Method for synthesizing complement factor D inhibitors and their intermediates

Abstract

This disclosure provides a method for synthesizing complement factor D inhibitors and their intermediates.

Description

[Technical Field]

[0001] The complement system is part of the innate immune system that does not adapt to lifelong changes in the host, but is mobilized and used by the adaptive immune system. For example, it assists or complements the ability of antibodies and phagocytic cells to eliminate pathogens. This sophisticated regulatory pathway enables a rapid response to pathogenic organisms while protecting host cells from destruction. More than 30 proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing antigen phagocytosis), chemotaxis (attracting macrophages and neutrophils), cytolysis (breaking down the membranes of foreign cells), and aggregation (clustering and binding pathogens together).

[0002] The complement system has three pathways: the classical pathway, the alternative pathway, and the lectin pathway. Complement factor D plays an initial central role in the activation of the alternative pathway in the complement cascade. Activation of the alternative complement pathway is initiated by the spontaneous hydrolysis of thioester bonds within the C3 protein, producing C3(H2O), which associates with factor B to form the C3(H2O)B complex. Complement factor D acts to cleave factor B within the C3(H2O)B complex to form Ba and Bb. The Bb fragment remains associated with C3(H2O) to form the alternative pathway C3 convertase C3(H2O)Bb. Additionally, C3b produced by any of the C3 convertases also associates with factor B to form C3bB, which is cleaved by complement factor D to produce the later alternative pathway C3 convertase C3bBb. This latter form of the alternative pathway C3 convertase provides crucial downstream amplification in all three of the defined complement pathways, ultimately leading to the recruitment and assembly of additional factors in the complement cascade pathway, including the cleavage of C5 into C5a and C5b. C5b acts in the assembly of factors C6, C7, C8, and C9 into the membrane invasion complex, which can destroy pathogenic cells by lysing them.

[0003] Complement dysfunction or excessive activation is associated with certain autoimmune diseases, inflammatory diseases, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, activation of alternative pathways in the complement cascade contributes to the production of C3a and C5a, both of which are potent anaphylatoxins and play a role in many inflammatory disorders. Therefore, in some cases, it is desirable to reduce the response of the complement pathway, including alternative complement pathways. Some examples of disorders mediated by the complement pathway include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and rheumatoid arthritis.

[0004] Further complement-mediated disorders include those classified as component 3 glomerulopathy (C3G). C3G is a recently defined disease type that comprises dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), encompassing a population of chronic kidney disease in which increased activity of alternative complement pathways and complement terminal pathways leads to glomerular deposition consisting solely of complement C3 and lacking immunoglobulin (Ig).

[0005] Immune complex-type membranoproliferative glomerulonephritis (IC-MPGN) is a renal disease that shares many clinical, pathological, genetic, and experimental features with C3G and can therefore be considered a sister disease of C3G. In the majority of IC-MPGN patients, infection, autoimmune disease, or monoclonal hypergammaglobulinemia is most commonly identified as the underlying disease or disorder with secondary renal disease. Patients with idiopathic IC-MPGN may have low C3 and normal C4 levels similar to those observed in C3G, as well as many of the same genetic or acquired factors associated with abnormal secondary pathway activity. Current hypotheses suggest that the majority of IC-MPGN cases are due to excessive activity of the classical pathway, but patients with low C3 and normal C4 are likely to have significantly excessive activity of the secondary pathway. IC-MPGN patients with low C3 and normal C4 may benefit from inhibition of the secondary pathway.

[0006] Other disorders associated with the complement cascade include atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis, neuromyelitis optica (NMO), myasthenia gravis (MG), fatty liver, non-alcoholic steatohepatitis (NASH), hepatitis, cirrhosis, hepatic failure, dermatomyositis, and amyotrophic lateral sclerosis (ALS).

[0007] Factor D is an attractive target for inhibiting or modulating the complement cascade due to its early essential role in the alternative complement pathway, as well as its potential role in signal amplification within the classical and lectin complement pathways. Inhibition of factor D effectively disrupts the pathway and attenuates the formation of membrane invasion complexes.

[0008] For this purpose, many small molecule factor D inhibitors have been developed and are being studied for their potential therapeutic applications. Examples of these factor D inhibitor compounds and methods for preparing them are described, for example, in International Publications 2015 / 130838, 2017 / 035353, 2017 / 035409, 2018 / 160889, 2020 / 041301, and 2021 / 168320.

[0009] Novel methods for synthesizing small molecule factor D inhibitors and their intermediates are desirable. [Overview of the project]

[0010] This disclosure relates, in general terms, to improved methods for preparing compounds and intermediates useful for treating complement factor D-mediated disorders.

[0011] In particular, this disclosure relates to formula (VI)

[0012] [ka] [In the formula, P 1 and P 2 With respect to compounds of the formula (XI) as defined herein, they are

[0013] [Chemical formula] [wherein, variable elements R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , m, and B are as defined herein] is an intermediate for the synthesis of a complement factor D inhibitor.

[0014] The present disclosure is based in part on the unexpected discovery that the compounds of formula (VI) can be prepared via a cyclopropanation reaction without using dangerous reagents, such as diethylzinc required for the Simmons–Smith cyclopropanation reaction. In addition to eliminating the use of dangerous reagents, this method also provides improved selectivity in cyclopropanation, the ability to use readily available starting materials, shortening of the total reaction steps for preparing the compounds of formula (VI), and improved yields.

[0015] Thus, in one aspect, the present disclosure provides a method for preparing a compound of formula (VI). This method comprises providing a compound of formula (V)

[0016] [Chemical formula] [wherein, P 1 and P 2 are as defined herein], and forming a compound of formula (VI) from the compound of formula (V). Forming the compound of formula (VI) comprises contacting the compound of formula (V) with a Co(II) catalyst in the presence of Zn and CH2Br2.

[0017] Also, herein, from a compound of formula (VI) prepared by any one of the methods disclosed herein to formula (XI)

[0018] [ka] This provides a method for preparing the compound.

[0019] definition To facilitate understanding of this disclosure, several terms are defined below. Terms as defined herein have meanings commonly understood by those skilled in the art relating to this disclosure. Terms such as "a," "an," and "the" are not intended to refer only to singular entities, but include general classes for which specific examples may be used for illustrative purposes. Terms herein are used to describe specific embodiments of the invention, but their use is not intended to limit the invention except as outlined in the claims.

[0020] When used herein, any value provided within a range of values ​​includes both the upper and lower limits, as well as any value that falls within the upper and lower limits.

[0021] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound that, within reasonable medical judgment, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, etc., and is described as having a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PHStahl and CGWermuth), Wiley-VCH, 2008. These salts may be acid addition salts with inorganic or organic acids. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable acid. Methods for preparing suitable salts are well established in the art.

[0022] As used herein, the term “acyl” refers to a monovalent radical having the structure -COR, where R is alkyl, alkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. The acyl may be optionally substituted as defined for each R group.

[0023] As used herein, the term “alkyl” refers to a branched or linear monovalent saturated aliphatic radical containing only C and H in the unsubstituted case. Monovalent alkyl groups do not include any substituents on the alkyl group. For example, if an alkyl group is bonded to a compound, monovalent alkyl groups refer to their bond to the compound and do not include any additional substituents that may be present on the alkyl group. In some embodiments, alkyl groups may contain, for example, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 2 carbon atoms (e.g., C1 to C1). 12 , C1~C 10 (C1-C8, C1-C6, C1-C4, or C1-C2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, and tert-butyl.

[0024] As used herein, the term "alkylene" refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an alkyl group. The divalent alkylene group does not include any substituents on the alkylene group.

[0025] As used herein, the term “alkenyl” refers to a branched or linear monovalent unsaturated aliphatic radical containing at least one carbon-carbon double bond, but not a carbon-carbon triple bond, and containing only C and H in the unsubstituted case. The monovalent nature of an alkenyl group does not include any substituents on the alkenyl group. For example, if an alkenyl group is bonded to a compound, the monovalent nature of the alkenyl group refers to its bond to the compound and does not include any additional substituents that may be present on the alkenyl group. In some embodiments, the alkenyl group may contain, for example, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms (e.g., C2 to C2). 12 , C2~C 10 (C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, and 3-butenyl.

[0026] As used herein, the term “alkenyloxy” refers to a monovalent radical having the structure -O-alkenyl, and “alkenyl” is as defined herein. Examples include, but are not limited to, ethenyloxy and propenyloxy.

[0027] As used herein, the term "alkoxy" refers to a monovalent radical having the structure -O-alkyl, and "alkyl" is as defined herein. Examples include, but are not limited to, methoxy, ethoxy, and n-butoxy, i-butoxy, and t-butoxy.

[0028] As used herein, the term "alkynyl" refers to a branched or linear monovalent unsaturated aliphatic radical containing at least one carbon-carbon triple bond and, in the unsubstituted case, only C and H. The monovalent nature of the alkynyl group does not include any substituents on the alkynyl group. For example, if the alkynyl group is bonded to a compound, the monovalent nature of the alkynyl group refers to its bond to the compound and does not include any additional substituents that may be present on the alkynyl group. In some embodiments, the alkynyl group may contain, for example, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C2). 12 , C2~C 10 (C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, ethinyl, 1-propynyl, and 3-butynyl.

[0029] As used herein, the term "aryl" refers to a monovalent monocyclic, fused-bicyclic, or polycyclic system having aromatic characteristics in terms of the electron distribution throughout the ring system, such as phenyl, naphthyl, or phenanthryl. An aryl group may have, for example, 6 to 16 carbon atoms (e.g., C6 to C6). 16 Aryl, C6~C 14 Aryl, C6~C 13 Aryl, or C6~C 10 Ariel).

[0030] As used herein, the term "arylalkyl" refers to a monovalent radical having the structure -R'R'', where R' is alkylene and R'' is aryl. Arylalkyls may be optionally substituted in the same manner as defined for each R' and R'' group.

[0031] As used herein, the term "carbocyclyl" refers to a monovalent saturated or unsaturated non-aromatic cyclic group containing only C and H in the unsubstituted case. Carbocyclyls (e.g., cycloalkyl or cycloalkenyl) may have, for example, 3 to 14 carbon atoms (e.g., C3-C7, C3-C8, C3-C9, C3-C 10 , C3~C11 , C3~C 12 , C3~C 14 Carbocyclyl). The term "carbocyclyl" also includes bicyclic and polycyclic (e.g., tricyclic and tetracyclic) fused ring structures.

