HK40085939A - Diol desymmetrization by nucleophilic aromatic substitution - Google Patents

Description

De-symmetrization by nucleophilic aromatic substitution of diols

Background

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional application No. 63/074,241, filed on 3 months 9 of 2020, which is incorporated by reference in its entirety and for all purposes as if fully set forth herein.

Technical Field

The present disclosure relates to processes for synthesizing intermediates useful in the preparation of (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 ]Cyclopentadec carbon [8,16,18,24 ]]Tetraenes]-15' -keto 13',13' -dioxide (compound A1; AMG 176), salts or solvates thereof, and is useful for preparing (1S, 3' R,6' R,7' R,8' E,11' S,12' R) -6-chloro-7 ' -methoxy-11 ',12' -dimethyl-7 ' - ((9 aR) -octahydro-2H-pyrido [1, 2-a)]Pyrazin-2-ylmethyl) -3, 4-dihydro-2 h,15 'h-spiro [ naphthalene-1, 22' - [20 ]]Oxa [13 ]]Thia [1,14]Diazatetracyclo [14.7.2.0 ^3,6 .0 ^19,24 ]Cyclopentadec carbon [8,16,18,24 ]]Tetraenes]-15' -ketone 13',13' -dioxide (compound A2; AMG 397), a salt or solvate thereof. These compounds are inhibitors of the myeloid leukemia 1 protein (Mcl-1).

Description of the Related Art

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 ]Twenty-five carbon8,16,18,24]Tetraenes]-15' -keto 13',13' -dioxide (compound A1) is useful as an inhibitor of myeloid leukemia 1 (Mcl-1):

compound (1S, 3'R,6' R,7'R,8' E,11'S,12' R) -6-chloro-7 '-methoxy-11', 12 '-dimethyl-7' - ((9 aR) -octahydro-2H-pyrido [1, 2-a)]Pyrazin-2-ylmethyl) -3, 4-dihydro-2 h,15 'h-spiro [ naphthalene-1, 22' - [20 ]]Oxa [13 ]]Thia [1,14]Diazatetracyclo [14.7.2.0 ^3,6 .0 ^19,24 ]Cyclopentadec carbon [8,16,18,24 ]]Tetraenes]-15' -keto 13',13' -dioxide (compound A2) is useful as an inhibitor of myeloid leukemia 1 (Mcl-1):

one common feature of human cancers is Mcl-1 overexpression. Mcl-1 overexpression prevents cancer cells from undergoing apoptosis (apoptosis), allowing these cells to survive despite extensive genetic damage.

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 homooligomers in the outer mitochondrial membrane, which lead to pore formation and leakage of mitochondrial content, a step that triggers 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 are useful in the treatment of cancer. Mcl-1 is overexpressed in a variety of cancers.

U.S. patent No. 9,562,061, which is incorporated herein by reference in its entirety, discloses compound A1 as an Mcl-1 inhibitor and provides a method for preparing the same. However, there is a need for improved synthetic methods that produce compound A1, particularly for commercial production of compound A1, at reduced cost and with reduced manufacturing time lines.

U.S. patent No. 10,300,075, which is incorporated herein by reference in its entirety, discloses compound A2 as an Mcl-1 inhibitor and provides a method for preparing the same. However, there is a need for improved synthetic methods that produce compound A2 at reduced cost and with reduced manufacturing time lines, particularly for commercial production of compound A2.

Disclosure of Invention

Provided herein are methods for synthesizing compound Y or a salt thereof:

the method comprises the following steps:

mixing compound (I), compound (II), catalyst and base in a biphasic solvent system to form compound Y:

wherein R is ¹ Is CO ₂ C _1-6 Alkyl, CO ₂ H、CON(C _1-6 Alkyl group ₂ 、CO ₂ Ar ¹ 、CO ₂ Bn or CN, lg is a leaving group, and Ar ¹ Is C ₆ -C ₂₂ Aryl or a 5-12 membered heteroaryl containing from 1 to 3 ring heteroatoms selected from O, N and S. In various embodiments, compound Y may have a stereochemistry as shown in compound Y1In various embodiments, compound Y may have stereochemistry +.>

In various embodiments, compound Y is used to synthesize compound A3 or a salt or solvate thereofAt each ofIn a seed embodiment, compound Y1 is used for the synthesis of compound A3A or a salt or solvate thereof>In various embodiments, compound Y is used to synthesize compound A3B or a salt or solvate thereof>

In various embodiments, compound Y1 is used to synthesize compound A1 or a salt or solvate thereof

In various embodiments, compound Y1 is used to synthesize compound A2 or a salt or solvate thereof

Other aspects and advantages will become apparent to those of ordinary skill in the art upon reading the following detailed description. The following description includes specific embodiments, it being understood that the present disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein.

