Method for preparing benzodioxole or salt thereof

Abstract

Disclosed is a method for preparing a benzodioxole derivative or a salt thereof, specifically a method for preparing (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine. The method has a good yield.

Description

Methods for preparing benzodioxane or its salts Technical Field

[0001] This disclosure belongs to the field of pharmaceutical technology and relates to a method for preparing benzodioxane derivatives. Background Technology

[0002] Glucagon-like peptide-1 (GLP-1) is an intestinal hypoglycemic hormone secreted by L-cells in the lower digestive tract. GLP-1 exerts its effects by binding to its widely distributed specific receptors. Organs where GLP-1 receptors are known to exist include pancreatic islet cells, gastrointestinal tract, lungs, brain, kidneys, hypothalamus, and cardiovascular system. GLP-1 receptors may also be present in the liver, adipose tissue, and skeletal muscle. GLP-1 not only acts on β-cells to promote insulin secretion but also acts on α-cells to inhibit glucagon secretion. Serum GLP-1 levels generally do not differ significantly among patients with normal glucose tolerance, impaired glucose tolerance, and type II diabetes. However, the β-cell response to GLP-1 after eating is defective, and under certain conditions, this response is significantly enhanced after continuous GLP-1 infusion. Because the duration of action of the body's own GLP-1 is very short (t1 / 2 < 1.5 minutes after intravenous injection), the body's own GLP-1 is not suitable for the clinical treatment of diabetes.

[0003] WO2022007979A1 discloses a small molecule GLP-1 receptor agonist having the formula AA. WO2022007979A1 discloses a method for synthesizing (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperidine:

[0004] This method uses expensive raw materials, and the route involves several reaction steps with low yields and numerous side reactions, resulting in a low overall yield. Furthermore, the method requires chiral preparative chromatographic separation and purification to obtain the desired intermediates, which further reduces the yield and is not conducive to industrial-scale production.

[0005] This disclosure provides a new synthetic approach and route, which is concise and reduces synthesis costs. At the same time, it avoids harsh reaction conditions, has simple reaction conditions, strong process operability, is conducive to industrial production needs, and reduces environmental pressure. Summary of the Invention

[0006] This disclosure provides a method for preparing a compound of formula H or a salt thereof.

[0007] The method includes the step of reacting compound B with compound II to form compound C. in,

[0008] Ring A is selected from 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally converted by one or more halogens, hydroxyl groups, nitro groups, cyano groups, or C-membered rings. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0009] R1 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally oxidized by one or more halogens, nitro groups, cyano groups, C6 groups, or C4 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted, and n is 0, 1, 2 or 3;

[0010] R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, and carbon. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more halogen, amino, hydroxyl, or cyano groups;

[0011] R6 and R7 are each independently selected from hydrogen or hydroxyl protecting groups, or R6 and R7 together with the atoms attached to them form a 3-8 membered heterocycle, wherein the 3-8 membered heterocycle is optionally independently protected by 0, 1, 2 or 3 R groups. a replace;

[0012] Each R a Each is independently selected from hydrogen, carbonyl, and C. 1-6 Alkyl, C 1-6 alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, aryl, or heteroaryl group is optionally converted to one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0013] PG is an amino protecting group.

[0014] In some implementations, R1 is independently selected from hydrogen.

[0015] In some implementations, R1 is independently selected from halogen, amino, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally oxidized by one or more halogens, nitro groups, cyano groups, C6 groups, or C4 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0016] In some implementation schemes, R2 and R3 are each independently selected from hydrogen and C. 1-6 alkyl.

[0017] In some implementations, R2 and R3 are each independently selected from hydrogen and methyl.

[0018] In some embodiments, R2 and R3 are hydrogen. In some embodiments, R2 and R3 are each independently selected from halogens, C, and other organic compounds. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more halogen, amino, hydroxyl or cyano groups.

[0019] In some implementation schemes, R4 and R5 are each independently selected from hydrogen and C. 1-6 alkyl.

[0020] In some implementation schemes, R4 and R5 are each independently selected from hydrogen and methyl.

[0021] In some embodiments, R4 and R5 are hydrogen. In some embodiments, R4 and R5 are each independently selected from halogens, C, and other organic compounds. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more halogen, amino, hydroxyl or cyano groups.

[0022] In some embodiments, the amino protecting group is selected from (C 1-10 alkyl or aromatic group) acyl group, (C 1-6 Alkyl or C 6-10 aryl)sulfonyl, (C 1-6 Alkoxy or C 6-10 Aryloxy)carbonyl, triphenylmethyl (Tr), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB) or benzyl (Bn).

[0023] In some implementations, PG is selected from tert-butyloxycarbonyl.

[0024] In some embodiments, compound II is selected from...

[0025] In some embodiments, compound II is compound II-1.

[0026] In some implementation schemes, R6 and R7 are each independently selected from hydrogen, (C 1-10 alkyl or aryl) 3-silyl, C 1-10 Alkyl, alkoxy or aryl substituted alkyl, (C 1-10 alkyl or aromatic group) acyl group, (C 1-6 Alkyl or C 6-10 aryl)sulfonyl, (C 1-6 Alkoxy or C 6-10 Aryloxy)carbonyl.

[0027] In some embodiments, R6 and R7 are each independently selected from triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, (trimethylsilyl)ethoxymethyl (SEM), methyl, ethyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, N,N-diethylformyl, acetyl, and benzoyl.

[0028] In some embodiments, R6, R7, together with the atoms they are attached to, form a 3-8 membered heterocycle, which is optionally independently bounded by 0, 1, 2, or 3 R atoms. a replace.

[0029] In some embodiments, R6, R7, and the atoms they are attached to form a 5-membered heterocycle, which is optionally independently bounded by one or two R atoms. a Replace, each R a Each is independently selected from carbonyl, phenyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl, alkoxy, or phenyl group is optionally oxidized by one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0030] In some implementations, R6, R7, and the atoms they are bonded to form The Optionally and independently controlled by 1 or 2 R a Replace, each R a Each is independently selected from carbonyl, phenyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl, alkoxy, or phenyl group is optionally oxidized by one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0031] In some implementations, each R a It is hydrogen. In some implementations, each R... a Each is independently selected from carbonyl, C 1-6 Alkyl, C 1-6 alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, aryl, or heteroaryl group is optionally converted to one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted. In some embodiments, each R... a Each is independently selected from C 1-6 Alkyl or C 1-6 Alkyl group.

[0032] In some implementations, R6, R7, and the atoms they are bonded to form Each R a Each is independently selected from carbonyl, phenyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl, alkoxy, or phenyl group is optionally oxidized by one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0033] In some embodiments, compound B is compound B-1. R1, R a , n as defined above.

[0034] In some embodiments, compound B is compound B-2. R1 and n are defined as described above.

[0035] In some implementations, compound B is selected from...

[0036] In some implementations, compound B is compound b.

[0037] In some embodiments, compound C is compound C-1. PG, R1, R4, R5, R a And n as defined above.

[0038] In some embodiments, compound C is compound C-2. PG, R1, R4, R5 and n are as defined above.

[0039] In some embodiments, compound C is compound c.

[0040] In some implementations, ring A is selected from... Each R8 group is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy group, m is selected from 0, 1, 2, 3, 4.

[0041] In some embodiments, each R8 is independently selected from hydrogen, methyl, methoxy, cyano, fluorine, chlorine, and bromine.

[0042] In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2.

[0043] In some implementations, ring A is selected from...

[0044] In some implementations, ring A is selected from...

[0045] In some embodiments, compound H in the method is (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine (compound h-2) or (R)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine (compound h-3).

[0046] In some embodiments, compound H in the method is compound h-2. In some embodiments, compound H in the method is compound h-3.

[0047] In some embodiments, the method for preparing the compound of formula H further includes the step of reacting compound B with compound II in the presence of base I.

[0048] In some embodiments, the base I is selected from lithium hexylene, lithium phenylene, lithium mesitylene, lithium n-butylene, lithium tert-butylene, or lithium sec-butylene.

[0049] In some embodiments, the base I is n-butyllithium.

[0050] In some implementations, the solvent used for the reaction of compound B is selected from tetrahydrofuran, n-hexane, and toluene.

[0051] In some embodiments, the solvent used for the reaction of compound B is selected from tetrahydrofuran.

[0052] In some embodiments, the molar ratio of compound B to compound 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 other embodiments, the molar ratio of compound B to compound II is 1:1 to 1:1.5.

[0053] In some embodiments, the molar ratio of compound B to compound II is 1:1.

[0054] In some embodiments, the molar ratio of compound B 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 other embodiments, the molar ratio of compound B to base I is 1:1.5. In still other embodiments, the molar ratio of compound B to base I is 1:1.1.

[0055] In some embodiments, the molar ratio of compound B to n-butyllithium is 1:1. In some embodiments, the molar ratio of compound B to n-butyllithium is 1:1.1.

[0056] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound B with compound II in the presence of base I to form compound C. PG, R1, R4 to R7 and n are as defined above.

[0057] In some embodiments, compound B is compound B-1, and the method for preparing compound H or a salt thereof includes the step of reacting compound B-1 with compound II in the presence of base I to generate compound C-1. PG, R1, R a R4, R5 and n are as defined above.

[0058] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound B-2 with compound II in the presence of base I to generate compound C-2. PG, R1, R4, R5 and n are as defined above.

[0059] In some implementations, n is 0.

[0060] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound b with compound II-1 under n-butyllithium conditions to generate compound c.

[0061] In some embodiments, the method for preparing the compound of formula H further includes the step of reacting compound B with compound II in the presence of base I, stabilizer I and stabilizer II.

[0062] In some embodiments, the stabilizer I is selected from N,N,N',N'-tetramethylethylenediamine, hexamethylphosphoric triamine, crown ether, 1,2-dimethoxyethane, ethylenediamine, and N,N'-dimethylpropanediamine.

[0063] In some embodiments, the stabilizer I is N,N,N',N'-tetramethylethylenediamine.

[0064] In some embodiments, the molar ratio of compound B to stabilizer I is 1:0.5 to 1:2, including but not limited to 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 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 other embodiments, the molar ratio of compound B to N,N,N',N'-tetramethylethylenediamine is 1:1.

[0065] In some embodiments, the stabilizer II is selected from lithium bromide, lithium chloride, lithium iodide, lithium nitrate, lithium tetrafluoroborate, lithium trifluoromethanesulfonate, magnesium chloride, cesium chloride, zinc chloride, and lanthanum chloride.

[0066] In some embodiments, stabilizer II is lithium chloride. In some embodiments, stabilizer II is lithium bromide.

[0067] In some embodiments, the molar ratio of compound B to stabilizer II is 1:0.5 to 1:2, including but not limited to 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 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 other embodiments, the molar ratio of compound B to lithium bromide is 1:1.

[0068] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound B-1 with compound II in the presence of base I and stabilizer I / stabilizer II to generate compound C-1. PG, R1, R a R4, R5 and n are as defined above.

[0069] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound B-2 with compound II in the presence of base I and stabilizer I / stabilizer II to generate compound C-2. PG, R1, R4, R5 and n are as defined above.

[0070] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound b with compound II-1 under n-butyllithium, N,N,N',N'-tetramethylethylenediamine / lithium bromide conditions to generate compound c.

[0071] In some embodiments, the preparation method of the compound of formula H further includes the step of reacting compound B with compound II in the presence of base I, stabilizer I and stabilizer II, and base II, wherein base II is selected from potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, KHMDS, and NaHMDS.

[0072] In some implementations, base II is selected from potassium tert-butoxide.

[0073] In some embodiments, the molar ratio of compound B to base II is 1:1% to 1:100%, 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%, 1:20%, 1:30%, 1:40%, 1:50%, 1:60%, 1:70%, 1:80%, 1:90%, 1:100%, or any value between any two numbers. In other embodiments, the molar ratio of compound B to potassium tert-butoxide is 1:10%.

[0074] In some embodiments, the reaction temperature between compound B and compound II is -50°C to 0°C, specifically -50°C, -45°C, -40°C, -35°C, -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, -0°C, or any value between any two numbers. In some embodiments, the reaction temperature is -10°C to 0°C.

[0075] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound B-1 with compound II in the presence of base I, stabilizer I / stabilizer II, and potassium tert-butoxide to generate compound C-1. PG, R1, R a R4, R5 and n are as defined above.

[0076] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound B-2 with compound II in the presence of base I, stabilizer I / stabilizer II, and potassium tert-butoxide to generate compound C-2. PG, R1, R4, R5 and n are as defined above.

[0077] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound b with compound II-1 under conditions of n-butyllithium, N,N,N',N'-tetramethylethylenediamine / lithium bromide, and potassium tert-butoxide to generate compound c.

[0078] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound B with compound II in the presence of base I, stabilizer I and stabilizer II, and potassium tert-butoxide, said reaction being carried out in a batch reactor.

[0079] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound B with compound II in the presence of base I, stabilizer I and stabilizer II, and potassium tert-butoxide, said reaction being carried out in a continuous flow microchannel reactor.

[0080] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound b with compound II-1 under conditions of n-butyllithium, N,N,N',N'-tetramethylethylenediamine / lithium bromide, and potassium tert-butoxide, said reaction being carried out in a batch reactor.

[0081] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound b with compound II-1 under conditions of n-butyllithium, N,N,N',N'-tetramethylethylenediamine / lithium bromide, and potassium tert-butoxide, said reaction being carried out in a continuous flow microchannel reactor.

[0082] Some embodiments provide methods for preparing compound H or its salts, including the step of reacting compound C with catalyst I / reducing agent I to generate compound D. R1, R4 to R7, PG and n are as defined above.

