160] Ms(ESI): m / z 402[M+1] + .

[0161] Step 3

[0162] (1S,3S,5R)-1-(4-bromophenyl)-3-ethoxy-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane DL-camphor sulfonate compound 1d-HA

[0163] Add 7wt% sodium bicarbonate aqueous solution and compound 1c (16.8 kg, 1.0 eq.) sequentially to the reaction vessel and stir for 1 h. Extract with dichloromethane, combine the organic phases, and concentrate until no droplets remain. Add DMF (320 kg, 20-22 vol). Add sodium tert-butoxide (4.8 kg, 1.3 eq.) and iodoethane (6.0 kg, 1.0 eq.) in portions to the reaction vessel at 0-10 °C, and continue stirring at room temperature for 1 h after the addition is complete. Raise the temperature to 25 °C and continue stirring for 6-12 h. After the reaction is complete, add purified water to the reaction vessel, slowly add 25% ammonium chloride aqueous solution, and stir for 0.5 h. Add methyl tert-butyl ether and isopropyl acetate to the reaction vessel, stir, and let stand for 0.5 h. Separate the layers; extract the aqueous phase again with methyl tert-butyl ether and isopropyl acetate, combine the organic phases, and concentrate until no droplets remain. Isopropyl acetate (130 kg, 9-10 vol) and DL-camphorsulfonic acid (8.9 kg, 1 eq) were added to a reaction vessel, heated to 50 °C and stirred for 4 hours. After centrifugation, the mixture was dried under vacuum at 45 °C to obtain compound 1d-HA, 22.8 kg, with a yield of 90%.

[0164] 1 H NMR (400MHz, DMSO-d6) δ9.87 (s, 1H), 7.97-755 (m, 4H), 7.44 (d, 2H, J = 8.0Hz), 6.99 (d, 2H, J = 8.0Hz), 3.95-3.56 (m,7H),3.47-3.35(m,1H),3.10-2.85(d,1H,J=14.6Hz),2.81-1.70(m,13H),1.42-0.95(m,10H),0.76(s,3H).

[0165] Ms(ESI): m / z 430[M+1] + .

[0166] Step 4

[0167] 4-((1S,3S,5R)-3-ethoxy-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane-1-yl)benzoic acid compound 1e-HA

[0168] Compound 1d-HA (21.6 kg, 1.0 eq.) and methyl tert-butyl ether (110 kg, 7-8 vol) were added to a 300 L reactor, and stirring was started. Sodium hydroxide aqueous solution (2.6 kg sodium hydroxide added to 120 kg purified water) was slowly added dropwise. After the addition was complete, the mixture was extracted twice with methyl tert-butyl ether, and the organic phases were combined and concentrated until no droplets remained. Under nitrogen protection, anhydrous tetrahydrofuran (70 kg, 4-5 vol) was added to the reactor, and the temperature was controlled below -50 °C. A 2.0 M solution of isopropyl magnesium chloride in tetrahydrofuran (12 kg, 0.7 eq) was slowly added to the reactor, and the mixture was stirred for 0.5 hours. A 2.5 M solution of n-butyllithium in hexane (13.3 kg, 1.4 eq) was slowly added to the reactor, and the mixture was stirred continuously at -50 °C for 4 hours. Dry carbon dioxide gas was slowly introduced into the reaction system, and the mixture was stirred continuously at -50 °C for 24 hours. After the reaction was complete, the temperature was raised to -5°C and water was added to quench the reaction. Dichloromethane, acetic acid, and purified water were added for extraction. The mixture was separated, and the organic phases were combined and concentrated until no droplets remained. Acetonitrile was added to the reaction vessel, and the temperature was raised to 40°C. 4-Dimethylaminopyridine (4.2 kg, 1.05 eq) was added to the reaction vessel, stirred, and the solid was collected by centrifugation. The solid was dried under vacuum at 45°C to give compound 1e-HA, 13.6 kg, yield 80%.

