Methods and Compounds

Abstract

Useful methods for the preparation of compound 1, a selective estrogen receptor alpha (ERα) modulator / degrader (SERM / SERD) that has utility in the treatment of ER+ cancers such as breast cancer, and intermediates useful in the preparation of said compound are described.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 USC § 119(e) to U.S. Provisional Application No. 62 / 804,391, filed February 12, 2019. The disclosure of this prior application is considered part of the disclosure of this application and is incorporated by reference in its entirety herein.

[0002] FIELD OF THEINVENTION Described are useful methods for the preparation of, and intermediates useful in the preparation of, compound 1, a selective estrogen receptor alpha (ERα) modulator / degrader (SERM / SERD) that has utility in the treatment of ER+ cancers, such as breast cancer. [Background technology]

[0003] background Breast cancer is the second leading cause of cancer-related deaths in women, with an estimated 246,660 new cases and 40,450 deaths in the United States in 2016. Breast cancer is a heterogeneous disease classified into three subtypes 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 seen in many breast cancer patients. ER-positive (ER+) breast cancers comprise two-thirds of all breast cancers. Besides breast cancer, estrogen and ER are associated with, for example, ovarian, colon, prostate and endometrial cancers.

[0004] Compound 1 has shown 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 as a SERD at higher doses. With the growing demand for compound 1, a more efficient synthesis is needed to provide increased quantities of compound 1 for further clinical trials and potential future commercial use. Summary of the Invention

[0005] Summary of the Invention In one embodiment, compounds (a) to (g) [ka] are useful in the preparation of the selective estrogen receptor modulators / degraders described herein.

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

[0007] In some embodiments, preparation of intermediates and compound 1 [ka] Methods useful for the preparation of

[0008] In one embodiment, a compound of formula (I) in the presence of a base and a transition metal catalyst: [ka] and a compound of formula (II): [ka] comprising the reaction of a compound of formula (III) [ka] A method is provided for the preparation of a compound of the formula: In the formula, 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 group or a boron-containing group, wherein X and X' are suitable for cross-coupling compound (I) with compound (II).

[0009] In some embodiments of the process for the preparation of a compound of formula (III), 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 Aryl; P 2 is H, Et, or (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)-; X is an amino protecting group selected from B(OR) 2 , B(-O-(C(R a ) 2 ) n -O-), Cl, Br, I, OSO 2 CF 3 or OSO 2 (aryl); X' is B(OR) 2 , B(-O-(C(R a ) 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 R a is independent, C 1-3 alkyl or aryl; each n is independently an integer of 2 or 3, where X is B(OR) 2 or B(-O-(C(R a ) 2 ) n-O-); X' is Cl, Br, I, OSO 2 CF 3 or OSO 2 (aryl).

[0010] In a related embodiment of the process for the preparation of a compound of formula (III), P 1 is H, (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl or CH 2 Aryl; P 2 is H, Et, or (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl or (C=O)-OC 1 -C 8 alkylaryl; X is an amino protecting group selected from B(OR) 2 and B(-O-(C(R a ) 2 ) n -O-) and X' is Cl, Br, I or OSO 2 CF 3 R is independently H, C 1-3 alkyl or aryl; each R a is independent, C 1-3 alkyl or aryl; and n is an integer of 2 or 3.

[0011] In some embodiments of the process for the preparation of a compound of formula (III), P 1 is H, (C=O)-C 1 -C 8 Alkyl or CH 2 Aryl; P 2 is H, Et, or (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl and (C=O)-OC 1 -C 8 alkyl; X is an amino protecting group selected from B(OR) 2 or B(-O-(C(R a )2) n -O-) and X' is Cl, Br, I or OSO2 CF 3 R is H and R a CH 3 where n=2.

[0012] In certain embodiments regarding the process for the preparation of a compound of formula (III), the process is carried out in the presence of a transition metal catalyst, wherein the transition metal catalyst comprises Pd(II), Cu(O), or Pd(O), or any combination thereof.

[0013] In a related embodiment of the process for the preparation of a compound of formula (III), the transition metal catalyst is Pd(OAc) 2 , Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd(dppf)Cl 2 , Pd 2 (DBA) 3 , Cu(O) and Pd(PCy 3 ) 2 and any combination thereof.

[0014] In some embodiments of the process for the preparation of a compound of formula (III), the process is carried out in the presence of an inorganic or organic base or any combination thereof.

[0015] 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 NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , K.H.C.O. 3 and CsHCO 3 In a further embodiment, the inorganic base is selected from KHCO 3 It is.

