ENANTIOSELECTIVE SYNTHESIS OF AMINOTROPANE COMPOUND

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application Number 63/188,644, filed May 14, 2021, the entire disclosure of which is hereby incorporated herein by reference.

FIELD

Provided herein are novel processes for preparing tert- butyl (1R,3s,5S)-3-amino-8- azabicyclo[3.2.1]octane-8-carboxylate or a salt thereof. Also provided herein are enantioselective processes for preparing exo-aminotropane derivatives from tropinone oximes.

BACKGROUND

The inflammatory bowel diseases (IBDs), such as ulcerative colitis (UC) and Crohn’s disease (CD), adversely impact the quality of life of patients. The disorders are associated with rectal bleeding, diarrhea, abdominal pain, weight loss, nausea and vomiting, and also lead to an increased incidence of gastrointestinal cancers. The direct and indirect societal costs of IBD are substantial; 2014 estimates for the USA ranged from $14.6 to $31.6 billion, reflecting the deficiencies of available therapies.

Because inhibition of the Janus kinase (“JAK”) family of enzymes could inhibit signaling of many key pro-inflammatory cytokines, JAK inhibitors may be useful in the treatment of UC and other inflammatory diseases such as CD, allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD). However, due to the modulating effect of the JAK/STAT pathway on the immune system, systemic exposure to JAK inhibitors may have an adverse systemic immunosuppressive effect. Therefore, JAK inhibitors that are locally acting at the site of action without significant systemic effects would be particularly beneficial. Thus, for the treatment of gastrointestinal inflammatory diseases, such as UC and CD, it would be desirable to provide efficient, industrially scalable synthetic routes to JAK inhibitors which can be administered orally and achieve therapeutically relevant exposure in the gastrointestinal tract with minimal systemic exposure. It would also, accordingly, be desirable to provide efficient, industrially scalable synthetic routes to starting materials useful in the preparation of such JAK inhibitors.

As discussed in U.S. Patent Nos. 9,725,470 and 10,072,026, 3-((1R,3s,5S)-3-((7- ((5-methyl-1/-/-pyrazol-3-yl)amino)-1,6-naphthyridin-5-yl)am ino)-8-azabicyclo[3.2.1]octan-8- yl)propanenitrile is a potent gut-selective pan- JAK inhibitor that may have clinical potential in inflammatory bowel diseases such as UC and CD. This compound has the following formula:

As discussed above, the ongoing need to treat UC and other inflammatory diseases such as CD demonstrates a need for an efficient, scalable synthetic route to the above-depicted pan-JAK inhibitor, including efficient and scalable processes for preparing starting materials used in its preparation. The processes disclosed herein meet this need by providing a concise, scalable synthetic route to tert- butyl (1R,3s,5S)-3-amino-8- azabicyclo[3.2.1]octane-8-carboxylate or a salt thereof, including the acetic acid salt (1/1), which is a starting material in an industrially scalable, efficient, and sustainable route to the pan-JAK inhibitor. The synthetic route includes a versatile and enantioselective reduction of a tropinone oxime to an exo-aminotropane.

SUMMARY

The present disclosure provides, inter alia, a process for preparing a compound of Formula (lll-A):

Boc

(lll-A), or a salt thereof, comprising combining a compound of Formula (II):

Bo with a nickel catalyst and hydrogen to provide the compound of Formula (lll-A).

In some embodiments, the compound of Formula (II), the nickel catalyst, and the hydrogen are combined in an organic solvent. In some embodiments, the organic solvent comprises tetrahydrofuran (THF) and propylene glycol methyl ether. In other embodiments, the organic solvent comprises about 95% THF and about 5% PGME by volume.

The nickel catalyst can be sponge nickel. In some embodiments, the hydrogen is provided in molar excess with respect to the compound of Formula (II). In other embodiments, the process is performed in neutral pH conditions. In some embodiments, the compound of Formula (lll-A) is provided substantially free of a compound of Formula (lll-B):

In other embodiments, the process is at least 10 times more selective for the compound of Formula (lll-A) than for the compound of Formula (lll-B).