[0032] As used herein, the term “cycloalkyl” refers to a saturated carbocyclic ring. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkyl” also includes cyclic groups having a bridging polycyclic structure in which one or more carbons bridge two non-adjacent members of a monocyclic ring, such as bicyclo[2.2.1]heptyl and adamantyl. The term “cycloalkyl” also includes bicyclic, tricyclic, and tetracyclic fused ring structures, such as decalin and spirocyclic compounds.

[0033] As used herein, the term "cyano" refers to a monovalent radical having the structure -CN.

[0034] As used herein, the term "cycloalkenyl" refers to a monovalent unsaturated carbocyclyl group that contains at least one carbon-carbon double bond, does not contain a carbon-carbon triple bond, contains only C and H in the unsubstituted case, and is not entirely aromatic. Cycloalkenyls can have, for example, 4 to 14 carbon atoms (e.g., C4-C7, C4-C8, C4-C9, C4-C 10 , C4~C 11 , C4~C 12 , C4~C 13 , or C4~C 14Cycloalkenyls). Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. The term “cycloalkenyl” also includes cyclic groups having a bridging polycyclic structure in which one or more carbons bridge two non-adjacent members of a monocyclic ring, such as bicyclo[2.2.2]octa-2-ene. The term “cycloalkenyl” also includes fused bicyclic and polycyclic systems containing one or more double bonds, such as fluorene.

[0035] As used herein, the term "halo" refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0036] As used herein, the term “heteroarylalkyl” refers to a monovalent radical of the structure –R'R” where R' is alkylene and R” is heteroaryl. Heteroarylalkyls may be optionally substituted in the same manner as the definitions for each R' and R” group.

[0037] As used herein, the term “heterocyclyl” refers to a saturated or unsaturated monocyclic, fused-bicyclic, or polycyclic system having one or more carbon atoms and at least one heteroatom selected from N, O, and S, for example, 1 to 4 heteroatoms (e.g., 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, or 4 heteroatoms). Heterocyclyl groups include both non-aromatic and aromatic systems. Aromatic heterocyclyl groups are called “heteroaryl” groups. In some embodiments, a heterocyclyl group is a ring or ring system having 3 to 8-membered rings, 3 to 6-membered rings, 4 to 6-membered rings, 4 to 10-membered rings, 6 to 10-membered rings, 6 to 12-membered rings, 5-membered rings, or 6-membered rings, or a number of ring atoms falling within any of the above ranges. An exemplary five-membered heterocyclyl group may have 0 to 2 double bonds, and an exemplary six-membered heterocyclyl group may have 0 to 3 double bonds. Examples of exemplary five-membered groups include optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxatriazole, and optionally substituted 1,2,3,4-thiatriazole. Examples of six-membered heterocyclyl groups include, but are not limited to, optionally substituted pyridines, optionally substituted piperidines, optionally substituted piperazines, optionally substituted pyrimidines, optionally substituted pyrazines, optionally substituted pyridazines, optionally substituted triazines, optionally substituted 2H-pyrans, optionally substituted 4H-pyrans, and optionally substituted tetrahydropyrans.Examples of 7-membered heterocyclyl groups include, but are not limited to, optionally substituted azepines, optionally substituted 1,4-diazepines, optionally substituted thiepines, and optionally substituted 1,4-thiazepines. Examples of 8- to 10-membered bicyclic groups include, but are not limited to, optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyrimidinyl, optionally substituted thiazolo[5,4-b]pyrimidinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyrimidinyl, 1H-thieno[3,2-c]pyrazolyl, imidazo[1,2-b]pyridadinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1H-benzo[d]imidazolyl.

[0038] As used herein, the term “carboxyl protecting group” refers to any group that can protect the oxygen atom of the -OH functional group of a carboxyl group from involvement in one or more undesirable reactions during chemical synthesis. Carboxyl protecting groups are introduced by reacting a molecule having an unprotected carboxyl group with a carboxyl protecting reagent, which can be removed by a carboxyl protecting agent. Carboxyl protecting groups, their corresponding carboxyl protecting reagents, and carboxyl protecting agents suitable for the removal of carboxyl protecting groups are known in the art, for example, as described in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006. Examples of carboxyl protecting groups include, but are not limited to, alkyl (e.g., methyl, ethyl, or tert-butyl), benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, pentamethylbenzyl, benzydryl, 3,4-methylenedioxybenzyl, 4,4-dimethoxytrityl, 4,4',4”-trimethoxytrityl, 2-phenylpropyl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, and 1-(trimethylsilylmethyl)-propenyl.

[0039] As used herein, the term “N-protecting group” refers to a group that protects a nitrogen atom in a molecule from involvement in one or more undesirable reactions during chemical synthesis. N-protecting groups are introduced by reacting a molecule containing a nitrogen atom with an N-protecting reagent and can be removed using an N-protecting group remover. Commonly used N-protecting groups, their corresponding N-protecting reagents, and N-protecting group removers are disclosed in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006.Examples of N-protecting groups include acyls (e.g., formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, and 4-bromobenzoyl), sulfonyl-containing groups (e.g., benzenesulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl), carbamate-forming groups (e.g., benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4- Examples include methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl), arylalkyl groups (e.g., triphenylmethyl), silyl groups (e.g., trimethylsilyl), and imine-forming groups (e.g., diphenylmethylene). Further examples of N-protecting groups include acetyl, benzoyl, phenylsulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, o-nitrobenzenesulfonyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0040] As used herein, the term "oxo" refers to a divalent oxygen atom represented by the structure = O.

[0041] As used herein, the term "thioalkyl" refers to a monovalent group having a -S-alkyl structure, and "alkyl" is as defined herein.

[0042] As used herein, the phrase “optionally substituted X” is intended to be equivalent to “X which is optionally substituted” (e.g., “an alkyl which is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) itself is optional. As used herein, the term “optionally substituted” means having zero, one, or more substituents (e.g., 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0 or 1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents).

[0043] The alkyl, alkylene, alkenyl, alkynyl, carbocyryl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl groups may be substituted with one or more of the following: carbocyryl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, halo, OH, cyanoalkoxy, alkenyloxy, thioalkyl, NO2, N3, NRR' [wherein R and R' are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl], SO2R [wherein R is H, alkyl, or aryl], SO2NRR' [wherein R and R' are each independently H, alkyl, or aryl], or NRSO2R [wherein R and R' are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl]. The aryl, carbocyryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclyl groups may also be substituted with alkyl, alkenyl, or alkynyl groups. The alkyl, alkoxy, carbocyryl, cycloalkyl, cycloalkenyl, and unsaturated heterocyclyl groups may also be substituted with oxo groups. In some embodiments, substituents are further substituted as described herein. For example, a C6 aryl group, i.e., phenyl, may be substituted with an alkyl group, which may be further substituted with a heterocyclyl group. [Brief explanation of the drawing]

[0044] [Figure 1] This is a schematic diagram of the continuous flow setup used for the synthesis of compound 2d described in Example 3. [Modes for carrying out the invention]

[0045] This disclosure provides a method for synthesizing a small molecule complement factor D inhibitor and its intermediates. The complement factor D inhibitor is given by formula (XIII)

[0046] [ka] [In the formula, variable element R 1 ~R 6 , X 1 ~X 5 , m, and B are compounds of [as defined herein] or pharmaceutically acceptable salts thereof. Exemplary compounds of formula (XIII) are described, for example, in International Publications 2015 / 130838, 2017 / 035353, 2017 / 035409, 2018 / 160889, 2020 / 041301, and 2021 / 168320, the entire contents of which are incorporated herein by reference.

[0047] In particular, the method described herein is based on formula (VI)

[0048] [ka] [In the formula, P 1 is an H or N protecting group (e.g., tert-butoxycarbonyl), and P 2 This relates to the preparation of compounds of formula (V)

[0049] [ka] [In the formula, P 1 is an H or N protecting group, and P 2 The present invention provides a compound of which is H or a carboxyl protecting group (e.g., an alkyl group such as methyl), and involves forming a compound of formula (VI) from a compound of formula (V) by a cyclopropanation reaction carried out using a Co(II) catalyst in the presence of Zn and CH2Br2. In some embodiments, the reaction is carried out using a Co(II) catalyst in the presence of Zn, CH2Br2, and ZnCl2.

[0050] In some embodiments, Zn is in the form of zinc powder (e.g., having a particle size of less than 10 microns). In some embodiments, Zn, for example in the form of zinc powder, is activated (e.g., with HCl). Methods for preparing activated Zn are generally known in the art.

[0051] In some embodiments, Zn is present in amounts of 2 to 10 equivalents (e.g., 3 to 8 equivalents, 4 to 6 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents, 7 equivalents, 8 equivalents, 9 equivalents, or 10 equivalents) relative to the compound of formula (V). In some embodiments, Zn is present in amounts of 5 equivalents relative to the compound of formula (V). In some embodiments, Zn is added sequentially in two or more portions. In some embodiments, Zn is added sequentially in two portions (e.g., a first portion of 3 equivalents relative to the compound of formula (V), followed by a second portion of 2 equivalents relative to the compound of formula (V)).

[0052] In some embodiments, ZnCl2 is present in amounts of 2 to 10 equivalents (e.g., 3 to 8 equivalents, 4 to 6 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents, 7 equivalents, 8 equivalents, 9 equivalents, or 10 equivalents) relative to the compound of formula (V). In some embodiments, ZnCl2 is present in amounts of 5 equivalents relative to the compound of formula (V). In some embodiments, ZnCl2 is added sequentially in two or more portions. In some embodiments, ZnCl2 is added sequentially in two portions (e.g., a first portion of 3 equivalents relative to the compound of formula (V), followed by a second portion of 2 equivalents relative to the compound of formula (V)).

