Synthesis of TERT-butyl(lr,2s,5s)-2-((s)-l-hydroxyethyl)-2-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate and intermediates thereto

Abstract

Provided herein are improved methods to produce diazabicyclo compounds, which may be useful in the production of small molecule KRAS inhibitors. Also provided are new intermediates compounds that may be useful in said processes.

Description

Docket No.: P39382-WO-1SYNTHESIS OF TERT-BUTYL(lR,2S,5S)-2-((S)-l-HYDROXYETHYL)-2-METHYL-3,8- DIAZABICYCLO[3.2.1]OCTANE-8-CARBOXYLATEAND INTERMEDIATES THERETOCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of United Stated Provisional Application No. 63 / 713,485, filed October 29, 2024. The disclosure of the foregoing application is incorporated herein by reference in its entirety.BACKGROUND

[0002] The present disclosure relates generally to methods of preparing compounds that may be useful in the synthesis of small molecule inhibitors of KRAS. A number of inhibitors of KRAS-mutant proteins are small organic molecules that require complex synthetic processes to realize desired yields, purity, and stereochemical selectivity. Previously existing routes to such compounds include syntheses of certain key intermediates that have low yield and / or enantiomeric selectivity. Provided herein are alternative routes to intermediates with improved yields, including enantiomeric enrichment.

[0003] The diazacyclo compounds described herein, which are components incorporated into the larger overall synthesis of small molecule inhibitors of KRAS, have multiple chiral centers and require complex synthetic routes. The current processes of preparing these diazacyclo compounds produce mixtures of diastereomers and enantiomers in various steps, resulting in overall significant chemical waste and poor mass throughput to achieve the final desired compounds. This is particularly challenging in the context of potential pharmaceutical compound production, which requires high volumes of product, large scale production (introducing restrictions on certain types of reactions and materials for cost and / or safety reasons), and high standards of purity. Provided herein are improved syntheses for needed diazacyclo compounds, and various key intermediates therein, which have one or more of improved mass intensity, more energy efficient processing conditions, and better scalability.Docket No.: P39382-WO-1SUMMARY OF THE DISCLOSURE

[0004] In some aspects, provided herein is a method of producing compound 100, or a salt thereof:the method comprising: reacting compound 4 or salt thereof with compound 9 or salt thereof to produce compound 11 :cyclizing compound 11 to produce compound 12:and reducing compound 12 to produce compound 100, or a salt thereof:wherein:Docket No.: P39382-WO-1PG and PG1are independently protecting groups; andR4ais =0 and R4bis H; or R4ais -OH and R4bis -SO3H.

[0005] In some embodiments, the yield of compound 100 or salt thereof is greater than 90% based on compound 12. In some embodiments, the reaction of compound 4 or salt thereof with compound 9 or salt thereof comprises forming a reaction mixture comprising compound 4 or salt thereof, compound 9 or salt thereof, a solvent system comprising a nonpolar solvent, and a metal carbonate, and reacting the reaction mixture at a temperature between 0°C to 25°C to form a product mixture comprising compound 11. In some embodiments, cyclizing compound 11 comprises forming a reaction mixture comprising compound 11, a metal catalyst, a reducing agent, an oxidizer, and a solvent system comprising a protic organic solvent, and producing a reaction product mixture comprising compound 12. In some embodiments, the metal catalyst is a Mn catalyst; the catalyst is present at between 1-20 mol% relative to compound 11; the reducing agent is an organosilane; the oxidizer is a peroxide; and the solvent system comprises a Ci-ealkyl alcohol. In further embodiments, reducing compound 12 comprises forming a reaction mixture comprising compound 12, a palladium catalyst, a transfer hydrogenation reagent, and a solvent system comprising a Ci-ealkyl alcohol, and reacting the reaction mixture to produce a reaction product mixture comprising compound 100 or a salt thereof.

[0006] In some embodiments of the methods provided herein, compound 12 is reduced in the presence of an acid to form compound 100, or a salt thereof. In some embodiments, the acid is an organic acid, a phosphoric acid, or a mineral acid. In some embodiments, compound 12 is reduced in the presence of succinic acid, camphoric acid, oxalic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, (S)-mandelic acid, phosphoric acid, tosylic acid, methanesulfonic acid, or benzoic acid, to form compound 100, or a salt thereof.

[0007] Further provided is a method of producing compound 4, or a salt thereof, by : reacting compound 1 with compound 13 to produce compound 2:reacting compound 2 with a protecting group reagent to produce compound 3 :Docket No.: P39382-WO-1and reducing compound 3 to produce compound 4 or a salt thereof:wherein:R1is Ci-ealkyl, Ci-ehaloalkyl, or aryl; n is an integer from 1 to 3;R4ais =0 and R4bis H; or R4ais -OH and R4bis -SO3H; and PG1is a protecting group.[00 8J In some embodiments, producing compound 2 comprises forming a reaction mixture comprising compound 1 and compound 13, wherein the ratio of compound 1 to compound 13 is between 1 : 1 and 1 :6; and reacting the reaction mixture at a temperature between 10°C and 40°C to form a reaction product mixture comprising compound 2. In some embodiments, producing compound 3 comprises forming a reaction mixture comprising compound 2, a protecting group reagent, a phase transfer agent, an inorganic base, and a solvent system predominantly comprising a non-polar solvent, wherein the ratio of compound 2 to the protecting group reagent is between 1 : 1 and 1 :2; and reacting the reaction mixture to form a reaction product mixture comprising compound 3.[0009J Further provided herein are methods of producing compound 9 or a salt thereof, by: reducing compound 5 to produce compound 6:reducing compound 6 to produce compound 7 :Docket No.: P39382-WO-1reacting compound 7 with a leaving group reagent to produce compound 8:reacting compound 8 with ammonium hydroxide to produce compound 9 or a salt thereof:wherein R5is Ci-ealkyl or Ci-ehaloalkyl; PG is a protecting group; and LG is a leaving group.

[0010] In some embodiments, reducing compound 5 comprises forming a first reaction mixture comprising compound 5, LiBHEts, and a solvent system predominantly comprising a non-polar solvent; and reacting the first reaction mixture at a temperature between -50°C to - 90°C; then combining the first reaction mixture with trifluoroacetic anhydride, diisopropyl ethylamine (DIPEA), and 4-Dimethylaminopyridine (DMAP) to form a second reaction mixture; and reacting the second reaction mixture at a temperature between -70°C to 25°C to form a reaction product mixture comprising compound 6. In some embodiments, reducing compound 6 comprises forming a reaction mixture comprising compound 6, lithium aluminum hydride, and a solvent system predominantly comprising a non-polar solvent, wherein the ratio of compound 6 to lithium aluminum hydride is between 1 :4 to 1 : 1; and reacting the reaction mixture at a temperature between -15°C to 25°C to form a reaction product mixture comprising compound 7. In some embodiments, reacting compound 7 with a leaving group reagent comprises forming a reaction mixture comprising compound 7, tosylDocket No.: P39382-WO-1 chloride, DMAP, and a solvent system predominantly comprising a polar aprotic organic solvent, wherein the ratio of compound 7 to tosyl chloride is between 1 : 1 to 1:3; and reacting the reaction mixture at a temperature between 0°C to 30°C to form a reaction product mixture comprising compound 8. In some embodiments, reacting compound 8 with ammonium hydroxide comprises forming a reaction mixture comprising compound 8, ammonium hydroxide, and a Ci-ealkyl-OH solvent; and reacting the reaction mixture at a temperature between 70°C to 90°C to form a reaction product mixture comprising compound 9 or salt thereof. In some embodiments, the method further comprises forming a reaction mixture comprising compound 9, acetic acid, and a polar aprotic organic solvent, wherein the ratio of compound 9 to acetic acid is 1 : 1 to 1 :3; and reacting the reaction mixture at a temperature between 0°C to 20°C to produce a reaction product mixture comprising compound 9 acetate salt.

[0011] In yet other aspects, provided herein is a compound of formula:, wherein PG and PG1are independently protecting groups.[oonj In still other aspects, provided herein is a compound of formula:, wherein PG is a protecting group and LG is a leaving group.

[0013] Further provided herein is a method of producing a compound of formula 8:Docket No.: P39382-WO-1 the method comprising: reducing compound 5 to produce compound 6:reducing compound 6 to produce compound 7 :reacting compound 7 with a leaving group reagent to produce compound 8:wherein PG is a protecting group, LG is a leaving group, and R5is Ci-ealkyl or Ci-ehaloalkyl.[0014J In some embodiments, compound 5 is reduced by forming a first reaction mixture comprising compound 5, LiBHEts, and a solvent system predominantly comprising a nonpolar solvent, and reacting the first reaction mixture is reacted at a temperature between - 50°C to -90°C; then combining the first reaction mixture with trifluoroacetic anhydride, diisopropyl ethylamine (DIPEA), and 4-dimethylaminopyridine (DMAP) to form a second reaction mixture; and reacting the second reaction mixture at a temperature between -80°C to -60°C, then warming to a temperature between 10°C to 40°C, to form a reaction product mixture comprising compound 6. In some embodiments, reducing compound 6 comprises forming a reaction mixture comprising compound 6, lithium aluminum hydride, and a solvent system predominantly comprising an non-polar solvent, wherein the ratio of compound 6 to lithium aluminum hydride is between 1:4 to 1 : 1; and reacting the reaction mixture at a temperature between -15°C to 25°C to form a reaction product mixture comprising compound 7. In some embodiments, reacting compound 7 with a leaving group reagent comprises forming a reacting group comprising compound 7, tosyl chloride, DMAP, and aDocket No.: P39382-WO-1 solvent system predominantly comprising a polar aprotic organic solvent, wherein the ratio of compound 7 to tosyl chloride is between 1 : 1 to 1 :3; and reacting the reaction mixture at a temperature between 0°C to 30 °C to form a reaction product mixture comprising compound 8.

[0001] In other aspects, provided herein is a method of producing the compound of formula 11 :the method comprising: reacting compound 4 or a salt thereof with compound 9 or a salt thereof to produce compound 11 :wherein R4ais =0 and R4bis H; or R4ais -OH and R4bis -SO3H; and PG and PG1are independently protecting groups.

[0016] In some embodiments, compound 4 or salt thereof is combined with compound 9 or salt thereof in the presence of an inorganic base and a solvent system comprising a polar aprotic organic solvent and water to form a reaction mixture, and the reaction mixture is reacted at a temperature between 0°C to 20°C to form a reaction product mixture comprising compound 11.DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 provides a synthesis scheme of general procedures to produce compound 100.Docket No.: P39382-WO-1 0010] FIG. 2 provides a detailed synthesis scheme to produce (lS,2S,5R)-8-(tert- butoxycarbonyl)-2-((S)-l-hydroxyethyl)-3,8-diazabicyclo[3.2. l]octan-3-ium succinate, an example of a salt of a compound 100.DETAILED DESCRIPTION

[0019] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. 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 invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.Definitions

[0020] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0021] The articles “a” and “an” as used in this disclosure may refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” may mean one element or more than one element.

[0022] “Alkyl”, as used herein, refers to an unbranched or branched saturated hydrocarbon chain. In some embodiments, if not otherwise described, alkyl comprises 1 to 20 carbon atoms (Ci- C2oalkyl), 1 to 12 carbon atoms (Ci-Cnalkyl), 1 to 8 carbon atoms (Ci-Csalkyl), 1Docket No.: P39382-WO-1 to 6 carbon atoms (Ci-Cealkyl), or 1 to 4 carbon atoms (Ci-C4alkyl). Examples of alkyl groups may include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, and 3-methyl pentyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed. Thus, for example, "butyl" can include n-butyl, secbutyl, isobutyl and t-butyl, and "propyl" can include n-propyl and isopropyl.

[0023] As used herein, the term “salt” refers to both acid addition salts and base addition salts. “Acid addition salt” refers to salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid mesylate, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid. “Base addition salt” refers to salts formed with an organic or inorganic base.

[0024] As used herein an “inorganic base” generally includes sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Nonlimiting examples include phosphates such as dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diammonium monohydrogen phosphate, ammonium dihydrogen phosphate and triammonium phosphate; acetates such as potassium acetate, sodium acetate and ammonium acetate; formates such as potassium formate and sodium formate; carbonates such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide. The inorganic bases may be used singly, or in combination of two or more kinds thereof.

[0025] As used herein, an “organic base” generally includes primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as pyridine, isopropylamine, trimethylamine, diethylamine, triethylamine, triethanolamine, diisopropylamine, ethanolamine, 2- diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine,Docket No.: P39382-WO-1 procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0026] As used herein, “non-polar solvent” refers to a solvent without significant partial charges on any atoms or a solvent where polar bonds are arranged in such a way that the effect of their partial charges generally cancels out. Non-limiting examples of non-polar solvents include pentane, hexane, heptane, cyclopentane, cyclohexane, benzene, toluene, 1,4- dioxane, methyl tert-butyl ether (“MTBE”), chloroform, carbon tetrachloride, and diethyl ether.

