Method for preparing benzodioxane or salts thereof

Abstract

The present disclosure relates to a method for preparing a benzodioxane or salts thereof. Specifically, the method of the present disclosure comprises a step of reacting a compound of formula E under the presence of a tri-substituted phosphine / azodicarboxylate to form a compound of formula F.

Description

Method for preparing benzodioxetine or its salt Technical Field

[0001] The present invention belongs to the field of medicine and relates to a method for preparing benzodioxetine or a salt thereof. Background Art

[0002] 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperidine is a pharmaceutical intermediate and a fragment of many new drugs under development, such as the active molecule PF06882961 for the treatment of obesity reported in WO2018109607.

[0003] WO2022007979 discloses a method for synthesizing 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperidine. This method suffers from low atom utilization and yield, making it unsuitable for industrial production. Summary of the Invention

[0004] The present disclosure provides a method for preparing a compound of formula K or a salt thereof,

[0005] The method comprises the steps of reacting a compound of formula E under trisubstituted phosphine / azodicarboxylic acid diester conditions to form a compound of formula F,

[0006] in,

[0007] Ring A is selected from 6 to 10 membered aryl or 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy substitution;

[0008] is a double bond or a single bond,

[0009] when When it is a single bond, Y is selected from N or CR 14 ,

[0010] when When there is a double bond, Y is CR 14 ;

[0011] R 2 Selected from halogen, cyano, C 1-6 Alkyl or C 1-6 alkoxy;

[0012] R 3 、R 4 、R 5 are independently selected from hydrogen, halogen, cyano, C1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups;

[0013] R 14 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups;

[0014] y is selected from 0, 1, 2, and 3.

[0015] In some embodiments, the trisubstituted phosphine is triphenylphosphine.

[0016] In some embodiments, the azodicarboxylic acid diester is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate or di(4-chlorobenzyl) azodicarboxylate. In certain embodiments, the azodicarboxylic acid diester is diisopropyl azodicarboxylate.

[0017] In some embodiments, the reaction solvent of the compound of formula E is selected from tetrahydrofuran, diethyl ether, dichloromethane, toluene, ethyl acetate, acetonitrile, N,N-dimethylformamide. In certain embodiments, the reaction solvent of the compound of formula E is dichloromethane.

[0018] In some embodiments, the molar ratio of the compound of formula E to the trisubstituted phosphine compound 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 two numbers. In certain embodiments, the molar ratio of the compound of formula E to the trisubstituted phosphine compound is 1:1 to 1:1.5.

[0019] In certain embodiments, the molar ratio of the compound of formula E to triphenylphosphine is 1:1 to 1:1.5.

[0020] In some embodiments, the molar ratio of the compound of formula E to the azodicarboxylic 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 two numbers. In certain embodiments, the molar ratio of the compound of formula E to the azodicarboxylic acid diester is 1:1 to 1:1.5.

[0021] In certain embodiments, the molar ratio of the compound of formula E to diisopropyl azodicarboxylate is 1:1 to 1:1.5.

[0022] In some embodiments, Ring A is selected from R 1 is selected from fluorine, chlorine, bromine, iodine or cyano, and x is selected from 0, 1, 2, 3, or 4.

[0023] In certain embodiments, Ring A is selected from In certain embodiments, Ring A is

[0024] In some embodiments, the compound of formula K is a compound of formula K-1, A method for preparing a compound of formula K-1 or a salt thereof, comprising the steps of reacting a compound of formula E-1 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form a compound of formula F-1,

[0025] Among them, R 2 、R 3 、R 4 、R 5 、R 6 、R 8 , y are as defined above.

[0026] In some embodiments, y is 0.

[0027] In some embodiments, the compound of formula K is a compound of formula K-2, A method for preparing a compound of formula K-2 or a salt thereof, comprising the steps of reacting a compound of formula E-2 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form a compound of formula F-2,

[0028] Among them, R 3 、R 4 、R 5 As defined above.

[0029] In some embodiments, R 4 、R 5 Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, and cyano. In certain embodiments, R 4 、R 5 are each independently hydrogen.

[0030] In some embodiments, the compound of formula K is a compound of formula K-3, A method for preparing a compound of formula K-3 or a salt thereof, comprising the steps of reacting a compound of formula E-3 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form a compound of formula F-3,

[0031] Among them, R 3 As defined above.

[0032] In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, and cyano. In certain embodiments, R 3 Selected from hydrogen and methyl.

[0033] In some embodiments, the compound of formula K is a compound of formula K-4, A method for preparing a compound of formula K-4 or a salt thereof, comprising the steps of reacting a compound of formula E-4 under triphenylphosphine / diisopropyl azodicarboxylate conditions to form a compound of formula F-4,

[0034] In some embodiments, the compound of formula K is a compound of formula K-4a, A method for preparing a compound of formula K-4a or a salt thereof, comprising the steps of reacting a compound of formula E-4a under triphenylphosphine / diisopropyl azodicarboxylate conditions to form a compound of formula F-4a,

[0035] Furthermore, the method for preparing the compound of formula K or a salt thereof disclosed herein further comprises the step of converting the compound of formula D into the compound of formula M under acidic conditions, and the step of converting the compound of formula M into the compound of formula E.

[0036] in,

[0037] R 6 、R 8 are each independently selected from hydrogen or a hydroxy protecting group;

[0038] R 9 、R 10 are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups;

[0039] Ring A, R 2 、R 3 、R 4 、R 5 , y are as defined above.

[0040] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, formic acid, acetic acid, and p-toluenesulfonic acid. In certain embodiments, the acid is hydrochloric acid.

[0041] In some embodiments, the reaction solvent for the compound of formula D is an alcohol. In some embodiments, the alcohol is selected from methanol, ethanol, propanol, butanol, pentanol, and hexanol. In certain embodiments, the alcohol is methanol.

[0042] In some embodiments, the compound of formula K is a compound of formula K-1. The method for preparing the compound of formula K-1 or a salt thereof further comprises the step of converting the compound of formula D-1 into a compound of formula M-1 under acidic conditions, and the step of converting the compound of formula M-1 into a compound of formula E-1.

[0043] Among them, R 9 、R 10 、R 2 、R 3 、R 4 、R 5 、R 6 、R 8 , y are as defined above.

[0044] In some embodiments, the compound of formula K is a compound of formula K-2. The method for preparing the compound of formula K-2 or a salt thereof further comprises the step of converting the compound of formula D-2 into a compound of formula M-2 under acidic conditions, and the step of converting the compound of formula M-2 into a compound of formula E-2.

[0045] Among them, R 6 、R 8 、R 9 、R 10 、R 3 、R 4 、R 5 As defined above.

[0046] In some embodiments, the compound of formula K is a compound of formula K-3. The method for preparing the compound of formula K-3 or a salt thereof further comprises the step of converting the compound of formula D-3 into a compound of formula M-3 under acidic conditions, and the step of converting the compound of formula M-3 into a compound of formula E-3.

[0047] Among them, R 6 、R 8 、R 9 、R 10 、R 3 As defined above.

[0048] In some embodiments, R 9 is selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl. In certain embodiments, R 9 For ethyl.

[0049] In some embodiments, R 10 is selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl. In certain embodiments, R 10 It is a methyl group.

[0050] In some embodiments, the compound of formula K is a compound of formula K-4. The method for preparing the compound of formula K-4 or a salt thereof further comprises the step of converting the compound of formula D-4 into a compound of formula M-4 under hydrochloric acid / methanol conditions, and the step of converting the compound of formula M-4 into a compound of formula E-4.

[0051] Among them, R 6 、R 8 As defined above.

[0052] In some embodiments, the compound of formula K is a compound of formula K-4a. The method for preparing the compound of formula K-4a or a salt thereof further comprises the step of converting the compound of formula D-4a to the compound of formula M-4a under hydrochloric acid / methanol conditions, and the step of converting the compound of formula M-4a to the compound of formula E-4a.

[0053] Among them, R 6 、R 8 As defined above.

[0054] Furthermore, the method for preparing the compound of formula K or a salt thereof disclosed herein further comprises the step of reacting the compound of formula C under the conditions of an oxazolidinone catalyst / reducing agent represented by formula (I) to form a compound of formula D.

[0055] Wherein: Ar is independently selected from 6-membered aryl or 5-10-membered heteroaryl, and the aryl and heteroaryl are optionally substituted by one or more halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy substitution;

[0056] R a Selected from hydrogen, C 1-6 Alkyl, wherein the alkyl is optionally substituted by one or more halogen, hydroxy, cyano, or amino groups;

[0057] Ring A, R 8 、R 9 、R 10 、R 2 、R 3 、R 4 、R 5 , y are as defined above.

[0058] In certain embodiments, each Ar is independently phenyl.

[0059] In certain embodiments, R a C 1-6 In certain embodiments, R ais methyl, ethyl, n-propyl, isopropyl. In certain embodiments, R a It is a methyl group.

[0060] In certain embodiments, the oxazolidinone catalyst represented by formula (I) is represented by formula (Ia)

[0061] In some embodiments, the reducing agent is a borane ligand compound. In certain specific embodiments, the reducing agent is BH3·THF, BH3·Me2S, or BH3·DEA. In certain specific embodiments, the reducing agent is BH3·THF.

[0062] In some embodiments, the compound of formula K is a compound of formula K-1. The method for preparing the compound of formula K-1 or a salt thereof further comprises the step of reacting the compound of formula C-1 with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form a compound of formula D-1.

[0063] Among them, Ar, R a 、R 8 、R 9 、R 10 、R 2 、R 3 、R 4 、R 5 , y are as defined above.

[0064] In some embodiments, the compound of formula K is a compound of formula K-2. The method for preparing the compound of formula K-2 or a salt thereof further comprises the step of reacting the compound of formula C-2 with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form a compound of formula D-2.