The process can further comprise the step of combining a compound of Formula (I): with hydroxylamine, or a salt thereof, and a Lewis base to provide the compound of Formula (II) prior to combining the compound of Formula (II) with the nickel catalyst and hydrogen.

In some embodiments, the hydroxylamine is hydroxylamine hydrochloride. In other embodiments, the Lewis base is pyridine.

The process can further comprise combining the compound of Formula (lll-A) with acetic acid to provide a compound of Formula (IV):

(IV).

The present disclosure also provides a process for preparing a compound of Formula

(IV): comprising: (a) combining a compound of Formula (I): with hydroxylamine, or a salt thereof, and a Lewis base to provide a compound of Formula (II):

(b) combining the compound of Formula (II) with a nickel catalyst and hydrogen to provide the compound of Formula (lll-A):

(c) combining the compound of Formula (lll-A) with acetic acid to provide the compound of Formula (IV).

The present disclosure also provides a process for preparing a compound of Formula

(VII):

(VII), or a salt thereof, comprising combining a compound of Formula (VI): with a nickel catalyst and hydrogen to provide the compound of Formula (VII); wherein:

X is NR ⁴ , NC(O)R ⁵ , O, S, or CH ₂ ;

R ¹ and R ² taken together form a C ₂ -C ₄ alkyl bridge and R ³ is H, or R ¹ and R ³ taken together form a Ci or C ₃ alkyl bridge and R ² is H;

R ⁴ is benzyl, Boc, or C ₁ -C ₆ alkyl; and R ⁵ is C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; wherein the compound of Formula (VII) is selectively provided as the exo isomer.

In some embodiments, the nickel catalyst and the hydrogen are combined in an organic solvent. In some embodiments, the organic solvent comprises THF and propylene glycol methyl ether. In other embodiments, the nickel catalyst is sponge nickel. In additional embodiments, the process is performed in neutral pH conditions. In some embodiments, the exo isomer of the compound of Formula (VII) is provided substantially free of the endo isomer of the compound of Formula (VII). In some embodiments, the process is at least 4 times more selective for the exo isomer of the compound of Formula (VII) than for the endo isomer of the compound of Formula (VII).

In some embodiments, the process further comprises the step of combining a compound of Formula (V): with hydroxylamine, or a salt thereof, and a Lewis base to provide the compound of Formula (VI) prior to combining the compound of Formula (VI) with the nickel catalyst and hydrogen. In some embodiments, the hydroxylamine is hydroxylamine hydrochloride. In some embodiments, the Lewis base is pyridine.

In some embodiments, the compound of Formula (VI) has a structure according to Formula (Vl-A): and the compound of Formula (VII) has a structure according to Formula (Vll-A): wherein: n is 2, 3, or 4;

X is NR ⁴ , NC(O)R ⁵ , O, S, or CH ₂ ;

R ⁴ is benzyl, Boc, or C ₁ -C ₆ alkyl; and

R ⁵ is C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound of Formula (Vll-A) is provided substantially free of a compound of Formula (Vll-B): In some embodiments the process is at least 4 times more selective for the compound of Formula (Vll-A) than for the compound of Formula (Vll-B).

In some embodiments, n is 2 or 3. In some embodiments, X is NR ⁴ or NC(O)R ⁵ , and when n is 3, X is not N-Bn. In some embodiments of this synthesis, R ⁴ is benzyl, Boc, or methyl. In some embodiments, R ⁵ is phenyl, methyl, or trifluoromethyl.

In some embodiments, X is selected from the group consisting of:

In some embodiments, X is selected from the group consisting of: _ provided that when n is 3, X is not

DETAILED DESCRIPTION

1) General

Disclosed herein are processes for preparing the compound of Formula (IV) according to the following scheme:

The processes disclosed herein are suitable for performance at an industrial scale and proceed with high yield and purity of each intermediate. Further, the compound of Formula (lll-A) is provided with high exo selectivity.

2) Definitions

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a solvent” includes a combination of two or more such solvents, reference to “a base” includes one or more bases, or mixtures of bases, and the like. Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive and covers both “or” and “and.”