[0169] 1 HNMR(400MHz,DMSO-d6)δ8.17-8.10(m,2H),7.95(d,2H,J=4.0Hz),7.64(d,2 H,J=8.0Hz),7.25(d,2H,J=8.0Hz),6.87(d,2H,J=8.0Hz),6.68-6.60(m,2H), 6.78-6.64(m,4H),3.48-3.31(m,3H),3.17-2.98(m,2H),2.97(s,6H),2.48-2 .31(m,1H),2.18-1.71(m,6H),1.52(d,1H,J=12.0Hz),1.13(t,3H,J=8.0Hz).

[0170] Ms(ESI): m / z 396[M+1] + .

[0171] Step 5

[0172] 4-((1S,3S,5R)-3-ethoxy-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane-1-yl)methyl benzoate compound 1f

[0173] At room temperature, compound 1e-HA (13.5 kg, 1.0 eq), 5% hydrochloric acid (70 kg, 5-6 vol), and dichloromethane (130 kg, 7-8 vol) were added sequentially to a flask. The mixture was stirred, separated, and extracted once more with dichloromethane. The organic phases were combined and concentrated until no droplets remained. Methanol (50 kg, 5-6 vol) was added to the reaction vessel, and the temperature was lowered to 5°C. Thionyl chloride (3.4 kg, 1.1 eq) was slowly added dropwise to the reaction vessel. After the addition was complete, the temperature was raised to 50°C and stirred for 12 hours. After the reaction was complete, the temperature was lowered to 5°C, and purified water and a 7 wt% sodium bicarbonate aqueous solution were slowly added. The organic phase was concentrated to 9-10 vol, and dichloromethane was added. The mixture was stirred and separated. The organic phases were extracted once more with dichloromethane, combined, and concentrated to 1-2 vol. Methanol was added to the reaction vessel, heated to 50°C and stirred, then cooled to 10-15°C and stirred for 3 hours. The mixture was filtered, the solid was collected by centrifugation, and dried under vacuum at 45°C to give compound 1f, 9.6 kg, yield 90%.

[0174] 1 HNMR (400MHz, DMSO-d6) δ7.95(d,2H,J=8.0Hz),7.68(d,2H,J=8.0Hz),7.24(d,2H,J=8.0Hz),6.86(d,2H,J=8.0Hz),3.83(s,3H),3.78- 3.65(m,4H),3.48-3.39(m,3H),3.15-2.98(m,2H),2.45-2.30(m,1H),2.16-1.75(m,6H),1.51(d,1H,J=16.0Hz),1.12(t,3H,J=8.0Hz).

[0175] Ms(ESI): m / z 410[M+1] + .

[0176] Step 6

[0177] 4-((1S,3S,5R)-3-ethoxy-8-azabicyclo[3.2.1]octane-1-yl)methyl benzoate compound 1

[0178] Method 1:

[0179] Under nitrogen protection, acetonitrile (50 kg, 6-7 vol) and compound 1f (9.4 kg, 1.0 eq) were added to a reaction vessel. The mixture was cooled to 10 °C, and a solution of cerium ammonium nitrate (38 kg, 3.0 eq) in water (60 kg, 6-7 vol) was slowly added dropwise to the reaction vessel. The reaction was carried out at 25 °C for 15 hours. After the reaction was completed, methyl tert-butyl ether and isopropyl acetate were added for extraction twice. The organic phases were combined and concentrated until no droplets remained. Methyl tert-butyl ether was added to the reaction vessel, the temperature was raised to 50 °C, and the mixture was stirred for 3 hours. The temperature was then lowered to 10 °C, and the mixture was stirred for 2 hours. The mixture was centrifuged and dried under vacuum at 45 °C to obtain 7.4 kg of compound 1, with a yield of 85%.

