Method for preparing tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate and related compounds

Abstract

Provided herein are methods for preparing 2-azabicyclo[2.2.1]heptan-4-amine, a key structural motif found in numerous synthetic compounds that are Rho kinase inhibitors, and its primary amine-protected counterpart, tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate, as well as their enantiomers. Also provided herein are novel intermediate compounds and their enantiomers for use in preparing the aforementioned target compound, 2-azabicyclo[2.2.1]heptanyl.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 408,695, filed September 21, 2022, which is incorporated by reference herein in its entirety for all purposes. (Technical field)

[0002] The present disclosure relates generally to methods for making tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate, its enantiomers, and novel intermediate compounds. [Background technology]

[0003] The compound 2-azabicyclo[2.2.1]heptan-4-amine (defined herein as compound of formula T-1) is an important structural motif found in many synthetic compounds that are inhibitors of Rho kinase. These inhibitors may be useful for treating or preventing a variety of diseases or conditions. See, e.g., U.S. Publication No. 2011 / 0144150. The chemical structure of compound of formula T-1 is shown below. [ka]

[0004] The selectively protected compound of formula T-1 and its enantiomers are interesting as building blocks for various compounds. Thus, in one embodiment, a method for preparing tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate, its enantiomers, and their salts is provided. The chemical structure of the compound of formula T-2, which is the primary amine-protected compound of formula T-1, is shown below. [ka]

[0005] Also provided herein are intermediate compounds used in the preparation of T-1 and / or T-2. Summary of the Invention

[0006] In certain embodiments, the present disclosure describes methods for preparing tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate, its enantiomers, and their salts as building blocks for various inhibitor compounds. Also described herein are intermediate compounds used in the preparation of the compounds.

[0007] The present embodiments will be further understood by reference to the detailed description and examples, which are illustrative of the embodiments and are not intended to be limiting.

[0008] In certain embodiments, the present specification provides a method for preparing a compound of formula T-2 or a salt thereof. [ka]

[0009] In another aspect, provided herein are methods for preparing compounds of formula T-3 and T-4, which are enantiomers of the compound of formula T-2, or salts thereof. [ka]

[0010] In some embodiments, the present description provides compounds of formula T-2: [ka] or a salt thereof, comprising the steps of: (a) A compound of Formula 1: [ka] or a salt thereof, wherein the compound of formula 2: [ka] or a salt thereof to form a compound of formula 3: [ka] or form a salt thereof; (b) reacting a compound of formula 3 or a salt thereof with phthalimide to form a compound of formula 4: [ka] or form a salt thereof; (c) deprotecting the compound of formula 4 or a salt thereof to obtain a compound of formula 5: [ka] or form a salt thereof; (d) reacting a compound of formula 5 or a salt thereof with a base to form a compound of formula 6: [ka] or form a salt thereof; (e) reacting a compound of formula 6 or a salt thereof with ROH in the presence of diphenylphosphoryl azide and an amine base to give a compound of formula 7: [ka] or a salt thereof; and (f) The compound of formula 7 or a salt thereof is converted into a compound of formula 8: [ka] or a salt thereof to form PgX; and (g) reducing a compound of formula 8 or a salt thereof to form a compound of formula 9: [ka] or a salt thereof; and (h) reducing a compound of formula 9 or a salt thereof to obtain a compound of formula 10: [ka] or a salt thereof; and (i) protecting the primary amine of a compound of formula 10, or a salt thereof, to provide a compound of formula 11: [ka] or a salt thereof; and (j) reducing the compound of formula 11 or a salt thereof to form a compound of formula T-2 The present invention provides a method characterized by:

[0011] In some embodiments, the present description provides compounds of formula T-2: [ka] or a salt thereof, comprising the steps of: (a) A compound of formula 7: [ka] or a salt thereof, the primary amine is deprotected and then protected to give a compound of formula 7.5: [ka] Forming (b) hydrolyzing a compound of formula 7.5 or a salt thereof to give a compound of formula 8.5: [ka] or a salt thereof; and (c) reducing a compound of formula 8.5 or a salt thereof to give a compound of formula 9.5: [ka] or a salt thereof; and (d) Sequentially protecting the substituents and heterocyclic amines of a compound of formula 9.5 or a salt thereof and selectively deprotecting the substituent amines to give a compound of formula 10: [ka] or forming a salt thereof Also provided is a method characterized by: DETAILED DESCRIPTION OF THE INVENTION

[0012] (definition) Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments of the present disclosure. The foregoing general description and the following detailed description are intended to be exemplary and explanatory only and are not intended to be limiting of any claimed subject matter. In the event that any reference referenced herein conflicts with the express content of this disclosure, the express content of this disclosure shall control. In this application, the use of the singular includes the plural unless expressly stated otherwise. It should be noted that the singular forms "a," "an," and "the" used in the specification and the appended claims include the plural unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the terms "comprises" and "includes" does not imply limitation.

[0013] Unless the context otherwise requires, throughout this specification and claims, the word "comprise" and its variations, such as "comprises" and "comprising," are to be understood in their open and inclusive sense, including but not limited to.

[0014] In this disclosure, any concentration range, percentage range, ratio range, or integer range is understood to include any integer in the recited range and, where appropriate, fractions thereof (e.g., tenths and hundredths of integers) unless otherwise specified. Also, any numerical range recited herein with respect to any physical characteristic (such as the number of subunits, size, or viscosity of a polymer) is understood to include any integer within the recited range unless otherwise specified. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the stated range, value, or structure, unless otherwise specified.

[0015] Throughout this specification, the reference to "an embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. That is, the appearance of the phrase "in an embodiment" or "in an embodiment" in various places throughout this specification does not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0016] As used herein, the term "salt" refers to an acid or base salt of a compound of the present disclosure. "Pharmaceutically acceptable salts" are understood to be non-toxic. Examples of pharmaceutically acceptable salts include, but are not limited to, acid addition salts and base addition salts.

[0017] Pharmaceutically acceptable acid addition salts include those with inorganic acids (such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), and organic acids (such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, 10-camphorsulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, etc.). acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0018] Pharmaceutically acceptable base addition salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Examples of inorganic salts include, but are not limited to, ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, naturally occurring substituted amines, substituted amines including cyclic amines, and basic ion exchange resins, including, but not limited to, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.

[0019] The term "optionally" means that the event of the subsequently described situation may or may not occur, and examples in which the event or situation occurs and examples in which the event or situation does not occur are described. For example, "optionally converting compound X to its salt" means that compound X may or may not be converted to a salt. In some embodiments, compound X is converted to a salt, while in other embodiments, compound X is not converted to a salt.

[0020] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, the invention may also be practiced in a single embodiment that may for clarity be described separately herein.

[0021] In certain embodiments, the present application provides a method for preparing a compound of formula T-2, or a salt thereof, according to the synthetic route outlined in Scheme 1 ("Synthetic Route 1"). Scheme 1. Synthesis of Compounds of Formula T-2 [ka]

[0022] Now, in certain embodiments, the description provides compounds of formula T-2: [ka] or a salt thereof, comprising the steps of: (a) A compound of Formula 1: [ka] or a salt thereof, wherein the compound of formula 2: [ka] or a salt thereof to form a compound of formula 3: [ka] or form a salt thereof; (b) reacting a compound of formula 3 or a salt thereof with phthalimide to form a compound of formula 4: [ka] or form a salt thereof; (c) deprotecting the compound of formula 4 or a salt thereof to obtain a compound of formula 5: [ka] or form a salt thereof; (d) reacting a compound of formula 5 or a salt thereof with a base to form a compound of formula 6: [ka] or form a salt thereof; (e) reacting a compound of formula 6 or a salt thereof with ROH to form a compound of formula 7: [ka] or a salt thereof; and (f) reacting a compound of formula 7 or a salt thereof with PgX to form a compound of formula 8: [ka] or a salt thereof; and (g) reducing a compound of formula 8 or a salt thereof to form a compound of formula 9: [ka] or a salt thereof; and (h) reducing a compound of formula 9 or a salt thereof to obtain a compound of formula 10: [ka] or a salt thereof; and (i) protecting the primary amine of a compound of formula 10, or a salt thereof, to provide a compound of formula 11: [ka] or a salt thereof; and (j) reducing the compound of formula 11 or a salt thereof to form a compound of formula T-2 A method is disclosed, characterized by:

[0023] In certain embodiments, step (a) is carried out in the presence of a base. In some embodiments, the base is sodium hydride, potassium tert-butoxide, or sodium ethoxide. In other embodiments, the base is sodium ethoxide.

[0024] In certain embodiments, step (a) is carried out using an alcohol as a solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is ethanol.

[0025] In certain embodiments, step (a) is carried out at a temperature of about 0-30° C. In some embodiments, step (a) is carried out at a starting temperature of about 0-10° C., then 20-30° C.

[0026] In certain embodiments, step (a) is performed using a compound of Formula 1, or a salt thereof, separated into enantiomers of Formula 1a and Formula 1b, or salts thereof, using kinetic resolution. In certain embodiments, the kinetic resolution is Jacobsen kinetic resolution. In certain embodiments, the kinetic resolution is hydrolysis kinetic resolution catalyzed by a chiral salen-cobalt complex.

[0027] In certain embodiments, step (b) further comprises triphenylphosphine and diisopropyl azodicarboxylate.

[0028] In certain embodiments, step (b) is carried out using an aprotic solvent. In some embodiments, the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. In certain embodiments, the aprotic solvent is tetrahydrofuran.

[0029] In certain embodiments, step (b) is carried out at a temperature of about 0-30° C. In some embodiments, step (b) is carried out at a starting temperature of about 0-10° C., then 20-30° C.

[0030] In certain embodiments, step (c) is carried out in the presence of a base. In some embodiments, the base is sodium borohydride, methylamine, methylhydrazine, or hydrazine. In other embodiments, the base is hydrazine.

[0031] In certain embodiments, step (c) is carried out using a mixed solvent of alcohol and organic solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In some embodiments, the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, or 2-methyltetrahydrofuran. In certain embodiments, the alcohol is methanol, and the organic solvent is dichloromethane.

[0032] In certain embodiments, step (d) is carried out using an inorganic base. In some embodiments, the inorganic base is sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, or cesium carbonate. In other embodiments, the inorganic base is cesium carbonate.

[0033] In certain embodiments, step (d) is carried out using an alcohol as a solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is methanol.

[0034] In certain embodiments, step (d) is carried out at a temperature of about 25-80° C. In certain embodiments, step (d) is carried out at a temperature of about 50-70° C.

[0035] In certain embodiments, step (e) is carried out using an amine base. In some embodiments, the amine base is 2,2,6,6-tetramethylpiperidine, trimethylamine, triethylamine, or N,N-diisopropylethylamine. In other embodiments, the amine base is N,N-diisopropylethylamine.

[0036] In certain embodiments, step (e) is carried out using an organic solvent. In some embodiments, the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof. In certain embodiments, the organic solvent is 2-methyltetrahydrofuran.

[0037] In certain embodiments, step (e) is carried out at a starting temperature of about 40-70° C., followed by reflux at a temperature above 50° C. to 120° C. In certain embodiments, step (e) is carried out at a starting temperature of about 50-60° C., followed by reflux at a temperature above 70° C. to 100° C.