[0083] In some embodiments, the catalyst I is selected from Pd / C, Pt / C, Ru / C, Pd(OH)2 / C, Pd(OH)2 / Al2O3, Pt / Al2O3, Ru / Al2O3, and Pd / Al2O3.

[0084] In some embodiments, the reducing agent I is selected from hydrogen.

[0085] In some embodiments, the solvent used for the reaction of compound C is selected from tetrahydrofuran, water / tetrahydrofuran, methanol, water / methanol, ethanol, and water / ethanol.

[0086] In some embodiments, the solvent used for the reaction of compound C is selected from tetrahydrofuran.

[0087] In some embodiments, the solvent used for the reaction of compound C is selected from water / tetrahydrofuran.

[0088] In some embodiments, the method for preparing compound H or its salt further includes the step of reacting compound C with an acid in the presence of catalyst I / reducing agent I to generate compound D.

[0089] In some embodiments, the acid is selected from salicylic acid, sulfuric acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, and hydrochloric acid.

[0090] In some embodiments, the acid is selected from acetic acid. In some embodiments, the acid is selected from salicylic acid.

[0091] In some embodiments, compound C is compound C-1, and the method for preparing compound H or a salt thereof includes the step of reacting compound C-1 in the presence of catalyst I / reducing agent I to generate compound D. PG, R1, R a R4, R5 and n are as defined above.

[0092] In some embodiments, compound C is compound C-2, and the method for preparing compound H or a salt thereof includes the step of reacting compound C-2 in the presence of catalyst I / reducing agent I to generate compound D. PG, R1, R4, R5 and n are as defined above.

[0093] In some embodiments, compound C is compound c, and the method for preparing compound H or a salt thereof includes the step of reacting compound c with hydrogen in the presence of Pd / C to generate compound d.

[0094] In some embodiments, compound C is compound c, and the method further includes the step of reacting compound c with hydrogen in the presence of acetic acid and Pd / C to generate compound d.

[0095] In some embodiments, compound C is compound c, and the method further includes the step of reacting compound c with hydrogen in the presence of salicylic acid and Pd / C to generate compound d.

[0096] This disclosure provides compounds of formula C or salts thereof.

[0097] in,

[0098] Each R1 is independently selected from H, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy group, wherein the alkyl or alkoxy group is optionally surrounded by one or more elements selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is substituted by a substituent, where n is 0, 1, 2, or 3;

[0099] R4 and R5 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more halogen, amino, hydroxyl, or cyano groups;

[0100] R6 and R7 are each independently selected from hydrogen or hydroxyl protecting groups, or R6 and R7 together with the atoms attached to them form a 3-8 membered heterocycle, wherein the 3-8 membered heterocycle is optionally independently protected by 1, 2 or 3 R groups. a replace;

[0101] Each R a Each is independently selected from hydrogen, carbonyl, and C. 1-6 Alkyl, C 1-6 alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, aryl, or heteroaryl group is optionally converted to one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0102] PG is an amino protecting group.

[0103] In some embodiments, R1 is independently selected from hydrogen. In some embodiments, R1 is independently selected from halogen, amino, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy group, wherein the alkyl or alkoxy group is optionally surrounded by one or more elements selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is replaced by a substituent.

[0104] In some implementation schemes, R4 and R5 are each independently selected from hydrogen and C. 1-6 Alkyl group. In some embodiments, R4 and R5 are each independently selected from hydrogen and methyl groups. In some embodiments, R4 and R5 are hydrogen. In some embodiments, R4 and R5 are each independently selected from halogens and C. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more halogen, amino, hydroxyl, or cyano groups.

[0105] In some embodiments, the amino protecting group is selected from (C 1-10 alkyl or aromatic group) acyl group, (C 1-6 Alkyl or C 6-10 aryl)sulfonyl, (C 1-6 Alkoxy or C 6-10 The amino protecting group is aryloxycarbonyl, triphenylmethyl (Tr), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB), or benzyl (Bn). In some embodiments, the amino protecting group is tert-butyloxycarbonyl (Boc).

[0106] In some implementation schemes, R6 and R7 are each independently selected from hydrogen, (C 1-10 alkyl or aryl) 3-silyl, C 1-10 Alkyl, alkoxy or aryl substituted alkyl, (C 1-10alkyl or aromatic group) acyl group, (C 1-6 Alkyl or C 6-10 aryl)sulfonyl, (C 1-6 Alkoxy or C 6-10 Aryloxy)carbonyl.

[0107] In some embodiments, R6 and R7 are each independently selected from triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, (trimethylsilyl)ethoxymethyl (SEM), methyl, ethyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, N,N-diethylformyl, acetyl, and benzoyl.

[0108] In some embodiments, R6 and R7 are each independently selected from methyl, (trimethylsilyl)ethoxymethyl (SEM), methoxymethyl (MOM), ethoxyethyl, and N,N-diethylformyl.

[0109] In some embodiments, R6, R7, and the atoms they are attached to form a 3-8 membered heterocycle, which is optionally surrounded by 0, 1, 2, or 3 R atoms. a replace.

[0110] In some embodiments, R6, R7, and the atoms they are attached to form a 5-membered heterocycle, which is optionally bounded by one or two R atoms. a Replace, each R a Each is independently selected from carbonyl, phenyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl, alkoxy, or phenyl group is optionally oxidized by one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0111] In some implementations, R6, R7, and the atoms they are bonded to form The Choose one or two Rs a Replace, each R a Each is independently selected from carbonyl, phenyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl, alkoxy, or phenyl group is optionally oxidized by one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0112] In some implementations, R6, R7, and the atoms they are bonded to form Compound C is compound C-1. Each Ra Each is independently selected from carbonyl, phenyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl, alkoxy, or phenyl group is optionally oxidized by one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkoxy groups are substituted, R1, R4, R5, PG, n as defined above.

[0113] In some implementations, each R a Each is independently hydrogen. In some implementations, each R... a Each is independently selected from carbonyl, C 1-6 Alkyl, C 1-6 alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, aryl, or heteroaryl group is optionally converted to one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted. In some embodiments, each R... a Each independently is C 1-6 Alkyl or C 1-6 Alkyl group.

[0114] In some embodiments, each R in the C-1 compound a Each is independently selected from C 1-6 Alkyl, C 1-6 Alkyl group.

[0115] In some embodiments, each R in the C-1 compound a Each is independently selected from methyl, methoxy, and ethoxy.

[0116] This disclosure also provides a method for preparing a compound of formula C, comprising the step of reacting compound B with compound II. R1, R4, R5, R6, R7, PG, and n are as described above.

[0117] In some embodiments, the preparation method of the compound of formula C further includes the step of reacting compound B with compound II in the presence of base I.

[0118] In some embodiments, the base I is selected from lithium hexylene, lithium phenylene, lithium mesitylene, lithium n-butylene, lithium tert-butylene, or lithium sec-butylene.

[0119] In some embodiments, the base I is n-butyllithium.

[0120] In some implementations, the solvent used for the reaction of compound B is selected from tetrahydrofuran, n-hexane, and toluene.

[0121] In some embodiments, the solvent used for the reaction of compound B is selected from tetrahydrofuran.

[0122] In some embodiments, the molar ratio of compound B to compound 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 other embodiments, the molar ratio of compound B to compound II is 1:1 to 1:1.5.

[0123] In some embodiments, the molar ratio of compound B to compound II is 1:1.

[0124] In some embodiments, the molar ratio of compound B 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 other embodiments, the molar ratio of compound B to base I is 1:1.5. In some embodiments, the molar ratio of compound B to base I is 1:1.1.

[0125] In some embodiments, the molar ratio of compound B to n-butyllithium is 1:1. In some embodiments, the molar ratio of compound B to n-butyllithium is 1:1.1.

[0126] In some embodiments, the method for preparing compound C or a salt thereof includes the step of reacting compound B with compound II in the presence of base I. PG, R1, R4 to R7 and n are as defined above.

[0127] In some embodiments, compound C is compound C-1, and the method for preparing compound C-1 or a salt thereof includes the step of reacting compound B-1 with compound II in the presence of base I:

[0128] PG, R1, R a R4, R5 and n are as defined above.

[0129] In some embodiments, the method for preparing compound C or a salt thereof includes the step of reacting compound C-2 with compound II in the presence of base I. PG, R1, R4, R5 and n are as defined above.

[0130] In some implementations, n is 0.

[0131] In some embodiments, the method for preparing compound c or a salt thereof includes the step of reacting compound b with compound II-1 under n-butyllithium conditions.

[0132] In some embodiments, the preparation method of the compound of formula C further includes the step of reacting compound B with compound II in the presence of base I, stabilizer I and stabilizer II.

[0133] In some embodiments, the stabilizer I is selected from N,N,N',N'-tetramethylethylenediamine, hexamethylphosphoric triamine, crown ether, 1,2-dimethoxyethane, ethylenediamine, and N,N'-dimethylpropanediamine.

[0134] In some embodiments, the stabilizer I is N,N,N',N'-tetramethylethylenediamine.

[0135] In some embodiments, the molar ratio of compound B to stabilizer I is 1:0.5 to 1:2, including but not limited to 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 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 other embodiments, the molar ratio of compound B to N,N,N',N'-tetramethylethylenediamine is 1:1.

[0136] In some embodiments, the stabilizer II is selected from lithium bromide, lithium chloride, lithium iodide, lithium nitrate, lithium tetrafluoroborate, lithium trifluoromethanesulfonate, magnesium chloride, cesium chloride, zinc chloride, and lanthanum chloride.

[0137] In some embodiments, stabilizer II is lithium bromide. In some embodiments, stabilizer II is lithium chloride.

[0138] In some embodiments, the molar ratio of compound B to stabilizer II is 1:0.5 to 1:2, including but not limited to 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 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 other embodiments, the molar ratio of compound B to lithium bromide is 1:1.

[0139] In some embodiments, the method for preparing compound C-1 or a salt thereof includes the step of reacting compound B-1 with compound II in the presence of base I and stabilizer I / stabilizer II. PG, R1, R a R4, R5 and n are as defined above.

[0140] In some embodiments, the method for preparing compound C-2 or a salt thereof includes the step of reacting compound B-2 with compound II in the presence of base I and stabilizer I / stabilizer II:

[0141] PG, R1, R4, R5 and n are as defined above.

[0142] In some embodiments, the method for preparing compound c or a salt thereof includes the step of reacting compound b with compound II-1 under conditions of n-butyllithium, N,N,N',N'-tetramethylethylenediamine / lithium bromide:

[0143] In some embodiments, the preparation method of compound C further includes the step of reacting compound B with compound II in the presence of base I, stabilizer I and stabilizer II, and base II, wherein base II is selected from potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, KHMDS, and NaHMDS.

[0144] In some embodiments, the base II is selected from potassium tert-butoxide.

[0145] In some embodiments, the molar ratio of compound B to base II is 1:1% to 1:100%, 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%, 1:20%, 1:30%, 1:40%, 1:50%, 1:60%, 1:70%, 1:80%, 1:90%, 1:100%, or any value between any two numbers. In other embodiments, the molar ratio of compound B to potassium tert-butoxide is 1:10%.

[0146] In some embodiments, the reaction temperature between compound B and compound II is -50°C to 0°C, specifically -50°C, -45°C, -40°C, -35°C, -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, -0°C, or any value between any two numbers. In some embodiments, the reaction temperature is -10°C to 0°C.

[0147] In some embodiments, the method for preparing compound C-1 or a salt thereof includes the step of reacting compound B-1 with compound II in the presence of base I, stabilizer I / stabilizer II, and potassium tert-butoxide:

[0148] PG, R1, R a R4, R5 and n are as defined above.

[0149] In some embodiments, the method for preparing compound C-2 or a salt thereof includes the step of reacting compound B-2 with compound II in the presence of base I, stabilizer I / stabilizer II, and potassium tert-butoxide:

[0150] PG, R1, R4, R5 and n are as defined above.

[0151] In some embodiments, the method for preparing compound c or a salt thereof includes the step of reacting compound b with compound II-1 under conditions of n-butyllithium, N,N,N',N'-tetramethylethylenediamine / lithium bromide, and potassium tert-butoxide.

[0152] In some embodiments, the method for preparing compound C or a salt thereof includes the step of reacting compound B with compound II in the presence of base I, stabilizer I and stabilizer II, and potassium tert-butoxide, said reaction being carried out in a continuous flow microchannel reactor.

[0153] In some embodiments, the method for preparing compound c or a salt thereof includes the step of reacting compound b with compound II-1 under conditions of n-butyllithium, N,N,N',N'-tetramethylethylenediamine / lithium bromide, and potassium tert-butoxide, said reaction being carried out in a continuous flow microchannel reactor.

[0154] In some embodiments, the preparation method includes the following steps:

[0155] 1) After mixing solution A containing n-butyllithium and solution B containing potassium tert-butoxide, reaction solution 1 is obtained;

[0156] 2) Solution C containing stabilizer I and compound b is mixed with reaction solution 1 to obtain reaction solution 2;

[0157] 3) The solution D containing stabilizer II and compound II-1 is mixed with reaction solution 2 to obtain compound c.

[0158] This disclosure also provides a method for preparing a compound of formula D, comprising the aforementioned method for preparing a compound of formula C, and further comprising a step of reacting the compound of formula C under catalyst I / reducing agent I to generate compound D. R1, R4 to R7, PG and n are as defined above.

[0159] In some embodiments, the preparation method of compound D includes the following steps:

[0160] Step 1: Compound B reacts with compound II under alkaline conditions to form compound C;

[0161] Step 2: Compound C is converted to compound D under the conditions of catalyst I / reducing agent I;

[0162] In some embodiments, the catalyst I is selected from Pd / C, Pt / C, Ru / C, Pd(OH)2 / C, Pd(OH)2 / Al2O3, Pt / Al2O3, Ru / Al2O3, and Pd / Al2O3.

