An estrogen receptor degrader intermediate and methods of making the same

Abstract

The present application relates to the technical field of medicine synthesis, and provides a series of compounds as synthesis intermediates, constructs a new method for synthesizing an intermediate of an estrogen receptor degrader, and the synthesis method route is short and the yield is high.

Description

An intermediate for estrogen receptor degradation and its preparation method Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to an intermediate for estrogen receptor degradation and its preparation method. Background Technology

[0002] PROTAC degraders are a novel drug form that has emerged in recent years, representing a new frontier in small molecule drug development. Estrogen receptor degraders are a class of PROTAC degraders designed to target the estrogen receptor (ER). Their main mechanism of action is to accelerate the degradation of the estrogen receptor within cells, thereby weakening or eliminating the effects of estrogen on target cells. Estrogen receptors play a crucial role in various physiological processes, particularly in the female reproductive system, bone metabolism, and cardiovascular health.

[0003] Several PROTAC degraders targeting the estrogen receptor (ER) have entered clinical trials, such as Vepdegestrant (ARV-471), which has entered Phase III clinical trials. Other ER PROTAC degraders in clinical development include AC699 and HRS-1358. Relevant literature includes WO2018102725, US10800770, WO2022206737, and WO2023241598. The structural formulas of Vepdegestrant and representative compounds from the aforementioned patents are as follows:

[0004] In addition, there are several estrogen receptor degraders with similar structures currently in the preclinical research stage. These include ERD-1233 (J.Med.Chem.2024,67,21,19010–19037), WO2022206737, WO2022187588, and WO2023023531.

[0005] However, existing synthetic routes for estrogen receptor degraders and their intermediates are too lengthy and have low yields, limiting their large-scale industrial production. For example, the intermediate for synthesizing ARV-471 in WO2018102725:

[0006] The intermediate 1-(4-(7-(benzyloxy)-3-(2,3-difluorophenyl)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine, a representative estrogen degrader compound 16 in WO2023241598, requires seven steps to synthesize with an overall yield of only 7.4%.

[0007] There is still an urgent need in this field to develop synthetic methods for estrogen receptor degraders and their intermediates with shorter synthetic routes and higher yields. Summary of the Invention

[0008] To address the problems of existing technologies, this invention provides an estrogen receptor degrading intermediate and its preparation method.

[0009] Compounds represented by any one of Formula I, Formula II, or Formula IV, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or solvates thereof, or their crystal forms:

[0010] A is selected from hydroxyl, amino, hydroxyl group protected by a protecting group, and amino group protected by a protecting group.

[0011] R A Selected from H, halogens,

[0012] Or, A and R A They connect to form 5-6 membered heterocyclic rings;

[0013] B is selected from substituted or unsubstituted C6-C. 10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 cycloalkyl, wherein the substituents are selected from halogens;

[0014] X is selected from CR X1 R X2 O, S, SO2, NR X1 , where R X1 and R X2 Each is independently selected from H and C1-C6 alkyl groups;

[0015] R 1 and R 2 Each is independently selected from H, halogens, and C1-C6 alkyl groups;

[0016] R 5 Selected from hydroxyl groups protected by the protecting group or

[0017] R 34 Selected from aldehyde group, aldehyde group protected by a protecting group, Among them, R 3 R 4 Each of the following is independently selected from H, halogen, hydroxyl group, hydroxyl group protected by a protecting group, and C1-C. 10 Alkoxy, C1-C 10 alkylsulfonyloxy;

[0018] Z is selected from coupling groups, which are capable of undergoing coupling reactions under transition metal catalysis.

[0019] Preferably, A is selected from hydroxyl group, OBn, and O. t Bu;

[0020] R A Selected from H;

[0021] B is selected from phenyl groups that are substituted with 1-2 F atoms or are unsubstituted;

[0022] X is selected from CH2 and O;

[0023] R 1 and R 2 Each was independently selected from H and F;

[0024] R 5 Selected from O t Bu or

[0025] R 34 Selected from aldehyde group, Among them, R 3 R 4 Each is independently selected from H, methoxy, Cl, and hydroxyl groups;

[0026] Z is selected from Br, I, OTf, borate group, C1-C 10 Boronate group.

[0027] Preferably, the protecting group of the hydroxyl group is selected from: methyl, tert-butyl, benzyl, p-methoxybenzyl, triphenylmethyl, fluorenemethoxycarbonyl;

[0028] The protecting group of the amino group is selected from: benzyloxycarbonyl, 9-fluorenoxycarbonyl, tert-butoxycarbonyl, nitrobenzyl, phthaloyl, sulfonyl, tetrahydropyranone, and aminomethylbenzenesulfonate.

[0029] The aldehyde group protected by the protecting group is selected from: ethylene glycol acetal, propylene glycol acetal, benzyloxymethyl acetal, allyl acetal, ether-protected aldehyde group, thioacetal, 1,3-dioxopentane, 1,3-dioxane, ketal, and dimethyl acetal.

[0030] Preferably, the compound represented by Formula I is selected from:

[0031] Preferably, the compound represented by Formula II is selected from:

[0032] Preferably, the compound represented by Formula IV is selected from:

[0033] The present invention also provides a method for preparing the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, comprising at least one step of steps 1 to 3:

[0034] Step 1: Prepare the compound of formula IV or formula IV-A by any of reactions 1 to 3;

[0035] Step 2: Prepare the compound represented by formula II via reaction 4;

[0036] Step 3: Prepare the compound represented by Formula I through reaction 5;

[0037] Reaction 1 involves the reaction of the compound shown in formula VI with the compound shown in formula VII to obtain the compound shown in formula IV:

[0038] Reaction 2 involves the reaction of the compound shown in Formula VIII with the compound shown in Formula IX to obtain the compound shown in Formula IV:

[0039] Reaction 3 involves the reaction of the compound shown in formula X with the compound shown in formula XI to obtain the compound shown in formula IV-A:

[0040] Reaction 4 involves the reaction of the compound of formula IV with reagent V to obtain the compound of formula II:

[0041] Reaction 5 involves the reaction of the compound shown in Formula II with the compound shown in Formula III to obtain the compound shown in Formula I:

[0042] in,

[0043] X' is selected from halogens, hydroxyl groups, and C1-C. 10 alkylsulfonyloxy;

[0044] "X" is selected from halogen, hydroxyl group, C1-C 10 Alkylsulfonyloxy, borate group, C1-C 10 Boronate group;

[0045] X”' is selected from halogen, hydroxyl group, C1-C 10 Alkylsulfonyloxy, borate group, C1-C 10 Boronate group;

[0046] The reagent V is an electrophilic halogenated reagent.

[0047] Preferably, in reaction 1:

[0048] When X' is a hydroxyl group, reaction 1 proceeds under the action of an organophosphorus reagent and an azodicarboxylic acid ester; or, when X' is a halogen, hydroxyl, or C1-C... 10 When sulfonyloxy is involved, reaction 1 proceeds under the action of a base;

[0049] The organophosphorus reagent is selected from PPh3, P t At least one of Bu3 or PCy3;

[0050] The azodicarboxylic acid ester is selected from at least one of DIAD, DEAD or DtBAD;

[0051] The alkali is selected from at least one of KOAc, K2CO3, KHCO3, K3PO4, K2HPO4, KH2PO4, KOOCCF3, KOPiv, K2C2O4, KPF6, K2SO4, KHSO4, tBuOK, KOH, KOMe, KOEt, NaOHCO, NaOAc, Na2CO3, NaHCO3, Na3PO4, Na2HPO4, NaH2PO4, NaOOCCF3, NaOPiv, NaOMs, Na2C2O4, NaPF6, Na2SO4, NaHSO4, NaOH, NaOMe, NaOEt, Cs2CO3, tBuONa, CsOH, Et3N, EDA, DIPEA, DABCO, DBU, Pyridine, LDA, LiHMDS, NaHMDS, KHMDS, imidazole, NaNH2, or NaH.

[0052] The reaction solvent is selected from at least one of MeOH, EtOH, iPrOH, tBuOH, tAmylOH, H2O, Dioxane, THF, DME, MeCN, DMF, DMAc, DMSO, NMP, Benzene, Toluene, Xylene, Mesitylene, Chlorobenzene, H2O, HOAc, MTBE, BHT, chloroform, cyclohexane, DCM, DCE, Et2O, diglyme, EA, ethyl methyl ketone, Ethylene glycol, n-hexane, HMPA, CH3NO2, or n-pentane;

[0053] The reaction temperature is 0℃-100℃.

[0054] Preferably, in reaction 1:

[0055] The organophosphorus reagent is selected from PPh3 or P.t At least one of Bu3;

[0056] The azodicarboxylic acid ester is selected from DIAD;

[0057] The base is selected from at least one of Cs2CO3, tBuONa or tBuOK;

[0058] The reaction solvent is selected from at least one of THF, Toluene, DMF, or MeCN;

[0059] The reaction temperature is 0℃, 25℃ or 80℃.

[0060] Preferably, in reaction 2:

[0061] The reaction proceeds under the action of a transition metal catalyst and a base.

[0062] The transition metal catalyst is selected from Pd(OAc)2, Pd(CF3CO2)2, Pd(Opiv)2, Pd(acac)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(dba)2, PdCl2, PdBr2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(phen)Cl2, Pd(phen)2(PF6)2, Pd(NH3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(P tBu3)2,(allylPdCl)2,P(t-Bu)3Pd G2,P(t-Bu)3Pd G3,Pd(PCy3)2,Pd(PCy3)2Cl2,PCy3 Pd G1,PCy3 Pd G2,PCy3 Pd G3,Pd(MeCN)2Cl2,Pd(DIPHOS)2,XPhos Pd G1,XPhos Pd G2,XPhos Pd G3,Xphos Pd G4,tBuXPhos Pd G1,tBuXPhos Pd G2,tBuXPhos Pd G3,SPhos Pd G1,SPhos Pd G2,SPhos Pd G3,SPhos Pd G4,APhos Pd G1,APhos Pd G2,APhos Pd G3,EPhos Pd G1,EPhos Pd G2,EPhos Pd G3,EPhos Pd G4,EPhos Pd G6 TES,Xantphos Pd G1,Xantphos Pd G2,XantPhos Pd G3,XantPhos Pd G4,BrettPhos Pd G1,BrettPhos Pd G3,BrettPhos Pd G4,tBuBrettPhos Pd G1,tBuBrettPhos Pd G2,tBuBrettPhos Pd G3,RuPhos Pd G1,RuPhos Pd G2,RuPhos Pd G3,RuPhos Pd G4,Ruphos Pd(Crotyl)Cl,BINAP Pd G1,BINAP Pd G2,BINAP Pd G3,PdCl2(Amphos)2,CataCXium APd G1,CataCXium APd G2,CataCXium A Pd G3,t-BuDavePhos Pd G1,t-BuDavePhos Pd G2,t-BuDavePhos Pd G3,tBuBrettPhos Pd G6 TES,BrettPhos Pd G6 TES,AdBrettPhos Pd G1,AdBrettPhos Pd G2,AdBrettPhos Pd G3,NHC-PD(II)-IM,BEDFORD Catalyst,RockPhos Pd G1,RockPhos Pd G2,RockPhos Pd G3,MorDalphos Pd G1,MorDalphos Pd G2,MorDalphos Pd G3,Najera Catalyst II,Josiphos SL-J009-1Pd G3,PEPPSI-SIPr catalyst,Pd(A-taPhos)2,N-XantPhos Pd G3,Pd-PEPPSI-Ipr,JackiePhos Pd G3,DavePhos Pd G1,DavePhos Pd G2,DavePhos Pd G3,CuCl,CuCl2,Li2CuCl4,XantPhos·CuCl,SIPrCuCl,SIPOMeMesCuCl,IAdCuCl,CuBr,CuBr2,CuBr·SMe2,IPrCuBr,CuI, CuTc, Cu2O, CuCN, Cu(OAc)2, Cu(TFA)2, Cu(OTf)2, Cu(acac)2, Cu(CH3CN)4PF6, Cu(CH3CN)4BF4, Cu(CH3CN)4OTf or Cu-TMEDA At least one of Catalyst;,

[0063] The alkali is selected from at least one of KOAc, K2CO3, KHCO3, K3PO4, K2HPO4, KH2PO4, KOOCCF3, KOPiv, K2C2O4, KPF6, K2SO4, KHSO4, tBuOK, KOH, KOMe, KOEt, NaOHCO, NaOAc, Na2CO3, NaHCO3, Na3PO4, Na2HPO4, NaH2PO4, NaOOCCF3, NaOPiv, NaOMs, Na2C2O4, NaPF6, Na2SO4, NaHSO4, NaOH, NaOMe, NaOEt, Cs2CO3, tBuONa, CsOH, Et3N, EDA, NaH, DIPEA, DABCO, DBU, Pyridine, LDA, LiHMDS, NaHMDS, KHMDS, imidazole, or NaNH2.

