Methods and compounds

Abstract

Useful preparation processes and intermediates for the preparation of Compound 1, which are selective estrogen receptor alpha (ER alpha) modulators / degraders (SERM / SERD), which have utility in the treatment of ER + cancers, including breast cancer, are described.

Description

This application is a divisional application of the invention patent application with the application date of February 11, 2020, application number 202080011109.9 (international application number PCT / US2020 / 017777), and name “Methods and Compounds”. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 804,391 filed on February 12, 2019. The disclosure of this prior application is considered part of the disclosure of this application, and its entirety is incorporated herein by reference. Technical Field

[0002] Useful preparation methods and intermediates for preparing Compound 1, a selective estrogen receptor alpha (ERα) modulator / degrader (SERM / SERD) with utility in treating ER+ cancers, including breast cancer, are described. Background Art

[0003] Breast cancer is the second leading cause of cancer-related death among women, with an estimated 246,660 newly diagnosed cases and 40,450 deaths in the United States alone in 2016. Breast cancer is classified into three subtypes of a heterogeneous disease based on the expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her2). Overexpression of ER is found in many breast cancer patients. ER-positive (ER+) breast cancers comprise two-thirds of all breast cancers. In addition to breast cancer, estrogen and ER are associated with, for example, ovarian cancer, colon cancer, prostate cancer, and endometrial cancer.

[0004] Compound 1 has demonstrated promising mixed activity as a selective estrogen receptor alpha (ERα) modulator / degrader (SERM / SERD) for ER+ breast cancer, acting as a SERM at low doses and a SERD at high doses. In response to the growing demand for compound 1, more efficient synthetic processes are needed to provide larger quantities of compound 1 for additional clinical studies and potential future commercial use. Summary of the invention

[0005] In certain embodiments, compounds (a)-(g) can be used to prepare the selective estrogen receptor modulators / degraders disclosed herein.

[0006] In certain aspects, the enantiomeric excess of compounds of formula (e) and (g) is >50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%. In some embodiments, the enantiomeric excess of compounds of formula (e) or (g) is >50%.

[0007] In several embodiments, methods for preparing intermediates and preparing Compound 1 are provided.

[0008] In one embodiment, a method for preparing a compound of formula (III) is provided:

[0009] Including in the presence of a base and a transition metal catalyst,

[0010] The compound of formula (I):

[0011] Reaction with a compound of formula (II):

[0012] Among them, P 1 is H or a phenol protecting group, P 2 is H, Et or an amino protecting group, X is a halogen, a transition metal or a boron-containing compound, and X' is a halogen, a transition metal-containing functional group or a boron-containing functional group, wherein X and X' are suitable for cross-coupling of compound (I) and compound (II).

[0013] In some embodiments of the method for preparing a compound of formula (III), P 1 H, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(C 1 -C 5 alkyl) 3 、Si(aryl) 2 (C 1 -C 5 alkyl) or CH 2 Aryl; P 2 is H, Et or an amino protecting group selected from the following: (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-OC 1 -C 8 alkyl, (C=O)-O-aryl, (C=O)-O-heteroaryl, (C=O)-OC 1 -C8 Alkylaryl and (C=O-(CH 2 ) n -C=O)-; X is B(OR) 2 、B(-O-(C(Ra) 2 ) n -O-), Cl, Br, I, OSO 2 CF 3 or OSO 2 (aryl); X' is B(OR) 2 、B(-O-(C(Ra) 2 ) n -O-), Cl, Br, I, OSO 2 CF 3 or OSO 2 (aryl); each R is independently H, C 1-3 Alkyl or aryl; each Ra is independently C 1-3 alkyl or aryl; and each n is independently an integer of 2 or 3, wherein when X is B(OR) 2 or B(-O-(C(Ra) 2 ) n -O-), X' is Cl, Br, I, OSO 2 CF 3 or OSO 2 (aryl).

[0014] In a related embodiment of the method for preparing a compound of formula (III), P 1 H, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl or CH 2 Aryl; P 2 is H, Et or selected from (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl or (C=O)-OC 1 -C 8 An amino protecting group of an alkylaryl group; X is B(OR) 2 and B(-O-(C(Ra) 2 ) n -O-); X' is Cl, Br, I or OSO 2 CF 3 ; R is independently H, C 1-3 Alkyl or aryl; each Ra is independently C 1-3 An alkyl group or an aryl group; n is an integer of 2 or 3.

[0015] In some embodiments of the method for preparing a compound of formula (III), P 1H, (C=O)-C 1 -C 8 Alkyl or CH 2 Aryl; P 2 is H, Et or selected from (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl and (C=O)-OC 1 -C 8 An amino protecting group of an alkyl group; X is B(OR) 2 or B(-O-(C(Ra) 2 ) n -O-); X' is Cl, Br, I or OSO 2 CF 3 ; R is H, Ra is CH 3 , and n=2.

[0016] In certain embodiments of the method of preparing a compound of formula (III), the method is performed in the presence of a transition metal catalyst comprising Pd(II), Cu(0) or Pd(0) or any combination thereof.

[0017] In a related embodiment of the method for preparing a compound of formula (III), the transition metal catalyst is selected from Pd(OAc) 2 、Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 、Pd(dppf)Cl 2 , Pd 2 (dba) 3 、Cu(0), Pd(PCy 3 ) 2 and any combination thereof.

[0018] In some embodiments of the method of preparing a compound of formula (III), the method is carried out in the presence of an inorganic base or an organic base or any combination thereof.

[0019] In some embodiments of the method for preparing a compound of formula (III), the method is carried out in the presence of an inorganic base. In some further embodiments, the inorganic base is selected from NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 、NaHCO 3 , KHCO 3 and CsHCO 3In a further embodiment, the inorganic base is KHCO 3 .

[0020] In some embodiments, the compounds of Formula (I), (II), and (III) have structures (a), (aa'), and (b).

[0021] In some aspects, methods of preparing compounds of formula (IV) are described:

[0022] The method comprises reducing a compound of formula (III) in the presence of a reducing agent:

[0023] in,

[0024] P 1 is H or a phenol protecting group, P 2 is H, Et or an amino protecting group.

[0025] In some embodiments, a method of preparing a compound of formula (IV) is described, wherein the reducing agent is H in the presence of a transition metal catalyst. 2 .

[0026] In certain embodiments, methods of preparing compounds of formula (IV) are described wherein the transition metal catalyst comprises Pd(II).

[0027] In some embodiments, a method of preparing a compound of formula (IV) is described, wherein the transition metal catalyst is Pd(OH) 2 .