[0180] Method 2:

[0181] Under nitrogen protection, ethanol (130 kg, 5 vol), compound 1f (32.36 kg, 1.0 eq), and formic acid (14.50 kg, 4 eq) were added to a reaction vessel and stirred until dissolved. The mixture was then purged with nitrogen three times. Palladium on carbon (3.24 kg, 10% wt) and water (16 kg) were added to the reaction vessel. The temperature was controlled at 20–30 °C, and the mixture was stirred for 10 h. After the reaction was completed, the reaction solution was filtered under nitrogen protection and washed successively with ethanol and purified water. All filtrates were combined, concentrated under reduced pressure to remove ethanol, and then extracted with n-heptane. After adjusting the aqueous phase with alkali, the product was precipitated, centrifuged, and dried to obtain 20.48 kg of compound 1, with a yield of 89.6%.

[0182] 1 H NMR (400MHz, DMSO-d6) δ7.90 (d, 2H, J = 8.0Hz), 7.53 (d, 2H, J = 8.0Hz), 3.83 (s, 3H), 3.64-3.55 (m, 1H), 3.53-3.45 (m, 1H), 3.45-3.34 (m, 2H),2.53-2.52(m,1H),2.44(s,1H),2.10-1.98(m,2H),1.85-1.70(m,3H),1.68-1.61(m,1H),1.56-1.47(m,1H),1.32(t,3H,J=8.0Hz).

[0183] Ms(ESI): m / z 290[M+1] + .

[0184] Example 2

[0185] Preparation of (1S,5R)-1-(4-bromophenyl)-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane-3-one D-(+)-di-p-methoxybenzoyl tartrate

[0186] Compound 1a (1 g, 2.5 mmol, 1.0 eq.) and dichloromethane (10 mL, 10 V) were added to a 50 mL dry reaction flask and stirred at room temperature until dissolved. (+)-di-p-methoxybenzoyl-D-tartaric acid (0.471 g, 1.12 mmol, 0.45 eq.) was added, and the reaction solution was heated to 40 °C and refluxed for 2 h. The solution was then cooled to 0–5 °C and stirred for 1 h. The mixture was filtered and dried under reduced pressure at 40 °C to obtain 0.518 g of compound 1b-HA, with a yield of 25.3% and an ee value of 95.30%.

[0187] Compound 1a (1 g, 2.5 mmol, 1.0 eq.) and dichloromethane (10 mL, 10 V) were added to a 50 mL dry reaction flask and stirred at room temperature until dissolved. (+)-di-p-methoxybenzoyl-D-tartaric acid (0.523 g, 1.25 mmol, 0.5 eq.) was added, and the reaction solution was heated to 40 °C and refluxed for 2 h. The temperature was then lowered to 0–5 °C and stirred for 1 h. The mixture was filtered and dried under reduced pressure at 40 °C to obtain 0.727 g of compound 1b-HA, with a yield of 35.5% and an ee value of 95.10%.

[0188] Compound 1a (1 g, 2.5 mmol, 1.0 eq.) and dichloromethane (10 mL, 10 V) were added to a 50 mL dry reaction flask and stirred at room temperature until dissolved. (+)-di-p-methoxybenzoyl-D-tartaric acid (0.678 g, 1.62 mmol, 0.65 eq.) was added, and the reaction solution was heated to 40 °C and refluxed for 2 h. The solution was then cooled to 0–5 °C and stirred for 1 h. The mixture was filtered and dried under reduced pressure at 40 °C to obtain 0.871 g of compound 1b-HA, with a yield of 42.6% and an ee value of 31.30%.