[0064] The reaction solvent is selected from at least one of MeOH, EtOH, iPrOH, tBuOH, tAmylOH, H2O, Dioxane, THF, DME, MeCN, DMF, DMAc, DMSO, NMP, Benzene, Toluene, Xylene, Mesitylene, Chlorobenzene, H2O, HOAc, MTBE, BHT, chloroform, cyclohexane, DCM, DCE, Et2O, diglyme, EA, ethyl methyl ketone, Ethylene glycol, n-hexane, HMPA, CH3NO2, or n-pentane;

[0065] The reaction temperature is selected from -78℃ to 100℃.

[0066] Preferably, in reaction 2:

[0067] The transition metal catalyst is selected from at least one of Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2 or CuI;

[0068] The base is selected from at least one of Et3N, DIPEA, or DIPA;

[0069] The reaction solvent is selected from at least one of DMF, Dioxane, MeOH, or Toluene;

[0070] The reaction temperature is selected from 0℃ or 25℃.

[0071] Preferably, in reaction 3:

[0072] The reaction proceeds in the presence of a transition metal catalyst, ligands, and a base.

[0073] The transition metal catalyst is selected from Pd(OAc)2, Pd(OAc)2, Pd(CF3CO2)2, Pd(Opiv)2, Pd(acac)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(dba)2, PdCl2, PdBr2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(phen)Cl2, Pd(phen)2(PF6)2, Pd(NH3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(P tBu3)2,(allylPdCl)2,P(t-Bu)3Pd G2,P(t-Bu)3Pd G3,Pd(PCy3)2,Pd(PCy3)2Cl2,PCy3 Pd G1,PCy3 Pd G2,PCy3 Pd G3,Pd(MeCN)2Cl2,Pd(DIPHOS)2,XPhos Pd G1,XPhos Pd G2,XPhos Pd G3,Xphos Pd G4,tBuXPhos Pd G1,tBuXPhos Pd G2,tBuXPhos Pd G3,SPhos Pd G1,SPhos Pd G2,SPhos Pd G3,SPhos Pd G4,APhos Pd G1,APhos Pd G2,APhos Pd G3,EPhos Pd G1,EPhos Pd G2,EPhos Pd G3,EPhos Pd G4,EPhos Pd G6 TES,Xantphos Pd G1,Xantphos Pd G2,XantPhos Pd G3,XantPhos Pd G4,BrettPhos Pd G1,BrettPhos Pd G3,BrettPhos Pd G4,tBuBrettPhos Pd G1,tBuBrettPhos Pd G2,tBuBrettPhos Pd G3,RuPhos Pd G1,RuPhos Pd G2,RuPhos Pd G3,RuPhos Pd G4,Ruphos Pd(Crotyl)Cl,BINAP Pd G1,BINAP Pd G2,BINAP Pd G3,PdCl2(Amphos)2,CataCXium A Pd G1,CataCXium A Pd G2,CataCXium A Pd G3,t-BuDavePhos Pd G1,t-BuDavePhos Pd G2,t-BuDavePhos Pd G3,tBuBrettPhos Pd G6 TES,BrettPhos Pd G6 TES,AdBrettPhos Pd G1,AdBrettPhos Pd G2,AdBrettPhos Pd G3,NHC-PD(II)-IM,BEDFORD Catalyst,RockPhos Pd G1,RockPhos Pd G2,RockPhos Pd G3,MorDalphos Pd G1,MorDalphos Pd G2,MorDalphos Pd G3,At least one of the following: Najera Catalyst II, Josiphos SL-J009-1Pd G3, PEPPSI-SIPr catalyst, Pd(A-taPhos)2, N-XantPhos Pd G3, Pd-PEPPSI-Ipr, JackiePhos Pd G3, DavePhos Pd G1, DavePhos Pd G2, DavePhos Pd G3, CuI, CuBr, CuCl, CuBr2, CuCl2, or Cu(OTf)2;

[0074] The ligand is selected from at least one of PPh3, dppf, PtBu3, P(1-Adm)3, dppp, dppe, BINAP, X-phos, S-Phos, XantPhos, BrettPhos, tBuBrettPhos, DavePhos, t-BuDavePhos, RockPhos, MorDalphos, trans-N,N'-dimethylcyclohexane-1,2-diamine, 2-pyridinecarboxylic acid, or L-proline.

[0075] The molar ratio of the transition metal catalyst to the ligand is 1:(1-3);

[0076] The alkali is selected from at least one of KOAc, K2CO3, KHCO3, K3PO4, K2HPO4, KH2PO4, KOOCCF3, KOPiv, K2C2O4, KPF6, K2SO4, KHSO4, tBuOK, KOH, KOMe, KOEt, NaOHCO, NaOAc, Na2CO3, NaHCO3, Na3PO4, Na2HPO4, NaH2PO4, NaOOCCF3, NaOPiv, NaOMs, Na2C2O4, NaPF6, Na2SO4, NaHSO4, NaOH, NaOMe, NaOEt, Cs2CO3, tBuONa, CsOH, Et3N, EDA, NaH, DIPEA, DABCO, DBU, Pyridine, LDA, LiHMDS, NaHMDS, KHMDS, imidazole, or NaNH2.

[0077] The reaction solvent is selected from at least one of MeOH, EtOH, iPrOH, tBuOH, tAmylOH, H2O, Dioxane, THF, DME, MeCN, DMF, DMAc, DMSO, NMP, Benzene, Toluene, Xylene, Mesitylene, Chlorobenzene, H2O, HOAc, MTBE, BHT, chloroform, cyclohexane, DCM, DCE, Et2O, diglyme, EA, ethyl methyl ketone, Ethylene glycol, n-hexane, HMPA, CH3NO2, or n-pentane;

[0078] The reaction temperature is selected from 0℃ to 150℃;

[0079] The molar ratio of the compound shown in Formula X, the compound shown in Formula XI, and the base is (1-5):(1-5):(1-5).

[0080] Preferably, in reaction 3:

[0081] The transition metal catalyst is selected from at least one of Pd(OAc)2, Pd(dppf)Cl2, XPhos Pd G3 or CuI;

[0082] The ligand is selected from at least one of BINAP, X-phos, S-phos, XantPhos, DavePhos, trans-N,N'-dimethylcyclohexane-1,2-diamine, 2-pyridinecarboxylic acid or L-proline.

[0083] The molar ratio of the transition metal catalyst to the ligand is 1:1 or 1:2.

[0084] The base is selected from at least one of tBuONa, K3PO4, Cs2CO3, DIPEA, Et3N or DBU;

[0085] The reaction solvent is selected from at least one of DMF, Toluene, THF, Dioxane, or H2O;

[0086] The reaction temperature is selected from 80℃ or 110℃;

[0087] The molar ratio of the compound shown in Formula X, the compound shown in Formula XI, and the base is 1:2:2 or 2:1:2.

[0088] Preferably, in reaction 4:

[0089] The electrophilic halogenated reagent is selected from at least one of Br2, I2, NCS, NBS, NIS or DBDMH;

[0090] The reaction solvent is selected from at least one of MeCN, DMF, DMAc, or THF;

[0091] The reaction temperature is selected from -75℃ to 40℃.

[0092] Preferably, in reaction 4:

[0093] The electrophilic halogenated reagent is selected from at least one of I2, NBS, NIS or DBDMH;

[0094] The reaction solvent is selected from MeCN;

[0095] The reaction temperature is selected from 0℃ or 25℃.

[0096] Preferably, in reaction 5:

[0097] The reaction proceeds in the presence of a transition metal catalyst, ligands, and a base.

[0098] The transition metal catalyst is selected from at least one of palladium catalyst, nickel catalyst, iron catalyst, cobalt catalyst or copper catalyst;

[0099] The palladium catalyst is selected from Pd(OAc)2, Pd(CF3CO2)2, Pd(Opiv)2, Pd(acac)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(dba)2, PdCl2, PdBr2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(phen)Cl2, Pd(phen)2(PF6)2, Pd(NH3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(P tBu3)2,(allylPdCl)2,P(t-Bu)3Pd G2,P(t-Bu)3Pd G3,Pd(PCy3)2,Pd(PCy3)2Cl2,PCy3 Pd G1,PCy3 Pd G2,PCy3 Pd G3,Pd(MeCN)2Cl2,Pd(DIPHOS)2,XPhos Pd G1,XPhos Pd G2,XPhos Pd G3,Xphos Pd G4,tBuXPhos Pd G1,tBuXPhos Pd G2,tBuXPhos Pd G3,SPhos Pd G1,SPhos Pd G2,SPhos Pd G3,SPhos Pd G4,APhos Pd G1,APhos Pd G2,APhos Pd G3,EPhos Pd G1,EPhos Pd G2,EPhos Pd G3,EPhos Pd G4,EPhos Pd G6 TES,Xantphos Pd G1,Xantphos Pd G2,XantPhos Pd G3,XantPhos Pd G4,BrettPhos Pd G1,BrettPhos Pd G3,BrettPhos Pd G4,tBuBrettPhos Pd G1,tBuBrettPhos Pd G2,tBuBrettPhos Pd G3,RuPhos Pd G1,RuPhos Pd G2,RuPhos Pd G3,RuPhos Pd G4,Ruphos Pd(Crotyl)Cl,BINAP Pd G1,BINAP Pd G2,BINAP Pd G3,PdCl2(Amphos)2,CataCXium APd G1,CataCXium APd G2,CataCXium APd G3,t-BuDavePhos Pd G1,t-BuDavePhos Pd G2,t-BuDavePhos Pd G3,tBuBrettPhos Pd G6 TES,BrettPhos Pd G6 TES,AdBrettPhos Pd G1,AdBrettPhos Pd G2,AdBrettPhos Pd G3,NHC-PD(II)-IM,BEDFORD Catalyst,RockPhos Pd G1,RockPhos Pd G2,RockPhos Pd G3,MorDalphos Pd G1,MorDalphos Pd G2,MorDalphos Pd G3,At least one of Najera Catalyst II, Josiphos SL-J009-1Pd G3, PEPPSI-SIPr catalyst, Pd(A-taPhos)2, N-XantPhos Pd G3, Pd-PEPPSI-Ipr, JackiePhos Pd G3, DavePhos Pd G1, DavePhos Pd G2 or DavePhos Pd G3;

[0100] The nickel catalyst is selected from at least one of _Ni(cod)2, Ni(acac)2, Ni(OAc)2, Ni(OTf)2, Ni(TFA)2, Ni(OTs)2, NiSO4, NiPF6, NiO, NiCl2, Ni(PPh3)(Cypde)Cl, Ni(DME)Cl2, Ni(dppe)Cl2, Ni(PBu3)2Cl2, Ni(PPh3)2Cl2, Ni(PPh3)3Cl, Ni(2,2’-bipy)Cl2, Ni(MeCN)Cl2, [(dppf)Ni(cinnamyl)]Cl, NiBr2, Ni(phen)Br2, Ni(2,2’-bipy)3Br2, Ni(Diglyme)Br2, Ni(PBu3)2Br2, Ni(PPh3)2Br2, Ni(PPh3)3Br, (Dtpby)NiBr2, NiF2, NiI2, Ni(2,2’-bipy)I2, Ni(PPh3)2I2, Ni(PPh3)3, Ni(PPh3)4, Ni(PPh3)2(CO)2, Ni(tBustb)3, Ni(4-Fstb)3 or Ni-(S)-BPB-Gly;

[0101] The iron catalyst is selected from FeCl2, FeCl 2· 4H2O, FeCl2(dppbz)2, Fe(dppe)Cl2, Fe(salen)Cl, FeCl2(3,5-t-Bu2-SciOPP), FeCl3, FeBr2, FeBr 2· 2H2O, FeBr3, Fe2Br 6· 3H2O, Fe(PPh3)2Br2, FeSO 4· H2O, FeSO 4· 2H2O, FeF 2· 4H2O, Fe(NO3)3, Fe(OTs)3, Fe(NO3) 3·At least one of the following: 9H2O, Fe(acac)3, Fe(PPh3)(CO)4, [Fe(Pc)], Ethynylferrocene, 1,1'-Dibromoferrocene, Fe(PPh3)(CO)3I2, Fe(Cp*)2, Fe4[Fe(CN)6]3, Fe2MnO4, CuFeS2, FeO, Fe(OH)3, Fe2O3 or FeTiO3;