[0038] In certain embodiments, step (e) is carried out at a temperature of about 40-70° C., followed by a temperature of about 50-120° C. In certain embodiments, step (e) is carried out at a temperature of about 50-60° C. or about 50-70° C., followed by a temperature of about 70-100° C.

[0039] In certain embodiments, after step (e), the compound of formula 7 or a salt thereof is separated into the enantiomers formula 7a and formula 7b, or salts thereof, using supercritical fluid chromatography.

[0040] In certain embodiments, step (f) is carried out in the presence of a non-nucleophilic base. In some embodiments, the non-nucleophilic base is N,N-diisopropylethylamine, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, or lithium bis(trimethylsilyl)amide. In other embodiments, the non-nucleophilic base is lithium bis(trimethylsilyl)amide.

[0041] In certain embodiments, step (f) is carried out using an ethereal solvent. In some embodiments, the ethereal solvent is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, or a mixture thereof. In certain embodiments, the ethereal solvent is tetrahydrofuran.

[0042] In certain embodiments, step (g) is catalyzed by a transition metal. In some embodiments, the transition metal is palladium chloride, palladium / barium sulfate, or palladium on carbon (Pd / C). In other embodiments, the transition metal is palladium on carbon (Pd / C).

[0043] In certain embodiments, step (g) is carried out using an alcohol as a solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is methanol.

[0044] In certain embodiments, step (h) is carried out using a reducing agent. In some embodiments, the reducing agent is a metal hydride, aluminum hydride, borohydride, or a borane reagent. In some embodiments, the reducing agent is lithium aluminum hydride, triphenylphosphine borane, tetrahydrofuran borane, or dimethyl sulfide borane. In other embodiments, the reducing agent is dimethyl sulfide borane.

[0045] In certain embodiments, step (h) is carried out using an aprotic solvent. In some embodiments, the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. In certain embodiments, the aprotic solvent is tetrahydrofuran.

[0046] In certain embodiments, step (h) is carried out at a temperature of about 25-80° C. In certain embodiments, step (h) is carried out at a temperature of about 60-70° C.

[0047] In certain embodiments, step (i) is carried out using an organic solvent. In some embodiments, the organic solvent is chloroform, dichloroethane, toluene, methanol, ethanol, isopropanol, or 2-methyl-THF, dioxane, ethyl acetate, or tetrahydrofuran. In certain embodiments, the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran.

[0048] In certain embodiments, step (j) is catalyzed by a transition metal. In some embodiments, the transition metal is palladium chloride, palladium / barium sulfate, or palladium on carbon (Pd / C). In other embodiments, the transition metal is palladium on carbon (Pd / C).

[0049] In certain embodiments, step (j) is carried out using an alcohol as a solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is methanol.

[0050] Synthetic Route 2 In another embodiment, the present application provides a method for preparing a compound of formula T-2, or a salt thereof, according to the synthetic route outlined in Scheme 2 (“Synthetic Route 2”). Scheme 2. Synthetic Route 2 for Compounds of Formula T-2 [ka]

[0051] Here, in certain embodiments, the present specification provides compounds of formula T-2: [ka] or a salt thereof, comprising the steps of: (a) then reacting a compound of formula 7: [ka] or a salt thereof, the primary amine is deprotected and then protected to give a compound of formula 7.5: [ka] Forming; (b) hydrolyzing a compound of formula 7.5 or a salt thereof to give a compound of formula 8.5: [ka] or a salt thereof; and (c) reducing a compound of formula 8.5 or a salt thereof to give a compound of formula 9.5: [ka] or a salt thereof; and (d) sequentially protecting the substituents and heterocyclic amines of a compound of formula 9.5 or a salt thereof, and selectively deprotecting the substituent amines to give a compound of formula 10: [ka] or forming a salt thereof A method is disclosed, characterized by:

[0052] In certain embodiments, step (a) is catalyzed by a transition metal. In some embodiments, the transition metal is palladium chloride, palladium / barium sulfate, or palladium on carbon (Pd / C). In other embodiments, the transition metal is palladium on carbon (Pd / C).

[0053] In certain embodiments, step (a) is carried out using an alcohol as a solvent. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In certain embodiments, the alcohol is methanol.

[0054] In certain embodiments, step (a) is carried out using an organic solvent. In some embodiments, the organic solvent is chloroform, dichloromethane, carbon tetrachloride, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran. In certain embodiments, the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran.

[0055] In certain embodiments, step (b) is performed with an acid. In some embodiments, the acid is trifluoroacetic acid, hydrochloric acid, or phosphoric acid. In certain embodiments, the acid is trifluoroacetic acid.

[0056] In certain embodiments, step (b) is carried out using an organic solvent. In some embodiments, the organic solvent is chloroform, dichloromethane, carbon tetrachloride, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran. In certain embodiments, the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran.

[0057] In certain embodiments, step (b) is carried out at a temperature of about 20-30°C.

[0058] In certain embodiments, step (c) is carried out using a reducing agent. In some embodiments, the reducing agent is a metal hydride, aluminum hydride, borohydride, or a borane reagent. In some embodiments, the reducing agent is lithium aluminum hydride, triphenylphosphine borane, tetrahydrofuran borane, or dimethylsulfide borane. In other embodiments, the reducing agent is lithium aluminum hydride.

[0059] In certain embodiments, step (c) is carried out using an aprotic solvent. In some embodiments, the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. In certain embodiments, the aprotic solvent is diethyl ether, tetrahydrofuran, or a mixture thereof.

[0060] In certain embodiments, step (d) is carried out using an organic solvent. In some embodiments, the organic solvent is chloroform, dichloromethane, carbon tetrachloride, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran. In certain embodiments, the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran.

[0061] In certain embodiments, the selective deprotection of the amine of the substituent in step (d) is carried out using an acid, hi some embodiments, the acid is hydrochloric acid.

[0062] compound In some embodiments, the present application provides a compound of formula T-2, wherein Pg1 is a first protecting group: [ka] or a salt thereof.

[0063] In certain embodiments, Pg1 is tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene or fluorenylmethyloxycarbonyl.In certain embodiments, Pg1 is tert-butyloxycarbonyl.

[0064] In certain embodiments, the compound of formula T-2 is the enantiomer of compounds of formula T-3 and formula T-4: [ka] or its salt.

[0065] In certain embodiments, the present disclosure provides novel intermediate compounds useful in the synthesis of compounds of formula T-2 or salts thereof. In certain embodiments, the novel intermediate compounds are [ka] or a salt thereof.

[0066] In certain embodiments, Pg2 is a second protecting group.In certain embodiments, Pg2 is tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimide, triphenylmethyl, diarylmethyl, benzylidene or fluorenylmethyloxycarbonyl.In certain embodiments, Pg2 is optionally substituted with C1-C6 alkoxy, C1-C6 alkyl or halide benzyl group.

[0067] In certain embodiments, R1 is benzyl carbamate optionally substituted with a C1-C6 alkoxy, C1-C6 alkyl, halide, or amino protecting group.

[0068] In certain embodiments, the novel intermediate compounds are separated into enantiomers, and the novel intermediate compounds are [ka] or a salt thereof.