[0163] In some embodiments, the reducing agent I is selected from hydrogen.

[0164] In some embodiments, the solvent used for the reaction of compound C is selected from tetrahydrofuran, water / tetrahydrofuran, methanol, water / methanol, ethanol, and water / ethanol.

[0165] In some embodiments, the solvent used for the reaction of compound C is selected from tetrahydrofuran.

[0166] In some embodiments, the solvent used for the reaction of compound C is selected from water / tetrahydrofuran.

[0167] In some embodiments, the method for preparing compound H or its salt further includes the step of reacting compound C in the presence of an acid and a reducing agent I to generate compound D.

[0168] In some embodiments, the acid is selected from salicylic acid, sulfuric acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, and hydrochloric acid.

[0169] In some embodiments, the acid is selected from acetic acid. In some embodiments, the acid is selected from salicylic acid.

[0170] In some embodiments, the preparation method of compound D includes the following steps:

[0171] Step 1: Compound B reacts with Compound II under the conditions of base I, stabilizer I / stabilizer II, and potassium tert-butoxide to generate compound C;

[0172] Step 2: Compound C is converted into compound D under the conditions of catalyst I / reducing agent I.

[0173] In some embodiments, the preparation method of compound D includes the following steps:

[0174] Step 1: Compound B reacts with Compound II under the conditions of base I, stabilizer I / stabilizer II, and potassium tert-butoxide to generate compound C;

[0175] Step 2: Compound C is converted into compound D under the conditions of catalyst I / reducing agent I and acid.

[0176] In some embodiments, the preparation method of compound D includes the following steps:

[0177] Step 1: Compound A reacts with triethyl orthoacetate to form compound B;

[0178] Step 2: Compound B reacts with compound II under n-butyllithium conditions to generate compound C;

[0179] Step 3: Compound C is converted to compound D under Pd / C / hydrogen conditions;

[0180] In some embodiments, the preparation method of compound D includes the following steps:

[0181] Step 1: Compound A reacts with triethyl orthoacetate to form compound B;

[0182] Step 2: Compound B reacts with Compound II under the conditions of n-butyllithium, tetramethylethylenediamine, lithium bromide and potassium tert-butoxide to generate Compound C;

[0183] Step 3: Compound C is converted into compound D under Pd / C / hydrogen conditions.

[0184] In some embodiments, the preparation method of compound D includes the following steps:

[0185] Step 1: Compound A reacts with triethyl orthoacetate to form compound B;

[0186] Step 2: Compound B reacts with Compound II under the conditions of n-butyllithium, tetramethylethylenediamine, lithium bromide and potassium tert-butoxide to generate Compound C;

[0187] Step 3: Compound C is converted into compound D under Pd / C / hydrogen and acetic acid conditions.

[0188] In some embodiments, the preparation method of compound D includes the following steps:

[0189] Step 1: Compound A reacts with triethyl orthoacetate to form compound B;

[0190] Step 2: Compound B reacts with Compound II under the conditions of n-butyllithium, tetramethylethylenediamine, lithium bromide and potassium tert-butoxide to generate Compound C;

[0191] Step 3: Compound C is converted into compound D under Pd / C / hydrogen and salicylic acid conditions.

[0192] In some embodiments, compound D is compound d, and the method for preparing compound d or a salt thereof includes the following steps:

[0193] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0194] Step 2: Compound b reacts with compound II-1 under n-butyllithium conditions to generate compound c;

[0195] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0196] In some embodiments, the method for preparing the d-compound or a salt thereof includes the following steps:

[0197] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0198] Step 2: Compound b reacts with compound II-1 under the conditions of n-butyllithium, tetramethylethylenediamine, lithium bromide and potassium tert-butoxide to generate compound c;

[0199] Step 3: Compound c is reacted with Pd / C / hydrogen to form compound d.

[0200] In some embodiments, the method for preparing the d-compound or a salt thereof includes the following steps:

[0201] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0202] Step 2: Compound b reacts with compound II-1 under the conditions of n-butyllithium, tetramethylethylenediamine, lithium bromide and potassium tert-butoxide to generate compound c;

[0203] Step 3: Compound c is reacted with Pd / C / hydrogen and acetic acid to form compound d.

[0204] In some embodiments, the method for preparing the d-compound or a salt thereof includes the following steps:

[0205] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0206] Step 2: Compound b reacts with compound II-1 under the conditions of n-butyllithium, tetramethylethylenediamine, lithium bromide and potassium tert-butoxide to generate compound c;

[0207] Step 3: Compound c is reacted with Pd / C / hydrogen and salicylic acid to form compound d.

[0208] Some embodiments provide methods for preparing compound H or its salts, including the step of reacting compound D with compound III in the presence of base III to generate compound E. Where X is selected from halogens, and rings A, R1 to R5, PG and n are as defined above.

[0209] In some embodiments, the base III is selected from inorganic bases such as sodium carbonate (Na2CO3) and potassium carbonate (K2CO3), sodium bicarbonate (NaHCO3), potassium tert-butoxide (tBuOK), sodium tert-butoxide (tBuONa), lithium tert-butoxide (tBuOLi), sodium phosphate (Na3PO4), potassium phosphate (K3PO4), and cesium carbonate (Cs2CO3); and organic bases such as triethylamine, tetramethylguanidine, triethylenediamine (DABCO), DBU, N,N-diisopropylethylamine (DIPEA), and 2,2,6,6-tetramethylpiperidine (TMP).

[0210] In some embodiments, the base III is selected from organic bases, such as triethylenediamine (DABCO), DBU, N,N-diisopropylethylamine (DIPEA), and 2,2,6,6-tetramethylpiperidine (TMP).

[0211] In some embodiments, the base III is selected from 2,2,6,6-tetramethylpiperidine (TMP).

[0212] In some embodiments, the solvent used in the reaction of compound D is selected from dichloromethane, 1,2-dichloroethane, chloroform, methyl tert-butyl ether, toluene, cyclopentyl methyl ether, acetone, ethyl acetate, n-heptane, N,N-dimethylformamide, and acetonitrile.

[0213] In some embodiments, the solvent used in the reaction of compound D is selected from dichloromethane. In some embodiments, the solvent used in the reaction of compound D is selected from chloroform.

[0214] In some embodiments, the molar ratio of compound D to compound III 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 other embodiments, the molar ratio of compound D to compound III is 1:1.2 to 1:1.7.

[0215] In some embodiments, the molar ratio of compound D to compound III is 1:1.5.

[0216] In some embodiments, the molar ratio of compound D to base III 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 other embodiments, the molar ratio of compound B to base III is 1:2.

[0217] In other embodiments, the molar ratio of compound B to 2,2,6,6-tetramethylpiperidine (TMP) is 1:2.

[0218] In some implementations, X in compound III is selected from chlorine, bromine, and iodine.

[0219] In some embodiments, ring A in compound III is selected from... R8 is independently selected from hydrogen, methyl, methoxy, fluorine, chlorine or cyano, and m is selected from 0, 1, 2, 3, 4. In some embodiments, R8 is independently selected from methyl, methoxy, fluorine, chlorine or cyano.

[0220] In some embodiments, ring A in compound III is selected from... R8 is independently selected from hydrogen, cyano, fluorine, chlorine, and m is selected from 0, 1, 2, 3, 4. In some embodiments, R8 is independently selected from methyl, methoxy, fluorine, chlorine, or cyano.

[0221] In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2.

[0222] In some embodiments, ring A in compound III is selected from... In some embodiments, ring A in compound III is selected from...

[0223] In some embodiments, compound H is compound H-1. The method for preparing compound H-1 or its salt includes the step of reacting compound D with compound III-1 in the presence of base III to generate compound E-1.

[0224] R1, R4, R5, R8, PG, n, and m are defined as described above.

[0225] In some embodiments, compound H is compound H-2. The method for preparing compound H-2 or its salt includes the step of reacting compound D with compound III-2 in the presence of base III to generate compound E-2.

[0226] R1, R4, R5, PG, and n are defined as described above.

[0227] In some implementations, n is 0.

[0228] In some embodiments, compound H is compound h-1. The method for preparing compound h-1 or its salt includes the step of reacting compound d with compound III-2 in the presence of 2,2,6,6-tetramethylpiperidine (TMP) to generate compound e.

[0229] Some embodiments provide a method for preparing compound H or a salt thereof, including the step of reducing compound E in the presence of catalyst I' / reducing agent I' to produce compound F.

[0230] Among them, rings A, PG, R1-R5, and n are as defined above.

[0231] In some embodiments, the reducing agent I' is selected from reducing agent I or reducing agent II, wherein reducing agent I is selected from hydrogen and reducing agent II is selected from boron reducing agent.

[0232] In some embodiments, the boron reducing agent is selected from BH3·THF, BH3·DMS, B2H6·THF, and BH3·S(CH3)2.

[0233] In some embodiments, the boron reducing agent is selected from BH3·THF.

[0234] In some embodiments, catalyst I' is selected from catalyst II or catalyst III, wherein catalyst II is selected from metal catalysts and catalyst III is selected from CBS catalysts.

[0235] In some embodiments, the CBS catalyst is selected from (R)-2-methyl-CBS-oxazolborane, (R)-2-butyl-CBS-oxazolborane, and (R)-2-phenyl-CBS-oxazolborane.

[0236] In some embodiments, the CBS catalyst is selected from (R)-2-methyl-CBS-oxazolium borane.

[0237] In some embodiments, the catalyst I' / reducing agent I' combination is selected from CBS catalyst / boron reducing agent.

[0238] In some embodiments, the catalyst in the catalyst I' / reducing agent I' combination is selected from (R)-2-methyl-CBS-oxazolborane, (R)-2-butyl-CBS-oxazolborane, and (R)-2-phenyl-CBS-oxazolborane, and the reducing agent is selected from BH3·THF, BH3·DMS, B2H6·THF, and BH3·S(CH3)2.

[0239] In some embodiments, the catalyst I' / reducing agent I' is selected from (R)-2-methyl-CBS-oxazolium borane / BH3·THF.

[0240] In some embodiments, the molar ratio of compound E to the CBS catalyst is 1:5% to 1:20%, including but not limited to 1:5%, 1:6%, 1:7%, 1:8%, 1:9%, 1:10%, 1:11%, 1:12%, 1:13%, 1:14%, 1:15%, 1:16%, 1:17%, 1:18%, 1:19%, 1:20%, or any two values ​​between them. In other embodiments, the molar ratio of compound E to the CBS catalyst is 1:10% to 1:15%. In some embodiments, the molar ratio of compound E to the CBS catalyst is 1:12%.

[0241] In some embodiments, the molar ratio of compound E to the boron 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 other embodiments, the molar ratio of compound E to the boron reducing agent is 1:1 to 1:1.5. In some embodiments, the molar ratio of compound E to the boron reducing agent is 1:1.2.

[0242] In some embodiments, the catalyst I' is selected from metal catalysts. In some embodiments, the metal catalyst is selected from [Ir(COD)Cl]2, RuCl2[(R)-DM-SEGPHOS][(R)-DAIPEN], RuCl[(R)-xylbinap], RuCl2[(R)-dm-segphos][(R,R)-dpen], RuCl[(R)-xylbinap][(R,R)-dpen], and (R,R)-Ts-DENEB.

[0243] In some embodiments, catalyst I' is an iridium compound, such as [Ir(COD)Cl]2. In some embodiments, catalyst I' is a ruthenium compound, such as RuCl2[(R)-DM-SEGPHOS][(R)-DAIPEN], RuCl[(R)-xylbinap], RuCl2[(R)-dm-segphos][(R,R)-dpen], RuCl[(R)-xylbinap][(R,R)-dpen], (R,R)-Ts-DENEB.

[0244] In some embodiments, the metal catalyst is selected from [Ir(COD)Cl]2.

[0245] In some embodiments, the catalyst I' / reducing agent I' combination is selected from metal catalyst / hydrogen.

[0246] In some embodiments, the catalyst I' / reducing agent I' is selected from [Ir(COD)Cl]2 / hydrogen.

[0247] In some embodiments, the molar ratio of compound E to the metal catalyst is 1:0.1% to 1:0.3%, including but not limited to 1:0.1%, 1:0.11%, 1:0.12%, 1:0.13%, 1:0.14%, 1:0.15%, 1:0.16%, 1:0.17%, 1:0.18%, 1:0.19%, 1:0.2%, 1:0.21%, 1:0.22%, 1:0.23%, 1:0.24%, 1:0.25%, 1:0.26%, 1:0.27%, 1:0.28%, 1:0.29%, 1:0.3%, or any two values ​​in between. In other embodiments, the molar ratio of compound E to the metal catalyst is 1:0.2% to 1:0.3%. In some embodiments, the molar ratio of compound E to the metal catalyst is 1:0.25%.

[0248] In some embodiments, the metal catalyst further includes a ligand selected from (R)-f-phamidol and f-amphox.

[0249] In some implementations, the ligand is selected from (R)-f-phamidol.

[0250] In some embodiments, the molar ratio of compound E to the ligand is 1:0.01% to 1:0.02%, including but not limited to 1:0.01%, 1:0.02%, 1:0.03%, 1:0.04%, 1:0.05%, 1:0.06%, 1:0.07%, 1:0.08%, 1:0.09%, 1:0.1%, or any value between any two numbers. In other embodiments, the molar ratio of compound E to the ligand is 1:0.03% to 1:0.07%. In some embodiments, the molar ratio of compound E to the ligand is 1:0.05%.