[0027] As used herein, an “aprotic solvent” refers to a solvent that does not donate hydrogen. As used herein, “polar aprotic solvent” refers to solvents having high dielectric constants and high dipole movements and that lack an acidic hydrogen. Non-limiting examples of polar aprotic solvents include tetrahydrofuran (“THF”), methyl tetrahydrofuran (“Me-THF”), ethyl acetate (“EA”), acetone, dimethylformamide (“DMF”), acetonitrile (“ACN”), cyclopropylmethyl ether (“CPME”), petroleum ether, N-methyl-2-pyrrolidone (“NMP”), trifluorotoluene, chlorobenzene, anisole, dimethyl sulfoxide, and dichloromethane (“DCM”). In some aspects, the aprotic solvent is a low molecular weight ester. Non-limiting examples of aprotic low molecular weight ester solvents include methyl acetate, ethyl acetate, / / -propyl acetate, / -propyl acetate, / -butyl acetate, propylene glycol methyl ether acetate, monoethyl ether acetate, and combinations thereof. In some embodiments, an aprotic solvent is a an aprotic, non-polar solvent. Non-limiting examples of aprotic, non-polar solvents may include pentane, hexane, heptane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, methyl tert-butyl ether (“MTBE”), carbon tetrachloride, and diethyl ether.

[0028] As used herein, “polar protic solvent” refers to a solvent having a labile hydrogen bound to an oxygen atom or a nitrogen atom. Non-limiting examples of polar protic solvents include formic acid, w-butanol, / -propanol, w-propanol, ethanol, methanol, acetic acid and water. A “polar protic organic solvent” is a polar protic solvent, wherein the solvent comprises at least one carbon atom (e.g., does not include water).

[0029] As used herein, “solvent” refers to a non-polar solvent, an aprotic solvent, a polar protic solvent, and combinations thereof.

[0030] As used herein “reducing agent” refers to a compound that donates an electron. Non-limiting examples of reducing agents include sodium borohydride, potassium borohydride, sodium bi s(2 -methoxy ethoxy)aluminum hydride, sodium bisulfite, sodiumDocket No.: P39382-WO-1 hydrogensulfite, sodium hydrosulfite, sodium tetrahydroborate, potassium tetrahydroborate, sodium triacetoxyborohydride, trichlorosilane, triphenylphosphite, triethylsilane, trimethylphosphine, triphenylphosphine, diborane, diethoxymethylsilane, diisobutylaluminum hydride, diisopropylaminoborane, lithium aluminum hydride, and lithium triethylborohydride.[0031 J As used herein “protecting group” refers to a group used for protection of a functional group (e.g., primary or secondary amine, or a hydroxyl group) of an intermediate, for example to prevent that functional group from being changed during one or more reaction steps. The need for such protection will vary depending on the nature of the functionality and the conditions of the reaction step methods. In some embodiments, the protecting group is an amine protecting group. In some embodiments, the protecting group comprises a carbamate group, such as when used to protect an amine functional group. Suitable amino-protecting groups comprising a carbamate include acetyl trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyleneoxycarbonyl (Fmoc), or methyl carbamate. In some embodiments, the amine protecting group is Boc, Fmoc, Cbz, p-methoxybenzyl (PMB), 2,2,2-trichloroethoxycarbonyl chloride (Troc), or methyl carbamate. In some embodiments, the protecting group is a hydroxyl protecting group. In some embodiments, the protecting group forms an ether or ester with the oxygen of the hydroxyl, and is a hydroxyl protecting group. Suitable hydroxyl-protecting groups may include those comprising a silyl moiety, for example / crt-butyldiphenylsilyl (TBDPS), tertbutyldimethylsilyl (TBS), triisopropyl silyl (TIPS), trimethyl silyl (TMS) or triethylsilyl (TES); or benzyl and its derivatives, such as p-methoxybenzyly (PMB), halobenzyl, 4- methylbenzyl, 2-methylbenzyl, or a benzyl substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, and amino. In some embodiments, the hydroxyl protecting group is benzyl or a benzyl derivative. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.[0 32J As used herein, “predominant” and “predominantly” refer to greater than 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 99% or at least 99.9% on any of a weight, volume, molar, equivalent, v / w%, w / w%, w / v% or v / v% basis.Preparation of Compound 100Docket No.: P39382-WO-1

[0033] In some embodiments, provided herein are methods of making compound 100, or a salt thereof:

[0034] In some embodiments, the protecting group PG is an amine protecting group. In some embodiments, the protecting group PG comprises a carbamate. In some embodiments, the protecting group comprises a carbamate wherein the carbonyl carbon of the carbamate moiety is bonded to the nitrogen atom of compound 100, or salt thereof. In some embodiments, the protecting group is selected from the group consisting of Boc, CBz, FMOC, Troc, benzyl, p-methoxybenzyl (PMB), or methyl carbamate. In certain specific embodiments, the protecting group is Boc, and compound 100 is compound 101, or a salt thereof:

[0035] Compound 101 may also be known as tert-butyl (lS,2S,5R)-2-((S)-l -hydroxy ethyl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0036] In some aspects of the present disclosure, compound 100 or a salt thereof may be prepared by reducing compound 12 to produce compound 100 or a salt thereof:Docket No.: P39382-WO-1wherein PG and PG1are independently protecting groups.

[0037] In some embodiments, PG1is an alcohol protecting group. Such alcohol protecting groups may include those comprising a silyl moiety, for example tert-butyl diphenyl silyl (TBDPS), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), trimethyl silyl (TMS) or triethylsilyl (TES); or benzyl and its derivatives, such as p-methoxybenzyl (PMB), halobenzyl, 4-methylbenzyl, 2-methylbenzyl, or a benzyl substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, and amino. In some embodiments, PG1is benzyl. PG, as described elsewhere herein, may in some embodiments be any suitable amine protecting group, including a protecting group comprising a carbamate, such as Boc, CBz, FMOC, PMB, Troc, benzyl, or methyl carbamate. In certain embodiments, PG1is benzyl and PG is Boc.

[0038] In some embodiments, compound 12 is reduced in the presence of hydrogen, for example in the presence of a transition metal catalyst, hydrogen, and a suitable solvent. In other embodiments, the process comprises forming a reaction mixture comprising compound 12, a palladium catalyst, a transfer hydrogenation reagent, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising compound 100, or a salt thereof. In some embodiments, the solvent system comprises a protic organic solvent, such as an alcohol. In some embodiments, the solvent system comprises a Ci-ealkyl alcohol, for example methanol, ethanol, n-propanol, isopropanol, n-butanol, or t-butanol. In some embodiments, the solvent system comprises isopropanol. The transfer hydrogenation reagent may be any reagent suitable to provide a source of hydrogen atoms for reduction. Such a reagent may be, for example, a formate salt, a cyclohexadiene, or a terpinene; for example ammonium formate, 1 -methyl- 1,4-cy cl ohexadiene, 1, 4-cy cl ohexadiene, or terpinene. In some embodiments, the transfer hydrogenation reagent is terpinene. The transfer hydrogenation reagent is present, in some embodiments, at a ratio between 1 : 1 and 20: 1 relative to compound 12, such as 2: 1 to 20: 1, 4: 1 to 20:1, 6: 1 to 18: 1, 10: 1 to 14: 1, or aboutDocket No.: P39382-WO-112: 1. In some embodiments, the transfer hydrogenation reagent is present at a ratio between 6: 1 to 18: 1 relative to compound 12, or at about 12: 1 relative to compound 12.

[0039] The reaction mixture also comprises a transition metal catalyst. The transition metal catalyst is one that comprises one or more transition metals, and may optionally comprise one or more additional components such as one or more non-transition metals, non-metals, metal oxides, solid supports, or any combinations thereof. In some embodiments, the one or more transition metals are selected from the group consisting of Pd, Pt, Co, Ra, and Ni. In certain particular embodiments, the transition metal catalyst comprises palladium. In some embodiments, the transition metal catalyst is a heterogeneous palladium catalyst system. In some embodiments, the transition metal catalyst comprises Pd(OH)2, Pd / C, Pd(OH)2 / C (Pearlman’s catalyst). In certain embodiments, the transition metal catalyst is palladium (II) hydroxide (i.e., Pd(OH)2). In some embodiments, the transition metal catalyst is present at a catalyst loading of between 1 and 20% relative to compound 12, such as between 2 and 18%, 5 and 15%, 8 and 12%, or at about 10%. In some embodiments, the catalyst loading is about 10% relative to compound 12.

[0040] The transition metal catalyst is selected from Pd / C, Sponge-Ni (which may include Ra-Ni), Ra-Co, Pt / V@C, and Beller type catalysts such as Co@Chitin, Ni-phen@SiC>2, or Ni-phen@TiC>2. In some aspects, the catalyst is selected from Ra-Ni, Ra-Co, Pt / V@C, and Beller type catalysts such as Co@Chitin, Ni-phen@SiC>2, or Ni-phen@TiC>2. In some aspects, the catalyst is selected from Pd / C, Sponge-Ni (which may include Ra-Ni), Pt / V@C, Co@Chitin, and Ni-phen@TiC>2. In one aspect, the catalyst is Pt / V@C. Pt / V@C (that is, platinum and vanadium supported on carbon) may also be known as Pt-V / C or Pt / V / C. In some embodiments, such catalyst is used in a batch processing method. In some embodiments, the catalyst comprises Pd, Pt, Al, or C, or any combinations thereof, such as comprising Pd or Pt and Al or C. In some embodiments, the catalyst is Pd / AhCh, Pt / AhCh, Pd / C, or Pt / C. In some embodiments, the catalyst comprises Pd and Al, for example is Pd / AhCh. As known to those of skill in the art, there exist alternative formats of describing catalysts - for example, a support may sometimes be referenced using thesymbol in some formats, or alternatively using “ / ”. For example, Pt / V@C may also be referred to as Pt / V / C or Pt-V / C; Pd / C may be referred to as Pd@C; Co@Chitin, Ni-phen@SiC>2, and Ni- phen@TiC>2 may alternatively be referenced as Co / Chitin, Ni-phen / SiCh, and Ni-phen / TiCh, respectively; and so on.Docket No.: P39382-WO-1L0041J The reaction for forming compound 100 or a salt thereof may be done under an inert atmosphere, for example under N2 or Ar atmosphere. The reaction is typically carried out (that is, the reaction mixture is reacted) at a temperature of about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, about 100°C, about 125°C, about 150°C, about 175°C, or about 200°C, and any range constructed therefrom, such as from about 20°C to about 200°C, or from about 40°C to about 80°C, or from about 60°C to 100°C, or between about 60°C to 85°C, or between about 70°C to 80°C. In some embodiments, the reaction mixture is reacted at a temperature between 60°C to 100°C, or at about 75°C.

[0042] In some embodiments, the method comprises forming a reaction mixture comprising compound 12, a transition metal catalyst, a transfer hydrogenation reagent, and a solvent system comprising a protic organic solvent, and producing a product mixture comprising compound 100 or a salt thereof. In certain embodiments, the transition metal catalyst is present at 1-20 mol.% relative to compound 12, such as 2-15 mol.%, or about 10 mol.%. In some embodiments, the transfer hydrogenation reagent is present at a ratio between 1 : 1 and 20: 1 relative to compound 12, such as between 6: 1 and 18: 1, or between 10: 1 and 14: 1, or about 12: 1. In some embodiments, the reduction occurs between 60-100°C, such as 70-90°C, or about 80°C. In some embodiments, PG is Boc, CBz, FMOC, PMB, Troc, benzyl, or methyl carbamate. In some embodiments, PG is Boc, CBz, or FMOC. In some embodiments, PG1is benzyl or a benzyl derivative. In some embodiments, PG is Boc and PG1is benzyl.

[0043] In some embodiments, the method comprises forming a reaction mixture comprising compound 12, a palladium catalyst, a transfer hydrogenation reagent, and a solvent system comprising a Ci-ealkyl alcohol, and producing a product mixture comprising compound 100 or a salt thereof. In certain embodiments, the palladium catalyst is present at 1-20 mol.% relative to compound 12, such as 2-15 mol.%, or about 10 mol.%. In some embodiments, the transfer hydrogenation reagent is present at a ratio between 1 : 1 and 20: 1 relative to compound 12, such as between 6: 1 and 18: 1, or between 10:1 and 14: 1, or about 12: 1. In some embodiments, the reduction occurs between 60-100°C, such as 70-90°C, or about 80°C. In some embodiments, PG is Boc, CBz, or FMOC. In some embodiments, PG1is benzyl or a benzyl derivative. In some embodiments, PG is Boc and PG1is benzyl.

[0044] In some embodiments, the palladium catalyst is palladium (II) hydroxide; the transfer hydrogenation reagent is terpinene; the solvent system predominantly comprises 2-Docket No.: P39382-WO-1 propanol; and the reduction occurs between 60-100°C. In certain embodiments, the palladium catalyst is present at 1-20 mol.% relative to compound 12, such as 2-15 mol.%, or about 10 mol.%. In some embodiments, the transfer hydrogenation reagent is present at a ratio between 1 :1 and 20: 1 relative to compound 12, such as between 6: 1 and 18: 1, or between 10: 1 and 14:1, or about 12: 1. In some embodiments, the reduction occurs between 60-100°C, such as 70-90°C, or about 80°C. In some embodiments, PG is Boc, CBz, or FMOC. In some embodiments, PG1is benzyl or a benzyl derivative. In some embodiments, PG is Boc and PG1is benzyl.

