Asymmetric Derivatization of Diols by Nucleophilic Aromatic Substitution

Abstract

Mcl-1 inhibitors, and compounds Y (variable R 1 Provided herein are methods for synthesizing intermediates such as Compound A1 and salts or solvates thereof, Compound A2 and salts and solvates thereof, and Compound A3 and salts and solvates thereof. TIFF2023540083000066.tif69170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 074,241, filed September 3, 2020, which is incorporated by reference in its entirety for all purposes as if fully set forth herein.

[0002] The present disclosure relates to (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24 ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (compound A1; AMG 176), its salts or solvates, and (1S,3'R,6'R,7'R,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-7'-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'-

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0]phenyl]-2,2-dioxa[1 ... 3,6 .0 19,24 The present invention relates to a process for the synthesis of intermediates useful for preparing pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (compound A2; AMG 397), a salt or solvate thereof. These compounds are inhibitors of myeloid cell leukemia 1 protein (Mcl-1). [Background technology]

[0003] The compound (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24 ]Pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Compound A1) is useful as an inhibitor of myeloid cell leukemia 1 (Mcl-1): [ka]

[0004] The compound (1S,3'R,6'R,7'R,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-7'-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'-

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24 ]Pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (compound A2) is useful as an inhibitor of myeloid cell leukemia 1 (Mcl-1): [ka]

[0005] One common characteristic of human cancers is overexpression of Mcl-1, which prevents cancer cells from undergoing programmed cell death (apoptosis) and allows them to survive despite extensive genetic damage.

[0006] Mcl-1 is a member of the Bcl-2 family of proteins. The Bcl-2 family includes pro-apoptotic members (such as BAX and BAK) that, upon activation, form homo-oligomers in the outer mitochondrial membrane, which leads to pore formation and release of mitochondrial contents, a step in the induction of apoptosis. Anti-apoptotic members of the Bcl-2 family (such as Bcl-2, Bcl-XL, and Mcl-1) block the activity of BAX and BAK. Other proteins (such as BID, BIM, BIK, and BAD) exhibit additional regulatory functions. Studies have shown that Mcl-1 inhibitors may be useful in the treatment of cancer. Mcl-1 is overexpressed in many cancers.

[0007] US Patent No. 9,562,061, the entirety of which is incorporated herein by reference, discloses compound A1 as an Mcl-1 inhibitor and provides a method for its preparation. However, improved synthetic methods that result in lower costs and shorter manufacturing timelines for compound A1 are desirable, particularly for commercially producing compound A1.

[0008] U.S. Patent No. 10,300,075, the entirety of which is incorporated herein by reference, discloses compound A2 as an Mcl-1 inhibitor and provides a method for its preparation. However, improved synthetic methods that result in reduced costs and reduced manufacturing timelines for compound A2 are desirable, particularly for commercially producing compound A2. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent No. 9,562,061 [Patent Document 2] U.S. Patent No. 10,300,075 Summary of the Invention [Means for solving the problem]

[0010] As used herein, compound Y: [ka] or a salt thereof, comprising the steps of: Compound (I), Compound (II) [ka] (In the formula, R 1 is CO2C 1~6 Alkyl, CO2H, CON(C 1~6 Alkyl)2, CO2Ar 1 , CO2Bn, or CN, Lg is a leaving group, and Ar 1 is C6~C 22 In one embodiment, the compound Y is a 5-12 membered heteroaryl having 1-3 ring heteroatoms selected from O, N, and S), a catalyst, and a base in a biphasic solvent system to form a compound Y. In various embodiments, the compound Y is a compound Y1. [ka] In various embodiments, compound Y may have the stereochemistry shown in [ka] It may have the stereochemistry shown in

[0011] In various embodiments, compound Y is used to prepare compound A3 [ka] or a salt or solvate thereof. In various embodiments, compound Y1 is used to synthesize compound A3A [ka] or a salt or solvate thereof. In various embodiments, compound Y is used to synthesize compound A3B [ka] Or, a salt or solvate thereof is synthesized.

[0012] In various embodiments, compound Y1 is used to prepare compound A1 [ka] Or, a salt or solvate thereof is synthesized.

[0013] In various embodiments, compound Y1 is used to prepare compound A2 [ka] Or, a salt or solvate thereof is synthesized.

[0014] Further aspects and advantages will be apparent to those skilled in the art from a consideration of the following detailed description. The following description herein includes specific embodiments, with the understanding that the disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Methods for synthesizing Mcl-1 inhibitors and corresponding Mcl-1 inhibitor intermediates are provided herein, specifically, (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (compound A1), or a salt or solvate thereof, and a method for the synthesis of (1S,3'R,6'R,7'R,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-7'-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'-

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24

[0023] In one embodiment, an intermediate that can be used in a process for synthesizing pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (compound A2), or a salt or solvate thereof, is provided: [ka]

[0016] U.S. Patent No. 9,562,061, the entirety of which is incorporated herein by reference, discloses compound A1 or a salt or solvate thereof as an Mcl-1 inhibitor and provides a method for preparing the same. U.S. Patent No. 9,562,061 also discloses compound A3A: [ka] Also disclosed are methods for synthesizing the Mcl-1 inhibitor intermediates shown below, which are used in the synthesis of

[0017] US Patent No. 10,300,075, the entirety of which is incorporated herein by reference, discloses compound A2 or its salts or solvates as Mcl-1 inhibitors and provides methods for their preparation. The disclosure of salts and solvates of compound A1 from US Patent No. 10,300,075 is incorporated by reference in its entirety. This patent also discloses methods for synthesizing macrocyclic Mcl-1 inhibitor intermediates as shown above, which are used in the synthesis of compound A3A.