[0065] Among them, Ar, R a 、R 8 、R 9 、R 10 、R 2 、R 3 、R 4 、R 5 , y are as defined above.

[0066] In some embodiments, the compound of formula K is a compound of formula K-3. The method for preparing the compound of formula K-3 or a salt thereof further comprises the step of reacting the compound of formula C-3 with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form a compound of formula D-3.

[0067] Among them, Ar, R a 、R 8 、R 9 、R10 、R 3 As defined above.

[0068] In some embodiments, the compound of formula K is a compound of formula K-4. The method for preparing the compound of formula K-4 or a salt thereof further comprises the step of reacting the compound of formula C-4 with an oxazolidinone catalyst / reducing agent as represented by formula (Ia) to form a compound of formula D-4.

[0069] where R 8 As defined above.

[0070] In some embodiments, the compound of formula K is a compound of formula K-4a. The method for preparing the compound of formula K-4a or a salt thereof further comprises the step of reacting the compound of formula C-4 with an oxazolidinone catalyst of formula (Ia) in the presence of BH3·THF to form a compound of formula D-4a.

[0071] Furthermore, the method for preparing the compound of formula K or a salt thereof disclosed herein further comprises the steps of reacting the compound of formula (II) with the orthoester represented by formula (III) to form a compound of formula A, and reacting the compound of formula A with the compound of formula B under alkaline conditions to form a compound of formula C.

[0072] Where: R 11 、R 12 are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups;

[0073] X is a halogen;

[0074] Ring A, R 9 、R 10 、R 2 、R 4 、R 5 , y are as defined above.

[0075] In some embodiments, the base is selected from potassium carbonate and sodium carbonate. In certain embodiments, the base is potassium carbonate.

[0076] In some embodiments, the compound of formula K is a compound of formula K-1. The method for preparing the compound of formula K-1 or a salt thereof further comprises the steps of reacting the compound of formula (II) with an orthoester represented by formula (III) to form a compound of formula A, and reacting the compound of formula A with a compound of formula B1 under alkaline conditions to form a compound of formula C-1.

[0077] Where: R 9、R 10 、R 11 、R 12 , X, R 2 、R 4 、R 5 , y are as defined above.

[0078] In some embodiments, the compound of formula K is a compound of formula K-2. The method for preparing the compound of formula K-2 or a salt thereof further comprises the steps of reacting the compound of formula (IIa) with an orthoester represented by formula (III) to form a compound of formula A1, and reacting the compound of formula A1 with a compound of formula B1 under alkaline conditions to form a compound of formula C-2.

[0079] Where: R 9 、R 10 、R 11 、R 12 , X, R 4 、R 5 As defined above.

[0080] In some embodiments, the compound of formula K is a compound of formula K-3. The method for preparing the compound of formula K-3 or a salt thereof further comprises the steps of reacting the compound of formula (IIa) with an orthoester represented by formula (III) to form a compound of formula A1, and reacting the compound of formula A1 with a compound of formula B2 under alkaline conditions to form a compound of formula C-3.

[0081] Where: R 9 、R 10 、R 11 、R 12 , X are as defined above.

[0082] In some embodiments, X is selected from fluorine, chlorine, bromine, and iodine. In certain specific embodiments, X is bromine.

[0083] In some embodiments, R 11 、R 12 Each independently is C 1-6 In some embodiments, R 11 、R 12 Each is independently selected from methyl, ethyl, propyl, butyl, isopropyl. In certain embodiments, R 11 、R 12 All are ethyl.

[0084] In some embodiments, the compound of formula K is a compound of formula K-4. The method for preparing the compound of formula K-4 or a salt thereof further comprises the steps of reacting the compound of formula (IIa) with an orthoester represented by formula (IIIa) to form a compound of formula A2, and reacting the compound of formula A2 with a compound of formula B3 under potassium carbonate conditions to form a compound of formula C-4.

[0085] Furthermore, the method for preparing the compound of formula K or a salt thereof disclosed herein further comprises the steps of converting the compound of formula F into a compound of formula G, and reacting the compound of formula G with a compound of formula H under palladium catalyst / cocatalyst conditions to form a compound of formula J.

[0086] Where: R 7 is a hydroxyl protecting group; R 13 is an amino protecting group;

[0087] Ring A, R 2 、R 3 、R 4 、R 5 、y、 Y is as defined above.

[0088] In some embodiments, the hydroxy protecting group is selected from allyl, methoxymethyl ether, tetrahydropyran, (trimethylsilyl)ethoxymethyl, dimethylaminosulfonyl, trifluoromethanesulfonyl, alkyl groups (e.g., methyl, tert-butyl, trityl, etc.), benzyl groups (e.g., benzyl, p-methoxybenzyl, etc.), silicon groups (e.g., tert-butyldimethylsilyl, etc.), acyl groups (e.g., acetyl, benzoyl, etc.), alkoxycarbonyl groups (e.g., benzyloxycarbonyl, etc.). In certain embodiments, the hydroxy protecting group is trifluoromethanesulfonyl. In certain embodiments, the R 7 It is a trifluoromethanesulfonyl group.

[0089] In some embodiments, the amino protecting group is selected from benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, p-toluenesulfonylmethoxycarbonyl, ethoxycarbonyl, phthaloyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl. In certain embodiments, the amino protecting group is tert-butoxycarbonyl. In certain embodiments, the R 13 It is tert-butoxycarbonyl.

[0090] In some embodiments, the palladium catalyst is a palladium phosphine complex. In some embodiments, the palladium catalyst is selected from Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppe)Cl2, Pd(dppp)Cl2, Pd(dppf)Cl2, a solvate of Pd(PPh3)4, a solvate of Pd(PPh3)2Cl2, a solvate of Pd(dppe)Cl2, a solvate of Pd(dppp)Cl2, a solvate of Pd(dppf)Cl2. In some embodiments, the palladium catalyst is selected from Pd(dppf)Cl2 or a solvate of Pd(dppf)Cl2. In some embodiments, the solvate of Pd(dppf)Cl2 is Pd(dppf)Cl2·CH2Cl2

[0091] In some embodiments, the palladium catalyst is Pd(dppf)Cl2·CH2Cl2.

[0092] In some embodiments, the promoter is selected from silver oxide or cuprous iodide.

[0093] In some embodiments, the solvent used in the reaction of the compound of formula G is selected from organic amines and diethyl ether. In some embodiments, the solvent used in the reaction of the compound of formula G is selected from triethylamine, ethylenediamine, dimethylformamide, and dimethylacetamide. In some specific embodiments, the solvent used in the reaction of the compound of formula G is dimethylacetamide.

[0094] In some embodiments, Selected from In certain embodiments, for

[0095] In some embodiments, the compound of formula K is a compound of formula K-1. The method for preparing the compound of formula K-1 or a salt thereof further comprises the steps of converting the compound of formula F-1 into a compound of formula G-1, and reacting the compound of formula G-1 with a compound of formula H-1 under palladium catalyst / cocatalyst conditions to form a compound of formula J-1.

[0096] where R 7 、R 13 、R 2 、R 3 、R 4 、R 5 , y are as defined above.

[0097] In some embodiments, the compound of formula K is a compound of formula K-2. The method for preparing the compound of formula K-2 or a salt thereof further comprises the steps of converting the compound of formula F-2 into a compound of formula G-2, and reacting the compound of formula G-2 with a compound of formula H-1 under palladium catalyst / cocatalyst conditions to form a compound of formula J-2.

[0098] where R 7 、R 13 、R 3 、R 4 、R 5 As defined above.

[0099] In some embodiments, the compound of formula K is a compound of formula K-3. The method for preparing a compound of formula K-3 or a salt thereof further comprises the steps of converting a compound of formula F-3 into a compound of formula G-3, and reacting the compound of formula G-3 with a compound of formula H-2 under palladium catalyst / cocatalyst conditions to form a compound of formula J-3.

[0100] where R 7 、R 13 、R 3 As defined above.

[0101] In some embodiments, the compound of formula K is a compound of formula K-4. The method for preparing a compound of formula K-4 or a salt thereof further comprises the steps of converting a compound of formula F-4 into a compound of formula G-4, and reacting the compound of formula G-4 with a compound of formula H-2 under Pd(dppf)Cl2 / copper iodide conditions to form a compound of formula J-4.

[0102] In some embodiments, the compound of formula K is a compound of formula K-4a. The method for preparing a compound of formula K-4a or a salt thereof further comprises the steps of converting a compound of formula F-4a into a compound of formula G-4a, and reacting the compound of formula G-4a with a compound of formula H-2 under Pd(dppf)Cl2 / copper iodide conditions to form a compound of formula J-4a.

[0103] Furthermore, the method for preparing the compound of formula K or a salt thereof disclosed herein further comprises the step of converting the compound of formula J into the compound of formula K.

[0104] Ring A, R 2 、R 3 、R 4 、R 5 ,y,R 13 , Y, As defined above.

[0105] In some embodiments, the step of converting the compound of formula J to the compound of formula K is carried out under conditions of hydrochloric acid, Me3SiI or p-toluenesulfonic acid. In some embodiments, the step of converting the compound of formula J to the compound of formula K is carried out under conditions of hydrochloric acid.

[0106] In some embodiments, the solvent used in the reaction of the compound of formula J is selected from EtOAc, MeOH, CH2Cl2, CHCl3, CH3CN or dioxane. In some embodiments, the solvent used in the reaction of the compound of formula J is selected from dioxane.

[0107] In some embodiments, the method for preparing the compound of formula K or a salt thereof further comprises the step of converting the compound of formula J into the compound of formula K under hydrochloric acid / dioxane conditions.

[0108] In some embodiments, the compound of formula K is a compound of formula K-1. The method for preparing the compound of formula K-1 or a salt thereof further comprises the step of converting the compound of formula J-1 into the compound of formula K-1 under hydrochloric acid / dioxane conditions,

[0109] R 2 、R 3 、R 4 、R 5 ,y,R 13 As defined above.