[0053] In some embodiments, CH2Br2 is present in amounts of 1 to 10 (e.g., 2 to 9 equivalents, 3 to 7 equivalents, 4 to 6 equivalents, 2 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents, 7 equivalents, 8 equivalents, 9 equivalents, or 10 equivalents) relative to the compound of formula (V). In some embodiments, CH2Br2 is present in amounts of 4 equivalents relative to the compound of formula (V). In some embodiments, CH2Br2 is added sequentially in two or more portions. In some embodiments, CH2Br2 is added sequentially in three portions (e.g., a first portion of 1.5 equivalents relative to the compound of formula (V), a second portion of 1 equivalent relative to the compound of formula (V), and then a third portion of 1.5 equivalents relative to the compound of formula (V)).

[0054] The embodiments of the method disclosed herein unexpectedly yield compounds of formula (VI) with high stereoselectivity (about 97:3), which is maintained, for example, in subsequent reactions in the multi-step synthesis of compounds of formula (XI).

[0055] Prior to this disclosure, the compound of formula (VI) was typically prepared using the procedure reported in U.S. Patent Application Publication No. 2011 / 0274648(A1), which yields a diastereomer mixture of the compound of formula (VI) and its diastereomer in a ratio of approximately 1:3. Other published procedures use a silyl protecting group (Bioorg. Med. Chem, 21(2013) 5725-5737), which makes product purification more difficult compared to the reaction disclosed herein. Another published procedure relies on LiHMDS and methyl iodide for methyl insertion into the compound of formula (I), resulting in a mixture of mono and dimethylated compounds in addition to unreacted starting materials, thus requiring further chromatographic separation.

[0056] The ability to prepare intermediates with high stereoselectivity in the synthesis of compounds of formula (VI) substantially improves the overall yield of the entire process for preparing compounds of formula (XI).

[0057] In some embodiments, the Co(II) catalyst is a Co(II) complex containing a pyridine(diimine) (PDI) ligand. In some embodiments, the Co(II) complex has the following structure

[0058] [ka] [In the formula, each X is independently Cl, Br, or I, and each R is independently C 1-6 It is an alkyl group, where each R is independently H or C1-C6 alkyl, and R'' is H, halo, C1-C6 haloalkyl, C1-C6 alkoxy, or C6-C 10 It is an aryl complex. For example, the Co(II) complex has the following structure.

[0059] [ka] [wherein each X is independently Br or I, and each R is independently C1-C6 alkyl]. In some embodiments, the Co(II) catalyst is used as a pre-formed complex (i.e., as opposed to construction in situ).

[0060] In some embodiments, each X is independently Cl and Br. In some embodiments, each X is independently Cl or I. In some embodiments, each X is independently Br or I. In some embodiments, each X is Cl. In some embodiments, each X is Br. In some embodiments, each X is I.

[0061] In some embodiments, each R is independently ethyl, n-propyl, isopropyl, or tert-butyl. In some embodiments, each R is ethyl. In some embodiments, each R is n-propyl. In some embodiments, each R is isopropyl. In some embodiments, each R is tert-butyl.

[0062] Compound of formula (V) In some embodiments, formula (V)

[0063] [ka] [In the formula, P 1 and P 2 The compound is as defined above.

[0064] [ka] [In the formula, P 1 is an N-protecting group (e.g., t-butoxycarbonyl), and P 2 The compounds of formula (V) are prepared by dehydrating (eliminating) a compound of a carboxyl protecting group (e.g., an alkyl group such as methyl). The dehydration reaction is typically carried out at high temperature in the presence of a strong acid such as sulfuric acid, phosphoric acid, or trifluoroacetic acid (e.g., formed from the hydrolysis of trifluoroacetic anhydride). Dehydration can also be carried out under reflux of methylene chloride in the presence of the catalyst p-toluenesulfonic acid (TsOH). Such reactions are well known in the art. In some embodiments, the compound of formula (V) is prepared by reacting the compound of formula (IV) with trifluoroacetic anhydride, for example, in the presence of 2,6-lutidine.

[0065] Compound of formula (IV) In some embodiments, formula (IV)

[0066] [ka] [In the formula, P 1 and P 2 The compound is as defined above.

[0067] [ka] [In the formula, P 1 is an N-protecting group (e.g., t-butoxycarbonyl), and P2 Compounds of formula (IV) are prepared by reducing a compound of which is a carboxyl protecting group (e.g., an alkyl group such as methyl). Compounds of formula (IV) can be reduced using a reducing agent such as lithium triethylborohydride ("Superhydride") or sodium borohydride. In some embodiments, compounds of formula (IV) are reduced with lithium triethylborohydride.

[0068] Compound of formula (III) In some embodiments, formula (III)

[0069] [ka] [In the formula, P 1 and P 2 The compound is as defined above.

[0070] [ka] [In the formula, P 1 is an H or N protecting group (e.g., tert-butoxycarbonyl), and P 2 The compounds are prepared by hydrocracking a compound of H or a carboxyl protecting group (e.g., an alkyl group such as methyl) in the presence of a hydrogenation catalyst. Suitable hydrogenation catalysts include, but are not limited to, palladium carbon, platinum(IV) oxide, palladium(II) hydroxide, Raney Ni, and platinum metal. In some embodiments, the hydrocracking reaction is carried out in the presence of palladium carbon (Pd / C).

[0071] Compound of formula (II) In some embodiments, formula (II)

[0072] [ka] [In the formula, P 1 and P 2The compound of [as defined above] is given by formula (I)

[0073] [ka] [In the formula, P 1 is an N-protecting group (e.g., tert-butylcarbonyl), and P 2 It is prepared by reacting a compound of a carboxyl-protecting group (e.g., an alkyl group such as methyl) with Bredereck's reagent (tert-butoxy-bis(dimethylamino)methane) (see, e.g., Rosso, Synlett. 2006; 5: 0809-0810).

[0074] Compounds of formulas (VI'), (VII), and (VIII) In some embodiments, formula (VI)

[0075] [ka] [In the formula, P 1 is an H or N protecting group (e.g., t-butoxycarbonyl), and P 2 A compound of which is a carboxyl protecting group (e.g., an alkyl group such as methyl) is reacted with a carboxyl protecting group removal agent to form formula (VI').

[0076] [ka] [In the formula, P 1A compound is obtained in which the carboxyl protecting group is H or N-protecting. In some embodiments, the carboxyl protecting group is alkyl (e.g., methyl), and the carboxyl protecting group removal agent is a base (e.g., NaOH, LiOH, or KOH). Suitable carboxyl protecting reagents and reaction conditions required for the introduction and removal of carboxyl protecting groups are well known in the art (see, for example, Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006). In some embodiments, the carboxyl protecting group removal agent is NaOH. In some embodiments, NaOH is added in a sufficient amount to obtain a pH greater than 11.

[0077] In some embodiments, the compound of formula (VI') is purified by first reacting it with an organic amine (e.g., in an organic solvent such as THF or toluene) to form an organic ammonium salt of the compound of formula (I), and then reacting the organic ammonium salt of the compound of formula (I) with an acid to reformulate the compound of formula (I). Suitable organic amines include, but are not limited to, benzylamine and chiral amines such as (R)-α-methylbenzylamine. In some embodiments, the organic amine is benzylamine, thereby forming a benzyl ammonium salt of the compound of formula (I). In some embodiments, the organic amine is (R)-α-methylbenzylamine, thereby forming a (R)-α-methylbenzyl ammonium salt of the compound of formula (I).

[0078] Next, the compound of formula (VI') is given by formula (VII)

[0079] [ka] [In the formula, R 1 is H or optionally substituted C1-C6 alkyl, and R 2 and R 3Each of the following is independently H or alkyl, m is 0, 1, or 2, and B is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 14 A compound of an aryl, an optionally substituted 5-10 membered heterocycline, or an optionally substituted 5-10 membered heteroaryl, or a salt thereof, can be coupled by amidation to form formula (VIII).

[0080] [ka] [In the formula, P 1 The compound can be formed by [where is an N-protecting group (e.g., tert-butoxycarbonyl), and all other variable elements are as defined for formula (VII). Alternatively, P 1 A compound of formula (VI') in which is H can be first reacted with an N-protecting reagent (e.g., d-tert-butyl dicarbonate), and then coupled with a compound of formula (VII) or a salt thereof to form a compound of formula (VIII). Subsequently, the N-protecting group P in the compound of formula (VIII) is added. 1 By removing it with an N-protecting group remover, formula (IX)

[0081] [ka] A compound of the formula [wherein all variable elements are as defined for formula (VIII)], or a salt thereof, is obtained. Suitable N-protecting reagents and reaction conditions required for the introduction and removal of N-protecting groups are well known in the art (see, for example, Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006).

[0082] In some embodiments, the N-protecting reagent is di-tert-butyl dicarbonate (Boc2O), the reaction is carried out in an organic solvent (e.g., acetonitrile) in the presence of a base (e.g., 4-dimethylaminopyridine), and the N-protecting group is tert-butoxycarbonyl (Boc). In some embodiments where the N-protecting group is Boc, the deprotection reaction involves treating the compound of formula (VIII) with an acid as an N-protecting group remover in an organic solvent. In some embodiments, the N-protecting group remover is hydrogen chloride (4N HCl in dioxane), the reaction is carried out, for example, in dioxane, and the deprotection reaction forms a hydrochloride salt of the compound of formula (IX). In some embodiments, the acid is hydrogen bromide (e.g., a 33% HBr solution in acetic acid), the reaction is carried out, for example, in ethyl acetate, and the deprotection reaction forms a hydrobromide salt of the compound of formula (IX). In some embodiments, the acid is trifluoroacetic acid, and the reaction is carried out, for example, in dichloromethane, to form a trifluoroacetic acid salt of the compound of formula (IX) by a deprotection reaction.

[0083] In some embodiments, the compound of formula (VI') and the compound of formula (VII) or a salt thereof are coupled in an organic solvent in the presence of a base and a coupling reagent. In some embodiments, the organic solvent is dimethylformamide. In some embodiments, the base is diisopropylethylamine. In some embodiments, the coupling reagent is (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU). Other suitable coupling reagents include, but are not limited to, n-propanephosphonic anhydride (T3P) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU).

[0084] Exemplary compounds of formulas (VIII) and (IX), as well as methods for preparing such compounds, are described, for example, in U.S. Publication Nos. 2015 / 130838, 2017 / 035353, 2017 / 035409, 2018 / 160889, 2020 / 041301, and 2021 / 168320, the entire contents of which are incorporated herein by reference.