[0045] In some embodiments of the methods provided herein, the yield of compound 100 or salt thereof is at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% based on compound 12. In some embodiments, the yield of compound 100 or salt thereof is at least 90% based on compound 12.[W46] In still further embodiments, which may be combined with any of the other embodiments of producing compound 100 or a salt thereof, compound 12 is reduced in the presence of an acid to form compound 100 or a salt thereof. In some embodiments, the acid is an organic acid, a phosphoric acid, or a mineral acid.Salts of Compound 100

[0047] In some embodiments of the methods and compounds provided herein, compound 100 (or compound 101) is a salt. The methods of making such salts are known to those of skill in the art, and may include adding an acid to compound 100 (or 101) to form a salt (which may further include adjusting the pH of the composition), or forming compound 100 (or 101) in the presence of an acid to form a salt. In some embodiments, compound 100 is formed and then an acid is added to form the corresponding salt. Any suitable acid may be used, including but not limited to organic acids, mineral acids, and phosphoric acids. In certain embodiments, compound 100 is formed and then an organic acid, mineral acid, or a phosphoric acid is added form compound 100 salt. In yet other embodiments, compound 12 is reduced in the presence of an acid to form compound 100, or a salt thereof. In certain embodiments, compound 12 is reduced in the presence of an organic acid or a phosphoric acid to form compound 100, or a salt thereof. One of skill in the art will understand that in instances wherein compound 12 is reduced in the presence of an organic acid, a phosphoric acid, or a mineral acid, depending on the pH of the reaction mixture, compound 12 and the acid may be in the form of their corresponding conjugate acid and base, e.g., may be in theDocket No.: P39382-WO-1 form of a salt. Such organic, phosphoric, or mineral acids (e.g., that are added to compound 100, or that compound 100 is formed in the presence of), may include, but are not limited to, succinic acid, camphoric acid, oxalic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, (S)-mandelic acid, phosphoric acid, tosylic acid, methanesulfonic acid, benzoic acid, hydrochloric acid, and hydrobromic acid, and combinations thereof. In some embodiments, compound 100 is reduced in the presence of an organic acid, the organic acid is also reduced in the reaction, and compound 100 salt is form. In some embodiments, provided herein is compound 100 succinate, compound 100 camphorate, compound 100 oxalate, compound 100 maleate, compound 100 fumarate, compound 100 citrate, compound 100 L-tartrate, compound 100 (S)-mandelate, compound 100 phosphate, compound 100 tosylate, compound 100 methansulfonate, and compound 100 benzoate. In some embodiments, PG of compound 100 is Boc, and provided herein is compound 101 succinate, compound 101 camphorate, compound 101 oxalate, compound 101 maleate, compound 101 fumarate, compound 101 citrate, compound 101 L-tartrate, compound 101 (S)-mandelate, compound 101 phosphate, compound 101 tosylate, compound 101 methansulfonate, and compound 101 benzoate. In certain embodiments, provided is compound 100 succinate:

[0040] In other embodiments, provided herein is compound 101 succinate:

[0049] Compound 101 succinate may also be known as tert-butyl (lR,2S,5S)-2-((S)-l- hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate succinate

[0050] In certain embodiments, compound 100 is combined with, or formed in the presence of, camphoric acid, oxalic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid,Docket No.: P39382-WO-1(S)-mandelic acid, phosphoric acid, tosylic acid, methansulfonic acid, benzoic acid, succinic acid, hydrobromic acid, or hydrochloric acid, or any combinations thereof, and forms the corresponding salt. In some embodiments, compound 100 is reduced in the presence of an organic acid, the organic acid is also reduced in the reaction, and compound 100 salt is form. For example, in some embodiments compound 100 is reduced in the presence of maleic acid, and compound 100 succinate is formed. In some such embodiments, compound 12 maleate is reduced to form compound 100 succinate.Preparation of Compound 12

[0051] Also provided herein are methods of preparing compound 12, or a salt thereof, comprising cyclizing compound 11 :independently protecting groups as described elsewhere herein.

[0052] In some embodiments, PG1is a protecting group comprising a silyl moiety, for example / c / V-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS), triisopropyl silyl (TIPS), trimethyl silyl (TMS) or triethylsilyl (TES); or is benzyl or a derivatives, such as p- methoxybenzyl (PMB), halobenzyl, 4-methylbenzyl, 2-methylbenzyl, or a benzyl substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, and amino. In some embodiments, PG is any suitable amine protecting group, including a protecting group comprising a carbamate, such as Boc, CBz, FMOC, PMB, Troc, benzyl, or methyl carbamate. In certain embodiments, PG1is benzyl and PG is Boc.

[0053] In some embodiments, cyclizing compound 11 to produce compound 12 comprises forming a reaction mixture comprising compound 11, a metal catalyst, a reducing agent, an oxidizer and a solvent system comprising a protic organic solvent, and producing a product mixture comprising compound 12 or a salt thereof. In some embodiments, the metal catalyst is a transition metal catalyst. In some embodiments, the catalyst is an iron, cobalt, or manganese catalyst. In some embodiments, the catalyst comprises an acetylacetonate (acac), 2,2,6,6-tetramethyl-3,5-heptanedionato (dpm), salen, diketone, or porphyrin ligand. In someDocket No.: P39382-WO-1 embodiments, the catalyst is Fe(dpm)3, Co(dpm)3, Mn(acac)3, Mn(dpm)3, Fe(acac)3, Co(acac)3; a catalyst comprising Mn, Fe, Co, and a diketone ligand; a catalyst comprising Mn and pophyrin ligands; or a catalyst comprising Mn or Co and salen ligands. In some embodiments, the catalyst is a Mn catalyst. In some embodiments, the catalyst is Mn(dpm)3. The catalyst may be present in the reaction mixture at, for example, 1-20% relative to compound 11, or about 5-15% relative to compound 11, or about 5% relative to compound 11. A person of skill in the art will be able to convert a catalyst loading in % to another unit, for example, molar equivalents (10% loading = 0.1 molar equivalents). The reducing agent may be any suitable reducing agent, and may include but not be limited to

[0054] In some embodiments, the solvent system comprises a protic organic solvent such as an alcohol. In some embodiments, the solvent system comprises a Ci-ealkyl alcohol, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, or t-butanol. In some embodiments, the solvent system comprises isopropyl alcohol. The solvent system may also comprise water. Thus, in some embodiments, the solvent system comprises a protic organic solvent and water; such as an alcohol and water; for example Ci-ealkyl alcohol and water; for example isopropyl alcohol and water.

[0055] The reaction mixture comprises a reducing agent. Suitable reducing agents may include, for example, an organosilane, such as one of formula Ph(RO)SiH2 wherein R is Ci-6 alkyl (for example (Ph(i-PrO)SiH2); one of formula (RO)2RSiH wherein each R is independently Ci-ealkyl (for example (EtO)2MeSiH); or one of formula RnSiHmwherein n is 1, 2 or 3, m is 1 or 2, the sum of n and m is 4, and each R is independently Ci-6 alkyl or aryl (for example EtsSiH, Et2SiH2, Pt^SiEE, PhsSiH, or PhMeSiFE). In some embodiments, the organosilane is PhSiEE.

[0056] The reaction mixture comprises an oxidizer. In some embodiments, the oxidizer is oxygen, a peroxide, or an N-oxide. In some embodiments the oxidizer is a peroxide and the peroxide is an organic peroxide or an inorganic peroxide. The peroxide may be, for example, hydrogen peroxide, magnesium monoperoxyphthalate, cumyl hydroperoxide, urea hydroperoxide, benzolyl peroxide, dicumyl peroxide, DDM-9, 2-butanone peroxide solution, or tert-butyl hydroperoxide. Inorganic peroxides such as potassium persulfate can be used. In some embodiments, the oxidizer is oxygen, which may be introduced for example by bubbling through the reaction mixture or otherwise exposing the reaction mixture to air and / or oxygen-enriched gas (such as air with a higher than typical amount of oxygen; or oxygen gas; or a gas that comprises 5-90% oxygen, such as 5-10%, or 5-20%, or greater thanDocket No.: P39382-WO-120% oxygen). Such exposure may include performing the reaction mixture in the presence of oxygen-containing gas. In some embodiments, the oxidizer is an N-oxide. Such N-oxide may include, for example, 4-methylmorpholine N-oxide (NMO) or pyridine N-oxide. In some embodiments, the peroxide is an organic peroxide, and the organic peroxide is tert-butyl hydroperoxide.

[0057] In some embodiments, provided herein is a method of preparing compound 12 or salt thereof by forming a reaction mixture comprising compound 11, a metal catalyst, a reducing agent, an oxidizer, and a solvent system comprising a protic organic solvent, and forming a product mixture comprising compound 12, wherein: the metal catalyst is a Mn catalyst; the catalyst is present at between 1-20 mol% relative to compound 11; the reducing agent is an organosilane; the oxidizer is a peroxide; and the solvent system comprises a Ci-ealkyl alcohol.

[0058] In some embodiments of the method: the metal catalyst is Mn(dpm)s; the reducing agent is PhSiHa; the oxidizer is tert-butyl hydroperoxide; and the solvent system comprises isopropyl alcohol and water.

[0059] In any of the embodiments preparing compound 12, the reaction mixture may be reacted at a temperature between 10°C and 50°C, such as between 20°C and 40°C, or between 25°C and 35°C, for example 30°C. In some embodiments, the reaction mixture is reacted at about 30°C. In some embodiments, compound 12 is produced at a yield of at least 50% relative to compound 11. In some embodiments, compound 12 is produced at a yield of at least 60%, at least 65%, or at least 70%, relative to compound 11 or salt thereof.

[0060] In some embodiments, the metal catalyst and compound 11 are combined with a solvent system comprising a polar solvent to form a first reaction mixture; a reducing agent, an oxidizer, and a solvent system comprising a polar solvent are combined to form a reactant mixture; and the reactant mixture is added to the reaction mixture over a period of time to form a reaction product mixture comprising compound 12 or a salt thereof. In some embodiments, the period of time is from 30 min to 24 hours, from 30 min to 12 hours, to 30 min to 6 hours, from 30 min to 3 hours, from 1 hour to 3 hours, or about 1 or 2 hours.Docket No.: P39382-WO-1

[0061] In some embodiments, compound 12 is combined with an acid to produce a salt of compound 12, which may be taken on to form compound 100 or a salt thereof. This may be done, for example, in embodiments wherein compound 12 is reduced in the presence of an acid to produce compound 100 salt. For example, in some embodiments, compound 12 is formed, then maleic acid is added to compound 12 to form compound 12 maleate, and compound 12 maleate is reduced to form compound 100 succinate. Thus, in some of the methods provided herein, after forming compound 12 from compound 11, the compound 12 is then combined with an organic acid or a phosphoric acid to form the corresponding compound 12 salt. A person of skill in the art will understand the conversion of compound 12 and an acid to the corresponding conjugate acid and base, forming a salt, depends on the pH of the mixture.Preparation of Compound 11

[0062] Also provided herein are methods of producing compound 11, comprising reacting compound 4 or a salt thereof with compound 9 or a salt thereof to produce compound 11 :wherein R4ais =0 and R4bis H; or R4ais -OH and R4bis -SO3H; and PG and PG1are independently protecting groups.

[0063] The identity of protecting groups PG and PG1are as have been described elsewhere for other intermediates in the reactions described herein. In some embodiments, PG1is a protecting group comprising a silyl moiety, for example / cvV-butyldiphenylsilyl (TBDPS), / c77-butyldimethylsilyl (TBS), triisopropyl silyl (TIPS), trimethyl silyl (TMS) or triethylsilyl (TES); or is benzyl or a derivatives, such as p-methoxybenzyl (PMB), halobenzyl, 4- methylbenzyl, 2-methylbenzyl, or a benzyl substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, and amino. In some embodiments, PG is any suitable amine protecting group, including a protecting group comprising a carbamate, such as Boc, CBz, FMOC, PMB, Troc, benzyl, or methyl carbamate. In certain embodiments, PG1is benzyl and PG is Boc. In some embodiments, when reacting compound 4 or salt thereof and compound 10 or salt thereof, compound 4 or salt thereof isDocket No.: P39382-WO-1 present at a ratio of between 1 :3 to 4: 1 relative to compound 10 or salt thereof, such as about 1 :3 to 3 : 1, or about 1 :2 to 2: 1, or about 2:3 to 3 :2, or about 1 : 1 relative to compound 10 or salt thereof.

[0064] In some embodiments, the reaction mixture further comprises a solvent system. In some embodiments, the reaction mixture further comprises an inorganic base, such as a basic metal salt. Such basic metal salts may include metal carbonates or metal phosphates. In embodiments wherein the reaction mixture comprises a metal carbonate, the metal carbonate is an alkali metal carbonate of the formula M2CO3 where M is an alkali metal, such as Na or K. In some embodiments, wherein the reaction mixture comprises an inorganic base, the inorganic base is present at a ratio of 3 : 1 to 4: 1 relative to compound 10 or salt thereof, such as at a ratio of about 1 : 1 to 3: 1, or 2: 1 to 5: 1, or about 2: 1, or 1 : 1 to 2: 1, relative to compound 10 or salt thereof. In some embodiments, the reaction mixture further comprises both a solvent system and a metal carbonate. In certain embodiments, the solvent system comprises an aprotic organic solvent, for example predominately comprises an aprotic organic solvent. Such aprotic organic solvent may be, for example, an aprotic, non-polar solvent. In some embodiments, the aprotic organic solvent is an ether, such as a low molecular weight ether. In certain embodiments, the aprotic organic solvent is an ether of the formula R-O-R’, wherein R and R’ are independently Ci-ealkyl. In some embodiments the aprotic organic solvent is pentane, hexane, heptane, cyclopentane, cyclohexane, benzene, toluene, 1,4- dioxane, MTBE, carbon tetrachloride, diethyl ether, cyclopentyl methyl ether (CPME), anisole, methylcyclohexane, 2-methyltetrahydrofuran, tetrahydrofuran, isopropyl ether, xylene, or ethyl tert-butyl ether, or any combinations thereof. In some embodiments, the aprotic organic solvent is MTBE. In some embodiments, the solvent system further comprises water. For example, wherein the reaction mixture comprises a metal carbonate, the metal carbonate may be introduced as an aqueous solution, and the solvent system in the reaction mixture comprises water.