Detailed Description

Provided herein are methods for synthesizing Mcl-1 inhibitors and corresponding Mcl-1 inhibitor intermediates. In particular, intermediates are provided which can be used in the synthesis of (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 ]Cyclopentadec carbon [8,16,18,24 ]]Tetraenes]-15' -keto 13',13' -dioxide (compound A1) or a salt or solvate thereof and use in the synthesis of (1 s,3' r,6' r,7' r,8' e,11's,12' r) -6-chloro-7 ' -methoxy-11 ',12' -dimethyl-7 ' - ((9 aR) -octahydro-2H-pyrido [1, 2-a)]Pyrazin-2-ylmethyl) -3, 4-dihydro-2 h,15 'h-spiro [ naphthalene-1, 22' - [20 ]]Oxa-type[13]Thia [1,14]Diazatetracyclo [14.7.2.0 ^3,6 .0 ^19,24 ]Cyclopentadec carbon [8,16,18,24 ]]Tetraenes]-15' -keto 13',13' -dioxide (compound A2) or a salt or solvate thereof:

U.S. patent No. 9,562,061, which is incorporated herein by reference in its entirety, discloses compound A1, or a salt or solvate thereof, as an Mcl-1 inhibitor and provides a process for preparing the same. U.S. patent No. 9,562,061 also discloses a method for synthesizing Mcl-1 inhibitor intermediates for the synthesis of compound A3A shown below:

U.S. patent No. 10,300,075, which is incorporated herein by reference in its entirety, discloses compound A2, or a salt or solvate thereof, as an Mcl-1 inhibitor and provides a process for preparing the same. The disclosure of compound A1 salts and solvates in us patent No. 10,300,075 is incorporated by reference in its entirety. This patent also discloses a method of synthesizing a macrocyclic Mcl-1 inhibitor intermediate, such as the intermediate shown above for the synthesis of compound A3A.

In particular, the '061 patent describes a method for synthesizing compound A3, as shown in scheme 1 below, for example, at columns 55-63 of the' 061 patent.

Scheme 1-Prior Art Synthesis of Compound A3A

The method shown above has several drawbacks. The process of scheme 1 requires at least seven chemical steps to obtain compound A3A from the diol starting material. In addition, one of these steps uses a catalyst that requires custom-manufacture (referred to as the "Kang catalyst" in the' 061 patent). The above-described methods also have extremely high costs and long manufacturing timelines due to the large number of chemical steps involved in the method. Finally, the above process is not atomically economical because it uses 2-naphthoate and dimethyl acetal protecting groups.

Advantageously, the methods disclosed herein significantly reduce the cost and manufacturing time line of compound A3A by using fewer steps and avoiding the need to manage simultaneous supply of Kang catalyst. In addition, the methods disclosed herein have a greener manufacturing process, in part because of reduced solvent and reagent use, and in part because of the direct introduction of aryl groups during the enantioselective steps of the methods.

Synthesis of Compound Y

Provided herein are methods for synthesizing compound Y or a salt thereof:

the method comprises mixing compound (I), compound (II), a catalyst and a base in a biphasic solvent system to form compound Y:

wherein R is ¹ Is CO ₂ C _1-6 Alkyl, CO ₂ H、CON(C _1-6 Alkyl group ₂ 、CO ₂ Ar ¹ 、CO ₂ Bn or CN, lg is a leaving group, and Ar ¹ Selected from C _6-22 Aryl or a 5-12 membered heteroaryl containing from 1 to 3 ring heteroatoms selected from O, N and S. In various embodiments, compound Y may have a stereochemistry as shown in compound Y1In some embodiments, compound Y may have a stereochemistry as shown in compound Y2: />In some embodiments, the method may include mixing compound (I), compound (II), and catalyst in an aprotic organic solvent prior to adding the base.

As used herein, the term "alkyl" refers to straight and branched chain saturated hydrocarbon groups containing one to twenty carbon atoms, for example, one to twenty carbon atoms, or one to ten carbon atoms, or one to four carbon atoms. Term C _n Meaning an alkyl group having "n" carbon atoms. For example, C ₄ Alkyl refers to an alkyl group having 4 carbon atoms. C (C) _1-22 Alkyl and C ₁ -C ₂₂ Alkyl refers to an alkyl group having a number of carbon atoms that encompasses the entire range (i.e., 1 to 22 carbon atoms) as well as 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), tert-butyl (1, 1-dimethylethyl), 3-dimethylpentyl, and 2-ethylhexyl. Unless otherwise indicated, an alkyl group may be an unsubstituted alkyl group or a substituted alkyl group. Specific substitutions on alkyl groups may be indicated by inclusion in the term, for example "haloalkyl" indicates an alkyl group substituted with one or more (e.g. one to 10) halo groups; or "hydroxyalkyl" indicates an alkyl group substituted with one or more (e.g., one to 10) hydroxy groups.

As used herein, the term "cycloalkyl" refers to an aliphatic cyclic hydrocarbon group containing five to eight carbon atoms (e.g., 5, 6, 7, or 8 carbon atoms). Term C _n Meaning cycloalkyl having "n" carbon atoms. For example, C ₅ Cycloalkyl refers to cycloalkyl groups having 5 carbon atoms in the ring. C (C) _5-8 Cycloalkyl and C ₅ -C ₈ Cycloalkyl refers to cycloalkyl groups having a number of carbon atoms that encompasses the entire range (i.e., 5 to 8 carbon atoms) as well as 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, cycloalkyl groups may be absentSubstituted cycloalkyl or substituted cycloalkyl. Cycloalkyl groups described herein may be alone or fused to another cycloalkyl, heterocycloalkyl, aryl, and/or heteroaryl group. Cycloalkyl groups may be substituted or unsubstituted.