[0251] In some embodiments, the solvent used in the reaction of compound E is selected from isopropanol, toluene, dichloromethane, and tetrahydrofuran. In some embodiments, the solvent used in the reaction of compound E is selected from isopropanol. In some embodiments, the solvent used in the reaction of compound E is selected from toluene.

[0252] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reducing compound E in the presence of a metal catalyst / hydrogen and base IV to produce compound F.

[0253] The metal catalyst, ring A, PG, R1-R5, and n are as defined above.

[0254] In some embodiments, the base IV is selected from cesium carbonate, potassium carbonate, sodium carbonate, sodium tert-butoxide (tBuONa), potassium tert-butoxide (tBuOK), and lithium tert-butoxide (tBuOLi).

[0255] In some embodiments, the base IV is selected from cesium carbonate.

[0256] In some embodiments, the molar ratio of compound E to base IV is 1:0.1 to 1:1.5, including but not limited to 1:0.1, 1:0.2, 1:0.3, 1:0.04%, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, or any value between any two numbers. In other embodiments, the molar ratio of compound E to base IV is 1:0.1 to 1:0.5. In some embodiments, the molar ratio of compound E to base IV is 1:0.1. In some embodiments, the molar ratio of compound E to base IV is 1:1.5.

[0257] In some embodiments, compound H is compound H-1, and the method for preparing compound H-1 or a salt thereof includes the step of reacting compound E-1 in the presence of a CBS catalyst / boron reducing agent to generate compound F-1.

[0258] PG, R1, R8, R4, R5, m, and n are defined as described above.

[0259] In some embodiments, the method for preparing compound H-1 or a salt thereof includes the step of reacting compound E-1 in the presence of [Ir(COD)Cl]2 / hydrogen to generate compound F-1.

[0260] In some embodiments, compound H is compound H-2, and the method for preparing compound H-2 or its salt includes the step of reacting compound E-2 in the presence of a CBS catalyst / boron reducing agent to generate compound F-2.

[0261] In some embodiments, the method for preparing compound H-2 or a salt thereof includes the step of reacting compound E-2 in the presence of a metal catalyst / hydrogen to produce compound F-2. In some embodiments, the metal catalyst further comprises the ligand (R)-f-phamidol.

[0262] In some embodiments, compound H is compound h-1, and the method for preparing compound h-1 or a salt thereof includes the step of reacting compound e with (R)-2-methyl-CBS-oxazolium borane in the presence of BH3·THF to generate compound f-1.

[0263] In some embodiments, the method for preparing compound h-1 or a salt thereof includes the step of reacting compound e in the presence of a metal catalyst / hydrogen to generate compound f-1. In some embodiments, the method for preparing compound h-1 or a salt thereof includes the step of reacting compound e in the presence of [Ir(COD)Cl]2 / hydrogen and cesium carbonate to generate compound f-1.

[0264] In some embodiments, the method for preparing compound h-1 or a salt thereof includes the step of reacting compound e in the presence of [Ir(COD)Cl]2 / (R)-f-phamidol / hydrogen and cesium carbonate to generate compound f-1.

[0265] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound E in the presence of a CBS catalyst / boron reducing agent to generate compound F'.

[0266] Among them, rings A, PG, R1-R5, and n are as defined above.

[0267] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound E in the presence of a metal catalyst / hydrogen to generate compound F'. In some embodiments, the metal catalyst further comprises the ligand (R)-f-phamidol.

[0268] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound E in the presence of [Ir(COD)Cl]2 / (R)-f-phamidol / hydrogen and cesium carbonate to generate compound F'.

[0269] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound E in the presence of RuCl2[(R)-dm-segphos][(R)-daipen] / hydrogen and cesium carbonate to generate compound F'.

[0270] In some embodiments, the method for preparing compound H or a salt thereof includes the step of reacting compound E in the presence of RuCl[(R)-xylbinap][(R)-daipen] / hydrogen and cesium carbonate to generate compound F'.

[0271] In some embodiments, compound H is compound H'-1. The method for preparing compound H'-1 or its salt includes the step of reducing compound E-1 in the presence of a CBS catalyst / boron reducing agent to generate compound F'-1.

[0272] PG, R1, R8, R4, R5, m, and n are defined as described above.

[0273] In some embodiments, the method for preparing compound H'-1 or a salt thereof includes the step of reacting compound E-1 under metal catalyst / hydrogen conditions to generate compound F'-1. In some embodiments, the metal catalyst further comprises the ligand (R)-f-phamidol.

[0274] In some embodiments, the method for preparing compound H'-1 or a salt thereof includes the step of reacting compound E-1 in the presence of [Ir(COD)Cl]2 / (R)-f-phamidol / hydrogen and cesium carbonate to generate compound F'-1.

[0275] In some embodiments, compound H is compound H'-2. The method for preparing compound H'-2 or its salt includes the step of reacting compound E-2 in the presence of a CBS catalyst / boron reducing agent to generate compound F'-2.

[0276] In other embodiments, the method for preparing compound H-2 or a salt thereof includes the step of reacting compound E-2 under metal catalyst / hydrogen conditions to produce compound F'-2. In some embodiments, the metal catalyst further comprises the ligand (R)-f-phamidol.

[0277] In some embodiments, the method for preparing compound H-2 or its salts includes the step of reacting compound E-2 in the presence of [Ir(COD)Cl]2 / (R)-f-phamidol / hydrogen and cesium carbonate to generate compound F'-2.

[0278] In some embodiments, compound H is compound h-2 The method for preparing compound h-2 or its salt includes the step of reacting compound e with (R)-2-methyl-CBS-oxazolborane in the presence of BH3·THF to generate compound f-2.

[0279] In some embodiments, the method for preparing compound h-2 or a salt thereof includes the step of reacting compound e under metal catalyst / hydrogen conditions to generate compound f-2.

[0280] In some embodiments, the method for preparing compound h-2 or a salt thereof includes the step of reacting compound e in the presence of base IV under [Ir(COD)Cl]2 / hydrogen conditions to generate compound f-2.

[0281] In some embodiments, the method for preparing compound h-2 or a salt thereof includes the step of reacting compound e under metal catalyst / hydrogen conditions to generate compound f-2, said metal catalyst further comprising a ligand such as (R)-f-phamidol.

[0282] In some embodiments, the method for preparing compound h-2 or a salt thereof includes the step of reacting compound e in the presence of Cs2CO3 under [Ir(COD)Cl]2 / hydrogen conditions to generate compound f-2. In some embodiments, [Ir(COD)Cl]2 further comprises the ligand (R)-f-phamidol.

[0283] In some embodiments, the method for preparing compound h-2 or a salt thereof includes the step of reacting compound e in the presence of Cs2CO3 under (R)-f-phamidol, [Ir(COD)Cl]2 / hydrogen conditions to generate compound f-2.

[0284] In some embodiments, the method for preparing compound h-2 or a salt thereof includes the step of reacting compound e in the presence of RuCl2[(R)-dm-segphos][(R)-daipen] / hydrogen and cesium carbonate to generate compound f-2.

[0285] In some embodiments, the method for preparing compound h-2 or a salt thereof includes the step of reacting compound e in the presence of RuCl[(R)-xylbinap][(R)-daipen] / hydrogen and cesium carbonate to generate compound f-2.

[0286] Some embodiments provide methods for preparing compound H or its salts, including the step of reacting compound F in the presence of a trisubstituted phosphine / azodicarboxylic acid diester to generate compound G.

[0287] Among them, rings A, PG, R1-R5, and n are as defined above.

[0288] In some embodiments, the trisubstituted phosphide is triphenylphosphine.

[0289] In some embodiments, the azodicarboxylic acid diester is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di(4-chlorobenzyl) azodicarboxylate.

[0290] In some embodiments, the azodicarboxylic acid diester is diisopropyl azodicarboxylate.

[0291] In some embodiments, the reaction solvent for compound F is selected from dichloromethane, 1,2-dichloroethane, methyl tert-butyl ether, cyclopentyl methyl ether, ethyl acetate, n-heptane, N,N-dimethylformamide, and acetonitrile. In some embodiments, the reaction solvent for compound F is selected from dichloromethane.

[0292] In some embodiments, the molar ratio of compound F to the trisubstituted phosphine 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 other embodiments, the molar ratio of compound B to the trisubstituted phosphine is 1:1.3.

[0293] In some embodiments, the molar ratio of compound F to triphenylphosphine is 1:1 to 1:1.5.

[0294] In some embodiments, the molar ratio of compound F to azodiacetic acid diester 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 other embodiments, the molar ratio of compound B to azodiacetic acid diester is 1:1.3.

[0295] In some embodiments, the molar ratio of compound F to diisopropyl azodicarbonate is 1:1 to 1:1.5.

[0296] In some embodiments, compound H is compound H-1, and the method for preparing compound H-1 or a salt thereof includes the step of reacting compound F-1 in the presence of a trisubstituted phosphine / azodicarboxylic acid diester to generate compound G-1.

[0297] PG, R1, R8, R4, R5, m, and n are defined as described above.

[0298] In some embodiments, compound H is compound H-2, and the method for preparing compound H-2 or a salt thereof includes the step of reacting compound F-2 in the presence of a trisubstituted phosphine / azodicarboxylic acid diester to generate compound G-2.

[0299] Among them, PG, R1, R 10 R4, R5, m, and n are defined as described above.

[0300] In some embodiments, compound H is compound h-1, and the method for preparing compound h-1 or a salt thereof includes the step of reacting compound f-1 in the presence of triphenylphosphine / diisopropyl azodicarboxylate to generate compound g-1.

[0301] In some embodiments, compound H is compound H'-1, and the method for preparing compound H'-1 or a salt thereof includes the step of reacting compound F'-1 in the presence of a trisubstituted phosphine / azodicarboxylic acid diester to generate compound G'-1.

[0302] PG, R1, R8, R4, R5, m, and n are defined as described above.

[0303] In some embodiments, compound H is compound H'-2, and the method for preparing compound H'-2 or a salt thereof includes the step of reacting compound F'-2 in the presence of a trisubstituted phosphine / azodicarboxylic acid diester to generate compound G'-2.

[0304] PG, R1, R4, R5, and n are defined as described above.

[0305] In some embodiments, compound H is compound h-2, and the method for preparing compound h-2 or a salt thereof includes the step of reacting compound f-2 in the presence of triphenylphosphine / diisopropyl azodicarboxylate to generate compound g-2.

[0306] Furthermore, the method for preparing compound H or its salt disclosed herein further includes the step of deprotecting compound G to form compound H. Among them, rings A, PG, R1-R5, and n are as defined above.

[0307] In some embodiments, compound G is converted to compound H under acidic conditions. In some embodiments, compound G is converted to compound H under hydrochloric acid, trifluoroacetic acid, or p-toluenesulfonic acid conditions. In some embodiments, compound G is converted to compound H under hydrochloric acid conditions.

[0308] In some embodiments, the solvent used for the reaction of compound G is selected from dichloromethane, ethyl acetate, chloroform, acetonitrile, or dioxane. In some embodiments, the solvent used for the reaction of compound G is selected from dioxane. In some embodiments, the solvent used for the reaction of compound G is selected from ethyl acetate.

[0309] In some embodiments, the method for preparing compound H or a salt thereof according to this disclosure further includes the step of deprotecting compound G under hydrochloric acid / dioxane conditions to form compound H. In some embodiments, the method for preparing compound H or a salt thereof according to this disclosure further includes the step of deprotecting compound G under hydrochloric acid / ethyl acetate conditions to form compound H.

[0310] In some embodiments, the method for preparing compound H-1 or a salt thereof disclosed herein includes the step of deprotecting compound G-1 under hydrochloric acid / dioxane conditions to form compound H-1. Wherein PG, R1, R8, R4, R5, m, and n are as defined above. In some embodiments, the method for preparing compound H-1 or a salt thereof disclosed herein includes the step of deprotecting compound G-1 under hydrochloric acid / ethyl acetate conditions to form compound H-1.

[0311] In some embodiments, the method for preparing compound H-2 or a salt thereof disclosed herein includes the step of deprotecting compound G-2 under hydrochloric acid / dioxane conditions to form compound H-2. Wherein PG, R1, R4, R5, and n are as defined above. In some embodiments, the method for preparing compound H-2 or a salt thereof disclosed herein includes the step of deprotecting compound G-2 under hydrochloric acid / ethyl acetate conditions to form compound H-2.

[0312] In some embodiments, the method for preparing compound h-1 or a salt thereof disclosed herein includes the step of deprotecting compound g-1 under hydrochloric acid / dioxane conditions to form compound h-1. In some embodiments, the method for preparing compound h-1 or a salt thereof disclosed herein includes the step of deprotecting compound g-1 under hydrochloric acid / ethyl acetate conditions to form compound h-1.

[0313] In some embodiments, the method for preparing compound H'-1 or a salt thereof disclosed herein includes the step of deprotecting compound G'-1 under hydrochloric acid / dioxane conditions to form compound H'-1. Wherein PG, R1, R8, R4, R5, m, and n are as defined above. In some embodiments, the method for preparing compound H'-1 or a salt thereof disclosed herein includes the step of deprotecting compound G'-1 under hydrochloric acid / ethyl acetate conditions to form compound H'-1.

[0314] In some embodiments, the method for preparing compound H'-2 or a salt thereof disclosed herein includes the step of deprotecting compound G'-2 under hydrochloric acid / dioxane conditions to form compound H'-2. Wherein PG, R1, R4, R5, and n are as defined above. In some embodiments, the method for preparing compound H'-2 or a salt thereof disclosed herein includes the step of deprotecting compound G'-2 under hydrochloric acid / ethyl acetate conditions to form compound H'-2.