[0065] In some embodiments, compound 11 is produced by: forming a reaction mixture comprising compound 4 or a salt thereof, compound 10 or a salt thereof, a solvent system, and a metal carbonate, wherein the solvent system comprises a non-polar solvent and water; and reacting the reaction mixture to form a reaction product mixture comprising compound 11.

[0066] In some embodiments, compound 11 is produced by:Docket No.: P39382-WO-1 forming a reaction mixture comprising compound 4 or a salt thereof, compound 10 or a salt thereof, a solvent system comprising MTBE and water, and sodium carbonate; and reacting the reaction mixture to form a reaction product mixture comprising compound 11.

[0067] In some embodiments, compound 11 is produced by: forming a reaction mixture comprising compound 4 or a salt thereof, compound 10 or a salt thereof, and a solvent system, wherein the solvent system comprises a non-polar solvent; and reacting the reaction mixture to form a reaction product mixture comprising compound 11.

[0068] In some embodiments, compound 11 is produced by: forming a reaction mixture comprising compound 4 or a salt thereof, compound 10 or a salt thereof, a solvent system, and optionally a metal carbonate, wherein the solvent system comprises a non-polar solvent and optionally comprises water; and reacting the reaction mixture to form a reaction product mixture comprising compound 11.

[0063] In some embodiments, compound 4 or a salt thereof is present at a ratio of 3 :2 to 2:3 relative to compound 10 or salt thereof; and the inorganic base is present at a ratio of about 1 : 1 to 3 : 1 relative to compound 10 or salt thereof. In any of the embodiments preparing compound 11, the reaction mixture may be reacted at a temperature between 0°C and 30°C, such as between 0°C and 20°C, or between 0°C and 25°C, or between 5°C and 15°C. In some embodiments, the reaction mixture is reacted at about 10°C. In some embodiments, compound 11 is produced at a yield of at least 50% relative to compound 10. In some embodiments, compound 11 is produced at a yield of at least 60%, at least 70%, at least 80%, or at least 85% relative to compound 10 or salt thereof.

[0070] Also provided herein is compound 11 :Docket No.: P39382-WO-111, wherein PG and PG1are independently protecting groups.

[0071] In some embodiments, PG is an amine protecting group, such as one comprising a carbamate wherein the carbonyl carbon of the carbamate moiety is bonded to the nitrogen atom of compound 11. In some embodiments, PG is any suitable amine protecting group, including a protecting group comprising a carbamate, such as Boc, CBz, FMOC, PMB, Troc, benzyl, or methyl carbamate. In some embodiments, PG is Boc. In some embodiments, PG1is a protecting group comprising a silyl moiety, for example tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS), triisopropyl silyl (TIPS), trimethyl silyl (TMS) or triethylsilyl (TES); or is benzyl or a derivatives, such as p-methoxybenzyl (PMB), halobenzyl, 4- methylbenzyl, 2-methylbenzyl, or a benzyl substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, and amino. In some embodiments, PG1is benzyl. In certain embodiments, PG1is benzyl and PG is Boc, and compound 11 is:BocPreparing Compound 4

[0072] Also provided herein are methods of preparing compound 4, or a salt thereof. Such methods comprise reacting compound 1 with compound 13 to produce compound 2:Docket No.: P39382-WO-1then reacting compound 2 with a protecting group reagent to produce compound 3 :and reducing compound 3 to produce compound 4 or a salt thereof:wherein:R1is Ci-ealkyl; n is an integer from 1 to 4;R4ais =0 and R4bis H; or R4ais -OH and R4bis -SO3H; and PG1is a protecting group.

[0073] In some embodiments, n is an integer from 1 to 4. In certain embodiments, n is 1 or 2. In some embodiments, n is 2 and compound 13 is pyrrolidine. In some embodiments, R1is Ci-ealkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In some embodiments, R1is methyl or ethyl. In some embodiments, R1is ethyl.

[0074] In some embodiments, reacting compound 1 with compound 13 comprises forming a reaction mixture comprising compound 1 and compound 13 at a ratio of between 1 : 1 and 1 : 10, such as about 1 : 1 to 1 :8, or about 1 : 1 : to 1 :6, or about 1 :2 to about 1 :4, or at about 1 :3; and reacting the reaction mixture to form a product mixture comprising compound 2. In some embodiments, the reaction mixture is reacted at a temperature between 0°C to 50°C, such as for example 10°C and 40 °C, or 20°C to 30°C, or at about 25°C. In someDocket No.: P39382-WO-1 embodiments, producing compound 2 comprises forming a reaction mixture comprising compound 1 and compound 13, wherein the ratio of compound 1 to compound 13 is between 1 : 1 and 1 :6; and reacting the reaction mixture at a temperature between 10°C and 40°C to form a reaction product mixture comprising compound 2. In some embodiments, no solvent system is used, for example in embodiments wherein compound 13 is a liquid and effectively serves as a solvent and reactant. In other embodiments, a solvent system comprising a polar aprotic solvent is used, for example by combining compound 1, compound 13, and a solvent system comprising a polar aprotic solvent to form a reaction mixture. Suitable solvents may include, for example, DMF, DMSO, DMAc, NMP, DCM, THF, and dimethyl carbonate.[0075J Compound 3 is produced by reacting compound 2 with a protecting group reagent. In some embodiments, the protecting group reagent is any suitable reagent to install a hydroxyl protecting group, forming PG1. As has been described elsewhere for PG1in other intermediates in the reactions described herein, PG1may be any suitable hydroxyl protecting group. For example, in some embodiments, PG1is an alcohol protecting group, such as a hydroxyl protecting group that comprises a silyl moiety, such as TBDPS, TBS, TIPS, TMS, or TES, or is benzyl or its derivatives, such as p-methoxybenzyly, halobenzyl, 4- methylbenzyl, 2-methylbenzyl, or a benzyl substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, and amino. In some embodiments, PG1is a hydroxyl protecting group that comprises a silyl moiety, and the protecting group reagent is a reagent that install such group, for example TBDPS-C1, TBS-C1, TIPS-C1, TMS- Cl, or TES-C1. In some embodiments PG1is a benzyl or benzyl derivative, and the protecting group reagent is a benzylation reagent, that is, a reagent that installs a benzyl group or derivative thereof. In some embodiments, PG1is benzyl and the benzylation reagent installs the benzyl group. In some embodiments, the benzylation reagent is benzyl bromide, benzyl chloride, or benzyl trichloroimidate. In some embodiments, the benzylation reagent is benzyl chloride. In some embodiments, the ratio of compound 2 to the protecting group reagent is between 2: 1 and 1 :6, or between 1.5: 1 and 1 :4, or between 1 : 1 and 1 :3, or between 1 :1 and 1 :2, or between 1 : 1 and 1 : 1.5, or between 0.8: 1 and 1 : 1.5. In some embodiments, the ratio of compound 2 to the protecting group reagent the protecting group reagent (such as the benzylation reagent) is between 1 : 1 and 1 :2, or is about 1 : 1.5, or is about 1 : 1. In some embodiments, the reaction of compound 2 with the protecting group reagent (such as a benzylation reagent) is carried out in the presence of a base and a solvent system predominantly comprising a non-polar solvent. In some embodiments, the base is anDocket No.: P39382-WO-1 inorganic base or an organic base. In some embodiments, the reaction of compound 2 with the protecting group reagent (such as a benzylation reagent) is carried out in the presence of a phase transfer agent, an inorganic base, and a solvent system predominantly comprising a non-polar solvent. Thus, in some embodiments, the method of producing compound 3 comprises forming a reaction mixture comprising compound 2, a protecting group reagent, a phase transfer agent, an inorganic base, and a solvent system predominantly comprising a non-polar solvent, and reacting the reaction mixture to form a reaction product mixture comprising compound 3. In some embodiments, the phase transfer agent is a quaternary ammonium salt or a phosphonium phase transfer catalyst. Such quaternary ammonium salts may be of the formula R4NX, wherein each R is independently selected from alkyl and aryl; and X is a halide or pseudohalide anion. Such pseudohalide anions may include, for example, trifluoromethanesulfonate, methanesulfonate, or tosylate. In some embodiments, the quaternary ammonium salt is tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutylammonium fluoride, tetrabutyl ammonium iodide, benzyltrimethyl ammonium bromide, decyltrimethylammonium bromide, tetraethylammonium trifluoromethanesulfonate, or N-methyl-N,N,N-trioctylammonium chloride (Aliquat 336). Phosphonium phase transfer catalysts may include those of the formula R4PX where each R is independently alkyl or aryl; and X is halide or pseudohalide. In some embodiments, the phase transfer agent is a quaternary ammonium salt. In some embodiments, the phase transfer agent is Aliquat 336, which may also be known as Starks’ catalyst or N-methyl- N,N,N-trioctylammonium chloride. In embodiments wherein the reaction of compound 2 with a protecting group reagent occurs in the presence of a phase transfer reagent, the phase transfer reagent is present at a loading of 1-10 mol% relative to compound 2. In some embodiments, the phase transfer reagent is present at a loading of 2-8 mol.%, or 3-7 mol.%, or 4-6 mol.%, or 4-10 mol.%, or about 5 mol.%, relative to compound 2. In embodiments wherein the reaction of compound 2 with a protecting group reagent occurs in the presence of an inorganic base, such inorganic base may be a metal hydroxide or a metal carbonate, or any combinations thereof. In some embodiments, the inorganic base is an alkali metal hydroxide or an alkali metal carbonate, or a combination thereof. In some embodiments, the inorganic metal base is NaOH, KOH, LiOH, CsOH, Ba(OH)2, Mg(OH)2, Ca(OH)2, A1(OH)3, Fe(OH)2, or an alkali metal carbonate of the formula M2CO3where M is an alkali metal, such as Na or K. In some embodiments, the inorganic base is NaOH. In embodiments wherein the reaction of compound 2 with a protecting group reagent occurs in the presence of an inorganic base, the ratio of compound 2 to the inorganic base is between 2:1 and 1 : 10, or 1 : 1 and 1 : 10, or 1 :2Docket No.: P39382-WO-1 and 1 :8, or 1:2 and 1:7, or 1 :3 and 1 :6, or is about 1 :5, or 1 :4, or 1 :6. In embodiments wherein the reaction of compound 2 with a protecting group reagent occurs in the presence of an a solvent system predominantly comprising a non-polar solvent, any suitable non-polar solvent may be used. This may include, but is not limited to, pentane, hexane, heptane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, di chloromethane, methyl tert-butyl ether, chloroform, carbon tetrachloride, or diethyl ether, or any combinations thereof. In some embodiments, the solvent system predominantly comprises toluene. In some embodiments, the reaction occurs between 0°C to 40°C, or between 10°C to 30°C, or between 15°C to 25°C, or at about 20°C.[0O76J In some embodiments, producing compound 3 comprises forming a reaction mixture comprising compound 2, a protecting group reagent, a phase transfer agent, an inorganic base, and a solvent system predominantly comprising a non-polar solvent, and reacting the reaction mixture to form a reaction product mixture comprising compound 3, wherein: the phase transfer agent is Aliquat 336, and the Aliquat 336 is present at a loading of 1-10 mol.% relative to compound 2; the inorganic base is NaOH, and the ratio of compound 2 to NaOH is 1 :2 to 1 :7; the solvent system comprises predominantly toluene; the protecting group reagent is a benzylation reagent; and the reaction mixture is reacted at a temperature between 10°C and 30°C to form the reaction product mixture comprising compound 3.

[0077] In the methods provided herein of producing compound 4 or a salt thereof, compound 3 is reduced to produce compound 4 or a salt thereof. Compound 3 may be reduced under any suitable conditions to produce compound 4, or a salt thereof. In some embodiments, compound 3 is combined with sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH) and a solvent system to form a reaction mixture, and the reaction mixture is reacted to form a product reaction mixture comprising compound 4 or a salt thereof. The ratio of compound 3 to SMEAH may be, for example, between 1 :2 and 2: 1, or between 1 :4 and 4: 1, or between 1 :3 and 3: 1, or between 1 : 1.5 and 1.5: 1, or between 1 : 1.2 to 1.2: 1. In some embodiments, the ratio is about 1 : 1, or is between 1 : 1.2 to 1.2: 1, or is between 1 :2 and 2: 1. In some embodiments, the solvent system predominately comprises a protic solvent, such as a protic organic solvent. In some embodiments, the solvent system predominately comprises a protic organic solvent such as an alcohol. In some embodiments, the solventDocket No.: P39382-WO-1 system comprises a Ci-ealkyl alcohol, such as methanol, ethanol, n-propanol, isopropanol, n- butanol, or t-butanol. In some embodiments, the solvent system comprises ethanol. The solvent system may also comprise water. Thus, in some embodiments, the solvent system comprises a protic organic solvent and water; such as an alcohol and water; for example Ci- ealkyl alcohol and water; for example ethanol and water.