[0016] In some embodiments, the compounds of formula (I), (II) and (III) have the structures (a), (aa') and (b): [ka] has.

[0017] In some aspects, a compound of formula (III) in the presence of a reducing agent: [ka] comprising reducing a compound of formula (IV): [ka] A method for preparing a compound of the formula: P 1 is H or a phenol protecting group, P 2 is H, Et or an amino protecting group.

[0018] In some embodiments, a method for the preparation of a compound of formula (IV) is described, wherein the reducing agent is H 2 It is.

[0019] In one embodiment, a method for preparing a compound of formula (IV) is described, wherein the transition metal catalyst comprises Pd(II).

[0020] In some embodiments, a method for preparing a compound of formula (IV) is described, wherein the transition metal catalyst is Pd(OH). 2 It is.

[0021] In some embodiments, a method for preparing a compound of formula (IV) is described, wherein 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 -C5 alkyl) or CH 2 Aryl, P 2 is H, Et, or (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).

[0022] In one embodiment, a method for preparing a compound of formula (IV) is described, wherein P 1 is H, (C=O)-C 1 -C 8 Alkyl or CH 2 Aryl; P 2 Et, or (C=O)-C 1 -C 8 Alkyl, (C=O)-aryl and (C=O)-OC 1 -C 8 The amino protecting group is selected from alkyl.

[0023] In one embodiment, a method for preparing a compound of formula (IV) is described, wherein P 1 CH 2 Ph and P 2 is (C=O)-CH 3 It is.

[0024] In one embodiment, a method for preparing a compound of formula (IV) is described, wherein P 1 is H and P 2 is (C=O)-CH 3 It is.

[0025] In some aspects, the compound of formula (IV): [ka] with an acid, base, nucleophile or reducing agent, [ka] A method for preparing a compound of the formula: P 1 is H or a phenol protecting group, P 2 is an amino protecting group, R b is H or Et.

[0026] In one aspect, a method for preparing a compound of formula (V) is described, wherein P 2 is (C=O)-CH 3 and R b is Et, and 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 still further embodiments, the reducing agent is a borohydride or aluminum 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 , B.H. 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.

[0027] In some aspects, the compound of formula (IV): [ka] with an acid, base, nucleophile or reducing agent, [ka] A method for preparing a compound of the formula: P 1 is H or a phenol protecting group, P 2 is (C=O)-CH 3 and R b is H or Et.

[0028] In one aspect, a method for preparing a compound of formula (V) is described, wherein P 2 is (C=O)-CH 3 and R b is Et, and 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 still further embodiments, the reducing agent is a borohydride or aluminum 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 , B.H. 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.

[0029] In one aspect, a method for preparing a compound of formula (V) is described, wherein P 2is (C=O)-CH 3 and R b is H, and the compound of formula (IV) is treated with an acid, in some embodiments, the acid is hydrochloric acid or another protic acid.

[0030] In one aspect, a method for preparing a compound of formula (V) is described, wherein a compound according to formula (IV) is treated with an acid, base or nucleophile to form R b is H.

[0031] In one aspect, a method of preparing a compound of formula (V) is described, wherein a compound according to claim (IV) is treated with an acid or base, in some embodiments, the acid or base is in an aqueous solution.

[0032] 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 Alkylaryl or (C=O-(CH 2 ) n In some embodiments, P 2 is (C=O)-CH 3 It is.

[0033] 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 is aryl. 1 is H or -CH 2-C 6 H 5 It is.

[0034] In yet another aspect, the mixture (V): [ka] and selectively crystallizing the enantiomerically enriched diastereomeric salt of formula (VI) followed by liberation of the base. [ka] A method for increasing the enantiomeric excess of a compound of formula (I) is described, 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%.

[0035] In another aspect, formula (V) [ka] with a chiral acid to form an enantiomerically enriched salt, crystallizing the enantiomerically enriched salt, and liberating a compound of formula (VI): [ka] A method for increasing the enantiomeric excess of a compound of formula (I) is described, wherein P 1 is H or a phenol protecting group; R b is H or Et.

[0036] In some aspects, the method of increasing the enantiomeric excess of the compound of formula (VI) uses a (+) or (-) chiral acid selected from aspartic acid, O-acetyl-mandelic acid, cis-2-benzamidocyclohexanecarboxylic acid, 1,1'-binapthyl-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)phthalamic acid, 2-(6-methoxy-2-napthyl)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.

[0037] In some embodiments, a method for increasing the enantiomeric excess of a compound of formula (VI); 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 is aryl. 1 is H, (C=O)-C 1 -C 8 Alkyl or CH 2 In some embodiments, P is aryl. 1 Ha-CH 2 In some further embodiments, P 1 is H. In some embodiments, P 1 is H and P 2 is H.