[0028] In some embodiments, a method of preparing a compound of formula (IV) is described, wherein P 1 H, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(C 1 -C 5 alkyl) 3 、Si(aryl) 2 (C 1 -C 5 alkyl) or CH 2 Aryl, P 2 is H, Et or selected from (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-OC 1 -C 8alkyl, (C=O)-O-aryl, (C=O)-O-heteroaryl, (C=O)-OC 1 -C 8 Alkylaryl and -(C=O-(CH 2 ) n -C=O) amino protecting group.

[0029] In certain embodiments, a method of preparing a compound of formula (IV) is described, wherein P 1 H, (C=O)-C 1 -C 8 Alkyl or CH 2 Aryl; P 2 is Et, or is selected from (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl and (C=O)-OC 1 -C 8 Alkyl amino protecting groups.

[0030] In certain embodiments, a method of preparing a compound of formula (IV) is described, wherein P 1 CH 2 Ph, P 2 (C=O)-CH 3 .

[0031] In certain embodiments, a method of preparing a compound of formula (IV) is described, wherein P 1 For H, P 2 (C=O)-CH 3 .

[0032] In some aspects, methods of preparing compounds of formula (V) are provided:

[0033] This comprises making the compound of formula (IV):

[0034] Reacts with acids, bases, nucleophiles or reducing agents, where:

[0035] P 1 is H or a phenol protecting group; P 2 is an amino protecting group; R b It is H or Et.

[0036] In certain aspects, methods of preparing compounds of formula (V) are described, wherein P 2 (C=O)-CH 3 , R bis Et, and wherein the compound of formula (IV) is treated with a hydride-containing reducing agent. In some embodiments, the reducing agent is an inorganic reducing agent. In some embodiments, the reducing agent is an inorganic hydride-containing reducing agent. In some further embodiments, the reducing agent comprises boron or aluminum. In other embodiments, the reducing agent is a boron or aluminum hydride containing sodium, lithium or potassium. In some embodiments, the reducing agent is AlH 3 , AlH 2 Cl、AlHCl 2 , NaBH 4 、LiAlH 4 , LiBH 4 ,LiEt 3 BH, BH 3 , BH 3 .THF, CH 3 CH 2 C(O)OBH 3 Na、Zn(OAc) 2 / (EtO) 3 SiH、Mg / TiCL 4 , (HBpin) / tris(4,4-dimethyl-2-oxazolinyl)phenylborate MgMe or a combination thereof.

[0037] In some aspects, methods of preparing compounds of formula (V) are provided:

[0038] This comprises making the compound of formula (IV):

[0039] Reacts with acids, bases, nucleophiles or reducing agents, where:

[0040] P 1 is H or a phenol protecting group, P 2 (C=O)-CH 3 , R b It is H or Et.

[0041] In certain aspects, methods of preparing compounds of formula (V) are described, wherein P 2 (C=O)-CH 3 , R b is Et, and wherein the compound of formula (IV) is treated with a hydride-containing reducing agent. In some embodiments, the reducing agent is an inorganic reducing agent. In some embodiments, the reducing agent is an inorganic hydride-containing reducing agent. In some further embodiments, the reducing agent comprises boron or aluminum. In other embodiments, the reducing agent is a boron or aluminum hydride containing sodium, lithium or potassium. In some embodiments, the reducing agent is AlH 3, AlH 2 Cl、AlHCl 2 , NaBH 4 、LiAlH 4 , LiBH 4 ,LiEt 3 BH, BH 3 , BH 3 .THF, CH 3 CH 2 C(O)OBH 3 Na、Zn(OAc) 2 / (EtO) 3 SiH、Mg / TiCL 4 , (HBpin) / tris(4,4-dimethyl-2-oxazolinyl)phenylborateMgMe or a combination thereof.

[0042] In certain aspects, methods of preparing compounds of formula (V) are described, wherein P 2 (C=O)-CH 3 And R b is H, and wherein the compound of formula (IV) is treated with an acid, in some embodiments, the acid is hydrochloric acid or another protic acid.

[0043] In certain aspects, a method of preparing a compound of formula (V) is described, wherein a compound of formula (IV) is treated with an acid, a base or a nucleophile, and R b For H.

[0044] In certain aspects, methods of preparing compounds of formula (V) are described, wherein a compound according to claim (IV) is treated with an acid or a base, in some embodiments, the acid or base is in aqueous solution.

[0045] In some embodiments, P 2 is (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-OC 1 -C 8 alkyl, (C=O)-O-aryl, (C=O)-O-heteroaryl, (C=O)-OC 1 -C 8 Alkyl aryl or (C=O-(CH 2 ) n -C=O). In some embodiments, P 2 is (C=O)-CH 3 .

[0046] In some embodiments, P 1 is H, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(C 1 -C 5 alkyl) 3 、Si(aryl) 2 (C 1 -C 5 alkyl) or CH 2 In some embodiments, P 1 is H or -CH 2 -C 6 H 5 .

[0047] In other aspects, a method of increasing the enantiomeric excess of a compound of formula (VI) is described:

[0048] Including diastereomeric acid addition to form a mixture (V):

[0049] and selectively crystallizing a diastereomeric salt of formula (VI) enhanced with enantiomers, followed by removal of the base, wherein P 1 is H or a phenol protecting group, R b is H or Et. In some embodiments, the enantiomeric excess is >10%, >50%, >75%, >90%, >95%, >98%, or >99%.

[0050] In another aspect, a method of increasing the enantiomeric excess of a compound of formula (VI) is described:

[0051] comprising contacting a compound of formula (V) with a chiral acid to form an enantiomerically enriched salt,

[0052] The enantiomerically enriched salt is crystallized to release the compound of formula (VI) wherein P 1 is H or a phenol protecting group; R b It is H or Et.

[0053] In some aspects, the method for increasing the enantiomeric excess of the compound of formula (VI) is to use a (+) or (-) chiral acid selected from aspartic acid, O-acetyl-mandelic acid, cis-2-benzamidocyclohexanecarboxylic acid, 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, camphoric acid, 10-camphorsulfonic acid, trans-1,2-cyclohexanedicarboxylic acid, dibenzoyl-tartaric acid, diacetyl-tartaric acid, di-p-toluoyl-tartaric acid, N-(3,5-dinitrobenzoyl)-α-phenylglycine, diacetyl-tartaric anhydride, diacetyl-tartaric acid, glutamic acid, malic acid, mandelic acid, N-(α-methylbenzyl)phthalic acid, 2-(6-methoxy-2-naphthyl)propionic acid, pyroglutamic acid, quinic acid and tartaric acid or a combination thereof. In some embodiments, the acid is (+)-2,3-dibenzoyl-D-tartaric acid.