[0078] In some embodiments, a bisulfite source is then added to the product reaction mixture to form compound 4 wherein R4ais -OH and R4bis -SO3H, or a salt thereof. This may be, for example, a metal bisulfite. In some embodiments, an alkali metal bisulfite is added and compound 4 wherein R4ais =0 and R4bis H is converted to compound 4 wherein R4ais -OH and R4bis -SO3H, or a salt thereof (such as a sodium salt, or a potassium salt). In some embodiments, the alkali metal bisulfite is potassium bisulfite, or sodium bisulfite.

[0079] Further provided herein is an alternative synthesis of compound 4 or salt thereof, the method comprising reacting compound 1 with compound 14 to produce compound 15:then reducing compound 15 to produce compound 4 or a salt thereof, wherein R4ais =0 andR4bis H:and optionally reacting compound 4, wherein R4ais =0 and R4bis H, with a bisulfite source to produce compound 4 or a salt thereof wherein R4ais -OH and R4bis -SO3H; wherein R1is Ci-ealkyl, Ci-ehaloalkyl, or aryl; and PG1is a protecting group.

[0080] In some embodiments, R1is Ci-ealkyl or Ci-ehaloalkyl. In some embodiments, R1is Ci-ealkyl. In certain embodiments of any of the methods provided herein, such as producing compound 4 or a salt thereof, including reactions of compound 1 and 13 to produceDocket No.: P39382-WO-1 compound 2; producing compound 3 from compound 2; and producing compound 4 from compound 3, n is 2; R4ais -OH and R4bis -SO3H; R1is ethyl, and PG1is benzyl.Preparing Compound 8

[0081] Provided herein are methods of preparing compound 8. Such methods comprise reducing compound 5 to produce compound 6:reducing compound 6 to produce compound 7 :and reacting compound 7 with a leaving group reagent to produce compound 8wherein PG is a protecting group, LG is a leaving group, and R5is Ci-ealkyl or Ci-ehaloalkyl.

[0082] PG, as described elsewhere herein, may in some embodiments be any suitable amine protecting group, including a protecting group comprising a carbamate. In some embodiments, PG is Boc, CBz, FMOC, PMB, Troc, benzyl, or methyl carbamate. In some embodiments, PG is Boc, CBz, or FMOC. In certain embodiments, PG is Boc. In some embodiments, R5is Ci-ealkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl; or is a halo-substituted version thereof. In some embodiments, R5is methyl or ethyl. In some embodiments, R5is ethyl. LG may be any suitable leaving group that converts a hydroxyl to an improved leaving group. In some embodiments, the leavingDocket No.: P39382-WO-1 group is a sulfonate of the formula -S(O)2R, wherein R is a Ci-ealkyl or an aryl unsubstituted or substituted by one or more Ci-ealkyl or Ci-ehaloalkyl. In some embodiments, the leaving group is p-toluenesulfonate (tosylate, or Ts), or is methanesulfonate (mesylate, or Ms). In some embodiments, the leaving group is Ts.

[0083] Compound 5 may be reduced by combining it with any suitable reducing agent. In some embodiments, compound 5 is reduced by forming a first reaction mixture comprising compound 5, a reducing agent, and a solvent system predominantly comprising a non-polar solvent, and reacting the first reaction mixture. In some embodiments, the first reaction mixture is reacted at a temperature between -40°C to -100°C, or between -50°C to -90°C, or between -60°C to -80°C, for example at about -70°C. Any suitable reducing agent may be used, for example LiBHEts, DIBAL (diisobutylaluminium hydride), or Red-Al (sodium bis(2-methoxyethoxy)aluminum hydride). In some embodiments, the reducing agent is LiBHEts. In some embodiments the non-polar solvent is pentane, hexane, heptane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, di chloromethane, methyl tertbutyl ether, chloroform, carbon tetrachloride, or diethyl ether, or any combinations thereof. In some embodiments, the non-polar solvent is toluene. In some embodiments, after forming and reacting the first reaction mixture, the first reaction mixture is then combined with a dehydrating agent, organic base, and nucleophilic catalyst to form a reaction product mixture comprising compound 6. In some embodiments, the dehydrating agent is an anhydride. In some embodiments, the anhydride has the formula (RC(O))2O wherein each R is independently Ci-ealkyl or Cj-shaloalkyl. In some embodiments, the dehydrating agent is trifluoroacetic anhydride, acetic anhydride, maleic anhydride, propionic anhydride, lactic anhydride, or butanoic anhydride. In some embodiments, the dehydrating agent is trifluoroacetic anhydride. In some embodiments, the organic base is an organic amine. In some embodiments, the organic base is a tertiary amine. In some embodiments, the organic base is diisopropylethylamine (DIPEA), triethylamine, DBU, trimethylamine, N-methyl morpholine, or 1 -methylimidazole. In some embodiments, the organic base is DIPEA. In some embodiments, the nucleophilic catalyst is 4-Dimethylaminopyridine (DMAP), or 1- methylimidazole. In some embodiments, the nucleophilic catalyst is DMAP. In some embodiments, the second reaction mixture is reacted at a temperature between -90 to -40°C, then warmed to a temperature between 0°C to 50°C. In some embodiments, the second reaction mixture is reacted at a temperature between -90°C to -50°C, such as -80°C to -60°C, or -70°C to -50°C, or -70°C to -60°C, or -75°C to -65°C, or about -70°C; then warmed to aDocket No.: P39382-WO-1 temperature between 0°C to 50°C, such as between 10°C to 40°C, or between 15°C to 35°C, or between 20°C to 30°C, or about 25°C. In some embodiments, the second reaction mixture is reacted at a temperature between -80°C to -60°C, then warmed to a temperature between 10°C to 40°C. In some embodiments, the second reaction mixture is reacted at a temperature between -75°C to -65°C, then warmed to a temperature between 20°C to 30°C.

[0084] Without wishing to be bound by theory, in some embodiments producing compound 7 from compound 5 comprises a two-step reduction, wherein the first step is under milder conditions to reduce the lactam, and under conditions resulting in the hydroxyl leaving to form an alkene in compound 6; then second reduction under stronger reducing conditions to form the final compound 7.

[0085] In some embodiments, reducing compound 5 comprises forming a first reaction mixture comprising compound 5, LiBHEts, and a solvent system predominantly comprising a non-polar solvent, and reacting the first reaction mixture at a temperature between -50°C to - 90°C; then combining the first reaction mixture with trifluoroacetic anhydride, diisopropyl ethylamine (DIPEA), and 4-dimethylaminopyridine (DMAP) to form a second reaction mixture; and reacting the second reaction mixture at a temperature between -80°C to -60°C, then warming to a temperature between 10°C to 40°C, to form a reaction product mixture comprising compound 6. In some embodiments, the solvent system predominantly comprises toluene.

[0086] In some embodiments, reducing compound 6 comprises forming a first reaction mixture comprising compound 6, a reducing agent, and a solvent system predominantly comprising a non-polar solvent, and reacting the reaction mixture to form a reaction product mixture comprising compound 7. Any suitable reducing agent may be used. In some embodiments, the reducing agent is lithium aluminum hydride, lithium borohydride, L- selectride or Red-Al. In some embodiments, reducing compound 6 comprises forming a reaction mixture comprising compound 6, lithium aluminum hydride, and a solvent system predominantly comprising a non-polar solvent, wherein the ratio of compound 6 to lithium aluminum hydride is between 1 :4 to 1 :1; and reacting the reaction mixture at a temperature between -15°C to 25°C to form a reaction product mixture comprising compound 7.

[0087] In some embodiments, producing compound 8 comprises reacting compound 7 with a leaving group reagent to form compound 8. Any suitable leaving group that converts the hydroxyl to an improved leaving group can be used. In some embodiments, the leavingDocket No.: P39382-WO-1 group is a sulfonate of the formula -S(O)2R, wherein R is a Ci-ealkyl or an aryl unsubstituted or substituted by one or more Ci-ealkyl or Ci-ehaloalkyl. In some embodiments, the leaving group is p-toluenesulfonate (tosylate, or Ts), or is methanesulfonate (mesylate, or Ms). In some embodiments, the leaving group reagent is C1-S(O)2R, wherein R is a Ci-ealkyl or an aryl unsubstituted or substituted by one or more Ci-ealkyl or Ci-ehaloalkyl. In some embodiments, the leaving group reagent is tosyl chloride or mesyl chloride. In some embodiments, the leaving group is tosylate, and the leaving group reagent is tosyl chloride. In some embodiments, producing compound 8 comprises forming a reaction mixture comprising compound 7, a leaving group reagent, and a solvent system comprising an polar aprotic solvent. Any suitable polar aprotic solvent may be used, for example, THF, Me-THF, ethyl acetate, acetone, DMF, acetonitrile, petroleum ether, NMP, chlorobenzene, anisole, dimethyl sulfoxide, or DCM. In some embodiments, the polar aprotic solvent is DCM. In some embodiments, the reaction mixture further comprises a nucleophilic catalyst such as DMAP; and a base. In some embodiments, the base is an amine, such as a tertiary amine, for example trimethylamine. In some embodiments, the reaction mixture is reacted at a temperature between -20°C to 60°C, or -10°C to 50°C, or -10°C to 40°C, or 0°C to 30°C, or 5°C to 25°C, or 10°C to 20°C, or about 15°C. In some embodiments, the ratio of compound 7 to the leaving group reagent is between about 2: 1 to 1 :5, or between about 1.5: 1 to 1 :4, or between about 1 : 1 to 1 :3, or between about 1 : 1 and 1 :2, or about 1 :2, or between about 1 : 1.5 to 1 :2.5.

[0088] Further provided herein is compound 8:wherein LG is a leaving group and PG is a protecting group.

[0089] PG, as described elsewhere herein, may in some embodiments be any suitable amine protecting group, including a protecting group comprising a carbamate. In some embodiments, PG is Boc, CBz, FMOC, PMB, Troc, benzyl, or methyl carbamate. In some embodiments, PG is Boc, CBz, or FMOC. In certain embodiments, PG is Boc. LG may be any suitable leaving group that converts a hydroxyl to an improved leaving group. In some embodiments, the leaving group is a sulfonate of the formula -S(O)2R, wherein R is a Ci-Docket No.: P39382-WO-1 ealkyl or an aryl unsubstituted or substituted by one or more Ci-ealkyl or Ci-ehaloalkyl. In some embodiments, the leaving group is p-toluenesulfonate (tosylate, or Ts), or is methanesulfonate (mesylate, or Ms). In some embodiments, the leaving group is Ts.Preparing Compound 9

[0090] Provided herein are methods of preparing compound 9 or a salt thereof. Such methods comprise combining compound 8 with ammonium hydroxide to produce compound 9 or a salt thereof.

[0091] In some embodiments, the methods comprise forming a reaction mixture comprising compound 8, ammonium hydroxide, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising compound 9 or a salt thereof. In some embodiments, the solvent system predominantly comprises an alcohol solvent. In some embodiments, the solvent system predominantly comprises a Ci-ealkyl-OH solvent. In some embodiments, the reaction mixture is reacted a temperature between 50°C to 110°C, or between 60°C to 100°C, or between 70°C to 90°C, or between 75°C to 85°C, such as about 80°C, or about 75°C, or about 70°C, or between 60°C to 80°C, to form a reaction product mixture comprising compound 9 or salt thereof.

[0092] In some embodiments, after the formation of compound 9, compound 9 is combined with an acid or acid salt. Without wishing to be bound by any theory, in some embodiments adding an acid or acid salt to compound 9 may improve the ability to isolate compound 9 (or salt thereof) compared to compound 9 without the presence of an acid or acid salt. In some embodiments, the acid is an organic acid or a mineral acid; and the acid salt is an organic acid salt. In some embodiments, compound 9 is combined with oxalic acid, fumaric acid, L- tartaric acid, succinic acid, methansulfonic acid, acetic acid, oxalic acid, tartaric acid, or HC1, HBr. In some embodiments, compound 9 is combined with an acid at a ratio of 3: 1 to 1 :6, such as 2: 1 to 1 :4, or 3:2 to 1 :3, or 1 :1 to 1 :2, or 1 : 1 to 1 :3. In some embodiments, compound 9 is combined with acetic acid or tartaric acid. In some embodiments, compound 9 isDocket No.: P39382-WO-1 combined with acetic acid or tartaric acid in a polar aprotic organic solvent at a temperature between 0°C to 20°C to produce compound 10, wherein the ratio of compound 9 to acetic acid or tartaric acid is 2: 1 to 1 :6, or 1 : 1 to 1 :3, or about 2: 1 to 1 :2, or about 3:2 to 2:3. In some embodiments, compound 9 is combined with tartaric acid. In some embodiments, the ratio of tartaric acid to compound 9 is about 3:2 to 2:3.[0093J As will be appreciated by one of skill in the art, the methods provided herein may be combined in sequence to form longer methods of preparing compounds. For example, provided herein are methods of preparing compound 9 or a salt thereof, comprising: reducing compound 5 to produce compound 6:reducing compound 6 to produce compound 7 :reacting compound 7 with a leaving group reagent to produce compound 8and reacting compound 8 with ammonium hydroxide to produce compound 9 or a salt thereof:Docket No.: P39382-WO-1wherein PG is a protecting group, LG is a leaving group, and R5is Ci-ealkyl or Ci-ehaloalkyl.|0094 | Also provided is a method of producing compound 100, or a salt thereof:the method comprising: reacting compound 4 or salt thereof with compound 9 or salt thereof to produce compound 11 :cyclizing compound 11 to produce compound 12:and reducing compound 12 to produce compound 100, or a salt thereof:Docket No.: P39382-WO-1100. wherein:PG and PG1are independently protecting groups; andR4ais =0 and R4bis H; or R4ais -OH and R4bis -SO3H.[0 95J Further provided herein is a method of producing compound 4 or a salt thereof, comprising: reacting compound 1 with compound 13 to produce compound 2:reacting compound 2 with a protecting group reagent to produce compound 3:and reducing compound 3 to produce compound 4 or a salt thereof:wherein:R1is Ci-ealkyl; n is an integer from 1 to 3;R4ais =0 and R4bis H; or R4ais -OH and R4bis -SO3H; and PG1is a protecting group.Docket No.: P39382-WO-1

[0096] In some embodiments, compound 100 or salt thereof may be prepared according to the method depicted in FIG. 1. FIG. 2 provides further specific embodiments of a synthetic scheme to produce a salt of a compound of 100, in addition to detailed schemes to produce intermediates, such as compounds 11 and 8. Without wishing to be bound by theory, the previous route developed for the preparation of compound 100, or a salt thereof (including compound 101, or salt thereof), had an overall yield of less than 10% over 9 synthetic steps. In contrast, the methods and processes herein provide compound 100 or salt thereof (such as compound 101 or salt thereof) with an overall yield of greater than 20% over 7 synthetic steps. This more than doubling of total yield and decrease of synthetic complexity is in addition to an improved better mass intensity using the present process.