[0102] The cobalt catalysts are selected from CoCl2, Co(dppf)Cl2, Co(XantPhos)Cl2, Co(PPh3)2Cl2, Co(PPh3)3Cl, Co(phen)Cl2, Co(acac)2, Co(acac)(dppbz), Co(acac)(depe), Co(acac)(depbz), Co(acac)(dppe), ( i At least one of the following: PrPNP)CoCl, CoBr2, Co(PPh3)3Br, Co-EDTA, Co(BF4)2, Co(NO3)2, Bis(hexafluoroacetylacetonato)cobalt(II), Tris(2,2,6,6-tetramethyl-3,5-heptanedionato)cobalt(III), Cobalt bis(trifluoroMethylsulfonyl)iMide or Bis(hexafluoroacetylacetonato)cobalt(II);

[0103] The copper catalyst is selected from at least one of CuCl, CuCl2, Li2CuCl4, XantPhos·CuCl, SIPrCuCl, SIPOMeMesCuCl, IAdCuCl, CuBr, CuBr2, CuBr·SMe2, IPrCuBr, CuI, CuTc, Cu2O, CuCN, Cu(OAc)2, Cu(TFA)2, Cu(OTf)2, Cu(acac)2, Cu(CH3CN)4PF6, Cu(CH3CN)4BF4, Cu(CH3CN)4OTf, or Cu-TMEDACatalyst;

[0104] The weight ratio of transition metal catalyst to substrate is 0-100%;

[0105] The ligands are selected from P n Bu3,P tBu3,PCy3,S-Phos,sSPhos,PyBroP,cataCXium A,PPh3,P(oMePh)3,P(1-Adm)3,dppp,dppe,dppb,dppf,BINAP,X-phos,tBuXPhos,Me3(OMe)tBuXPhos,XantPhos,N-Xantphos,BISBI,BrettPhos,tBuBrettPhos,AdBrettPhos,DavePhos,tBuDavePhos,Tri-2-furanylphosphine,tBuMePhos,RuPhos,JohnPhos,PhDave-Phos,JackiePhos,Amphos,RockPhos,MorDalphos,Sphos,Vphos,Cphos,4MetBuXPhos,Tri(thiophen-2-yl)phosphine,Cyjohnphos,BIPHEPHOS,TrixiePhos,PhenCar-Phos,MePhos,BINAP,TrippyPhos,Ad-BippyPhos,Zheda-Phos,DPEPO,TETRAPHOS-II,catASium T3,SPANphos,iPrN[P(C6H4-p-Si(nBu)3)2]2,2,2'-Bipyridine,,2,3'-Bipyridine,2,4'-Bipyridine,4,4'-Bipyridine,2,2'-Bipyrazyl,(NH2)2bpy,4,4'-Di-tert-butyl-2,2'-dipyridyl,2,2'-Bipyridine-6,6'-dicarbonitrile,[2,2'-Bipyridine]-3,3'-dicarboxylic acid,2,2':6',2”-Terpyridine,1,10-Phen,IcHex·HCl,IiPr·HBF4,SIMes-HBF4,ItBu·HBF4,H8-BINAM,trans-N,N'-Dimethyl-1,2-cyclohexanediamine,(1R,2R)-N1,N1,N2,N2-Tetramethylcyclohexane-1,2-diamine,(1S,2S)-Cyclohexane-1,2-diamine,trans-1,2-Cyclohexanediamine,cis-Cyclohexane-1,2-diamine,At least one of DMCyDA, H-DL-Pro-NH2.HCl, TMCyDA, or DMEDA;

[0106] The molar ratio of the transition metal catalyst to the ligand is (1-5):(1-5);

[0107] The base is selected from at least one of KOAc, K2CO3, KHCO3, K3PO4, K2HPO4, KH2PO4, KOOCCF3, KOPiv, K2C2O4, KPF6, K2SO4, KHSO4, tBuOK, KOH, KOMe, KOEt, NaOHCO, NaOAc, Na2CO3, NaHCO3, Na3PO4, Na2HPO4, NaH2PO4, NaOOCCF3, NaOPiv, NaOMs, Na2C2O4, NaPF6, Na2SO4, NaHSO4, NaOH, NaOMe, NaOEt, Cs2CO3, tBuONa, CsOH, Et3N, EDA, NaH, DIPEA, DABCO, DBU, Pyridine, LDA, LiHMDS, NaHMDS, KHMDS, imidazole, or NaNH2.

[0108] The reaction solvent is selected from at least one of MeOH, EtOH, iPrOH, tBuOH, tAmylOH, H2O, Dioxane, THF, DME, MeCN, DMF, DMAc, DMSO, NMP, Benzene, Toluene, Xylene, Mesitylene, Chlorobenzene, H2O, HOAc, MTBE, BHT, chloroform, cyclohexane, DCM, DCE, Et2O, diglyme, EA, ethyl methyl ketone, Ethylene glycol, n-hexane, HMPA, CH3NO2, or n-pentane;

[0109] The reaction temperature is selected from 0℃ to 150℃;

[0110] The molar ratio of the compound shown in Formula II, the compound shown in Formula III, and the base is (1-5):(1-5):(1-10).

[0111] Preferably, in reaction 5:

[0112] The transition metal catalyst is selected from at least one of XPhos Pd G2, SPhos Pd G3 or RockPhos Pd G3.

[0113] The transition metal catalyst was used at a weight ratio of 10% relative to the substrate.

[0114] The ligand is selected from at least one of RockPhos, X-phos, SPhos or DavePhos;

[0115] The molar ratio of the transition metal catalyst to the ligand is 1:1 or 1:2.

[0116] The base is selected from at least one of KOAc, K3PO4 or Na3PO4;

[0117] The reaction solvent is selected from at least one of DMF, THF, Dioxane, or H2O;

[0118] The reaction temperature is selected from 30℃, 80℃ or 150℃;

[0119] The molar ratio of the compound shown in Formula II, the compound shown in Formula III, and the base is 1:1:10, 1:2:7, or 2:1:8.

[0120] Preferably, the compound shown in Formula X is prepared by reaction 6, wherein reaction 6 is: the compound shown in Formula VIII reacts with the compound shown in Formula XII to obtain the compound shown in Formula X;

[0121] Preferably, in reaction 6:

[0122] The reaction proceeds under the action of a transition metal catalyst and a base.

[0123] Transition metal catalysts are selected from Pd(OAc)2, Pd(CF3CO2)2, Pd(Opiv)2, Pd(acac)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(dba)2, PdCl2, PdBr2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(phen)Cl2, Pd(phen)2(PF6)2, Pd(NH3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(P tBu3)2,(allylPdCl)2,P(t-Bu)3Pd G2,P(t-Bu)3Pd G3,Pd(PCy3)2,Pd(PCy3)2Cl2,PCy3 Pd G1,PCy3 Pd G2,PCy3 Pd G3,Pd(MeCN)2Cl2,Pd(DIPHOS)2,XPhos Pd G1,XPhos Pd G2,XPhos Pd G3,Xphos Pd G4,tBuXPhos Pd G1,tBuXPhos Pd G2,tBuXPhos Pd G3,SPhos Pd G1,SPhos Pd G2,SPhos Pd G3,SPhos Pd G4,APhos Pd G1,APhos Pd G2,APhos Pd G3,EPhos Pd G1,EPhos Pd G2,EPhos Pd G3,EPhos Pd G4,EPhos Pd G6 TES,Xantphos Pd G1,Xantphos Pd G2,XantPhos Pd G3,XantPhos Pd G4,BrettPhos Pd G1,BrettPhos Pd G3,BrettPhos Pd G4,tBuBrettPhos Pd G1,tBuBrettPhos Pd G2,tBuBrettPhos Pd G3,RuPhos Pd G1,RuPhos Pd G2,RuPhos Pd G3,RuPhos Pd G4,Ruphos Pd(Crotyl)Cl,BINAP Pd G1,BINAP Pd G2,BINAP Pd G3,PdCl2(Amphos)2,CataCXium A Pd G1,CataCXium A Pd G2,CataCXium A Pd G3,t-BuDavePhos Pd G1,t-BuDavePhos Pd G2,t-BuDavePhos Pd G3,tBuBrettPhos Pd G6 TES,BrettPhos Pd G6 TES,AdBrettPhos Pd G1,AdBrettPhos Pd G2,AdBrettPhos Pd G3,NHC-PD(II)-IM,BEDFORD Catalyst,RockPhos Pd G1,RockPhos Pd G2,RockPhos Pd G3,MorDalphos Pd G1,MorDalphos Pd G2,MorDalphos Pd G3,Najera Catalyst II,Josiphos SL-J009-1Pd G3,PEPPSI-SIPr catalyst,Pd(A-taPhos)2,N-XantPhos Pd G3,Pd-PEPPSI-Ipr,JackiePhos Pd G3,DavePhos Pd G1,DavePhos Pd G2,DavePhos Pd G3,CuCl,CuCl2,Li2CuCl4,XantPhos·CuCl,SIPrCuCl,SIPOMeMesCuCl,IAdCuCl,CuBr,CuBr2,CuBr·SMe2,IPrCuBr,CuI, CuTc, Cu2O, CuCN, Cu(OAc)2, Cu(TFA)2, Cu(OTf)2, Cu(acac)2, Cu(CH3CN)4PF6, Cu(CH3CN)4BF4, Cu(CH3CN)4OTf or Cu-TMEDA At least one of Catalyst;,

[0124] The base is selected from at least one of KOAc, K2CO3, KHCO3, K3PO4, K2HPO4, KH2PO4, KOOCCF3, KOPiv, K2C2O4, KPF6, K2SO4, KHSO4, tBuOK, KOH, KOMe, KOEt, NaOHCO, NaOAc, Na2CO3, NaHCO3, Na3PO4, Na2HPO4, NaH2PO4, NaOOCCF3, NaOPiv, NaOMs, Na2C2O4, NaPF6, Na2SO4, NaHSO4, NaOH, NaOMe, NaOEt, Cs2CO3, tBuONa, CsOH, Et3N, EDA, NaH, DIPEA, DABCO, DBU, Pyridine, LDA, LiHMDS, NaHMDS, KHMDS, imidazole, or NaNH2.

[0125] The solvent is selected from at least one of MeOH, EtOH, iPrOH, tBuOH, tAmylOH, H2O, Dioxane, THF, DME, MeCN, DMF, DMAc, DMSO, NMP, Benzene, Toluene, Xylene, Mesitylene, Chlorobenzene, H2O, HOAc, MTBE, BHT, chloroform, cyclohexane, DCM, DCE, Et2O, diglyme, EA, ethyl methyl ketone, Ethylene glycol, n-hexane, HMPA, CH3NO2, or n-pentane;

[0126] The reaction temperature is selected from -78℃ to 40℃.

[0127] Preferably, in reaction 6:

[0128] The transition metal catalysts are selected from Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, and Pd(PCy3)2Cl. 2, At least one of Pd(MeCN)2Cl2 or CuI;

[0129] The base is selected from at least one of Et3N, DIPEA, DIPA, or DBU;

[0130] The solvent is selected from at least one of DMF, Dioxane, MeOH, or Toluene;

[0131] The reaction temperature is selected from 0℃ or 25℃.

[0132] Preferably, the compound shown in Formula VIII is prepared by reaction 7, wherein reaction 7 is: the compound shown in Formula XIII reacts with an propylene acetylation reagent via a propyrylation reaction to obtain the compound shown in Formula VIII;

[0133] Wherein, X”” is selected from halogen, hydroxyl, C1-C 10 Alkylsulfonyloxy, borate group, C1-C 10 Boronate group.

[0134] Preferably, in reaction 7:

[0135] The reaction is carried out in the presence of organophosphorus reagents and azodicarboxylic acid esters, or in the presence of a base;

[0136] Organophosphorus reagents are selected from PPh3, P t At least one of Bu3 or PCy3;

[0137] Azodicarboxylic acid esters are selected from at least one of DIAD, DEAD or DBAD;

[0138] The base is selected from at least one of KOAc, K2CO3, KHCO3, K3PO4, K2HPO4, KH2PO4, KOOCCF3, KOPiv, K2C2O4, KPF6, K2SO4, KHSO4, tBuOK, KOH, KOMe, KOEt, NaOHCO, NaOAc, Na2CO3, NaHCO3, Na3PO4, Na2HPO4, NaH2PO4, NaOOCCF3, NaOPiv, NaOMs, Na2C2O4, NaPF6, Na2SO4, NaHSO4, NaOH, NaOMe, NaOEt, Cs2CO3, tBuONa, CsOH, Et3N, EDA, NaH, DIPEA, DABCO, DBU, Pyridine, LDA, LiHMDS, NaHMDS, KHMDS, imidazole, or NaNH2.