[0054] In some embodiments, for the method of increasing the enantiomeric excess of a compound of formula (VI); 1 H, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(C 1 -C 5 alkyl) 3 、Si(aryl) 2 (C 1 -C 5 alkyl) or CH 2 In certain embodiments, P 1 H, (C=O)-C 1 -C 8 Alkyl or CH 2 In some embodiments, P 1 Yes-CH 2 Ph or H, in some further embodiments, P 1 is H, in some embodiments, P 1 is H, and P 2 It's H.

[0055] In certain embodiments, methods of preparing compounds of formula (VII) are described:

[0056] Among them, P 1 is H or a phenol protecting group; comprising, in the presence of a reducing agent, reacting a compound of formula (f):

[0057] Reaction with a compound of formula (VI):

[0058] Among them, P 1 is H or a phenol protecting group, and Rb is H or Et. In some embodiments, P 1 is H, Rb is H.

[0059] In R b In some embodiments where H is present, the reducing agent is NaBH n (OAc) n’ ; wherein n is an integer from 1 to 3, n' is an integer from 1 to 3, and n+n'=4. In some embodiments, NaBH n (OAc) n’ is NaBH(OAc) 3 .

[0060] In certain embodiments, R b is Et and the reducing agent is an inorganic hydride-containing reducing agent. In some embodiments, the inorganic hydride-containing reducing agent comprises boron or aluminum. In further embodiments, the reducing agent is boron or aluminum hydride containing sodium, lithium or potassium. In some embodiments, the reducing agent is AlH 3 , AlH 2 Cl、AlHCl 2 , NaBH 4 、LiAlH 4 , LiBH 4 ,LiEt 3 BH, BH 3 , BH 3 .THF, CH 3 CH 2 C(O)OBH 3 Na、Zn(OAc) 2 / (EtO) 3 SiH、Mg / TiCL 4 , (HBpin) / tris(4,4-dimethyl-2-oxazolinyl)phenylborate MgMe or a combination thereof.

[0061] In some embodiments of the method of preparing a compound of formula (VII), P 1 For H.

[0062] In some embodiments of Formula (VIII), P 1 is H, the compound of formula (VIII) is compound 1.

[0063] In certain embodiments, methods of preparing compounds of formula (VIII) are described:

[0064] Including reducing the compound of formula (VII):

[0065] Among them, P 1 is H or a phenol protecting group.

[0066] In certain embodiments of the method, the reduction is carried out in AlH 3 , AlH 2 Cl、AlHCl 2 , NaBH 4 、LiAlH 4 , LiBH 4 ,LiEt 3 BH, BH 3 , BH 3 .THF, CH 3 CH 2 C(O)OBH 3 Na、Zn(OAc) 2 / (EtO) 3 SiH、Mg / TiCL 4 , (HBpin) / tris(4,4-dimethyl-2-oxazolinyl)phenylborate MgMe or a combination thereof, and in some embodiments, the method generates BH in situ. 3 In some embodiments, the reaction is carried out in the presence of NaBH 4 / I 2 in the presence of .

[0067] In some embodiments, methods of preparing compounds of formula (VIII) are described:

[0068] comprising reducing a compound of formula (VII);

[0069] Among them, P 1 is H or a phenol protecting group; and wherein the compound of formula (VII) is prepared by reductive amination of a compound of formula (VI);

[0070] Among them, R b Is Et or H, P 1 is hydrogen or a phenol protecting group; in the presence of a compound of formula (f);

[0071] wherein the compound of formula (VI) is prepared by crystallizing a mixture of diastereomeric acid addition salts of formula (V), wherein R b Is Et or H, P1 is hydrogen or a phenol protecting group;

[0072] Among them, when P 2 (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-OC 1 -C 8 alkyl, (C=O)-O-aryl, (C=O)-O-heteroaryl, (C=O)-OC 1 -C 8 Alkyl aryl or -(C=O-(CH 2 ) n -C=O), the compound of formula (V) is prepared by treating the compound of formula (IV) with an acid, a base or a nucleophile, or when P 2 (C=O)-CH 3 And among them, P 1 When is hydrogen or a phenol protecting group, the compound of formula (V) is optionally treated with a reducing agent;

[0073] Wherein, the compound of formula (IV) is prepared by reducing the compound of formula (III), wherein P 1 is H or a phenol protecting group, P 2 is H, Et or selected from (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-OC 1 -C 8 alkyl, (C=O)-O-aryl, (C=O)-O-heteroaryl, (C=O)-OC 1 -C 8 Alkylaryl and (C=O-(CH 2 ) n -C=O) amino protecting group;

[0074] Wherein, the compound of formula (III) is prepared by coupling the compound of formula (I) with the compound of formula (II), wherein P 1 is H or a phenol protecting group, and X is a halogen, a transition metal or a boron-containing compound;

[0075] In formula (II), X' is a halogen, a transition metal-containing functional group or a boron-containing functional group, P 2 is H, Et or an amino protecting group:

[0076] And wherein, the X and X' are suitable for the cross-coupling of compound (I) and compound (II).

[0077] In one aspect, a method for preparing a compound of formula (VIII) is described,

[0078] Including the reduced compound of formula (VII)

[0079] Wherein, the compound of formula (VII) is prepared by reductive amination of the compound of formula (VI)

[0080] In the presence of a compound of formula (f),

[0081] wherein the compound of formula (VI) is prepared by contacting the compound of formula (V) with a chiral acid,

[0082] Forming an enantiomerically enriched salt, crystallizing the enantiomerically enriched salt, and liberating the compound of formula (VI),

[0083] wherein the compound of formula (V) is prepared by treating the compound of formula (IV) with a reducing agent;

[0084] Wherein, the compound of formula (IV) is prepared by reducing the compound of formula (III)

[0085] The compound of formula (III) is obtained by compound of formula (I)

[0086] Coupling with a compound of formula (II) to prepare

[0087] And among them, P 1 is H or a phenol protecting group; R b is H or Et; P 2 (C=O)-CH 3 ; X is a halogen, a transition metal or a boron-containing compound; and X' is a halogen, a transition metal-containing functional group or a boron-containing functional group; and wherein X and X' are suitable for cross-coupling of compound (I) and compound (II).

[0088] In some embodiments of the method of preparing a compound of formula (VII), P 1 is H. In some embodiments of Formula (VIII), P 1 is H, and the compound of formula (VIII) is compound 1. DETAILED DESCRIPTION

[0089] Compound 1 has demonstrated promising mixed activity as a selective estrogen receptor alpha (ERα) modulator / degrader (SERM / SERD) against ER+ breast cancer, acting as a SERM at low doses and a SERD at high doses.