As used herein, the term "heterocycloalkyl" is defined similarly to cycloalkyl except that the ring contains one to three heteroatoms independently selected from oxygen, nitrogen and sulfur. In particular, the term "heterocycloalkyl" refers to a ring containing a total of three to eight atoms, wherein 1,2,3 or three of those 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. Heterocyclylalkyl groups can be optionally substituted, for example, by one to three groups independently selected from alkyl, alkenyl, OH, C (O) NH ₂ 、NH ₂ A saturated or partially unsaturated ring system substituted by oxo (=o), aryl, haloalkyl, halogen and OH groups. Heterocycloalkyl groups optionally may be further N-substituted with alkyl, hydroxyalkyl, alkenyl-aryl, and alkenyl-heteroaryl groups. The heterocycloalkyl groups described herein can be alone or fused to another heterocycloalkyl, cycloalkyl, aryl, and/or heteroaryl group. When a heterocycloalkyl group is fused to another heterocycloalkyl group, then each of the heterocycloalkyl groups may contain three to eight total ring atoms and one to three heteroatoms. In some embodiments, heterocycloalkyl groups described herein include one oxygen ring atom (e.g., oxiranyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl).

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, phenanthryl, biphenylene (biphenyl), indanyl, indenyl, anthracenyl, and fluorenyl. Unless otherwise indicated, an aryl group may be an unsubstituted aryl group or a substituted aryl group.

"Bn" means benzyl, CH ₂ Phenyl, and in some cases, phenyl may be substituted.

As used herein, the term "heteroaryl" refers to a cyclic aromatic ring having five to twelve total ring atoms in the aromatic ring (e.g., a monocyclic aromatic ring having 5-6 total ring atoms) and containing one to three heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, heteroaryl groups may be unsubstituted or substituted by one or more, and in particular one to four, groups selected from, for example, halogen, alkyl, alkenyl, OCF ₃ 、NO ₂ CN, NC, OH, alkoxy, amino, CO ₂ H、CO ₂ Substituents for alkyl, aryl and heteroaryl groups. In some cases, heteroaryl is substituted with one or more of alkyl and alkoxy. Heteroaryl groups may be alone (e.g., pyridinyl) or fused to another heteroaryl group (e.g., purinyl), cycloalkyl (e.g., tetrahydroquinolinyl), heterocycloalkyl (e.g., dihydronaphthyridinyl), and/or aryl (e.g., benzothiazolyl and quinolinyl). Examples of heteroaryl groups include, but are not limited to, thienyl (thienyl), furyl, pyridyl, pyrrolyl, oxazolyl, quinolinyl, thienyl (thiophenyl), isoquinolinyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl. When a heteroaryl group is fused to another heteroaryl group, then each ring may contain five or six total ring atoms in its aromatic ring and one to three heteroatoms. Unless otherwise indicated, heteroaryl groups may be unsubstituted or substituted.

As used herein, the term "heterocycle" refers to heteroaryl or heterocycloalkyl.

In general, R ¹ May include CO ₂ C _1-6 Alkyl, CO ₂ H、CON(C _1-6 Alkyl group ₂ 、CO ₂ Ar ¹ 、CO ₂ Bn or CN. In some embodiments, R ¹ May include CO ₂ C _1-6 Alkyl, CO ₂ H or CO ₂ Ar ¹ . In some embodiments, R ¹ Is CO ₂ H. In some embodiments, R ¹ Is CO ₂ C _1-6 An alkyl group. In some embodiments, R ¹ Is CO ₂ Ar ¹ . In some embodimentsIn the example, R ¹ Is CO ₂ Me、CO ₂ Et、CO ₂ iPr、CO ₂ nPr、CO ₂ tBu、CO ₂ nBu、CO ₂ secBu、CO ₂ Bn or CO ₂ Ph. In some embodiments, R ¹ Is CO ₂ Me、CO ₂ Et、CO ₂ iPr or CO ₂ tBu. In some embodiments, R ¹ Is CO ₂ Me. In some embodiments, R ¹ Is CO ₂ Ph. In some embodiments, R ¹ Is CO ₂ Bn. In some embodiments, the CO ₂ Bn is CO ₂ CH ₂ (p-OMeC ₆ H ₄ ). In some embodiments, R ¹ Is CN.

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 upon nucleophilic aromatic substitution. Non-limiting examples of suitable leaving groups include halogens such as F, cl, br or I, or sulfonyl. In some embodiments, the leaving group is F.