[0097] Additional embodiments and details about each of the steps of these multi-step processes are described in detail throughout the specification.EXAMPLES

[0098] Abbreviations used in the following examples may include:DCM: dichloromethaneDEA: diethylamineDIPEA: N,N-diisopropylethylamineDMAP: 4-dimethylaminopyridineDMF: dimethylformamide DMSO: dimethyl sulfoxide EtOAc: ethyl acetate EtOH: ethanolHO Ac: acetic acidHPLC: high performance liquid chromatography IPA: isopropanol IPC: in process controlLCMS: liquid chromatography -mass spectrometryMeOH: methanolMsCl: methanesulfonyl chloride MTBE: methyl tert-butyl ether NBS: N-bromosuccinimide NMR: nuclear magnetic resonanceDocket No.: P39382-WO-1PTSA: p-toluenesulfonic acidTBAF: tetra-n -butylammonium fluorideTBHP: tert-butyl hydroperoxi deTBSC1: tert-butyl dimethyl silyl chlorideTEA: triethylamineTFA: trifluoroacetic acidTFAA: trifluoroacetic anhydrideTHF: tetrahydrofuranTLC: thin layer chromatography prep-TLC: preparative thin layer chromatographySFC: supercritical fluid chromatography

[0099] FIG. 1 shows the synthetic pathway in overview. Other steps to prepare various starting materials are described elsewhere herein.Example 1: Synthesis of sodium (2S)-2-(benzyloxy)-l-hydroxypropane-l-sulfonate (Compound 200)

[0100] The compound sodium (2S)-2-(benzyloxy)-l-hydroxypropane-l-sulfonate(Compound 200) was prepared following a synthesis adapted from Li et al., Organic Process Research & Development 2019 23 (10), 2253-2260. Compound 200 can also be synthesized following a synthesis adapted from Enders et al., Org. Synth. 2002, 78, 177.Example 2: Synthesis of l-(tert-butyl) 2-ethyl (R)-2,3-dihydro-lH-pyrrole-l,2- dicarboxylate (Compound 202)Boc2) TFAA / DIPEA; cat. DMAP Boc 201-70 to 25°C 202

[0191] The procedure to produce Compound 202 was adapted from Yu et al., Tetrahedron Letters, Volume 46, Issue 23, 6 June 2005, Pages 4011-4013.[0.102] To a flask was added 1 -(tert-butyl) 2-methyl (R)-5-oxopyrrolidine-l,2-dicarboxylate (Compound 201; 60 g, 230.868 mmol, 1.0 equiv.) and toluene (420 mL, 7 vol.) under N2. TheDocket No.: P39382-WO-1 reaction mixture was cooled to (-70)-(-80) °C. LiEtsBH (1 M in THF, 230.9 mL, 230.868 mmol, 1.0 equiv.) was added dropwise at (-70)-(-80) °C and the reaction mixture was stirred at (-70) to (-80) °C for 1 h. A sample was taken for IPC showing no Compound 201 remained. DMAP (282.1 mg, 2.309 mmol, 0.01 equiv.) dissolved in THF (6 mL, 0.1 vol.) was added dropwise at (-70) to (-80) °C. DIPEA (170.07 g, 1.316 mol, 5.7 equiv.) was added dropwise via a syringe at (-70) to (-80) °C. TFAA (58.19 g, 277.04 mmol, 1.2 equiv.) was added dropwise at (-60) to (-70) °C before the reaction mixture was warmed to 20-25 °C and stirred for 2 h. A sample was taken for IPC, showing 94.03 A% of 1 -(tert-butyl) 2-ethyl (R)- 2,3-dihydro-lH-pyrrole-l,2-dicarboxylate (Compound 202). The reaction mixture was cooled to (-5) to 0 °C. The reaction mixture was quenched by slow addition of water (600 mL, 10 vol.). After phase separation, the aqueous layer was extracted with toluene (300 mL, 5 vol.). The organic phase was washed twice with water (600 mL, 10 vol. x 2). After phase separation, the organic phase was dried over Na2SC>4. Filtered and the filtrate was solventswapped with toluene for five times to provide 271.88 g (96.4 A %, 17.8 wt%, KF: 700 ppm) of crude 1 -(tert-butyl) 2-ethyl (R)-2,3-dihydro-lH-pyrrole-l,2-dicarboxylate (Compound 202) in toluene solution in 86.9% corrected yield.

[0103] 'H NMR (400 MHz, DMSO-tL) 8 6.56-6.50 (m, 1H), 5.02-4.97 (m, 1H), 4.58-4.55 (m, 1H), 4.16-4.08 (m, 3H), 3.05 (m, 1H), 2.58-2.50 (m, 1H), 1.42-1.35 (m, 9H), 1.21-1.16 (m, 3H. LCMS: calculated for C12H19O4N [M+H-tBu]+: 185.1, found: 185.1Example 3: Synthesis of tert-butyl (R)-2-(hydroxymethyl)-2,3-dihydro-lH-pyrrole-l- carboxylate (Compound 203)Boc 5 °C Boc202 203

[0104] To a flask was added 1 -(tert-butyl) 2-ethyl (R)-2,3-dihydro-lH-pyrrole-l,2- dicarboxylate (Compound 202; 258.43 g toluene solution, 46 g, 190.64 mmol, 1.0 equiv.) under N2. The reaction mixture was cooled between -10 to 0°C before LiAlH4 (1 M in THF, 190.64 mL, 190.64 mmol, 1.0 equiv.) was added dropwise between -10 to 0°C. The mixture was stirred for 1 h between -10 to 0°C before a sample was taken for IPC, showing 94.66 A% of tert-butyl (R)-2-(hydroxymethyl)-2,3 -dihydro- IH-pyrrole-l -carboxylate (Compound 203) with 0.15 A% of Compound 202 remaining. The mixture was quenched with H2O (7.2 mL,Docket No.: P39382-WO-10.157 vol.) between -10 to 0°C. Note: a large amount of hydrogen was released. To the mixture was added 15% aqueous sodium hydroxide (7.2 mL, 0.157 vol.) between -10 to 0°C followed by H2O (21.7 mL, 0.472 vol. The mixture was warmed to 20-25°C and stirred for 30 min. To the mixture was added anhydrous sodium sulfate (46 g, 1 wt / wt) and stirred for 15 min. The mixture was filtered and the cake was washed with toluene (240 mL, 5vol.x2). The combined organic phase was washed with H2O (480 mL, 10 vol.). After phase separation, the aqueous phase was extracted with toluene (240 mL, 5 vol. x 2). After phase separation, the combined organic phase was washed with saturated aqueous Rochelle salt solution (480 mL, 10 vol.). After phase separation, the organic phase was washed with brine (480 mL, 10 vol.). The combined organic phase was dried over Na2SC>4, filtered, and the filtrate was concentrated to afford 35.16 g of crude Compound 203 (95.24 A%) in quantitative yield.

[0105] 'H NMR (400 MHz, DMSO-tL) 8 6.44-6.39 (m, 1H), 4.98-4.95 (m, 1H), 4.78 (s, 1H), 4.03-4.02 (m, 1H), 3.51 (s, 1H), 3.33-3.31 (m, 1H), 2.56-2.50 (m, 1H), 2.50-2.49 (m, 1H). 1.39 (s, 9H). LCMS: calculated for CIOHI503N [M+H+MeCN]+: 263.0, found: 263.0Example 4: Step 6: tert-butyl (R)-2-((tosyloxy)methyl)-2,3-dihydro-lH-pyrrole-l- carboxylate (Compound 204)Et3N (2.5 eq)

[0106] To a flask was added tert-butyl (R)-2-(hydroxymethyl)-2,3-dihydro-lH-pyrrole-l- carboxylate (Compound 203; 34.44 g, 155.94 mmol, 1.0 equiv.) and CH2CI2 (516.6 mL, 15 vol.) under Ar. The mixture was cooled to between -5 and 0°C before E ?N (39.45 g, 389.86 mmol, 2.5 equiv.) was added to the mixture. DMAP (2.886 g, 23.625 mmol, 0.1515 equiv.) was added to the mixture followed by TsCI (39.54 g, 207.405 mmol, 1.25 equiv.). The reaction mixture was stirred between -5 to 0°C for 5 min and then warmed to 20-25°C for 2 h. A sample was taken for IPC, showing 94.23 A% of tert-butyl (R)-2-((tosyloxy)methyl)- 2,3-dihydro-lH-pyrrole-l-carboxylate (Compound 204) with 0.33 A% of Compound 203 remaining. The mixture was cooled to between -5 to 0°C and H2O (344 mL, 10 vol.) was added. After phase separation, the aqueous phase was extracted with CH2CI2 (344 mL, 10 vol. x 2). The organic phase was washed with aqueous citric acid (10 wt%, 344 mL, 10 vol. x 2). After phase separation, the organic phase was washed with NaHCCL (5 wt%, 45 mL, 10 vol.).Docket No.: P39382-WO-1After phase separation, the organic phase was washed with brine (344 mL, 10 vol.). The organic phase was dried over Na2SC>4. Filtered and the filtrate were concentrated to afford 59.63 g of crude Compound 204 (94.5 A%, 92 wt%) in 99.5% corrected yield.[0.167] To a flask with over-head stirring was added the crude Compound 204 (58.6 g, 152.54 mmol, 1.0 equiv.), and EtOH (293 mL, 5.0 vol.) under N2. The reaction mixture was stirred at 10-20°C for 20 min before charging H2O (293 mL, 5.0 vol.) via syringe pump for 2 h. Note: The mixture becomes cloudy. The reaction mixture was aged at 5-10°C for 15 h before being filtered at 6°C. The solid was dried under reduced pressure to afford 53.37 g of Compound 204 (95.4 A%, 95.99 wt%) in 95% corrected yield. The total isolation yield is 94.5%.[01 BJ Characterization data for tert-butyl (R)-2-((tosyloxy)methyl)-2,3-dihydro-lH- pyrrole-1 -carboxylate (Compound 204): 'H NMR. (400 MHz, DMSO) 8 7.75 (d, J= 8.0 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 6.46 - 6.28 (m, 1H), 5.04 - 4.88 (m, 1H), 4.30 - 3.93 (m, 3H), 2.89 - 2.68 (m, 1H), 2.41 (s, 3H), 2.37 - 2.24 (m, 1H), 1.43 - 1.23 (m, 9H).13C NMR (101 MHz, DMSO) 6 150.7, 145.0, 132.0, 130.2, 129.4, 127.5, 106.6, 79.9, 70.3, 69.8, 54.7, 32.9, 31.6, 27.8, 21.1. HRMS (ESI) m / z: [M + Na]+Calcd for Cn^NOsNaS 376.1195; Found 376.1182.Example 5: Synthesis of tert-butyl (R)-2-(aminomethyl)-2,3-dihydro-lH-pyrrole-l- carboxylate (Compound 205)Boc Boc204 205

[0109] To an autoclave was added tert-butyl (R)-2-((tosyloxy)methyl)-2,3-dihydro-lH- pyrrole-1 -carboxylate (Compound 204; 45.4 g, 128.46 mmol, 1.0 equiv.) and EtOH (299.6 mL, 6.6 vol.). Ammonium hydroxide solution (25wt%, 1498.2 mL, 33 vol.) was added to the mixture before being heated to 80-82°C for 6 h. A sample was taken for IPC, showing 92.4 A% of tert-butyl (R)-2-(aminomethyl)-2,3-dihydro-lH-pyrrole-l-carboxylate (Compound 205) with no Compound 204 remaining. The mixture was extracted with CH2Q2 (504 mL, 10 vol. x 3). The combined organic phase was washed with brine (504 mL, 10 vol.). The organic phase was dried over Na2SC>4, filtered, and the filtrate was concentrated to afford 25.58 g ofDocket No.: P39382-WO-1 crude tert-butyl (R)-2-(aminomethyl)-2,3-dihydro-lH-pyrrole-l-carboxylate (Compound 205; 93.6 A%) in 90.5% uncorrected yield.