[0110] In some embodiments, the compound of formula K is a compound of formula K-2. The method for preparing the compound of formula K-2 or a salt thereof further comprises the step of converting the compound of formula J-2 into the compound of formula K-2 under hydrochloric acid / dioxane conditions,

[0111] R 3 、R 4 、R 5 、R 13 As defined above.

[0112] In some embodiments, the compound of formula K is a compound of formula K-3. The method for preparing the compound of formula K-3 or a salt thereof further comprises the step of converting the compound of formula J-3 into the compound of formula K-3 under hydrochloric acid / dioxane conditions,

[0113] R 3 、R 13 As defined above.

[0114] In some embodiments, the compound of formula K is a compound of formula K-4. The method for preparing the compound of formula K-4 or a salt thereof further comprises the step of converting the compound of formula J-4 into the compound of formula K-4 under hydrochloric acid / dioxane conditions,

[0115] In some embodiments, the compound of formula K is a compound of formula K-4a. The method for preparing the compound of formula K-4a or a salt thereof further comprises the step of converting the compound of formula J-4a into the compound of formula K-4a under hydrochloric acid / dioxane conditions,

[0116] Some embodiments provide a method for preparing a compound of formula K or a salt thereof comprising:

[0117] Step 1) reacting a compound of formula (II) with an orthoester represented by formula (III) to form a compound of formula A, and reacting the compound of formula A with a compound of formula B under alkaline conditions to form a compound of formula C;

[0118] Step 2) Compound C is reacted with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form a compound of formula D;

[0119] Step 3) converting the compound of formula D into the compound of formula E under acidic conditions;

[0120] Step 4) reacting the compound of formula E under trisubstituted phosphine / azodicarboxylic acid diester conditions to form a compound of formula F;

[0121] Step 5) converting the compound of formula F into the compound of formula G, and reacting the compound of formula G with the compound of formula H under palladium catalyst / cocatalyst conditions to form the compound of formula J;

[0122] Step 6) converting the compound of formula J into the compound of formula K;

[0123] Among them, ring A, R 2 、R 3 、R 4 、R 5 、R 8 ,y,R 9 、R 10 ,Ar,R a 、R 11 、R 12 , X, R 7 、R 13 、 As defined above.

[0124] Some embodiments provide a method for preparing a compound of formula K-1 or a salt thereof comprising:

[0125] Step 1) reacting a compound of formula (II) with an orthoester represented by formula (III) to form a compound of formula A, and reacting the compound of formula A with a compound of formula B1 under alkaline conditions to form a compound of formula C-1;

[0126] Step 2) Compound C-1 is reacted with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form compound D-1;

[0127] Step 3) converting the compound of formula D-1 into the compound of formula E-1 under acidic conditions;

[0128] Step 4) reacting the compound of formula E-1 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form the compound of formula F-1;

[0129] Step 5) converting the compound of formula F-1 into the compound of formula G-1, and reacting the compound of formula G-1 with the compound of formula H-1 under palladium catalyst / cocatalyst conditions to form the compound of formula J-1;

[0130] Step 6) converting the compound of formula J-1 into the compound of formula K-1 under hydrochloric acid / dioxane conditions;

[0131] Among them, R 2 、R 3 、R 4 、R 5 、R 8 ,y,R 9 、R 10 ,Ar,R a 、R 11 、R 12 , X, R 7 、R 13 As defined above.

[0132] Some embodiments provide a method for preparing a compound of formula K-2 or a salt thereof comprising:

[0133] Step 1) reacting a compound of formula (IIa) with an orthoester represented by formula (III) to form a compound of formula A1, and reacting the compound of formula A1 with a compound of formula B1 under alkaline conditions to form a compound of formula C-2;

[0134] Step 2) Compound C-2 is reacted with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form compound D-2;

[0135] Step 3) converting the compound of formula D-2 into the compound of formula E-2 under acidic conditions;

[0136] Step 4) reacting the compound of formula E-2 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form the compound of formula F-2;

[0137] Step 5) converting the compound of formula F-2 into the compound of formula G-2, and reacting the compound of formula G-2 with the compound of formula H-1 under palladium catalyst / cocatalyst conditions to form the compound of formula J-2;

[0138] Step 6) converting the compound of formula J-2 into the compound of formula K-2 under hydrochloric acid / dioxane conditions;

[0139] Among them, R 3 、R 4 、R 5 、R 9 、R 10 ,Ar,R a 、R 11 、R 12 , X, R 7 、R 13 As defined above.

[0140] Some embodiments provide a method for preparing a compound of formula K-3 or a salt thereof comprising:

[0141] Step 1) reacting a compound of formula (IIa) with an orthoester represented by formula (III) to form a compound of formula A1, and reacting the compound of formula A1 with a compound of formula B2 under alkaline conditions to form a compound of formula C-3;

[0142] Step 2) Compound C-3 is reacted with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form compound D-3;

[0143] Step 3) converting the compound of formula D-3 into the compound of formula E-3 under acidic conditions;

[0144] Step 4) reacting the compound of formula E-3 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form the compound of formula F-3;

[0145] Step 5) converting the compound of formula F-3 into the compound of formula G-3, and reacting the compound of formula G-3 with the compound of formula H-2 under palladium catalyst / cocatalyst conditions to form the compound of formula J-3;

[0146] Step 6) converting the compound of formula J-3 into the compound of formula K-3 under hydrochloric acid / dioxane conditions;

[0147] Among them, R 7 、R 13 , X, Ar, R a 、R 8 、R 9 、R 10 、R 3 、R 11 、R 12 As defined above.

[0148] Some embodiments provide a method for preparing a compound of formula K-4 or a salt thereof comprising:

[0149] Step 1) reacting a compound of formula (IIa) with an orthoester represented by formula (IIIa) to form a compound of formula A2, and reacting the compound of formula A2 with a compound of formula B3 under potassium carbonate conditions to form a compound of formula C-4;

[0150] Step 2) Compound C-4 is reacted with an oxazolidinone catalyst / reducing agent as shown in formula (Ia) to form compound D-4a;

[0151] Step 3) converting the compound of formula D-4 into the compound of formula E-4 under hydrochloric acid / methanol conditions;

[0152] Step 4) reacting the compound of formula E-4 under triphenylphosphine / diisopropyl azodicarboxylate conditions to form the compound of formula F-4;

[0153] Step 5) converting the compound of formula F-4 into the compound of formula G-4, and reacting the compound of formula G-4 with the compound of formula H-2 under Pd(dppf)Cl2 / copper iodide conditions to form the compound of formula J-4;

[0154] Step 6) converting the compound of formula J-4 into the compound of formula K-4 under hydrochloric acid / dioxane conditions;

[0155] Among them, R 8 As defined above.

[0156] Some embodiments provide a method for preparing a compound of formula K-4a or a salt thereof comprising:

[0157] Step 1) reacting a compound of formula (IIa) with an orthoester represented by formula (IIIa) to form a compound of formula A2, and reacting the compound of formula A2 with a compound of formula B3 under potassium carbonate conditions to form a compound of formula C-4;

[0158] Step 2) Compound C-4 is reacted with an oxazolidinone catalyst represented by formula (Ia) in the presence of BH3·THF to form compound D-4a;

[0159] Step 3) Compound D-4a is reacted under hydrochloric acid / methanol conditions to form compound E-4a

[0160] Step 4) a step of reacting the compound of formula E-4a under triphenylphosphine / diisopropyl azodicarboxylate conditions to form the compound of formula F-4a,

[0161] Step 5) converting the compound of formula F-4a into the compound of formula G-4a, and reacting the compound of formula G-4a with the compound of formula H-2 under Pd(dppf)Cl2 / copper iodide conditions to form the compound of formula J-4a;

[0162] Step 6) converting the compound of formula J-4a into the compound of formula K-4a under hydrochloric acid / dioxane conditions;

[0163] Among them, R 8 As defined above.

[0164] The present disclosure provides a method for preparing a compound of formula F or a salt thereof,

[0165] The method comprises the steps of reacting a compound of formula E under trisubstituted phosphine / azodicarboxylic acid diester conditions to form a compound of formula F,

[0166] in,

[0167] Ring A is selected from 6 to 10 membered aryl or 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy substitution;

[0168] is a double bond or a single bond,

[0169] when When it is a single bond, Y is selected from N or CR 14 ,

[0170] when When there is a double bond, Y is CR 14 ;

[0171] R 2 Selected from halogen, cyano, C 1-6 Alkyl or C 1-6 alkoxy;

[0172] R 3 、R 4 、R 5 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups;

[0173] R 14 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups;

[0174] y is selected from 0, 1, 2, and 3.

[0175] In some embodiments, the trisubstituted phosphine is triphenylphosphine.

[0176] In some embodiments, the azodicarboxylic acid diester is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate or di(4-chlorobenzyl) azodicarboxylate. In certain embodiments, the azodicarboxylic acid diester is diisopropyl azodicarboxylate.

[0177] In some embodiments, the reaction solvent of the compound of formula E is selected from tetrahydrofuran, diethyl ether, dichloromethane, toluene, ethyl acetate, acetonitrile, N,N-dimethylformamide. In certain embodiments, the reaction solvent of the compound of formula E is dichloromethane.

[0178] In some embodiments, the molar ratio of the compound of formula E to the trisubstituted phosphine compound 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 two numbers. In certain embodiments, the molar ratio of the compound of formula E to the trisubstituted phosphine compound is 1:1 to 1:1.5.

[0179] In certain embodiments, the molar ratio of the compound of formula E to triphenylphosphine is 1:1 to 1:1.5.

[0180] In some embodiments, the molar ratio of the compound of formula E to the azodicarboxylic 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 two numbers. In certain embodiments, the molar ratio of the compound of formula E to the azodicarboxylic acid diester is 1:1 to 1:1.5.