Unless specifically stated otherwise or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.”

Unless specifically stated otherwise or obvious from context, as used herein, the term “substantially” is understood as within a narrow range of variation or otherwise normal tolerance in the art. Substantially can be understood as within 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01% or 0.001% of the stated value.

As used herein “substantially free of” refers to a compound of the disclosure or a composition comprising a compound of the disclosure containing no significant amount of such other compound, crystalline form or amorphous solid form identified herein. For example, an isolated compound of the disclosure can be substantially free of a given impurity when the isolated compound constitutes at least about 95% by weight of the compound, or at least about 96%, 97%, 98%, 99%, or at least about 99.5% by weight of the compound.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although other methods and materials similar, or equivalent, to those described herein can be used in the practice of the present invention, the preferred materials and methods are described herein.

The term “alkyl” refers to a straight- or branched-chain alkyl group having the indicated number of carbon atoms in the chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. The term C1-C3 alkyl as used herein refers to a straight- or branched-chain alkyl group having from 1 to 3 carbon atoms in the chain. The term C1-C6 alkyl as used here refers to a straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain.

The term “haloalkyl” is used in its conventional sense, and refers to an alkyl group, as defined herein, substituted with one or more halo substituents. Examples of haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

The terms “halo” or “halogen” represent chloro, fluoro, bromo, or iodo. The term “aryl,” unless otherwise stated,” refers to a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Examples of aryl groups include phenyl, naphthyl, anthracenyl.

As used herein, the term “solvate” refers to a complex formed by the combining of a compound of the disclosure and a solvent. The term includes stoichiometric as well as non- stoichiometric solvates and includes hydrates.

As used herein, the term “hydrate” refers to a complex formed by the combining of a compound of the disclosure and water. The term includes stoichiometric as well as non- stoichiometric hydrates.

The present disclosure also includes salt forms of the compounds described herein. Examples of salts (or salt forms) include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference in its entirety.

The compounds of the disclosure may, accordingly, be used or synthesized as free bases, solvates, hydrates, salts, or as combination salt-solvates or salt-hydrates.

The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. In some embodiments, reactions can be carried out in the absence of solvent, such as when at least one of the reagents is a liquid or gas.

As used herein, “organic solvent” refers to any solvent that contains one or more carbon-hydrogen bonds. Example nonlimiting organic solvents include hexane, heptane, tetrahydrofuran, dichloromethane, methanol, ethanol, isopropanol, ethyl acetate, propylene glycol methyl ether, A/./V-dimethylformamide, A/./V-dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile, and the like.

As used herein, “protic solvent” refers to any solvent that contains a labile hydrogen atom. Typically, the labile hydrogen atom is bound to an oxygen (as in a hydroxyl group), a nitrogen (as in an amino group), or a sulfur (as in a thiol group). Suitable protic solvents can include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2- methoxyethanol, 1 -butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, propylene glycol methyl ether, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.

As used herein, “aprotic solvent” refers to any solvent that does not contain a labile hydrogen atom. Suitable aprotic solvents can include, by way of example and without limitation, tetrahydrofuran (THF), A/./V-dimethylformamide (DMF), A/./V-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2- imidazolidinone (DMI), /V-methylpyrrolidinone (NMP), formamide, /V-methylacetamide, N- methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N- dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.

The reactions of the processes described herein can be carried out at appropriate temperatures which can be readily determined by the skilled artisan. Reaction temperatures will depend on, for example, the melting and boiling points of the reagents and solvent, if present; the thermodynamics of the reaction (e.g., vigorously exothermic reactions may need to be carried out at reduced temperatures); and the kinetics of the reaction (e.g., a high activation energy barrier may need elevated temperatures).

The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan.

In some embodiments, preparation of compounds can involve the addition of acids or bases to effect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.

Example acids can be inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Organic acids include formic acid, acetic acid, propionic acid, butanoic acid, benzoic acid, 4- nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid and decanoic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate. Some example strong bases include, but are not limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides.