[0018] In particular, the '061 patent describes methods for synthesizing compound A3, shown in Scheme 1 below, for example, at lines 55-63 of the '061 patent.

[0019] Scheme 1 - Preliminary synthesis of compound A3A [ka] The method shown above has several problems. The method of Scheme 1 requires at least seven chemical steps to reach compound A3A from the diol starting material. Furthermore, one of the steps uses a catalyst that requires custom manufacturing (referred to as "Kang catalyst" in the '061 patent). The method also has significant costs and long manufacturing timelines due to the large number of chemical steps involved in the method. Finally, the method is not atom-efficient due to the use of 2-naphthoate and dimethylacetal protecting groups.

[0020] Advantageously, the methods disclosed herein significantly reduce the cost and production timeline of compound A3A by using fewer steps and avoiding the need to manage a co-feed of Kang's catalyst. Additionally, the methods disclosed herein are more environmentally friendly, in part due to reduced solvent and reagent usage, and in part because the aryl group is directly introduced in the enantioselective step of the method.

[0021] Synthesis of Compound Y As used herein, compound Y [ka] or a salt thereof, comprising compound (I), compound (II), [ka] (R in the formula 1 is CO2C 1~6 Alkyl, CO2H, CON(C 1~6 Alkyl)2, CO2Ar 1, CO2Bn, or CN, Lg is a leaving group, and Ar 1 is C 6~22 aryl, or 5-12 membered heteroaryl containing 1-3 ring heteroatoms selected from O, N and S), a catalyst and a base in a biphasic solvent system to form compound Y. In various embodiments, compound Y is compound Y1. [ka] In some embodiments, compound Y may have the stereochemistry shown in [ka] In some embodiments, the method may include combining Compound (I), Compound (II) and the catalyst in an aprotic organic solvent prior to adding the base.

[0022] As used herein, the term "alkyl" refers to straight-chain and branched saturated hydrocarbon groups containing 1 to 22 carbon atoms, e.g., 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 4 carbon atoms. n means that the alkyl group has "n" carbon atoms. For example, C4 alkyl refers to an alkyl group having 4 carbon atoms. 1~22 Alkyl and C1-C 22Alkyl refers to alkyl groups having any number of carbon atoms, including the entire range (i.e., 1-22 carbon atoms) and all subgroups (e.g., 1-6, 2-20, 1-10, 3-15, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 carbon atoms). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), t-butyl (1,1-dimethylethyl), 3,3-dimethylpentyl, and 2-ethylhexyl. Unless otherwise specified, the alkyl group can be an unsubstituted alkyl group or a substituted alkyl group. Specific substitutions on an alkyl can be indicated by inclusion in the term, for example, "haloalkyl" indicates an alkyl group substituted with one or more (e.g., 1-10) halo; or "hydroxyalkyl" indicates an alkyl group substituted with one or more (e.g., 1-10) hydroxy.

[0023] As used herein, the term "cycloalkyl" refers to an aliphatic cyclic hydrocarbon group containing 5 to 8 carbon atoms (e.g., 5, 6, 7, or 8 carbon atoms). n means that the cycloalkyl group has "n" carbon atoms. For example, C5 cycloalkyl means that the cycloalkyl group has 5 carbon atoms in the ring. 5~8 Alkyl and C5-C8 cycloalkyl refer to cycloalkyl groups having any number of carbon atoms, including the entire range (i.e., 5-8 carbon atoms) and all subgroups (e.g., 5-6, 6-8, 7-8, 5-7, 5, 6, 7, and 8 carbon atoms). Non-limiting examples of cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise indicated, a cycloalkyl group can be an unsubstituted cycloalkyl group or a substituted cycloalkyl group. The cycloalkyl groups described herein can be separated or fused to another cycloalkyl group, a heterocycloalkyl group, an aryl group, and / or a heteroaryl group. A cycloalkyl group can be substituted or unsubstituted.

[0024] As used herein, the term "heterocycloalkyl" is defined similarly to cycloalkyl, except that the ring contains 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In particular, the term "heterocycloalkyl" refers to a ring containing a total of 3-8 atoms, of which 1, 2, 3, or 3 atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, and the remaining atoms in the ring are carbon atoms. Non-limiting examples of heterocycloalkyl groups include piperidine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, and the like. Heterocycloalkyl groups can be, for example, saturated or partially unsaturated ring systems optionally substituted with 1-3 groups independently selected from alkyl, alkenyl, OH, C(O)NH2, NH2, oxo(=O), aryl, haloalkyl, halo, and OH. Heterocycloalkyl groups can be optionally further N-substituted with alkyl, hydroxyalkyl, alkylene-aryl, and alkylene-heteroaryl. The heterocycloalkyl groups described herein can be separated or fused to another heterocycloalkyl group, a cycloalkyl group, an aryl group, and / or a heteroaryl group. When a heterocycloalkyl group is fused to another heterocycloalkyl group, each of the heterocycloalkyl groups can contain a total of 3 to 8 ring atoms and 1 to 3 heteroatoms. In some embodiments, the heterocycloalkyl groups described herein contain one oxygen ring atom (e.g., oxiranyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl).

[0025] As used herein, the term "aryl" refers to a monocyclic or polycyclic (e.g., fused bicyclic and fused tricyclic) carbocyclic aromatic ring system having 6 to 22 ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl, indanyl, indenyl, anthracenyl, and fluorenyl. Unless otherwise indicated, an aryl group can be an unsubstituted aryl group or a substituted aryl group.

[0026] "Bn" refers to a benzyl group, CH2phenyl, where the phenyl may be optionally substituted.