In some embodiments, lg is a sulfonyl leaving group. The term "sulfonyl leaving group" as used herein refers to a group formed from-SO ₂ R 'represents a leaving group, wherein R' may be an alkyl group, an aryl group, a haloalkyl group, a heteroaryl group, or the like. In some embodiments, the sulfonyl leaving group is selected from the group consisting of: methanesulfonyl (SO) ₂ Me), tosyl (SO) ₂ Tolyl), nitrobenzenesulfonyl (SO ₂ -nitrophenyl) and trifluoromethanesulfonyl (SO) ₂ CF ₃ ). In some embodiments, the sulfonyl leaving group comprises a methanesulfonyl group.

In general, compound (II) is present in 0.9 to 2 molar equivalents based on 1.0 molar equivalent of compound (I). In some embodiments, compound (II) is present in 1 to 2 molar equivalents, 1 to 1.5 molar equivalents, or 1 to 1.2 molar equivalents based on 1.0 molar equivalents of compound (I). In some embodiments, compound (II) is present at 1 molar equivalent based on 1.0 molar equivalent of compound (I).

In general, the catalyst may be one which facilitates the coupling of compounds (I) and (II)The catalyst may be used in sub-stoichiometric amounts, but not always, for example, by decreasing 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 decreasing the desired reaction temperature, or any other way to promote the formation of compound (Y). In some cases, the catalyst is an asymmetric catalyst. In some embodiments, the asymmetric catalyst may have a structureWherein each R is ² Independently C _1-22 Alkyl, C _5-8 Cycloalkyl or Ar ¹ Or each R ² Together with the atoms to which they are attached, form a five to eight membered cycloalkyl group; each R ³ 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 five to twenty-five membered heterocyclic ring 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 The method comprises the steps of carrying out a first treatment on the surface of the Each R ^N H, C independently _1-12 Alkyl or Ar ¹ The method comprises the steps of carrying out a first treatment on the surface of the And Z is a counterion. In some embodiments, the asymmetric catalyst may have a structureIn some embodiments, the asymmetric catalyst may have the structure +.>In some embodiments, the asymmetric catalyst may have a structure

In general, each R ² Independently C ₁ -C ₂₂ Alkyl, C _5- C ₈ Cycloalkyl or Ar ¹ Or two R ² Together with the atoms to which they are attached, form a five to eight membered cycloalkyl. In some embodiments, at least one R ² Is C ₁ -C ₂₂ An alkyl group. In some embodiments, at least one R ² Is C _5- C ₈ Cycloalkyl groups. In some embodiments, at least one R ² Is Ar ¹ . In some embodiments, two R ² Together with the atoms to which they are attached, form a five to eight membered cycloalkyl. In some embodiments, each R ² Independently selected from Me, et, iPr, sBu, tBu, phenyl, tolyl, and combinations thereof,/>

Or each R ² Together with the atoms to which they are attached form a cyclohexyl or cyclopentyl group.

In general, 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 . In some embodiments, X may be OH,-NH-SO ₂ Me、-NH-SO ₂ (tolyl), -NH-SO ₂ (nitrophenyl), ->-CF ₂ H、-SH、-NH ₂ 、-NHMe、-NHPh、/>In some embodiments, X is OH. In some embodiments, X is SH. In some embodiments, X is NHSO ₂ (C _1-6 Alkyl). In some embodiments, X is NHSO ₂ Ar ¹ . In some embodiments, X is NHSO (C _1-6 Alkyl). 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 An alkyl group. 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 Ar ¹ 。

In general, each R ³ Independently C ₁ -C ₂₂ Alkyl, C _5- C ₈ Cycloalkyl or Ar ¹ Or two R ³ Together with the nitrogen to which they are attached, form a five to twenty-five membered heterocyclic ring containing 0-1 additional ring heteroatoms selected from N, O and S. In some embodiments, at least one R ³ Is C ₁ -C ₂₂ An alkyl group. In some embodiments, at least two R ³ Is C ₁ -C ₂₂ An alkyl group. In some embodiments, at least two R ³ Is Ar ¹ . In some embodiments, two R ³ Together with the nitrogen to which they are attached, form a five to twenty-five membered heterocyclic ring containing 0-1 additional ring heteroatoms selected from N, O and S. In some embodiments, at least one R ³ Is C ₁₂ An alkyl group. In some embodiments, the asymmetric catalyst may comprise-N (R) ³ ) ₃ ⁺ ：–NMe ₃ ⁺ 、-NMe ₂ Bn ⁺ 、-NMeBn ₂ ⁺ 、-NBn ₃ ⁺ 、

In some embodiments, -N (R ³ ) ₃ ⁺ Is->

In some embodiments, the asymmetric catalyst may have a structureWherein each Ar is ² Independently selected from C _6-22 Aryl or a 5-12 membered heteroaryl containing from 1 to 3 ring heteroatoms selected from O, N 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 a substituted phenyl group. In some embodiments, each Ar ² Is a substituted phenyl group. In some embodiments, the substituted phenyl groups may comprise one or two groups independently selected from C _1-4 Alkyl, CF ₃ Cl, br, F and OC _1-4 Substituents of alkyl groups. In some embodiments, at least one Ar ² Is an anthryl group. In some embodiments, each Ar ² Independently selected from

And Ph.