[0085] Compound of formula (XI) In some embodiments, formula (IX)

[0086] [ka] A compound or salt thereof, of formula (X)

[0087] [ka] [In the formula, R 4 This includes H, halo, OH, NH2, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3-8 member heterocyclyl, and -C(O)NR. a R a '(In the formula, R a and R a ' is independently H, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted C3-C8 cycloalkyl, -C(O)R b -OC(O)R b , or -C(O)OR b (In the formula, R b (In each instance, is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted C3-C8 carbocyric), R 5 and R 6 Each of these is independently H, halo, or C1-C6 alkyl. X1 is N or CR c (where R c is H, halo, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy), and X 2 and X 5 are each independently N or CR d (where each R d is independently selected from H, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 carbocyclic, and optionally substituted 5-8 member heteroaryl), and X 3 and X 4 one of which is selected from N and CR e and the other of X 3 and X 4 is CR f (where R e is selected from H, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, -C(O)OR g (where R g is H or optionally substituted C1-C6 alkyl), R f is optionally substituted C4-C 10 aryl, optionally substituted 5-10 member heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally substituted 4-10 member saturated or unsaturated non-aromatic heterocyclyl containing 1-4 heteroatoms selected from N, O, and S), and coupling with a compound of Formula (XI)

[0088]

Chemical formula

[0089] Exemplary compounds of formulas (IX), (X), and (XI) and their synthesis procedures are described, for example, in International Publications 2015 / 130838, 2017 / 035353, 2017 / 035409, 2018 / 160889, 2020 / 041301, and 2021 / 168320, the entire contents of which are incorporated herein by reference.

[0090] Further embodiments of this disclosure In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), R 1 is H. In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), R 1 It is CH3.

[0091] In some embodiments of any of the embodiments described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), m is 0. In some embodiments of any of the embodiments described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), m is 1. In some embodiments of any of the embodiments described herein (e.g., formulas (VII), (VIII), (IX), and (XI)), m is 2.

[0092] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), R 2 and R 3 Each of them is H. In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), R 2 H is R 3 is CH3. In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), R 2 and R 3 Each of them is CH3.

[0093] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted 5- to 10-membered heteroaryl compound.

[0094] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted six-membered heteroaryl, such as optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl.

[0095] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted with pyridyl, for example,

[0096] [ka]

[0097] [ka] In some embodiments, B is

[0098] [ka] In some embodiments, B is

[0099] [ka] That is the case.

[0100] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted with pyrazinyl, for example,

[0101] [ka] That is the case.

[0102] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted with pyrimidinyl, for example,

[0103] [ka] That is the case.

[0104] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted with pyridazinyl, for example,

[0105] [ka] That is the case.

[0106] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted with a five-membered heteroaryl, for example,

[0107] [ka] That is the case.

[0108] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is a bicyclic 9-membered or 10-membered heteroaryl, for example,

[0109] [ka] That is the case.

[0110] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted with C6-C 14 Aryl, for example,

[0111] [ka] These are phenyl compounds with arbitrary substitutions, such as those mentioned above.

[0112] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is an optionally substituted 5- to 9-membered unsaturated heterocycline, for example,

[0113] [ka] That is the case.

[0114] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted with C3-C 10 Cycloalkyl, for example,

[0115] [ka] That is the case.

[0116] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted with a C2-C6 alkenyl, for example,

[0117] [ka] That is the case.

[0118] In some embodiments of any of the embodiments described herein (for example, formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted with a C1-C6 alkyl, for example,

[0119] [ka] That is the case.

[0120] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 1 is N. In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 1 CR d In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 1 is C(CH3). In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 1 It is CH.

[0121] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 2 CR d In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 2 is C(C1-C6 alkyl). In some embodiments of any of the embodiments described herein (for example, formula (X) and (XI)), X 2 is C(CH3). In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 2 It is CH.

[0122] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 5 CR d In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 5 It is CH.

[0123] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 3 CR f X 4 is N. In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 3 CR f X 4 It is CH.

[0124] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 4 CR f X c is N. In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), X 4 CR f X 3 It is CH.

[0125] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), R f It is an optionally substituted 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0126] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), R f This is an arbitrarily substituted pyrimidinyl, for example,

[0127] [ka]

[0128] [ka] In some embodiments, R f teeth

[0129] [ka] That is the case.

[0130] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), R f This refers to optionally substituted pyridinyl, optionally substituted pyrazinyl, or optionally substituted pyridazinyl, for example,

[0131] [ka] That is the case.

[0132] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), R f R is an optionally substituted 8-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R fThis includes optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyrimidinyl, optionally substituted thiazolo[5,4-b]pyrimidinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyrimidinyl, 1H-thieno[3,2-c]pyrazolyl, imidazo[1,2-b]pyridadinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1H-benzo[d]imidazolyl, for example,

[0133] [ka] In some embodiments, R f teeth

[0134] [ka] In some embodiments, R f teeth

[0135] [ka] That is the case.

[0136] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), R f This is C6~C which is arbitrarily substituted. 14 Aryl, for example,

[0137] [ka] These are arbitrarily substituted phenyl compounds.

[0138] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), R f R is an optionally substituted 6-9 member unsaturated heterocycline containing 1-4 heteroatoms selected from N, O, or S. For example, R f teeth,

[0139] [ka] It may also be a heterocycline in which the carbon atom to which it is bonded is bonded via a carbon ring atom contained within it. Another example is R f For example,

[0140] [ka] It may also be a heterocycline, such as one to which it is bonded, via a nitrogen atom contained within it.

[0141] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), R f This is an optionally substituted five-membered heteroaryl compound containing one, two, or three heteroatoms selected from N, O, and S, for example,

[0142] [ka] That is the case.

[0143] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), R 4 is -C(O)R b In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), R 4 teeth,

[0144] [ka] In some embodiments of any of the embodiments described herein (for example, formulas (X) and (XI)), R 4 teeth,

[0145] [ka] is as follows.

[0146] In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 4 is -C(O)NR a R a ’. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 4 is

[0147]

Chemical formula

[0148]

Chemical formula

[0149] In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 4 is -C(O)OR b is as follows. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 4 is -C(O)OCH3. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 4 is -C(O)OH.

[0150] In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 4 is optionally substituted C1-C6 alkyl. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 4 is

[0151]

Chemical formula

[0152]

Chemical formula

[0153] In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 4 is

[0154]

Chemical formula

[0155] In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 4 is cyano. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 4 is halo, e.g., Br.

[0156] In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 5 is H.

[0157] In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 6 is H.

[0158] In some embodiments, the compound of Formula (XI) is

[0159]

Chemical formula

[0160] In some embodiments, the compound of Formula (XI) is

[0161]

Chem.

[0162] In some embodiments, the compound of formula (XI) is

[0163]

Chem.

[0164] In some embodiments, the compound of formula (XI) is

[0165]

Chem.

[0166] In some embodiments, the compound of formula (XI) is

[0167]

Chem.

[0168] In some embodiments, the compound of formula (XI) is

[0169]

Chem.

[0170] In some embodiments, the compound of formula (XI) is

[0171]

Chem.

Examples

[0172] The examples described herein are illustrative of the disclosure, and the disclosure is not limited to the examples shown.

[0173] Example 1. Synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid

[0174] [ka]

[0175] Step 1: Synthesis of 1-(tert-butyl)2-methyl(S,E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate (2b)

[0176] [ka]

[0177] To a stirred solution of methyl-(S)-Boc-5-pyrrolidone-2-carboxylate (2a) (100 g, 0.411 mol) in toluene (250 mL), Bredereck's reagent (93.14 g, 0.534 mol) was added at room temperature, and the reaction mixture was stirred at 75-80 °C for 6 hours. After the reaction was complete, it was cooled to -5 °C and stirred for 0.5-1.5 hours. The resulting solid was filtered at -5 °C and washed with cold cyclohexane (200 mL). The product was dried under reduced pressure to obtain 1-(tert-butyl)2-methyl(E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate (2b) as a white solid (100 g, yield 82%). 1 H NMR (400MHz, CDCl3) δ 7.06(s,1H),4.56(dd,1H),3.75(s,3H),3.28-3.23(m,1H),3.02(s,6H),2.91-2.87(m,1H),1.49(s,9H).

[0178] Step 2: Synthesis of 1-(tert-butyl)2-methyl(2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate(2c)

[0179] [ka]

[0180] In a 300 mL HEL PolyBlock reactor, compound 1-(tert-butyl)2-methyl(E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate (2b) (20 g, 67.1 mmol), 10% Pd / C (50% wet) (2.0 g, 0.1 w / w), and IPA (140 mL) were added. The reaction mixture was purged twice with nitrogen, then the internal reaction temperature was raised to 50°C and pressurized to 45 psi with hydrogen gas. After the reaction was complete, the reaction mixture was passed through a Celite bed, and the filtrate was concentrated under reduced pressure at 45°C to obtain a light brown viscous oil. Cyclohexane (40 mL) was added to the oil and stirred at -5°C for 30-50 minutes. The resulting solid was filtered at -5°C. The product was dried under reduced pressure to obtain 1-(tert-butyl)2-methyl(4S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (2c) as a white solid with high diastereoselectivity (dr=88:12) (14.48 g, yield 84%). 1 H NMR(400MHz, CDCl3)δ 4.59-4.45(m,1H),3.77(s,3H),2.71-2.49(m,2H),1.68-1.57(m,1H),1.48(s,9H),1.30-1.17(m,3H).

[0181] Step 3: Synthesis of 1-(tert-butyl)2-methyl(2S)-5-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate(2d)

[0182] [ka]

[0183] 180 g (699.6 mmol, 1.00 equivalent) of 1-(tert-butyl)2-methyl(4S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (2c) was placed in a 5-liter four-necked round-bottom flask and dissolved in toluene (1.7 L) under nitrogen. The reaction solution was cooled to -78°C, and a 1.0 M superhydride (1.3 equivalents) THF solution was slowly added using a syringe pump (4 hours). The mixture was stirred at approximately -75°C for 2 hours. After the reaction was complete, 180 mL of 10% NH4Cl aqueous solution was added to the reaction mixture at -75°C, and the reaction mixture was gradually heated to room temperature. The organic layer was separated, and the aqueous layer was further extracted with toluene (180 mL). The combined organic layer was used directly in the next step.