[0038] In some embodiments, a compound of formula (f) in the presence of a reducing agent: [ka] and a compound of formula (VI): [ka] comprising reacting a compound of formula (VII): [ka] (In the formula, P 1 is H or a phenol protecting group) A method for preparing a compound of formula (I) is described, wherein P 1 is H or a phenol protecting group, R b is H or Et. In some embodiments, P 1 is H and R b is H.

[0039] In some embodiments, R b is H, and the reducing agent is NaBH n (OAc) n' where 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 It is.

[0040] In one embodiment, R b is E 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 a borohydride or aluminum 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, BH3 , B.H. 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.

[0041] In some embodiments of the method for preparing a compound of formula (VII), P 1 is H.

[0042] In some embodiments of formula (VIII), P 1 is H, and the compound of formula (VIII) is compound 1.

[0043] In one embodiment, a compound of formula (VII): [ka] by reducing a compound of formula (VIII): [ka] A method for preparing a compound of formula (I) is described, wherein P 1 is H or a phenol protecting group.

[0044] In one embodiment of the method, the reduction is with AlH 3 , AlH 2 Cl, AlHCl 2 , NaBH 4 , LiAlH 4 , LiBH 4 , LiEt 3 BH, BH 3 , B.H. 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 is carried out in the presence of in situ generated BH 3 In some embodiments, the reaction is carried out in the presence of NaBH 4 / I 2 It is carried out in the presence of

[0045] In some embodiments, the formula (VII); [ka] by reducing a compound of formula (VIII): [ka] A method for preparing a compound of formula (I) is described, wherein P 1 is H or a phenol protecting group; the compound of formula (VII) has formula (f); [ka] in the presence of a compound of formula (VI); [ka] is prepared by reductive amination of a compound of formula (I), b is Et or H, P 1 is hydrogen or a phenol protecting group; The compound of formula (VI) is represented by the formula (V) [ka] wherein R is a diastereomeric acid addition salt of the mixture having b is Et or H, P 1 is hydrogen or a phenol protecting group; The compound of formula (V) has the formula (IV): [ka] Compound P 2 (C=O)-C1 -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 or -(C=O-(CH 2 ) n -C=O), an acid, base or nucleophile or optionally P 2 (C=O)-CH 3 wherein P 1 is hydrogen or a phenol protecting group; The compound of formula (IV) has the formula (III): [ka] is prepared by reduction of the compound 1 is H or a phenol protecting group, P 2 is H, Et, or (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); The compound of formula (III) has the formula (I); [ka] (In the formula, P 1 is H or a phenol protecting group, and X is a halogen, a transition metal, or a boron-containing compound, with a compound of formula (II): [ka] (wherein X' is a halogen, a transition metal-containing group, or a boron-containing group; P 2 is H, Et or an amino protecting group), where X and X' are suitable for cross-coupling of compound (I) with compound (II).

[0046] In one aspect, formula (VII) [ka] including reduction of a compound of formula (VIII) [ka] A method for preparing a compound of the formula The compound of formula (VII) has the formula (f) [ka] in the presence of a compound of formula (VI) [ka] is prepared by reductive amination of a compound of The compound of formula (VI) is represented by the formula (V) [ka] with a chiral acid to form an enantiomerically enriched salt, crystallizing the enantiomerically enriched salt and liberating a compound of formula (VI), The compound of formula (V) is represented by formula (IV) [ka] with a reducing agent; The compound of formula (IV) is represented by the formula (III) [ka] is prepared by reduction of the compound The compound of formula (III) is a compound of formula (I) [ka] and a compound of formula (II) [ka] wherein P 1 is H or a phenol protecting group; R b is H or Et; P 2 is (C=O)-CH 3 X is a halogen, a transition metal or a boron-containing compound; X' is a halogen, a transition metal-containing group or a boron-containing group; and X and X' are suitable for cross-coupling compound (I) with compound (II).

[0047] In some embodiments of the method for 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 OF THE PREFERRED EMBODIMENTS

[0048] Detailed Description of the Invention compound 1 [ka] has shown promising mixed activity as a selective estrogen receptor alpha (ERα) modulator / degrader (SERM / SERD) against breast cancer, acting as a SERM at low doses and as a SERD at high doses.

[0049] Due to the interest in further development of one of the compounds, more quantities from innovation and effective synthesis are needed for both preclinical and clinical testing, with the ultimate hope of the compound being approved for commercial use, and even more quantities are needed to be manufactured thereafter.Therefore, a new and more effective synthesis is needed.The present disclosure provides a new and unexpected improved synthesis over the prior art disclosures (see, for example, U.S. Patent No. 7,612,114).