In some embodiments, the asymmetric catalyst may have a structureWherein Ar is ³ Selected from C _6-22 Aryl or a 5-12 membered heteroaryl containing from 1 to 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 groups may comprise one or two groups independently selected from C _1-4 Alkyl, CF ₃ Cl, br, F and OC _1-4 Substituents of alkyl groups. In some embodiments, ar ³ Is an anthryl group. In some embodiments, each Ar ³ Selected from the group consisting of

And Ph.

Generally, Z is a counterion. In some embodiments, Z is halide, triflate, mesylate, tosylate, or m-nitrobenzenesulfonate. In some embodiments, Z is F ^- 、Cl ^- 、Br ^- Or I ^- . In some embodiments, Z is Br ^- 。

In some embodiments, the asymmetric catalyst used in the disclosed methods may be selected from the group consisting of:/>

in some embodiments, the asymmetric catalyst is +.>In some particular instances of the embodiments shown herein, Z is bromide or chloride. In some embodiments, Z is chloride. In some embodiments, Z is bromide.

In general, the asymmetric catalyst is present in 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 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 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 at 0.25 molar equivalents based on 1.0 molar equivalent of compound (I).

Generally, the base may comprise an inorganic base. Contemplated inorganic bases include, but are not limited to, 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 PO ₄ 、Na ₃ PO ₄ 、Li ₃ PO ₄ 、K ₂ HPO ₄ 、Na ₂ HPO ₄ 、Li ₂ HPO ₄ 、NaHCO ₃ 、LiHCO ₃ And KHCO ₃ . In some embodiments, the base comprises Cs ₂ CO ₃ . 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 based on 1.0 molar equivalent of compound (I)Is 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. For example, the inorganic base may be present at 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).

Generally, the solvent system is biphasic. In some embodiments, the biphasic solvent system may comprise an aprotic organic solvent and water. Contemplated aprotic organic solvents include, but are not limited to, methylene chloride, tetrahydrofuran, toluene, benzene, cyclopentylmethyl ether, t-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 at a concentration of 3L/kg to 30L/kg based on the weight of compound (I).

Generally, the methods disclosed herein can include mixing at a temperature of-40 ℃ to 30 ℃. In some embodiments, the mixing is performed at a temperature of-30 ℃ to 30 ℃, -20 ℃ to 20 ℃, -20 ℃ to 10 ℃, or-20 ℃ to 5 ℃. For example, the mixing is carried out at a temperature of-40 ℃, -30 ℃, -20 ℃, -15 ℃, -10 ℃, -5 ℃,0 ℃,5 ℃,10 ℃,20 ℃, or 30 ℃.

Generally, the methods disclosed herein can comprise mixing for 1 hour to 72 hours. In some embodiments, the mixing 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, the mixing 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.

In general, the methods disclosed herein can produce compound Y in high enantiomeric excess (e.g., 30% or more). In some embodiments, compound Y is produced in an enantiomeric excess of 30% or more. In some embodiments, compound Y is produced in an enantiomeric excess of 40% or more. In some embodiments, compound Y is produced in an enantiomeric excess of 50% or more. In some embodiments, compound Y is produced in enantiomeric excess with 60% or more.

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, compound Y (when R ¹ Is CO ₂ Me or CN) may undergo, for example, a hydrolysis reaction, oxidation, hydrogenation to form compound A3A, and then the salt of compound A3A may be crystallized. In some cases, compound Y (when R ¹ Is CO ₂ Me or CN) may be subjected to oxidation, hydrolysis reaction, hydrogenation to form compound A3A, for example, and then the salt of compound A3A may be crystallized. In some cases, compound Y (when R ¹ Is CO ₂ Me or CN), for example, can undergo hydrogenation, oxidation/reduction amination to cyclize the aniline to the alcohol by oxidation/reduction neutrality (by hydrogen) to form compound A3A, and then the salt of compound A3A can be crystallized. In some cases, compound Y (when R ¹ Is CO ₂ H) may be subjected to oxidation, hydrogenation to form compound A3A, for example, and then the salt of compound A3A may be allowed to crystallize.

Scheme 2-general procedure for the Synthesis of Compound A3A

The compound Y1 prepared by the methods 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 salts and solvates thereof. Compound Y1 can then be used via compound A3A to synthesize compound A1 as shown in scheme 3. As shown in scheme 4, compound A1 can be used to synthesize compound A2 as shown in scheme 4. It will be appreciated that compound Y can be used to prepare A3 and also to prepare the enantiomer of A3A, and that the choice of catalyst and conditions can also be used to produce the enantiomer of compound Y1.

Scheme 3-conversion of Compound A3 to Compound A1

As shown above and described in us patent No. 9,562,061, compound A3A can be used to synthesize compound A1 and salts and solvates thereof. Compound Y1 may be used to prepare compound A1 as described herein.

Scheme 4 conversion of Compound A1 to Compound A2

As shown above and described in us patent No. 10,300,075, compound C can be used to synthesize compound A2 and salts and solvates thereof. Compound C may be oxidized to provide a cyclic ketene I as disclosed in us patent No. 10,300,075. Ketene I can then be converted to epoxide J using the procedure 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 us patent No. 10,300,075.