[0181] In certain embodiments, the molar ratio of the compound of formula E to diisopropyl azodicarboxylate is 1:1 to 1:1.5.

[0182] In some embodiments, Ring A is selected from R 1 is selected from fluorine, chlorine, bromine, iodine or cyano, and x is selected from 0, 1, 2, 3, or 4.

[0183] In certain embodiments, Ring A is selected from In certain embodiments, Ring A is

[0184] In some embodiments, the compound of formula F is a compound of formula F-1, A method for preparing a compound of formula F-1 or a salt thereof, comprising the steps of reacting a compound of formula E-1 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form a compound of formula F-1,

[0185] Among them, R 2 、R 3 、R 4 、R 5 、R 6 、R 8 , y are as defined above.

[0186] In some embodiments, y is 0.

[0187] In some embodiments, the compound of formula F is a compound of formula F-2, A method for preparing a compound of formula F-2 or a salt thereof, comprising the steps of reacting a compound of formula E-2 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form a compound of formula F-2,

[0188] Among them, R 3 、R 4 、R 5 As defined above.

[0189] In some embodiments, R 4 、R 5 Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, and cyano. In certain embodiments, R 4 、R 5 are each independently hydrogen.

[0190] In some embodiments, the compound of formula F is a compound of formula F-3, A method for preparing a compound of formula F-3 or a salt thereof, comprising the steps of reacting a compound of formula E-3 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form a compound of formula F-3,

[0191] Among them, R 3 As defined above.

[0192] In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, and cyano. In certain embodiments, R 3 Selected from hydrogen and methyl.

[0193] In some embodiments, the compound of formula F is a compound of formula F-4, A method for preparing a compound of formula F-4 or a salt thereof, comprising the steps of reacting a compound of formula E-4 under triphenylphosphine / diisopropyl azodicarboxylate conditions to form a compound of formula F-4,

[0194] In some embodiments, the compound of formula F is a compound of formula F-4a, A method for preparing a compound of formula F-4a or a salt thereof, comprising the steps of reacting a compound of formula E-4a under triphenylphosphine / diisopropyl azodicarboxylate conditions to form a compound of formula F-4a,

[0195] Furthermore, the method for preparing the compound of formula F or a salt thereof disclosed herein further comprises the step of converting the compound of formula D into the compound of formula M under acidic conditions, and the step of converting the compound of formula M into the compound of formula E.

[0196] in,

[0197] R 6 、R 8 are each independently selected from hydrogen or a hydroxy protecting group;

[0198] R 9 、R 10 are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups;

[0199] Ring A, R 2 、R 3 、R 4 、R 5 , y are as defined above.

[0200] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, formic acid, acetic acid, and p-toluenesulfonic acid. In certain embodiments, the acid is hydrochloric acid.

[0201] In some embodiments, the reaction solvent for the compound of formula D is an alcohol. In some embodiments, the alcohol is selected from methanol, ethanol, propanol, butanol, pentanol, and hexanol. In certain embodiments, the alcohol is methanol.

[0202] In some embodiments, the compound of formula F is a compound of formula F-1. The method for preparing the compound of formula F-1 or a salt thereof further comprises the step of converting the compound of formula D-1 into a compound of formula M-1 under acidic conditions, and the step of converting the compound of formula M-1 into a compound of formula E-1.

[0203] Among them, R 9 、R 10 、R 2 、R 3 、R 4 、R 5 、R 6 、R8 , y are as defined above.

[0204] In some embodiments, the compound of formula F is a compound of formula F-2. The method for preparing the compound of formula F-2 or a salt thereof further comprises the step of converting the compound of formula D-2 into the compound of formula M-2 under acidic conditions, and the step of converting the compound of formula M-2 into the compound of formula E-2.

[0205] Among them, R 6 、R 8 、R 9 、R 10 、R 3 、R 4 、R 5 As defined above.

[0206] In some embodiments, the compound of formula F is a compound of formula F-3. The method for preparing a compound of formula F-3 or a salt thereof further comprises the step of converting a compound of formula D-3 into a compound of formula M-3 under acidic conditions, and the step of converting a compound of formula M-3 into a compound of formula E-3.

[0207] Among them, R 6 、R 8 、R 9 、R 10 、R 3 As defined above.

[0208] In some embodiments, R 9 is selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl. In certain embodiments, R 9 For ethyl.

[0209] In some embodiments, R 10 is selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl. In certain embodiments, R 10 It is a methyl group.

[0210] In some embodiments, the compound of formula F is a compound of formula F-4. The method for preparing the compound of formula F-4 or a salt thereof further comprises the step of converting the compound of formula D-4 into the compound of formula M-4 under hydrochloric acid / methanol conditions, and the step of converting the compound of formula M-4 into the compound of formula E-4.

[0211] Among them, R 6 、R 8 As defined above.

[0212] In some embodiments, the compound of formula F is a compound of formula F-4a. The method for preparing the compound of formula F-4a or a salt thereof further comprises the step of converting the compound of formula D-4a to the compound of formula M-4a under hydrochloric acid / methanol conditions, and the step of converting the compound of formula M-4a to the compound of formula E-4a.

[0213] Among them, R 6 、R 8 As defined above.

[0214] Furthermore, the method for preparing the compound of formula F or a salt thereof disclosed herein further comprises the step of reacting the compound of formula C under the conditions of an oxazolidinone catalyst / reducing agent represented by formula (I) to form a compound of formula D.

[0215] Wherein: Ar is independently selected from 6-membered aryl or 5-10-membered heteroaryl, and the aryl and heteroaryl are optionally substituted by one or more halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy substitution;

[0216] R a Selected from hydrogen, C 1-6 Alkyl, wherein the alkyl is optionally substituted by one or more halogen, hydroxy, cyano, or amino groups;

[0217] Ring A, R 8 、R 9 、R 10 、R 2 、R 3 、R 4 、R 5 , y are as defined above.

[0218] In certain embodiments, each Ar is independently phenyl.

[0219] In certain embodiments, R a C 1-6 In certain embodiments, R a is methyl, ethyl, n-propyl, isopropyl. In certain embodiments, R a It is a methyl group.

[0220] In certain embodiments, the oxazolidinone catalyst represented by formula (I) is represented by formula (Ia)

[0221] In some embodiments, the reducing agent is a borane ligand compound. In certain specific embodiments, the reducing agent is BH3·THF, BH3·Me2S, or BH3·DEA. In certain specific embodiments, the reducing agent is BH3·THF.

[0222] In some embodiments, the compound of formula F is a compound of formula F-1. The method for preparing the compound of formula F-1 or a salt thereof further comprises the step of reacting the compound of formula C-1 with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form a compound of formula D-1.

[0223] Among them, Ar, R a 、R 8 、R 9 、R 10 、R 2 、R 3 、R 4 、R 5 , y are as defined above.

[0224] In some embodiments, the compound of formula F is a compound of formula F-2. The method for preparing the compound of formula F-2 or a salt thereof further comprises the step of reacting the compound of formula C-2 with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form a compound of formula D-2.

[0225] Among them, Ar, R a 、R 8 、R 9 、R 10 、R 2 、R 3 、R 4 、R 5 , y are as defined above.

[0226] In some embodiments, the compound of formula F is a compound of formula F-3. The method for preparing the compound of formula F-3 or a salt thereof further comprises the step of reacting the compound of formula C-3 with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form a compound of formula D-3.

[0227] Among them, Ar, R a 、R 8 、R 9 、R 10 、R 3 As defined above.

[0228] In some embodiments, the compound of formula F is a compound of formula F-4. The method for preparing the compound of formula F-4 or a salt thereof further comprises the step of reacting the compound of formula C-4 with an oxazolidinone catalyst / reducing agent as shown in formula (Ia) to form a compound of formula D-4.

[0229] where R 8 As defined above.

[0230] In some embodiments, the compound of formula F is a compound of formula F-4a. The method for preparing the compound of formula F-4a or a salt thereof further comprises the step of reacting the compound of formula C-4 with an oxazolidinone catalyst of formula (Ia) in the presence of BH3·THF to form a compound of formula D-4a.

[0231] Furthermore, the method for preparing the compound of formula F or a salt thereof disclosed herein further comprises the steps of reacting the compound of formula (II) with the orthoester represented by formula (III) to form a compound of formula A, and reacting the compound of formula A with the compound of formula B under alkaline conditions to form a compound of formula C.

[0232] Where: R 11 、R 12 are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups;

[0233] X is a halogen;

[0234] Ring A, R 9 、R 10 、R 2 、R 4 、R 5 , y are as defined above.

[0235] In some embodiments, the base is selected from potassium carbonate and sodium carbonate. In certain embodiments, the base is potassium carbonate.

[0236] In some embodiments, the compound of formula F is a compound of formula F-1. The method for preparing the compound of formula F-1 or a salt thereof further comprises the steps of reacting the compound of formula (II) with an orthoester represented by formula (III) to form a compound of formula A, and reacting the compound of formula A with a compound of formula B1 under alkaline conditions to form a compound of formula C-1.

[0237] Where: R 9 、R 10 、R 11 、R 12 , X, R 2 、R 4 、R 5 , y are as defined above.

[0238] In some embodiments, the compound of formula F is a compound of formula F-2. The method for preparing the compound of formula F-2 or a salt thereof further comprises the steps of reacting the compound of formula (IIa) with an orthoester represented by formula (III) to form a compound of formula A1, and reacting the compound of formula A1 with a compound of formula B1 under alkaline conditions to form a compound of formula C-2.

[0239] Where: R 9 、R 10 、R 11 、R 12 , X, R 4 、R 5 As defined above.

[0240] In some embodiments, the compound of formula F is a compound of formula F-3. The method for preparing the compound of formula F-3 or a salt thereof further comprises the steps of reacting the compound of formula (IIa) with an orthoester represented by formula (III) to form a compound of formula A1, and reacting the compound of formula A1 with a compound of formula B2 under alkaline conditions to form a compound of formula C-3.