[0139] The reaction solvent is selected from at least one of MeOH, EtOH, iPrOH, tBuOH, tAmylOH, H2O, Dioxane, THF, DME, MeCN, DMF, DMAc, DMSO, NMP, Benzene, Toluene, Xylene, Mesitylene, Chlorobenzene, H2O, HOAc, MTBE, BHT, chloroform, cyclohexane, DCM, DCE, Et2O, diglyme, EA, ethyl methyl ketone, Ethylene glycol, n-hexane, HMPA, CH3NO2, or n-pentane;

[0140] The reaction temperature is selected from 0℃ to 100℃.

[0141] Preferably, in reaction 7:

[0142] The reaction is carried out in the presence of organophosphorus reagents and azodicarboxylic acid esters, or in the presence of a base;

[0143] Organophosphorus reagents are selected from PPh3 or P t Bu3;

[0144] Azodicarboxylic acid esters are selected from at least one of DIAD;

[0145] The base is selected from at least one of K2CO3, Cs2CO3, tBuONa, tBuOK, NaOH, KOH or NaH;

[0146] The reaction solvent is selected from at least one of THF, Toluene, DMF, MeCN, or acetone;

[0147] The reaction temperature is selected from 0℃, 25℃ or 80℃.

[0148] The present invention also provides the use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, in the preparation of estrogen receptor degraders or estrogen receptor degrader intermediates.

[0149] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0150] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0151] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0152] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a -C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C1-C4 alkyl" refers to alkyl groups containing 1 to 4 carbon atoms.

[0153] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as C1-C6 alkoxy groups.

[0154] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms, no heterocyclic atoms, and a single or multiple rings (including fused, bridged, and spirocyclic systems). For polycyclic systems having aromatic and non-aromatic rings without heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8-tetrahydronaphthalene-5-yl) applies when the connecting point is located on a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polycyclic dicycloalkyl ring systems are dicyclohexyl, dicyclopentyl, dicyclooctyl, etc. Examples and names are listed below.

[0155] Two such bicyclic alkyl polycyclic structures: Dicyclohexyl and Dicyclohexyl. "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least one vinyl unsaturated site (>C=C<). For example, (Ca-Cb)alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, etc.

[0156] "Alynyl" refers to a straight-chain monovalent hydrocarbon group or a branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include hydrocarbon groups having one triple bond and one double bond. For example, (C2-C6) alkynyl is intended to include ethynyl, propynyl, etc.

[0157] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0158] "Heterocyclic" or "heterocyclic alkyl" refers to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; where heteroatoms refer to nitrogen, oxygen, or sulfur atoms.

[0159] "Aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom; where the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom.

[0160] "alkylsulfonyloxy" refers to a sulfonyloxy group comprising one alkyl group, with the structural formula: Where R represents an alkyl group.

[0161] "Borate ester group" refers to the group formed after the esterification of borate group, with the structural formula as follows: Where R represents an alkyl group.

[0162] When two substituents are "linked together to form a ring," it means that at least one atom in each of the two substituents is connected by a chemical bond, so that a part of the molecular skeleton to which the two substituents are linked together forms a ring structure together with the two substituents.

[0163] "Stereoisomers" include enantiomers and diastereomers.

[0164] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0165] The terms "salt" and "pharmaceutical salt" refer to acidic and / or basic salts formed by the above-described compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-described compounds or their stereoisomers with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0166] This invention provides a series of novel compounds as synthetic intermediates, and uses these compounds as synthetic intermediates to construct a novel method for synthesizing estrogen receptor degrading agent intermediates. Through optimization of the synthetic route and reaction conditions at each step, the synthetic method provided by this invention has the advantages of a shorter synthetic route and higher yield compared to existing methods for synthesizing estrogen receptor degrading agent intermediates, making it more suitable for large-scale industrial production. Therefore, this invention has excellent application prospects.

[0167] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0168] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0169] In the following examples and experimental cases, reagents and raw materials not specifically described are all commercially available products.

[0170] Example 1

[0171] Step 1: Synthesis of intermediate 1-(benzyloxy)-3-(but-3-yn-1-yl)benzene

[0172] 3-(but-3-yn-1-yl)phenol (1.46 g, 10 mmol), benzyl chloride (1.39 g, 11 mmol), and potassium carbonate (2.72 g, 20 mmol) were dissolved in 30 mL of acetonitrile. The mixture was stirred overnight at room temperature. After the reaction was monitored by TLC until complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 2.0 g of the target compound, yield: 85%. LC / MS (ESI+) calcd for C 17 H 16 O([M+H] + )m / z:237.1; found 237.1.

[0173] Step 2: Synthesis of intermediate 1-(benzyloxy)-3-(4-(4-bromophenyl)but-3-en-1-yl)benzene

[0174] p-Bromoiodobenzene (843 mg, 3 mmol), bis(triphenylphosphine)palladium dichloride (210 mg, 0.3 mmol), cuprous iodide (170 mg, 0.9 mmol), and diisopropylamine (3.03 g, 30 mmol) were dissolved in toluene (10 mL). The reaction system was argon atmosphere. 1-(benzyloxy)-3-(but-3-yn-1-yl)benzene (3.03 g, 6 mmol) was slowly added under ice bath conditions. The reaction was carried out overnight at room temperature, monitored by TLC until the reactants were completely reacted. The mixture was filtered through diatomaceous earth and column chromatography yielded 1.42 g of product. Yield: 84%. LC / MS (ESI+) calcd for C 23 H 19 BrO([M+H] + )m / z:391.1;found 391.1.

[0175] Step 3: Synthesis of intermediate 1-(4-(4-(3-(benzyloxy)phenyl)but-1-yn-1-yl)phenyl]-4-(dimethoxymethyl)piperidine

[0176] 1-(benzyloxy)-3-(4-(4-bromophenyl)but-3-en-1-yl)benzene (780 mg, 2 mmol), 4-(dimethoxymethyl)piperidine (636 mg, 4 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol), S-Phos (164 mg, 0.4 mmol), and sodium tert-butoxide (576 mg, 6 mmol) were dissolved in toluene (10 mL). The reaction system was replaced with argon gas, and the reaction was carried out overnight at 110 °C. TLC monitoring continued until the reactants were completely reacted. The product was filtered through diatomaceous earth and column chromatography yielded 740 mg of product. Yield: 79%. LC / MS (ESI+) calcd for C 31 H 35 NO3([M+H)) + )m / z:470.3; found 470.3.

[0177] Step 4: Synthesis of intermediate 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphth-1-yl)phenyl)-4-(dimethoxymethyl)piperidine

[0178] 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphth-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (469 mg, 1 mmol) was dissolved in 10 mL of acetonitrile. NBS (196 mg, 1.1 mmol) was slowly added under ice bath conditions and stirred overnight at room temperature. After the reaction was monitored by TLC until complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 448 mg of the target compound (yield: 82%). LC / MS (ESI+) calcd for C 31 H 34 BrNO3([M+H] + )m / z:548.2; found 548.2.

[0179] Step 5: Synthesis of intermediate 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphth-1-yl)phenyl)-4-(dimethoxymethyl)piperidine

[0180] 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthyl-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (273 mg, 0.5 mmol), phenylboronic acid (122 mg, 1.0 mmol), Pd(dppf)Cl2 (37 mg, 0.05 mmol), and potassium carbonate (136 mg, 1.0 mmol) were dissolved in dioxane (5 mL) and water (2 mL). The reaction system was replaced with argon gas, and the reaction was carried out overnight at 90 °C. TLC monitoring continued until the reactants were completely reacted. The product was filtered through diatomaceous earth and column chromatography yielded 250 mg of product. Yield: 92%. LC / MS (ESI+) calcd for C 37 H 39 NO3([M+H)) + )m / z:546.3; found 546.3.

[0181] Step 6: Synthesis of 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalene-2-ol

[0182] 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphth-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (55 mg, 0.1 mmol) was dissolved in 10 mL of methanol, and palladium on carbon (5 mg, 10%) was added to replace the reaction system with hydrogen. The mixture was stirred overnight at room temperature. TLC was used to monitor the complete consumption of the starting material. The reaction mixture was filtered and concentrated to obtain 42 mg of the target compound, yield: 91%. 1 H NMR (400MHz, CDCl3) δ7.20-7.12(m,3H),6.87-6.78(m,3H),6.71(d,J=2.6Hz,1H),6.58(d, J=8.6Hz,2H),6.53(dd,J=8.3,2.7Hz,1H),6.28(d,J=8.6Hz,2H),4.23(d,J=4.8Hz,1H),4. 06(d,J=7.2Hz,1H),3.63-3.52(m,2H),3.41-3.30(m,7H),3.13-2.96(m,2H),2.54(dt,J=1 2,2.0Hz,2H),2.28-2.10(m,1H),1.86-1.63(m,4H),1.49-1.31(m,2H).LC / MS(ESI+)calcd for C 30 H 35 NO3([M+H)) + )m / z:458.3;found458.3.

[0183] Example 2

[0184] Step 1: Synthesis of intermediate 1-(but-3-en-1-yl)-3-(tert-butoxy)benzene

[0185] 3-(but-3-yn-1-yl)phenol (1.46 g, 10 mmol) was dissolved in 50 mL of dichloromethane. Trichloroacetylimine tert-butyl ester (8.72 g, 40 mmol) was added under ice bath conditions, replacing the reaction system with argon. Boron trifluoride diethyl ether (142 mg, 0.1 mmol) was added under argon protection, and the mixture was stirred at room temperature for 3 days. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated sodium chloride, washed with water, dried, concentrated, and obtained by column chromatography. LC / MS (ESI+) calcd for C 14 H 18 O([M+H-55] + )m / z:148.1; found 148.1.

[0186] Step 2: Synthesis of intermediate 1-(4-(4-(benzyloxy)phenyl)but-3-yn-1-yl)-3-(tert-butoxy)benzene

[0187] 4-Benzyloxyiodobenzene (930 mg, 3 mmol), bis(triphenylphosphine)palladium dichloride (210 mg, 0.3 mmol), cuprous iodide (170 mg, 0.9 mmol), and diisopropylamine (3.03 g, 30 mmol) were dissolved in toluene (10 mL). The reaction system was replaced with argon gas. 1-(but-3-en-1-yl)-3-(tert-butoxy)benzene (1.21 g, 6 mmol) was slowly added under ice bath conditions. The reaction was carried out overnight at room temperature, monitored by TLC until the starting material was completely reacted. The mixture was filtered through diatomaceous earth and column chromatography yielded 1.04 g of product. Yield: 90%. LC / MS (ESI+) calcd for C 27 H 28 O2([M+H-55] + )m / z:330.2;found 330.2.

[0188] Step 3: Synthesis of intermediate 4-(4-(benzyloxy)phenyl)-3-bromo-7-(tert-butoxy)-1,2-dihydronaphthalene

[0189] 1-(4-(4-(benzyloxy)phenyl)but-3-yn-1-yl)-3-(tert-butoxy)benzene (384 mg, 1 mmol) was dissolved in 10 mL of acetonitrile. NBS (196 mg, 1.1 mmol) was slowly added under ice bath conditions and stirred overnight at room temperature. After the reaction was monitored by TLC until complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 342 mg of the target compound (yield: 74%). LC / MS (ESI+) calcd for C 27 H 27 BrO2([M+H-55] + )m / z:408.1; found 408.1.

[0190] Step 4: Synthesis of intermediate 4-(4-(benzyloxy)phenyl)-7-(tert-butoxy)-3-phenyl-1,2-dihydronaphthalene

[0191] 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthyl-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (231 mg, 0.5 mmol), phenylboronic acid (122 mg, 1.0 mmol), Pd(dppf)Cl2 (37 mg, 0.05 mmol), and potassium carbonate (136 mg, 1.0 mmol) were dissolved in dioxane (5 mL) and water (2 mL). The reaction system was replaced with argon gas, and the reaction was carried out overnight at 90 °C. TLC monitoring continued until the reactants were completely reacted. The mixture was filtered through diatomaceous earth, and column chromatography yielded 202 mg of the product. The yield was 88%. LC / MS (ESI+) calcd for C 33 H 32 O2([M+H-55] + )m / z:406.3; found 406.3.