[0315] In some embodiments, the method for preparing compound h-2 or a salt thereof disclosed herein includes the step of deprotecting compound g-2 under hydrochloric acid / dioxane conditions to form compound h-2. In some embodiments, the method for preparing compound h-2 or a salt thereof disclosed herein includes the step of deprotecting compound g-2 under hydrochloric acid / ethyl acetate conditions to form compound h-2.

[0316] Some implementation schemes provide methods for preparing compound H or its salts, including:

[0317] Step 1: Compound A reacts with a hydroxyl protecting agent to form compound B;

[0318] Step 2: Compound B reacts with compound II under alkaline conditions to form compound C;

[0319] Step 3: Compound C is converted to compound D under the conditions of catalyst I / reducing agent I;

[0320] Step 4: Compound D reacts with compound III under alkaline conditions to form compound E;

[0321] Step 5: Compound E forms compound F under the conditions of catalyst I' / reducing agent I';

[0322] Step 6: Compound F is reacted with trisubstituted phosphine / azodicarboxylic acid diester to generate compound G;

[0323] Step 7: Compound G is converted into compound H.

[0324] Among them, rings A, R1-R7, PG, X, and n are as defined above.

[0325] Some implementations provide methods for preparing compound H-1 or its salts, including:

[0326] Step 1: Compound A reacts with orthoester to form compound B-1;

[0327] Step 2: Compound B-1 reacts with compound II under base I conditions, such as butyllithium, to generate compound C-1;

[0328] Step 3: Compound C-1 is converted to compound D under Pd / C / hydrogen conditions;

[0329] Step 4: Compound D reacts with compound III-1 under alkaline conditions to generate compound E-1;

[0330] Step 5: Compound E-1 forms compound F-1 under the conditions of catalyst I' / reducing agent I';

[0331] Step 6: Compound F-1 is converted to compound G-1 under the conditions of trisubstituted phosphide / azodicarboxylic acid diester;

[0332] Step 7: Compound G-1 is converted to compound H-1 under hydrochloric acid / dioxane conditions.

[0333] Among them, ring A, R1-R5, R a R8, PG, X, and n are defined as described above.

[0334] Some implementations provide methods for preparing compound H-1 or its salts, including:

[0335] Step 1: Compound A reacts with orthoester to form compound B-1;

[0336] Step 2: Compound B-1 reacts with compound II under base I conditions, such as butyllithium, to generate compound C-1;

[0337] Step 3: Compound C-1 is converted to compound D under Pd / C / hydrogen conditions;

[0338] Step 4: Compound D reacts with compound III-1 under alkaline conditions to generate compound E-1;

[0339] Step 5: Compound E-1 forms compound F-1 under the conditions of catalyst I' / reducing agent I';

[0340] Step 6: Compound F-1 is converted to compound G-1 under the conditions of trisubstituted phosphide / azodicarboxylic acid diester;

[0341] Step 7: Compound G-1 is converted to compound H-1 under hydrochloric acid / ethyl acetate conditions.

[0342] Some implementation schemes provide methods for preparing compound H-2 or its salts, including:

[0343] Step 1: Compound A reacts with triethyl orthoacetate to form compound B-2;

[0344] Step 2: Compound B-2 reacts with compound II under n-butyllithium conditions to generate compound C-2;

[0345] Step 3: Compound C-2 is converted to compound D under Pd / C / hydrogen conditions;

[0346] Step 4: Compound D reacts with compound III-2 under alkaline conditions to form compound E-2;

[0347] Step 5: Compound E-2 forms compound F-2 under the conditions of catalyst I' / reducing agent I';

[0348] Step 6: Compound F-2 is converted to compound G-2 under the conditions of trisubstituted phosphide / azodicarboxylic acid diester;

[0349] Step 7: Compound G-2 is converted to compound H-2 under hydrochloric acid / dioxane conditions.

[0350] R1, R4, R5, PG, and n are defined as described above.

[0351] Some implementation schemes provide methods for preparing compound H-2 or its salts, including:

[0352] Step 1: Compound A reacts with triethyl orthoacetate to form compound B-2;

[0353] Step 2: Compound B-2 reacts with compound II under n-butyllithium conditions to generate compound C-2;

[0354] Step 3: Compound C-2 is converted to compound D under Pd / C / hydrogen conditions;

[0355] Step 4: Compound D reacts with compound III-2 under alkaline conditions to form compound E-2;

[0356] Step 5: Compound E-2 forms compound F-2 under the conditions of catalyst I' / reducing agent I';

[0357] Step 6: Compound F-2 is converted to compound G-2 under the conditions of trisubstituted phosphide / azodicarboxylic acid diester;

[0358] Step 7: Compound G-2 is converted to compound H-2 under hydrochloric acid / ethyl acetate conditions.

[0359] Some implementations provide methods for preparing compound h-1 or its salts, including:

[0360] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0361] Step 2: Compound b reacts with compound II-1 under n-butyllithium conditions to generate compound c;

[0362] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0363] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0364] Step 5: Compound e forms compound f-1 under CBS catalyst / borane reducing agent conditions;

[0365] Step 6: Compound f-1 is reacted with trisubstituted phosphine / azodicarboxylic acid diester to generate compound g-1;

[0366] Step 7: Compound g-1 is converted to compound h-1 under hydrochloric acid / dioxane conditions.

[0367] Some implementations provide methods for preparing compound h-1 or its salts, including:

[0368] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0369] Step 2: Compound b reacts with compound II-1 under n-butyllithium conditions to generate compound c;

[0370] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0371] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0372] Step 5: Compound e forms compound f-1 under metal catalyst / hydrogen / alkaline conditions;

[0373] Step 6: Compound f-1 is reacted with trisubstituted phosphine / azodicarboxylic acid diester to generate compound g-1;

[0374] Step 7: Compound g-1 is converted to compound h-1 under hydrochloric acid / dioxane conditions.

[0375] Some implementations provide methods for preparing compound h-1 or its salts, including:

[0376] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0377] Step 2: Compound b reacts with compound II-1 under n-butyllithium conditions to generate compound c;

[0378] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0379] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0380] Step 5: Compound e forms compound f-1 under CBS catalyst / borane reducing agent conditions;

[0381] Step 6: Compound f-1 is reacted with trisubstituted phosphine / azodicarboxylic acid diester to generate compound g-1;

[0382] Step 7: Compound g-1 is converted to compound h-1 under hydrochloric acid / ethyl acetate conditions.

[0383] Some implementations provide methods for preparing compound h-1 or its salts, including:

[0384] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0385] Step 2: Compound b reacts with compound II-1 under n-butyllithium conditions to generate compound c;

[0386] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0387] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0388] Step 5: Compound e forms compound f-1 under metal catalyst / hydrogen / alkaline conditions;

[0389] Step 6: Compound f-1 is reacted with trisubstituted phosphine / azodicarboxylic acid diester to generate compound g-1;

[0390] Step 7: Compound g-1 is converted to compound h-1 under hydrochloric acid / ethyl acetate conditions.

[0391] Some implementations provide methods for preparing compound h-2 or its salts, including:

[0392] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0393] Step 2: Compound b reacts with compound II-1 under n-butyllithium conditions to generate compound c;

[0394] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0395] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0396] Step 5: Compound e is converted to compound f-2 under (R)-2-methyl-CBS-oxazolborane / BH3·THF conditions;

[0397] Step 6: Compound f-2 is converted to compound g-2 under the conditions of triphenylphosphine / diisopropyl azodicarboxylate;

[0398] Step 7: Compound g-2 is converted to compound h-2 under hydrochloric acid / dioxane conditions.

[0399] Some implementations provide methods for preparing compound h-2 or its salts, including:

[0400] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0401] Step 2: Compound b reacts with compound II-1 under n-butyllithium conditions to generate compound c;

[0402] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0403] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0404] Step 5: Compound e forms compound f-2 under the conditions of [Ir(COD)Cl]2 / (R)-f-phamidol / hydrogen and cesium carbonate;

[0405] Step 6: Compound f-2 is converted to compound g-2 under the conditions of triphenylphosphine / diisopropyl azodicarboxylate;

[0406] Step 7: Compound g-2 is converted to compound h-2 under hydrochloric acid / dioxane conditions.

[0407] Some implementations provide methods for preparing compound h-2 or its salts, including:

[0408] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0409] Step 2: Compound b reacts with compound II-1 under n-butyllithium conditions to generate compound c;

[0410] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0411] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0412] Step 5: Compound e is converted to compound f-2 under (R)-2-methyl-CBS-oxazolborane / BH3·THF conditions;

[0413] Step 6: Compound f-2 is converted to compound g-2 under the conditions of triphenylphosphine / diisopropyl azodicarboxylate;

[0414] Step 7: Compound g-2 is converted to compound h-2 under hydrochloric acid / ethyl acetate conditions.

[0415] Some implementations provide methods for preparing compound h-2 or its salts, including:

[0416] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0417] Step 2: Compound b reacts with compound II-1 under n-butyllithium conditions to generate compound c;

[0418] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0419] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0420] Step 5: Compound e forms compound f-2 under the conditions of [Ir(COD)Cl]2 / (R)-f-phamidol / hydrogen and cesium carbonate;

[0421] Step 6: Compound f-2 is converted to compound g-2 under the conditions of triphenylphosphine / diisopropyl azodicarboxylate;

[0422] Step 7: Compound g-2 is converted to compound h-2 under hydrochloric acid / ethyl acetate conditions.

[0423] Some implementations provide methods for preparing compound h-2 or its salts, including:

[0424] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0425] Step 2: Compound b reacts with compound II-1 under the conditions of n-butyllithium, tetramethylethylenediamine, lithium bromide and potassium tert-butoxide to generate compound c;

[0426] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0427] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0428] Step 5: Compound e is converted to compound f-2 under (R)-2-methyl-CBS-oxazolborane / BH3·THF conditions;

[0429] Step 6: Compound f-2 is converted to compound g-2 under the conditions of triphenylphosphine / diisopropyl azodicarboxylate;

[0430] Step 7: Compound g-2 is converted to compound h-2 under hydrochloric acid / dioxane conditions.

[0431] Some implementations provide methods for preparing compound h-2 or its salts, including:

[0432] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0433] Step 2: Compound b reacts with compound II-1 under the conditions of n-butyllithium, tetramethylethylenediamine, lithium bromide and potassium tert-butoxide to generate compound c;

[0434] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0435] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0436] Step 5: Compound e forms compound f-2 under the conditions of [Ir(COD)Cl]2 / (R)-f-phamidol / hydrogen and cesium carbonate;

[0437] Step 6: Compound f-2 is converted to compound g-2 under the conditions of triphenylphosphine / diisopropyl azodicarboxylate;

[0438] Step 7: Compound g-2 is converted to compound h-2 under hydrochloric acid / dioxane conditions.

[0439] Some implementations provide methods for preparing compound h-2 or its salts, including:

[0440] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0441] Step 2: Compound b reacts with compound II-1 under the conditions of n-butyllithium, tetramethylethylenediamine, lithium bromide and potassium tert-butoxide to generate compound c;

[0442] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0443] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0444] Step 5: Compound e is converted to compound f-2 under (R)-2-methyl-CBS-oxazolborane / BH3·THF conditions;

[0445] Step 6: Compound f-2 is converted to compound g-2 under the conditions of triphenylphosphine / diisopropyl azodicarboxylate;

[0446] Step 7: Compound g-2 is converted to compound h-2 under hydrochloric acid / ethyl acetate conditions.

[0447] Some implementations provide methods for preparing compound h-2 or its salts, including:

[0448] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0449] Step 2: Compound b reacts with compound II-1 under the conditions of n-butyllithium, tetramethylethylenediamine, lithium bromide and potassium tert-butoxide to generate compound c;

[0450] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0451] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0452] Step 5: Compound e forms compound f-2 under the conditions of [Ir(COD)Cl]2 / (R)-f-phamidol / hydrogen and cesium carbonate;

[0453] Step 6: Compound f-2 is converted to compound g-2 under the conditions of triphenylphosphine / diisopropyl azodicarboxylate;

[0454] Step 7: Compound g-2 is converted to compound h-2 under hydrochloric acid / ethyl acetate conditions.

[0455] This disclosure provides a method for preparing the aforementioned compound H, and the use of the aforementioned compound C in the preparation of GLP-1 receptor agonists.

[0456] In some implementations, the GLP-1 receptor agonist is selected from, but is not limited to:

[0457] 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 H.

[0458] In some embodiments, the method for preparing compound AA includes the steps of the aforementioned method for preparing compound H-1. In some embodiments, the method for preparing compound AA includes the steps of the aforementioned method for preparing compound H-2. In some embodiments, the method for preparing compound AA includes the steps of the aforementioned method for preparing compound h-1. In some embodiments, the method for preparing compound AA includes the steps of the aforementioned method for preparing compound H'-1. In some embodiments, the method for preparing compound AA includes the steps of the aforementioned method for preparing compound H'-2. In some embodiments, the method for preparing compound AA includes the steps of the aforementioned method for preparing compound h-2.

[0459] In some embodiments, the method for preparing compound AA or a salt thereof includes the step of reacting compound h-2 with compound X to form compound AA. The reaction conditions and procedures are in accordance with WO2022007979, and the relevant content is incorporated herein for illustrative purposes.

[0460] The preparation method described in this disclosure further includes one or more steps of filtration, washing, drying, concentration or recrystallization.

[0461] Salts of the compounds / intermediates disclosed herein include, but are not limited to, addition salts of the free compounds / intermediates with acids or bases, wherein the acid used for salt formation includes, but is not limited to, hydrochloric acid or methanesulfonic acid. In some embodiments, the salts of the compounds / intermediates include, but are not limited to, hydrochloride salts, p-toluenesulfonate salts, methanesulfonate salts, or oxalate salts.