[0069] Non-limiting embodiments Particular aspects of the invention are provided in the numbered embodiments below. 1. Compound of formula (T-2): [ka] or a salt thereof, [ka] wherein Pg1 is a first protecting group and Pg2 is a second protecting group, or a salt thereof, to form a compound of formula (T-2). A method characterized by: 2. a) The compound of formula (T-2) is converted into a compound of formula (T-3): [ka] and the compound of formula (11) is a compound of formula (11a): [ka] Or b) The compound of formula (T-2) is a compound of formula (T-4): [ka] and the compound of formula (11) is a compound of formula (11b): [ka] The method of embodiment 1, wherein 3. The method of embodiment 1 or embodiment 2, wherein Pg1 and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl. 4. The method of embodiment 1 or embodiment 2, wherein Pg1 is tert-butyloxycarbonyl. 5. The method of embodiment 1 or embodiment 2, wherein Pg2 is a benzyl group optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide. 6. The process of any one of embodiments 1-5, wherein the reduction of formula (11) or a salt thereof is catalyzed by a transition metal to form a compound of formula (T-2) or a salt thereof. 7. The method of embodiment 6, wherein the transition metal is palladium chloride, palladium / barium sulfate, or palladium on carbon (Pd / C). 8. The method of embodiment 6, wherein the transition metal is palladium on carbon (Pd / C). 9. The method of any one of embodiments 1 to 8, wherein the reaction is carried out using an alcohol as a solvent. 10. The method of embodiment 9, wherein the alcohol is methanol, ethanol, or isopropanol. 11. The method of embodiment 9, wherein the alcohol is methanol. 12. A compound of formula (11) or a salt thereof, wherein the compound of formula (10): [ka] 12. The method of any one of embodiments 1-11, wherein the compound is prepared by protecting the primary amine of the compound, or a salt thereof. 13. Equation (11): [ka] wherein Pg1 is a first protecting group and Pg2 is a second protecting group, or a salt thereof, comprising reacting a compound of formula (10): [ka] or a salt thereof, to form a compound of formula (11). 14. The method of embodiment 13, wherein Pg1 and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl. 15. The method of embodiment 13, wherein Pg1 is tert-butyloxycarbonyl. 16. The method of embodiment 13, wherein Pg2 is a benzyl group optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide. 17. a) The compound of formula (11) is a compound of formula (11a): [ka] and the compound of formula (10) is a compound of formula (10a): TIFF2025531921000057.tif2030 or b) The compound of formula (11) is a compound of formula (11b): [ka] and the compound of formula (10) is a compound of formula (10b): [ka] 17. The method of any one of embodiments 12 to 16, wherein: 18. The method of any one of embodiments 12-17, wherein the reaction is carried out using an organic solvent. 19. The method of embodiment 18, wherein the organic solvent is chloroform, dichloroethane, toluene, methanol, ethanol, isopropanol, or 2-methyl-THF, dioxane, ethyl acetate, or tetrahydrofuran. 20. The method of embodiment 18, wherein the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran. 21. A compound of formula (10) or a salt thereof is prepared by reacting a compound of formula (9.5): [ka] or a salt thereof with Pg2 and Pg1, respectively, followed by selective deprotection of the substituted amine to form the compound of formula (10). 22. A compound of formula (10) or a salt thereof, wherein the compound is a compound of formula (9): [ka] or a salt thereof to form a compound of formula (10). 23. A compound of formula (10): [ka] or a salt thereof, [ka] wherein Pg2 is a second protecting group, or a salt thereof, to form a compound of formula (10). 24. The method of embodiment 23, wherein Pg2 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl. 25. The method of embodiment 23, wherein Pg2 is a benzyl group optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide. 26. a) The compound of formula (10) is a compound of formula (10a): [ka] and the compound of formula (9) is a compound of formula (9a): [ka] Or b) The compound of formula (10) is a compound of formula (10b): [ka] and the compound of formula (9) is a compound of formula (9b): [ka] 26. The method of any one of embodiments 22 to 25, wherein 27. The method of any one of embodiments 22-26, wherein the reducing agent is a metal hydride, aluminum hydride, borohydride, or a borane reagent. 28. The method of embodiment 27, wherein the reducing agent is lithium aluminum hydride, triphenylphosphine borane, tetrahydrofuran borane, or dimethylsulfide borane. 29. The method of embodiment 27, wherein the reducing agent is dimethylsulfide borane. 30. The method of any one of embodiments 22-29, wherein the reaction is carried out using an aprotic solvent. 31. The method of embodiment 30, wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. 32. The method of embodiment 30, wherein the aprotic solvent is tetrahydrofuran. 33. The method of any one of embodiments 22-32, wherein the reaction is carried out at a temperature of about 25 to 80°C. 34. The method of embodiment 33, wherein the reaction is carried out at a temperature of about 60 to 70°C. 35. A compound of formula (9) or a salt thereof, wherein the compound of formula (8): [ka] (In the formula, R1 is a benzyl carbamate optionally substituted with a C1-C6 alkoxy, C1-C6 alkyl, halide, or amino protecting group; and Pg2 is a second protecting group or a salt thereof to form a compound of formula (9). 36. A compound of formula (9): [ka] or a salt thereof, [ka] (In the formula, R1 is a benzyl carbamate optionally substituted with a C1-C6 alkoxy, C1-C6 alkyl, halide, or amino protecting group; and Pg2 is a second protecting group or a salt thereof to form a compound of formula (9) A method characterized by: 37. The method of embodiment 36, wherein Pg2 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl. 38. The method of embodiment 36, wherein Pg2 is a benzyl group optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide. 39. a) The compound of formula (9) is a compound of formula (9a): [ka] and the compound of formula (8) is a compound of formula (8a): TIFF2025531921000072.tif2428 or b) The compound of formula (9) is a compound of formula (9b): [ka] and the compound of formula (8) is a compound of formula (8b): [ka] The method of any one of embodiments 35 to 38, wherein 40. The method of any one of embodiments 35-39, wherein the reduction is catalyzed by a transition metal. 41. The method of embodiment 40, wherein the transition metal is palladium chloride, palladium / barium sulfate, or palladium on carbon (Pd / C). 42. The method of embodiment 40, wherein the transition metal is palladium on carbon (Pd / C). 43. The method of any one of embodiments 35-42, wherein the reaction is carried out using an alcohol as a solvent. 44. The method of embodiment 43, wherein the alcohol is methanol, ethanol, or isopropanol. 45. The method of embodiment 43, wherein the alcohol is methanol. 46.Equation (7): [ka] (In the formula, R1 is a benzyl carbamate optionally substituted with a C1-C6 alkoxy, C1-C6 alkyl, halide, or amino protecting group; Pg2 is a second protecting group; and X is a leaving group. or a salt thereof with PgX to form the compound of formula (8). 47. A compound of formula (8): [ka] or a salt thereof, [ka] (In the formula, R1 is a benzyl carbamate optionally substituted with a C1-C6 alkoxy, C1-C6 alkyl, halide, or amino protecting group; Pg2 is a second protecting group; and X is a leaving group. or a salt thereof reacts with Pg2X to form a compound of formula (8). 48. a) The compound of formula (8) is a compound of formula (8a): [ka] and the compound of formula (7) is a compound of formula (7a): [ka] Or b) The compound of formula (8) is a compound of formula (8b): [ka] and the compound of formula (7) is a compound of formula (7b): [ka] 48. The method of embodiment 46 or embodiment 47, wherein 49. The method of any one of embodiments 46-48, wherein Pg2 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl. 50. The method of any one of embodiments 46-48, wherein Pg2 is a benzyl group optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide. 51. The method of any one of embodiments 46-50, wherein the reaction is carried out in the presence of a non-nucleophilic base. 52. The method of embodiment 51, wherein the non-nucleophilic base is N,N-diisopropylethylamine, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, or lithium bis(trimethylsilyl)amide. 53. The method of embodiment 51, wherein the non-nucleophilic base used in the reaction with the compound of formula (7) is lithium bis(trimethylsilyl)amide. 54. The method of any one of embodiments 46-53, wherein the reaction is carried out using an ether solvent. 55. The method of embodiment 54, wherein the ether solvent is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, or a mixture thereof. 56. The method of embodiment 54, wherein the ether solvent is tetrahydrofuran. 57. Equation (10): [ka] wherein Pg2 is a second protecting group, or a salt thereof, comprising reacting a compound of formula (9.5): [ka] or a salt thereof with Pg2 and Pg1, respectively, followed by selective deprotection of the substituent amine to form a compound of formula (10). 58. The method of embodiment 57, wherein Pg1 and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl. 59. The method of embodiment 57, wherein Pg1 is optionally substituted benzyl. 60. The method of embodiment 57, wherein Pg2 is optionally substituted carboxybenzyl. 61. a) The compound of formula (10) is a compound of formula (10a): [ka] and the compound of formula (9.5) is a compound of formula (9.5a): [ka] Or b) The compound of formula (10) is a compound of formula (10b): [ka] and the compound of formula (9.5) is a compound of formula (9.5b): [ka] The method of any one of embodiments 21 or 57-60, wherein 62. The method of any one of embodiments 21 or 57-61, wherein the protection reaction is carried out using an organic solvent. 63. The method of embodiment 62, wherein the organic solvent is chloroform, dichloromethane, carbon tetrachloride, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran. 64. The method of embodiment 62, wherein the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran. 65. The method of any one of embodiments 21 or 57-64, wherein selective deprotection of the amine of the substituent is carried out with an acid. 66. The method of embodiment 65, wherein the acid is hydrochloric acid. 67. A compound of formula (9.5) or a salt thereof is prepared by reacting a compound of formula (8.5): [ka] or a salt thereof to form a compound of formula (9.5). 68. Compound of formula (9.5): [ka] or a salt thereof, comprising reacting a compound of formula (8.5): [ka] or a salt thereof to form a compound of formula (9.5). 69. a) The compound of formula (9.5) is the compound of formula (9.5a): [ka] and the compound of formula (8.5) is a compound of formula (8.5a): [ka] Or c) The compound of formula (9.5) is a compound of formula (9.5b): [ka] and the compound of formula (8.5) is a compound of formula (8.5b): [ka] The method of embodiment 67 or embodiment 68, wherein 70. The method of any one of embodiments 67-69, wherein the reducing agent is a metal hydride, aluminum hydride, borohydride, or a borane reagent. 71. The method of embodiment 70, wherein the reducing agent is lithium aluminum hydride, triphenylphosphine borane, tetrahydrofuran borane, or dimethylsulfide borane. 72. The method of embodiment 70, wherein the reducing agent is lithium aluminum hydride. 73. The method of any one of embodiments 67-72, wherein the reaction is carried out using an aprotic solvent. 74. The method of embodiment 73, wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. 75. The method of embodiment 73, wherein the aprotic solvent is diethyl ether, tetrahydrofuran, or a mixture thereof. 76. A compound of formula (8.5) or a salt thereof is a compound of formula (7.5): [ka] 76. The method of any one of embodiments 67-75, wherein Pg1 is a first protecting group, prepared by hydrolyzing a compound of formula (8.5) or a salt thereof to form a compound of formula (8.5). 77. Compound of formula (8.5): [ka] or a salt thereof, [ka] wherein Pg1 is a first protecting group, or a salt thereof, to form a compound of formula (8.5). 78. The method of embodiment 76 or embodiment 77, wherein Pg1 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl. 79. The method of embodiment 76 or embodiment 77, wherein Pg1 is tert-butyloxycarbonyl. 80. a) The compound of formula (8.5) is the compound of formula (8.5a): [ka] and the compound of formula (7) is a compound of formula (7.5a): [ka] Or d) The compound of formula (8.5) is a compound of formula (8.5b): [ka] and the compound of formula (7.5) is a compound of formula (7.5b): [ka] The method of any one of embodiments 76 to 79, wherein 81. The method of any one of embodiments 76-80, wherein the hydrolysis is carried out with an acid. 82. The method of embodiment 81, wherein the acid is trifluoroacetic acid, hydrochloric acid, or phosphoric acid. 83. The method of embodiment 81, wherein the acid is trifluoroacetic acid. 84. The method of any one of embodiments 76-83, wherein the protection reaction is carried out using an organic solvent. 85. The method of embodiment 84, wherein the organic solvent is chloroform, dichloromethane, carbon tetrachloride, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran. 86. The method of embodiment 84, wherein the organic solvent is dichloromethane, methanol, or toluene. 87. The method of any one of embodiments 76-86, wherein the reaction is carried out at a temperature of about 20-30°C. 88. A compound of formula (7.5) or a salt thereof is prepared by reacting a compound of formula (7): [ka] 88. The method of any one of embodiments 76 to 87, wherein the compound is prepared by deprotecting the primary amine of the compound, or a salt thereof, followed by protection. 89. Equation (7.5): [ka] wherein Pg1 is a first protecting group, or a salt thereof, comprising reacting a compound of formula (7): [ka] wherein R1 is C1-C6 alkoxy, C1-C6 alkyl, halide, or benzyl carbamate optionally substituted with an amino protecting group, or a salt thereof, by deprotection and subsequent protection of the primary amine to form a compound of formula (7.5). 90. The method of embodiment 88 or embodiment 89, wherein Pg1 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl. 91. The method of embodiment 88 or embodiment 89, wherein Pg1 is tert-butyloxycarbonyl. 