[0050] This disclosure provides both general procedures and specific examples that demonstrate the efficacy of the procedures described.

[0051] As used herein, the following terms have the following definitions unless stated otherwise.

[0052] "Compound 1" or "RAD1901" has the following structure, including salts, solvates (e.g., hydrates) and prodrugs thereof: [ka] In some embodiments, a pharma- ceutically acceptable salt of Compound 1 has the following structure: [ka] Compound 1 dihydrochloride or compound 1 bishydrochloride (·2HCl) salt.

[0053] A "halogen" atom is fluorine, chlorine, bromine or iodine.

[0054] An "alkyl" group is an alkyl group consisting of up to five independently selected halogen atoms, hydroxyl groups (-OH), methyl, ethyl or propyl ether groups (-OMe, -OEt, -OPr or -OiPr), cyano groups (-CN) or -NO 2 is a linear or branched monovalent saturated hydrocarbon radical, optionally substituted with groups. For example, C 1-5Alkyl groups include -methyl, -ethyl, -isopropyl, -2-chloro-3-hydroxylbutyl, -2-fluoro-4-nitro-pentyl, and the like.

[0055] An "aryl" group is a group consisting of 6 to 20 carbon atoms (C 6 -C 20 Aryl is a monovalent aromatic hydrocarbon radical. Aryl includes structures such as phenyl, biphenyl, naphthyl, etc. Aryl is a substituted or unsubstituted aryl group, such as -halogen, -C 1-6 Alkyl ether, -hydroxyl, -CN, -C 1-6 Alkyl and -NO 2 It can be optionally substituted with up to five substituents independently selected from:

[0056] A "heteroaryl" group is a cyclic aromatic group containing 4-9 carbon atoms and 1-3 heteroatoms, such as nitrogen, oxygen, or sulfur. The heteroaryl group can be monocyclic or bicyclic. By way of non-limiting example, the heteroaryl includes, but is not limited to, oxazole, pyridine, quinoline, pyran, pyrrole, and the like. Additionally, the heteroaryl can include -halogen, -C 1-6 Alkyl ether, -hydroxyl, -CN, -C 1-6 Alkyl and -NO 2 It may be substituted with up to five substituents selected from:

[0057] For example -C 1 -C 8 When terms are joined, such as alkylaryl, separate functional groups (e.g., "C 1-8 The definitions for "alkyl" and "aryl" are intended to be taken separately to include, for example, substituents and branching. 1-8 The alkylaryl may include the alkyl radical of 1-(3-chloro-nitrobutyl)-3-methylbenzene, where the radical point of attachment is: [ka] As shown in Figure 1, the butyl fragment is at the end of the butyl fragment.

[0058] In the methods provided herein, reference is made to protecting groups such as "phenol protecting group" or "amino protecting group". When described as such, those skilled in the art will understand that the particular protecting group can be selected from protecting groups known to those skilled in the art, and also from protecting groups that are different from those known to those skilled in the art but are understood to be logical extensions of these groups, are understood or expected to operate by the same mechanism, and have similar performance to those most closely related to those known in the art. Without wishing to be bound by the examples, protecting groups useful in the methods outlined herein can be found in various textbooks, which are incorporated herein by reference. See, for example, Protective Groups in Organic Synthesis (Green (Wuts), Wiley Publishing), Protecting Groups in Organic Synthesis: (Postgraduate Chemistry Series) (Hanson, Wiley Publishing), Protecting Groups (Kocienski, Thieme Publishing). EXAMPLES