[0027] As used herein, the term "heteroaryl" refers to a cyclic aromatic ring having a total of 5-12 ring atoms (e.g., a monocyclic aromatic ring having a total of 5-6 ring atoms) and containing 1-3 heteroatoms in the aromatic ring selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted with one or more (e.g., 1-4) substituents selected from, for example, halo, alkyl, alkenyl, OCF3, NO2, CN, NC, OH, alkoxy, amino, CO2H, CO2 alkyl, aryl, and heteroaryl. Optionally, the heteroaryl group is substituted with one or more alkyl and alkoxy groups. Heteroaryl groups can be isolated (e.g., pyridyl) or fused to another heteroaryl group (e.g., purinyl), a cycloalkyl group (e.g., tetrahydroquinolinyl), a heterocycloalkyl group (e.g., dihydronaphthyridinyl), and / or an aryl group (e.g., benzothiazolyl and quinolyl). Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl. When a heteroaryl group is fused to another heteroaryl group, each ring can contain a total of 5 or 6 ring atoms and 1 to 3 heteroatoms in the aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted.

[0028] As used herein, the term "heterocycle" means either heteroaryl or heterocycloalkyl.

[0029] In general, R 1 is CO2C1~6 Alkyl, CO2H, CON(C 1~6 alkyl), COAr, COB, or CN. In some embodiments, R 1 is CO2C 1~6 Alkyl, CO2H, or CO2Ar 1 In some embodiments, R 1 is COH. In some embodiments, R 1 CO2C 1~6 In some embodiments, R 1 CO2Ar 1 In some embodiments, R 1 is COMe, COEt, COiPr, COnPr, COtBu, COnBu, COsecBu, COBn, or COPh. 1 is COMe, COEt, COiPr, or COtBu. 1 is COMe. In some embodiments, R 1 is CO2Ph. In some embodiments, R 1 In some embodiments, R is CO2Bn. In some embodiments, R is CO2CH2(p-OMeC6H4). 1 is CN.

[0030] Generally, Lg is a leaving group. As used herein, a leaving group refers to any suitable atom or functional group that can be displaced by a nucleophile during nucleophilic aromatic substitution. Non-limiting examples of suitable leaving groups include halides (e.g., F, Cl, Br, or I) or sulfonyl. In some embodiments, the leaving group is F.

[0031] In some embodiments, Lg is a sulfonyl leaving group. As used herein, the term "sulfonyl leaving group" refers to a leaving group represented by -SO2R', where R' can be alkyl, aryl, haloalkyl, heteroaryl, etc. In some embodiments, the sulfonyl leaving group is selected from the group consisting of mesyl (SO2Me), tosyl (SO2tolyl), nosyl (SO2-nitrophenyl), and triflyl (SO2CF3). In some embodiments, the sulfonyl leaving group comprises mesyl.

[0032] Typically, compound (II) is present in an amount of 0.9 to 2 molar equivalents based on 1.0 molar equivalent of compound (I). In some embodiments, compound (II) is present in an amount of 1 to 2 molar equivalents, 1 to 1.5 molar equivalents, or 1 to 1.2 molar equivalents based on 1.0 molar equivalent of compound (I). In some embodiments, compound (II) is present in an amount of 1 molar equivalent based on 1.0 molar equivalent of compound (I).

[0033] In general, the catalyst can be any moiety that aids in the coupling of compounds (I) and (II), for example, by reducing the activation energy, by increasing the rate, by increasing the yield, by increasing the purity profile, by increasing the enantiomeric purity of the product, by reducing the required reaction temperature, or by any other method that facilitates the formation of compound (Y), which can be used in substoichiometric quantities, although not always. In some embodiments, the catalyst is an asymmetric catalyst. In some embodiments, the asymmetric catalyst can have the following structure: [ka] (In the formula, each R 2 is independently 1~22 Alkyl, C 5~8 Cycloalkyl or Ar 1 or each R 2 together with the atom to which it is attached, forms a 5- to 8-membered cycloalkyl; each R3 is independently 1~22 Alkyl, C 5~8 Cycloalkyl, Bn, or Ar 1 or two R 3 together with the nitrogen to which it is attached, form a 5-25 membered heterocycle containing 0-1 additional ring heteroatoms selected from N, O and S; X is OH, NR N C(O)R N , C(O)N(R N )2, N(R N )2, C 1~6 Haloalkyl, SH, SC 1~6 Alkyl, NHSO2Ar 1 , NHSO2C 1~6 Alkyl, NHSOC 1~6 Alkyl, or NHSOAr 1 and each R N are independently H, C 1~12 Alkyl or Ar 1 and Z is a counterion.) In some embodiments, the asymmetric catalyst can have the structure: [ka] In some embodiments, the asymmetric catalyst may have the structure: [ka] In some embodiments, the asymmetric catalyst may have the structure: [ka]

[0034] In general, each R 2 are independent, C1~C 22 Alkyl, C5-C8 cycloalkyl or Ar 1 or two R 2 together with the atom to which it is attached form a 5-8 membered cycloalkyl. In some embodiments, at least one R 2 is C1~C 22In some embodiments, at least one R 2 is C5-C8 cycloalkyl. In some embodiments, at least one R 2 Ar 1 In some embodiments, two R 2 together with the atom to which it is attached form a 5- to 8-membered cycloalkyl. 2 are independently Me, Et, iPr, sBu, tBu, phenyl, tolyl, [ka] or each R 2 together with the atom to which it is attached forms a cyclohexyl or cyclopentyl.