[0184] Step 4: Synthesis of 1-(tert-butyl)2-methyl(S)-4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate(2e)

[0185] [ka]

[0186] The crude reaction mixture from the previous step was placed in a 5 L reactor (180 g, 694.1 mmol, 1 equivalent). The reaction solution was cooled to 0°C, and 2,6-lutidine (371.9 mL, 3.193 mol, 4.6 equivalents) was added. While maintaining the internal reaction temperature below 5°C, TFAA (221.9 mL, 1.597 mol, 2.3 equivalents) was slowly added to the reaction mixture. The mixture was then stirred at 60°C for 14 hours. After the reaction was complete, the reaction mixture was cooled to room temperature. Water (180 mL) was added, and the mixture was stirred for 10 minutes, after which the aqueous layer was collected. The combined organic layers were washed with 1 M HCl (360 mL). The reaction mixture was further washed with 10% NaHCO3 (360 mL) solution. The organic layer was recovered, dried over Na2SO4, filtered, and concentrated under vacuum to obtain 1-(tert-butyl)2-methyl4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (2e) as a yellow oil (116.9 g, 70% yield in 2 steps). 1H NMR(400MHz,CDCl3):δ 6.28(dd,J=45.6,1.9Hz,1H),4.61(ddd,J=31.2,11.8,5.3Hz,1H),3.76(s,3H),2.96(q, J=14.5Hz,1H), 2.52(ddd,J=22.3,16.4,5.3Hz,1H),1.68(d,J=1.7Hz,3H),1.45(s,9H).

[0187] Step 5: Synthesis of 2-(tert-butyl)3-methyl(1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(2f)

[0188] [ka]

[0189] Procedure A: In a clean, dry 100° three-neck round-bottom flask equipped with a magnetic stirring bar, the pre-prepared Co(PDI)I2 complex (2.3 g, 3.11 mmol, 25 mol%) and THF (10 volts) were added, followed by Zn powder (2.44 g, 37.3 mmol) (activated with dilute HCl). The reaction mixture was stirred for 20-40 minutes until a dark purple color appeared. 1-(tert-butyl)2-methyl4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (2e) (3.0 g, 12.43 mmol) was dissolved in THF (7.5 mL) and degassed with N2 for 10 minutes. CH2Br2 (8.65 g, 49.73 mmol) was weighed into a vial containing THF (22.5 mL) and degassed with N2 for 10 minutes. The THF solution of degassed 1-(tert-butyl)2-methyl4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (2e) was added dropwise to the reaction mixture and stirred for 10 minutes. The THF solution of degassed CH2Br2 (one of three total volumes) was added dropwise to the reaction mixture over 30 minutes and stirred at room temperature for 1 hour. The internal temperature was gradually raised to 41°C and then cooled to 22°C within 1 hour. The second dose of Zn (1.63 g, 24.87 mmol, 2.0 equivalents) was added to the reaction mixture and the reaction mixture was stirred for 10-20 minutes. Then the second dose of CH2Br2 (one of three total solutions) was added dropwise over 10 minutes, and the reaction mixture was stirred for 1 hour. The remaining third dose of Zn (1.63 g, 24.87 mmol) was added to the reaction mixture and stirred for 10 minutes. The third portion of CH2Br2 (the remaining portion of the three) was added dropwise over 10 minutes, and the reaction mixture was stirred for 2 hours. After monitoring by HPLC to confirm complete conversion, it was diluted with SiO2 (30 mL) and washed with 0.1 M HCl (40 mL). The aqueous layer was extracted with SiO2, and the organic layer was filtered through a short Celite bed to remove solid impurities. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure.The crude reaction mixture was purified by flash column chromatography using 5 to 20% siRNA / hexane to obtain 2-(tert-butyl)3-methyl(1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2f) as a liquid with high diastereoselectivity (dr=97:3) (2.7 g, yield 85%). 1 H NMR(400MHz,CDCl3)δ 3.89-3.91(m,1H),3.71-3.76(s,3H),3.17(m,1H),2.46-2.30(m,1H),1.93(dt,J=1 3.7,6.2Hz,1H),1.37(s,9H),1.18(s,3H),0.63-0.58(m,1H),0.57(d,J=6.4Hz,1H). 13 C NMR(101MHz, CDCl3)δ 172.63,80.27,59.98,52.10,42.99,38.65,37.96,28.26,23.16,22.03,20.68.

[0190] Procedure B: In a clean, dry 1 L three-necked round-bottom flask equipped with a magnetic stirring bar, the first dose of Co(PDI)Br2 complex (0.43 g, 0.66 mmol, 8 mol%), THF (20 mL), ZnCl2 (0.56 g, 4.14 mmol), and the first dose of Zn powder (1.08 g, 16.58 mmol, used directly from a commercially available bottle) were added. The reaction mixture was stirred until a dark purple color appeared. 1-(tert-butyl)2-methyl4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (2e) (2.0 g, 8.29 mmol) was dissolved in THF (5 mL) and degassed with N2 for 10 minutes. CH2Br2 (5.76 g, 33.16 mmol) was weighed into a vial containing THF (15 mL) and degassed with N2 for 10 minutes. The degassed 2e THF solution was added dropwise to the reaction mixture and stirred for 10 minutes. The first dose of the degassed CH2Br2 THF solution (one of three doses of the total solution) was added dropwise to the reaction mixture over 10 minutes and stirred at room temperature for 1 hour. The internal reaction temperature gradually rose to 28.3°C. The second dose of the Co(PDI)Br2 complex (0.43 g, 0.66 mmol, 8 mol%) and Zn (1.08 g, 16.58 mmol) were added to the reaction mixture and stirred for 10 minutes. The second dose of CH2Br2 (one-third of the total solution) was added dropwise over 10 minutes and the reaction mixture was stirred for 1 hour. Finally, the third dose of the Co(PDI)Br2 complex (0.43 g, 0.66 mmol, 8 mol%) and 2.0 equivalents of Zn (1.08 g, 16.58 mmol) were added to the mixture and stirred for 10 minutes. The third dose of CH2Br2 (the remaining dose of the three) was added dropwise over 10 minutes. The mixture was stirred for 16 hours. After the reaction was complete, the workup was carried out as described above to obtain the crude product 2-(tert-butyl)3-methyl(1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2f) with high diastereoselectivity (dr=97:3).

[0191] Step 6: Synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (2g)

[0192] [ka]

[0193] Procedure A: Compound 2f (3.7 g, 14.49 mmol) was stirred in a 3:1 mixture of EtOH / H2O (37 mL). LiOH (0.85 g, 36.23 mmol) was added and the mixture was stirred for 6-8 hours. After the reaction was complete, the reaction mixture was diluted with HCl (14.8 mL), and the aqueous layer was further washed with 7.4 mL of HCl. The aqueous layer was collected, and its pH was adjusted to 1-2 by adding 2 M aqueous HCl. The solution was extracted with HCl (18.5 mL), and the organic layers were washed together with 10% NaCl solution (7.4 mL). The organic layers were collected and concentrated under reduced pressure at 45°C to obtain the product as a bright yellow viscous oil (3.0 g, yield 85%). 1 1H NMR (400MHz, CDCl3):δ 11.28(s,1H),4.09(dd,J=31.9,18.4Hz,1H),3.20(d,J=49.3Hz,1H),2.57-2.39 (m,1H),2.25-2.08(m,1H),1.63-1.30(m,11H),1.25(s,3H),0.79-0.53(m,2H).

[0194] Procedure B: To a stirred solution of compound 2f (5 g, 14.49 mmol) in a 3:1 mixture of EtOH / H2O (50 mL), NaOH (0.85 g, 36.23 mmol) was added and the mixture was stirred for 6-8 hours. After the reaction was complete, the reaction mixture was diluted with HCl (20 mL), and the aqueous layer was further washed with 10 mL of HCl. The aqueous layer was collected, and its pH was adjusted to between 1 and 2 by adding 2 M aqueous HCl. The solution was extracted with HCl (25 mL), and the organic layers were washed together with 10% NaCl solution (10 mL). The organic layers were collected and concentrated under reduced pressure at 45°C to obtain the product (2 g of compound) as a bright yellow viscous oil (3.0 g, yield 85%). 1H NMR(400MHz,CDCl3):δ 11.28(s,1H),4.09(dd,J=31.9,18.4Hz,1H),3.20(d,J=49.3Hz,1H),2.57-2.39 (m,1H),2.25-2.08(m,1H),1.63-1.30(m,11H),1.25(s,3H),0.79-0.53(m,2H).

[0195] Example 2. Preparation of Co(PDI)X2 complex The Co(PDI)X2 complex can be prepared according to the following procedure.

[0196] Step 1. Synthesis of PDI ligand

[0197] [ka]

[0198] In a clean, dry 1 L round-bottom flask equipped with a magnetic stirrer, 2,6-diacetylpyridine (50 g, 1 equivalent) in toluene (350 mL) was added at room temperature under N2. 2-t-butylaniline (50 mL, 2.2 equivalents) was added to the reaction mixture at room temperature. After adding p-TsOH (500 mg), the solution was refluxed for 6 hours and then distilled. After cooling to room temperature, 1 M NaOH (2V) was added, and the reaction mixture was filtered through a funnel. The product was diluted with ethanol and refluxed for 0.5 hours. After cooling, the slurry was filtered through a filtration flask, washed with cold ethanol, and dried overnight in a vacuum oven (50°C) (isolation yield: 93 g, 62%). Product identification was performed. 1 1H NMR and 13 This was confirmed by 13C NMR.

[0199] Other sterically and electronically diverse PDI ligands were prepared using appropriate pyridines and aniline synthones according to the procedure described above.

[0200] [Table 1]

[0201] Step 2: Synthesis of the Co(PDI)X2 complex

[0202] [ka]

[0203] General Procedure In a clean, dry 100-1000 mL round-bottom flask containing 20-45 V THF and a magnetic stirrer, add the required amount of PDI ligand (1.0 equivalent) and CoX2 salt (1.0 equivalent, X=I or Br) under a stream of nitrogen. Then, stir the reaction mixture under nitrogen for 48-60 hours and concentrate under reduced pressure. Add hexane (3 V) to the resulting solid, sonicate the mixture for 5-10 minutes, then filter to obtain the Co(PDI)X2 complex, which is dried overnight under vacuum. The prepared complex can be used without any further purification.