[0090] Due to the interest in further development of compound 1, both preclinical and clinical studies require larger quantities from innovative and efficient synthetic processes, and ultimately it is hoped that the compound will be approved for commercial use, after which even larger quantities will need to be produced. Therefore, new and more efficient synthetic methods are needed. The present invention provides new and unexpectedly improved synthetic methods that are superior to the disclosures of the prior art (see, e.g., U.S. Patent 7,612,114).

[0091] The present invention provides a general process as well as specific examples that demonstrate the efficacy of the process.

[0092] Unless otherwise indicated, the following terms used herein have the following definitions.

[0093] "Compound 1" or "RAD1901" has the following structure:

[0094] Including salts, solvates (such as hydrates) and prodrugs thereof. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is "Compound 1 dihydrochloride" or "Compound 1 dihydrochloride (·2HCl) salt" having the following structure:

[0095] A "halogen" atom is a fluorine, chlorine, bromine or iodine.

[0096] An "alkyl" group is a straight or branched, monovalent saturated hydrocarbon group optionally substituted with up to five independently selected halogen atoms, hydroxyl (-OH), methyl, ethyl or propyl ether groups (-OMe, -OEt, -OPr or -OiPR), cyano (-CN) or -NO 2 For example, C 1-5 Alkyl groups include -methyl, -ethyl, -isopropyl, -2-chloro-3-hydroxybutyl, -2-fluoro-4-nitro-pentyl and the like.

[0097] "Aryl" is a monovalent aromatic hydrocarbon radical of 6 to 20 carbon atoms (C 6 -C 20 ). Aryl includes structures such as phenyl, biphenyl, naphthyl, etc. Aryl may be optionally substituted with up to five substituents independently selected from -halogen, -C 1-6 Alkyl ether, -hydroxy, -CN, -C 1-6 Alkyl and -NO 2 .

[0098] "Heteroaryl" is a cyclic aromatic group containing 4-9 carbon atoms and 1-3 heteroatoms such as nitrogen, oxygen or sulfur. The heteroaryl can be monocyclic or bicyclic. As non-limiting examples, the heteroaryl includes but is not limited to oxazole, pyridine, quinoline, pyran, pyrrole, etc. In addition, the heteroaryl can be substituted with up to five substituents selected from the following: -halogen, -C 1-6 Alkyl ether, -hydroxy, -CN, -C 1-6 Alkyl and -NO 2 .

[0099] When as in -C 1 -C 8 When the terms are used together in alkylaryl, the separate functional groups (e.g., "C 1-8 The definitions of "alkyl" and "aryl") are each as defined separately, including, for example, substitution and branching. Thus, C 1-8 The alkylaryl group may include the alkyl group of 1-(3-chloro-nitrobutyl)-3-methylbenzene, wherein the additional point of attachment is at the end of the butyl fragment as shown below:

[0100] In the methods provided herein, reference is made to protecting groups, such as a "phenol protecting group" or an "amino protecting group." When described accordingly, one of ordinary skill in the art will understand that the specific protecting group can be selected from protecting groups known to those skilled in the art, as well as protecting groups that are different from those known to those skilled in the art but are understood to be logical extensions of those groups, and are understood or predicted to operate by the same mechanism and have similar properties to those most closely related to those known in the art. Although not wishing to be bound by the examples, protecting groups that can be used in the methods outlined herein can be found in various textbooks and are incorporated herein by reference. For example, see Protecting groups in organic synthesis (Green (Wuts), published by Wiley), Protecting groups in organic synthesis: (Post-Research Chemistry Series) (Hanson, Wiley Publishing), Protecting Group (Kocienski, Thieme Publishing).

[0101] Examples of the methods described herein are shown in Scheme 1 and are briefly described below. The vinyl bromide exemplified by compound (a') can be converted to its boron derivative (a)(2-(6-(benzyloxy)-3,4-dihydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane)) and then reacted with (aa')(N-(2-bromo-5-methoxyphenyl)-1,4-dihydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in the presence of a base. )acetamide)((N-(2-bromo-5-methoxyphenyl)acetamide)) to obtain the coupled compound (b) (N-(2-(6-(benzyloxy)-3,4-dihydronaphthalen-2-yl)-5-methoxyphenyl)acetamide) with an overall yield of >70%. Compound (b) was then treated with Pd(OH) 2 / H 2 Reduction, which both reduces the double bond and debenzylates the phenol to give (c), which is subsequently deacetylated to give compound (d) in >90% yield in two steps (b to d). Compound (d) is typically a 50:50 racemic mixture, with the desired compound having the (R)-stereoisomer at the 6-position. In this regard, it has been found that forming an acid addition salt with a suitable chiral acid (as described herein) followed by crystallization of the product is effective in increasing the chiral purity of compound (e) and related derivatives. In this example, the racemic mixture is treated with (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA, 0.5 equiv], and the desired salt is then crystallized with >90% ee and >90% theoretical yield of the desired enantiomer. The next step is the reductive amination of compound (e) with benzaldehyde (f), wherein a Schiff base is first formed between the aldehyde (f) and the aniline (e), and then reacted with NaBH(OAc) 3 The reduction yield of the crude product was >90%. This reaction reduced the Schiff base formed between the amine (e) and the benzaldehyde (f) and surprisingly also ethylated the aniline to give the desired tertiary aniline. Without wishing to be bound by theory, it is believed that acetyl transfer and the reaction of NaBH(OAc) with ethyl aniline with ethyl aniline from the amine (e) and the benzaldehyde (f) occurred. 3 The product (g) was treated with NaBH 4 / I 2 reduction, which is believed to generate BH in situ 3 , followed by Na 2 S 2 O 3After reduction work-up, the product was purified and treated with HCl (MeOH, EtOH and / or EtOAc) to give a bis-HCl salt of compound 1 in >50% yield.

[0102] Scheme 1 - Preparation of Compound 1·2HCl

[0103] Step 1 - Preparation of N-(2-(6-(benzyloxy)-3,4-dihydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (b).