[0035] Generally, X is OH, NR N C(O)R N , C(O)N(R N )2, N(R N )2, C 1~6 Haloalkyl, SH, SC 1~6 Alkyl, NHSO2Ar 1 , NHSO2C 1~6 Alkyl, NHSOC 1~6 Alkyl, or NHSOAr 1 In some embodiments, X is OH [ka] , -NH-SO2Me, -NH-SO2(tolyl), -NH-SO2(nitrophenyl), [ka] , -CF2H, -SH, -NH2, -NHMe, -NHPh, [ka] In some embodiments, X is OH. In some embodiments, X is SH. In some embodiments, X is NHSO2(C 1~6In some embodiments, X is NHSOAr 1 In some embodiments, X is NHSO(C 1~6 In some embodiments, X is NHSOAr 1 In some embodiments, X is NR N C(O)R N , C(O)N(R N )2, or N(R N )2 and at least one R N is H. In some embodiments, X is NR N C(O)R N , C(O)N(R N )2, or N(R N )2 and at least one R N is C 1~6 In some embodiments, X is NR N C(O)R N , C(O)N(R N )2, or N(R N )2 and at least one R N Ar 1 It is.

[0036] In general, each R 3 are independent, C1~C 22 Alkyl, C5-C8 cycloalkyl, or Ar 1 or two R 3 together with the nitrogen to which it is attached form a 5-25 membered heterocycle containing 0-1 additional ring heteroatoms selected from N, O, and S. In some embodiments, at least one R 3 is C1~C 22 In some embodiments, at least two R 3 is C1~C 22 In some embodiments, at least two R 3 Ar 1 In some embodiments, two R 3together with the nitrogen to which it is attached form a 5-25 membered heterocycle containing 0-1 additional ring heteroatoms selected from N, O, and S. In some embodiments, at least one R 3 is C 12 In some embodiments, the asymmetric catalyst is -NMe3 + , -NMe2Bn + , -NMeBn2 + , -NBn3 + , [ka] -N(R 3 )3 + In some embodiments, -N(R 3 )3 + teeth, [ka] It is.

[0037] In some embodiments, the asymmetric catalyst may have the structure: [ka] (In the formula, each Ar 2 is independently 6~22 aryl, or 5-12 membered heteroaryl containing 1-3 ring heteroatoms selected from N, O and S, and Z is a counterion. In some embodiments, at least one Ar 2 is phenyl or substituted phenyl. In some embodiments, at least one Ar 2 is phenyl. In some embodiments, each Ar 2 is phenyl. In some embodiments, at least one Ar 2 is substituted phenyl. In some embodiments, each Ar 2 is a substituted phenyl. In some embodiments, the substituted phenyl is independently selected from the group consisting of C 1~4 Alkyl, CF3, Cl, Br, F, and OC 1~4In some embodiments, at least one Ar may include one or two substituents selected from alkyl. 2 is anthracenyl. In some embodiments, each Ar 2 is, independently, [ka] and Ph.

[0038] In some embodiments, the asymmetric catalyst may have the structure: [ka] (In the formula, Ar 3 is C 6~22 aryl, or 5-12 membered heteroaryl containing 1-3 ring heteroatoms selected from O, N, and S, and Z is a counterion. In some embodiments, Ar 3 is phenyl or substituted phenyl. In some embodiments, Ar 3 is phenyl. In some embodiments, the substituted phenyl is independently selected from C 1~4 Alkyl, CF3, Cl, Br, F, and OC 1~4 In some embodiments, Ar may include one or two substituents selected from alkyl. 3 is anthracenyl. In some embodiments, each Ar 3 teeth, [ka] and Ph.

[0039] Typically, Z is a counterion. In some embodiments, Z is a halide, triflate, mesylate, tosylate, or nosylate. In some embodiments, Z is F - , Cl - , Br - , or I - In some embodiments, Z is Br - It is.

[0040] In some embodiments, the asymmetric catalyst used in the disclosed methods can be selected from the group consisting of: [ka] In some embodiments, the asymmetric catalyst is [ka] In some specific examples of the embodiments provided herein, Z is bromide or chloride. In some embodiments, Z is chloride. In some embodiments, Z is bromide.

[0041] Typically, the asymmetric catalyst is present in an amount of 0.005 to 1.50 molar equivalents based on 1.0 molar equivalent of compound (I). In some embodiments, the asymmetric catalyst is present in an amount of 0.005 to 1 molar equivalent, 0.05 to 0.5 molar equivalent, or 0.05 to 0.25 molar equivalent. For example, the asymmetric catalyst is present in an amount of 0.005, 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.5, 0.75, 1, 1.25, or 1.5 molar equivalents based on 1.0 molar equivalent of compound (I). In some embodiments, the asymmetric catalyst is present in an amount of 0.25 molar equivalents based on 1.0 molar equivalent of compound (I).

[0042] In general, the base may comprise an inorganic base. Contemplated inorganic bases include, but are not limited to, Cs2CO3, K2CO3, Rb2CO3, Na2CO3, Na2CO3, Li2CO3, CaCO3, MgCO3, K3PO4, Na3PO4, Li3PO4, K2HPO4, Na2HPO4, Li2HPO4, NaHCO3, LiHCO3, and KHCO3. In some embodiments, the base comprises Cs2CO3. In some embodiments, the inorganic base is present in 0.95 to 6 molar equivalents based on 1.0 molar equivalent of compound (I). In some embodiments, the inorganic base may be present in 1 to 5 molar equivalents, 1 to 4 molar equivalents, 1 to 3 molar equivalents, 1 to 2 molar equivalents, or 1.5 molar equivalents based on 1.0 molar equivalent of compound (I). For example, the inorganic base can be present in 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 2, 3, 4, 5, or 6 molar equivalents based on 1.0 molar equivalent of Compound (I).