[0241] Where: R 9 、R 10 、R 11 、R 12 , X are as defined above.

[0242] In some embodiments, X is selected from fluorine, chlorine, bromine, and iodine. In certain specific embodiments, X is bromine.

[0243] In some embodiments, R 11 、R 12 Each independently is C 1-6 In some embodiments, R 11 、R 12 Each is independently selected from methyl, ethyl, propyl, butyl, isopropyl. In certain embodiments, R 11 、R 12 All are ethyl.

[0244] In some embodiments, the compound of formula F is a compound of formula F-4. The method for preparing the compound of formula F-4 or a salt thereof further comprises the steps of reacting the compound of formula (IIa) with an orthoester represented by formula (IIIa) to form a compound of formula A2, and reacting the compound of formula A2 with a compound of formula B3 under potassium carbonate conditions to form a compound of formula C-4.

[0245] Some embodiments provide a method for preparing a compound of formula F or a salt thereof comprising:

[0246] Step 1) reacting a compound of formula (II) with an orthoester represented by formula (III) to form a compound of formula A, and reacting the compound of formula A with a compound of formula B under alkaline conditions to form a compound of formula C;

[0247] Step 2) Compound C is reacted with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form a compound of formula D;

[0248] Step 3) converting the compound of formula D into the compound of formula E under acidic conditions;

[0249] Step 4) reacting the compound of formula E under trisubstituted phosphine / azodicarboxylic acid diester conditions to form a compound of formula F;

[0250] Among them, ring A, R 2 、R 3 、R 4 、R 5 、R 8 ,y,R 9 、R 10 ,Ar,R a 、R 11 、R 12 , X are as defined above.

[0251] Some embodiments provide a method for preparing a compound of formula F-1 or a salt thereof comprising:

[0252] Step 1) reacting a compound of formula (II) with an orthoester represented by formula (III) to form a compound of formula A, and reacting the compound of formula A with a compound of formula B1 under alkaline conditions to form a compound of formula C-1;

[0253] Step 2) Compound C-1 is reacted with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form compound D-1;

[0254] Step 3) converting the compound of formula D-1 into the compound of formula E-1 under acidic conditions;

[0255] Step 4) reacting the compound of formula E-1 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form the compound of formula F-1;

[0256] Among them, R 2 、R 3 、R 4 、R 5 、R 8 ,y,R 9 、R 10 ,Ar,R a 、R 11 、R 12 , X are as defined above.

[0257] Some embodiments provide a method for preparing a compound of formula F-2 or a salt thereof comprising:

[0258] Step 1) reacting a compound of formula (IIa) with an orthoester represented by formula (III) to form a compound of formula A1, and reacting the compound of formula A1 with a compound of formula B1 under alkaline conditions to form a compound of formula C-2;

[0259] Step 2) Compound C-2 is reacted with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form compound D-2;

[0260] Step 3) converting the compound of formula D-2 into the compound of formula E-2 under acidic conditions;

[0261] Step 4) reacting the compound of formula E-2 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form the compound of formula F-2;

[0262] Among them, R 3 、R 4 、R 5 、R 9 、R 10 ,Ar,R a 、R 11 、R 12 , X are as defined above.

[0263] Some embodiments provide a method for preparing a compound of formula F-3 or a salt thereof comprising:

[0264] Step 1) reacting a compound of formula (IIa) with an orthoester represented by formula (III) to form a compound of formula A1, and reacting the compound of formula A1 with a compound of formula B2 under alkaline conditions to form a compound of formula C-3;

[0265] Step 2) Compound C-3 is reacted with an oxazolidinone catalyst / reducing agent as shown in formula (I) to form compound D-3;

[0266] Step 3) converting the compound of formula D-3 into the compound of formula E-3 under acidic conditions;

[0267] Step 4) reacting the compound of formula E-3 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form the compound of formula F-3;

[0268] Among them, X, Ar, R a 、R 8 、R 9 、R 10 、R 3 、R 11 、R 12 As defined above.

[0269] Some embodiments provide a method for preparing a compound of formula F-4 or a salt thereof comprising:

[0270] Step 1) reacting a compound of formula (IIa) with an orthoester represented by formula (IIIa) to form a compound of formula A2, and reacting the compound of formula A2 with a compound of formula B3 under potassium carbonate conditions to form a compound of formula C-4;

[0271] Step 2) Compound C-4 is reacted with an oxazolidinone catalyst / reducing agent as shown in formula (Ia) to form compound D-4a;

[0272] Step 3) converting the compound of formula D-4 into the compound of formula E-4 under hydrochloric acid / methanol conditions;

[0273] Step 4) reacting the compound of formula E-4 under triphenylphosphine / diisopropyl azodicarboxylate conditions to form the compound of formula F-4;

[0274] Among them, R 8 As defined above.

[0275] Some embodiments provide a method for preparing a compound of formula F-4a or a salt thereof comprising:

[0276] Step 1) reacting a compound of formula (IIa) with an orthoester represented by formula (IIIa) to form a compound of formula A2, and reacting the compound of formula A2 with a compound of formula B3 under potassium carbonate conditions to form a compound of formula C-4;

[0277] Step 2) Compound C-4 is reacted with an oxazolidinone catalyst represented by formula (Ia) in the presence of BH3·THF to form compound D-4a;

[0278] Step 3) Compound D-4a is reacted under hydrochloric acid / methanol conditions to form compound E-4a

[0279] Step 4) a step of reacting the compound of formula E-4a under triphenylphosphine / diisopropyl azodicarboxylate conditions to form the compound of formula F-4a,

[0280] Among them, R 8 As defined above.

[0281] In another aspect, the present disclosure also provides a compound of formula C or a salt thereof, Among them, ring A, R 2 ,y,R 4 、R 5 、R 9 、R 10 As defined above.

[0282] In some embodiments, the compound of formula C or a salt thereof is a compound of formula C-1 or a salt thereof, where R 2 ,y,R 4 、R 5 、R 9 、R 10 As defined above.

[0283] In some embodiments, the compound of formula C or a salt thereof is a compound of formula C-2 or a salt thereof, where R 4 、R 5 、R 9 、R 10 As defined above.

[0284] In some embodiments, the compound of formula C or a salt thereof is a compound of formula C-3 or a salt thereof, where R 9 、R 10 As defined above.

[0285] In some embodiments, the compound of formula C or a salt thereof is a compound of formula C-4 or a salt thereof,

[0286] In another aspect, the present disclosure also provides a compound of formula D or a salt thereof, Among them, ring A, R 2 ,y,R 3 、R 4 、R 5 、R 8 、R 9 、R 10 As defined above.

[0287] In some embodiments, the compound of formula D or a salt thereof is a compound of formula D-1 or a salt thereof, where R 2 ,y,R 3 、R 4 、R 5 、R 8 、R 9 、R 10 As defined above. In some embodiments, the compound of formula D or a salt thereof is a compound of formula D-2 or a salt thereof, where R 3 、R 4 、R 5 、R 8 、R 9 、R 10 As defined above.

[0288] In some embodiments, the compound of formula D or a salt thereof is a compound of formula D-3 or a salt thereof, where R 3 、R 8 、R 9 、R 10 As defined above.

[0289] In some embodiments, the compound of formula D or a salt thereof is a compound of formula D-4 or a salt thereof, where R 8 As defined above.

[0290] In some embodiments, the compound of formula D or a salt thereof is a compound of formula D-4a or a salt thereof, where R 8 As defined above.

[0291] In another aspect, the present disclosure also provides a compound of formula E or a salt thereof, Among them, ring A, R 2 ,y,R 3 、R 4 、R 5 As defined above.

[0292] In some embodiments, the compound of formula E or a salt thereof is a compound of formula E-1 or a salt thereof, where R 2 ,y,R 3 、R 4 、R 5 As defined above.

[0293] In some embodiments, the compound of formula E or a salt thereof is a compound of formula E-2 or a salt thereof, where R 3 、R 4 、R 5 As defined above.

[0294] In some embodiments, the compound of formula E or a salt thereof is a compound of formula E-3 or a salt thereof, where R 3 As defined above.

[0295] In some embodiments, the compound of formula E or a salt thereof is a compound of formula E-4 or a salt thereof,

[0296] In some embodiments, the compound of formula E or a salt thereof is a compound of formula E-4a or a salt thereof,

[0297] In another aspect, the present disclosure also provides a compound of formula M or a salt thereof, Among them, ring A, R 2 ,y,R 3 、R 4、R 5 、R 6 、R 8 As defined above.

[0298] In some embodiments, the compound of formula M or a salt thereof is a compound of formula M-1 or a salt thereof, where R 2 ,y,R 3 、R 4 、R 5 、R 6 、R 8 As defined above.

[0299] In some embodiments, the compound of formula M or a salt thereof is a compound of formula M-2 or a salt thereof, where R 3 、R 4 、R 5 、R 6 、R 8 As defined above.

[0300] In some embodiments, the compound of formula M or a salt thereof is a compound of formula M-3 or a salt thereof, where R 3 、R 6 、R 8 As defined above.

[0301] In some embodiments, the compound of formula M or a salt thereof is a compound of formula M-4 or a salt thereof, where R 6 、R 8 As defined above.

[0302] In some embodiments, the compound of formula M or a salt thereof is a compound of formula M-4a or a salt thereof, where R 6 、R 8 As defined above.

[0303] The present invention discloses the method for preparing the compound of formula K, the use of the compound of formula C, the compound of formula D, the compound of formula E, and the compound of formula M in preparing a GLP-1 receptor agonist.

[0304] In some embodiments, the GLP-1 receptor agonist is selected from, but not limited to:

[0305] In another aspect, the present disclosure further provides a method for preparing a compound of Formula 1 or a salt thereof, the method comprising the steps of the aforementioned method for preparing a compound of Formula F.