[0204] Co( t Bu-PDI)Br2 complex THF (4v) was placed in a 5 L reactor, followed by the addition of PDI ligand (200 g, 469.9 mmol, 1.0 equivalent) under a nitrogen stream. Then, additional THF (11v) was added to the reactor, and the mixture was stirred for 10-30 minutes to obtain a homogeneous solution. CoBr2 (102.8 g, 469.9 mmol, 1.0 equivalent) was added to the reaction mixture under a nitrogen stream, followed by the addition of THF (5v). The reaction mixture was stirred under a nitrogen stream at room temperature for 60-72 hours. After 60-72 hours, the reaction mixture was filtered and dried at room temperature under vacuum for 8-12 hours, and used without further purification. The isolation yield was quantitative.

[0205] Other PDI complexes were prepared using the PDI ligands disclosed above and the procedure described above.

[0206] Example 3. Improved synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid

[0207] [ka]

[0208] Step 1: Synthesis of 1-(tert-butyl)2-methyl(S,E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate (2b)

[0209] [ka]

[0210] An overhead stirrer, thermocouple, and nitrogen line were installed in a 2 L reactor. Compound 2a (250 g, 1027.71 mmol, 1.0 equivalent) was added to the reactor, followed by toluene (2.5 V, 625 mL). Bredereck's reagent (250.75 g, 1336.02 mmol, 1.3 equivalents) was added to the reactor, and the reaction mixture was heated at 75 ± 3 °C for 6 to 8 hours. After the reaction was complete, the reaction mixture was cooled to -5 ± 3 °C. The cooled reaction mixture was filtered, and the cake was washed with cold cyclohexane (2.5 V). The cake was dried under vacuum at room temperature for 18 to 24 hours. Compound 2b was obtained as a bright yellow solid in 86% yield and 99.99 wt% purity. 1 H NMR (400MHz, CDCl3): δ 7.06(s,1H),4.56(dd,1H),3.75(s,3H),3.28-3.23(m,1H),3.02(s,6H),2.91-2.87(m,1H),1.49(s,9H). 13 C NMR (100MHz, CDCl3): δ 172.60,168.40,150.40,146.41,128.18.90.83.82.36,82.17,55.91,52.29,41.97,28.20,28.02,27.81,26.22.

[0211] Step 2: Synthesis of 1-(tert-butyl)2-methyl(2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate(2c)

[0212] [ka]

[0213] Compound 2b (40 g, 298.34 mmol, 1.0 equivalent) was placed in a reactor, followed by IPA (4-7 w / w, 160-280 mL) and 10% w / w 10% Pd / C (50% wet) (Pd content 0.5 w / w). An overhead was attached to the reactor, it was sealed, and the reactor was placed in a polyblock at 1500 rpm for 12-18 hours. After the reaction was complete, the mass was passed through a Celite (2-4 w / w) bed. The IPA was removed by azeotrope with toluene, and the solution of the compound was then used directly in the next step. 1 H NMR (400MHz, CDCl3) (dr=8.8:1.2)δ 4.59-4.45(m,1H),3.77(s,3H),2.71-2.49(m,2H),1.68-1.57(m,1H),1.48(s,9H),1.30-1.17(m,3H). 1 H NMR(100MHz,CDCl3)δ 175.62,172.03,171.82,149.58,149.44,83.65,83.53,57.35,56.87, 52.56,52.48,37.51,36.60,30.46,29.71,27.92,27.88,16.11,15.13.

[0214] Multiple batches of compound 2c were prepared according to this procedure, and the corrected isolation yield was 81–89% as determined by quantitative NMR, and the product purity was 75–89% as determined by HPLC.

[0215] Step 3: Synthesis of 1-(tert-butyl)2-methyl(2S)-5-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate(2d)

[0216] [ka]

[0217] Continuous flow protocol The synthesis of compound 2d using continuous flow chemistry was also investigated. For the synthesis, a continuous flow setup (Figure 1) was used, providing a throughput of 148 g / h based on a 1 / 4-inch outer diameter PFA tubular reactor (170 mL). Supply 1: A carboy containing compound 2c (411.5 g, 1612.80 mmol, 1.0 equivalent) and toluene (3320 mL, 8 v) under an N2 atmosphere. Supply 2: SuperHydride (1 M in THF, 2096.9 mL, 1.3 equivalents) was used from a 2 L glass bottle under an N2 atmosphere. A three-way valve was used to switch between the stock solution and the SuperHydride bottle (Sure / Seal) when the stock solution was empty. Methanol for quenching was supplied by a third flow. Each flow contained a 7 mL pre-cooling loop of 1 / 8-inch outer diameter PFA. The reactants and pre-cooling loop were cooled to maintain the temperature at -78 to -70°C. The flow containing compound 2c and Super-Hydride was then subjected to t R Assuming 5 minutes, the solution is supplied to the reaction loop (by a peristaltic pump) at flow rates of 21.81 and 12.19 mL / min, respectively. After the solution has passed through the first loop, t R Assuming 2 minutes, the methanol-containing stream is further supplied at a flow rate of 7.72 mL / min (by the HPLC pump).

[0218] Batch protocol Compound 2c (238.52 g, 1.0 equivalent) was placed in a 5 L four-necked round-bottom flask connected to an overhead stirrer and dissolved in toluene (10V) under nitrogen. The reaction solution was cooled to -78°C, and 1.0 M superhydride THF solution (834.34 mL, 0.9 equivalents) was slowly added using a peristaltic pump (4 mL / min). The mixture was stirred at approximately -75°C to -70°C for 2 hours. 1 The reaction was monitored by 1H NMR analysis. Based on the conversion of compound 2c, an additional 0.16 equivalents of superhydride were slowly added using a peristaltic pump (4 mL / min), and the reaction mixture was stirred at approximately -75°C to -70°C for 30 minutes. 1The reaction was monitored by 1H NMR. Based on the converted compound 2c, an additional 0.09 equivalents of superhydride were slowly added using a peristaltic pump (4 mL / min), and the reaction mixture was stirred at approximately -75°C to -70°C for 30 minutes. 1 The reaction was monitored by 1H NMR. After the reaction was complete, an aqueous NH4Cl solution (1v) was slowly added to the reaction mixture at -75°C to -65°C using a peristaltic pump (4 mL / min), and then slowly heated to room temperature. The reaction mixture was placed in a 5 L reactor, and the aqueous layer was removed. The organic layer was washed with water (1v) and brine (1v), and then distilled under reduced pressure to 4-5v while maintaining the jacket temperature at 50°C to 55°C. Water was removed by azeotrope to reduce the water content to 0.3% or less.

[0219] Step 4: Synthesis of 1-(tert-butyl)2-methyl(S)-4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate(2e)

[0220] [ka]

[0221] Compound 2d (240.4 g, 927.1 mmol, 1.0 equivalent) in 10V toluene (2.4 L) was placed in a 5 L reactor using a wide-mouthed funnel under a nitrogen stream. The reaction mixture was cooled to 0°C. 2,6-Lutidine (280.7 mL, 2410.4 mmol, 2.6 equivalents) was added under a nitrogen stream. While maintaining the reaction temperature below -10±5°C, trifluoroacetic anhydride (TFAA) (167.5 mL, 1205.2 mmol, 1.3 equivalents) was added dropwise to the reaction mixture using a dropping funnel (connected to a long tube to drop TFAA below the liquid surface of the reaction mixture). After the addition was complete, the reaction mixture was slowly heated to 60±5°C and stirred for 14-16 hours. 1The reaction was monitored by 1H NMR analysis. After the completion of the reaction, the reaction mixture was slowly cooled to 22±5°C. The reaction mixture was washed with water (1v), followed by two washes with 1N HCl, and then washed together with 10% NaHCO3 (1v) and 10% brine (1v). Toluene was distilled until the reaction mixture was 1-2v, and then the mixture was diluted with cyclohexane (2-4v) and distilled to remove as much of the toluene content as possible. The pale yellow liquid was then dried under vacuum for 8-10 hours. Compound 2e was obtained as a pale yellow liquid (176.1g), which had a purity of 94 wt% based on quantitative NMR, and the isolation yield in two steps was 74% (corrected based on the purity of the starting material). 1 H NMR(400MHz,CDCl3)δ 6.28(dd,J=45.6,1.9Hz,1H),4.61(ddd,J=31.2,11.8,5.3Hz,1H),3.76(s,3H),2.96(q, J=14.5Hz,1H), 2.52(ddd,J=22.3,16.4,5.3Hz,1H),1.68(d,J=1.7Hz,3H),1.45(s,9H).