[0192] Step 5: Synthesis of 4-(-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenol

[0193] 4-(4-(benzyloxy)phenyl)-7-(tert-butoxy)-3-phenyl-1,2-dihydronaphthalene (46 mg, 0.1 mmol) was dissolved in 10 mL of methanol, and palladium on carbon (5 mg, 10%) was added to replace the reaction system with hydrogen. The mixture was stirred overnight at room temperature. TLC was used to monitor the complete consumption of the starting material. The reaction mixture was filtered and concentrated to obtain 35 mg of the target compound, yield: 95%. 1H NMR(400MHz, DMSO-d6)δ9.02(s,1H),7.21-7.06(m,3H),6.87-6.78(m,3H),6.78-6.72(m,1H),6.71-6.65(m,1H),6.35(d,J=8.6Hz,2H),6.17(d, J=8.6Hz,2H),4.20(d,J=4.8Hz,1H),3.31-3.28(m,1H),3.08-2.89(m,2H),2.16-2.05(m,1H),1.78-1.65(m,1H),1.29(s,9H).LC / MS(ESI+)calcd for C 26 H 28 O2([M+H-56)) + )m / z:317.2; found 317.2.

[0194] This intermediate is an important intermediate for the synthesis of Vepdegestrant (ARV-471), see reference WO2018102725.

[0195] Example 3

[0196] Step 1: Synthesis of intermediate 1-(benzyloxy)-3-(prop-2-yn-1-yloxy)benzene

[0197] 3-(benzyloxy)phenol (4.0 g, 20 mmol), 3-chloroprop-1-yne (1.63 g, 22 mmol), and potassium carbonate (5.45 g, 40 mmol) were dissolved in acetonitrile (50 mL). The reaction mixture was replaced with argon gas and reacted overnight at 80 °C. TLC monitoring continued until the reactants were fully reacted. The mixture was filtered through diatomaceous earth and column chromatography yielded 4.18 g of product. Yield: 88%. LC / MS (ESI+) calcd for C 16 H 14 O2([M+H-56)) + m / z:239.1; found

[0198] 239.1.

[0199] Step 2: Synthesis of intermediate 1-(4-(3-(benzyloxy)phenoxy)prop-1-yn-1-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

[0200] p-Bromoiodobenzene (1.14 g, 3 mmol), bis(triphenylphosphine)palladium dichloride (210 mg, 0.3 mmol), cuprous iodide (170 mg, 0.9 mmol), and diisopropylamine (3.03 g, 30 mmol) were dissolved in toluene (10 mL). The reaction system was argon atmosphere. 1-(benzyloxy)-3-(prop-2-yn-1-yloxy)benzene (1.43 g, 6 mmol) was slowly added under ice bath conditions. The reaction was carried out overnight at room temperature, monitored by TLC until the starting material was completely reacted. The mixture was filtered through diatomaceous earth and column chromatography yielded 1.35 g of product. Yield: 92%. LC / MS (ESI+) calcd for C 30 H 32 FNO4([M+H-56)) + )m / z:490.2; found 490.2.

[0201] Example 4

[0202] Step 1: Synthesis of intermediate 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)prop-2-yn-1-ol

[0203] 4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine (3.79 g, 10 mmol), bis(triphenylphosphine)palladium dichloride (701 mg, 1.0 mmol), cuprous iodide (570 mg, 3.0 mmol), and diisopropylamine (10.1 g, 100 mmol) were dissolved in toluene (40 mL). The reaction system was argon atmosphere. Propylene alcohol (1.12 g, 20 mmol) was slowly added under ice bath conditions. The reaction was carried out overnight at room temperature, monitored by TLC until the reactants were completely reacted. The product was filtered through diatomaceous earth and column chromatography yielded 2.89 g of product. Yield: 94%. LC / MS (ESI+) calcd for C 17 H 22 FNO3([M+H-56)) + )m / z:308.2; found 308.2.

[0204] Step 2: Synthesis of 1-(4-(3-(benzyloxy)phenoxy)prop-1-yn-1-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

[0205] Compounds 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)prop-2-yn-1-ol (1.53 g, 5.0 mmol), 3-(benzyloxy)phenol (1.0 g, 5.0 mmol), and triphenylphosphine (1.45 g, 5.5 mmol) were dissolved in 30 mL of toluene. The reaction system was replaced with an argon atmosphere and heated to 90 °C. Then, DIAD (1.12 g, 5.5 mmol) was added under argon protection, and the reaction was maintained at 90 °C overnight. After the reaction was complete as monitored by TLC, the reaction solvent was concentrated, and the target compound was obtained by column chromatography. LC / MS (ESI+) calcd for C 30 H 32 FNO4([M+H-56)) + )m / z:490.2; found 490.2.

[0206] Example 5

[0207] Step 1: Synthesis of intermediate 1-(4-(3-chloropropyl-1-yn-1-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

[0208] 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)prop-2-yn-1-ol (1.53 g, 5.0 mmol) (307 mg, 1.0 mmol) was dissolved in pyridine (10 mL). The reaction system was replaced with argon gas. Thionyl chloride (178 mg, 1.5 mmol) was slowly added under ice bath conditions. The reaction was carried out overnight at room temperature, monitored by TLC until the reactants were fully reacted. Most of the reaction solution was concentrated, washed with a weak acid, extracted with ethyl acetate, and concentrated by column chromatography to obtain the product. LC / MS (ESI+) calcd for C 17 H 21 ClFNO2([M+H-56)) + )m / z:326.1; found 326.1.

[0209] Step 2: Synthesis of 1-(4-(3-(benzyloxy)phenoxy)prop-1-yn-1-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

[0210] 3-(benzyloxy)phenol (60 mg, 0.3 mmol), 1-(4-(3-chloropropyl-1-yn-1-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (107 mg, 0.33 mmol), and potassium carbonate (136 mg, 1.0 mmol) were dissolved in 10 mL of acetonitrile. The mixture was stirred overnight at 80 °C. After the reaction was monitored by TLC until complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 115 mg of the target compound (yield: 79%). LC / MS (ESI+) calcd for C 30 H 32 FNO4([M+H-56)) + )m / z:490.2; found 490.2.

[0211] Example 6

[0212] Step 1: Synthesis of intermediate 1-(4-(7-(benzyloxy)-3-iodo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

[0213] 1-(4-(3-(benzyloxy)phenoxy)prop-1-yn-1-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (489 mg, 1 mmol) was dissolved in 10 mL of acetonitrile, and NIS (248 mg, 1.1 mmol) was slowly added under ice bath conditions. The mixture was stirred overnight at room temperature. After the reaction was monitored by TLC until complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 504 mg of the target compound, yield: 82%. LC / MS (ESI+) calcd for C 30 H 31 FINO4([M+H-56] + )m / z:616.1;found616.1.

[0214] Step 2: Synthesis of intermediate 1-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-methylene-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

[0215] 1-(4-(7-(benzyloxy)-3-iodo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (308 mg, 0.5 mmol), (2,6-difluorophenyl)boronic acid (158 mg, 1.0 mmol), Xphos Pd G3 (42 mg, 0.05 mmol), and potassium phosphate (850 mg, 4 mmol) were dissolved in tetrahydrofuran (9 mL) and water (3 mL). The reaction mixture was purged with argon and reacted overnight at 30 °C. TLC monitoring continued until the reactants were fully reacted. The mixture was filtered through diatomaceous earth and column chromatography yielded 195 mg of product. The yield was 65%. 1 H NMR (400MHz, DMSO-d6) δ7.49-7.36 (m, 4H), 7.37-7.29 (m, 2H), 7.01 (t, J = 8.0Hz, 2H), 6. 90(t,J=8.8Hz,1H),6.77-6.68(m,3H),6.64(d,J=2.4Hz,1H),6.59(dd,J=8.6,2.5Hz,1 H),5.12(s,2H),4.86(s,2H),4.09(d,J=6.3Hz,1H),3.33(d,J=1.3Hz,2H),3.26(s,6H) ,2.57(t,J=11.8Hz,2H),1.69(d,J=11.9Hz,3H),1.42-1.27(m,2H).LC / MS(ESI+)calcd for C 36 H 34 F3NO4([M+H-56)) + )m / z:602.3;found602.3.

[0216] Example 7

[0217] Step 1: Synthesis of intermediate (1-(4-(3-(benzyloxy)phenoxy)prop-1-yn-1-yl)-2-fluorophenyl)piperidin-4-yl)methanol

[0218] p-Bromoiodobenzene (1.01 g, 3 mmol), bis(triphenylphosphine)palladium dichloride (210 mg, 0.3 mmol), cuprous iodide (170 mg, 0.9 mmol), and diisopropylamine (3.03 g, 30 mmol) were dissolved in toluene (10 mL). The reaction system was argon atmosphere. 1-(benzyloxy)-3-(prop-2-yn-1-yloxy)benzene (1.43 g, 6 mmol) was slowly added under ice bath conditions. The reaction was carried out overnight at room temperature, monitored by TLC until the starting material was completely reacted. The mixture was filtered through diatomaceous earth and column chromatography yielded 1.27 g of product. Yield: 95%. LC / MS (ESI+) calcd for C 28 H28 FNO3([M+H-56)) + )m / z:446.2; found 446.2.

[0219] Step 2: Synthesize intermediate (1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)piperidin-4-yl)methanol

[0220] (445 mg, 1 mmol) of (1-(4-(3-(benzyloxy)phenoxy)prop-1-yn-1-yl)-2-fluorophenyl)piperidin-4-yl)methanol was dissolved in 10 mL of acetonitrile. NBS (196 mg, 1.1 mmol) was slowly added under ice bath conditions and stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 408 mg of the target compound (yield: 78%). LC / MS (ESI+) calcd for C 28 H 27 BrFNO3([M+H-56] + )m / z:524.1; found 524.1.

[0221] Step 3: Synthesize intermediate (1-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-methylene-4-yl)-2-fluorophenyl)piperidin-4-yl)methanol

[0222] (1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)piperidin-4-yl)methanol (262 mg, 0.5 mmol), (2,6-difluorophenyl)boronic acid (158 mg, 1.0 mmol), Xphos Pd G3 (42 mg, 0.05 mmol), and potassium phosphate (850 mg, 4 mmol) were dissolved in tetrahydrofuran (9 mL) and water (3 mL). The reaction mixture was replaced with argon gas and reacted overnight at 30 °C. TLC monitoring continued until the reactants were fully reacted. The mixture was filtered through diatomaceous earth and column chromatography yielded 172 mg of product. Yield: 62%. 1H NMR (400MHz, CDCl3-d) δ7.40 (dddd, J=12.6, 7.7, 6.3, 1.6Hz, 4H), 7.35-7.31 (m, 1H),7.16-7.09(m,1H),6.81-6.72(m,7H),6.59(d,J=2.5Hz,1H),6.49(dd,J=8.6 ,2.5Hz,1H),5.06(s,2H),4.89(s,2H),3.61-3.54(m,3H),3.48(d,J=11.0Hz,2H ),2.67(s,2H),1.85(d,J=13.0Hz,2H),1.27(d,J=7.9Hz,3H).LC / MS(ESI+)calcd for C 34 H 30 F3NO3([M+H-56)) + )m / z:558.2; found 558.2.

[0223] Example 8

[0224] Step 1: Synthesis of intermediate 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

[0225] 1-(4-(3-(benzyloxy)phenoxy)prop-1-yn-1-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (489 mg, 1 mmol) was dissolved in 10 mL of acetonitrile, and NBS (196 mg, 1.1 mmol) was slowly added under ice bath conditions with stirring overnight at room temperature. After the reaction was monitored by TLC until complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 488 mg of the target compound, yield: 86%. LC / MS (ESI+) calcd for C 30 H 31 BrFNO4([M+H-56] + )m / z:568.1;found568.1.

[0226] Step 2: Synthesis of intermediate 1-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-methylene-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine

[0227] 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (284 mg, 0.5 mmol), (2,6-difluorophenyl)boronic acid (158 mg, 1.0 mmol), Xphos Pd G3 (42 mg, 0.05 mmol), and potassium phosphate (850 mg, 4 mmol) were dissolved in tetrahydrofuran (9 mL) and water (3 mL). The reaction system was replaced with argon gas, and the reaction was carried out overnight at 30 °C. TLC monitoring continued until the reactants were completely reacted. The mixture was filtered through diatomaceous earth, and column chromatography yielded 234 mg of the product. The yield was 78%. LC / MS (ESI+) calcd for C 36 H 34 F3NO4([M+H-56)) + )m / z:602.3; found 602.3.

[0228] Example 9

[0229] The same method as in Examples 6, 7 or 8 was used for preparation, except that the corresponding raw materials were selected according to the different functional groups.