[0306] In certain embodiments, a method for preparing a compound of Formula 1 or a salt thereof, the method comprising the steps of the aforementioned method for preparing a compound of Formula F-1. In certain embodiments, a method for preparing a compound of Formula 1 or a salt thereof, the method comprising the steps of the aforementioned method for preparing a compound of Formula F-2. In certain embodiments, a method for preparing a compound of Formula 1 or a salt thereof, the method comprising the steps of the aforementioned method for preparing a compound of Formula F-3. In certain embodiments, a method for preparing a compound of Formula 1 or a salt thereof, the method comprising the steps of the aforementioned method for preparing a compound of Formula F-4. In certain embodiments, a method for preparing a compound of Formula 1 or a salt thereof, the method comprising the steps of the aforementioned method for preparing a compound of Formula F-4a.

[0307] In certain embodiments, the method for preparing a compound of Formula 1 or a salt thereof further comprises the steps of converting a compound of Formula F into a compound of Formula G, and reacting the compound of Formula G with a compound of Formula H to form a compound of Formula J. In certain embodiments, the method for preparing a compound of Formula 1 or a salt thereof further comprises the steps of converting a compound of Formula F-1 into a compound of Formula G-1, and reacting the compound of Formula G-1 with a compound of Formula H-1 to form a compound of Formula J-1. In certain embodiments, the method for preparing a compound of Formula 1 or a salt thereof further comprises the steps of converting a compound of Formula F-2 into a compound of Formula G-2, and reacting the compound of Formula G-2 with a compound of Formula H-2 to form a compound of Formula J-2. In certain embodiments, the method for preparing a compound of Formula 1 or a salt thereof further comprises the steps of converting a compound of Formula F-3 into a compound of Formula G-3, and reacting the compound of Formula G-3 with a compound of Formula H-3 to form a compound of Formula J-3. In certain embodiments, the method for preparing a compound of Formula 1 or a salt thereof further comprises the steps of converting a compound of Formula F-4 into a compound of Formula G-4, and reacting the compound of Formula G-4 with a compound of Formula H-4 to form a compound of Formula J-4. In certain embodiments, the method for preparing a compound of Formula 1 or a salt thereof further comprises the steps of converting a compound of Formula F-4a into a compound of Formula G-4a, and reacting the compound of Formula G-4a with a compound of Formula H-4a to form a compound of Formula J-4a.

[0308] In certain embodiments, the method for preparing a compound of formula 1 or a salt thereof further comprises the step of converting a compound of formula J into a compound of formula K. In certain embodiments, the method for preparing a compound of formula 1 or a salt thereof further comprises the step of converting a compound of formula J-1 into a compound of formula K-1. In certain embodiments, the method for preparing a compound of formula 1 or a salt thereof further comprises the step of converting a compound of formula J-2 into a compound of formula K-2. In certain embodiments, the method for preparing a compound of formula 1 or a salt thereof further comprises the step of converting a compound of formula J-3 into a compound of formula K-3. In certain embodiments, the method for preparing a compound of formula 1 or a salt thereof further comprises the step of converting a compound of formula J-4 into a compound of formula K-4. In certain embodiments, the method for preparing a compound of formula 1 or a salt thereof further comprises the step of converting a compound of formula J-4a into a compound of formula K-4a.

[0309] In another aspect, the present disclosure further provides a method for preparing a compound of formula 1 or a salt thereof, the method comprising the steps of the aforementioned method for preparing a compound of formula K.

[0310] In certain embodiments, the method for preparing a compound of Formula 1 or a salt thereof comprises the steps of the aforementioned method for preparing a compound of Formula K-1. In certain embodiments, the method for preparing a compound of Formula 1 or a salt thereof comprises the steps of the aforementioned method for preparing a compound of Formula K-2. In certain embodiments, the method for preparing a compound of Formula 1 or a salt thereof comprises the steps of the aforementioned method for preparing a compound of Formula K-3. In certain embodiments, the method for preparing a compound of Formula 1 or a salt thereof comprises the steps of the aforementioned method for preparing a compound of Formula K-4. In certain embodiments, the method for preparing a compound of Formula 1 or a salt thereof comprises the steps of the aforementioned method for preparing a compound of Formula K-4a.

[0311] In certain embodiments, the compound of Formula 1 is a compound of Formula 1a. The method for preparing the compound of Formula 1a or a salt thereof further comprises the step of reacting a compound of Formula K-4a with a compound of Formula L to form a compound of Formula 1a.

[0312] The reaction conditions and operations refer to those in WO2022007979, and the relevant contents are introduced herein for illustration.

[0313] The preparation method disclosed herein further comprises one or more steps of filtration, washing, drying, concentration or recrystallization.

[0314] Salts of the disclosed compounds / intermediates include, but are not limited to, addition salts of the free form of the compounds / intermediates with acids or bases, wherein the acid used to form the salts includes, but is not limited to, hydrochloric acid or methanesulfonic acid. In some embodiments, salts of the compounds / intermediates include, but are not limited to, hydrochloride, p-toluenesulfonate, methanesulfonate, or oxalate.

[0315] The terms "to form" and "to convert" do not necessarily imply a single-step conversion reaction between two substrates; they may be a single-step or multi-step reaction. If an intermediate contains a protecting group, the intermediate is subjected to a one-step removal of the protecting group and then reacted with the corresponding substrate to obtain the corresponding target product.

[0316] The numerical values ​​in this disclosure are instrumental measurements and are subject to a certain degree of error. Generally speaking, within a reasonable error range of plus or minus 10%. The context in which the numerical value is used must be considered. For example, the particle size of an active ingredient, where the error after measurement does not exceed plus or minus 10%, may be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

[0317] The technical solution disclosed in the present invention has the following beneficial effects: (1) The process steps are simple, which significantly reduces the production cost; (2) Compared with the existing technology, the reaction yield is significantly improved; 3) Most of the existing technologies report using chiral hydroxyl groups to attack the halogen on the benzene ring to construct chiral benzodioxane, while the present invention uses Mitsunobu reaction to construct chiral benzodioxane.

[0318] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations. Indicates the presence of chiral isomers in the structure, and also contains Two configurations.

[0319] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as the compounds of the present disclosure comprising tautomeric changes between A, and B as shown below.

[0320] All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomers.

[0321] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0322] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0323] Explanation of terms:

[0324] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0325] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, including, but not limited to, halogen, hydroxyl, cyano, and amino.

[0326] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including, but not limited to, halogen, hydroxy, cyano, and amino.

[0327] The term "aryl" or "aromatic ring" refers to any stable, monocyclic or bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl or binaphthyl. Unless otherwise specified, an aryl group or aromatic ring may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including, but not limited to, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, cyano and amino groups.

[0328] The term "heteroaryl" or "heteroaromatic ring" refers to a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from O, N and S. Heteroaromatic rings within the scope of this definition include, but are not limited to, pyridine, thiazine, pyrimidine, pyridazine, furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzofuran, isobenzofuran, isoindole, indole, benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, purine, benzothiazole, quinoline, isoquinoline, quinazoline, quinazolinone, and thioquinazolinone. Unless otherwise specified, heteroaryl or heteroaromatic rings may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including, but not limited to, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, cyano and amino groups.

[0329] The term "hydroxy protecting group" refers to a group that prevents or inhibits a hydroxy group from participating in further reactions until the protecting group is removed. Examples of hydroxy protecting groups include, but are not limited to, acetyl, allyl, benzoyl, benzyl, β-methoxyethoxymethyl, methoxymethyl, dimethoxytrityl [di-(4-methoxyphenyl)phenylmethyl], methoxytriphenyl [(4-methoxyphenyl)diphenylmethyl], p-methoxybenzyl ether, methylthiomethyl, pivaloyl, tetrahydropyranyl, triphenylmethyl, silyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsiloxymethyl, and triisopropylsilyl). Other examples include alkyl groups such as methyl and tert-butyl, and other ethers such as ethoxyethyl.

[0330] The term "amino-protecting group" refers to a group that prevents or inhibits an amino group from participating in further reactions until the protecting group is removed. Examples of amino-protecting groups include, but are not limited to, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, p-toluenesulfonylmethoxycarbonyl, ethoxycarbonyl, phthaloyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, and benzyl.

[0331] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0332] The term "hydroxy" refers to -OH.

[0333] The term "cyano" refers to -CN.

[0334] The term "amino" refers to -NH2.

[0335] The term "DEAD" refers to diethyl azodicarboxylate.

[0336] The term "DIAD" refers to diisopropyl azodicarboxylate.

[0337] The term "DCAD" refers to bis(4-chlorobenzyl) azodicarboxylate.

[0338] The term "DEA" refers to diethylaniline.

[0339] The term "Pd(PPh3)4" refers to tetrakis(triphenylphosphine)palladium.

[0340] The term "Pd(PPh3)2Cl2" refers to bistriphenylphosphine palladium dichloride.

[0341] The term "Pd(dppe)Cl2" refers to bis(diphenylphosphine)ethanepalladium dichloride.

[0342] The term "Pd(dppp)Cl2" refers to [1,3-bis(diphenylphosphino)propane]palladium dichloride.

[0343] The term "Pd(dppf)Cl2" refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

[0344] The term "Pd(dppf)Cl2·DCM" or "Pd(dppf)Cl2·CH2Cl2" refers to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex.

[0345] The term "DMF" refers to dimethylformamide.

[0346] The term "DCM" refers to dichloromethane.

[0347] The term "DIPEA" refers to N,N-diisopropylethylamine.

[0348] The term "n-BuLi" refers to n-butyllithium. DETAILED DESCRIPTION

[0349] The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

[0350] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0351] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectroscopy (MS). NMR shifts (δ) are given in units of 10-6 (ppm).