[0059] An example of the method described herein is shown in Scheme 1 and briefly described below. A 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 coupled with (aa') (N-(2-bromo-5-methoxyphenyl)acetamide) in the presence of base to the coupled compound (b) (N-(2-(6-(benzyloxy)-3,4-dihydronaphthalen-2-yl)-5-methoxyphenyl)acetamide) in >70% overall yield. Compound (b) can then be reacted with Pd(OH) to reduce the double bond and debenzylate the phenol. 2 / H 2to (c), which was then deacetylated to give compound (d) in a yield exceeding both steps (b-d) of >90%. Compound (d) is typically a 50:50 racemic mixture, with the desired compound having (R) stereochemistry at the 6-position. In this regard, it has been discovered that formation of an acid addition salt with a suitable chiral acid (as described herein), followed by crystallization of the product, can effectively increase the enantiopurity of compound (e) and related derivatives. In this example, the racemic mixture was treated with (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA, 0.5 equivalents], and the desired salt crystallized in >90% ee and >90% of the theoretical yield of the desired enantiomer. The next step was the reductive amination of compound (e) with benzaldehyde (f), where a Schiff base is first formed between aldehyde (f) and aniline (e), followed by NaBH(OAc) 3 This is followed by reduction with NaBH(OAc) resulting in a crude product yield of >90%. The reaction reduces the Schiff base formed between the amine (e) and benzaldehyde (f) and surprisingly also ethylates the aniline to give the desired tertiary aniline. Without wishing to be bound by theory, NaBH(OAc) 3 It is believed that acetyl transfer and reduction from the reagent occurs. The product (g) was then in situ treated with BH 3 NaBH 4 / I 2 , followed by Na 2 S 2 O 3 The product was purified and treated with HCl (MeOH, EtOH and / or EtOAc) in >50% yield of the bis-HCl salt of compound 1.

[0060] Scheme 1 – Preparation of compound 1·2HCl [ka]

[0061] Step 1 - Preparation of N-(2-(6-(benzyloxy)-3,4-dihydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (b). A solution of (a', 1 equiv.) and diboron bis(pinacolato) (1.3 equiv.) was dissolved in 7 volumes of 1,2-dimethoxyethane (DME) and treated with KOAc (3.1 equiv.) 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 diluted with 25 wt % KHCO 3 (aqueous, 3 vol) and 2-bromo-5-methoxyacetanilide (aa', 1 eq), then heated to 85° C. and monitored for completion by HPLC. The reaction was then cooled to 55° C., the mixture filtered and the solid washed with DME. The aqueous layer was separated off and the remaining organic layer was cooled to 20° C. and diluted with 6.9 vol. of water. The mixture was then stirred for ≧1 hour, the solid formed was filtered and washed with 3.1 vol. of water and the cake was dried at ≦55° C. The combined solid was treated with 10 vol. of dichloromethane (DCM) and carbon (0.25 wt eq.) and the resulting mixture was stirred and heated to reflux (approximately 40° C.) for ≧6 hours. The mixture was then cooled to 20° C. and the solid was filtered and washed with 3 vol. of DCM. The resulting filtrate was concentrated under vacuum to 3 volumes at ≦45° C., treated with 6 volumes of ethanol (EtOH) and concentrated under vacuum to 4.9 volumes at ≦45° C. An additional 6 volumes of EtOH were added and the volume was once again concentrated under vacuum to 4.9 volumes at ≦45° C., 1 volume of EtOH was added, cooled to 20° C., and the product was recovered by filtration, rinsed with 1 volume of EtOH and diluted with N 2 and drying at ≦50° C. afforded (b) in >70% yield.

[0062] Step 2 - Preparation of (+ / -)N-(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (c) (b) (1 equivalent), Pd(OH) 2 A solution of 0.1 wt eq. / C, 7 vol. THF, and 7 vol. MeOH was diluted with N 2 and then H 2 The reaction mixture was purged with H at 20° C.2 The reaction was stirred at 20° C. for ≥12 hours and monitored for completion. 2 After purging at 20° C., 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 under vacuum at ≦45° C. to 2.4 volumes, treated with 12 volumes of EtOAc, concentrated under vacuum at ≦45° C. to 2.4 volumes, treated again with 12 volumes of EtOAc, concentrated under vacuum at ≦45° C. to 2.4 volumes, treated with 3.3 volumes of EtOAc, the temperature was adjusted to 20° C., stirred at 20° C. for ≧1 hour, and the product was collected by filtration and washed with 1.4 volumes of EtOAc. If desired, the solid can be recrystallized in MeOH / EtOAc and the product (c) can be dried at a temperature of ≦50° C.

[0063] Step 3 - Preparation of (+ / -) 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronapthalen-2-ol (d) A solution of ((c), 1 equiv.) in 9 volumes of MeOH and concentrated HCl (1.5 wt equiv.) was heated and stirred at reflux for ≧16 hours (approx. 65° C.) and monitored for completion. The reaction was cooled to ≦35° C., concentrated to 3.8 volumes under vacuum at ≦45° C., charged with 3 volumes of 2-MeTHF and concentrated to 3.8 volumes under vacuum at ≦45° C., charged with 3 volumes of 2-MeTHF and concentrated to 3.8 volumes under vacuum at ≦45° C., added 12 volumes of 2-MeTHF, then 10 volumes of 1M NaOH, then 1.5 wt equiv. of 25% KHCO while maintaining an internal temperature at ≦35° C. 3 The internal temperature was adjusted to 20°C and stirred for ≥15 min. The pH was adjusted / maintained at 8-10 with 1M HCl or 1M NaOH. After stopping the stirring and settling, the aqueous phase was separated and washed with 1 volume of H 2 O was added and the solution was stirred for >15 min. After settling, the aqueous phase was removed and an additional 1 volume of H 2O was added and after standing the aqueous layer was separated. The organic layer was concentrated under vacuum to 3 volumes at ≦45° and the solution was treated with 3 volumes of heptane and stirred at 20° C. for 12 h. 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 give the title compound (d) in >90% yield.