[0043] Generally, the solvent system is biphasic. In some embodiments, the biphasic solvent system may include an aprotic organic solvent and water. Contemplated aprotic organic solvents include, but are not limited to, dichloromethane, tetrahydrofuran, toluene, benzene, cyclopentyl methyl ether, tert-butyl methyl ether, 2-methyltetrahydrofuran, anisole, xylene, benzotrifluoride, 1,2-dichloroethane, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, or combinations thereof. In some embodiments, the aprotic organic solvent may include toluene. In some embodiments, the aprotic organic solvent is present at a concentration of 3L / kg to 30L / kg based on the weight of Compound (I). For example, the aprotic organic solvent is present at a concentration of 3L / kg, 4L / kg, 5L / kg, 6L / kg, 7L / kg, 8L / kg, 9L / kg, 10L / kg, 15L / kg, 20L / kg, 25L / kg, or 30L / kg. In some embodiments, toluene is present in a concentration of 3 L / kg to 30 L / kg, based on the weight of Compound (I).

[0044] Generally, methods disclosed herein can include blending at a temperature of -40° C. to 30° C. In some embodiments, blending is performed at a temperature of -30° C. to 30° C., -20° C. to 20° C., -20° C. to 10° C., or -20° C. to 5° C. For example, blending is performed at a temperature of -40° C., -30° C., -20° C., -15° C., -10° C., -5° C., 0° C., 5° C., 10° C., 20° C., or 30° C.

[0045] Generally, the methods disclosed herein may include blending for 1 hour to 72 hours. In some embodiments, blending is performed for 1 hour to 48 hours, 1 hour to 24 hours, 1 hour to 20 hours, 10 hours to 20 hours, or 14 hours to 18 hours. For example, blending may be performed for 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 36 hours, 48 ​​hours, or 72 hours.

[0046] In general, the methods disclosed herein can produce compound Y in high enantiomeric excess (e.g., 30% or greater). In some embodiments, compound Y is produced in 30% or greater enantiomeric excess. In some embodiments, compound Y is produced in 40% or greater enantiomeric excess. In some embodiments, compound Y is produced in 50% or greater enantiomeric excess. In some embodiments, compound Y is produced in 60% or greater enantiomeric excess.

[0047] Synthesis of compound A3A Compound Y prepared by the methods disclosed herein can be used to synthesize compound A3A or a salt thereof, as shown in Scheme 2. Compound Y can be used to synthesize compound A3A using a variety of different methods. In some cases, R 1 Compound Y, when R is CO2Me or CN, can undergo, for example, hydrolysis, oxidation, hydrogenation to form compound A3A, and then crystallization of a salt of compound A3A. 1Compound Y, when R is CO2Me or CN, can undergo, for example, oxidation, hydrolysis, hydrogenation to form compound A3A, and then crystallization of a salt of compound A3A. 1 Compound Y, where R is CO2Me or CN, can undergo redox-neutral (hydrogen-borrowing) cyclization of aniline on alcohol, for example, via hydrogenation, oxidation / reductive amination, to form compound A3A, followed by crystallization of a salt of compound A3A. 1 Compound Y, when is CO2H, can be, for example, oxidized, hydrogenated to form compound A3A, and then the salt of compound A3A can be crystallized.

[0048] Scheme 2 - General method for the synthesis of compound A3A [ka] Compound Y1 prepared by the method disclosed herein can be used to synthesize compounds A1 and A2. As shown in Scheme 2, compound Y1 can be used to synthesize compound A3A and its salts and solvates. As shown in Scheme 3, compound Y1 can be used to synthesize compound A1 via compound A3A. As shown in Scheme 4, compound A1 can be used to synthesize compound A2 shown in Scheme 4. It will be appreciated that compound Y can be used to prepare A3, and can further be used to prepare the enantiomer of A3A, and the choice of catalyst and conditions can be used to generate the enantiomer of compound Y1.

[0049] Scheme 3 - Conversion of compound A3 to compound A1 [ka] Compound A3A may be used to synthesize compound A1 and its salts and solvates as shown above and described in U.S. Patent No. 9,562,061. Compound A1 may be prepared using compound Y1 as described herein.

[0050] Scheme 4 - Conversion of compound A1 to compound A2 [ka] Compound C can be used to synthesize compound A2 and its salts and solvates as shown above and described in U.S. Pat. No. 10,300,075. Compound C can be oxidized to provide cyclic enone I as disclosed in U.S. Pat. No. 10,300,075. Enone I can then be converted to epoxide J using the procedures disclosed in U.S. Pat. No. 10,300,075. Epoxide J can then be reacted with bicyclic compound K to provide hydroxy compound L. Finally, methylation of compound L provides compound A2 as disclosed in U.S. Pat. No. 10,300,075.

[0051] While this disclosure is to be read in conjunction with its detailed description, it should be understood that the foregoing description and the following examples are illustrative and are not intended to limit the scope of the disclosure, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. EXAMPLES

[0052] The following examples are offered for illustrative purposes and are not intended to limit the scope of the present invention.