It is to be understood that while the disclosure has been read in conjunction with the specific embodiments thereof, the foregoing description and the following examples are intended to illustrate and not limit the scope of the disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Examples

The following examples are provided for illustration and are not intended to limit the scope of the invention.

Example 1:SN forming Compound Y _Ar Reaction

Synthesis of Compound Y2

(R) -4- ((6-chloro-1- (hydroxymethyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methoxy) -3-nitrobenzoic acid methyl ester (Compound Y2, wherein R) ¹ Is CO ₂ Me): into an easy Max reactor vessel (glass, 100 mL) was charged in sequence [ 6-chloro-1- (hydroxymethyl) tetralin-1-yl ]]Methanol (THN-DIOL, 3.00g,13.2mmol,1.0 eq.) 4-fluoro-3-nitrobenzoic acid methyl ester (2.64 g,13.2mmol,1.0 eq.) wherein Lg is F and R ¹ Methyl) and (1R, 2S) -N-ethyl-1-hydroxy-N, N-dimethyl-1-phenylpropane-2-ammonium bromide (11, 1.43g,3.31mmol,0.25 eq.). The vessel was placed in an EasyMax Advanced synthesis workstation and sealed with a six port reactor cover equipped with overhead stirrer, nitrogen (N2) input line, temperature probe and baffles to aid mixing. The reactor was charged with toluene (82.5 ml,27.5 volumes, 0.15M relative to THN-DIOL) and the remaining oral rubber septum sealed. The reaction mixture was stirred (overhead, 800 rpm) to give an off-white slightly heterogeneous solution (fines). The reaction mixture was cooled (jacket temperature-20.0 ℃) until the internal temperature reached-17.0 ℃. At this point, cesium carbonate aqueous solution (4.54 ml,13.2mmol,1.0 eq, 50wt% aqueous solution) was added to the reaction mixture through the septum by syringe (drop by drop, 2 min). After the addition of the base, the reaction mixture became pale yellow. The solution was stirred for 16h (jacket temperature-20.0 ℃). After this time, stirring was stopped, the mixture was warmed (5 ℃) 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 volumes) was added to the separatory funnel and the mixture was gently shaken and vented. The biphasic mixture was allowed to stand (10 min) and the phases were allowed to separate. After LC analysis of the two phases, the organic layer was concentrated by means of a rotary evaporator to give a thick yellow oil. The crude reaction mixture was purified by automated silica gel column chromatography (Biotage, 340g column, 5% -40% EtOAc in heptane gradient16 column volumes) to provide compound Y2 (wherein R ¹ Is CO ₂ Me) (0.930 g,17.3% yield, 54% ee).

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),7.16-7.10(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。

Although compound Y1 was not synthesized above, this chemical reaction was intended to demonstrate the progress of asymmetric nucleophilic aromatic substitution with the catalyst. Without intending to be bound by theory, the enantiomer using asymmetric catalyst 11 is believed to be capable of yielding compound Y1.

Synthesis of Y1

(S) -4- ((6-chloro-1- (hydroxymethyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methoxy) -3-nitrobenzoic acid methyl ester (Compound Y1, wherein R) ¹ Is CO ₂ Me): the vials were filled with N- [4- (trifluoromethyl) benzyl group]Cinchonine bromide (0.10 eq,6.7 mg), [ 6-chloro-1- (hydroxymethyl) tetrahydronaphthalen-1-yl]Methanol (THN-DIOL, 1.0eq,23 mg), methyl 4-fluoro-3-nitrobenzoate (1.0 eq,20mg, wherein Lg is F and R ¹ Methyl) and CHCl ₃ (167. Mu.L). The vial was cooled to +1℃andcharged with cesium carbonate (50 wt% solution, 1 eq). The vial was shaken for 16hr and then quenched with 1N HCl (50. Mu.L). HPLC analysis indicated that the title compound (Y1) was formed at 32% conversion, 32% ee.

EXAMPLE 2 hydrolysis and Oxidation of Compounds Y, e.g. Y1

Hydrolysis reaction

(S) -4- ((6-chloro-1- (hydroxymethyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methoxy) -3-nitrobenzoic acid (Compound Y1, wherein R) ¹ Is CO ₂ H) The method comprises the following steps A100 mL EasyMax reactor was charged with solid compound Y1 (wherein R ¹ Is CO ₂ Me) (2.00 g,4.93mmol,1.0 eq.) and THF (20.0 mL, 10V). The reactor was equipped with an overhead stirrer, N ₂ The inlet and the six-port reactor cover of the temperature probe were sealed. The internal reaction temperature was maintained between 22℃and 25℃by syringe stepwise addition of a 5N aqueous solution of sodium hydroxide (4.93 mL,24.6mmol,5.0 eq.). The reaction mixture was stirred at 22 ℃ for 23 hours, while stirring 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) and the combined organic extracts were extracted with H ₂ O (20 mL) washing over MgSO ₄ Dried, filtered, and concentrated in vacuo. The residue was taken up in a small amount of DCM and concentrated to remove excess 2-MeTHF. Crude compound Y1 (wherein R is ¹ Is CO ₂ H) (1.72 g,87% w/w,96% yield).