As used herein, the term “Lewis base” refers to any species that contains a filled orbital containing an electron pair which is not involved in bonding. Example Lewis bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, pyridine, imidazole, triethylamine, triethylamine, A/,/\/-Diisopropylethylamine (DIPEA), sodium ethoxide, potassium ethoxide, and the like.

Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al. , Protective Groups in Organic Synthesis, 4d. Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. Adjustments to the protecting groups and formation and cleavage methods described herein may be adjusted as necessary in light of the various substituents.

Upon carrying out preparation of compounds according to the processes described herein, isolation and purification operations such as concentration, filtration, extraction, solid- phase extraction, recrystallization, chromatography, and the like may be used, to isolate the desired products.

Specific compounds of the disclosure may be referred to by the following identifiers: tert- Butyl (1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate is referred to, alternately, as a compound of Formula (I) or Compound I:

(I)· tert- Butyl (1R,5S,Z)-3-(hydroxyimino)-8-azabicyclo[3.2.1]octane-8-carbo xylate is referred to, alternately, as a compound of Formula (II) or Compound II:

Boc

(II). tert- Butyl (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate is referred to, alternately, as a compound of Formula (lll-A) or Compound lll-A: tert- Butyl (1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate is referred to, alternately, as a compound of Formula (lll-B) or Compound lll-B:

Acetic acid-terf-butyl (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (1/1) is referred to, alternately, as a compound of Formula (IV) or Compound IV:

3) Processes for preparing the compound of Formula ( IV)

The present disclosure provides, inter alia, processes for preparing a compound of Formula (IV), which is useful as a starting material in the synthesis of the pan-JAK inhibitor (3-((1R,3s,5S)-3-((7-((5-methyl-1/-/-pyrazol-3-yl)amino)-1,6 -naphthyridin-5-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile). In one aspect, the the process comprises an oxime-formation reaction. In another aspect, the process comprises an oxime reduction reaction. In yet another aspect, the process comprises a salt formation reaction.

3.1) Oxime-formation reaction

The compound of Formula (IV) may be formed via condensation of a compound of Formula (I) with hydroxylamine to provide a compound of Formula (II), which can then be converted to a compound of Formula (IV) through additional steps (e.g., oxime reduction and salt formation). Accordingly, in one aspect, the present disclosure provides a process of preparing a compound of Formula (II): comprising combining a compound of Formula (I): with hydroxylamine, or a salt thereof, and a Lewis base to provide the compound of Formula (II).

In some embodiments, the compound of Formula (I), the hydroxylamine, or salt thereof, and the Lewis base are combined in a solvent. In some embodiment, the solvent is a protic solvent. In some embodiments, the solvent comprises water and an alcohol. In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is ethanol or methanol. In some embodiments, the solvent is methanol.

In some embodiments, the hydroxylamine is hydroxylamine hydrochloride.

In some embodiments, the Lewis base has a pK _b greater than about 7. In some embodiments, the Lewis base is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, and pyridine. In some embodiments, the Lewis base is selected from the group consisting of sodium bicarbonate, sodium carbonate, sodium acetate, and pyridine. In some embodiments, the Lewis base is pyridine.

In some embodiments, the molar ratio of the compound of Formula (I) to the hydroxylamine is from about 1:1 to about 1:3. In some embodiments, the molar ratio of the compound of Formula (I) to the hydroxylamine is from about 1:1.5 to about 1:2.5. the molar ratio of the compound of Formula (I) to the hydroxylamine is about 1:2.

In some embodiments, the process is performed at room temperature. In some embodiments, the process is performed at a temperature from about 20 °C to about 25 °C.

In some embodiments, the compound of Formula (I), the hydroxylamine, or salt thereof, and the Lewis base are stirred for about 2 to about 5 hours. In some embodiments, the compound of Formula (I), the hydroxylamine, or salt thereof, and the Lewis base are stirred for about 2 hours.

In some embodiments, the compound of Formula (II) is isolated by filtration. In some embodiments, the compound of Formula (II) is purified by washing with methanol, water, or a mixture thereof.