92. a) The compound of formula (7.5) is a compound of formula (7.5a): [ka] and the compound of formula (7) is a compound of formula (7a): [ka] Or b) The compound of formula (7.5) is a compound of formula (7.5b): [ka] and the compound of formula (7) is a compound of formula (7b): [ka] The method of any one of embodiments 88 to 91, wherein 93. The method of any one of embodiments 88-92, wherein the deprotection is catalyzed by a transition metal. 94. The method of embodiment 93, wherein the transition metal is palladium chloride, palladium / barium sulfate, or palladium on carbon (Pd / C). 95. The method of embodiment 93, wherein the transition metal is palladium on carbon (Pd / C). 96. The method of any one of embodiments 88-95, wherein the reaction is carried out using an alcohol as a solvent. 97. The method of embodiment 96, wherein the alcohol is methanol, ethanol, or isopropanol. 98. The method of embodiment 96, wherein the alcohol is methanol. 99. The method of any one of embodiments 88-98, wherein the protection reaction is carried out using an organic solvent. 100. The method of embodiment 99, wherein the organic solvent is chloroform, dichloromethane, carbon tetrachloride, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran. 101. The method of embodiment 99, wherein the organic solvent is dichloromethane, methanol, toluene, or tetrahydrofuran. 102. A compound of formula (6): [ka] or a salt thereof, is prepared by reacting ROH, wherein R is benzyl optionally substituted with C-C alkoxy, C-C alkyl, or halide, in the presence of diphenylphosphoryl azide and an amine base to form a compound of formula (7). 103. Formula (7): [ka] wherein R1 is benzyl carbamate optionally substituted with a C1-C6 alkoxy, C1-C6 alkyl, halide, or amino protecting group, or a salt thereof, comprising the step of: [ka] or a salt thereof, is reacted with R3OH (wherein R3 is benzyl optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide) in the presence of diphenylphosphoryl azide and an amine base to form a compound of formula (7). 104. a) The compound of formula (7) is a compound of formula (7a): [ka] and the compound of formula (6) is a compound of formula (6a): [ka] Or b) The compound of formula (7) is a compound of formula (7b): [ka] and the compound of formula (6) is a compound of formula (6b): [ka] The method of embodiment 102 or embodiment 103, wherein 105. The method of any one of embodiments 102-104, wherein the amine base is 2,2,6,6-tetramethylpiperidine, trimethylamine, triethylamine, or N,N-diisopropylethylamine. 106. The method of embodiment 105, wherein the amine base is N,N-diisopropylethylamine. 107. The method of any one of embodiments 102-106, wherein the reaction is carried out using an organic solvent. 108. The process of embodiment 107, wherein the organic solvent used in the reaction is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof. 109. The process of embodiment 107, wherein the organic solvent used in the reaction is 2-methyltetrahydrofuran. 110. The method of any one of embodiments 102-109, wherein the reaction is carried out at an initial temperature of about 40-70°C, followed by reflux at a temperature of greater than 50°C to 120°C. 111. The process of embodiment 110, wherein the reaction is carried out at an initial temperature of about 50-60°C or about 60-70°C, followed by reflux at a temperature of about 70-100°C. 112. The method of any one of embodiments 102-111, wherein the compound of formula (7), or a salt thereof, is separated into enantiomers, a compound of formula (7a) and a compound of formula (7b), or a salt thereof, using supercritical fluid chromatography. 113. A compound of formula (5): [ka] 113. The method of any one of embodiments 102-112, wherein the compound of formula (6) or a salt thereof is prepared by reacting the compound of formula (6) or a salt thereof with a base to form the compound of formula (6). 114. A compound of formula (6): [ka] or a salt thereof, comprising the step of: [ka] or a salt thereof, reacting with a base to form a compound of formula (6). 115. a) The compound of formula (6) is a compound of formula (6a): [ka] and the compound of formula (5) is a compound of formula (5a): [ka] Or b) The compound of formula (6) is a compound of formula (6b): [ka] and the compound of formula (5) is a compound of formula (5b): [ka] The method of embodiment 113 or 114, wherein 116. The method of any one of embodiments 113-115, wherein the base is an inorganic base. 117. The method of embodiment 116, wherein the inorganic base is sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, or cesium carbonate. 118. The method of embodiment 116, wherein the inorganic base is cesium carbonate. 119. The method of any one of embodiments 113-118, wherein the reaction is carried out using an alcohol as a solvent. 120. The method of embodiment 119, wherein the alcohol is methanol, ethanol, or isopropanol. 121. The method of embodiment 119, wherein the alcohol is methanol. 122. The method of any one of embodiments 113-121, wherein the reaction is carried out at a temperature of about 25 to 80°C. 123. The method of embodiment 122, wherein the reaction is carried out at a temperature of about 50 to 70°C. 124. A compound of formula (5) or a salt thereof is a compound of formula (4): [ka] or a salt thereof to form a compound of formula (5). 125. A compound of formula (5): [ka] or a salt thereof, comprising the step of: [ka] or a salt thereof to form a compound of formula (5). 126. a) The compound of formula (5) is a compound of formula (5a): [ka] and the compound of formula (4) is a compound of formula (4a): [ka] Or b) The compound of formula (5) is a compound of formula (5b): [ka] and the compound of formula (4) is a compound of formula (4b): [ka] The method of embodiment 124 or embodiment 125, wherein 127. The method of any one of embodiments 124-126, wherein deprotection is carried out using a base. 128. The method of embodiment 127, wherein the base is sodium borohydride, methylamine, methylhydrazine, or hydrazine. 129. The method of embodiment 127, wherein the base is hydrazine. 130. The method of any one of embodiments 124-129, wherein the reaction is carried out using a mixture of an alcohol and an organic solvent. 131. The method of embodiment 130, wherein the alcohol is methanol, ethanol, or isopropanol. 132. The method of embodiment 130, wherein the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, or 2-methyltetrahydrofuran. 133. The method of embodiment 130, wherein the alcohol is methanol and the organic solvent is dichloromethane. 134. A compound of formula (3): [ka] The method of any one of embodiments 124-133, wherein the compound of formula (4) or a salt thereof is prepared by reacting 1, or a salt thereof with phthalimide to form the compound of formula (4). 135. A compound of formula (4): [ka] or a salt thereof, comprising the step of: [ka] or a salt thereof, reacting with phthalimide to form a compound of formula (4). 136. a) The compound of formula (4) is a compound of formula (4a): [ka] and the compound of formula (3) is a compound of formula (3a): [ka] Or b) The compound of formula (4) is a compound of formula (4b): [ka] and the compound of formula (3) is a compound of formula (3b): [ka] The method of embodiment 134 or embodiment 135, wherein 137. The method of any one of embodiments 134-136, wherein the reaction further includes triphenylphosphine and diisopropyl azodicarboxylate. 138. The method of any one of embodiments 134-137, wherein the reaction is carried out using an aprotic solvent. 139. The method of embodiment 138, wherein the aprotic solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof. 140. The method of embodiment 138, wherein the aprotic solvent is tetrahydrofuran. 141. The method of any one of embodiments 134-140, wherein the reaction is carried out at a temperature of about 0 to 30°C. 142. The method of embodiment 141, wherein the reaction is carried out at a starting temperature of about 0-10°C, followed by 20-30°C. 143. A compound of formula (1): [ka] or a salt thereof, wherein the compound is a compound of formula (2): [ka] or a salt thereof to form a compound of formula (3). 144. Compound of formula (3): [ka] or a salt thereof, comprising the step of: [ka] or a salt thereof, wherein the compound is a compound of formula (2): [ka] or a salt thereof to form a compound of formula (3). 145. a) The compound of formula (3) is a compound of formula (3a): [ka] and the compound of formula (1) is a compound of formula (1a): [ka] Or b) The compound of formula (3) is a compound of formula (3b): [ka] and the compound of formula (1) is a compound of formula (1b): [ka] The method of embodiment 143 or embodiment 144, wherein 146. The method of any one of embodiments 143-145, wherein the reaction is carried out in the presence of a base. 147. The method of embodiment 146, wherein the base is sodium hydride, potassium tert-butoxide, or sodium ethoxide. 148. The method of embodiment 146, wherein the base is sodium ethoxide. 149. The method of any one of embodiments 143-148, wherein the reaction is carried out using an alcohol as a solvent. 150. The method of embodiment 149, wherein the alcohol is methanol, ethanol, or isopropanol. 151. The method of embodiment 149, wherein the alcohol is ethanol. 152. The method of any one of embodiments 143-151, wherein the reaction is carried out at a temperature of about 0 to 30°C. 153. The method of embodiment 152, wherein the reaction is carried out at an initial temperature of about 0-10°C, then 20-30°C. 154. The method of any one of embodiments 143-153, wherein the compound of formula (1) or a salt thereof is separated into the enantiomers of formula (1a) and formula (1b) or salts thereof using kinetic resolution. 155. The method of embodiment 154, wherein the kinetic resolution is Jacobsen kinetic resolution or hydrolytic kinetic resolution catalyzed by a chiral salen-cobalt complex. 156. A method for producing a compound of formula (T-2) or a salt thereof, comprising the following steps: [ka] (In the formula, R3 is benzyl optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide; R1 is a benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide; Pg1 is the first protecting group; Pg2 is a second protecting group; and X is a leaving group. A method characterized by: 157. A method for producing a compound of formula (T-2) or a salt thereof, comprising the following steps: [ka] (In the formula, R1 is a benzyl carbamate optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide; Pg1 is the first protecting group; Pg2 is a second protecting group; and X is a leaving group. A method characterized by: 158. The method of embodiment 156 or embodiment 157, wherein Pg1 and Pg2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl. 159. Formula (T-3): [ka] (wherein Pg1 is a first protecting group) or a salt thereof. 160. Formula (T-4): [ka] (wherein Pg1 is a first protecting group) or a salt thereof. 161. The compound of embodiment 159 or embodiment 160, wherein Pg1 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl. 162. The compound of embodiment 159 or embodiment 160, wherein Pg1 is tert-butyloxycarbonyl. 163. A compound of formula (3): [ka] Or its salt. 164. A compound of formula (3) or a salt thereof is a compound of formula (3a): [ka] or a salt thereof, or a compound of formula (3b): [ka] or a salt thereof. 165. A compound of formula (4): [ka] Or its salt. 166. A compound of formula (4) or a salt thereof is a compound of formula (4a): [ka] or a salt thereof, or a compound of formula (4b): [ka] or a salt thereof. 167. A compound of formula (5): [ka] Or its salt. 168. A compound of formula (5) or a salt thereof is a compound of formula (5a): [ka] or a salt thereof, or a compound of formula (5b): [ka] or a salt thereof. 169. A compound of formula (6): [ka] Or its salt. 170. A compound of formula (6) or a salt thereof is a compound of formula (6a): [ka] or a salt thereof, or a compound of formula (6b): [ka] 170. The compound of embodiment 169, which is: 171. Formula (7): [ka] wherein R1 is C1-C6 alkoxy, C1-C6 alkyl, or halide, or benzyl carbamate optionally substituted with an amino protecting group, or a salt thereof. 172. A compound of formula (7) or a salt thereof, wherein the compound is a compound of formula (7a): [ka] or a salt thereof, or a compound of formula (7b): [ka] 172. The compound of embodiment 171, which is: 173. Formula (8): [ka] (In the formula, R1 is a benzyl carbamate optionally substituted with a C1-C6 alkoxy, C1-C6 alkyl, halide, or amino protecting group; and Pg2 is the second protecting group or a salt thereof. 174. A compound of formula (8) or a salt thereof is a compound of formula (8a): [ka] or a salt thereof, or a compound of formula (8b): [ka] or a salt thereof. 175. Formula (9): [ka] wherein Pg2 is a second protecting group, or a salt thereof. 176. A compound of formula (9) or a salt thereof is a compound of formula (9a): [ka] or a salt thereof, or a compound of formula (9b): [ka] 176. The compound of embodiment 175, which is: 177. Equation (7.5): [ka] (wherein Pg1 is a first protecting group) or a salt thereof. 178. A compound of formula (7.5) or a salt thereof is a compound of formula (7.5a): [ka] or a salt thereof, or a compound of formula (7.5b): [ka] 178. The compound of embodiment 177, which is: 179. Compound of formula (8.5): [ka] Or its salt. 180. A compound of formula (8.5) or a salt thereof is a compound of formula (8.5a): [ka] or a salt thereof, or a compound of formula (8.5b): [ka] 180. The compound of embodiment 179, which is: 181. Compound of formula (9.5): [ka] Or its salt. 182. A compound of formula (9.5) or a salt thereof is a compound of formula (9.5a): [ka] or a salt thereof, or a compound of formula (9.5b): [ka] 182. The compound of embodiment 181, which is: 183. Formula (10): [ka] wherein Pg2 is a second protecting group, or a salt thereof. 184. A compound of formula (10) or a salt thereof is a compound of formula (10a): [ka] or a salt thereof, or a compound of formula (10b): [ka] or a salt thereof. 185. Formula (11): [ka] (wherein Pg1 is a first protecting group and Pg2 is a second protecting group) or a salt thereof. 186. A compound of formula (11) or a salt thereof is a compound of formula (11a): [ka] or a salt thereof, or a compound of formula (11b): [ka] 186. The compound of embodiment 185, which is: 187. The compound of embodiment 185 or embodiment 186, wherein Pg1 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl. 188. The compound of embodiment 185 or embodiment 186, wherein Pg1 is tert-butyloxycarbonyl. 189. The compound of any one of embodiments 233-242, wherein Pg2 is selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl. 190. The compound of any one of embodiments 173-176 or 183-189, wherein Pg2 is a benzyl group optionally substituted with C1-C6 alkoxy, C1-C6 alkyl, or halide.