[0222] Step 5: Synthesis of 2-(tert-butyl)3-methyl(1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(2f)

[0223] [ka]

[0224] Exemplary procedure An overhead stirrer was attached to a clean, dry 5L reactor. The pre-prepared Co( tBu-PDI)Br2 complex (40.06 g, 62.17 mmol, 25 mol%) was added to the reactor, followed by 15V THF. ZnCl2 (101.68 g, 745.99 mmol, 3.0 equivalents) was added to the reactor, followed by activated Zn powder (48.78 g, 745.99 mmol, 3.0 equivalents), and the reactor was rinsed with 3V THF. Next, the reaction mixture in the reactor was purged deep below the liquid surface with N2 using a long tube for 10-15 minutes, and then stirred for 20-50 minutes. A deep purple color appeared. Compound 2e (60.0 g, 248.66 mmol, 1.0 equivalent) was dissolved in THF (1.5V), degassed with N2 in a separate round-bottom flask over 15-20 minutes, and then added to the reactor. The round-bottom flask was rinsed with 0.5V THF and placed in the reactor. The color of the reaction mixture did not change. The reaction mixture was stirred for 20-50 minutes. CH2Br2 (64.84g, 373.0 mmol, 1.5 equivalents) was added dropwise to the reactor using a dropping funnel over 10-25 minutes. After stirring the reaction mixture for 1 hour, CH2Br2 (43.23g, 248.66 mmol, 1.0 equivalent) was added dropwise to the reactor using a dropping funnel over 10-25 minutes. After stirring for another hour, the remaining ZnCl2 (67.79g, 497.33 mmol, 2.0 equivalents) and Zn (32.52g, 497.33 mmol, 2.0 equivalents) were added to the reactor, and the reaction mass in the reactor was purged again deep below the liquid surface with N2 using a long tube for 10-15 minutes. CH2Br2 (64.84 g, 373.0 mmol, 1.5 equivalents) was added dropwise to the reactor using a dropping funnel over a period of 10-25 minutes. The progress of the reaction was measured at 6 hours of the reaction. 1 The reaction mixture was monitored again by 1H NMR, and the conversion was 97%. The reaction mixture was passed through a sloka floc (4 w / w) bed moistened with MTBE, and the bed was washed with MTBE at 6-8 v. The filtrate was placed in a 5 L reactor, followed by a solution of 10% NH4Cl (2 v) and 10% NaCl in a 1:1 ratio (2 v), and the RM was stirred for 20-40 minutes. The phases were separated and the aqueous layer was removed. The reaction mixture was distilled to 2-3 v, and the crude RM was used in the next step. 1H NMR(400MHz,CDCl3)δ 3.89-3.91(m,1H),3.71-3.76(s,3H),3.17(m,1H),2.46-2.30(m,1H),1.93(dt,J=1 3.7,6.2Hz,1H),1.37(s,9H),1.18(s,3H),0.63-0.58(m,1H),0.57(d,J=6.4Hz,1H). 13 C NMR(101MHz, CDCl3)δ 172.63,80.27,59.98,52.10,42.99,38.65,37.96,28.26,23.16,22.03,20.68.

[0225] Step 5 was tested using Zn activated with 1N HCl, unactivated Zn, and various amounts of ZnCl2. The results are shown in Tables 1-3 below.

[0226] [Table 2] * These are the yields of the solution after workup of the reaction, as determined by qNMR. ￥ The particle size of zinc is NMT 10 mm. a All reagents were added to the reaction mixture in two separate additions. b All reagents were added to the reaction mixture in three separate additions.

[0227] [Table 3] * These are the yields of the solution after workup of the reaction, as determined by qNMR. ￥ The zinc particles are 10 mm or smaller in size. a All reagents were added to the reaction mixture in 12 equal portions. a Add all reagents to the reaction mixture in two separate additions.

[0228] [Table 4] * Corrected isolation yield, ￥Solution yield based on qNMR. a Add all of these reagents in four separate additions. b Add all of these reagents in four separate additions. c Add all of these reagents in six separate additions. d Add all of these reagents in 12 separate additions.

[0229] It was discovered that using activated Zn and a larger amount of ZnCl2 unexpectedly shortened the reaction time and yielded the product in high yield and with a high enantiomer ratio.

[0230] Step 6: Synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (2g)

[0231] [ka]

[0232] A crude mixture of compound 2f (84.6 g, 331.1 mmol, 1.0 equivalent) was diluted with EtOH (5 v) and placed in a 5 L reactor, followed by the addition of 10 v EtOH to the reactor. The reaction mixture was cooled to 5 ± 10 °C while stirring at 500 RPM. NaOH (124.2 g, 3105 mmol, 9.4 equivalents) was added while maintaining the internal temperature below 15 °C until the pH reached > 12. The reaction mixture was brought to room temperature and stirred for 4 hours.

[0233] After confirmation by HPLC and completion of the reaction, the reaction mixture was distilled to 3-4V, azeotrope with water to remove ethanol, and the aqueous reaction mixture was washed with SiO2. The organic layer was washed with 1N NaOH (2V). The aqueous layer was placed in the reactor and cooled to 0±5°C. An ice-cold 3M HCl solution was added to the reactor until the pH reached 1-2. The aqueous layer was extracted twice with IPAc (10-15V). The IPAc solution was handed over to the crystallization team for isolation.

[0234] Steps 7 and 8: Chiral resolution and crystallization of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (2g).

[0235] [ka]

[0236] Process impurities can be removed from 2g of the crude compound by forming a salt with an amine such as benzylamine. If the chiral purity of 2g of the crude compound was lower than expected, chiral resolution was performed using a chiral amine. (R)-α-methylbenzylamine was selected as the chiral amine because (1) it is easy to handle as a liquid at 25°C and could be added directly to the crude product to form a salt, (2) its salt with 2g of the compound had lower solubility compared to other chiral amines considered for salt formation, and (3) this simultaneously achieved an improvement in chirality.

[0237] A reaction mixture (containing approximately 45 g of compound in a solution of approximately 225 mL (5 v) of isopropyl acetate, washed twice with 3 v water) was placed in a 1 L reactor. 1.35 g of activated carbon (Acticarbone HPX7) (3 mass%) of the compound was added to the solution. The mixture was stirred at 20-25°C for 2 hours. The slurry was then filtered through Celite. The filtrate was collected and the apparatus was washed with approximately 90 mL (2 v) of isopropyl acetate. The filtrate from the activated carbon treatment was distilled at 50°C under a vacuum of 200 Torr to reduce its volume to 225 mL (5.0 v). 225 mL (5.0 v) of isopropyl acetate was added to the reactor. The solution was distilled at 50°C under a vacuum of 200 Torr to reduce its volume to 225 mL (5.0 v). The water content in the solution must be <350 ppm (otherwise, 5.0V isopropyl acetate should be added and reduced to 5.0V by distillation under vacuum). The solution was maintained at 50-55°C. The reaction mixture after activated carbon treatment and azeotropic distillation was maintained at 50-55°C under a nitrogen atmosphere with stirring, and (R)-α-methylbenzylamine (0.5 equivalents) was added over 2 hours. The system was aged for 1 hour, and an additional (R)-α-methylbenzylamine (0.5 equivalents) was added over 2 hours. The final mixture was stirred at 50-55°C for 1 hour. The reaction mixture was then cooled to 20°C over 4 hours with a linear temperature profile, and stirred at 20°C for at least 16 hours.

[0238] After drying, (R)-α-methylbenzylamine salt was dispersed in 10V isopropyl acetate while stirring at 20-25°C. 4.5V 2M HCl(aq.) was added to the mixture over 15 minutes at 20-25°C. The mixture was then stirred for 10-15 minutes. The aqueous layer was discarded. 3V water was added to the remaining organic layer and stirred for 30 minutes. The aqueous layer was discarded. The organic layer was heated to 55-60°C while stirring and distilled under vacuum to 1.5-2V. 3V isopropyl acetate was added to the solution, and the solution was distilled under vacuum to 1.5-2V.

[0239] While maintaining the temperature at 55-60°C, 10V n-heptane was added over 1 hour with stirring. The solution was distilled under vacuum to 10-11V. Seed (1 mass%) was added. The mixture was then stirred at 55-60°C for 1 hour. The mixture was then distilled under vacuum to 1.5-2V. 8V n-heptane was added over 1 hour at 55-60°C with stirring. The solution was distilled under vacuum to 1.5-2V. 3V n-heptane was added over 0.5 hours at 55-60°C with stirring. The mixture was stirred at 55-60°C for 1 hour and then cooled to 20-25°C for more than 2 hours. The mixture was stirred at 20-25°C for more than 16 hours.

[0240] The mixture was filtered under vacuum. The cake was washed with n-heptane (2 × 1V, slurry washing and displacement washing). The cake was then dried under vacuum at 50-55°C for at least 16 hours.

[0241] This procedure consistently yielded 2 g of purified compound with a yield of >95% and a chiral purity of >99.5% as determined by HPLC.

[0242] Other Embodiments Various modifications and variations of the compositions and methods described herein will be apparent to those skilled in the art without departing from the scope and spirit of this disclosure. While this disclosure is described in relation to specific embodiments, it should be understood that the claimed disclosure should not be unduly limited to such specific embodiments. Indeed, various modifications of the described forms for performing the disclosed methods, which will be apparent to those skilled in the art, are intended to be within the scope of this disclosure.

[0243] Other embodiments are described in the claims.

Claims

1. Equation (VI) 【Chemistry 1】 [In the formula, P １ is an H or N-protecting group, and P ２ A method for preparing a compound of formula (V) which is H or a carboxyl protecting group 【Chemistry 2】 [In the formula, P １ is an H or N-protecting group, and P ２ The objective is to provide compounds that are H or carboxyl protecting groups, and This includes forming a compound of formula (VI) from a compound of formula (V), wherein the formation of the compound of formula (VI) involves Zn and CH ２ Br ２ A method comprising contacting the compound of formula (V) with a Co(II) catalyst in the presence of .

2. Forming the compound of formula (VI) is carried out using Zn, CH ２ Br ２ , and ZnCl ２ , and contacting the compound of formula (V) with a Co(II) catalyst in the presence thereof. The method according to claim 1.

3. The method according to claim 1 or 2, wherein the Zn is a Zn end.

4. The method according to claim 3, wherein the Zn is activated Zn powder.

5. The method according to any one of claims 1 to 4, wherein the Zn is present in an amount of 2 to 10 equivalents relative to the compound of formula (V).

6. The aforementioned ZnCl ２ The method according to any one of claims 2 to 5, wherein the compound of formula (V) is present in an amount of 2 to 10 equivalents.

7. The aforementioned CH ２ Br ２ The method according to any one of claims 1 to 6, wherein the compound of formula (V) is present in an amount of 1 to 10 equivalents.

8. The Co(II) catalyst has the following structure 【Transformation 3】 [In the formula, each X is independently Cl, Br, or I, and each R is independently C １－６ It is an alkyl group, and each R is independently H or C １ ~C ６ It is alkyl, and R'' is H, halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, or C ６ ~C １０ The method according to any one of claims 1 to 7, wherein the compound is an aryl compound.

9. The Co(II) catalyst has the following structure 【Chemistry 4】 [In the formula, each X is independently Br or I, and each R is independently C １ ~C ６ The method according to claim 8, wherein the compound is alkyl.

10. The method according to claim 9, wherein each R is tert-butyl.

11. The method according to claim 9 or 10, wherein each X is Br.

12. To provide the compound of formula (V) mentioned above, Formula (IV) 【Transformation 5】 [In the formula, P １ is an N-protecting group, and P ２ To provide compounds in which is a carboxyl protecting group, and The method according to any one of claims 1 to 11, comprising dehydrating the compound of formula (IV).