In some embodiments, the compound of Formula (II) is isolated in high yield. In some embodiments, the compound of Formula (II) is isolated in at least about 85% yield. In some embodiments, the compound of Formula (II) is isolated in at least about 86% yield. In some embodiments, the compound of Formula (II) is isolated in at least about 87% yield. In some embodiments, the compound of Formula (II) is isolated in at least about 88% yield. In some embodiments, the compound of Formula (II) is isolated in at least about 89% yield. In some embodiments, the compound of Formula (II) is isolated in at least about 90% yield.

In some embodiments, the compound of Formula (II) is isolated with high purity. In some embodiments, the high purity is determined via gas chromatography. In some embodiments, the compound of Formula (II) is isolated with at least about 90% purity. In some embodiments, the compound of Formula (II) is isolated with at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% purity. In some embodiments, the compound of Formula (II) is isolated with at least about 95% purity. In some embodiments, the compound of Formula (II) is isolated with at least about 97% purity. In some embodiments, the compound of Formula (II) is isolated with at least about 99% purity.

3.2) Oxime reduction

The compound of Formula (IV) may be formed via a reduction reaction of a compound of Formula (II) to provide a compound of Formula (lll-A), which can then be converted to a compound of Formula (IV) through an additional step (e.g., salt formation). Accordingly, in one aspect, the present disclosure provides a process of preparing a compound of Formula (lll-A): or a salt thereof, comprising combining a compound of Formula (II): with a transition metal catalyst and hydrogen to provide the compound of Formula (lll-A).

In some embodiments, the compound of Formula (II), the transition metal catalyst, and the hydrogen are combined in a solvent. In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent comprises a protic organic solvent. Solvents suitable for use in the methods described herein include, but are not limited to, tetrahydrofuran (THF), propylene glycol methyl ether (PGME), 2-methyltetrahydrofuran, methanol, isopropyl alcohol, and tert- amyl alcohol. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises PGME. In some embodiments, the solvent comprises THF and PGME. In some embodiments, the solvent comprises THF and PGME in a ratio (v/v) ranging from about 5:1 to about 50:1. In some embodiments, the solvent comprises THF and PGME in a ratio (v/v) ranging from about 10:1 to about 40:1. In some embodiments, the solvent comprises THF and PGME in a ratio (v/v) of about 19:1.

In some embodiments, the solvent comprises about 85% to about 99% THF by volume. In some embodiments, the solvent comprises about 90% to about 99% THF by volume. In some embodiments, the solvent comprises about 95% THF by volume.

In some embodiments, the solvent comprises about 1% to about 15% PGME by volume. In some embodiments, the solvent comprises about 1% to about 10% PGME by volume. In some embodiments, the solvent comprises about 5% PGME by volume.

In some embodiments, the solvent comprises about 95% THF and about 5% PGME by volume.

In some embodiments, the transition metal catalyst is a nickel catalyst or a cobalt catalyst. In some embodiments, the transition metal catalyst is a heterogenous catalyst. In some embodiments, the transition metal catalyst is a nickel catalyst. Transition metal catalysts suitable for use in the methods described herein include, but are not limited to, sponge nickel, Raney nickel, sponge cobalt, Raney cobalt, and Ni on S1O2. In some embodiments, the transition metal catalyst is sponge nickel. In some embodiments, the transition metal catalyst is sponge nickel A-5000. In some embodiments, the transition metal catalyst is sponge nickel A-4000. In some embodiments, the transition metal catalyst is sponge cobalt. In some embodiments, the transition metal catalyst is sponge cobalt A-8B46. In some embodiments, the transition metal catalyst is Raney cobalt. In some embodiments, the transition metal catalyst is Ni on S1O2. In some embodiments, the transition metal catalyst is Ni 65% on S1O2.

In some embodiments, the compound of Formula (II) and the transition metal catalyst are combined in a ratio from about 1:0.1 (w/w) to about 1:0.9 (w/w). In some embodiments, the compound of Formula (II) and the transition metal catalyst are combined in a ratio from about 1:0.25 (w/w) to about 1:0.75 (w/w). In some embodiments, the compound of Formula (II) and the transition metal catalyst are combined in a ratio from about 1:0.25 (w/w) to about 1:0.5 (w/w). In some embodiments, the compound of Formula (II) and the transition metal catalyst are combined in a ratio of about 1:0.5 (w/w).