[0064] Step 4 - Preparation of compound (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (e) 1 equivalent of (d) in 14.2 volumes of MeCN and 4.8 volumes of DCM was heated to 40° C. To this was added (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA, 0.5 equivalents] and heated to reflux (about 65° C.). The reactor was cooled to 50° C. for about 1 hour, to 40° C. for about 1 hour, and 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 for ≧1 h (about 44° C.). The solution was cooled to 25° C. at a rate of 15° C. / h and stirred at 25° C. for ≧1 h. The slurry was filtered and washed with 2 volumes of DCM, and the cake was again slurried in 8 volumes of DCM for 1 hour at ambient temperature, then filtered, washed with 2 volumes of DCM and dried. (At this point the chiral purity was assayed to give >90% enantiomeric excess).

[0065] A solution containing (+)-DBTA salt, 15 volumes of water and 3 volumes of methanol, was dissolved in 4.6 volumes of 25% KHCO 3 The solid was collected by filtration and rinsed with 4 volumes of water. 25% KHCO 3The aqueous layer was adjusted to a pH of ≧8 using hexanes and the resulting solid was collected by filtration. The filter cake was washed with 4 volumes of water. The combined solids were added to 4 volumes of water, the resulting slurry was stirred for ≧1 h, and then the solid was collected by filtration. The filter cake was washed with 4 volumes of water and 4 volumes of heptane and dried at ≦50° C. to provide the title compound (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (e). The yield was determined to be >90% and the ee was determined to be >90%.

[0066] 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) A mixture containing 1 equivalent of compound (e) along with 1 wt equivalent of activated molecular sieves and anhydrous THF was stirred at ambient temperature for ≥2 hours. The mixture was filtered through THF-packed Celite and rinsed with 10 volumes of THF. To the solution was added N-ethyl-2-(4-formylphenyl)acetamide (f) (1.2 equivalents) and 7.5 volumes of heptane and DBTA (0.1%) and heated to reflux (approximately 65° C.). The mixture was distilled at ambient reflux to 10 volumes. The reaction was monitored for completion by TLC. 2.9 volumes of heptane and 7.1 volumes of THF were added and the reaction was distilled at ambient reflux to 10 volumes and monitored for completion by TLC. The solution was cooled to 20° C. and stirred for ≥5 hours to ensure crystallization occurred. The solid product was collected by filtration, rinsed with 2 volumes of heptane, dissolved in 40 volumes of anhydrous THF and diluted with 4.5 equivalents of NaBH(OAc). 3 The mixture was heated to 50° C. for ≧16 h and monitored by TLC. An additional 4.5 equiv. of NaBH(OAc) 3 was added (at this point additional N-ethyl-2-(4-formylphenyl)acetamide (f) could be added if the reaction was not complete). The reaction was cooled to 20° C. and quenched with 15 volumes of 3M NaOH. The solution / mixture was stirred for ≧30 min and the pH was adjusted as needed with 9% aqueous NaHCO 3The aqueous solution was adjusted to 8-9 with (approximately 14 vol). The aqueous layer was separated and the organic layer was concentrated to 5 vol in vacuo at ≦45° C. The resulting solution was diluted with 10 vol EtOAc and concentrated to 5 vol in vacuo at ≦45° C. The solution was treated with 10 vol EtOAc and 5 vol 5.6% NaCl solution, stirred, then allowed to settle and the aqueous layer was removed. The mixture was diluted with Na 2 SO 4 The mixture was dried (4 wt), filtered, concentrated under vacuum at ≦45° C. to 5 volumes, treated with 10 volumes of heptane, concentrated under vacuum at ≦45° C. to 5 volumes, treated with 10 volumes of heptane, concentrated under vacuum at ≦45° C. to 5 volumes, treated with 10 volumes of heptane, concentrated under vacuum at ≦45° C. to 5 volumes. The solution was then treated with 10 volumes of THF, dried under vacuum at ≦45° C., treated with 10 volumes of THF, dried under vacuum at ≦45° C. to 5 volumes, treated with 5 volumes of THF, the residual heptane was evaporated by GC (<4%), and the THF solution was carried forward to the next reaction. The yield of the final product was determined to be >90%.