[0230] Example 10

[0231] The same method as in Examples 6, 7 or 8 was used for preparation, except that the corresponding raw materials were selected according to the different functional groups.

[0232] Example 11

[0233] The same method as in Examples 6, 7 or 8 was used for preparation, except that the corresponding raw materials were selected according to the different functional groups.

[0234] Example 12

[0235] The same method as in Examples 6, 7 or 8 was used for preparation, except that the corresponding raw materials were selected according to the different functional groups.

[0236] As can be seen from the above embodiments, the synthesis method of the present invention has a short route, high yield, and is superior to the prior art. The synthesis method of the present invention achieves excellent results, is suitable for industrial production, and has good application prospects.

Claims

a compound of any of Formula I, Formula II, or Formula IV, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystalline form thereof: A is selected from the group consisting of hydroxyl, amino, hydroxyl protected by a protecting group, amino protected by a protecting group, R A selected from H, halogen, or, A and R A to form a 5-6 membered heterocyclic ring; B is selected from substituted or unsubstituted C6-C. 10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 cycloalkyl, wherein, the substituent is selected from the group consisting of halogen; X is selected from CR X1 R X2 , O, S, SO2, NR X1 wherein R X1 and R X2 are each independently selected from H, C1-C6 alkyl; R 1 and R 2 are each independently selected from H, halogen, C1-C6alkyl; R 5 selected from hydroxyl protected by a protecting group or R 34 selected from an aldehyde group, an aldehyde group protected by a protecting group, wherein R 3 , R 4 are each independently selected from H, halogen, hydroxyl, hydroxyl protected with a protecting group, C1-C 10 alkoxy, C1-C 10 alkylsulfonyloxy; Z is selected from the group consisting of a coupling group capable of undergoing a coupling reaction under the catalysis of a transition metal. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, characterized in that: A is selected from the group consisting of hydroxyl, OBn, O t Bu; R A selected from H; B is selected from the group consisting of phenyl substituted by 1-2 F or unsubstituted; X is selected from the group consisting of CH2, O; R 1 and R 2 are each independently selected from H, F; R 5 selected from O t Bu or R 34 selected from aldehyde groups, wherein R 3 , R 4 are each independently selected from H, methoxy, Cl, hydroxy; Z is selected from Br, I, OTf, boronic acid group, C1-C 10 boronate group. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, characterized in that: the protecting group of hydroxyl is selected from the group consisting of methyl, tert-butyl, benzyl, p-methoxybenzyl, trityl, fluorenylmethyloxycarbonyl; the protecting group of amino is selected from the group consisting of benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, tert-butoxycarbonyl, nitrobenzoyl, phthaloyl, sulfonyl, tetrahydropyranyl ketone, aminomethyl benzenesulfonate; the aldehyde group protected by a protecting group is selected from the group consisting of ethylene glycol acetal, propylene glycol acetal, benzyloxymethyl acetal, allyl acetal, silyl ether-protected aldehyde group, thioacetal, 1,3-dioxolane, 1,3-dioxane, aminal ketone, dimethyl acetal. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, characterized in that, The compound of formula I is selected from: The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, characterized in that, The compound of Formula II is selected from: The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, characterized in that, The compound of Formula IV is selected from: A process for the preparation of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystalline form thereof, characterized in that, comprising at least one of steps 1 to 3: Step 1, preparing a compound represented by formula IV or formula IV-A by any one of reactions 1 to 3; Step 2, preparing a compound represented by formula II by reaction 4; Step 3, preparing a compound represented by formula I by reaction 5; The reaction 1 is the reaction of the compound shown in formula VI with the compound shown in formula VII to obtain the compound shown in formula IV: Reaction 2 is the reaction of a compound of Formula VIII with a compound of Formula IX to give a compound of Formula IV: Reaction 3 is the reaction of a compound of Formula X with a compound of Formula XI to give a compound of Formula IV-A: Reaction 4 is the reaction of a compound of Formula IV with reagent V to give a compound of Formula II: The reaction 5 is the reaction of the compound shown in the formula II with the compound shown in the formula III to obtain the compound shown in the formula I: wherein A, R A , B, X, R 1 , R 2 , R 5 , R 34 , Z are as described in any one of claims 1 to 6; X' is selected from halogen, hydroxy, C1-C 10 alkylsulfonyloxy; X" is selected from the group consisting of halogen, hydroxyl, C1-C 10 alkylsulfonyloxy, boronic acid group, C1-C 10 boronate group; X”' is selected from halogen, hydroxyl group, C1-C 10 Alkylsulfonyloxy, borate group, C1-C 10 Boronate group; the reagent V is an electrophilic halogenating reagent. The production method according to claim 7, characterized in that in the reaction 1: When X' is hydroxy, reaction 1 is carried out in the presence of an organic phosphorus reagent and an azodicarboxylate; or, when X' is halogen, hydroxy, C1-C 10 sulfonyloxy, reaction 1 is carried out in the presence of a base; the organic phosphorus reagent is selected from the group consisting of PPh3, P t at least one of Bu3or PCy3. the azodicarboxylate is selected from at least one of DIAD, DEAD or DtBAD; the base is selected from at least one of KOAc, K2CO3, KHCO3, K3PO4, K2HPO4, KH2PO4, KOOCCF3, KOPiv, K2C2O4, KPF6, K2SO4, KHSO4, tBuOK, KOH, KOMe, KOEt, NaOHCO, NaOAc, Na2CO3, NaHCO3, Na3PO4, Na2HPO4, NaH2PO4, NaOOCCF3, NaOPiv, NaOMs, Na2C2O4, NaPF6, Na2SO4, NaHSO4, NaOH, NaOMe, NaOEt, Cs2CO3, tBuONa, CsOH, Et3N, EDA, DIPEA, DABCO, DBU, Pyridine, LDA, LiHMDS, NaHMDS, KHMDS, imidazole, NaNH2 or NaH; The reaction solvent is selected from at least one of MeOH, EtOH, iPrOH, tBuOH, tAmylOH, H2O, Dioxane, THF, DME, MeCN, DMF, DMAc, DMSO, NMP, Benzene, Toluene, Xylene, Mesitylene, Chlorobenzene, H2O, HOAc, MTBE, BHT, chloroform, cyclohexane, DCM, DCE, Et2O, diglyme, EA, ethyl methyl ketone, Ethylene glycol, n-hexane, HMPA, CH3NO2 or n-pentane; The reaction temperature is 0°C-100°C. The production method according to claim 8, characterized in that In the reaction 1: the organic phosphorus reagent is selected from PPh3or P t at least one of Bu3. The azodicarboxylate is selected from DIAD; The base is selected from at least one of Cs2CO3, tBuONa or tBuOK; The reaction solvent is selected from at least one of THF, Toluene, DMF or MeCN; The reaction temperature is 0°C, 25°C or 80°C. The production method according to claim 7, characterized in that In the reaction 2: The reaction is carried out under the action of a transition metal catalyst and a base; The transition metal catalyst is selected from Pd(OAc)2, Pd(CF3CO2)2, Pd(Opiv)2, Pd(acac)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(dba)2, PdCl2, PdBr2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(phen)Cl2, Pd(phen)2(PF6)2, Pd(NH3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(P t Bu)2, (allylPdCl)2, P(t-Bu)3Pd G2, P(t-Bu)3Pd G3, Pd(PCy3)2, Pd(PCy3)2Cl2, PCy3Pd G1, PCy3Pd G2, PCy3Pd G3, Pd(MeCN)2Cl2, Pd(DIPHOS)2, XPhos Pd G1, XPhos Pd G2, XPhos Pd G3, Xphos Pd G4, tBuXPhos Pd G1, tBuXPhos Pd G2, tBuXPhos Pd G3, SPhos Pd G1, SPhos Pd G2, SPhos Pd G3, SPhos Pd G4, APhos Pd G1, APhos Pd G2, APhos Pd G3, EPhos Pd G1, EPhos Pd G2, EPhos Pd G3, EPhos Pd G4, EPhos Pd G6 TES, Xantphos Pd G1, Xantphos Pd G2, XantPhos Pd G3, XantPhos Pd G4, BrettPhos Pd G1, BrettPhos Pd G3, BrettPhos Pd G4, tBuBrettPhos Pd G1, tBuBrettPhos Pd G2, tBuBrettPhos Pd G3, RuPhos Pd G1, RuPhos Pd G2, RuPhos Pd G3, RuPhos Pd G4, Ruphos Pd(Crotyl)Cl, BINAP Pd G1, BINAP Pd G2, BINAP Pd G3, PdCl2(Amphos)2, CataCXium A Pd G1, CataCXium A Pd G2, CataCXium A Pd G3, t-BuDavePhos Pd G1, t-BuDavePhos Pd G2, t-BuDavePhos Pd G3, tBuBrettPhos Pd G6 TES, BrettPhos Pd G6 TES, AdBrettPhos Pd G1, AdBrettPhos Pd G2, AdBrettPhos Pd G3, NHC-PD(II)-IM, BEDFORD Catalyst, RockPhos Pd G1, RockPhos Pd G2, RockPhos Pd G3, MorDalphos Pd G1, MorDalphos Pd G2, MorDalphos Pd G3,Najera Catalyst II, Josiphos SL-J009-1Pd G3, PEPPSI-SIPr catalyst, Pd(A-taPhos)2, N-XantPhos Pd G3, Pd-PEPPSI-Ipr, JackiePhos Pd G3, DavePhos Pd G1, DavePhos Pd G2, DavePhos Pd G3, CuCl, CuCl2, Li2CuCl4, XantPhos-CuCl, SIPrCuCl, SIPOMeMesCuCl, IAdCuCl, CuBr, CuBr2, CuBr-SMe2, IPrCuBr, Cul, CuTc, Cu2O, CuCN, Cu(OAc)2, Cu(TFA)2, Cu(OTf)2, Cu(acac)2, Cu(CH3CN)4PF6, Cu(CH3CN)4BF4, Cu(CH3CN)4OTf, or Cu-TMEDA Catalyst; The base is selected from at least one of KOAc, K2CO3, KHCO3, K3PO4, K2HPO4, KH2PO4, KOOCCF3, KOPiv, K2C2O4, KPF6, K2SO4, KHSO4, tBuOK, KOH, KOMe, KOEt, NaOHCO, NaOAc, Na2CO3, NaHCO3, Na3PO4, Na2HPO4, NaH2PO4, NaOOCCF3, NaOPiv, NaOMs, Na2C2O4, NaPF6, Na2SO4, NaHSO4, NaOH, NaOMe, NaOEt, Cs2CO3, tBuONa, CsOH, Et3N, EDA, NaH, DIPEA, DABCO, DBU, Pyridine, LDA, LiHMDS, NaHMDS, KHMDS, imidazole or NaNH2; The reaction solvent is selected from at least one of MeOH, EtOH, iPrOH, tBuOH, tAmylOH, H2O, Dioxane, THF, DME, MeCN, DMF, DMAc, DMSO, NMP, Benzene, Toluene, Xylene, Mesitylene, Chlorobenzene, H2O, HOAc, MTBE, BHT, chloroform, cyclohexane, DCM, DCE, Et2O, diglyme, EA, ethyl methyl ketone, Ethylene glycol, n-hexane, HMPA, CH3NO2 or n-pentane; The reaction temperature is selected from -78℃ to 100℃. The production method according to claim 10, characterized in that In the reaction 2: The transition metal catalyst is selected from at least one of Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2 or CuI; The base is selected from at least one of Et3N, DIPEA or DIPA; The reaction solvent is selected from at least one of DMF, Dioxane, MeOH or Toluene; The reaction temperature is selected from 0℃ or 25℃. The production method according to claim 7, characterized in that In the reaction 3: The reaction is carried out under the action of a transition metal catalyst, a ligand and a base; The transition metal catalyst is selected from Pd(OAc)2, Pd(OAc)2, Pd(CF3CO2)2, Pd(Opiv)2, Pd(acac)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(dba)2, PdCl2, PdBr2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(phen)Cl2, Pd(phen)2(PF6)2, Pd(NH3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(P t Bu)2, (allylPdCl)2, P(t-Bu)3Pd G2, P(t-Bu)3Pd G3, Pd(PCy3)2, Pd(PCy3)2Cl2, PCy3Pd G1, PCy3Pd G2, PCy3Pd G3, Pd(MeCN)2Cl2, Pd(DIPHOS)2, XPhos Pd G1, XPhos Pd G2, XPhos Pd G3, Xphos Pd G4, tBuXPhos Pd G1, tBuXPhos Pd G2, tBuXPhos Pd G3, SPhos Pd G1, SPhos Pd G2, SPhos Pd G3, SPhos Pd G4, APhos Pd G1, APhos Pd G2, APhos Pd G3, EPhos Pd G1, EPhos Pd G2, EPhos Pd G3, EPhos Pd G4, EPhos Pd G6 TES, Xantphos Pd G1, Xantphos Pd G2, XantPhos Pd G3, XantPhos Pd G4, BrettPhos Pd G1, BrettPhos Pd G3, BrettPhos Pd G4, tBuBrettPhos Pd G1, tBuBrettPhos Pd G2, tBuBrettPhos Pd G3, RuPhos Pd G1, RuPhos Pd G2, RuPhos Pd G3, RuPhos Pd G4, Ruphos Pd(Crotyl)Cl, BINAP Pd G1, BINAP Pd G2, BINAP Pd G3, PdCl2(Amphos)2, CataCXium A Pd G1, CataCXium A Pd G2, CataCXium A Pd G3, t-BuDavePhos Pd G1, t-BuDavePhos Pd G2, t-BuDavePhos Pd G3, tBuBrettPhos Pd G6 TES, BrettPhos Pd G6 TES, AdBrettPhos Pd G1, AdBrettPhos Pd G2, AdBrettPhos Pd G3, NHC-PD(II)-IM, BEDFORD Catalyst, RockPhos Pd G1, RockPhos Pd G2, RockPhos Pd G3, MorDalphos Pd G1, MorDalphos Pd G2, MorDalphos Pd G3,at least one of Najera Catalyst II, Josiphos SL-J009-1Pd G3, PEPPSI-SIPr catalyst, Pd(A-taPhos)2, N-XantPhos Pd G3, Pd-PEPPSI-Ipr, JackiePhos Pd G3, DavePhos Pd G1, DavePhos Pd G2, DavePhos Pd G3, Cul, CuBr, CuCl, CuBr2, CuCl2, or Cu(OTf)2; The ligand is selected from at least one of PPh3, dppf, PtBu3, P(1-Adm)3, dppp, dppe, BINAP, X-phos, S-Phos, XantPhos, BrettPhos, tBuBrettPhos, DavePhos, t-BuDavePhos, RockPhos, MorDalphos, trans-N,N'-dimethylcyclohexane-1,2-diamine, 2-picolinic acid or L-proline; The transition metal catalyst and the ligand are used in a molar ratio of 1:(1-3); The base is selected from at least one of KOAc, K2CO3, KHCO3, K3PO4, K2HPO4, KH2PO4, KOOCCF3, KOPiv, K2C2O4, KPF6, K2SO4, KHSO4, tBuOK, KOH, KOMe, KOEt, NaOHCO, NaOAc, Na2CO3, NaHCO3, Na3PO4, Na2HPO4, NaH2PO4, NaOOCCF3, NaOPiv, NaOMs, Na2C2O4, NaPF6, Na2SO4, NaHSO4, NaOH, NaOMe, NaOEt, Cs2CO3, tBuONa, CsOH, Et3N, EDA, NaH, DIPEA, DABCO, DBU, Pyridine, LDA, LiHMDS, NaHMDS, KHMDS, imidazole or NaNH2; The reaction solvent is selected from at least one of MeOH, EtOH, iPrOH, tBuOH, tAmylOH, H2O, Dioxane, THF, DME, MeCN, DMF, DMAc, DMSO, NMP, Benzene, Toluene, Xylene, Mesitylene, Chlorobenzene, H2O, HOAc, MTBE, BHT, chloroform, cyclohexane, DCM, DCE, Et2O, diglyme, EA, ethyl methyl ketone, Ethylene glycol, n-hexane, HMPA, CH3NO2 or n-pentane; The reaction temperature is selected from 0℃ to 150℃; The compound of Formula X, the compound of Formula XI and the base are used in a molar ratio of (1-5):(1-5):(1-5). The production method according to claim 12, characterized in that In the reaction 3: The transition metal catalyst is selected from at least one of Pd(OAc)2, Pd(dppf)Cl2, XPhos Pd G3 or CuI; The ligand is selected from at least one of BINAP, X-phos, S-phos, XantPhos, DavePhos, trans-N,N'-dimethylcyclohexane-1,2-diamine, 2-picolinic acid or L-proline; The transition metal catalyst and the ligand are used in a molar ratio of 1:1 or 1:2; The base is selected from at least one of tBuONa, K3PO4, Cs2CO3, DIPEA, Et3N or DBU; The reaction solvent is selected from at least one of DMF, Toluene, THF or Dioxane or H2O; The reaction temperature is selected from 80°C or 110°C. The compound of Formula X, the compound of Formula XI and the base are used in a molar ratio of 1:2:2 or 2:1:

2. The production method according to claim 7, characterized in that In the reaction 4: The electrophilic halogenating agent is selected from at least one of Br2, I2, NCS, NBS, NIS or DBDMH; The reaction solvent is selected from at least one of MeCN, DMF, DMAc or THF; The reaction temperature is selected from -75°C to 40°C. The production method according to claim 14, characterized in that In the reaction 4: The electrophilic halogenating agent is selected from at least one of I2, NBS, NIS or DBDMH; The reaction solvent is selected from MeCN; The reaction temperature is selected from 0°C or 25°C. The production method according to claim 7, characterized in that In the reaction 5: The reaction is carried out in the presence of a transition metal catalyst, a ligand and a base; The transition metal catalyst is selected from at least one of a palladium catalyst, a nickel catalyst, an iron catalyst, a cobalt catalyst or a copper catalyst; The palladium catalyst is selected from Pd(OAc)2, Pd(CF3CO2)2, Pd(Opiv)2, Pd(acac)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(dba)2, PdCl2, PdBr2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(phen)Cl2, Pd(phen)2(PF6)2, Pd(NH3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(P t Bu)2, (allylPdCl)2, P(t-Bu)3Pd G2, P(t-Bu)3Pd G3, Pd(PCy3)2, Pd(PCy3)2Cl2, PCy3Pd G1, PCy3Pd G2, PCy3Pd G3, Pd(MeCN)2Cl2, Pd(DIPHOS)2, XPhos Pd G1, XPhos Pd G2, XPhos Pd G3, Xphos Pd G4, tBuXPhos Pd G1, tBuXPhos Pd G2, tBuXPhos Pd G3, SPhos Pd G1, SPhos Pd G2, SPhos Pd G3, SPhos Pd G4, APhos Pd G1, APhos Pd G2, APhos Pd G3, EPhos Pd G1, EPhos Pd G2, EPhos Pd G3, EPhos Pd G4, EPhos Pd G6 TES, Xantphos Pd G1, Xantphos Pd G2, XantPhos Pd G3, XantPhos Pd G4, BrettPhos Pd G1, BrettPhos Pd G3, BrettPhos Pd G4, tBuBrettPhos Pd G1, tBuBrettPhos Pd G2, tBuBrettPhos Pd G3, RuPhos Pd G1, RuPhos Pd G2, RuPhos Pd G3, RuPhos Pd G4, Ruphos Pd(Crotyl)Cl, BINAP Pd G1, BINAP Pd G2, BINAP Pd G3, PdCl2(Amphos)2, CataCXium A Pd G1, CataCXium A Pd G2, CataCXium A Pd G3, t-BuDavePhos Pd G1, t-BuDavePhos Pd G2, t-BuDavePhos Pd G3, tBuBrettPhos Pd G6 TES, BrettPhos Pd G6 TES, AdBrettPhos Pd G1, AdBrettPhos Pd G2, AdBrettPhos Pd G3, NHC-PD(II)-IM, BEDFORD Catalyst, RockPhos Pd G1, RockPhos Pd G2, RockPhos Pd G3, MorDalphos Pd G1, MorDalphos Pd G2, MorDalphos Pd G3,at least one of Najera Catalyst II, Josiphos SL-J009-1Pd G3, PEPPSI-SIPr catalyst, Pd(A-taPhos)2, N-XantPhos Pd G3, Pd-PEPPSI-Ipr, JackiePhos Pd G3, DavePhos Pd G1, DavePhos Pd G2, or DavePhos Pd G3; the nickel catalyst is selected from at least one of Ni(cod)2, Ni(acac)2, Ni(OAc)2, Ni(OTf)2, Ni(TFA)2, Ni(OTs)2, NiSO4, NiPF6, NiO, NiCl2, Ni(PPh3)(Cypde)Cl, Ni(DME)Cl2, Ni(dppe)Cl2, Ni(PBu3)2Cl2, Ni(PPh3)2Cl2, Ni(PPh3)3Cl, Ni(2,2’-bipy)Cl2, Ni(MeCN)Cl2, [(dppf)Ni(cinnamyl)]Cl, NiBr2, Ni(phen)Br2, Ni(2,2’-bipy)3Br2, Ni(Diglyme)Br2, Ni(PBu3)2Br2, Ni(PPh3)2Br2, Ni(PPh3)3Br, (Dtpby)NiBr2, NiF2, NiI2, Ni(2,2’-bipy)I2, Ni(PPh3)2I2, Ni(PPh3)3, Ni(PPh3)4, Ni(PPh3)2(CO)2, Ni(tBustb)3, Ni(4-Fstb)3, or Ni-(S)-BPB-Gly; FeCl2, FeCl 2· 4H2O, FeCl2(dppbz)2, Fe(dppe)Cl2, Fe(salen)Cl, FeCl2(3,5-t-Bu2-SciOPP), FeCl3, FeBr2, FeBr 2· 2H2O, FeBr3, Fe2Br 6· 3H2O, Fe(PPh3)2Br2, FeSO 4· H2O, FeSO 4· 2H2O, FeF 2· 4H2O, Fe(NO3)3, Fe(OTs)3, Fe(NO3) 3· 9H2O, Fe(acac)3, Fe(PPh3)(CO)4, [Fe(Pc)], Ethynylferrocene, 1,1'-Dibromoferrocene, Fe(PPh3)(CO)3I2, Fe(Cp*)2, Fe4[Fe(CN)6]3, Fe2MnO4, CuFeS2, FeO, Fe(OH)3, Fe2O3, or FeTiO3. The cobalt catalysts are selected from CoCl2, Co(dppf)Cl2, Co(XantPhos)Cl2, Co(PPh3)2Cl2, Co(PPh3)3Cl, Co(phen)Cl2, Co(acac)2, Co(acac)(dppbz), Co(acac)(depe), Co(acac)(depbz), Co(acac)(dppe), ( i At least one of the following: PrPNP)CoCl, CoBr2, Co(PPh3)3Br, Co-EDTA, Co(BF4)2, Co(NO3)2, Bis(hexafluoroacetylacetonato)cobalt(II), Tris(2,2,6,6-tetramethyl-3,5-heptanedionato)cobalt(III), Cobalt bis(trifluoroMethylsulfonyl)iMide or Bis(hexafluoroacetylacetonato)cobalt(II); the copper catalyst is selected from at least one of CuCl, CuCl2, Li2CuCl4, XantPhos-CuCl, SIPrCuCl, SIPOMeMesCuCl, IAdCuCl, CuBr, CuBr2, CuBr-SMe2, IPrCuBr, CuI, CuTC, Cu2O, CuCN, Cu(OAc)2, Cu(TFA)2, Cu(OTf)2, Cu(acac)2, Cu(CH3CN)4PF6, Cu(CH3CN)4BF4, Cu(CH3CN)4OTf, or Cu-TMEDA Catalyst; the amount of the transition metal catalyst used relative to the substrate is 0-100% by weight; The ligand is selected from P n Bu3, P t Bu3, PCy3, S-Phos, sSPhos, PyBroP, cataCXium A, PPh3, P(oMePh)3, P(l-Adm)3, dppp, dppe, dppb, dppf, BINAP, X-phos, tBuXPhos, Me3(OMe)tBuXPhos, XantPhos, N-Xantphos, BISBI, BrettPhos, tBuBrettPhos, AdBrettPhos, DavePhos, tBuDavePhos, Tri-2-furanylphosphine, tBuMePhos, RuPhos, JohnPhos, PhDave-Phos, JackiePhos, Amphos, RockPhos, MorDalphos, Sphos, Vphos, Cphos, 4MetBuXPhos, Tri(thiophen-2-yl)phosphine, Cyjohnphos, BIPHEPHOS, TrixiePhos, PhenCar-Phos, MePhos, BINAP, TrippyPhos, Ad-BippyPhos, Zheda-Phos, DPEPO, TETRAPHOS-II, catASium T3, SPANphos, iPrN[P(C6H4-p-Si(nBu)3)2]2, 2,2'-Bipyridine, 2,3'-Bipyridine, 2,4'-Bipyridine, 4,4'-Bipyridine, 2,2'-Bipyrazyl, (NH2)2bpy, 4,4'-Di-tert-butyl-2,2'-dipyridyl, 2,2'-Bipyridine-6,6'-dicarbonitrile, [2,2'-Bipyridine]-3,3'-dicarboxylic acid, 2,2':6',2"-Terpyridine, 1,10-Phen, IcHex-HCl, IiPr-HBF4, SIMes-HBF4, ItBu-HBF4, H8-BINAM, trans-N,N'-Dimethyl-1,2-cyclohexanediamine, (1R,2R)-N1,N1,N2,N2-Tetramethylcyclohexane-1,2-diamine, (1S,2S)-Cyclohexane-1,2-diamine, trans-1,2-Cyclohexanediamine, cis-Cyclohexane-1,2-diamine,at least one of DMCyDA, H-DL-Pro-NH2.HCl, TMCyDA, or DMEDA; the molar ratio of the transition metal catalyst to the ligand used is (1-5):(1-5); and the nickel catalyst is selected from at least one of Ni(cod)2, Ni(acac)2, Ni(OAc)2, Ni(OTf)2, Ni(TFA)2, Ni(OTs)2, NiSO4, NiPF6, NiO, NiCl2, Ni(PPh3)(Cypde)Cl, Ni(DME)Cl2, Ni(dppe)Cl2, Ni(PBu3)2Cl2, Ni(PPh3)2Cl2, Ni(PPh3)3Cl, Ni(2,2’-bipy)Cl2, Ni(MeCN)Cl2, [(dppf)Ni(cinnamyl)]Cl, NiBr2, Ni(phen)Br2, Ni(2,2’-bipy)3Br2, Ni(Diglyme)Br2, Ni(PBu3)2Br2, Ni(PPh3)2Br2, Ni(PPh3)3Br, (Dtpby)NiBr2, NiF2, NiI2, Ni(2,2’-bipy)I2, Ni(PPh3)2I2, Ni(PPh3)3, Ni(PPh3)4, Ni(PPh3)2(CO)2, Ni(tBustb)3, Ni(4-Fstb)3, or Ni-(S)-BPB-Gly; the copper catalyst is selected from at least one of CuCl, CuCl2, Li2CuCl4, XantPhos-CuCl, SIPrCuCl, SIPOMeMesCuCl, IAdCuCl, CuBr, CuBr the base is selected from at least one of KOAc, K2CO3, KHCO3, K3PO4, K2HPO4, KH2PO4, KOOC CF3, KOPiv, K2C2O4, KPF6, K2SO4, KHSO4, tBuOK, KOH, KO Me, KO Et, NaOHCO, NaOAc, Na2CO3, NaHCO3, Na3PO4, Na2HPO4, NaH2PO4, NaOOCCF3, NaOPiv, NaOMs, Na2C2O4, NaPF6, Na2SO4, NaHSO4, NaOH, NaOMe, NaOEt, Cs2CO3, tBuONa, CsOH, Et3N, EDA, NaH, DIPEA, DABCO, DBU, Pyridine, LDA, LiHMDS, NaHMDS, KHMDS, imidazole, or NaNH2; the reaction solvent is selected from at least one of MeOH, EtOH, iPrOH, tBuOH, tAmylOH, H2O, Dioxane, THF, DME, MeCN, DMF, DMAc, DMSO, NMP, Benzene, Toluene, Xylene, Mesitylene, Chlorobenzene, H2O, HOAc, MTBE, BHT, chloroform, cyclohexane, DCM, DCE, Et2O, diglyme, EA, ethyl