[0053] Example 1: SN to form compound Y Ar reaction [ka]

[0054] Synthesis of compound Y2 Methyl (R)-4-((6-chloro-1-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoate (compound Y2, where R1 In an EasyMax reaction vessel (glass, 100 mL), add [6-chloro-1-(hydroxymethyl)tetralin-1-yl]methanol (THN-DIOL, 3.00 g, 13.2 mmol, 1.0 equiv.), methyl 4-fluoro-3-nitrobenzoate (2.64 g, 13.2 mmol, 1.0 equiv., where Lg is F and R is COMe). 1 is methyl) and (1R,2S)-N-ethyl-1-hydroxy-N,N-dimethyl-1-phenylpropan-2-aminium bromide (11, 1.43 g, 3.31 mmol, 0.25 equiv.). The vessel was placed in an EasyMax Advanced Synthesis Workstation and sealed with a 6-port reactor head equipped with an overhead stirrer, nitrogen (N2) inlet line, temperature probe, and baffles to aid mixing. The reactor was charged with toluene (82.5 mL, 27.5 vol, 0.15 M with respect to THN-DIOL) and the remaining ports were sealed with rubber septa. The reaction mixture was stirred (overhead, 800 rpm), which gave an off-white, slightly heterogeneous solution (particulate). The reaction mixture was cooled until the internal temperature reached -17.0 °C (jacket temperature was -20.0 °C). At this time, aqueous cesium carbonate (4.54 mL, 13.2 mmol, 1.0 equiv, 50 wt % aqueous solution) was added to the reaction mixture via syringe through the septum (dropwise, 2 min). Upon addition of the base, the reaction mixture turned pale yellow. The solution was stirred for 16 h (jacket temperature was -20.0 °C). After this time, stirring was stopped, the mixture was allowed to warm (5 °C), and the yellow reaction mixture was transferred to a separatory funnel (250 mL). An aliquot of this solution was removed for LC analysis. Water (30 mL, 10 vol) was added to the separatory funnel and the mixture was gently shaken and aerated. The biphasic mixture was allowed to settle (10 min) and the phases separated. After LC analysis of both phases, the organic layer was concentrated on a rotary evaporator to give a dark yellow oil. The crude reaction mixture was purified by automated column chromatography on silica gel (Biotage, 340 g column, 5-40% EtOAc in heptane gradient, 16 column volumes) to obtain R 1Compound Y2, in which is CO2Me, was obtained as a slightly yellow glassy solid (0.930 g, 17.3% yield, 54% ee).

[0055] 1 H NMR(500MHz,CDCl3)δ(ppm)=8.53(d,J=2.1Hz,1H),8.18(dd,J=2.2,8.7Hz,1H),7.51(d,J=8.3Hz,1H),7.1 6-7.10(m,3H),4.34-4.21(m,2H),4.01-3.96(m,1H),3.94(s,3H),3.90-3.82(m,1H),2.79(s,2H),2.38(br s,1H),2.03-1.92(m,2H),1.91-1.74(m,2H). 13 C NMR(126MHz,CDCl3)δ(ppm)=164.9,155.5,140.4,138.9,135.6,135.5,132.7,129.3,129.1,127.5,126.3,122.8,114.1,74.5,67.6,52.5,30.2.

[0056] Although compound Y1 was not synthesized above, this chemical reaction was intended to demonstrate the progress of asymmetric nucleophilic aromatic substitution using this catalyst. Without intending to be bound by theory, it is believed that the use of the enantiomers of asymmetric catalyst 11 can produce compound Y1. [ka]

[0057] Synthesis of Y1 Methyl (S)-4-((6-chloro-1-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoate (compound Y1, where R 1In a vial, add N-[4-(trifluoromethyl)benzyl]cinchonium bromide (0.10 equiv., 6.7 mg), [6-chloro-1-(hydroxymethyl)tetralin-1-yl]methanol (THN-DIOL, 1.0 equiv., 23 mg), methyl 4-fluoro-3-nitrobenzoate (1.0 equiv., 20 mg, Lg is F, R is COMe) 1 is methyl) and CHCl3 (167 μL). The vial was cooled to +1 °C and charged with cesium carbonate (50 wt % solution, 1 equiv). The vial was shaken for 16 h and quenched with 1 N HCl (50 μL). HPLC analysis showed the title compound (Y1) was formed in 32% conversion, 32% ee.

[0058] Example 2 - Hydrolysis and oxidation of compound Y, e.g. Y1 Hydrolysis Reaction [ka] (S)-4-((6-chloro-1-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoic acid (compound Y1, where R 1 In a 100 mL EasyMax reactor, add solid compound Y1 (here R 1 is CO2Me) (2.00 g, 4.93 mmol, 1.0 equiv) and THF (20.0 mL, 10 V). The reactor was sealed with a 6-port reactor head equipped with an overhead stirrer, N2 inlet, and temperature probe. A 5N aqueous solution of sodium hydroxide (4.93 mL, 24.6 mmol, 5.0 equiv) was added slowly via syringe to maintain the internal reaction temperature between 22-25 °C. The reaction mixture was stirred at 22 °C for 23 h, at which time the pH was adjusted to pH 1 using 6N aqueous HCl (5 mL). The reaction mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with 2-MeTHF (15 mL), followed by washing the combined organic extracts with H2O (20 mL), drying over MgSO4, filtering, and concentrating in vacuo. The residue was taken up in a small amount of DCM and concentrated to remove excess 2-MeTHF. R 1The crude compound Y1, where is CO2H, was obtained as a white solid (1.72 g, 87% w / w, 96% yield).

[0059] 1 H NMR(500MHz,DMSO-d6):δ 13.28(br s,1H),8.38(d,J=2.2Hz,1H),8.18(dd,J=2.2,8.8Hz,1H),7.62(d,J=8.4Hz, 1H),7.51(d,J=9.0Hz,1H),7.20-7.19(m,1H),7.17(d,J=8.5Hz,1H),4.94(br s,1H),4.35(dd,J=9.5,27.5Hz,2H),3.67-3.64(m,2H),2.76(t,J=6.2Hz,2H),1.96-1.73(m,4H); 13 C NMR(126MHz,DMSO-d6):δ 166.3,155.8,141.6,139.6,137.7,136.2,131.6,130.7,129.2,127.1,126.2,123.7,116.1,74.9,66.4,30.7,28.5,19.3.