¹ H NMR(500MHz,DMSO-d ₆ ):δ13.28(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-d ₆ ):δ166.3,155.8,141.6,139.6,137.7,136.2,131.6,130.7,129.2,127.1,126.2,123.7,116.1,74.9,66.4,30.7,28.5,19.3。

Oxidation reaction

(R) -4- ((6-chloro-1-formyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methoxy) -3-nitrobenzoic acid: equipped with overhead stirrer, temperatureProbe and N ₂ An inlet 100mL EasyMax reactor was charged with compound Y1 (wherein R ¹ Is CO ₂ H) (1.85 g,4.72mmol,1.00 eq.) and DCM (9.25 mL, 5.0V). N, N-diisopropylethylamine (3.05 mL,23.6mmol,5.0 eq.) was added to the slurry. The resulting clear yellow solution was cooled to 0 ℃. Dimethyl sulfoxide (DMSO) (5.55 ml,3.0 v) was added stepwise by syringe followed by SO in triplicate ₃ Pyridine (1.88 g,11.8mmol,2.50 eq.). After the addition, the reaction was warmed to 20 ℃ over 1 hour and stirred at 20 ℃ for 2 hours. The reaction was then cooled to 0deg.C and purified by addition of 10% NaHSO ₄ The aqueous solution (15 mL) was acidified to pH 3. 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 washed with brine over MgSO ₄ Dried, filtered, and concentrated in vacuo. The crude residue was taken up in 2.5V acetic acid and 1.5V H was added dropwise ₂ O. The resulting slurry was aged for 1 hour, then filtered, with additional H ₂ And (3) washing. A light brown solid was obtained which was contaminated with excess diisopropylethylamine. Solids in H ₂ Repulping in O (5 mL), aging for 2.5 hours, and filtering with additional H ₂ And (3) flushing. Obtaining compound Y1 (wherein R is ¹ Is CO ₂ H) (1.18 g,90.5% w/w,67% yield).

¹ H NMR(500MHz,DMSO-d ₆ ):δ9.63(s,1H),8.30(d,J＝2.1Hz,1H),8.12(dd,J＝2.2,8.8Hz,1H),7.50(d,J＝9.0Hz,1H),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-d ₆ ):δ201.8,166.2,155.1,142.2,139.6,136.1,133.1,131.5,130.9,130.2,127.1,126.9,124.3,116.4,73.2,53.8,29.9,26.4,18.9。

Claims (55)

1. A process for the synthesis of compound Y or a salt thereof:

the method comprises the following steps:

mixing compound (I), compound (II), catalyst and base in a biphasic solvent system to form compound Y:

wherein the method comprises the steps of

R ¹ Is CO ₂ C _1-6 Alkyl, CO ₂ H、CON(C _1-6 Alkyl group ₂ 、CO ₂ Ar ¹ 、CO ₂ Bn or CN;

lg is a leaving group; and is also provided with

Ar ¹ Is C _6-22 Aryl or a 5-12 membered heteroaryl containing 1 to 3 ring heteroatoms selected from O, N and S.

2. The method of claim 1, wherein compound Y has a stereochemistry as shown in compound Y1

3. The method of claim 1, wherein compound Y has a stereochemistry as shown in compound Y2

4. A method according to any one of claims 1 to 3, wherein R ¹ Is CO ₂ C _1-6 An alkyl group.

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

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

7. A method according to any one of claims 1 to 3, wherein R ¹ Is CN.

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

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

10. The method of claim 9, wherein Lg is F, cl, br, I, methanesulfonyl, toluenesulfonyl, nitrobenzenesulfonyl or trifluoromethanesulfonyl.

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

12. The method of any one of claims 1-11, wherein the catalyst is an asymmetric catalyst.

13. The method of claim 12, wherein the asymmetric catalyst has a structureWherein the method comprises the steps of

Each R ² Independently C _1-22 Alkyl, C _5-8 Cycloalkyl or Ar ¹ Or (b)

Each R ² Together with the atoms to which they are attached, form a five to eight membered cycloalkyl group;

each R ³ Independently C _1-22 Alkyl, C _5-8 Cycloalkyl, bn or Ar ¹ Or (b)

Two R ³ Together with the nitrogen to which they are attached, form a five to twenty-five membered heterocyclic ring 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 H, C independently _1-12 Alkyl or Ar ¹ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

Z is a counter ion.

14. The method of claim 13, wherein the asymmetric catalyst has a structure

15. The method of claim 14, wherein the asymmetric catalyst can have a structure

16. The method of any one of claims 13-15, wherein each R ² Independently selected from Me, et, iPr, sBu, tBu, phenyl, tolyl, and combinations thereof,

Or each R ² Together with the atoms to which they are attached form a cyclohexyl or cyclopentyl group. />

17. The method of any one of claims 13-16, wherein X is OH,

-NHSO ₂ Me、-NHSO ₂ Tolyl, -NHSO ₂ (nitrophenyl), ->-CF ₂ H、-SH、-NH ₂ 、-NHMe、-NHPh、

18. The method of any one of claims 13-17, wherein the asymmetric catalyst comprises-N (R ³ ) ₃ ⁺ ：–NMe ₃ 、-NMe ₂ Bn、-NMeBn ₂ 、-NBn ₃ 、

/>

19. The method of claim 12, wherein the asymmetric catalyst has a structureWherein each Ar is ² Independently selected from C _6-22 Aryl or a 5-12 membered heteroaryl containing from 1 to 3 ring heteroatoms selected from O, N and S, and Z is a counterion.