[0462] Terminology Definition

[0463] 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.

[0464] 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%.

[0465] 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. For example, formula... Compounds can be represented by the formula or Or it may contain both of the aforementioned configurations.

[0466] "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.

[0467] 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.

[0468] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0469] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0470] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Alkyne group, 3- to 6-membered cycloalkoxy group, 3- to 6-membered heterocycloalkoxy group, C 3-8Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 The alkynyl group, 3 to 6 cycloalkoxy group, 3 to 6 heterocycloalkoxy group, 3 to 8 cycloalkenyl group, 5 to 6 aryl group, or heteroaryl group may be selected from one or more halogens, hydroxyl groups, cyano groups, amino groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl-substituted.

[0471] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrole, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazole, benzimidazolyl, etc. wait.

[0472] The heteroaryl ring may be fused to an aryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0473] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, cyano groups, amino groups, C4 groups, etc. 1-6 Alkyl or C 1-6 Alkyl group.

[0474] The term "heterocycle" refers to a saturated non-aromatic ring composed of carbon atoms and other heteroatoms, comprising a 3- to 8-membered monocyclic, a 4- to 12-membered bicyclic, or a 10- to 15-membered tricyclic system, and containing 1 to 3 heteroatoms selected from N, O, or S, including heterocyclic alkyl groups. Non-limiting examples of "heterocycle" include: etc.

[0475] "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.

[0476] "Amino protecting group" is a suitable group known in the art for amino protection, see amino protecting groups in the literature ("Protective Groups in Organic Synthesis", 5th. Ed. TW. Greene & P. ​​GMWuts). As an example, the amino protecting group may be (C 1-10 Alkyl or aromatic acyl group, such as formyl, acetyl, benzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 aryl)sulfonyl; or (C 1-6 Alkoxy or C 6-10 Aryloxy)carbonyl, such as Boc or Cbz; can also be substituted or unsubstituted alkyl, such as triphenylmethyl (Tr), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB) or benzyl (Bn).

[0477] A “hydroxyl protecting group” is a suitable group known in the art for protecting hydroxyl groups; see “Protective Groups in Organic Synthesis”, 5th Ed. TW Greene & P. ​​GMWuts for examples of hydroxyl protecting groups. As an example, the hydroxyl protecting group may be (C... 1-10 Alkyl or aryl) 3-silyl, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, (trimethylsilyl)ethoxymethyl (SEM), etc.; can be C 1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl-substituted alkyl, more preferably C 1-6 alkoxy-substituted C 1-6 alkyl or phenyl substituted C 1-6 Alkyl group, C is the most preferred. 1-4 alkoxy-substituted C 1-4 Alkyl groups, such as methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 Alkyl or aromatic acyl group, such as: formyl, acetyl, N,N-diethylformyl, benzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 aryl)sulfonyl; or (C 1-6 Alkoxy or C 6-10 Aryloxy)carbonyl.

[0478] DABCO: Triethylenediamine

[0479] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0480] DIPEA: N,N-Diisopropylethylamine

[0481] TMP: 2,2,6,6-Tetramethylpiperidine

[0482] DIAD: Diisopropyl azodicarbonate

[0483] f-amphox: Ferrocene aminophosphate oxazoline ligand Attached Figure Description

[0484] Figure 1: Schematic diagram of the preparation of compound C using a continuous flow microchannel reactor.

[0485] Figure 2: Schematic diagram of continuous centrifugal extraction for preparing compound C. Detailed Implementation

[0486] 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.

[0487] Test conditions of the instruments used in the experiment:

[0488] 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.

[0489] 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).

[0490] 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.

[0491] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0492] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0493] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0494] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0495] 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.

[0496] Example 1

[0497] first step

[0498] 2-Ethoxy-2-methylbenzo[d][1,3]dioxane compound 1b

[0499] Catechol 1a (2 kg, 18.2 mol) and triethyl orthoacetate (3.5 kg, 21.8 mol) were added to a 30 L reactor and stirred at 90 °C. After stirring for 5 hours, the reaction solution was cooled to approximately 40 °C, concentrated under reduced pressure for 20 minutes to remove the ethanol produced, the vacuum was removed, and the temperature was raised to 90 °C and reacted overnight. The reaction solution was then cooled to 40 °C, concentrated under reduced pressure for 30 minutes to remove the ethanol produced, the vacuum was removed, and the temperature was raised to 90 °C and reacted for approximately 2 hours, with TLC monitoring to ensure complete reaction. The reaction solution was cooled to approximately 10 °C, and water was slowly added to quench the reaction, maintaining the temperature between 10 and 20 °C. After the water was added, the mixture was stirred at this temperature for 30 minutes. After complete quenching, the aqueous phase was extracted once with petroleum ether. After separation, the aqueous phase was extracted once more with petroleum ether. The organic phases were combined and washed twice with sodium bicarbonate aqueous solution. The organic phase was concentrated under reduced pressure to obtain a yellow oily crude product. After separation and purification by column chromatography, compound 1b (2.9 kg, 88.6%) was obtained.

[0500] 1H NMR (400MHz, CDCl3), 6.84-6.79 (m, 4H), 3.59 (q, J = 6.8Hz, 2H), 1.80 (s, 3H), 1.20 (t, J = 6.8Hz, 3H).

[0501] Step 2

[0502] 4-(2-ethoxy-2-methylbenzo[d][1,3]dioxacyclopentan-4-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester compound 1c

[0503] Compound 1b (100 g, 555 mmol, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran, and n-butyllithium (555 mL, 1.0 M in THF, 1.0 eq.) was slowly added at -10 °C with stirring for 1 hour. Then, a THF solution of tert-butyl-4-oxopiperidin-1-carboxylic acid ester (110.57 g, 555 mmol, 1.0 eq.) was slowly added. The reaction system was maintained at -5 °C with stirring for 2 hours. After the starting material was completely eliminated by TLC, the reaction was quenched at 0 °C with a saturated ammonium chloride aqueous solution (500 mL). The resulting mixture was extracted with ethyl acetate (2 × 2000 mL), and the combined organic phases were concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain compound 1c (210 g, 70%).

[0504] 1 H NMR(400MHz, CDCl3),7.27(s,1H),6.85(m,2H),6.75(m,1H),4.02(m,2H),3.55(m,2H), 3.21(m,2H),2.12(m,2H),1.81(s,3H),1.78(m,2H),1.48(s,9H),1.24(t,J=7.0Hz,3H).

[0505] Step 3

[0506] 4-(2,3-dihydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester compound 1d

[0507] Under a nitrogen atmosphere, tetrahydrofuran (120 mL, 10 V), acetic acid (48 mL, 4 V), water (12 mL, 10 V), compound 1c (12 g, 31.6 mmol), and 5% palladium on carbon (0.6 g) were added to an autoclave. After purging with nitrogen, hydrogen was introduced to a pressure of 2.5 MPa, and the system was heated to 70 °C and reacted for 16 h. After the reaction was complete, the system temperature was lowered to room temperature, filtered through a diatomaceous earth liner (to recover the palladium on carbon), and the filtrate was concentrated under reduced pressure until no solvent evaporated, yielding a crude gray oily product. 4 mL of ethyl acetate was added to the crude product, followed by 80 mL of n-hexane. The mixture was stirred and slurried at 25 °C for 2 h, then cooled to 0–5 °C and stirred and slurried for 1 h. The mixture was filtered, the filter cake was washed with 40 mL of n-hexane, and dried to obtain compound 1d (7.4 g, 80%).

[0508] 1 H NMR(400MHz, DMSO-d6),9.24(s,1H),8.14(s,1H),6.63(m,1H),6.56(m,2H), 4.12(m,2H),3.0(m,1H),2.80(m,2H),1.68(m,2H),1.43(s,9H),1.40(m,2H).

[0509] Step 4

[0510] 4-(3-(2-(4-chloro-2-fluorophenyl)-2-oxoethoxy)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester compound 1e

[0511] Compound 1d (3 g, 10.2 mmol), TMP (2.89 g, 20.5 mmol), and anhydrous DCM (60 mL, 20 V) were added to a 250 mL three-necked flask, purged with nitrogen, and then heated to 45 °C and stirred for 10 minutes. 2-Bromo-1-(4-chloro-2-fluorophenyl)ethyl ketone (3.9 g, 15.3 mmol) was dissolved in dichloromethane (90 mL, 30 V) and slowly added dropwise to the reaction flask under nitrogen protection. After the addition was complete, the reaction mixture was stirred at 45 °C for 16 hours. After the reaction was complete as monitored by TLC, the reaction solution was cooled to 25 °C and quenched by adding an aqueous acetic acid solution (2.4 g / 150 mL). The mixture was allowed to stand and separated. The aqueous phase was washed once with 90 mL of dichloromethane. The combined organic phases were concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain compound 1e (3.8 g, 80%).

[0512] 1H NMR(400MHz, DMSO-d6),7.78(s,1H),7.68(m,1H),7.53(m,1H),7.40(m,1H),6.85-6.76(m,3H) ,4.20(m,1H),4.03(m,3H),3.04(m,1H),2.80(m,2H),1.78(m,2H),1.53(m,2H),1.42(m,9H),.

[0513] Step 5

[0514] (R)-4-(3-(2-(4-chloro-2-fluorophenyl)-2-hydroxyethoxy)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester compound 1f

[0515] (R)-2-methyl-CBS-oxazolium borane (143.4 mg, 0.5 mmol) was dissolved in THF (10 mL, 5 V), purged with nitrogen, and cooled to 0–5 °C. Boranetetrahydrofuran solution (5.2 mL, 5.2 mmol, 1 M in THF) was then added dropwise. After the addition was complete, the temperature was restored to 25 °C and the mixture was stirred for 30 minutes. At 25 °C, compound 1e (2 g, 4.3 mmol) dissolved in THF (20 mL, 10 V) was slowly added dropwise to the above reaction system. After the addition was complete, the mixture was stirred at 25 °C for 16 hours. TLC monitoring showed that the reaction proceeded completely. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 1f (1.6 g, 80%).

[0516] 1 H NMR(400MHz, DMSO-d6),8.31(s,1H),7.62(m,1H),7.42(m,1H),7.40(m,1H),6.84-6.70(m,3H),6.03(m,1H ),5.24(m,1H),3.70(s,3H),4.12(m,4H),3.05(m,1H),2.82(m,2H),1.71(m,2H),1.55(m,2H),1.42(s,9H).

[0517] Step 6

[0518] (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylic acid tert-butyl ester compound 1g

[0519] Compound 1f (1 g, 2.15 mmol) and PPh3 (731.8 mg, 2.79 mmol) were dissolved in anhydrous dichloromethane (10 mL, 10 V), and the mixture was purged with nitrogen for protection. The mixture was cooled to 0–5 °C, and DIAD (564.2 mg, 2.79 mmol) was slowly added dropwise. After the addition was complete, the temperature was maintained at 0–5 °C for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain compound 1 g (846.0 mg, 88%).

[0520] 1 H NMR(400MHz, CDCl3),7.40(m,1H),7.22(m,1H),7.16(d,J=10,2Hz,1H),6.85(m,1H),6.81-6.76(m,2H),5.45-5.35(m,1H),4.40(dd,J=11.2,2.4 Hz,1H),4.33-4.09(m,2H),3.96(dd,J=11.2,8.4Hz,1H),3.11-2.99(m,1 H),2.90-2.67(m,2H),1.91-1.72(m,2H),1.69-1.58(m,2H),1.46(s,9H)

[0521] Step 7

[0522] (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine compound 1h

[0523] 1 g (0.5 g, 1.1 mmol) of the compound was dissolved in THF (0.5 mL, 1 V), and dioxane hydrochloride solution (2 mL, 8 mmol, 4 M in dioxane) was added dropwise at a controlled temperature of about 10 °C. After the addition was complete, the mixture was stirred at 25 °C for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was added to 10 mL of 5% potassium carbonate aqueous solution at about 10 °C. The mixture was extracted twice with 10 mL of ethyl acetate each time. The organic phases were combined and concentrated under reduced pressure to obtain compound 1 h (380 mg, 98%).

[0524] 1H NMR(400MHz, CDCl3),12.00(t,J=8Hz,1H),7.25(m,1H),7.15(dd,J=12,2Hz,1H),6.85(m,3H),5.41(dd,J=8,2Hz,1H),4.41( dd,J=7.2,2.4Hz,1H),3.95(dd,J=11.2,8.4Hz,1H),3.17(m,2H),3.06(m,1H),2.74(m,2H),1.86(m,1H),1.81-1.60(m,4H).

[0525] Example 2

[0526] (R)-4-(3-(2-(4-chloro-2-fluorophenyl)-2-hydroxyethoxy)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester compound 1f

[0527] Catalyst solution preparation: In a reaction flask, [Ir(COD)Cl]2 (16.8 mg, 0.027 mmol), (R)-f-phamidol (prepared according to the method in Example 7 of CN116063355A) (34.3 mg, 0.06 mmol), and 4.0 mL of THF were added sequentially, and the mixture was stirred at room temperature for 0.5 h. In a glove box, Cs2CO3 (351 mg, 1.1 mmol), compound 1e (5 g, 10.8 mmol), catalyst solution, and THF (36 mL) were added sequentially. The reaction vessel was closed, the mixture was transferred out of the glove box, and hydrogen was purged three times. The hydrogen pressure was increased to 2.0 MPa, and the reaction was carried out at room temperature for 20 h. The pressure was released and the vessel was opened. The liquid phase showed a reaction conversion rate of 100% and an ee value of 96%. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain a crude product. After purification by column chromatography (PE / EA = 5:1), compound 1f (4.0 g, 80%) was obtained.