[0060] Oxidation Reaction [ka] (R)-4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoic acid: Compound Y1 (where R 1 is CO2H) (1.85 g, 4.72 mmol, 1.00 equiv) and DCM (9.25 mL, 5.0 V). To this slurry was added N,N-diisopropylethylamine (3.05 mL, 23.6 mmol, 5.0 equiv). The resulting clear yellow solution was cooled to 0 °C. Dimethylsulfoxide (DMSO) (5.55 mL, 3.0 V) was added slowly via syringe, followed by the addition of SO3-pyridine (1.88 g, 11.8 mmol, 2.50 equiv) in three portions. After the addition, the reaction was allowed to warm to 20 °C over 1 h and stirred at 20 °C for 2 h. The reaction was then cooled to 0 °C and NaHSO4 The mixture was acidified to pH 3 by the addition of a 10% aqueous solution of (15 mL). The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (15 mL) and the combined organic extracts were then washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was taken up in 2.5 V of acetic acid and 1.5 V of H2O was added dropwise. The resulting slurry was aged for 1 h before being filtered and washed with additional H2O. A light brown solid was obtained that was contaminated with excess diisopropylethylamine. The solid was reslurried in H2O (5 mL), aged for 2.5 h, filtered and washed with additional H2O. R 1 Compound Y1, in which is CO2H, was obtained as a white powder (1.18 g, 90.5% w / w, 67% yield).

[0061] 1 H NMR(500MHz,DMSO-d6):δ 9.63(s,1H),8.30(d,J=2.1Hz,1H),8.12(dd,J=2.2,8.8Hz,1H),7.50(d,J=9.0Hz,1 H),7.30(d,J=8.4Hz,1H),7.28-7.24(m,J=2.1Hz,1H),7.24-7.20(m,1H),4.73(d,J =9.6Hz,1H),4.44(d,J=9.6Hz,1H),2.74(t,J=6.2Hz,2H),2.16(ddd,J=3.2,9.2,13 .1Hz,1H),1.96(ddd,J=3.0,8.4,13.8Hz,1H),1.86-1.77(m,1H),1.77-1.68(m,1H); 13 C NMR(126MHz,DMSO-d6):δ 201.8,166.2,155.1,142.2,139.6,136.1,133.1,131.5,130.9,130.2,127.1,126.9,124.3,116.4,73.2,53.8,29.9,26.4,18.9.

Claims

1. Compound Y 【Chemistry 1】 or a salt thereof, comprising the steps of: combining compound (I), compound (II), an asymmetric catalyst, and a base in a biphasic solvent system to form compound Y; The compound (I) and the compound (II) are represented by the following formula: 【Chemistry 2】 (In the formula, R １ CO ２ C １～６ Alkyl, CO ２ H, CON (C １～６ Alkyl) ２ , CO ２ Ar １ , CO ２ Bn, or CN; Lg is a leaving group; Ar １ is C ６～２２ aryl, or a 5-12 membered heteroaryl containing 1-3 ring heteroatoms selected from O, N, and S. is a compound of The asymmetric catalyst is 【Chemistry 3】 (In the formula, each R 2 is independently C 1-22 alkyl, C 5-8 cycloalkyl, or Ar 1 ; or each R 2 together with the atom to which it is attached forms a 5- to 8-membered cycloalkyl; each R 3 is independently C 1-22 alkyl, C 5-8 cycloalkyl, Bn, or Ar 1 ; or two R 3 , together with the nitrogen to which they are attached, form a 5-25 membered heterocycle containing 0-1 additional ring heteroatoms selected from N, O and S; X is OH, NR N C(O)R N , C(O)N(R N ) 2 , N(R N ) 2 , C 1-6 haloalkyl, SH, SC 1-6 alkyl, NHSO 2 Ar 1 , NHSO 2 C 1-6 alkyl, NHSOC 1-6 alkyl, or NHSOAr 1 ; Each R N is independently H, C 1-12 alkyl, or Ar 1 ; Z is a counter ion. The method has the structure:

2. Compound Y is compound Y1 【Chemistry 4】 The method of claim 1 , wherein the compound has the stereochemistry shown in

3. Compound Y is compound Y2 【Chemistry 5】 The method of claim 1 , wherein the compound has the stereochemistry shown in

4. R １ CO ２ C １～６ The method of any one of claims 1 to 3, wherein the alkyl group is CO 2 Bn or CO 2 Ph.

5. R １ is -CO ２ Me, -CO ２ Et, -CO ２ iPr, -CO ２ nPr, -CO ２ tBu, -CO ２ nBu, or -CO ２ The method of claim 4, wherein the is secBu.

6. R １ Ha-CO ２ The method of claim 5, wherein Me is

7. R １ The method according to any one of claims 1 to 3, wherein is CN.

8. R １ Ha-CO ２ The method according to any one of claims 1 to 3, wherein H is

9. The method of any one of claims 1 to 8, wherein Lg is halo or sulfonyl.

10. 10. The method of claim 9, wherein Lg is F, Cl, Br, I, mesyl, tosyl, nosyl, or triflyl.

11. The method of claim 10 , wherein Lg is F.

12. The asymmetric catalyst is 【Chemistry 6】 The method according to any one of claims 1 to 11, having the structure:

13. The asymmetric catalyst is 【Chemistry 7】 The method of claim 12 having the structure:

14. Each R ２ are independently Me, Et, iPr, sBu, tBu, phenyl, tolyl, 【Chemistry 8】 or each R ２ The method of any one of claims 1 to 13, wherein together with the atom to which it is attached forms cyclohexyl or cyclopentyl.