20. The method of claim 19, wherein at least one Ar ² Is phenyl or substituted phenyl.

21. The method of claim 20, wherein each Ar ² Is phenyl.

22. The method of claim 20, wherein each Ar ² Independently selected from

And Ph. />

23. The method of claim 12, wherein the asymmetric catalyst has a structureWherein Ar is ³ Selected from C _6-22 Aryl or a 5-12 membered heteroaryl containing from 1 to 3 ring heteroatoms selected from O, N and S, and Z is a counterion.

24. The method of claim 23, wherein Ar ³ Is phenyl or substituted phenyl.

25. The method of claim 24, wherein Ar ³ Is phenyl.

26. The method of claim 24, wherein Ar ³ Selected from the group consisting of

And Ph.

27. The method of claim 12, wherein the asymmetric catalyst is selected from the group consisting of:

/>

28. the method of claim 27, wherein the asymmetric catalysisThe agent is

29. The method of any one of claims 12-28, wherein Z is a halide, triflate, mesylate, tosylate, or m-nitrobenzenesulfonate.

30. The method of claim 29, wherein Z is chloride or bromide.

31. The method of any one of claims 1-30, wherein the base comprises an inorganic base.

32. The method of claim 31, wherein the base comprises 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 PO ₄ 、Na ₃ PO ₄ 、Li ₃ PO ₄ 、K ₂ HPO ₄ 、Na ₂ HPO ₄ 、Li ₂ HPO ₄ 、NaHCO ₃ 、LiHCO ₃ Or KHCO ₃ 。

33. The method of claim 32, wherein the base comprises Cs ₂ CO ₃ 。

34. The process of any one of claims 31-33, wherein the inorganic base is present in 0.95 to 6 molar equivalents based on 1.0 molar equivalent of compound (I).

35. The method of any one of claims 1-34, wherein the biphasic solvent system comprises an aprotic organic solvent and water.

36. The method of claim 35, wherein the aprotic organic solvent comprises dichloromethane, tetrahydrofuran, toluene, benzene, cyclopentylmethyl ether, t-butyl methyl ether, 2-methyltetrahydrofuran, anisole, xylene, benzotrifluoride, 1, 2-dichloroethane, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, or a combination thereof.

37. The method of claim 36, wherein the aprotic organic solvent comprises toluene.

38. The process of claim 37, wherein the toluene is present at a concentration of 3L/kg to 30L/kg based on the weight of compound (I).

39. The process of any one of claims 35-38, comprising mixing compound (I), compound (II) and the catalyst in the aprotic organic solvent prior to adding the base.

40. The method of any one of claims 1-39, wherein the mixing is performed at a temperature of-40 ℃ to 30 ℃.

41. The method of claim 40, wherein the mixing is performed at a temperature of-15 ℃ to-25 ℃.

42. The method of any one of claims 1-41, wherein the mixing is performed for 1 hour to 72 hours.

43. The method of claim 42, wherein the mixing is performed for 14 hours to 18 hours.

44. The process of any of claims 1-43, wherein compound (II) is present in an amount of 0.9 to 2 molar equivalents based on 1.0 molar equivalent of compound (I).

45. The process of claim 44 wherein compound (II) is present at 1.0 molar equivalent based on 1.0 molar equivalent of compound (I).

46. The process of any of claims 1-45, wherein the asymmetric catalyst is present in 0.005 to 1.50 molar equivalents based on 1.0 molar equivalent of compound (I).

47. The process of claim 46 wherein the asymmetric catalyst is present at 0.25 molar equivalents based on 1.0 molar equivalent of compound (I).

48. The process of any one of claims 1-47, wherein compound Y is produced in an enantiomeric excess of 30% or more.

49. A process as set forth in claim 48 wherein compound Y is produced in an enantiomeric excess of 40% or greater.

50. The process of claim 49 wherein compound Y is produced in an enantiomeric excess of 50% or more.

51. The method of any one of claims 1-50, further comprising synthesizing compound A3, or a salt or solvate thereof, from compound Y:

52. the method of claim 51, wherein the compound A3 or a salt or solvate thereof has the structure A3A, or is a salt or solvate thereof

53. The method of claim 51, wherein the compound A3 or a salt or solvate thereof has the structure A3B, or a salt or solvate thereof

54. The method of any one of claims 1-53, further comprising synthesizing compound A1, or a salt or solvate thereof, from compound Y:

55. the method of any one of claims 1-53, further comprising synthesizing compound A2, or a salt or solvate thereof, from compound Y:

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