[0352] NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the solvent was deuterated chloroform (CDCl3).

[0353] MS was determined using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer in positive / negative ion mode with a mass scan range of 120-1300.

[0354] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) was 0.2 mm ± 0.03 mm. The specification used for thin layer chromatography separation and purification products was 0.4 mm - 0.5 mm.

[0355] Example 1: Preparation of Compound 1

[0356] Step 1:

[0357] Compound 1a (40.4 g, 320 mmol, purchased from Titan Technology) and triethyl orthoacetate (78.0 g, 480 mmol, purchased from Anaiji) were added to a 250 mL reaction flask. Under nitrogen protection, the temperature was raised until the reaction was complete. The temperature was lowered and the solvent was removed by concentration under reduced pressure. The temperature was lowered to 0-10°C, and dichloromethane (160 mL) and water (40 mL) were added. The liquids were separated, and the organic phase was washed with saturated sodium bicarbonate solution (40 mL × 1), water (40 mL × 2), and semi-saturated sodium chloride solution (40 mL × 1). Drying was performed over anhydrous sodium sulfate and filtered to obtain a dichloromethane solution of compound 1b, which was used directly in the next step.

[0358] 1 H NMR (400MHz, CDCl3): δ6.72 (t, J = 8, 1H), 6.50-6.44 (m, 2H), 5.06 (br, 1H), 3.62 (dd, J = 14.4, 7.2Hz, 2H), 1.82 (s, 3H), 1.23-1.19 (t, 3H).

[0359] MS (ESI): m / z 197 [M+H] + .

[0360] Step 2:

[0361] To a 250 mL reaction flask, a dichloromethane solution of compound 1b (10.0 g, 50.97 mmol), potassium carbonate (9.16 g, 66.26 mmol, purchased from Sinopharm), and dichloromethane (20 mL) were added. Under nitrogen, the reaction was allowed to proceed at room temperature until completion. Compound 1c (16.02 g, 63.71 mmol) was added to the reaction system and allowed to react at room temperature until completion. The mixture was then filtered through Celite and the filter cake was washed with dichloromethane (20 mL x 2). The combined filtrates were washed with 150 mL of purified water. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was crystallized from n-heptane and ethanol to afford 16.5 g of compound 1d (yield 88.3%, purity 99.2%).

[0362] 1 H NMR (400MHz, DMSO-d6): δ7.92(t,J=8.4,1H),7.71(dd,J=11.2,2Hz,1H),7.49(dd,J=8.4,2Hz,1H),6.76(dd,J=8.4 ,8Hz,1H),6.61-6.57(m,2H),5.44(d,J=2.8Hz,2H),3.47(dd,J=14.4,7.2Hz,2H),1.71(s,3H),1.10(t,J=7.2,3H).

[0363] MS(ESI):m / z 321[M-OEt] + , 755[2M+Na] + .

[0364] Steps 3 and 4:

[0365] To a 1L reaction flask, add (R)-CBS (4.14 g, 16.36 mmol, purchased from Bitec) and tetrahydrofuran (250 mL, purchased from Anergy). Under nitrogen, control the temperature at 0-20°C, add borane in tetrahydrofuran (1 M, 340.82 mL, purchased from Anergy), and stir at room temperature until the reaction is complete. Add a solution of compound 1d (50 g, 136.33 mmol) in tetrahydrofuran (500 mL) at room temperature, and stir at room temperature until the reaction is complete. Control the temperature at 0-10°C, then add 2M hydrochloric acid (250 mL) dropwise to quench the reaction. Stir at room temperature until the boron complex dissociates. Evaporate the tetrahydrofuran under reduced pressure, dilute with water (1000 mL), and extract twice with EA (500 mL x 2). Combine the organic phases and wash with 2M hydrochloric acid (500 mL x 3) and then with brine (500 mL). The residue was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was crystallized from ethyl acetate and n-heptane to obtain 38.38 g of compound 1f (yield 94.2%, chiral purity 96.9%).

[0366] 1 H NMR (400MHz, DMSO-d6): δ8.84(s,1H),8.10(s,1H),7.62(t,J=8.2Hz,1H),7.41(dd,J=10.1,2.1Hz,1H),7.33(dd,J=8.4,2.1Hz,1H),6. 52(t,J=8.1Hz,1H),6.46–6.36(m,2H),5.93(d,J=4.6Hz,1H),5.18(m,1H),4.06(dd,J=10.0,3.5Hz,1H),3.87(dd,J=10.1,7.8Hz,1H).

[0367] MS (ESI): m / z 299 [M+H] + .

[0368] Step 5:

[0369] To a 2L reaction flask, compound 1f (35.0 g, 1.0 eq.), triphenylphosphine (39.95 g, 1.3 eq., purchased from Titan Technology), and dichloromethane (910 mL, 26V) were added and stirred. Under nitrogen, diisopropyl azodicarboxylate (30.8 g, 1.3 eq., purchased from Titan Technology) was added dropwise at 0-5°C and stirred until the reaction was complete. The solvent was concentrated under reduced pressure at 35°C. Tetrahydrofuran (140 mL, 4V) and anhydrous calcium bromide (82 g, 3.5 eq., purchased from Titan Technology) were added to the residue. The atmosphere was replaced with nitrogen and the reaction was stirred at room temperature until the reaction was complete. The mixture was filtered and the filter cake was rinsed with tetrahydrofuran (17 mL x 2). The filtrate was concentrated under reduced pressure, dissolved in methyl tert-butyl ether (420 mL), and washed with water (140 mL x 3). The organic phase was concentrated under reduced pressure, and ethanol (35 mL) and n-heptane (245 mL) were added. The mixture was beaten at room temperature for 16 hours, filtered, and dried under reduced pressure to obtain 41.8 g of a complex (compound 1 g and diisopropyl hydrazine-1,2-dicarboxylate complexed at a ratio of 2:1). The yield of the complex was 127.1% (complex content was about 73%, containing about 30.5 g of compound 1 g, and the yield of compound 1 g was 92%).

[0370] 1 H NMR (400MHz, CDCl3) δ7.43(t,J=8.0Hz,1H),7.24-7.22(m,1H),7.19-7.16(m,1H),6.79(t,J=8.4Hz,1H),6. 60-6.58(m,1H),6.54-6.51(m,1H),6.36(br,1H),5.46-5.43(m,1H),4.42-4.39(m,1H),4.07-4.02(m,1H).

[0371] MS (ESI): m / z 281 [M+H] + ,283[M+3H] + .

[0372] Step 6:

[0373] To a 1L reaction flask, add compound 1g (35.5g), N,N-diisopropylethylamine (40.87g, purchased from Titan Technology), and dichloromethane (355mL). Under nitrogen, cool to 0-10°C and add a solution of trifluoromethanesulfonic anhydride (41.04g, purchased from Shaoyuan) in dichloromethane (177.5mL) dropwise. After addition, stir at 0-10°C until reaction is complete. Concentrate under reduced pressure at 30-35°C. Dissolve the residue in n-heptane (426mL) and water and stir until uniform. Filter through a pad of celite and separate the filtrate. Wash the organic phase with water (142mL x 4) and concentrate the solvent under reduced pressure at 35°C. The residue is crystallized from ethanol and water to obtain 32.2g of compound 1h (yield 61.7%, purity 98.62%).

[0374] 1 H NMR (400MHz, CDCl3) δ7.52(t,J=8.0Hz,1H),7.27-7.25(m,1H),7.17(dd,J=10,2Hz,1H),6.99-6.97(m,1H),6.92(t,J =8.4Hz,1H),6.89-6.87(m,1H),5.47(dd,J=8.8,2.4Hz,1H),4.51(dd,J=11.6,2Hz,1H),3.99(dd,J=11.6,8.8Hz,1H).

[0375] Step 7:

[0376] To a 250 mL reaction flask, compound 1h (10.0 g, 24.23 mmol), Pd(dppf)Cl2.CH2Cl2 (296.8 mg, 0.363 mmol, purchased from Leyan), and cuprous iodide (276.8 mg, 1.45 mmol, purchased from Anaiji) were added and the atmosphere was replaced with argon. Under argon, a solution of compound 1i in N,N-dimethylacetamide (44 mL, 48.46 mmol, purchased from WuXi AppTec) was added and the reaction was allowed to proceed until completion. The reaction mixture was cooled to 35°C. The mixture was quenched by addition of saturated ammonium chloride solution (100 mL), stirred for 20 minutes, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (n-heptane:ethyl acetate = 20:1 to 50:1) to afford 13.5 g of compound 1j (yield 124.4%, purity 85.3%).

[0377] 1HNMR (400MHz, CDCl3): δ7.41 (t, J=8.0Hz, 1H), 7.23 (dd, J=8.4, 1.6Hz, 1H), δ7. 16(dd,J=10,2Hz,1H), δ6.87-6.77(m,3H), 5.42(dd,J=8.4,2.4Hz,1H), 4.41(dd ,J=11.6,2.4Hz,1H), δ4.23-4.11(m,2H), 3.97(dd,J=11.2,8.4Hz,1H), 3.09-3. 03(m,1H), 2.84-2.74(m,2H), 1.88-1.77(m,2H), 1.66-1.60(m,2H), 1.47(s,9H)

[0378] MS (ESI): m / z 917 [2M+Na] +

[0379] Step 8:

[0380] Compound 1j (13.5 g, 24.23 mmol) and 10 mL of dioxane were added to a 250 mL reaction flask. Control the temperature below 30°C and add 4 M dioxane hydrochloride (50 mL) with stirring. Allow to react at room temperature until the reaction is complete. Concentrate the mixture under reduced pressure, add 45 mL of tetrahydrofuran, and dropwise add isopropyl ether (215 mL). Stir for 1 hour. Filter and wash the filter cake with isopropyl ether (8 mL). Add ethyl acetate (110 mL) and 5% potassium carbonate solution (55 mL) to the filter cake and stir for 20 minutes. Separate the layers, extract the aqueous phase with ethyl acetate (40 mL x 1), combine the organic phases, and wash with purified water (75 mL x 2). Dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain 7.05 g of compound 1 (yield 67.2%, chiral purity 100%).