[0070] Example These examples are provided for illustrative purposes only and are not intended to limit the scope of the claims herein.

[0071] Abbreviations used [Table 1]

[0072] Example 1. Synthesis of T-2 from 2-(2-bromoethyl)oxirane [ka]

[0073] Example S1.1 Synthesis of Compound 3 [ka] Diethyl malonate (156 g, 964 mmol) and EtOH (740 mL) were added to a three-necked round-bottom flask (3 L) and the solution was cooled to 0–5 °C. A brown solution of sodium ethoxide (396 mL, 21 wt %, in EtOH, 1060 mmol) was added via addition funnel over 20 min, resulting in a slight rise in temperature to 9 °C. The reaction mixture was stirred at 0–5 °C for 15 min, after which 2-(2-bromoethyl)oxirane (150 g, 964 mmol) was added and stirred at room temperature to give a brown suspension. After stirring at room temperature for 18 h, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with EtOAc (1 L) and brine (500 mL). The aqueous layer was extracted again with EtOAc (300 mL). The combined organic layers were separated, dried over NaSO, filtered, and concentrated under reduced pressure to give the product: 3-hydroxycyclopentane-1,1-dicarboxydiethyl (200 g, 782 mmol, 81% yield, ∼90% purity) as a brown oil, which was used directly in the next step without further purification. LC-MS[M+1] 231 1 H NMR (400 MHz, chloroform-d) δ 4.44-4.36 (m, 1H), 4.26-4.15 (m, 4H), 2.47-2.26 (m, 3H), 2.07 (br d, J = 4.5 Hz, 1H), 1.94 (dtd, J = 13.5, 8.5, 5.2 Hz, 1H), 1.84-1.67 (m, 1H), 1.33-1.20 (m, 6H).

[0074] Example S1.2 Synthesis of Compound 4 [ka] A three-necked round-bottom flask (5 L) was charged with triphenylphosphine (PPh3, 117 g, 443 mmol) and THF (1400 mL). The colorless solution was cooled to 5 °C in an ice-water bath, and diisopropyl azodicarboxylate (DIAD, 86 mL, 443 mmol) was added dropwise via an addition funnel over 35 min, while maintaining the internal temperature below 15 °C. The yellow color of DIAD almost disappeared before the addition. The clear reaction mixture became a white suspension during the addition of DIAD. This thick white suspension was stirred in the ice-water bath for 30 min. The formation of a pure, thick white slurry indicated the production of the PPh3-DIAD complex. A solution of 3-hydroxycyclopentane-1,1-dicarboxydiethyl (108 g, 422 mmol) was poured into the reaction mixture, and the temperature rose to 15 °C. Isoindoline-1,3-dione (59.9 g, 407 mmol) was then added portionwise while maintaining the reaction temperature below 15 °C. After the addition, the reaction mixture was warmed to room temperature and became a pale orange solution, which was stirred overnight at room temperature. The reaction mixture was quenched with brine (400 mL), and the aqueous layer was separated and extracted with EtOAc (300 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to 1 L under reduced pressure. Precipitation of colorless crystals (triphenylphosphine oxide (Ph3P=O)) was observed in the concentrated EtOAc solution. The suspension was allowed to stand overnight at room temperature. The filtrate from the brown oil was added to 500 mL of Et2O in a 2 L beaker with stirring, forming a suspension. After 30 min, the resulting pink solid was removed by filtration, and the Et2O filtrate was filtered again and then concentrated to give a crude brown oil. This was added to MeOH (200 mL) to form a white suspension. The precipitated pure product was collected by filtration and washed with methanol to give a white solid. The mother liquor was concentrated and purified by ISCO column chromatography (gradient: 0-10% acetone / hexane). A total of 93 g (61% yield) of 3-(1,3-dioxoisoindolin-2-yl)cyclopentane-1,1-dicarboxydiethyl was obtained as a white solid. LC-MS[M+1] 360.0 1H NMR (400MHz, chloroform-d) δ 7.83(dd, J=5.5, 3.0Hz, 2H), 7.73-7.69(m, 2H), 4.81(quin, J=8.8Hz, 1H), 4.29-4.20(m, 4H), 2.78-2.66(m, 3H), 2.36-2.28(m, 1H), 2.19(dt, J=13.3, 7.5Hz, 1H), 2.11-2.04(m, 1H), 1.29(td, J=7.1, 2.6Hz, 6H)

[0075] Example S1.3 Synthesis of Compound 5 [ka] 3-(1,3-Dioxoisoindolin-2-yl)cyclopentane-1,1-dicarboxydiethyl (120 g, 334 mmol), MeOH (1580 mL), DCM (1050 mL), and hydrazine (121 mL, 1336 mmol) were added to a three-necked flask (5 L) equipped with a mechanical stirrer and stirred at room temperature for 18 hours. The reaction mixture became a thick suspension and was filtered. The filter cake was rinsed with DCM (500 mL). The combined filtrate was concentrated under reduced pressure. To the resulting residue was then added DCM (900 mL) and 1N NaOH (440 mL). The organic layer was collected, washed with water (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the product: 3-aminocyclopentane-1,1-dicarboxydiethyl as a slightly yellow oil (68 g). The combined aqueous layers were back extracted with DCM to give an additional 3 g of product, totaling 71 g (93% yield) of the desired product, which was used directly in the next step without further purification. LC-MS [M+1]: 230 1H NMR (400MHz, chloroform-d) δ 4.19(quin, J=7.1Hz, 4H), 3.45(t, J=6.7Hz, 1H), 2.55-2.39(m, 2H), 2.17(dt, J=13.8, 7.9Hz, 1H), 2.01-1.90(m, 2H), 1.64-1.37(m, 3H), 1.25(td, J=7.1, 3.7Hz, 6H)

[0076] Example S1.4 Synthesis of Compound 6 [ka] A three-necked flask (2 L) equipped with a condenser was charged with 3-aminocyclopentane-1,1-dicarboxydiethyl (71 g, 310 mmol), cesium carbonate (202 g, 619 mmol), and MeOH (670 mL) under a nitrogen atmosphere and stirred at 65 °C for 4 hours. After 4 hours, the reaction was complete and cooled to room temperature. The mixture was then concentrated under reduced pressure below 35 °C to remove the MeOH and give a yellow oil. To this yellow residue was added HO (30 ml) and 2-MeTHF (120 mL), and the mixture was acidified to pH ∼3 with aqueous NaHSO (149 g, 170 mL of HO). The resulting solution was then extracted with 2-MeTHF (200 mL × 4). The combined extracts were concentrated under reduced pressure to give a yellow solid. This solid was then suspended in benzene (500 mL) and heated (azeotropically) in a Dean-Stark apparatus to remove water, yielding a yellow powder (43.5 g). This powder was azeotropically evaporated with toluene (200 mL x 3) on a rotary evaporator to remove any remaining water, yielding the desired product (42.8 g, 89% yield) as a yellow powder, which was used in the next step reaction without further purification. LC-MS [M+1]: 156.0 1 H NMR (400 MHz, methanol-d4) δ 3.91-3.87 (m, 1H), 2.23-2.10 (m, 2H), 2.08-1.91 (m, 1H), 1.84-1.66 (m, 3H)

[0077] Example S1.5 Synthesis of Compound 7 [ka] To a suspension of 3-oxo-2-azabicyclo[2.2.1]heptane-4-carboxylic acid (37.0 g, 238 mmol) in 2-Me-THF (610 mL), N,N-diisopropylethylamine (104 mL, 596 mmol) and diphenylphosphoryl azide (DPPA, 58.1 mL, 262 mmol) were added and heated at 70 °C until a clear solution formed (within 5 min). LC / MS confirmed complete consumption of the starting material within 20 min. After stirring at 70 °C for 50 min, benzyl alcohol (64.5 mL, 620 mmol) was added in one portion at 70 °C, and the mixture was stirred at 80 °C for a total of 9 h until the reaction was complete. After cooling to room temperature, most of the 2-MeTHF (~650 mL) was removed under reduced pressure. The resulting residue was diluted with EtOAc (650 mL), washed with water (250 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oil. The combined water and brine washes were back-extracted with 8 portions of 350 mL of EtOAc. The extracted organic layers were dried, concentrated, and combined to give the crude product (177 g) as a yellow oil. The crude product was first purified by ISCO column chromatography (gradient: 0-50% acetone / hexane) followed by SFC to give two enantiomers: Peak 1: 23.7 g (38.2% yield), and Peak 2: 23.5 g (37.9% yield). LC / MS [M+1]: 260.7 1 H NMR (400MHz, chloroform-d) δ 7.39-7.31(m, 5H), 5.69(br s, 2H), 5.12(br s, 2H), 3.87(br s, 1H), 2.53-2.44(m, 1H), 2.41(br d, J=9.1Hz, 1H), 2.06(br s, 1H), 1.92(dq, J=9.2, 2.3Hz, 1H), 1.78-1.67(m, 1H), 1.52-1.41(m, 1H)

[0078] Example S1.6 Synthesis of Compound 8 [ka] To a solution of benzyl (3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (1.66 g, 6.38 mmol) in THF (36 mL) was added dropwise LHMDS (1 M THF solution, 6.70 mL, 6.70 mmol) at 0-5 °C. After stirring for 10 min, benzyl bromide (0.834 mL, 7.02 mmol) was added dropwise. The reaction was slowly warmed to room temperature and stirred for 20 h. Saturated NH4Cl solution (20 mL) was added to quench the reaction. EtOAc (20 mL) was then added, and the organic layer was collected. The aqueous layer was washed with EtOAc (15 mL), and the combined organic layer and washing solution were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by ISCO column chromatography (gradient: 50 to 100% EtOAc / heptane) to afford benzyl (2-benzyl-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (2.0 g, 5.71 mmol, 89% yield) as a white solid. LC / MS [M+1]: 351.3 1 H NMR (400MHz, chloroform-d) δ ppm 1.25-1.51(m, 1H), 1.52-1.61(m, 1H), 1.76-1.94(m, 2H), 2.37(br d, J=9.05Hz, 1H), 2.47(td, J=11.43, 4.28Hz, 1H), 3.67(br s, 1H), 4.10(d, J=15.16Hz, 1H), 4.73(d, J=14.92Hz, 1H), 5.13 (s, 2H), 5.79 (s, 1H), 7.23-7.41(m, 10H)

[0079] Example S1.7 Synthesis of Compound 9 [ka] A solution of benzyl (2-benzyl-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (3.15 g, 8.99 mmol) in MeOH (30 mL) was added to a three-necked round-bottom flask (250 mL), and nitrogen was bubbled through the solution for 10 minutes. 10% Pd / C (wet, 300 mg, 10% w / w) was added under a nitrogen atmosphere, and the reaction mixture was then degassed until no more bubbles were observed. A hydrogen balloon was attached, and the reaction was stirred for 20 hours. LC / MS showed the reaction was complete. The hydrogen balloon was removed, and the reaction mixture was degassed until no more bubbles were observed. The flask was then filled with N2, and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give the product: 4-amino-2-benzyl-2-azabicyclo[2.2.1]heptan-3-one (1.9 g, 8.78 mmol, 98% yield) as a colorless oil. LC / MS [M+1]: 217.4 1 H NMR (400MHz, chloroform-d) δ ppm 1.55-1.63(m, 2H), 1.66-1.92(m, 6H), 3.58-3.61(m, 1H), 4.03(d, J=15.16Hz, 1H), 4.73(d, J=15.16Hz, 1H), 7.25-7.37(m, 5H)