[0104] A solution of (a', 1 eq) and bis(pinacolato)diboron (1.3 eq) was dissolved in 7 volumes of 1,2-dimethoxyethane (DME) and reacted with KOAc (3.1 eq) and PdCl 2 (PPh 3 ) 2 (2 mol%) and heated at 85°C. The reaction was then monitored for completion by HPLC. The solution was cooled to 20°C and treated with 25 wt% KHCO 3 (aqueous solution, 3 volumes) and 2-bromo-5-methoxyacetanilide (aa', 1 equivalent) were treated and then heated to 85°C and the reaction was monitored by HPLC to completion. The reaction was then cooled to 55°C, the mixture was filtered and the solid was washed with DME. The aqueous layer was separated and the remaining organic layer was cooled to 20°C and diluted with 6.9 volumes of water. The mixture was then stirred for ≥1 hour, the solid formed was filtered and washed with 3.1 volumes of water, and the filter cake was dried at ≤55°C. The combined solid was treated with 10 volumes of dichloromethane (DCM) and carbon (0.25 weight equivalents), the resulting mixture was stirred and heated to reflux (about 40°C) for ≥6 hours. The mixture was then cooled to 20°C, the solid was filtered, and washed with 3 volumes of DCM. The resulting filtrate solution was concentrated to 3 volumes at ≤45°C vacuum, treated with 6 volumes of ethanol (EtOH), and concentrated to 4.9 volumes at ≤45°C vacuum. An additional 6 volumes of EtOH were added and the volume was concentrated in vacuo at ≤45°C to 4.9 volumes, 1 volume of EtOH was added and cooled to 20°C, the product was collected by filtration, washed with 1 volume of EtOH and heated at ≤50°C for 3 hours. 2 The product was dried at 40 °C to give (b) with a yield of >70%.

[0105] Step 2 - Preparation of (+ / -)N-(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (c)

[0106] (b) (1 equivalent), Pd(OH) 2A solution of C / C (0.1 wt eq), THF (7 vol) and MeOH (7 vol) was heated with N 2 Purge, then use H 2 The reaction mixture was purged at 20°C under 100 psi H 2 The mixture was stirred at 20 °C for ≥ 12 h and the reaction was monitored for completion. 2 After purging the reactants, the reaction mixture was heated at 40°C for ≥1 hour, filtered and rinsed with 1.5 volumes of THF and 1.5 volumes of MeOH. The solution was concentrated to 2.4 volumes under vacuum at ≤45°C and treated with 12 volumes of EtOAc, concentrated to 2.4 volumes under vacuum at ≤45°C, treated with 12 volumes of EtOAc, concentrated to 2.4 volumes under vacuum at ≤45°C, treated with 12 volumes of EtOAc, and concentrated to 2.4 volumes under vacuum at ≤45°C, treated with 3.3 volumes of EtOAc, and the temperature was adjusted to 20°C and stirred at 20°C for ≥1 hour, the product was collected by filtration and washed with 1.4 volumes of EtOAc. If necessary, the solid can be recrystallized in MeOH / EtOAc, and the product (c) is dried at a temperature of ≤50°C. .

[0107] Step 3 - Preparation of (+ / -)6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (d)

[0108] A solution of ((c), 1 eq) in 9 volumes of MeOH and concentrated HCl (1.5 wt eq) was heated and stirred at reflux for ≥16 hours (about 65°C) and the reaction was monitored for completion. The reaction was cooled to ≤35°C and concentrated to 3.8 volumes in vacuo at ≤45°C, 3 volumes of 2-MeTHF were added and concentrated to 3.8 volumes in vacuo at ≤45°C, 3 volumes of 2-MeTHF were added and concentrated to 3.8 volumes in vacuo at ≤45°C, 12 volumes of 2-MeTHF were added, followed by 10 volumes of 1 M NaOH, followed by 1.5 wt eq of 25% KHCO 3 , while keeping the internal temperature ≤35°C. Adjust the internal temperature to 20°C and stir for ≥15 minutes. Adjust / maintain the pH between 8-10 using 1M HCl or 1M NaOH. Stop stirring, separate the aqueous layer after settling, and add 1 volume of H 2 O, stir the solution for ≥15 min, remove the water layer after settling, and add an additional volume of H 2 The organic layer was concentrated to 3 volumes under vacuum at ≤45°C, and the solution was treated with 3 volumes of heptane and stirred at 20°C for 12 hours. The solid was collected by filtration and the filter cake was rinsed with 2 volumes of heptane. The solvent was evaporated at ≤50°C to obtain the title compound (d) in a yield of >90%.

[0109] Step 4 - Preparation of compound (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (e)

[0110] A solution of 14.2 volumes of MeCN and 4.8 volumes of DCM containing 1 equivalent of (d) was heated to 40°C. (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA, 0.5 equivalent] was added and heated to reflux (about 65°C). The reactor was cooled to 50°C for about 1 hour, cooled to 40°C for about 1 hour, and cooled to 25°C for about 1 hour. The slurry was filtered and the filter cake was washed with 2 volumes of DCM. The wet filter cake was refluxed in 8 volumes of DCM (about 44°C) for ≥1 hour. The solution was cooled to 25°C at a rate of 15°C / hour and stirred at 25°C for ≥1 hour. The slurry was filtered, washed with 2 volumes of DCM, and the filter cake was slurried again with 8 volumes of DCM at ambient temperature for 1 hour, then filtered, washed with 2 volumes of DCM and dried. (The chiral purity was determined at this time, providing an enantiomeric excess value of >90%). a) Use 4.6 volumes of 25% KHCO 3 Aqueous treatment A solution containing (+)-DBTA salt, 15 volumes of water and 3 volumes of methanol was stirred at 25°C for ≥ 1 hour. The solid was collected by filtration and rinsed with 4 volumes of water. 25% KHCO 3 The pH of the aqueous layer was adjusted to ≥8 and the resulting solids were collected by filtration. The filter cake was washed with 4 volumes of water. The combined solids were added to 4 volumes of water and the resulting slurry was stirred for ≥1 hour before the solids were collected by filtration. The filter cake was washed with 4 volumes of water and 4 volumes of heptane and dried at ≤50°C to give the title compound (R)-6- (2-Amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (e). Yield was determined to be >90% and ee was determined to be >90%.