[0189] Compound 1a (4.0 g, 9.99 mmol, 1.0 eq.) and dichloromethane (40 mL, 10 V) were added to a 100 mL dry reaction flask and stirred at room temperature until dissolved. (+)-di-p-methoxybenzoyl-D-tartaric acid (2.09 g, 5.00 mmol, 0.5 eq.) was added, and the reaction mixture was heated to 40 °C and refluxed for 2 h. The mixture was then cooled to 0–5 °C and stirred for 1 h, followed by filtration. The filter cake was refluxed with dichloromethane (14.2 mL, 3.5 V) for 3 h, cooled to 0–5 °C, and stirred for 1 h. The mixture was then filtered, and the filter cake was dried under reduced pressure at 40 °C to obtain 2.67 g of compound 1b-HA as a white solid, with a yield of 32.6% and an ee value of 99.07%.

[0190] Compound 1a (5.0 g, 12.5 mmol, 1.0 eq.) and dichloromethane (75 mL, 15 V) were added to a 100 mL dry reaction flask. The mixture was heated to 35 °C and (+)-di-p-methoxybenzoyl-D-tartaric acid (2.61 g, 6.25 mmol, 0.5 eq.) was added. The mixture was then refluxed at 40 °C for 2 h, cooled to 0–5 °C and stirred for 1 h. The mixture was filtered and dried under reduced pressure at 40 °C to obtain a filter cake. The filter cake was then refluxed with ethyl acetate (16.75 mL, 3.4 V) for 3 h, cooled to 0–5 °C and stirred for 1 h, filtered, and dried under reduced pressure at 40 °C to obtain 2.64 g of compound 1b-HA, a white solid product with a yield of 25.8% and an ee value of 99.60%.

[0191] Example 3

[0192] (1S,5R)-1-(4-bromophenyl)-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane-3-one compound 1b

[0193] Compound 1b-HA (2.67 g, 3.26 mmol, 1.0 eq., ee value 99.07%), dichloromethane (37 mL), and 1 mol / L sodium hydroxide aqueous solution (18.7 mL) were added to a 100 mL dry reaction flask. The mixture was stirred at room temperature for 20 minutes. After the reaction solution became clear, it was separated into two phases. The aqueous phase was extracted with dichloromethane (18.7 mL). The organic phases were combined, washed with saturated brine (18.7 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 35 °C to obtain 1.20 g of compound 1b as a white foamy solid with a yield of 91.95%, purity of 99.87%, and ee value of 98.96%.

[0194] MS m / z(ESI): 400 / 402[M+1] + .

[0195] 1 H NMR(400MHz,Chloroform-d)δ:7.51(d,J=8.8Hz,2H),7.42(d,J=8.8Hz,2H),7.27(d,J=7.6Hz,2H),6.87(d,J=8.8H z,2H),3.81(s,3H),3.67–3.57(m,1H),3.57–3.42(m,2H),2.89–2.73(m,3H),2.23–1.92(m,4H),1.65–1.55(m,1H).

[0196] Comparative Example 1

[0197] Following the procedure in Example 1, a fixed amount of 500 mg of compound 1a was added, and the following resolution conditions were selected to investigate the factors affecting the resolution of compound 1a. The results are shown in Table 1.

[0198] Table 1 Note: *The method of Reference Example 2 is adopted according to WO2023237041A1. HA1: L-dibenzoyl tartaric acid; HA2: (+)-di-p-methoxybenzoyl-D-tartaric acid.

[0199] Conclusion: Using dibenzoyl tartaric acid cannot form a salt of compound 1a and does not have a resolving effect.

[0200] Comparative Example 2

[0201] Following the operating method in Example 1, 100 mg of compound 1a was added at a fixed rate. The following resolution conditions were selected to investigate the factors affecting the resolution of compound 1a. The results are shown in Table 2.

[0202] Table 2 Note: HA1': D-(+)-Dibenzoyl tartaric acid; HA3: D-(+)-Di-p-methylphenylbenzoyl tartaric acid.

[0203] Conclusion: (+)-di-p-methoxybenzoyl-D-tartaric acid exhibits superior resolution performance in DCM compared to acetonitrile and ethyl acetate; in dichloromethane, (+)-di-p-methoxybenzoyl-D-tartaric acid can precipitate as a salt with a salt formation ratio of 1 / 1.