methyl ketone, Ethylene glycol, n-hexane, HMPA, CH3NO2, or n-pentane; the reaction temperature is selected from 0 °C to 150 °C; the compound of Formula II, the compound of Formula III, and the base are used in a ratio of 1:1:10, 1:2:7, or 2:1:8 by molar ratio. The production method according to claim 16, characterized in that in the reaction 5: the transition metal catalyst is selected from at least one of XPhos Pd G2, SPhos Pd G3, or RockPhos Pd G3; the transition metal catalyst is used in a ratio of 10% by weight relative to the substrate; the ligand is selected from at least one of RockPhos, X-phos, SPhos, or DavePhos; the transition metal catalyst and the ligand are used in a ratio of 1:1 or 1:2 by molar ratio; the base is selected from at least one of KOAc, K3PO4, or Na3PO4; the reaction solvent is selected from at least one of DMF, THF, Dioxane, or H2O; the reaction temperature is selected from 30 °C, 80 °C, or 150 °C; the compound of Formula II, the compound of Formula III, and the base are in a ratio of 1:1:10, 1:2:7, or The production method according to claim 7, characterized in that Compounds of formula X are prepared by reaction 6, which is the reaction of a compound of formula VIII with a compound of formula XII to give a compound of formula X; The production method according to claim 18, characterized in that in the reaction 6: the reaction is carried out in the presence of a transition metal catalyst and a base; Transition metal catalysts are selected from Pd(OAc)2, Pd(CF3CO2)2, Pd(Opiv)2, Pd(acac)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(dba)2, PdCl2, PdBr2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(phen)Cl2, Pd(phen)2(PF6)2, Pd(NH3)2Cl2, Pd(dppf)Cl2, Pd(dtbpf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(P t Bu)2, (allylPdCl)2, P(t-Bu)3Pd G2, P(t-Bu)3Pd G3, Pd(PCy3)2, Pd(PCy3)2Cl2, PCy3Pd G1, PCy3Pd G2, PCy3Pd G3, Pd(MeCN)2Cl2, Pd(DIPHOS)2, XPhos Pd G1, XPhos Pd G2, XPhos Pd G3, Xphos Pd G4, tBuXPhos Pd G1, tBuXPhos Pd G2, tBuXPhos Pd G3, SPhos Pd G1, SPhos Pd G2, SPhos Pd G3, SPhos Pd G4, APhos Pd G1, APhos Pd G2, APhos Pd G3, EPhos Pd G1, EPhos Pd G2, EPhos Pd G3, EPhos Pd G4, EPhos Pd G6 TES, Xantphos Pd G1, Xantphos Pd G2, XantPhos Pd G3, XantPhos Pd G4, BrettPhos Pd G1, BrettPhos Pd G3, BrettPhos Pd G4, tBuBrettPhos Pd G1, tBuBrettPhos Pd G2, tBuBrettPhos Pd G3, RuPhos Pd G1, RuPhos Pd G2, RuPhos Pd G3, RuPhos Pd G4, Ruphos Pd(Crotyl)Cl, BINAP Pd G1, BINAP Pd G2, BINAP Pd G3, PdCl2(Amphos)2, CataCXium A Pd G1, CataCXium A Pd G2, CataCXium A Pd G3, t-BuDavePhos Pd G1, t-BuDavePhos Pd G2, t-BuDavePhos Pd G3, tBuBrettPhos Pd G6 TES, BrettPhos Pd G6 TES, AdBrettPhos Pd G1, AdBrettPhos Pd G2, AdBrettPhos Pd G3, NHC-PD(II)-IM, BEDFORD Catalyst, RockPhos Pd G1, RockPhos Pd G2, RockPhos Pd G3, MorDalphos Pd G1, MorDalphos Pd G2, MorDalphos Pd G3,Najera Catalyst II, Josiphos SL-J009-1Pd G3, PEPPSI-SIPr catalyst, Pd(A-taPhos)2, N-XantPhos Pd G3, Pd-PEPPSI-Ipr, JackiePhos Pd G3, DavePhos Pd G1, DavePhos Pd G2, DavePhos Pd G3, CuCl, CuCl2, Li2CuCl4, XantPhos-CuCl, SIPrCuCl, SIPOMeMesCuCl, IAdCuCl, CuBr, CuBr2, CuBr-SMe2, IPrCuBr, Cul, CuTc, Cu2O, CuCN, Cu(OAc)2, Cu(TFA)2, Cu(OTf)2, Cu(acac)2, Cu(CH3CN)4PF6, Cu(CH3CN)4BF4, Cu(CH3CN)4OTf, or Cu-TMEDA Catalyst; the base is at least one of KOAc, K2CO3, KHCO3, K3PO4, K2HPO4, KH2PO4, KOOC CF3, KOPiv, K2C2O4, KPF6, K2SO4, KHSO4, tBuOK, KOH, KO Me, KO Et, NaOHCO, NaOAc, Na2CO3, NaHCO3, Na3PO4, Na2HPO4, NaH2PO4, NaOOCCF3, NaOPiv, NaOMs, Na2C2O4, NaPF6, Na2SO4, NaHSO4, NaOH, NaOMe, NaOEt, Cs2CO3, tBuONa, CsOH, Et3N, EDA, NaH, DIPEA, DABCO, DBU, Pyridine, LDA, LiHMDS, NaHMDS, KHMDS, imidazole, or NaNH2; the solvent is at least one of MeOH, EtOH, iPrOH, tBuOH, tAmylOH, H2O, Dioxane, THF, DME, MeCN, DMF, DMAc, DMSO, NMP, Benzene, Toluene, Xylene, Mesitylene, Chlorobenzene, H2O, HOAc, MTBE, BHT, chloroform, cyclohexane, DCM, DCE, Et2O, diglyme, EA, ethyl methyl ketone, Ethylene glycol, n-hexane, HMPA, CH3NO2, or n-pentane; the reaction temperature is selected from -78 °C to 40 °C. The production method according to claim 19, characterized in that in the reaction 6: The transition metal catalyst is selected from Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(PCy3)2Cl 2, Pd(MeCN)2Cl2or CuI; the base is at least one of Et3N, DIPEA, DIPA, or DBU; the solvent is at least one of DMF, Dioxane, MeOH, or Toluene; the reaction temperature is selected from 0 °C or 25 °C. The production method according to claim 7 or 17, characterized in that The compound of formula VIII is prepared by reaction 7, which is propargylation of the compound of formula XIII with propargylating reagent to give the compound of formula VIII; wherein X'" is selected from the group consisting of halogen, hydroxyl, C1-C 10 alkylsulfonyloxy, boronic acid, C1-C 10 boronate. The production method according to claim 21, characterized in that in the reaction 7: the reaction is carried out in the presence of an organic phosphorus reagent and an azodicarboxylate, or, the reaction is carried out in the presence of a base; the organic phosphorus reagent is selected from the group consisting of PPh3, P t at least one of PPh3, P Bu3or PCy3. the azodicarboxylate is at least one of DIAD, DEAD, or DBAD; the base is selected from at least one of KOAc, K2CO3, KHCO3, K3PO4, K2HPO4, KH2PO4, KOOC CF3, KOPiv, K2C2O4, KPF6, K2SO4, KHSO4, tBuOK, KOH, KO Me, KO Et, NaOHCO, NaOAc, Na2CO3, NaHCO3, Na3PO4, Na2HPO4, NaH2PO4, NaOOCCF3, NaOPiv, NaOMs, Na2C2O4, NaPF6, Na2SO4, NaHSO4, NaOH, NaOMe, NaOEt, Cs2CO3, tBuONa, CsOH, Et3N, EDA, NaH, DIPEA, DABCO, DBU, Pyridine, LDA, LiHMDS, NaHMDS, KHMDS, imidazole, or NaNH2; the reaction solvent is selected from at least one of MeOH, EtOH, iPrOH, tBuOH, tAmylOH, H2O, Dioxane, THF, DME, MeCN, DMF, DMAc, DMSO, NMP, Benzene, Toluene, Xylene, Mesitylene, Chlorobenzene, H2O, HOAc, MTBE, BHT, chloroform, cyclohexane, DCM, DCE, Et2O, diglyme, EA, ethyl methyl ketone, Ethylene glycol, n-hexane, HMPA, CH3NO2, or n-pentane; the reaction temperature is selected from 0 °C to 100 °C. The production method according to claim 22, characterized in that in the reaction 7: the reaction is carried out in the presence of an organic phosphorus reagent and an azodicarboxylate, or the reaction is carried out in the presence of a base; The organic phosphorus reagent is selected from PPh3or P t Bu3; the azodicarboxylate is selected from at least one of DIAD; the base is selected from at least one of K2CO3, Cs2CO3, tBuONa, tBuOK, NaOH, KOH, or NaH; the reaction solvent is selected from at least one of THF, Toluene, DMF, MeCN, or acetone; the reaction temperature is selected from 0 °C, 25 °C, or 80 °C. Use of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystalline form thereof, in the manufacture of an estrogen receptor degrader or an estrogen receptor degrader intermediate.