[0110] JHNMR (400 MHz, DMSO-tZe) 8 6.41 (m, 1H), 4.95 (m, 1H), 3.95 (s, 1H), 2.75- 2.62 (m, 2H), 2.55-2.51 (m, 1H), 2.49-2.45 (m, 1H), 1.41 (s, 9H). LCMS: calculated for CIOHI802N2 [M+H]+: 199.1, found: 199.1Example 6: Synthesis of tert-butyl (R)-2-(aminomethyl)-2,3-dihydro-lH-pyrrole-l- carboxylate acetic acid salt (Compound 206)[I / "'\ AcOH (1.2 eq) N NH2- ►Boe MTBE, 10°C, 18 h Boc205 206

[0111] To a flask with over-head stirring was added tert-butyl (R)-2-(aminomethyl)-2,3- dihydro-lH-pyrrole-l-carboxylate (Compound 205; 18.99 g, 95.778 mmol, 1.0 equiv.) and MTBE (190 mL, 10 vol.) under N2. The mixture was cooled with a water bath to 10-15°C and acetic acid (6.902 g, 114.934 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at 10-15°C for 16 h, cooled to 8°C, filtered and the cake was washed with MTBE / n-Heptane (1 : 1, 38 mL, 2 vol.x2). The off-white solid was dried to afford 18.32 g of tert-butyl (R)-2- (aminomethyl)-2,3-dihydro-lH-pyrrole-l-carboxylate acetic acid salt (Compound 206; 99.74 A%, 97.09 wt%) in 81.1% corrected yield.

[0112] 1H NMR (400 MHz, DMSO-t / 6) 6 6.41 (m, 1H), 5.99 (s, 3H) 4.97 (m, 1H), 4.04 (s, 1H), 2.79-2.60 (m, 2H), 2.57 (m, 1H), 2.50-2.47 (m, 1H), 1.83 (s, 3H), 1.42 (s, 9H). LCMS: calculated for C10H18O2N2 [M+H]+: 199.1, found: 199.2Example 7: Synthesis of tert-butyl (R)-2-((((S,E)-2- (benzyloxy)propylidene)amino)methyl)-2,3-dihydro-lH-pyrrole-l-carboxylate (Compound 207)Docket No.: P39382-WO-1[01 HJ To a 30 L reactor at 5 °C was charged (2S)-2-(benzyloxy)-l-hydroxypropane-l- sulfonate (Compound 206; 1.0 kg, 3.82 mol, 1.0 equiv.), MTBE (10 L), and an aqueous 10 wt% sodium carbonate solution (7.4 L). The mixture stirred at 5 °C then (R)-2- (aminomethyl)-2,3-dihydro-lH-pyrrole-l-carboxylate acetic acid salt (Compound 200, 1.2 kg, 3.87 mol, 1.0 equiv.) was charged followed by MTBE (1 L). The reactor was warmed to 10 °C, stirred for a minimum of 1 h, and checked for completeness [(A)-2-(aminomethyl)-2,3- dihydro-lH-pyrrole-l-carboxylate acetic acid salt <5%], Agitation was stopped and the layers were separated. The solution was then held overnight at -20 °C. The mixture was distilled to ~10 L total volume (70 mBar, Tintemai <15 °C) then the organic was dried by azeotropic distillation (~20 L MTBE, 70 mBar, Tintemai < 15 °C) while maintaining a constant total volume of ~10 L (10V). The resulting organic was then drained and polish-filtered into an ice-lined carboy to measure the concentration and crude mass of (R)-2-((((S,E)-2- (benzyloxy)propylidene)amino)methyl)-2,3-dihydro-lH-pyrrole-l-carboxylate (Compound 207) as a solution in MTBE (13.9 w / w% or 118.6 mg / mL and 5.8 kg). 806 g of (R)-2- ((((S,E)-2-(benzyloxy)propylidene)amino)methyl)-2,3-dihydro-lH-pyrrole-l-carboxylate (Compound 207)was obtained in 61% uncorrected yield.[0.114] Characterization data for tert-butyl (R)-2-((((S,E)-2- (benzyloxy)propylidene)amino)methyl)-2,3-dihydro-lH-pyrrole-l-carboxylate: 'H NMR. (400 MHz, DMSO) 8 7.63 - 7.53 (m, 1H), 7.39 - 7.24 (m, 5H), 6.49 - 6.32 (m, 1H), 5.04 - 4.87 (m, 1H), 4.51 (d, J= 11.9 Hz, 1H), 4.43 (d, J= 12.0 Hz, 1H), 4.32 - 4.15 (m, 1H), 4.03 - 3.88 (m, 1H), 3.69 - 3.59 (m, 1H), 3.53 - 3.40 (m, 1H), 2.85 - 2.69 (m, 1H), 2.48 - 2.37 (m, 1H), 1.42 (s, 9H), 1.20 (d, J= 6.5 Hz, 3H).13C NMR (101 MHz, DMSO) 6 168.0, 151.0, 150.5, 138.4, 129.3, 128.1, 127.5, 127.3, 106.6, 79.4, 75.6, 69.9, 62.6, 61.4, 56.4, 33.9, 32.7, 27.9, 18.2. HRMS (ESI) m / z: [M + H]+Calcd for C20H29N2O3 345.2173; Found 345.2172.Example 8: (lS,2S,5R)-2-((S)-l-(benzyloxy)ethyl)-8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-ium maleate (Compound 208)M d 10 l % Boc207 208

[0115] Small scale reaction: To a flask was added tert-butyl (R)-2-((((S,E)-2-(benzyloxy)propylidene)amino)methyl)-2,3-dihydro-lH-pyrrole-l-carboxylate (CompoundDocket No.: P39382-WO-1207; 1.50 g, 86.5 wt%, 3.77 mmol, 1.0 equiv.) and zPrOH (60 mL, 40 vol.) under nitrogen. Mn(dpm)s (263 mg, 0.43 mmol, 0.10 equiv.) was added, followed by phenylsilane (1.08 mL, 8.69 mmol, 2.0 equiv.) and Zcz7-butyl hydroperoxi de (5 M in nonane, 0.87 mL, 4.40 mmol, 1.0 equiv.). The reaction mixture was stirred at 30°C for 1.5 h, then cooled to 20°C. Sodium bisulfite (784 mg, 8.71 mmol, 2.0 equiv.) was added and the mixture was stirred for 5 min. The mixture was filtered and the filtrate concentrated to dryness. zPrOAc (60 mL, 40 vol.) and brine (30 mL, 20 vol.) were added and stirred. After phase separation, the organic phase was dried over MgSCU, filtered and the filtrate was concentrated to dryness. The residue was dissolved in MTBE (15 mL, 10 vol.) and Maleic acid (306 mg, 2.64 mmol, 0.7 equiv.) was added. The mixture was stirred at 55 °C for 2 h, then cooled to 20°C and stirred for 1 h, then cooled to 0°C and stirred for 1 h. The suspension was filtered and the solids washed with MTBE (5 mL). After drying in vacuum oven at 60°C, 670 mg of (lS,2S,5R)-2-((S)-l- (benzyloxy)ethyl)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2. l]octan-3-ium maleate was obtained as an off-white solid in 38% uncorrected yield and 98.5 A% purity.[0116J Larger scale reaction: To a 60 L reactor containing Mn(dpm)s (213.8 g, 0.351 mol, 0.10 equiv.) was added 2-propanol (6.1 L). The mixture stirred at 30 °C while a solution of (R)-2-((((S,E)-2-(benzyloxy)propylidene)amino)methyl)-2,3-dihydro-lHpyrrole-l- carboxylate (Compound 207, 1.218 kg, 3.54 mmol, 1.0 equiv.) in MTBE (21 wt %) was added over the course of 1 hour together with separate streams containing phenylsilane (669.7 g, 6.18 mol, 1.75 equiv.) in 2-propanol (6.1 L) and ZcvZ-butyl hydroperoxi de (70 wt % in water, 455.2 g, 3.56 mol, 1.0 equiv.) in 2-propanol (6.1 L). Once the addition was complete, the reaction mixture was stirred at 30 °C for 1 h and checked for completeness [(R)-2-((((S,E)-2-(benzyloxy)propylidene)amino)methyl)-2,3-dihydro-lH-pyrrole-l- carboxylate (Compound 207) <2%] before being cooled to 20 °C. Sodium bisulfite solution (169.8 g, 0.884 mol, 0.25 equiv.) in water (600 mL) was added and the mixture was stirred overnight at 10 °C. The mixture was distilled to ~3 L (70 mBar, Tintemai <35 °C) before 2- MeTHF (~30 L) was added and then contents distilled down to 8V (~10 L). The reactor was then charged with 20 wt % sodium chloride in water (12.8 kg) and agitated for 30 minutes before allowing the layers to separate. The aqueous phase was removed [(lS,2S,5R)-2-((S)-l- (benzyloxy)ethyl)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-ium maleate (Compound 208) Loss <0.1 %] and the organic was dried by azeotropic distillation (~20 L MeTHF, 70 mBar, Tintemai < 35 °C) to ~10 L (8V) total volume. The suspension was then filtered and stirred at 20 °C before being charged with maleic acid (410.4 g, 3.53 mol, 1Docket No.: P39382-WO-1 equiv). The mixture was stirred at 20 °C for 0.5 h, before being seeded with 1 wt % (lS,2S,5R)-2-((S)-l-(benzyloxy)ethyl)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan- 3-ium maleate (Compound 208) seeds and stirred for 1 h. Heptane (2.05 kg) was then charged to the reactor and the suspension was cooled to 0 °C over the course of 3 hours. The suspension was then aged at this temperature for 64 h. The suspension was transferred to a filter drier and the solids washed with MeTHF / heptane (3: 1 v / v, ~3 L). After drying in the filter drier at 30 °C for 18 h with a nitrogen sweep / vacuum pull, 775.1 g of (lS,2S,5R)-2- ((S)-l-(benzyloxy)ethyl)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-ium maleate (Compound 208) was discharged as an off-white microcrystalline in 47 % uncorrected yield and 99.0 A% purity.

[0117] Characterization data for tert-butyl (lS,2S,5R)-2-((S)-l-(benzyloxy)ethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (freebase): 'H NMR. (400 MHz, CDCh) 8 7.36 - 7.25 (m, 5H), 4.61 (d, J= 11.0 Hz, 1H), 4.42 (d, J= 11.0 Hz, 1H), 4.24 - 3.89 (m, 2H), 3.43 - 3.27 (m, 1H), 3.02 - 2.73 (m, 2H), 2.70 (dd, J= 11.0, 2.3 Hz, 1H), 2.32 (br s, 1H), 1.95 - 1.79 (m, 3H), 1.77 - 1.65 (m, 1H), 1.46 (s, 9H), 1.27 - 1.18 (m, 3H).13C NMR (101 MHz, CDCh) 6 153.5, 138.4, 128.4, 127.8, 127.6, 79.3, 76.9, 71.2, 71.0, 64.1, 63.2, 55.9, 55.2, 54.6, 53.8, 50.6, 50.1, 28.5, 27.8, 27.3, 24.4, 23.7, 15.6. HRMS (ESI) m / z: [M + H]+Calcd. for C20H31N2O3 347.2329; Found 347.2326.Example 9: (lS,2S,5R)-8-(tert-butoxycarbonyl)-2-((S)-l-hydroxyethyl)-3,8- diazabicyclo [3.2.1] octan-3-ium succinate75 °C, 16 h208

[0118] To a flask was added (lS,2S,5R)-2-((S)-l -(benzyl oxy)ethyl)-8-(tert- butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-ium maleate (Compound 208; 1.0 g, 2.05 mmol, 1.0 equiv.) and succinic acid (0.243 mg, 2.05 mmol, 1 eq). The flask was purged with N2 and zPrOH (10 mL, 10 V) was added. Pearlman's catalyst (100 mg, 10 wt %) was then added, followed by y-terpinene (3.1 mL, 20.5 mmol, 12 equiv.) and the mixture stirred at 75°C for 16 h under N2 atmosphere. After completion, the reaction was then filtered through a pre-packed Celite® filter. Product remained present in the filter cake. The filter cake wasDocket No.: P39382-WO-1 reslurried in zPrOH (10 V) at 65°C for 30 min, filtered quickly, leading to a light yellow filtrate. The filtrate was concentrated in vacuo, dissolved in zPrOH (12 V) and stirred at 60°C for 1 h. The solution was then cooled to 4°C over the course of 5 h and stirred at this temperature for 16 h. The suspension was then filtered and the filter cake rinsed with cold zPrOH (4°C, 2 V) to give (lS,2S,5R)-8-(tert-butoxycarbonyl)-2-((S)-l-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octan-3-ium succinate (Compound 209) in 90% isolated yield as a colorless solid with 100.0 A% purity.

[0119] (1 S,2S,5R)-8-(tert-butoxycarbonyl)-2-((S)-l-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octan-3-ium succinate (Compound 209): 'H NMR (400 MHz, 65 °C, DMSO-t / r,) 8 4.00 (d, J = 5.5 Hz, 1H), 3.88 (d, J = 6.8 Hz, 1H), 3.36 (dt, J = 8.0, 6.0 Hz, 1H), 2.79 (d, J = 11.4, 2.0 Hz, 1H), 2.68 (d, J = 11.4, 2.2 Hz, 1H), 1.92 - 1 ,54(m, 4H), 1.43 (s, 10H), 1.08 (d, J = 6.2 Hz, 3H)

Claims

Docket No.: P39382-WO-1CLAIMSWhat is claimed:

1. A method of producing compound 100, or a salt thereof:the method comprising: reacting compound 4 or salt thereof with compound 9 or salt thereof to produce compound 11 :cyclizing compound 11 to produce compound 12:and reducing compound 12 to produce compound 100, or a salt thereof:Docket No.: P39382-WO-1 wherein:PG and PG1are independently protecting groups; andR4ais =0 and R4bis H; or R4ais -OH and R4bis -SO3H.