[0381] 1 HNMR (400MHz, CDCl3): δ7.43(t,J=8Hz,1H), 7.24(dd,J=8.4,2Hz,1H), 7.16(dd,J=10,1.6Hz,1H), 6.90-6.79(m,3H), 5.41(dd,J=8,2Hz,1H), 4.41(dd,J =11.2,2.4Hz,1H), 3.99-3.94(m,1H), 3.20-3.15(m,2H), 3.09-3.03(m,1H) , 2.80-2.69(m,2H), 1.90-1.86(m,1H), 1.82-1.77(m,1H), 1.68-1.61(m,2H)

[0382] MS (ESI): m / z 348 [M+H] +。

Claims

1. A method for preparing a compound of formula K-1 or a salt thereof, The method comprises the steps of reacting a compound of formula E-1 under trisubstituted phosphine / azodicarboxylic acid diester conditions to form a compound of formula F-1, in, R 2 Selected from halogen, cyano, C 1-6 Alkyl or C 1-6 alkoxy; R 3 、R 4 、R 5 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups; y is selected from 0, 1, 2, and 3.

2. The method according to claim 1, wherein the trisubstituted phosphine is selected from triphenylphosphine.

3. The method according to claim 1 or 2, wherein the azodicarboxylic acid diester is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate or bis(4-chlorobenzyl) azodicarboxylate, preferably diisopropyl azodicarboxylate.

4. The method according to any one of claims 1 to 3, further comprising the steps of converting the compound of formula D-1 into the compound of formula M-1 under acidic conditions, and converting the compound of formula M-1 into the compound of formula E-1. in, R 6 、R 8 are each independently selected from hydrogen or a hydroxy protecting group; R 9 、R 10 are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups; R 2 、R 3 、R 4 、R 5 , y as defined in claim 1.

5. The method according to claim 4, wherein R 6 Selected from hydrogen, allyl, methoxymethyl ether, tetrahydropyran, (trimethylsilyl)ethoxymethyl, dimethylaminosulfonyl, trifluoromethanesulfonyl, methyl, tert-butyl, trityl, benzyl, p-methoxybenzyl, tert-butyldimethylsilyl, acetyl, benzoyl, benzyloxycarbonyl, preferably hydrogen.

6. The method according to any one of claims 1 to 5, further comprising the step of converting the compound of formula C-1 into the compound of formula D-1 under the conditions of an oxazolidinone catalyst / reducing agent represented by formula (I), in, Ar is independently selected from 6-membered aryl or 5-10-membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy substitution; R a Selected from hydrogen, C 1-6 Alkyl, wherein the alkyl is optionally substituted by one or more halogen, hydroxy, cyano, or amino groups; R 2 、R 3 、R 4 、R 5 , y as defined in claim 1, R 8 、R 9 、R 10 As defined in claim 4.

7. The method according to claim 6, wherein the oxazolidinone catalyst represented by formula (I) is represented by formula (Ia) 8. The method according to claim 6 or 7, wherein the reducing agent is a borane ligand compound, preferably BH3.THF, BH3.Me2S, BH3.DEA, and most preferably BH3.THF.

9. The method according to any one of claims 1 to 8, further comprising the steps of reacting the compound of formula (II) with the orthoester represented by formula (III) to form the compound of formula A, and reacting the compound of formula A with the compound of formula B1 under alkaline conditions to form the compound of formula C-1. in, R 11 、R 12 are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups; X is a halogen; R 2 、R 4 、R 5 , y as defined in claim 1, R 9 、R 10 As defined in claim 4.

10. The method according to claim 9, wherein the base is selected from potassium carbonate and sodium carbonate, preferably potassium carbonate.

11. The method according to claim 9 or 10, wherein R 11 、R 12 Each independently is C 1-6 Alkyl, preferably methyl, ethyl, propyl, butyl, isopropyl, most preferably ethyl.

12. The method according to any one of claims 4 to 11, wherein R 9 、R 10 Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl, preferably methyl or ethyl.

13. The method according to any one of claims 1 to 12, further comprising the steps of converting the compound of formula F-1 into the compound of formula G-1, and reacting the compound of formula G-1 with the compound of formula H-1 under palladium catalyst / cocatalyst conditions to form the compound of formula J-1. in, R 7 is a hydroxyl protecting group; R 13 is an amino protecting group; R 2 、R 3 、R 4 、R 5 , y as defined in claim 1.

14. The method according to claim 13, wherein R 7 Selected from allyl, methoxymethyl ether, tetrahydropyran, (trimethylsilyl)ethoxymethyl, dimethylaminosulfonyl, trifluoromethanesulfonyl, methyl, tert-butyl, trityl, benzyl, p-methoxybenzyl, tert-butyldimethylsilyl, acetyl, benzoyl, benzyloxycarbonyl, preferably trifluoromethanesulfonyl.

15. according to the method for claim 13 or 14, wherein said palladium catalyst is selected from Pd(PPh ) , Pd(PPh ) , Pd(dppe)Cl , Pd(dppp)Cl , Pd(dppf)Cl , Pd(PPh ) , Pd(PPh ) , Pd(dppe)Cl , Pd(dppp)Cl , Pd(dppf)Cl , Pd(PPh ) , Pd(PPh ) , Pd(dppe)Cl , Pd(dppp)Cl , Pd(dppf)Cl , preferably Pd(dppf)Cl or Pd(dppf)Cl .

16. The method according to any one of claims 13 to 15, wherein the promoter is selected from silver oxide or cuprous iodide.

17. The method according to any one of claims 1 to 16, further comprising the step of converting the compound of formula J-1 into the compound of formula K-1 under hydrochloric acid / dioxane conditions, R 2 、R 3 、R 4 、R 5 , y as defined in claim 1, R 13 As defined in claim 13.

18. The method according to any one of claims 13 to 17, wherein R 13 Selected from benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, p-toluenesulfonylmethoxycarbonyl, ethoxycarbonyl, phthaloyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, preferably tert-butoxycarbonyl.

19. The method according to any one of claims 1 to 18, wherein y is 0.

20. The method according to any one of claims 1 to 19, wherein R 4 、R 5 are each independently hydrogen.

21. The method according to any one of claims 1 to 8 and 13 to 20, wherein R 3 Selected from hydrogen, methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, cyano, preferably hydrogen, methyl.

22. The method according to any one of claims 1 to 21, wherein the compound of formula K or the compound of formula K-1 is a compound of formula K-4a, 23. A process for preparing a compound of formula K-4a or a salt thereof, comprising: Step 1) reacting a compound of formula (IIa) with an orthoester represented by formula (IIIa) to form a compound of formula A2, and reacting the compound of formula A2 with a compound of formula B3 under potassium carbonate conditions to form a compound of formula C-4; Step 2) Compound C-4 is reacted with an oxazolidinone catalyst represented by formula (Ia) in the presence of BH3·THF to form compound D-4a; Step 3) Compound D-4a is reacted under hydrochloric acid / methanol conditions to form compound E-4a Step 4) a step of reacting the compound of formula E-4a under triphenylphosphine / diisopropyl azodicarboxylate conditions to form the compound of formula F-4a, Step 5) converting the compound of formula F-4a into the compound of formula G-4a, and reacting the compound of formula G-4a with the compound of formula H-2 in the presence of Pd(dppf)Cl2 or a solvate of Pd(dppf)Cl2 and cuprous iodide to form the compound of formula J-4a; Step 6) converting the compound of formula J-4a into the compound of formula K-4a under hydrochloric acid / dioxane conditions; where R 8 As defined in claim 4.

24. The method according to claim 15 or 23, wherein the solvate of Pd(dppf)Cl2 is Pd(dppf)Cl2.CH2Cl2.

25. The method according to any one of claims 4 and 23-24, wherein R 8 Selected from hydrogen, allyl, methoxymethyl ether, tetrahydropyran, (trimethylsilyl)ethoxymethyl, dimethylaminosulfonyl, trifluoromethanesulfonyl, methyl, tert-butyl, trityl, benzyl, p-methoxybenzyl, tert-butyldimethylsilyl, acetyl, benzoyl, benzyloxycarbonyl, preferably hydrogen.

26. A compound of formula C or a salt thereof, in, Ring A is selected from 6 to 10 membered aryl or 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy substitution; R 2 Selected from halogen, cyano, C 1-6 Alkyl or C 1-6 alkoxy; R 4 、R 5 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups; R 9 、R 10 are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups; y is selected from 0, 1, 2, 3; Furthermore, the compound of formula C is preferably a compound of formula C-1 Furthermore, the compound of formula C is preferably a compound of formula C-4 27. A compound of formula D or a salt thereof, in, R 3 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, and amino groups; R 8 is selected from hydrogen or a hydroxy protecting group; Ring A, R 2 、R 4 、R 5 、R 9 、R 10 , y as defined in claim 26; Furthermore, the compound of formula D is preferably a compound of formula D-1 Furthermore, the compound of formula D is preferably a compound of formula D-4a 28. A compound of formula E or a salt thereof, in, Ring A, R 2 、R 4 、R 5 , y as defined in claim 26, R 3 As defined in claim 27; Furthermore, the compound of formula E is preferably a compound of formula E-1 Furthermore, the compound of formula E is preferably a compound of formula E-4a 29. Use of the method according to any one of claims 1 to 25, the compound of formula C according to claim 26, the compound of formula D according to claim 27, or the compound of formula E according to claim 28 in the preparation of a GLP-1 receptor agonist.

30. A method for preparing a compound of formula 1 or a salt thereof, comprising the steps of the method according to any one of claims 1 to 25,

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