[0111] Step 5 - Preparation of (R)-N-ethyl-3-(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)propanamide (g)

[0112] A mixture containing 1 equivalent of compound (e) and 1 weight equivalent of active molecular sieves and anhydrous THF is stirred at ambient temperature for ≥2 hours. The mixture is filtered through THF-compacted celite and rinsed with 10 volumes of THF. N-ethyl-2-(4-formylphenyl)acetamide (f) (1.2 equivalents) and 7.5 volumes of heptane and DBTA (0.1%) are added to the solution and heated to reflux (about 65°C). The mixture is distilled to 10 volumes at reflux at atmospheric pressure. The completion of the reaction is monitored by TLC. 2.9 volumes of heptane and 7.1 volumes of THF are added, and the reactants are distilled to reflux 10 volumes at atmospheric pressure, and the completion of the reaction is monitored by TLC. The solution is cooled to 20°C and stirred for ≥5 hours to ensure that crystallization occurs. The solid product is collected by filtration, rinsed with 2 volumes of heptane, dissolved in 40 volumes of anhydrous THF, and washed with 4.5 equivalents of NaBH(OAc) 3 Work up. Heat the mixture to 50°C for ≥16 hours and monitor by TLC. Add another 4.5 equivalents of NaBH(OAc) 3 (If the reaction is incomplete, additional N-ethyl-2-(4-formylphenyl)acetamide (f) can be added at this point.) The reaction was cooled to 20°C and quenched with 15 volumes of 3M NaOH. The solution / mixture was stirred for ≥30 minutes and, if necessary, quenched with 9% NaHCO 3 The aqueous solution (about 14 volumes) was adjusted to pH 8-9. The aqueous layer was separated and the organic layer was concentrated to 5 volumes at ≤45°C under vacuum. The resulting solution was diluted with 10 volumes of EtOAc and concentrated to 5 volumes at ≤45°C under vacuum. The solution was treated with 10 volumes of EtOAc and 5 volumes of 5.6% NaCl solution, stirred, then settled and the aqueous layer removed. The mixture was washed with Na 2 SO 4 (4wt) was dried, filtered, and concentrated to 5 volumes at ≤45°C vacuum, treated with 10 volumes of heptanes and concentrated to 5 volumes at ≤45°C vacuum, treated with 10 volumes of heptanes and concentrated to 5 volumes at ≤45°C vacuum, then treated with 10 volumes of heptanes and concentrated to 5 volumes at ≤45°C vacuum. The solution was treated with 10 volumes of THF and dried at ≤45°C vacuum, then treated with 10 volumes of THF and dried to 5 volumes at ≤45°C vacuum, treated with 5 volumes of THF, residual heptanes were evaluated by GC (<4%), and the THF solution was used in the next reaction. The yield of the final product was determined to be >90%.

[0113] Step 6 - Preparation of (R)-6-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (Compound 1)