2. The method of claim 1 wherein the yield of compound 100 or salt thereof is greater than 80% based on compound 12.

3. The method of claim 1 or 2, wherein the reaction of compound 4 or salt thereof with compound 9 or salt thereof comprises forming a reaction mixture comprising compound 4 or salt thereof, compound 9 or salt thereof, a solvent system comprising a non-polar solvent, and a metal carbonate, and reacting the reaction mixture at a temperature between 0°C to 25 °C to form a product mixture comprising compound 11.

4. The method of claim 3, wherein the solvent system further comprises water.

5. The method of any one of claims 1 to 4, wherein cyclizing compound 11 comprises forming a reaction mixture comprising compound 11, a metal catalyst, a reducing agent, an oxidizer, and a solvent system comprising a protic organic solvent, and producing a reaction product mixture comprising compound 12.

6. The method of claim 5, wherein: the metal catalyst is a Mn catalyst; the catalyst is present at between 1-20 mol% relative to compound 11; the reducing agent is an organosilane; the oxidizer is a peroxide; and the solvent system comprises a Ci-ealkyl alcohol.

7. The method of claim 5, wherein: the metal catalyst is Mn(dpm)s; the reducing agent is PhSiH?; the oxidizer is tert-butyl hydroperoxide; the solvent system comprises isopropyl alcohol and water; and the reaction mixture is reacted at a temperature between 10°C and 35°C.Docket No.: P39382-WO-18. The method of any one of claims 1 to 7, wherein reducing compound 12 comprises forming a reaction mixture comprising compound 12, a palladium catalyst, a transfer hydrogenation reagent, and a solvent system comprising a Ci-ealkyl alcohol, and reacting the reaction mixture to produce a reaction product mixture comprising compound 100 or a salt thereof.

9. The method of claim 8, wherein: the palladium catalyst is palladium (II) hydroxide; the transfer hydrogenation reagent is terpinene; the solvent system predominantly comprises 2-propanol; and the reaction mixture is reacted at a temperature between 60°C and 100°C.

10. The method of claim 9, wherein: the palladium catalyst is present at 1-20 mol.% relative to compound 12; and the transfer hydrogenation reagent is present at a ratio between 6: 1 and 18: 1 relative to compound 12.

11. The method of any one of claims 1 to 10, wherein compound 12 is reduced in the presence of an organic acid, a phosphoric acid, or a mineral acid to form compound 100, or a salt thereof.

12. The method of any one of claims 1 to 11, wherein compound 12 is reduced in the presence of succinic acid, camphoric acid, oxalic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, (S)-mandelic acid, phosphoric acid, tosylic acid, methanesulfonic acid, benzoic acid, hydrochloric acid, or hydrobromic acid, or any combinations thereof, to form compound 100, or a salt thereof.

13. The method of any one of claims 1 to 11, wherein compound 12 is reduced in the presence of succinic acid, wherein the ratio of compound 12 to succinic acid is 1.5: 1 to 1 : 1.5, to produce compound 100 succinate salt.

14. The method of any one of claims 1 to 13, wherein:PG is Boc, CBz, FMOC, Troc, benzyl, p-methoxybenzyl (PMB), or methyl carbamate; andDocket No.: P39382-WO-1PG1is tert-butyldiphenylsilyl (TBDPS), tert-butyldimethyl silyl (TBS), triisopropyl silyl (TIPS), trimethyl silyl (TMS) or triethylsilyl (TES); or PG1is benzyl unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, and amino.

15. The method of any one of claims 1 to 14, wherein compound 4 or a salt thereof is produced by: reacting compound 1 with compound 13 to produce compound 2:reacting compound 2 with a protecting group reagent to produce compound 3 :and reducing compound 3 to produce compound 4 or a salt thereof:wherein:R1is Ci-ealkyl, Ci-ehaloalkyl, or aryl; n is an integer from 1 to 3;R4ais =0 and R4bis H; or R4ais -OH and R4bis -SO3H; and PG1is a protecting group.

16. The method of claim 15, wherein the protecting reagent is a benzylation reagent.

17. The method of claim 15 or 16, wherein the protecting group reagent is benzyl bromide, benzyl chloride, or benzyl trichloroimidate.Docket No.: P39382-WO-118. The method of any one of claims 15 to 17, wherein producing compound 2 comprises forming a reaction mixture comprising compound 1 and compound 13, wherein the ratio of compound 1 to compound 13 is between 1 : 1 and 1 :6; and reacting the reaction mixture at a temperature between 10°C and 40°C to form a reaction product mixture comprising compound 2.

19. The method of any one of claims 15 to 18, wherein producing compound 3 comprises forming a reaction mixture comprising compound 2, a protecting group reagent, a phase transfer agent, an inorganic base, and a solvent system predominantly comprising a non-polar solvent, wherein the ratio of compound 2 to the protecting group reagent is between 1 : 1 and1 :2; and reacting the reaction mixture to form a reaction product mixture comprising compound 3.

20. The method of claim 19, wherein: the phase transfer agent is Aliquat 336, and the Aliquat 336 is present at a loading of 1-10 mol.% relative to compound 2; the inorganic base is NaOH, and the ratio of compound 2 to NaOH is 1 :2 to 1 :7; the solvent system comprises predominantly toluene; the protecting group reagent is a benzylation reagent; and the reaction mixture is reacted at a temperature between 10°C and 30°C to form the reaction product mixture comprising compound 3.

21. The method of any one of claims 15 to 20, wherein compound 3 is reduced by forming a reaction mixture comprising compound 3, sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH), and a solvent system, wherein the ratio of compound 3 to SMEAH is between 1 :2 and 2: 1 and the solvent system comprises ethanol and water; then adding sodium bisulfate.

22. The method of any one of claims 15 to 21, wherein n is 2.

23. The method of any one of claims 15 to 22, wherein n is 2; R4ais -OH and R4bis - SO3H; R1is ethyl, and PG1is benzyl.

24. The method of claim 1, wherein compound 9 or salt thereof is produced by: reducing compound 5 to produce compound 6:Docket No.: P39382-WO-1reducing compound 6 to produce compound 7 :reacting compound 7 with a leaving group reagent to produce compound 8:reacting compound 8 with ammonium hydroxide to produce compound 9 or a salt thereof:wherein R5is Ci-ealkyl or Ci-ehaloalkyl; PG is a protecting group; and LG is a leaving group.

25. The method of claim 24, wherein:PG is Boc, CBz, FMOC, Troc, benzyl, p-methoxybenzyl (PMB), or methyl carbamate;PG1is / c / 7-butyl di phenyl silyl (TBDPS), te / 7-butyldimethyl silyl (TBS), triisopropyl silyl (TIPS), trimethyl silyl (TMS) or triethylsilyl (TES); or PG1isDocket No.: P39382-WO-1 benzyl unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, and amino; andLG is sulfonate of the formula -S(O)2R, wherein R is a Ci-ealkyl or an aryl unsubstituted or substituted by one or more Ci-ealkyl or Ci-ehaloalkyl.

26. The method of claim 24 or 25, wherein reducing compound 5 comprises forming a first reaction mixture comprising compound 5, LiBHEts, and a solvent system predominantly comprising a non-polar solvent; and reacting the first reaction mixture at a temperature between -50°C to -90°C; then combining the first reaction mixture with trifluoroacetic anhydride, diisopropyl ethylamine (DIPEA), and 4-Dimethylaminopyridine (DMAP) to form a second reaction mixture; and reacting the second reaction mixture at a temperature between -70°C to 25°C to form a reaction product mixture comprising compound 6.

27. The method of any one of claims 24 to 26, wherein reducing compound 6 comprises forming a reaction mixture comprising compound 6, lithium aluminum hydride, and a solvent system predominantly comprising a non-polar solvent, wherein the ratio of compound 6 to lithium aluminum hydride is between 1:4 to 1 : 1; and reacting the reaction mixture at a temperature between -15°C to 25°C to form a reaction product mixture comprising compound 7.

28. The method any one of claims 24 to 27, wherein reacting compound 7 with a leaving group reagent comprises forming a reaction mixture comprising compound 7, tosyl chloride, DMAP, and a solvent system predominantly comprising a polar aprotic organic solvent, wherein the ratio of compound 7 to tosyl chloride is between 1 : 1 to 1 :3; and reacting the reaction mixture at a temperature between 0°C to 30°C to form a reaction product mixture comprising compound 8.

29. The method of any one of claims 24 to 28, wherein reacting compound 8 with ammonium hydroxide comprises forming a reaction mixture comprising compound 8, ammonium hydroxide, and a Ci-ealkyl-OH solvent; and reacting the reaction mixture at a temperature between 70°C to 90°C to form a reaction product mixture comprising compound 9 or salt thereof.Docket No.: P39382-WO-130. The method of any one of claims 24 to 29, further comprising forming a reaction mixture comprising compound 9, acetic acid, and a polar aprotic organic solvent, wherein the ratio of compound 9 to acetic acid is 1 : 1 to 1 :3; and reacting the reaction mixture at a temperature between 0°C to 20°C to produce a reaction product mixture comprising compound 9 acetate salt.

31. A compound of formula:, wherein PG and PG1are independently protecting groups.

32. The compound of claim 31, wherein:PG is Boc, CBz, FMOC, Troc, benzyl, p-methoxybenzyl (PMB), or methyl carbamate; andPG1is / c / 7-butyl di phenyl silyl (TBDPS), / cvV-butyldimethyl silyl (TBS), triisopropyl silyl (TIPS), trimethyl silyl (TMS) or triethylsilyl (TES); or PG1is benzyl unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, and amino.

33. The compound of claim 31, wherein PG1is benzyl and PG is Boc.

34. A compound of formula:, wherein PG is a protecting group and LG is a leaving group.

35. The compound of claim 34, wherein:PG is Boc, CBz, FMOC, Troc, benzyl, p-methoxybenzyl (PMB), or methyl carbamate; andDocket No.: P39382-WO-1LG is sulfonate of the formula -S(O)2R, wherein R is a Ci-ealkyl or an aryl unsubstituted or substituted by one or more Ci-ealkyl or Ci-ehaloalkyl.

36. The compound of claim 34, wherein PG is Boc and LG is tosyl.

37. A method of producing a compound of formula 8:the method comprising: reducing compound 5 to produce compound 6:reducing compound 6 to produce compound 7 :reacting compound 7 with a leaving group reagent to produce compound 8:wherein PG is a protecting group, LG is a leaving group, and R5is Ci-ealkyl or Ci-ehaloalkyl.

38. The method of claim 37, wherein compound 5 is reduced by forming a first reaction mixture comprising compound 5, LiBHEts, and a solvent system predominantly comprising a non-polar solvent, and reacting the first reaction mixture is reacted at a temperature between -Docket No.: P39382-WO-150°C to -90°C; then combining the first reaction mixture with trifluoroacetic anhydride, diisopropyl ethylamine (DIPEA), and 4-dimethylaminopyridine (DMAP) to form a second reaction mixture; and reacting the second reaction mixture at a temperature between -80°C to -60°C, then warming to a temperature between 10°C to 40°C, to form a reaction product mixture comprising compound 6.

39. The method of claim 37 or 38, wherein reducing compound 6 comprises forming a reaction mixture comprising compound 6, lithium aluminum hydride, and a solvent system predominantly comprising an non-polar solvent, wherein the ratio of compound 6 to lithium aluminum hydride is between 1 :4 to 1 :1; and reacting the reaction mixture at a temperature between -15°C to 25°C to form a reaction product mixture comprising compound 7.

40. The method of any one of claims 37 to 39, wherein reacting compound 7 with a leaving group reagent comprises forming a reacting group comprising compound 7, tosyl chloride, DMAP, and a solvent system predominantly comprising a polar aprotic organic solvent, wherein the ratio of compound 7 to tosyl chloride is between 1 : 1 to 1 :3; and reacting the reaction mixture at a temperature between 0°C to 30 °C to form a reaction product mixture comprising compound 8.

41. A method of producing the compound of formula 11 :the method comprising: reacting compound 4 or a salt thereof with compound 9 or a salt thereof to produce compound 11 :Docket No.: P39382-WO-1 wherein R4ais =0 and R4bis H; or R4ais -OH and R4bis -SO3H; and PG and PG1are independently protecting groups.

42. The method of claim 41, wherein compound 4 or salt thereof is combined with compound 9 or salt thereof in the presence of an inorganic base and a solvent system comprising a polar aprotic organic solvent and water to form a reaction mixture, and the reaction mixture is reacted at a temperature between 0°C to 20°C to form a reaction product mixture comprising compound 11.

43. The method of claim 41 or 42, wherein compound 9 or a salt thereof is compound 9 acetate salt.

44. The method of any one of claims 41 to 43, wherein:PG is Boc, CBz, FMOC, Troc, benzyl, p-methoxybenzyl (PMB), or methyl carbamate; andPG1is / c / 7-butyl di phenyl silyl (TBDPS), / cvV-butyldimethyl silyl (TBS), triisopropyl silyl (TIPS), trimethyl silyl (TMS) or triethylsilyl (TES); or PG1is benzyl unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, and amino.

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