[0067] Step 6 - Preparation of (R)-6-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (Compound 1) To the reactor, add 7 volumes of THF and 2.5 equivalents of NaBH 4 and cooled to -10°C to 0°C. The solution was charged with the THF solution carried over from step 6 (1 equivalent of intermediate (g)) while maintaining the reactor temperature at ≦5°C. The solution was stirred and the internal temperature was adjusted to -25°C. 1 equivalent of I in 1 volume of THF was added while maintaining the temperature at ≦-10°C. 2was added to the solution. The mixture was stirred at ≦-10°C for ≧30 min, then heated to reflux and stirred at reflux (approximately 66°C) for 4 h and monitored by HPLC for completion. The reaction mixture was cooled to ≦5°C and quenched with 0.5 volumes of concentrated HCl while maintaining a reaction mixture temperature of ≦-10°C, then treated with 15 volumes of water. The pH was checked and adjusted to <1.5 if necessary. 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 h and the solid was isolated by filtration. The solid was charged back to the reactor along with 10 volumes of EtOAc and 5 volumes of 1M NaOH and the mixture was stirred at 10-20°C for up to 30 min. The pH was checked and adjusted to 8-9 if necessary. The organic and aqueous layers were separated and the aqueous layer was removed and washed with 10 volumes of EtOAc. The aqueous layer was removed and the combined organic layers were washed with 2x5 volumes of 5% sodium thiosulfate solution. The organic layer was washed with 4x10 volumes of 1% NaCl solution. The aqueous layer was removed and the organic layer was concentrated to 3 volumes at an external temperature up to 45°C. Three times the residue was dissolved in 10 volumes of EtOH and concentrated to 3 volumes at < 45°C. The solution was diluted with Na 2 SO 4 The mixture was dried at 50° C., filtered, and the filtrate was charged to a reactor, treated with 1 volume of EtOAc, stirred, and charged with 3.3 M HCl in EtOH (1.4 volumes), and the mixture was stirred at 15-25° C. for ≧2 hours and 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 rinsed with 3.1 volumes of EtOAc. The filter cake was dried at ≦50° C. The material can be assayed for purity and recrystallized from MeOH / EtOAc if desired. The final product yield was >50% and purity was >90%. If desired, the product can be recrystallized from EtOH / EtOAc to create polymorphs with good stability. The aspects of the present invention include the following. Item 1 (a)~(g) [ka] A compound selected from: Section 2 Item 1. The compound according to item 1, having formula (e) or (g), which is present in an enantiomeric excess of >50%. Section 3 Item 1. The compound according to item 1 having formula (e) or (g), which is present in an enantiomeric excess of >60%. Section 4 Item 1. The compound according to item 1 having formula (e) or (g), which is present in an enantiomeric excess of >70%. Section 5 Item 1. The compound according to item 1 having formula (e) or (g), which is present in an enantiomeric excess of >80%. Section 6 Item 1. The compound according to item 1, having formula (e) or (g), which is present in an enantiomeric excess of >90%. Section 7 Item 1. The compound according to item 1, having formula (e) or (g), which is present in an enantiomeric excess of >95%. Section 8 Item 1. The compound according to item 1 having formula (e) or (g), which is present in an enantiomeric excess of >98%. Section 9 Item 1. The compound according to item 1, having formula (e) or (g), which is present in an enantiomeric excess of >99%. Item 10 In the presence of a base and a transition metal catalyst, a compound of formula (I):

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Claims

1. The following compound: 【Chemistry 1】 A compound selected from:

2. 2. The compound of claim 1 having formula (g), present in an enantiomeric excess of >50%.

3. Formula (VII) 【Chemistry 2】 reduction of a compound of formula (VIII) 【Chemistry 3】 A method for preparing a compound of the formula: The compound of formula (VII) is represented by the formula (f) 【Chemistry 4】 in the presence of a compound of formula (VI) 【Chemistry 5】 is prepared by reductive amination of a compound of The compound of formula (VI) is represented by the formula (V) 【Chemistry 6】 with a chiral acid to form an enantiomerically enriched salt, crystallizing the enantiomerically enriched salt, and liberating a compound of formula (VI), The compound of formula (V) is converted to the compound of formula (IV) by the action of an acid, a base or a reducing agent. 【Chemistry 7】 is prepared by treating a compound of The compound of formula (IV) is represented by the formula (III) 【Chemistry 8】 is prepared by reduction of the compound The compound of formula (III) is represented by the formula (I) 【Chemistry 9】 and a compound of formula (II) 【Chemistry 10】 is prepared by coupling with a compound of Here, 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 aryl; R b is H; P 2 (C=O)-CH 3 and X is B(OR) 2 or B(-O-(C(R a ) 2 ) n -O-), R is independently H, C 1-3 alkyl or aryl, R a is independently C 1-3 alkyl or aryl, n is independently an integer of 2 or 3; X' is halogen, OSO 2 CF 3 or OSO 2 (aryl).