[0204] Comparative Example 3

[0205] According to the operating method in Example 1, different reducing agents were used to investigate their effect on the chiral configuration of the reduction product. The results are shown in Table 3 below.

[0206] Table 3

[0207] Conclusion: Using DIP-Cl can ensure the stability of the reduction product configuration.

Claims

1. A method for preparing a compound of formula G or a pharmaceutically acceptable salt thereof: The step includes the formation of compound B from compound A in the presence of a resolving agent selected from (+)-di-p-methoxybenzoyl-D-tartaric acid. in, R 1 Selected from C 1-6 Alkyl groups, wherein the alkyl group is optionally composed of one or more elements selected from deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or amino substitutions; R 2 Selected from C 1-6 Alkyl group, wherein the alkyl group is optionally composed of one or more elements selected from C10. 1-6 Alkyl, C 1-6 Alkoxy, halogen, or amino substitutions; X is selected from halogens; PG is selected from benzyl or p-methoxybenzyl.

2. According to the preparation method of claim 1, the molar ratio of compound A to resolving agent is selected from 1:0.4 to 1:0.6, preferably 1:0.

5.

3. The preparation method according to claim 1 or 2, wherein the solvent for resolving compound A is selected from dichloromethane, acetonitrile, and ethyl acetate, preferably dichloromethane.

4. The preparation method according to any one of claims 1-3 further includes the step of reducing compound B to compound C in a reducing agent. Wherein PG and X are as defined in claim 1.

5. The preparation method according to claim 4, wherein the reducing agent is selected from: (-)-diisopinepine chloroborane, (+)-diisopinepine chloroborane, triisobutyllithium borohydride, sodium borohydride, DIBAL-H, LiAlH[OC(CH3)3]3, preferably (-)-diisopinepine chloroborane.

6. A method for preparing a compound of formula G-1 or a pharmaceutically acceptable salt thereof, comprising the following steps: Step 1: Compound A-1 is converted into compound B-1 in the presence of (+)-di-p-methoxybenzoyl-D-tartaric acid; Step 2: Compound B-1 is reduced to compound C-1 in (-)-diisopinepine chloroborane; Step 3: Compound C-1 reacts with iodoethane in the presence of sodium tert-butoxide to generate compound D-1; Step 4: Compound D-1 reacts with carbon dioxide in the presence of n-butyllithium and isopropylmagnesium chloride to generate compound E-1; Step 5: Compound E-1 reacts with methanol under thionyl chloride to generate compound F-1; Step 6: Deprotect the compound F-1 to generate compound G-1; 7. The method according to claim 6, characterized in that, The deprotection conditions in step 6 are selected from: 1) Compound F-1 undergoes deprotection in the presence of cerium ammonium nitrate to form compound G-1, or 2) Compound F-1 is deprotected in the presence of Pd / C and formic acid to form compound G-1.

8. The method according to claim 6 or 7, characterized in that, In step 1, the molar ratio of compound A-1 to (+)-di-p-methoxybenzoyl-D-tartaric acid is selected from 1:0.4 to 1:0.6, preferably 1:0.

5.

9. The method according to any one of claims 6-8, characterized in that, In step 1, the solvent for the resolving compound A-1 is selected from dichloromethane, acetonitrile, and ethyl acetate, with dichloromethane being preferred.

10. A method for preparing a compound of formula AA, said method comprising the steps of the method according to any one of claims 1-9.

11. Preparation method of compound B-1 This includes the step of resolving compound A-1 using a resolving agent. The resolving agent is selected from (+)-di-p-methoxybenzoyl-D-tartaric acid, and the molar ratio of compound A-1 to (+)-di-p-methoxybenzoyl-D-tartaric acid is 1:0.

5. The resolving solvent is selected from dichloromethane.

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