13. The method according to claim 12, wherein the dehydration reaction comprises reacting the compound of formula (IV) with trifluoroacetic anhydride in the presence of 2,6-lutidine.

14. To provide the compound of formula (IV) mentioned above, Formula (III) 【Transformation 6】 [In the formula, P １ is an N-protecting group, and P ２ To provide compounds in which is a carboxyl protecting group, and The method according to claim 12 or 13, comprising reacting the compound of formula (III) with a reducing agent.

15. The method according to claim 14, wherein the reducing agent is a superhydride.

16. To provide the compound of formula (III) mentioned above, Formula (II) 【Transformation 7】 [In the formula, P １ is an H or N-protecting group, and P ２ The objective is to provide compounds that are H or carboxyl protecting groups, and The method according to claim 13 or 14, comprising hydrocracking a compound of formula (II) in the presence of a hydrogenation catalyst.

17. The method according to claim 16, wherein the hydrogenation catalyst is palladium-carbon.

18. To provide the compound of formula (II) mentioned above, Equation (I) 【Transformation 8】 [In the formula, P １ is an N-protecting group, and P ２ To provide compounds in which is a carboxyl protecting group, and The method according to claim 16 or 17, comprising reacting the compound of formula (I) with Bredereck's reagent.

19. P in equation (VI) ２ The method according to any one of claims 1 to 18, wherein the protecting group is a carboxyl protecting group.

20. The above method involves reacting the compound of formula (VI) with a carboxyl protecting group remover to obtain formula (VI'). 【Chemistry 9】 [In the formula, P １ The method according to claim 19, further comprising forming a compound of which is an H or N-protecting group.

21. P in equation (VI') １ The method according to claim 20, wherein is an N-protecting group.

22. Furthermore, The compound of formula (VI) is reacted with an organic amine to form an organic ammonium salt of the compound of formula (VI), and The method according to claim 20 or 21, comprising reacting the organic ammonium salt of the compound of formula (I) with an acid to form the compound of formula (VI).

23. The method according to claim 19, wherein the organic amine is (R)-α-methylbenzylamine and the organic ammonium salt is (R)-α-methylbenzylammonium salt.

24. The above method involves the compound of formula (VI') being expressed as formula (VII) 【Chemistry 10】 [In the formula, R １ is H or optionally substituted C １ ~C ６ It is alkyl, R ２ and R ３ Each is independently either H or methyl, m is 0, 1, or 2. B is C which is arbitrarily substituted. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally substituted C ６ ~C １４ By coupling with a compound or salt thereof of an aryl, an optionally substituted 5-10 membered heterocyclyl, or an optionally substituted 5-10 membered heteroaryl, Formula (VIII) 【Chemistry 11】 [In the formula, P １ [is an N-protecting group, and all other variable elements are as defined for formula (VII)] forming a compound of the form, and The compound of formula (VIII) is reacted with an N-protecting group remover to obtain formula (IX). 【Chemistry 12】 The method according to claim 23, further comprising forming a compound or salt thereof of [wherein all variable elements are as defined for formula (VIII)].

25. Furthermore, The compound of formula (IX) or a salt thereof, of formula (X) 【Chemistry 13】 [In the formula, R ４ H, Halo, OH, NH ２ , cyano, arbitrarily substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted 3- to 8-membered heterocyclyl, -C(O)NR ａ R ａ '(in the formula, R ａ and R ａ Each of the 's is independent of H and C which is arbitrarily substituted. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, or optionally substituted C ３ ~C ８ Cycloalkyl, -C(O)R ｂ , -OC(O)R ｂ , or -C(O)OR ｂ (In the formula, R ｂ In each existence, H and C are arbitrarily substituted. １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Alkoxy and optionally substituted C ３ ~C ８ (Selected from carbocyclyl) R ５ and R ６ Each of these is independently H, Halo, or C. １ ~C ６ It is alkyl, X １ is N or CR ｃ (In the formula, R ｃ H, halo, and C as arbitrarily substituted. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is an alkoxy, X ２ and X ５ are each independently N or CR ｄ (where each R ｄ is independently selected from H, halo, cyano, optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ alkoxy, optionally substituted C ３ to C ８ carbocyclyl, and optionally substituted 5- to 8-membered heteroaryl). X ３ and X ４ One of them is N and CR ｅ Selected from, X ３ and X ４ The other side is CR ｆ (In the formula, R ｅ This is C, which is H, halo, cyano, or optionally substituted. １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Alkoxy and -C(O)OR ｇ (In the formula, R ｇ is H or optionally substituted C １ ~C ６ Selected from (which is alkyl), R ｆ is an arbitrarily substituted C ４ ~C １０ This is selected from optionally substituted 5- to 10-membered heteroaryls containing 1, 2, or 3 heteroatoms selected from aryl, N, O, and S, and optionally substituted 4- to 10-membered saturated or unsaturated non-aromatic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S. By coupling with the compound or salt thereof, formula (XI) 【Chemistry 14】 [In the formula, R １ , R ２ , R ３ The method of claim 24, comprising forming a compound of [m, and B as defined for formula (IX), and all other variable elements as defined for formula (X)] or a pharmaceutically acceptable salt thereof.

26. P １ The method according to claim 24 or 25, wherein the carbonyl is tert-butoxycarbonyl.

27. The method according to claim 26, wherein the N-protecting group remover is hydrogen chloride, and the reaction of the compound of formula (VIII) with the N-protecting group remover forms a hydrochloride salt of the compound of formula (IX).

28. The method according to claim 27, wherein the hydrochloride salt of the compound of formula (IX) is coupled to the compound of formula (X) in dimethylformamide in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and N,N-diisopropylethylamine.

29. The method according to claim 26, wherein the N-protecting group removal agent is hydrogen bromide, and reacting the compound of formula (VIII) with the N-protecting group removal agent forms a hydrobromide salt of the compound of formula (IX).

30. The method according to claim 29, wherein the hydrobromide salt of the compound of formula (IX) is coupled to the compound of formula (X) in acetonitrile in the presence of propanephosphonic anhydride and N,N-diisopropylethylamine.

31. The method according to claim 26, wherein the N-protecting group removal agent is trifluoroacetic acid, and reacting the compound of formula (VIII) with the N-protecting group removal agent forms a trifluoroacetic acid salt of the compound of formula (IX).

32. The method according to claim 31, wherein the trifluoroacetate salt of the compound of formula (IX) is coupled to the compound of formula (X) in dimethylformamide in the presence of N,N-diisopropylethylamine and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate.

33. R １ The method according to any one of claims 24 to 32, wherein H is the case.

34. The method according to any one of claims 24 to 33, wherein m is 1.

35. The method according to any one of claims 24 to 33, wherein m is 0.

36. R ２ and R ３ The method according to any one of claims 24 to 34, wherein each of is H.

37. The method according to any one of claims 24 to 36, wherein B is an optionally substituted 5 to 10-membered heteroaryl.

38. The method according to claim 37, wherein B is an optionally substituted six-membered heteroaryl.

39. The method according to claim 38, wherein B is an optionally substituted pyridyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, or an optionally substituted pyrazinyl.

40. The method according to claim 39, wherein B is a pyridyl that is optionally substituted.

41. B, 【Chemistry 15】 The method according to claim 40.

42. B is arbitrarily replaced by C ６ ~C １４ The method according to any one of claims 24 to 36, wherein the material is aryl.

43. The method according to claim 42, wherein B is an optionally substituted phenyl.

44. The method according to any one of claims 24 to 36, wherein B is an optionally substituted 5- to 9-membered unsaturated heterocycline.

45. B is arbitrarily replaced by C ３ ~C １０ The method according to any one of claims 24 to 36, wherein the material is cycloalkyl.

46. B is arbitrarily replaced by C ２ ~C ６ The method according to any one of claims 24 to 36, wherein the alkenyl is used.

47. B is arbitrarily replaced by C １ ~C ６ The method according to any one of claims 24 to 36, wherein the alkyl group is alkyl.

48. X １ The method according to any one of claims 25 to 47, wherein N is the case.

49. X １ The method according to any one of claims 25 to 47, wherein CH is present.

50. X ２ However, CR ｄ The method according to any one of claims 25 to 49.

51. X ２ However, CH or C (CH ３ The method according to claim 50, which is:

52. X ５ However, CR ｄ The method according to any one of claims 25 to 51.

53. X ５ The method according to claim 52, wherein CH is present.

54. X ４ However, CR ｆ The method according to any one of claims 25 to 53.

55. X ３ The method according to claim 54, wherein the material is N or CH.

56. R ｆ The method according to any one of claims 25 to 55, wherein the selected heteroaryl is an optionally substituted 5 to 10-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, and S.

57. R ｆ The method according to claim 56, wherein the six-membered heteroaryl compound contains one, two, or three heteroatoms selected from N, O, and S.

58. R ｆ The method according to claim 57, wherein the pyrimidinyl is optionally substituted.

59. R ｆ The method according to claim 56, wherein the compound is an optionally substituted 8-10 membered bicyclic heteroaryl compound containing one, two, or three heteroatoms selected from N, O, and S.

60. R ｆ The method according to claim 59, wherein the optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyrimidinyl, optionally substituted thiazolo[5,4-b]pyrimidinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyrimidinyl, 1H-thieno[3,2-c]pyrazolyl, imidazo[1,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1H-benzo[d]imidazolyl.

61. R ｆ The method according to any one of claims 25 to 55, wherein the material is an optionally substituted 6-9 member unsaturated heterocycline containing 1 to 4 heteroatoms selected from N, O, or S.

62. R ｆ The method according to claim 61, wherein it is bonded to the carbon atom to which it is bonded via a carbon ring atom contained therein.

63. R ｆ The method according to claim 56, wherein the compound is an optionally substituted five-membered heteroaryl compound containing one, two, or three heteroatoms selected from N, O, and S.

64. R ４ but, 【Chemistry 16】 The method according to any one of claims 25 to 63.

65. R ５ and R ６ The method according to any one of claims 25 to 64, wherein each of is H.

66. The compound of formula (XI) above, 【Chemistry 17】 The method according to any one of claims 25 to 32, or a pharmaceutically acceptable salt thereof.

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