4. Formula (VII): 【Chemistry 11】 comprising reducing a compound of formula (VIII): 【Chemistry 12】 A method for preparing a compound of formula (I) comprising the steps of: 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 aryl, the compound of formula (VII) can be converted to the compound of formula (f): 【Chemistry 13】 and a compound of formula (VI): 【Chemistry 14】 wherein R b is H or Et.

5. The reduction of the compound of formula (VII) can be carried out with AlH 3 , AlH 2 Cl, AlHCl 2 , NaBH 4 , LiAlH 4 , LiBH 4 , LiEt 3 BH, BH 3 , B.H. 3 .THF, CH 3 CH 2 C(O)OBH 3 Na, Zn(OAc) 2 / (EtO) 3 SiH, Mg / TiCL 4 5. The method of claim 4, wherein the method is carried out in the presence of (HBpin) / tris(4,4-dimethyl-2-oxazolinyl)phenylborate MgMe or a combination thereof.

6. The reducing agent for the preparation of the compound of formula (VII) is NaBH(OAc) 3 The method according to claim 4, wherein

7. Formula (V) 【Chemistry 15】 with a chiral acid to form an enantiomerically enriched salt, crystallizing the enantiomerically enriched salt, and liberating the compound of formula (VI): 【Chemistry 16】 5. The method of claim 4, further comprising a method for increasing the enantiomeric excess of the compound of formula (I).

8. 8. The process of claim 7, wherein the enantiomeric excess of the compound of formula (VI) is >50%.

9. 9. The method according to claim 7 or 8, wherein a (+) or (-) chiral acid is used selected from aspartic acid, O-acetyl-mandelic acid, cis-2-benzamidocyclohexanecarboxylic acid, 1,1'-binapthyl-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)phthalamic acid, 2-(6-methoxy-2-napthyl)propionic acid, pyroglutamic acid, quinic acid and tartaric acid or a combination thereof.

10. Formula (IV): 【Chemistry 17】 with an acid, base, nucleophile or reducing agent, to produce a compound of formula (V): 【Chemistry 18】 The method further comprises the step of preparing a compound of the formula: 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 Alkylaryl or -(C=O-(CH 2 ) n -C=O) and n is independently an integer of 2 or 3.

11. 11. The process of claim 10, wherein the compound of formula (IV) is treated with a hydride-containing reducing agent.

12. R b is H; 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 Alkylaryl or -(C=O-(CH 2 ) n 11. The method of claim 10, wherein the compound according to formula (IV) is -C=O) and is treated with an acid, base or nucleophile.

13. In the presence of a reducing agent, a compound of formula (III): 【Chemistry 19】 by reducing a compound of formula (IV): 【Chemistry 20】 11. The method of claim 10, further comprising a method of preparing a compound of formula:

14. In the presence of a base and a transition metal catalyst, a compound of formula (I): 【Chemistry 21】 and a compound of formula (II): 【Chemistry 22】 comprising the reaction of a compound of formula (III): 【Chemistry 23】 The method further comprises a method for preparing a compound of the formula: X is B(OR) 2 or B(-O-(C(R a ) 2 ) n -O-), R is independently H, C 1-3 alkyl or aryl, and R a is independently C 1-3 alkyl or aryl; X' is halogen, OSO 2 CF 3 or OSO 2 14. The method of claim 13, wherein:

15. P 1 is H or (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 aryl; P 2 (C=O)-C 1 -C 8 alkyl or (C=O)-aryl; X is B(OR) 2 or B(-O-(C(R a ) 2 ) n -O-); X' is Cl, Br, I, OSO 2 CF 3 or OSO 2 (aryl), Each R is independent, H, C 1 - 3 is alkyl or aryl; Each R a became independent, C 1-3 is alkyl or aryl; 15. The method of claim 14, wherein each n is independently an integer of 2 or 3.

16. 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.

17. The compounds of formula (I), (II) and (III) are, respectively, (a), (aa') and (b): 【Chemistry 24】 The method according to any one of claims 3 and 13 to 16,

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