[0080] Example S1.8 Synthesis of Compound 10 [ka] To a solution of 4-amino-2-benzyl-2-azabicyclo[2.2.1]heptan-3-one (320 mg, 1.480 mmol) in THF (15 mL) was added dimethylsulfide borane complex (2.22 mL, 4.44 mmol) dropwise at room temperature. The mixture was heated to 65°C and stirred for 20 hours. After cooling to room temperature, the reaction mixture was quenched by adding HCl solution (6N, 4.0 mL). The mixture was then heated to 50°C and stirred for 20 hours. After cooling to room temperature, brine (20 mL) and EtOAc (20 mL) were added, followed by the addition of 1N NaOH to adjust the pH of the aqueous layer to ~14. The amine product was then extracted with DCM (20 mL x 3). The yield of 2-benzyl-2-azabicyclo[2.2.1]heptan-4-amine was considered to be 100%. LC / MS [M+1]: 203.4

[0081] Example S1.9 Synthesis of Compound 11 [ka] To a solution of 2-benzyl-2-azabicyclo[2.2.1]heptan-4-amine (~300 mg) in DCM (10 mL), di-tert-butyl dicarbonate (355 mg, 1.627 mmol) was added and stirred for 1 h. After removing the DCM, the resulting residue was purified by ISCO column chromatography (gradient: 20-100% EtOAc / heptane) to give tert-butyl (2-benzyl-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (330 mg, 1.091 mmol, 73.8% yield). LC / MS [M+1]: 303.3 1 H NMR (400MHz, chloroform-d) δ ppm 1.37-1.53(m, 9H), 1.59-1.72(m, 2H), 1.75-1.88(m, 2H), 1.92-2.14(m, 2H), 2.45-2.68(m, 1H), 2.87-3.09(m, 1H), 3.11-3.30(m, 1H), 3.59-3.85(m, 2H), 4.63-5.00(m, 1H), 7.16-7.46(m, 5H)

[0082] Example S1.10 Synthesis of Compound T-2 [ka] tert-Butyl (2-benzyl-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (2.0 g, 6.61 mmol) was dissolved in ethanol (6 mL) and 10% Pd(OH)2 / C (200 mg, 10% w / w) was added. The reaction vessel was evacuated, backfilled with N2, and backfilled with H2 via a H2 balloon. The mixture was then stirred for 18 h. The reaction vessel was then evacuated and backfilled with N2 multiple times. The reaction mixture was then filtered through Celite and concentrated under reduced pressure to give tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate (1.3 g, 6.12 mmol, 93% yield) as a white solid. LC / MS [M+1]: 213.3 1 H NMR (400 MHz, chloroform-d) δ ppm 1.45 (s, 9H), 1.57-1.67 (m, 1H), 1.69-1.78 (m, 1H), 1.81-1.97 (m, 5H), 3.01 (s, 2H), 3.40 (s, 1H), 4.92 (s, 1H).

[0083] Example 2. Synthesis of T-2 via selective protection of diamine [ka]

[0084] Example S2.1 Synthesis of Compound 7.5 [ka] To a solution of benzyl (3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (5.2 g, 19.98 mmol) in MeOH (100 mL) was added di-tert-butyl dicarbonate (4.80 g, 21.98 mmol) and 10% Pd / C (0.52 g, 0.489 mmol, 10% w / w). The reaction vessel was evacuated, backfilled with N, and backfilled with H via a H balloon. The mixture was stirred for 18 h, and the reaction vessel was then evacuated and backfilled with N multiple times. The reaction mixture was then filtered through Celite and concentrated under reduced pressure to give the crude product. This was then triturated with 2-MeTHF at room temperature to −20° C. to give the product: tert-butyl (3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (4.3 g, 19.00 mmol, 95% yield). LC / MS [M+1]: 227.3

[0085] Example S2.2 Synthesis of Compound 8.5 [ka] A 100 mL flask was charged with tert-butyl (3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (872 mg, 3.85 mmol) and DCM (10 mL) and stirred at room temperature until all solids dissolved. Trifluoroacetic acid (2.97 mL, 38.5 mmol) was then added. The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The mixture was concentrated under reduced pressure twice with toluene (10 mL) to give 4-amino-2-azabicyclo[2.2.1]heptan-3-one 2,2,2-trifluoroacetate (918 mg, 3.82 mmol, 99% yield). 1 H NMR (400MHz, DMSO-d6) δ ppm 8.81(br s, 3H), 8.36(s, 1H), 3.86(s, 1H), 1.98-2.09(m, 1H), 1.84-1.96(m, 2H), 1.76(d, J=8.8Hz, 1H), 1.52-1.68(m, 2H)

[0086] Example S2.3 Synthesis of Compound 9.5 [ka] A 100 mL flask was charged with 4-amino-2-azabicyclo[2.2.1]heptan-3-one 2,2,2-trifluoroacetate (711 mg, 2.96 mmol) and THF (15 mL). The mixture was cooled in an ice-water bath, and lithium aluminum hydride (1 M in THF, 14.80 mL, 14.80 mmol) was added dropwise. The mixture was stirred for 10 minutes, then the ice-water bath was removed and the mixture was allowed to warm to room temperature. The resulting mixture was heated at 55 °C (heater block temperature) for 5 hours and stirred at room temperature overnight. The mixture was cooled to 0 °C, and water (0.5 mL) was added dropwise. After stirring for 10 minutes, 15% NaOH solution (0.5 mL) was added, followed by water (1.5 mL). The mixture was diluted with ether (15 mL) and stirred for 1 hour. The suspension was filtered through Celite and washed with ether (15 mL). The filtrate was dried over Na2SO4, filtered, and concentrated to give crude 2-azabicyclo[2.2.1]heptan-4-amine, which was used in the next step without purification (estimated yield 100%). 1 H NMR (400MHz, DMSO-d6) δ ppm 9.90(br s, 1H), 9.36(s, 1H), 9.16(s, 2H), 8.96(s, 1H), 3.96(s, 1H), 3.09-3.28(m, 2H), 1.83-2.11(m, 6H), 1.71-1.83(m, 1H)

[0087] Example S2.4 Synthesis of Compound 10 [ka] The resulting crude 2-azabicyclo[2.2.1]heptan-4-amine (330 mg, 2.94 mmol) was dissolved in DCM (10 mL) and MeOH (10 mL) and to this was added benzaldehyde (0.313 mL, 3.09 mmol) and magnesium sulfate (2.08 g, 17.28 mmol). The mixture was stirred at room temperature overnight and then cooled to 0 °C. A solution of Cbz-OSu (0.770 g, 3.09 mmol) in MeOH·DCM (1:1, 5 mL) was added dropwise, stirred at 0 °C for 30 min, filtered through Celite, and concentrated under reduced pressure. The resulting residue was redissolved in MeOH (15 mL) and 1 N hydrochloric acid (15 mL, 15.00 mmol) and stirred at room temperature for 30 min to hydrolyze the imine. Most of the methanol was then removed under reduced pressure, and the aqueous layer was extracted with DCM (10 mL x 2). The first extracted layer was discarded, and the aqueous layer was basified to pH 12 with 1N NaOH solution, followed by extraction with DCM (10 mL x 3). The combined organic extracts were concentrated under reduced pressure to give 4-amino-2-azabicyclo[2.2.1]heptane-2-carboxybenzyl (367 mg, 1.490 mmol, 50.6% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) 7.27-7.52(m, 5H), 5.04-5.25(m, 2H), 4.09-4.35(m, 1H), 3.09-3.28(m, 2H), 1.35-1.98(m, 8H)

[0088] Example S2.5 Synthesis of Compound 11 [ka] To a solution of 4-amino-2-azabicyclo[2.2.1]heptane-2-carboxybenzyl (362 mg, 1.470 mmol) in DCM (10 mL) was added Boc anhydride (385 mg, 1.764 mmol) and stirred at room temperature for 20 h. LCMS indicated that almost all of the starting material had been consumed. The solvent was concentrated, and the resulting residue was purified by ISCO column chromatography (gradient: 20 to 100% EtOAc / heptane) to give 4-((tert-butoxycarbonyl)amino)-2-azabicyclo[2.2.1]heptane-2-carboxybenzyl (478 mg, 1.380 mmol, 94% yield). 1 H NMR (400MHz, DMSO-d6) 7.30-7.43(m, 5H), 5.08-5.21(m, 2H), 4.78-4.92(m, 1H), 4.09-4.32(m, 1H), 3.46-3.59(m, 1H), 3.36-3.45(m, 1H), 1.65-2.05(m, 6H), 1.45(s, 9H)

[0089] Example S2.6 Synthesis of Compound T-2 [ka] 4-((tert-Butoxycarbonyl)amino)-2-azabicyclo[2.2.1]heptane-2-carboxybenzyl (478 mg, 1.380 mmol) in MeOH (10 mL) was hydrogenated overnight with a balloon filled with H in the presence of 10% Pd / C (50 mg, 0.047 mmol). The resulting mixture was filtered through Celite, washed with methanol, and concentrated to give tert-butyl (2-azabicyclo[2.2.1]heptan-4-yl)carbamate (284 mg, 1.338 mmol, 97% yield). LC / MS [M+1]: 213.3

[0090] Example 3. Synthesis of T-3 Example S3.1 Synthesis of T-3 from chiral resolved compound 7a [ka] Compound T-3, the enantiomer of compound T-2, was prepared from enantiomer 7a obtained by chiral separation of compound 7. The reaction procedures for preparing compounds 8a from 7a, 9a from 8a, 10a from 9a, 10a from 11a, and T-3 from 11a are the same as those described in Examples 1.6, 1.7, 1.8, 1.9, and 1.10, respectively. In some embodiments, the kinetic resolution method used for the chiral separation is Jacobsen kinetic resolution. In some embodiments, the kinetic resolution method used for the chiral separation is hydrolysis kinetic resolution catalyzed by a chiral salen-cobalt complex.

[0091] Example S3.2 Synthesis of T-3 from chirally resolved compound 7a via selective protection of the diamine [ka] Compound T-3, the enantiomer of compound T-2, was prepared from enantiomer 7a obtained by chiral separation of compound 7. The reaction procedures for preparing T-3 from compounds 7a to 7.5a, 7.5a to 8.5a, 8.5a to 9.5a, 9.5a to 10a, and 11a are the same as those described in Examples 2.1, 2.2, 2.3, 2.4, 1.9, and 1.10, respectively. In some embodiments, the kinetic resolution method used for chiral separation is Jacobsen kinetic resolution. In some embodiments, the kinetic resolution method used for chiral separation is hydrolysis kinetic resolution catalyzed by a chiral salen-cobalt complex.

[0092] Example S3.3 Synthesis of T-3 from chiral separated compound 1a [ka] Compound T-3, the enantiomer of compound T-2, was prepared from enantiomer 1a obtained by chiral separation of compound 1 using Jacobsen kinetic resolution. The reaction procedure was the same as that described in Example 1. The Jacobsen kinetic resolution method used to prepare 1a is described below.