[0114] The reactor was charged with 7 volumes of THF and 2.5 equivalents of NaBH 4, cooled to -10°C to 0°C, and the THF solution obtained in step 6 (1 equivalent of intermediate (g)) was added to the solution while maintaining the reactor temperature ≤ 5°C. The solution was stirred while adjusting the internal temperature to -25°C. 1 equivalent of I was added to the solution. 2 1 volume of THF solution, while keeping the temperature ≤-10 ° C. The mixture was stirred at ≤-10 ° C for ≥30 minutes, then heated to reflux, stirred at reflux (about 66 ° C) for 4 hours, and the reaction was monitored by HPLC to complete. The reaction mixture was cooled to ≤5 ° C, quenched with 0.5 volumes of concentrated hydrochloric acid, while keeping the reaction mixture temperature ≤-10 ° C, and then treated with 15 volumes of water. Check the pH and adjust it to less than 1.5 as needed. The solution was then heated to reflux and distilled at atmospheric pressure until the internal temperature reached 80 ° C. The reaction mixture was cooled to 15-25 ° C, stirred for 6 hours and the solid was separated by filtration. The solid was loaded back into the reactor with 10 volumes of EtOAc and 5 volumes of 1M NaOH, and the mixture was stirred at 10-20 ° C for up to 30 minutes. Check the pH and adjust it to 8-9 as needed. Separate the organic layer and the aqueous layer, remove the aqueous layer, and wash with 10 volumes of EtOAc. Remove the aqueous layer and wash the combined organic layer with 2×5 volumes of 5% sodium thiosulfate solution. The organic layer was washed with 4×10 volumes of 1% NaCl solution. The aqueous layer was removed and the organic layer was concentrated to 3 volumes at an external temperature of up to 45°C. This was repeated three times, and the residue was dissolved in 10 volumes of EtOH and concentrated to 3 volumes at ≤45°C. 2 SO 4 The solution was dried and filtered, and the filtrate was added to a reactor where it was treated with 1 volume of EtOAc and stirred, 3.3M HCl in EtOH (1.4 volumes) was added, and the mixture was stirred at 15-25°C for ≥2 hours, then concentrated to 4.6 volumes at ≤45°C. The solution was treated with 12.4 volumes of EtOAc and stirred at 15-25°C for ≥2 hours to ensure that crystallization occurred. The solid was collected by filtration and washed with 3.1 volumes of EtOAc. The filter cake was dried at ≤50°C. The purity of the material was determined and, if necessary, recrystallized from MeOH / EtOAc. The final product had a yield of >50% and a purity of >90%. If necessary, the product can be recrystallized from EtOH / EtOAc to produce a polymorph with good stability. The present invention also relates to the following embodiments: Item 1. A compound selected from (a) to (g) Item 2. The compound according to Item 1, having formula (e) or (g), wherein the enantiomeric excess of the compound is >50%. Item 3. The compound according to Item 1, having formula (e) or (g), wherein the enantiomeric excess of the compound is > 60%. Item 4. The compound according to Item 1, having formula (e) or (g), wherein the enantiomeric excess of the compound is > 70%. Item 5. The compound according to Item 1, having formula (e) or (g), wherein the enantiomeric excess of the compound is > 80%. Item 6. The compound according to Item 1, having formula (e) or (g), wherein the enantiomeric excess of the compound is > 90%. Item 7. The compound according to Item 1, having formula (e) or (g), wherein the enantiomeric excess of the compound is > 95%. Item 8. The compound according to Item 1, having formula (e) or (g), wherein the enantiomeric excess of the compound is > 98%. Item 9. The compound according to Item 1, having formula (e) or (g), wherein the enantiomeric excess of the compound is > 99%. Item 10. A method for preparing a compound of formula (III): The method comprises reacting a compound of formula (I) in the presence of a base and a transition metal catalyst: Reaction with a compound of formula (II): in, P 1 is H or a phenol protecting group; P 2 is H, Et or an amino protecting group; X is a halogen, a transition metal, or a boron-containing compound; and X' is a halogen, a transition metal-containing functional group or a boron-containing functional group, wherein X and X' are suitable for cross-coupling of compound (I) and compound (II). Item 11. The method according to Item 10, wherein P 1 is H or selected from (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(C 1 -C 5 alkyl) 3 、Si(aryl) 2 (C 1 -C 5 alkyl) and CH 2 Protecting groups for aryl groups; P 2 H, Et, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-OC 1 -C 8 alkyl, (C=O)-O-aryl, (C=O)-O-heteroaryl, (C=O)-OC 1 -C 8 Alkyl aryl or (C=O-(CH 2 ) n -C=O)-; X is B (OR) 2 、B(-O-(C(Ra) 2 ) n -O-), Cl, Br, I, OSO 2 CF 3 or OSO 2 (aryl); X' is B (OR) 2 、B(-O-(C(Ra) 2 ) n -O-), Cl, Br, I, OSO 2 CF 3 or OSO 2 (aryl); Each R is independently H, C 1-3 Alkyl or aryl; Each Ra is independently C 1-3 an alkyl or aryl group; and Each n is independently an integer of 2 or 3, Among them, when X is B (OR) 2 or B(-O-(C(Ra) 2 ) n -O-), X' is Cl, Br, I, OSO 2 CF 3 or OSO 2 (aryl). Item 12. The method according to Item 10, wherein P 1 H, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl or CH 2 Aryl; P 2 H, Et, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl or (C=O)-OC 1 -C 8Alkyl aryl; X is B (OR) 2 or B(-O-(C(Ra) 2 ) n -O-); X' is Cl, Br, I or OSO 2 CF 3 ; R is independently H, C 1-3 Alkyl or aryl; Each Ra is independently C 1-3 an alkyl or aryl group; and n is an integer of 2 or 3. Item 13. The method according to Item 10, wherein P 1 H, (C=O)-C 1 -C 8 Alkyl or CH 2 Aryl; P 2 H, Et, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl or (C=O)-OC 1 -C 8 alkyl; X is B (OR) 2 or B(-O-(C(Ra) 2 ) n -O-); X' is Cl, Br, I or OSO 2 CF 3 ; R is H, Ra is CH 3 ;as well as n=2. Item 14. A method according to any one of Items 10-13, wherein the method is carried out in the presence of a transition metal catalyst, and the transition metal catalyst comprises Pd(II), Cu(0) or Pd(0) or any combination thereof. Item 15. The method according to any one of Items 10-14, which is carried out in the presence of a transition metal catalyst selected from Pd(OAc) 2 、Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 、Pd(dppf)Cl 2 , Pd 2 (dba) 3 、Cu(0), Pd(PCy 3 )2 and any combination thereof. Item 16. The method according to any one of Items 10 to 15, which is carried out in the presence of an inorganic base or an organic base or any combination thereof. Item 17. The method according to any one of Items 10 to 16, which is carried out in the presence of an inorganic base. Item 18. The method according to any one of Items 10-17, wherein the compounds of formula (I), (II) and (III) are (a), (aa') and (b): Item 19. A method for preparing a compound of formula (IV): The method comprises reducing a compound of formula (III) in the presence of a reducing agent: in: P 1 is H or a phenol protecting group, P 2 is H, Et or an amino protecting group. Item 20. The method according to Item 19, wherein the reducing agent is a transition metal catalyst and the reduction is carried out in H 2 In the presence of. Item 21. The method according to Item 20, wherein the transition metal catalyst contains Pd(II). Item 22. The method according to Item 21, wherein the transition catalyst is Pd(OH) 2 . Item 23. A method according to any one of Items 19-22, wherein P 1 H, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(C 1 -C 5 alkyl) 3 、Si(aryl) 2 (C 1 -C 5 alkyl) or CH 2 Aryl; and P 2 H, Et, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-OC 1 -C 8 alkyl, (C=O)-O-aryl, (C=O)-O-heteroaryl, (C=O)-OC 1 -C8 Alkyl aryl or -(C=O-(CH 2 ) n -C=O). Item 24. The method according to Item 23, wherein P 1 H, (C=O)-C 1 -C 8 Alkyl or CH 2 Aryl; and P 2 is Et, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl or (C=O)-OC 1 -C 8 alkyl. Item 25. The method according to Item 24, wherein P 1 is H; and P 2 is (C=O)-CH 3 . Item 26. A method for preparing a compound of formula (V): This comprises making the compound of formula (IV): Reacts with acids, bases, nucleophiles or reducing agents, where: P 1 is H or a phenol protecting group; P 2 is an amino protecting group; Rb is H or Et. Item 27. The method according to Item 26, wherein P 2 (C=O)-CH 3 ; Rb is H. Item 28. The method according to Item 27, wherein the compound of formula (IV) is treated with a hydride-containing reducing agent. Item 29. A method according to Item 28, wherein the hydride-containing reducing agent is an inorganic hydride-containing reducing agent. Item 30. A method according to Item 29, wherein the reducing agent containing an inorganic hydride contains boron or aluminum. Item 31. A method according to Item 30, wherein the reducing agent is boron or aluminum hydride containing sodium, lithium or potassium. Item 32. The method according to Item 26, wherein the reducing agent is AlH 3 , AlH 2 Cl、AlHCl 2 , NaBH 4 、LiAlH 4 , LiBH 4 ,LiEt 3BH, BH 3 , BH 3 .THF, CH 3 CH 2 C(O)OBH 3 Na、Zn(OAc) 2 / (EtO) 3 SiH、Mg / TiCL 4 , (HBpin) / tris(4,4-dimethyl-2-oxazolinyl)phenylborate MgMe or a combination thereof. Item 33. The method according to Item 26, wherein R b is H; and P 2 is an amino protecting group, and the compound of formula (IV) is treated with an acid, a base or a nucleophile. Item 34. The method according to Item 33, wherein the compound according to Item 33 is treated with an acid or a base. Item 35. A method according to Item 34, wherein the acid or base is in an aqueous solution. Item 36. A method for increasing the enantiomeric excess of a compound of formula (VI): comprising contacting a compound of formula (V) with a chiral acid to form an enantiomerically enriched salt, The enantiomerically enriched salt is crystallized to release the compound of formula (VI), wherein P 1 is H or a phenol protecting group; Rb is H or Et. Item 37. The method according to Item 36, wherein the enantiomeric excess of the compound of formula (VI) is >10%. Item 38. The method according to Item 36, wherein the enantiomeric excess of the compound of formula (VI) is >50%. Item 39. The method according to Item 36, wherein the enantiomeric excess of the compound of formula (VI) is >75%. Item 40. The method according to Item 36, wherein the enantiomeric excess of the compound of formula (VI) is >90%. Item 41. The method according to Item 36, wherein the enantiomeric excess of the compound of formula (VI) is >95%. Item 42. The method according to Item 36, wherein the enantiomeric excess of the compound of formula (VI) is >98%. Item 43. The method according to Item 36, wherein the enantiomeric excess of the compound of formula (VI) is >99%. Item 44. A method according to any one of Items 36-43, wherein the method uses a (+) or (-) chiral acid, and the (+) or (-) chiral acid is selected from aspartic acid, O-acetyl-mandelic acid, cis-2-benzamidocyclohexanecarboxylic acid, 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, camphoric acid, 10-camphorsulfonic acid, trans-1,2-cyclohexanedicarboxylic acid, dibenzoyl-tartaric acid, diacetyl-tartaric acid, di-p-toluoyl-tartaric acid, N-(3,5-dinitrobenzoyl)-α-phenylglycine, diacetyl-tartaric anhydride, diacetyl-tartaric acid, glutamic acid, malic acid, mandelic acid, N-(α-methylbenzyl)-o-aminobenzoic acid, 2-(6-methoxy-2-naphthyl)propionic acid, pyroglutamic acid, quinic acid and tartaric acid or a combination thereof. Item 45. The method of any one of Items 36-44, using (+)-2,3-dibenzoyl-D-tartaric acid. Item 46. A method according to any one of Items 36-45, wherein P 1 H, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(C 1 -C 5 alkyl) 3 、Si(aryl) 2 (C 1 -C 5 alkyl) or CH 2 Aryl. Item 47. A method according to any one of Items 36-46, wherein P 1 H, (C=O)-C 1 -C 8 Alkyl or CH 2 Aryl. Item 48. A method according to any one of Items 36-47, wherein P 1 -CH 2 Ph or H. Item 49. A method according to any one of Items 36-48, wherein P 1 For H. Item 50. A method for preparing a compound of formula (VII): Among them, P 1 is H or a phenol protecting group, the method comprises reacting a compound of formula (f) in the presence of a reducing agent: Reaction with a compound of formula (VI) Among them, P 1 is H or a phenol protecting group, R b It is H or Et. Item 51. The method according to Item 50, wherein the reducing agent is NaBH n (OAc) n’ ; R b is H; n is an integer of 1-3; n' is an integer of 1-3; and n+n'=4. Item 52. The method according to Item 51, wherein NaBH n (OAc) n’ is NaBH(OAc) 3 . Item 53. The method according to Item 50, wherein R b It's Et. Item 54. A method according to Item 53, wherein the reducing agent is a reducing agent containing an inorganic hydride. Item 55. A method according to Item 54, wherein the inorganic hydride-containing reducing agent comprises boron or aluminum. Item 56. A method according to Item 55, wherein the reducing agent is boron or aluminum hydride containing sodium, lithium or potassium. Item 57. The method according to Item 53, wherein the reducing agent is AlH 3 , AlH 2 Cl、AlHCl 2 , NaBH 4 、LiAlH 4 , LiBH 4 ,LiEt 3 BH, BH 3 , BH 3 .THF, CH 3 CH 2 C(O)OBH 3 Na、Zn(OAc) 2 / (EtO) 3 SiH、Mg / TiCL 4 , (HBpin) / tris(4,4-dimethyl-2-oxazolinyl)phenylborate MgMe or a combination thereof. Item 58. A method according to any one of Items 50-57, wherein P 1 For H. Item 59. A method for preparing a compound of formula (VIII): Including reducing the compound of formula (VII): Among them, P 1 is H or a phenol protecting group. Item 60. The method according to Item 59, wherein the method comprises: 3 , AlH 2 Cl、AlHCl 2 , NaBH 4 、LiAlH 4 , LiBH 4 ,LiEt 3 BH, BH 3 , BH 3 .THF, CH 3 CH 2 C(O)OBH 3 Na、Zn(OAc) 2 / (EtO) 3 SiH、Mg / TiCL 4 , (HBpin) / tris(4,4-dimethyl-2-oxazolinyl)phenylborate MgMe or a combination thereof. Item 61. The method according to Item 59, wherein the in situ generated BH 3 In the presence of. Item 62. The method according to Item 59, wherein the method comprises the following steps: 4 / I 2 In the presence of. Item 63. A method according to Item 59, wherein P 1 For H. Item 64. A method for preparing a compound of formula (VIII) Including the reduced compound of formula (VII) Wherein, the compound of formula (VII) is a compound of formula (VI) In the presence of a compound of formula (f), reductive amination is performed to obtain: wherein the compound of formula (VI) is prepared by contacting the compound of formula (V) with a chiral acid, Forming an enantiomerically enriched salt, crystallizing the enantiomerically enriched salt, and releasing the compound of formula (VI), wherein the compound of formula (V) is prepared by treating the compound of formula (IV) with a reducing agent; Wherein, the compound of formula (IV) is prepared by reducing the compound of formula (III), The compound of formula (III) is obtained by compound of formula (I) Prepared by coupling with a compound of formula (II), And among them, P 1 is H or a phenol protecting group; R b is H or Et; P 2 (C=O)-CH 3 ; X is a halogen, a transition metal or a boron-containing compound; and X' is a halogen, a transition metal-containing functional group or a boron-containing functional group; and wherein X and X' are suitable for cross-coupling of compound (I) and compound (II). Item 65. A method according to Item 64, wherein P 1 For H.