15. X is OH, 【Chemistry 9】 , -NHSO ２ Me, -NHSO ２ Tolyl, -NHSO ２ (nitrophenyl), 【Chemistry 10】 、-CF ２ H-SH-NH ２ 、-NHMe, -NHPh、 【Chemistry 11】 The method according to any one of claims 1 to 14, wherein

16. The asymmetric catalyst is -NMe ３ , -NMe ２ Bn, -NMeBn ２ , -NBn ３ , 【Chemistry 12】 -N(R ３ ) ３ ＋ The method according to any one of claims 1 to 15, comprising:

17. The asymmetric catalyst is 【Chemistry 13】 (In the formula, each Ar ２ is independently ６～２２ 12. The method of any one of claims 1 to 11, wherein the aryl has the structure:

18. At least one Ar ２ The method of claim 17 , wherein is phenyl or substituted phenyl.

19. Each Ar ２ The method of claim 18 , wherein is phenyl.

20. Each Ar ２ is, independently, 【Chemistry 14】 and Ph.

21. The asymmetric catalyst is 【Chemistry 15】 (In the formula, Ar ３ is C ６～２２ 12. The method of any one of claims 1 to 11, wherein the aryl has the structure:

22. Ar ３ 22. The method of claim 21 , wherein is phenyl or substituted phenyl.

23. Ar ３ The method of claim 22, wherein is phenyl.

24. Ar ３ teeth, 【Chemistry 16】 and Ph.

25. The asymmetric catalyst is 【Chemistry 17】 is selected from the group consisting of The method of any one of claims 1 to 11, wherein Z is a counter ion.

26. The asymmetric catalyst is 【Chemistry 18】 26. The method of claim 25, wherein:

27. 27. The method of any one of claims 1 to 26, wherein Z is a halide, triflate, mesylate, tosylate, or nosylate.

28. 28. The method of claim 27, wherein Z is chloride or bromide.

29. The method of any one of claims 1 to 28, wherein the solvent comprises an inorganic base.

30. The base is Cs ２ CO ３ , K ２ CO ３ , Rb ２ CO ３ , Na ２ CO ３ , Na ２ CO ３ , Li ２ CO ３ , CaCO ３ , MgCO ３ , K ３ P.O. ４ , Na ３ P.O. ４ , Li ３ P.O. ４ , K ２ H.P.O. ４ , Na ２ H.P.O. ４ , Li ２ H.P.O. ４ , NaHCO ３ , LiHCO ３ , or KHCO ３ 30. The method of claim 29, comprising:

31. The base is Cs ２ CO ３ 31. The method of claim 30, comprising:

32. The method according to any one of claims 29 to 31, wherein the inorganic base is present in an amount of 0.95 to 6 molar equivalents based on 1.0 molar equivalent of compound (I).

33. The method of any one of claims 1 to 32, wherein the biphasic solvent system comprises an aprotic organic solvent and water.

34. 34. The method of claim 33, wherein the aprotic organic solvent comprises dichloromethane, tetrahydrofuran, toluene, benzene, cyclopentyl methyl ether, tert-butyl methyl ether, 2-methyltetrahydrofuran, anisole, xylene, benzotrifluoride, 1,2-dichloroethane, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, or a combination thereof.

35. 35. The method of claim 34, wherein the aprotic organic solvent comprises toluene.

36. 36. The method of claim 35, wherein the toluene is present in a concentration of 3 L / kg to 30 L / kg, based on the weight of compound (I).

37. 37. The method of any one of claims 33 to 36, comprising combining compound (I), compound (II) and the catalyst in the aprotic organic solvent prior to adding the base.

38. The method according to any one of claims 1 to 37, wherein the admixing is carried out at a temperature of from -40°C to 30°C.

39. 39. The method of claim 38, wherein the combining is carried out at a temperature of from -15°C to -25°C.

40. 40. The method of any one of claims 1 to 39, wherein the blending is carried out for a period of from 1 hour to 72 hours.

41. 41. The method of claim 40, wherein the blending is carried out for a period of 14 to 18 hours.

42. 42. The method of any one of claims 1 to 41, wherein compound (II) is present in an amount of 0.9 to 2 molar equivalents based on 1.0 molar equivalent of compound (I).

43. 43. The method of claim 42, wherein compound (II) is present in 1.0 molar equivalent based on 1.0 molar equivalent of compound (I).

44. The method according to any one of claims 1 to 43, wherein the asymmetric catalyst is present in an amount of 0.005 to 1.50 molar equivalents, based on 1.0 molar equivalent of compound (I).

45. 45. The method of claim 44, wherein the asymmetric catalyst is present in an amount of 0.25 molar equivalents based on 1.0 molar equivalent of compound (I).

46. 46. ​​The method of any one of claims 1 to 45, wherein compound Y is produced in an enantiomeric excess of 30% or greater.

47. 47. The method of claim 46, wherein compound Y is produced in an enantiomeric excess of 40% or greater.

48. 48. The method of claim 47, wherein compound Y is produced in an enantiomeric excess of 50% or greater.

49. Compound Y to Compound A3 【Chemistry 19】 49. The method of any one of claims 1 to 48, further comprising synthesizing said compound, or a salt or solvate thereof.

50. The compound A3 or a salt or solvate thereof has the structure A3A 【Chemistry 20】 50. The method of claim 49, wherein said compound has the formula:

51. The compound A3 or a salt or solvate thereof has the structure A3B 【Chemistry 21】 50. The method of claim 49, wherein said compound has the formula:

52. Compound Y to Compound A1 【Chemical 22】 52. The method of any one of claims 1 to 51, further comprising synthesizing said compound, or a salt or solvate thereof.

53. Compound Y to Compound A2 【Chemistry 23】 52. The method of any one of claims 1 to 51, further comprising synthesizing said compound, or a salt or solvate thereof.

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