[0093] A 500 mL flask was charged with S,S-Co-salen (6.12 g, 10.13 mmol) and DCM (60 mL). After stirring for 10 min at room temperature, nonafluoro-tert-butanol (7.08 mL, 50.7 mmol) was added dropwise. The mixture was stirred vigorously under air for 1 h, causing the color to change from dark red to black. The mixture was concentrated to dryness on a rotary evaporator. The resulting solid was scraped off the wall with a spatula and dried under vacuum for 2 h to obtain the active catalyst. A separate 250 mL flask was charged with racemic 2-(2-bromoethyl)oxirane (102 g, 675 mmol), phenol (35.0 g, 372 mmol), and MTBE (50 mL). The mixture was cooled to 3-5 °C in an ice-water bath and then added to the flask containing the dried catalyst, which had been placed in an ice-water bath. The mixture was stirred in an ice-water bath for 30 minutes and then held at 0-5°C for 20 hours. The flask was then returned to room temperature, and MTBE was distilled off on a rotary evaporator (40°C / 70 mmHg). A short distillation adapter was then attached to the flask, and the mixture was distilled under reduced pressure to yield 47 g of product (boiling points: 66-68°C / 25 mmHg, then 43-45°C / 8 mmHg). At the end of the distillation, the water bath was heated to 100°C, and the pressure was reduced to 5-6 mmHg to maximize epoxide recovery. NMR indicated a purity of 89%. The resulting crude material was distilled again from a 100 mL flask using the same short distillation adapter to yield (S)-2-(2-bromoethyl)oxirane (36.0 g, 212 mmol, 31.4% yield, NMR purity: ∼95%). 1H NMR (400MHz, chloroform-d) δ 3.53(dd, J=6.0, 7.4Hz, 2H), 3.11(dtd, J=2.7, 4.2, 6.8Hz, 1H), 2.86(dd, J=3.8, 4.9Hz, 1H), 2.60(dd, J=2.7, 4.9Hz, 1H), 2.18(dtd, J=4.6, 7.5, 15.0Hz, 1H), 2.07(qd, J=6.0, 15.0Hz, 1H)

[0094] Example 4. Synthesis of T-4 Example S4.1 Synthesis of T-4 from chiral resolved compound 7b [ka] Compound T-4, the enantiomer of compound T-2, was prepared from enantiomer 7b obtained by chiral separation of compound 7. The reaction procedures for preparing T-4 from compounds 7b to 8b, 8b to 9b, 9b to 10b, 10b to 11b, and 11b are the same as those described in Examples 1.6, 1.7, 1.8, 1.9, and 1.10, respectively. In some embodiments, the kinetic resolution method used for chiral separation is Jacobsen kinetic resolution. In some embodiments, the kinetic resolution method used for chiral separation is hydrolysis kinetic resolution catalyzed by a chiral salen-cobalt complex.

[0095] Example S4.2 Synthesis of T-4 from chirally resolved compound 7b via selective protection of the diamine [ka] Compound T-4, the enantiomer of compound T-2, was prepared from enantiomer 7b obtained by chiral separation of compound 7. The reaction procedures for preparing T-4 from compounds 7b to 7.5b, 7.5b to 8.5b, 8.5b to 9.5b, 9.5b to 10b, and 11b are the same as those described in Examples 2.1, 2.2, 2.3, 2.4, 1.9, and 1.10, respectively. In some embodiments, the kinetic resolution method used for chiral separation is Jacobsen kinetic resolution. In some embodiments, the kinetic resolution method used for chiral separation is hydrolysis kinetic resolution catalyzed by a chiral salen-cobalt complex.

[0096] Example S4.3 Synthesis of T-3 from chiral resolved compound 1b [ka] Compound T-4, the enantiomer of compound T-2, was prepared from enantiomer 1b obtained by chiral separation of compound 1 using Jacobsen kinetic resolution. The reaction procedure was the same as that described in Example 1. The Jacobsen kinetic resolution method was the same as that described in Example S3.3.

Claims

1. Compound of formula (T-2): 【Chemical 1】 or a salt thereof, 【Chemistry 2】 (In the formula, Pg 1 is the first protecting group, and Pg 2 is a second protecting group) or a salt thereof to form a compound of formula (T-2). A method characterized by:

2. a) The compound of formula (T-2) is a compound of formula (T-3): 【Chemistry 3】 and the compound of formula (11) is a compound of formula (11a): 【Chemistry 4】 or c) The compound of formula (T-2) is a compound of formula (T-4): 【Chemistry 5】 and the compound of formula (11) is a compound of formula (11b): 【Chemistry 6】 The method of claim 1, wherein

3. 3. The method of claim 1 or claim 2, wherein the reduction of formula (11) or a salt thereof is catalyzed by a transition metal to form a compound of formula (T-2) or a salt thereof.

4. 4. The method of claim 3, wherein the transition metal is palladium chloride, palladium / barium sulfate, or palladium on carbon (Pd / C).

5. 5. The process according to any one of claims 1 to 4, wherein the reaction is carried out using an alcohol as a solvent, which may suitably be methanol, ethanol or isopropanol.

6. The compound of formula (11) or a salt thereof is a compound of formula (10): 【Chemistry 7】 6. The method according to any one of claims 1 to 5, wherein the compound is prepared by protecting the primary amine of the compound, or a salt thereof.

7. Equation (11): 【Chemistry 8】 (In the formula, Pg 1 is the first protecting group, and Pg 2 is a second protecting group), or a salt thereof, comprising reacting a compound of formula (10): 【Chemistry 9】 or a salt thereof, to form a compound of formula (11).

8. Pg 1 and Pg 2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.

9. 9. The method of any one of claims 6 to 8, wherein the reaction is carried out using an organic solvent, which may be chloroform, dichloroethane, toluene, methanol, ethanol, isopropanol, or 2-methyl-THF, dioxane, ethyl acetate, or tetrahydrofuran, as appropriate.

10. A method for preparing a compound of formula (10) or a salt thereof, comprising reacting a compound of formula (9.5): 【Chemistry 10】 or a salt thereof, the substituent and heterocyclic amine are each 2 and Pg 1 followed by selective deprotection of the amine substituent to form a compound of formula (10), or a compound of formula (9): 【Chemistry 11】 or a salt thereof, by reducing the compound of formula (10).

11. Compound of formula (10): 【Chemistry 12】 or a salt thereof, 【Chemistry 13】 (In the formula, Pg 2 is a second protecting group) or a salt thereof to obtain a compound of formula (10) 2 may be optionally selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.

12. 12. The method of claim 10 or 11, wherein the reducing agent is a metal hydride, aluminum hydride, borohydride, or borane reagent, and the reducing agent may suitably be lithium aluminum hydride, triphenylphosphine borane, tetrahydrofuran borane, or dimethylsulfide borane.

13. 13. The process according to any one of claims 10 to 12, wherein the reaction is carried out using an aprotic solvent, which is suitably diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof.

14. A method for producing a compound of formula (9) or a salt thereof, comprising reacting a compound of formula (8): 【Chemistry 14】 (In the formula, R 1 is C 1 -C 6 Alkoxy, C 1 -C 6 benzyl carbamate optionally substituted with an alkyl, halide, or amino protecting group; and Pg 2 is a second protecting group), or a salt thereof, to form a compound of formula (9).

15. Compound of formula (9): 【Chemistry 15】 or a salt thereof, 【Chemistry 16】 (In the formula, R 1 is C 1 -C 6 Alkoxy, C 1 -C 6 benzyl carbamate optionally substituted with an alkyl, halide, or amino protecting group; and Pg 2 is a second protecting group) or a salt thereof to obtain a compound of formula (9) 2 may be optionally selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.

16. 16. The method of claim 14 or 15, wherein the reduction is catalyzed by a transition metal, which may suitably be palladium chloride, palladium / barium sulfate, or palladium on carbon (Pd / C).

17. 17. The method of any one of claims 14 to 16, wherein the reaction is carried out using an alcohol as a solvent, which may suitably be methanol, ethanol, or isopropanol.

18. A method for preparing a compound of formula (8) or a salt thereof, comprising reacting a compound of formula (7): 【Chemistry 17】 or its salts are Pg 2 reacts with X (where R 1 is C 1 -C 6 Alkoxy, C 1 -C 6 benzyl carbamates optionally substituted with alkyl, halide, or amino protecting groups; Pg 2 is a second protecting group; and X is a leaving group), to form a compound of formula (8).

19. Compound of formula (8): 【Chemistry 18】 or a salt thereof, 【Chemistry 19】 or a salt thereof, 2 reacts with X (where R 1 is C 1 -C 6 Alkoxy, C 1 -C 6 benzyl carbamates optionally substituted with alkyl, halide, or amino protecting groups; Pg 2 is a second protecting group; and X is a leaving group), a compound of formula (8) (wherein Pg 2 may be optionally selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.

20. 20. The method of claim 18 or 19, wherein the reaction is carried out in the presence of a non-nucleophilic base, which may optionally be N,N-diisopropylethylamine, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, or lithium bis(trimethylsilyl)amide.

21. 21. The process according to any one of claims 18 to 20, wherein the reaction is carried out using an ethereal solvent, which may suitably be tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, or a mixture thereof.

22. Equation (10): 【Chemistry 20】 (In the formula, Pg 2 is a second protecting group), or a salt thereof, comprising reacting a compound of formula (9.5): 【Chemical Formula 21】 or a salt thereof, the substituent and heterocyclic amine are each 2 and Pg 1 (where Pg 1 and Pg 2 are each independently selected from optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl), followed by selective deprotection of the amine substituent to form a compound of formula (10).

23. 23. The method of claim 10 or 22, wherein the protection reaction is carried out using an organic solvent, which may optionally be chloroform, dichloromethane, carbon tetrachloride, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran.

24. 24. The method of any one of claims 10, 22 and 23, wherein the selective deprotection of the amine of the substituent is carried out with an acid, which may suitably be hydrochloric acid.

25. A method for preparing a compound of formula (9.5) or a salt thereof, comprising reacting a compound of formula (8.5): [Chemical 22] 25. The method of any one of claims 10 or 22-24, wherein the compound of formula (9.5) is formed by reducing 9.5 or a salt thereof.

26. Compounds of formula (9.5): 【Chemical 23】 or a salt thereof, comprising reacting a compound of formula (8.5): 【Chemistry 24】 or a salt thereof, by reducing the compound of formula (9.5).

27. 27. The method of claim 25 or 26, wherein the reducing agent is a metal hydride, aluminum hydride, borohydride, or borane reagent, which may suitably be lithium aluminum hydride, triphenylphosphine borane, tetrahydrofuran borane, or dimethylsulfide borane.

28. 28. The process according to any one of claims 25 to 27, wherein the reaction is carried out using an aprotic solvent, which may suitably be diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof.

29. A method for preparing a compound of formula (8.5) or a salt thereof, comprising: 【Chemistry 25】 (In the formula, Pg 1 is a first protecting group), or a salt thereof, is hydrolyzed to form a compound of formula (8.5).

30. Compounds of formula (8.5): 【Chemical 26】 or a salt thereof, 【Chemical 27】 (In the formula, Pg 1 is the first protecting group, where Pg 1 is optionally selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl), or a salt thereof, to form a compound of formula (8.5).

31. 31. A method according to claim 29 or 30, wherein the hydrolysis is carried out with an acid, which may suitably be trifluoroacetic acid, hydrochloric acid or phosphoric acid.