Claims

1. A compound selected from (a) to (g) 2. The compound according to claim 1, having formula (e) or (g), wherein The enantiomeric excess of the compound is >50%.

3. The compound according to claim 1, having formula (e) or (g), wherein The enantiomeric excess of the compound was > 60%.

4. The compound according to claim 1, having formula (e) or (g), wherein The enantiomeric excess of the compound was > 70%.

5. The compound according to claim 1, having formula (e) or (g), wherein The enantiomeric excess of the compound was >80%.

6. The compound according to claim 1, having formula (e) or (g), wherein The enantiomeric excess of the compound was >90%.

7. The compound according to claim 1, having formula (e) or (g), wherein The enantiomeric excess of the compound was >95%.

8. The compound according to claim 1, having formula (e) or (g), wherein The enantiomeric excess of the compound was >98%.

9. The compound according to claim 1, having formula (e) or (g), wherein The enantiomeric excess of the compound was >99%.

10. A method for preparing a compound of formula (III): The method comprises reacting a compound of formula (I) in the presence of a base and a transition metal catalyst: Reaction with a compound of formula (II): in, P1 is H or a phenol protecting group; P2 is H, Et or an amino protecting group; X is a halogen, a transition metal or a boron-containing compound; as well as X' is a halogen, a transition metal-containing functional group or a boron-containing functional group, wherein X and X' are suitable for cross-coupling of compound (I) and compound (II).

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