[0528] Example 3

[0529] In a glove box, Cs2CO3 (9.7 mg), compound 1e (9.4 mg), a THF solution of [Ir(COD)Cl]2 / (R)-f-phamidol (1 mol%), and THF (0.5 mL) were added sequentially to the reactor. The reactor was then closed, the mixture was transferred out of the glove box, and hydrogen was purged three times. The hydrogen pressure was increased to 2.0 MPa, and the reaction was carried out at room temperature for 4 hours. The pressure was released and the reactor was opened. The liquid phase showed that the reaction conversion rate of compound 1f was 99.3%, and the ee value was 97%.

[0530] Example 4

[0531] In a glove box, Cs2CO3 (0.7 mg), compound 1e (9.4 mg), a DCM solution of [Ir(COD)Cl]2 / (R)-f-phamidol (1 mol%), and DCM (0.5 mL) were added sequentially to the reactor. The reactor was then closed, the mixture was transferred out of the glove box, and hydrogen was purged three times. The hydrogen pressure was increased to 2.0 MPa, and the reaction was carried out at room temperature for 4 hours. The pressure was released and the reactor was opened. The liquid chromatography showed that the reaction conversion rate of compound 1f was 73.9%, and the ee value was 94%.

[0532] Example 5

[0533] Compound 1b (800 g, 4.44 mol, 1.0 eq.) and N,N,N',N'-tetramethylethylenediamine (512 g, 4.44 mol, 1.0 eq.) were dissolved in 5.6 L of anhydrous tetrahydrofuran under nitrogen protection. Lithium n-butyl (1.95 L, 2.5 M in Hexanes, 1.1 eq.) was slowly added dropwise at -50 °C, followed by potassium tert-butoxide (0.44 L, 1.0 M in THF, 0.1 eq.). After the addition was complete, the temperature was maintained at -50 °C and the mixture was stirred for 30 minutes. Then, a tetrahydrofuran mixture (4 L of tetrahydrofuran) of tert-butyl-4-oxopiperidin-1-carboxylic acid ester (888 g, 4.44 mol, 1.0 eq.) and lithium bromide (384 g, 4.44 mol, 1.0 eq.) was slowly added dropwise. The reaction system was maintained at -50℃ and stirred for 1 hour. After the starting material was completely eliminated by TLC monitoring, the reaction was quenched at 0℃ using NH4Cl aqueous solution (4L). The resulting mixture was extracted with EtOAc (2×8L). The organic phases were combined and washed with NH4Cl aqueous solution (8L). The organic phases were dried with anhydrous sodium sulfate and filtered to obtain the filtrate. The filtrate was concentrated under reduced pressure to obtain the crude product. n-Heptane (4L) was added to the crude product, and crystallization was carried out at about 10℃ for 2 hours. The mixture was filtered, and the filter cake was washed with n-Heptane. The filter cake was dried at 40℃ for 2 hours to obtain compound 1c (1.36kg, 80.7%).

[0534] Example 6

[0535] The procedure of Example 5 was followed, with the equivalent of n-butyllithium being 1.1 eq, the equivalent of piperidinone being 1.0 eq, the equivalent of TMEDA being 1.0 eq, the equivalent of LiBr being 1.0 eq, and the reaction temperature being -50℃. After the reaction was completed, each component was analyzed by HPLC to investigate the effect of different equivalents of potassium tert-butoxide on the reaction effect. The results are shown in Table 1 below.

[0536] Table 1

[0537] Conclusion: The catalytic amount of potassium tert-butoxide is superior to that used in equivalent amounts.

[0538] Example 7

[0539] The procedure of Example 5 was followed, with the following parameters maintained: 1.1 eq of n-butyllithium, 1.0 eq of piperidinone, 1.0 eq of TMEDA, 1.0 eq of lithium salt, and a reaction temperature of -50°C. After the reaction, each component was analyzed by HPLC to investigate the effect of different types of lithium salts on the reaction effect. The results are shown in Table 2 below.

[0540] Table 2

[0541] Conclusion: The chemical behavior of the two lithium salts is not significantly different.

[0542] Example 8

[0543] 1) Solution preparation:

[0544] Solution 1: 120 kg compound 1b, 77.4 kg tetramethylethylenediamine, 600 L tetrahydrofuran, stirred until dissolved at room temperature under nitrogen protection.

[0545] Solution 2: 293.1 L 2.5 M n-butyllithium / n-hexane solution, under nitrogen protection.

[0546] Solution 3: 66.6 L 1 M potassium tert-butoxide / tetrahydrofuran solution, under nitrogen protection.

[0547] Solution 4: 132.7 kg N-Boc piperidinone, 28.9 kg anhydrous lithium bromide, 663.4 L anhydrous tetrahydrofuran, stirred until dissolved at room temperature under nitrogen protection.

[0548] Solution 5: 106.9 kg ammonium chloride, 572.6 L water, stirred until dissolved at room temperature.

[0549] The flow chemical parameters are shown in Table 4.

[0550] Table 4

[0551] Operating steps:

[0552] Connect the reactor pipelines. Flush the pipelines of pumps A, C, and D with anhydrous THF, flush the pipeline of pump B with anhydrous n-hexane, and flush pump E with water. After flushing, connect the feed pipelines for each material. Place the reactor in a 0°C cold bath and start the pumps to feed the materials.

[0553] After the reaction was completed, continuous centrifugal extraction was performed using the apparatus shown in Figure 2.

[0554] 2) Continuous centrifugal extraction

[0555] Start two DN250 continuous centrifugal extractors, adjusting their speed to 600 rpm. Start pump P1 to pump the stirred reaction solution into the primary centrifugal extractor, and start pump P2 to pump ethyl acetate into the primary centrifugal extractor; simultaneously start pump P3 to pump a semi-saturated sodium chloride solution into the secondary centrifugal extractor.

[0556] The light phase (organic phase) from the secondary centrifugal extractor was collected. After concentration, approximately 5% n-heptane was added to induce crystallization and slurry formation at room temperature. The mixture was then filtered, and the wet filter cake was dried to obtain 187 kg of the target compound, with a yield of 74%.

[0557] List of implementation plans

[0558] 1. A method for preparing compound H or its salt,

[0559] The method includes the step of reacting compound B with compound II to form compound C. in,

[0560] Ring A is selected from 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally converted by one or more halogens, hydroxyl groups, nitro groups, cyano groups, or C-membered rings. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0561] R1 is selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally oxidized by one or more halogens, nitro groups, cyano groups, C6 groups, or C4 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted, and n is 0, 1, 2 or 3;

[0562] R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, and carbon. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more halogen, amino, hydroxyl, or cyano groups;

[0563] R6 and R7 are each independently selected from hydrogen or hydroxyl protecting groups, or R6 and R7 together with the atoms attached to them form a 3-8 membered heterocycle, wherein the 3-8 membered heterocycle is optionally independently protected by 0, 1, 2 or 3 R groups. a replace;

[0564] Each R a Each is independently selected from hydrogen, carbonyl, and C. 1-6 Alkyl, C 1-6 alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, aryl, or heteroaryl group is optionally converted to one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6Alkyl groups are substituted;

[0565] PG is an amino protecting group.

[0566] 2. According to the method described in Implementation Scheme 1, R6 and R7 together with the atoms they are attached to form a 5-membered heterocycle, preferably R6 and R7 together with the atoms they are attached to form The 5-membered heterocycle is optionally and independently bounded by 1 or 2 R... a Replace, each R a Each is independently selected from hydrogen, carbonyl, phenyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl, alkoxy, or phenyl group is optionally oxidized by one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0567] 3. The method according to embodiment 1 or 2, wherein compound B reacts with compound II in the presence of a base, wherein the base is selected from lithium hexylene, phenyllithium, mesitylenelithium, lithium n-butyllithium, lithium tert-butyllithium or lithium sec-butyllithium, preferably lithium n-butyllithium.

[0568] 4. The method according to any one of embodiments 1-3, further comprising reacting compound B in the presence of stabilizer I and stabilizer II, wherein stabilizer I is selected from tetramethylethylenediamine, hexamethylphosphoric triamine, crown ether, 1,2-dimethoxyethane, ethylenediamine, N,N'-dimethylpropanediamine, preferably tetramethylethylenediamine or hexamethylphosphoric triamine; and stabilizer II is selected from lithium bromide, lithium chloride, lithium iodide, lithium nitrate, lithium tetrafluoroborate, lithium trifluoromethanesulfonate, magnesium chloride, cesium chloride, zinc chloride, lanthanum chloride, preferably lithium bromide or lithium chloride.

[0569] 5. The method according to any one of embodiments 1-4, further comprising reacting in the presence of an ionic base, wherein the ionic base is selected from potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, KHMDS, NaHMDS, preferably potassium tert-butoxide.

[0570] 6. The method according to any one of embodiments 1-5, further comprising the step of reacting compound C in a reducing agent to generate compound D. R1, R4 to R7, PG and n are defined as in Implementation Scheme 1.

[0571] 7. The method according to embodiment 6, wherein the reducing agent is selected from Pd / C / hydrogen.

[0572] 8. The method according to any one of embodiments 1-7, further comprising the step of reacting compound D with compound III in the presence of a base to generate compound E.

[0573] Wherein, X is selected from chlorine, bromine, iodine, preferably bromine, and rings A, R1 to R5, PG and n are as defined in embodiment 1.

[0574] 9. The method according to embodiment 8, wherein the base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, DBU, tetramethylguanidine, 2,2,6,6-tetramethylpiperidine, N,N-diisopropylethylamine, preferably 2,2,6,6-tetramethylpiperidine.

[0575] 10. The method according to any one of embodiments 1-9, further comprising the step of generating compound F from compound E under catalytic / reducing conditions. Rings A, R1 to R5, PG, and n are as defined in Implementation Scheme 1.

[0576] 11. The method according to embodiment 10, wherein the reducing agent is selected from:

[0577] Reducing agent I: Hydrogen; or

[0578] Reducing agent II: BH3·THF, BH3·DMS, B2H6·THF, BH3·S(CH3)2.

[0579] 12. The method according to embodiment 10, wherein the catalyst is selected from:

[0580] Catalyst I: [Ir(COD)Cl] 2、 RuCl2[(R)-dm-segphos], RuCl[(R)-xylbinap]; or

[0581] Catalyst II: (R)-2-methyl-CBS-oxazolborane, (R)-2-butyl-CBS-oxazolborane, (R)-2-phenyl-CBS-oxazolborane.

[0582] 13. The method according to any one of embodiments 1-12, further comprising the step of reacting compound F under trisubstituted phosphine / azodicarboxylic acid diester conditions to generate compound G, and deprotecting compound G to form compound H. Wherein, the trisubstituted phosphide is triphenylphosphine, the azodicarboxylic acid diester is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, di(4-chlorobenzyl) azodicarboxylate, preferably diisopropyl azodicarboxylate, and rings A, R1 to R5, PG and n are as defined in embodiment 1.

[0583] 14. The method according to any one of embodiments 1-13, wherein compound F is compound F'.

[0584] 15. The method according to any one of embodiments 1-14, wherein ring A is selected from... R8 is selected from hydrogen, halogen, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy group, m is selected from 0, 1, 2, 3, 4.

[0585] 16. The method according to any one of embodiments 1-15, wherein ring A is selected from... Preferred

[0586] 17. The method according to any one of embodiments 1-16, wherein compound II is selected from... Preferred

[0587] 18. The method according to any one of embodiments 1-17, wherein compound H is compound h-2.

[0588] 19. A method for preparing a compound of formula H or a salt thereof, comprising:

[0589] Step 1: Compound A reacts with a hydroxyl protecting agent to form compound B;

[0590] Step 2: Compound B reacts with compound II under alkaline conditions to form compound C;

[0591] Step 3: Compound C is converted to compound D under catalytic / reducing conditions;

[0592] Step 4: Compound D reacts with compound III under alkaline conditions to form compound E;

[0593] Step 5: Compound E forms compound F under catalytic / reducing conditions;

[0594] Step 6: Compound F is reacted with trisubstituted phosphine / azodicarboxylic acid diester to generate compound G;

[0595] Step 7: Compound G is converted into compound H, wherein rings A, R1-R7, PG, X, and n are as defined in Scheme 1.

[0596] 20. A method for preparing compound h-2 or a salt thereof, comprising:

[0597] Step 1: Compound a reacts with triethyl orthoacetate to form compound b;

[0598] Step 2: Compound b reacts with compound II-1 under n-butyllithium conditions to generate compound c;

[0599] Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions;

[0600] Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e;

[0601] Step 5: Compound e forms compound f-2 under [Ir(COD)Cl]2 / hydrogen conditions;

[0602] Step 6: Compound f-2 is converted to compound g-2 under the conditions of triphenylphosphine / diisopropyl azodicarboxylate;

[0603] Step 7: Compound g-2 is converted to compound h-2 under hydrochloric acid / dioxane conditions.

[0604] Compound C of formula 21 or its pharmaceutically acceptable salt,

[0605] in,

[0606] R1 is selected from H, halogen, amino, hydroxyl, C. 1-6 Alkyl or C 1-6 Alkoxy group, wherein the alkyl or alkoxy group is optionally surrounded by one or more elements selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted, and n is 0, 1, 2 or 3;

[0607] R4 and R5 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more halogen, amino, hydroxyl, or cyano groups;

[0608] R6 and R7 are each independently selected from hydrogen or hydroxyl protecting groups, or R6 and R7 together with the atoms attached to them form a 3-8 membered heterocycle, wherein the 3-8 membered heterocycle is optionally independently protected by 1, 2 or 3 R groups. a replace;

[0609] Each R a Each is independently selected from hydrogen, carbonyl, and C. 1-6 Alkyl, C 1-6 alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, aryl, or heteroaryl group is optionally converted to one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0610] PG is an amino protecting group.