32. 32. The method of any one of claims 29 to 31, wherein the protection reaction is carried out using an organic solvent, which may optionally be chloroform, dichloromethane, carbon tetrachloride, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran.

33. The compound of formula (7.5) or a salt thereof is a compound of formula (7): 【Chemical 28】 or a salt thereof, by deprotecting the primary amine of said compound and subsequently protecting said compound.

34. Equation (7.5): 【Chemical 29】 (In the formula, Pg 1 is a first protecting group), or a salt thereof, comprising the steps of: 【Chemistry 30】 (In the formula, R 1 is C 1 -C 6 Alkoxy, C 1 -C 6 The primary amine of a compound of formula (7.5), or a salt thereof, is deprotected and subsequently protected to give a compound of formula (7.6), where Pg 1 may be optionally selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.

35. 35. The method of claim 33 or 34, wherein the deprotection is catalyzed by a transition metal, which may suitably be palladium chloride, palladium / barium sulfate, or palladium on carbon (Pd / C).

36. 36. The method of any one of claims 33 to 35, wherein the reaction is carried out using an alcohol as a solvent, which may suitably be methanol, ethanol, or isopropanol.

37. 37. The method of any one of claims 33 to 36, wherein the protection reaction is carried out using an organic solvent, which may optionally be chloroform, dichloromethane, carbon tetrachloride, dichloroethane, toluene, methanol, ethanol, isopropanol, toluene, or tetrahydrofuran.

38. A method for preparing a compound of formula (7) or a salt thereof, comprising reacting a compound of formula (6): 【Chemical 31】 or a salt thereof, 3 OH (in the formula, R 3 is C 1 -C 6 Alkoxy, C 1 -C 6 38. The method of any one of claims 18, 19, and 33-37, wherein the compound of formula (7) is formed by reacting a substituted aryl group (which is benzyl optionally substituted with alkyl, or halide) with diphenylphosphoryl azide and an amine base.

39. Formula (7): 【Chemical 32】 (In the formula, R 1 is C 1 -C 6 Alkoxy, C 1 -C 6 a benzyl carbamate optionally substituted with an alkyl, halide, or amino protecting group, or a salt thereof, comprising reacting a compound of formula (6): 【Chemical 33】 or a salt thereof, 3 OH (in the formula, R 3 is C 1 -C 6 Alkoxy, C 1 -C 6 (benzyl optionally substituted with alkyl, or halide) in the presence of diphenylphosphoryl azide and an amine base to form a compound of formula (7).

40. 40. The method of claim 38 or 39, wherein the amine base is 2,2,6,6-tetramethylpiperidine, trimethylamine, triethylamine, or N,N-diisopropylethylamine.

41. 41. The method according to any one of claims 38 to 40, wherein the reaction is carried out using an organic solvent, and the organic solvent may be dimethyl sulfoxide, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof.

42. The method according to any one of claims 38 to 41, wherein the compound of formula (7) or a salt thereof is separated into enantiomers, a compound of formula (7a) and a compound of formula (7b) or a salt thereof, using supercritical fluid chromatography.

43. A method for preparing a compound of formula (6) or a salt thereof, comprising reacting a compound of formula (5): 【Chemical 34】 43. The method of any one of claims 38 to 42, wherein the compound of formula (6) is formed by reacting the compound of formula (6) with a base.

44. Compound of formula (6): 【Chemistry 35】 or a salt thereof, comprising the step of: 【Chemical 36】 or a salt thereof reacts with a base to form a compound of formula (6).

45. 45. The method of claim 43 or 44, wherein the base is an inorganic base, which may be sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, or cesium carbonate, as appropriate.

46. 46. ​​The method of any one of claims 43 to 45, wherein the reaction is carried out using an alcohol as a solvent, which may suitably be methanol, ethanol, or isopropanol.

47. A method for preparing a compound of formula (5) or a salt thereof, comprising reacting a compound of formula (4): 【Chemical 37】 47. The method of any one of claims 43 to 46, wherein the compound of formula (5) is formed by deprotecting the amine of said compound, or a salt thereof.

48. Compound of formula (5): 【Chemical 38】 or a salt thereof, comprising the step of: 【Chemical 39】 or a salt thereof to form a compound of formula (5).

49. 49. The method of claim 47 or 48, wherein the deprotection is carried out using a base, which may suitably be sodium borohydride, methylamine, methylhydrazine, or hydrazine.

50. 50. The method of any one of claims 47 to 49, wherein the reaction is carried out using a mixture of an alcohol and an organic solvent, wherein the alcohol may suitably be methanol, ethanol, or isopropanol, and the organic solvent is dimethyl sulfoxide, dichloromethane, tetrahydrofuran, or 2-methyltetrahydrofuran.

51. A method for preparing a compound of formula (4) or a salt thereof, comprising reacting a compound of formula (3): 【Chemistry 40】 51. The method of any one of claims 47 to 50, wherein R 1 is 1 or a salt thereof, and R 2 is 1 or a salt thereof is reacted with phthalimide to form a compound of formula (4).

52. Compounds of formula (4): 【Chemistry 41】 or a salt thereof, comprising the step of: 【Chemistry 42】 or a salt thereof, reacting with phthalimide to form a compound of formula (4).

53. 53. The method of claim 51 or 52, wherein the reaction further includes triphenylphosphine and diisopropyl azodicarboxylate.

54. 54. The process of any one of claims 51 to 53, wherein the reaction is carried out using an aprotic solvent, which may suitably be diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, dichloroethane, chloroform, or a mixture thereof.

55. A method for preparing a compound of formula (3) or a salt thereof, comprising reacting a compound of formula (1): 【Chemistry 43】 or a salt thereof, wherein the compound is a compound of formula (2): 【Chemical 44】 or a salt thereof to form a compound of formula (3).

56. Compounds of formula (3): 【Chemistry 45】 or a salt thereof, comprising the step of: 【Chemistry 46】 or a salt thereof, wherein the compound is a compound of formula (2): 【Chemistry 47】 or a salt thereof to form a compound of formula (3).

57. 57. A process according to claim 55 or 56, wherein the reaction is carried out in the presence of a base, which may suitably be sodium hydride, potassium tert-butoxide, or sodium ethoxide.

58. 58. The method of any one of claims 55 to 57, wherein the reaction is carried out using an alcohol as a solvent, which may suitably be methanol, ethanol, or isopropanol.

59. 59. The method according to any one of claims 55 to 58, wherein the compound of formula (1) or a salt thereof is separated into its enantiomers, formula (1a) and formula (1b), or salts thereof, using kinetic resolution, which may optionally be Jacobsen kinetic resolution or chiral salen-cobalt complex catalyzed hydrolysis kinetic resolution.

60. A method for producing a compound of formula (T-2) or a salt thereof, comprising the following steps: 【Chemistry 48】 (where, R 3 is C 1 -C 6 Alkoxy, C 1 -C 6 benzyl optionally substituted with alkyl or halide; R 1 is C 1 -C 6 Alkoxy, C 1 -C 6 benzyl carbamates optionally substituted with alkyl or halide; Pg 1 is the first protecting group; Pg 2 is a second protecting group; and X is a leaving group. A method characterized by:

61. A method for producing a compound of formula (T-2) or a salt thereof, comprising the following steps: 【Chemistry 49】 (where, R 1 is C 1 -C 6 Alkoxy, C 1 -C 6 benzyl carbamates optionally substituted with alkyl or halide; Pg 1 is the first protecting group; Pg 2 is a second protecting group; and X is a leaving group. A method characterized by:

62. Pg 1 and Pg 2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.

63. below: (a) A compound of formula (T-3) or formula (T-4): 【Chemistry 50】 or salts thereof; (b) a compound of formula (3): 【Chemistry 51】 or a salt thereof, optionally a compound of formula (3a): 【Chemistry 52】 or a salt thereof, or a compound of formula (3b): 【Chemistry 53】 or a salt thereof; a compound of formula (3) or a salt thereof (c) a compound of formula (4): 【Chemical 54】 or a salt thereof, optionally a compound of formula (4a): 【Chemistry 55】 or a salt thereof, or a compound of formula (4b): 【Chemical 56】 or a salt thereof; a compound of formula (4) or a salt thereof (d) a compound of formula (5): 【Chemical 57】 or a salt thereof, optionally a compound of formula (5a): 【Chemistry 58】 or a salt thereof, or a compound of formula (5b): 【Chemical Formula 59】 or a salt thereof; a compound of formula (5) or a salt thereof (e) A compound of formula (6): 【Chemistry 60】 or a salt thereof, optionally a compound of formula (6a): 【Hua 61】 or a salt thereof, or a compound of formula (6b): 【Hua 62】 or a salt thereof; a compound of formula (6) or a salt thereof (f) A compound of formula (7): 【Chemistry 63】 or a salt thereof, optionally a compound of formula (7a): 【Hua 64】 or a salt thereof, or a compound of formula (7b): 【Chemistry 65】 or a salt thereof; a compound of formula (7) or a salt thereof (g) A compound of formula (8): 【Hua 66】 or a salt thereof, optionally a compound of formula (8a): 【Hua 67】 or a salt thereof, or a compound of formula (8b): 【Chemistry 68】 or a salt thereof. (h) a compound of formula (9): 【Chemical Formula 69】 or a salt thereof, optionally a compound of formula (9a): 【Chemistry 70】 or a salt thereof, or a compound of formula (9b): 【Chemical 71】 or a salt thereof. (i) A compound of formula (7.5): 【Chemical Formula 72】 or a salt thereof, optionally a compound of formula (7.5a): 【Chemical 73】 or a salt thereof, or a compound of formula (7.5b): 【Chemical 74】 or a salt thereof; a compound of formula (7.5) or a salt thereof; (j) Compound of formula (8.5): 【Chemistry 75】 or a salt thereof, optionally a compound of formula (8.5a): 【Chemical 76】 or a salt thereof, or a compound of formula (8.5b): 【Chemical 77】 or a salt thereof; a compound of formula (8.5) or a salt thereof; (k) Compound of formula (9.5): 【Chemical 78】 or a salt thereof, optionally a compound of formula (9.5a): 【Chemical 79】 or a salt thereof, or a compound of formula (9.5b): 【Chemistry 80】 or a salt thereof; a compound of formula (9.5) or a salt thereof; (l) Equation (10): 【Chemistry 81】 (In the formula, Pg 2 is a second protecting group), or a salt thereof, optionally comprising a compound of formula (10a): 【Chemistry 82】 or a salt thereof, or a compound of formula (10b): 【Chemistry 83】 or a salt thereof; and (m) A compound of formula (11): 【Chemistry 84】 or a salt thereof, optionally a compound of formula (11a): 【Chemistry 85】 or a salt thereof, or a compound of formula (11b): 【Chemistry 86】 or a salt thereof, A compound selected from the group consisting of 1 is the first protecting group; Pg 2 is a second protecting group; R 1 is C 1 -C 6 Alkoxy, C 1 -C 6 benzyl carbamates optionally substituted with alkyl, halide, or amino protecting groups).

64. Pg 1 and Pg 2 are each independently selected from tert-butyloxycarbonyl, toluenesulfonyl, methyl, methoxymethyl, optionally substituted benzyl, optionally substituted carboxybenzyl, optionally substituted acyl, phthalimido, triphenylmethyl, diarylmethyl, benzylidene, and fluorenylmethyloxycarbonyl.

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