[0611] 22. The compound of formula C or a pharmaceutically acceptable salt thereof according to embodiment 21, wherein the compound of formula C is a compound of formula C-1. Each R a Each is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, preferably methyl, methoxy, or ethoxy; PG is tert-butoxycarbonyl, and n, R1, R4, and R5 are as defined in embodiment 19.

[0612] 23. A method for preparing a compound of formula C, the method comprising the step of reacting compound B with compound II to form compound C. R1, R4, R5, R6, R7, PG, and n are as described in implementation scheme 21.

[0613] 24. The method according to embodiment 23, comprising reacting compound B with compound II in the presence of a base, wherein the base is selected from lithium hexylene, phenyllithium, mesitylenelithium, lithium n-butyllithium, lithium tert-butyllithium or lithium sec-butyllithium, preferably lithium n-butyllithium.

[0614] 25. The method according to embodiment 24 further comprises reacting compound B in the presence of stabilizer I and stabilizer II, wherein stabilizer I is selected from tetramethylethylenediamine, hexamethylphosphoric triamine, crown ether, 1,2-dimethoxyethane, ethylenediamine, N,N'-dimethylpropanediamine, preferably tetramethylethylenediamine or hexamethylphosphoric triamine; and stabilizer II is selected from lithium bromide, lithium chloride, lithium iodide, lithium nitrate, lithium tetrafluoroborate, lithium trifluoromethanesulfonate, magnesium chloride, cesium chloride, zinc chloride, lanthanum chloride, preferably lithium bromide or lithium chloride.

[0615] 26. The method according to any one of embodiments 23-25, further comprising reacting in the presence of an ionic base, wherein the ionic base is selected from potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, KHMDS, NaHMDS, preferably potassium tert-butoxide.

[0616] 27. The method according to embodiment 26, wherein the equivalent ratio of compound B to ionic base is 1:0.01 to 1:0.5; preferably 1:0.1.

[0617] 28. The method according to any one of embodiments 1-26 can be carried out in a batch reactor, a continuous flow microchannel reactor or a fixed bed reactor.

[0618] 29. A method for preparing compound AA, said method comprising the steps of any one of embodiments 1-20 and 23-28.

[0619] 30. Use of the preparation method according to any one of embodiments 1-20, 23-29, or the compound according to embodiments 21-22 in the preparation of a GLP-1 receptor agonist.

Claims

1. A method for preparing compound H or its salt, The method includes the step of reacting compound B with compound II to form compound C. in, Ring A is selected from 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally converted by one or more halogens, hydroxyl groups, nitro groups, cyano groups, or C-membered rings. 1-6 Alkyl or C 1-6 Alkyl groups are substituted; R1 is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally oxidized by one or more halogens, nitro groups, cyano groups, C6 groups, or C4 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted, and n is 0, 1, 2 or 3; R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, and carbon. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more halogen, amino, hydroxyl, or cyano groups; R6 and R7 are each independently selected from hydrogen or hydroxyl protecting groups, or R6 and R7 together with the atoms attached to them form a 3-8 membered heterocycle, wherein the 3-8 membered heterocycle is optionally independently protected by 0, 1, 2 or 3 R groups. a replace; Each R a Each is independently selected from hydrogen, carbonyl, and C. 1-6 Alkyl, C 1-6 alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, aryl, or heteroaryl group is optionally converted to one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted; PG is an amino protecting group.

2. The method according to claim 1, wherein R6, R7, together with the atoms attached to them, form a 5-membered heterocycle, preferably R6, R7, and the atoms attached to them form... The 5-membered heterocycle is optionally and independently bounded by 1 or 2 R... a Replace, each R a Each is independently selected from hydrogen, carbonyl, phenyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl, alkoxy, or phenyl group is optionally oxidized by one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

3. The method according to claim 1 or 2, wherein compound B reacts with compound II in the presence of base I, wherein base I is selected from lithium hexylene, phenyllithium, mesitylenelithium, lithium n-butyllithium, lithium tert-butyllithium or lithium sec-butyllithium, preferably lithium n-butyllithium.

4. The method according to any one of claims 1-3, further comprising reacting compound B in the presence of stabilizer I and stabilizer II, wherein stabilizer I is selected from tetramethylethylenediamine, hexamethylphosphoric triamine, crown ether, 1,2-dimethoxyethane, ethylenediamine, N,N'-dimethylpropanediamine, preferably tetramethylethylenediamine or hexamethylphosphoric triamine; and stabilizer II is selected from lithium bromide, lithium chloride, lithium iodide, lithium nitrate, lithium tetrafluoroborate, lithium trifluoromethanesulfonate, magnesium chloride, cesium chloride, zinc chloride, lanthanum chloride, preferably lithium bromide or lithium chloride.

5. The method according to any one of claims 1-4, further comprising reacting in the presence of base II, wherein base II is selected from potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, KHMDS, NaHMDS, preferably potassium tert-butoxide.

6. The method according to any one of claims 1-5, further comprising the step of reacting compound C with catalyst I / reducing agent I to generate compound D. R1, R4 to R7, PG and n are defined as in claim 1.

7. The method according to claim 6, wherein the catalyst I is selected from Pd / C, Pt / C, Ru / C, Pd(OH)2 / C, Pd(OH)2 / Al2O3, Pt / Al2O3, Ru / Al2O3, and Pd / Al2O3.

8. The method according to claim 6, wherein the reducing agent I is selected from hydrogen.

9. The method according to any one of claims 1-8, further comprising the step of reacting compound D with compound III in the presence of base III to generate compound E. in, X is selected from chlorine, bromine, iodine, preferably bromine, and rings A, R1 to R5, PG and n as defined in claim 1.

10. The method according to claim 9, wherein the base III is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, DBU, tetramethylguanidine, 2,2,6,6-tetramethylpiperidine, N,N-diisopropylethylamine, preferably 2,2,6,6-tetramethylpiperidine.

11. The method according to any one of claims 1-10, further comprising the step of generating compound F from compound E under catalyst I' / reducing agent I' conditions. Rings A, R1 to R5, PG, and n are as defined in claim 1.

12. The method according to claim 11, wherein the reducing agent I' is selected from: Reducing agent I: Hydrogen; or Reducing agent II: BH3·THF, BH3·DMS, B2H6·THF, BH3·S(CH3)2.

13. The method according to claim 11 or 12, wherein the catalyst I' is selected from: Catalyst II: [Ir(COD)Cl] 2、 RuCl2[(R)-dm-segphos], RuCl[(R)-xylbinap]; or Catalyst III: (R)-2-methyl-CBS-oxazolborane, (R)-2-butyl-CBS-oxazolborane, (R)-2-phenyl-CBS-oxazolborane.

14. The method according to claim 13, wherein catalyst II is selected from [Ir(COD)Cl]2.

15. The method according to claim 14, wherein the catalyst II further comprises a ligand selected from (R)-f-phamidol, f-amphox, preferably (R)-f-phamidol.

16. The method according to any one of claims 1-15, further comprising the step of reacting compound F under trisubstituted phosphide / azodicarboxylic acid diester conditions to generate compound G, in, The trisubstituted phosphide is triphenylphosphine, and the azodicarboxylic acid diester is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di(4-chlorobenzyl) azodicarboxylate, preferably diisopropyl azodicarboxylate, and rings A, R1 to R5, PG and n are as defined in claim 1.

17. The method according to any one of claims 1-16, further comprising the step of deprotecting compound G to form compound H, Wherein rings A, PG, R1-R5, and n are defined as in claim 1.

18. The method according to any one of claims 1-17, wherein compound F is compound F'.

19. The method according to any one of claims 1-18, wherein ring A is selected from... R8 is selected from hydrogen, halogen, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy group, m is selected from 0, 1, 2, 3, 4.

20. The method according to any one of claims 1-19, wherein ring A is selected from... Preferred 21. The method according to any one of claims 1-20, wherein compound II is selected from... Preferred 22. The method according to any one of claims 1-21, wherein compound H is compound h-2.

23. A method for preparing a compound of formula H or a salt thereof, comprising: Step 1: Compound A reacts with a hydroxyl protecting agent to form compound B; Step 2: Compound B reacts with compound II under alkaline conditions to form compound C; Step 3: Compound C is converted to compound D under the conditions of catalyst I / reducing agent I; Step 4: Compound D reacts with compound III under alkaline conditions to form compound E; Step 5: Compound E forms compound F under the conditions of catalyst I' / reducing agent I'; Step 6: Compound F is reacted with trisubstituted phosphine / azodicarboxylic acid diester to generate compound G; Step 7: Compound G is converted into compound H, wherein rings A, R1-R7, PG, X, and n are as defined in claim 1.

24. A method for preparing compound h-2 or a salt thereof, comprising: Step 1: Compound a reacts with triethyl orthoacetate to form compound b; Step 2: Compound b reacts with compound II-1 under n-butyllithium conditions to generate compound c; Step 3: Compound c is converted to compound d under Pd / C / hydrogen conditions; Step 4: Compound d reacts with compound III-2 under 2,2,6,6-tetramethylpiperidine (TMP) conditions to generate compound e; Step 5: Compound e forms compound f-2 under [Ir(COD)Cl]2 / hydrogen conditions; Step 6: Compound f-2 is converted to compound g-2 under the conditions of triphenylphosphine / diisopropyl azodicarboxylate; Step 7: Compound g-2 is converted to compound h-2 under hydrochloric acid / dioxane conditions.

25. A compound of formula C or a salt thereof, in, R1 is independently selected from H, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy group, wherein the alkyl or alkoxy group is optionally surrounded by one or more elements selected from halogen, oxo, nitro, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is substituted by a substituent, where n is 0, 1, 2, or 3; R4 and R5 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more halogen, amino, hydroxyl, or cyano groups; R6 and R7 are each independently selected from hydrogen or hydroxyl protecting groups, or R6 and R7 together with the atoms attached to them form a 3-8 membered heterocycle, wherein the 3-8 membered heterocycle is optionally independently protected by 1, 2 or 3 R groups. a replace; Each R a Each is independently selected from hydrogen, carbonyl, and C. 1-6 Alkyl, C 1-6 alkoxy, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, aryl, or heteroaryl group is optionally converted to one or more halogens, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted; PG is an amino protecting group.

26. The compound of formula C or a salt thereof according to claim 25, wherein the compound of formula C is a compound of formula C-1. Each R a Each is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, preferably methyl, methoxy, or ethoxy; PG is tert-butoxycarbonyl, and n, R1, R4, and R5 are as defined in claim 25.

27. A method for preparing a compound of formula C, the method comprising the step of reacting compound B with compound II to form compound C. in, R1, R4, R5, R6, R7, PG, n as described in claim 25.

28. The method according to claim 27, comprising reacting compound B with compound II in the presence of base I, wherein base I is selected from lithium hexylene, phenyllithium, mesitylenelithium, lithium n-butyllithium, lithium tert-butyllithium or lithium sec-butyllithium, preferably lithium n-butyllithium.

29. The method according to claim 28, further comprising reacting compound B in the presence of stabilizer I and stabilizer II, wherein stabilizer I is selected from tetramethylethylenediamine, hexamethylphosphoric triamine, crown ether, 1,2-dimethoxyethane, ethylenediamine, N,N'-dimethylpropanediamine, preferably tetramethylethylenediamine or hexamethylphosphoric triamine; and stabilizer II is selected from lithium bromide, lithium chloride, lithium iodide, lithium nitrate, lithium tetrafluoroborate, lithium trifluoromethanesulfonate, magnesium chloride, cesium chloride, zinc chloride, lanthanum chloride, preferably lithium bromide or lithium chloride.

30. The method according to any one of claims 27-29, further comprising reacting in the presence of base II, wherein base II is selected from potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, KHMDS, NaHMDS, preferably potassium tert-butoxide.

31. The method according to claim 30, wherein the equivalent ratio of compound B to base II is 1:0.01 to 1:0.5; preferably 1:0.

1.

32. A method for preparing a compound of formula D, the method comprising the method for preparing a compound of formula C according to any one of claims 27-31, and further comprising the step of reacting compound C with catalyst I / reducing agent I to generate compound D. R1, R4 to R7, PG and n are defined as in claim 1.

33. The method for preparing compound D according to claim 32, wherein the catalyst I is selected from Pd / C, Pt / C, Ru / C, Pd(OH)2 / C, Pd(OH)2 / Al2O3, Pt / Al2O3, Ru / Al2O3, and Pd / Al2O3.

34. The method for preparing compound D according to claim 32, wherein the reducing agent I is selected from hydrogen.

35. The method for preparing the compound of formula D according to any one of claims 32-34, the method further comprising reacting in the presence of an acid selected from salicylic acid, sulfuric acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, and hydrochloric acid, preferably salicylic acid and acetic acid.

36. The method for preparing the compound of formula D according to any one of claims 32-35, the method comprising the following steps: Step 1: Compound A reacts with triethyl orthoacetate to form compound B; Step 2: Compound B reacts with Compound II under the conditions of n-butyllithium, tetramethylethylenediamine, lithium bromide and potassium tert-butoxide to generate Compound C; Step 3: Compound C is converted into compound D under Pd / C / hydrogen and acetic acid conditions; 37. The method according to any one of claims 1-36, wherein it may be carried out in a batch reactor, a continuous flow microchannel reactor or a fixed bed reactor.

38. A method for preparing compound AA, said method comprising the steps of the method according to any one of claims 1-24 and 27-37.

39. Use of the preparation method according to any one of claims 1-24, 27-37, or the compound according to claims 25-26 in the preparation of a GLP-1 receptor agonist.

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