In some embodiments, the hydrogen is provided as hydrogen gas. In some embodiments, the pressure of hydrogen gas is maintained from about 0.5 bar to about 10 bar until the compound of Formula (II) is substantially consumed. In some embodiments, the pressure of hydrogen gas is maintained from about 1 bar to about 10 bar until the compound of Formula (II) is substantially consumed. In some embodiments, the pressure of hydrogen gas is maintained from about 0.5 bar to about 10 bar until the compound of Formula (II) is at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% consumed. In some embodiments, the pressure of hydrogen gas is maintained from about 1 bar to about 10 bar until the compound of Formula (II) is at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% consumed. In some embodiments, the hydrogen is provided in molar excess with respect to the compound of Formula (II).

In some embodiments, the compound of Formula (II), the transition metal catalyst, and the hydrogen are combined without the further addition of a basic additive. In some embodiments, the process for preparing the compound of Formula (lll-A) is performed in neutral pH conditions (e.g., without the addition of acidic or basic reagents). In some embodiments, the process for preparing the compound of Formula (lll-A) is performed from about pH 6 to about pH 8. In some embodiments, the process for preparing the compound of Formula (lll-A) is performed from about pH 6.5 to about pH 7.5.

In some embodiments, the process is performed at a temperature from about 50 °C to about 75 °C. In some embodiments, the process is performed at a temperature from about 50 °C to about 65 °C. In some embodiments, the process is performed at a temperature of about 65 °C.

In some embodiments, the compound of Formula (II), the transition metal catalyst, and the hydrogen are stirred for about 1 to about 18 hours. In some embodiments, the compound of Formula (II), the transition metal catalyst, and the hydrogen are stirred for about 1 to about 10 hours. In some embodiments, the compound of Formula (II), the transition metal catalyst, and the hydrogen are stirred for about 4 hours.

The process described herein for preparing the compound of Formula (lll-A) proceeds with high conversion, high exo-selectivity, and without substantial formation of undesirable side products. Accordingly, in some embodiments, the process for preparing the compound of Formula (lll-A) proceeds with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% conversion of the compound of Formula (II). In some embodiments, the process proceeds with at least 75% conversion of the compound of Formula (II). In some embodiments, the process proceeds with at least 85% conversion of the compound of Formula (II). In some embodiments, the process proceeds with at least 90% conversion of the compound of Formula (II). In some embodiments, the process proceeds with at least 95% conversion of the compound of Formula (II). In some embodiments, the process proceeds with at least 99% conversion of the compound of Formula (II).

In some embodiments, the compound of Formula (lll-A) is produced substantially free of side products. In some embodiments, the compound of Formula (lll-A) is provided substantially free of a compound of Formula (lll-B):

In some embodiments, the process selectively provides the compound of Formula (lll-A) over the compound of Formula (lll-B). In some embodiments, the process is at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times or at least 13 times more selective for the compound of Formula (lll-A) than for the compound of Formula (lll-B). In some embodiments, the process is at least 7 times more selective for the compound of Formula (lll-A) than for the compound of Formula (lll-B). In some embodiments, the process is at least 10 times more selective for the compound of Formula (lll-A) than for the compound of Formula (lll-B). In some embodiments, the process is at least 13 times more selective for the compound of Formula (lll-A) than for the compound of Formula (lll-B).

In some embodiments, the process for preparing the compound of Formula (lll-A) provides less than about 10% by molar yield of the compound of Formula (lll-B). In some embodiments, the process for preparing the compound of Formula (lll-A) provides less than about 9% by molar yield of the compound of Formula (lll-B). In some embodiments, the process for preparing the compound of Formula (lll-A) provides less than about 8% by molar yield of the compound of Formula (lll-B). In some embodiments, the process for preparing the compound of Formula (lll-A) provides less than about 7% by molar yield of the compound of Formula (lll-B).

In some embodiments, the compound of Formula (lll-A) is provided substantially free of a compound of Formula (I):

In some embodiments, the compound of Formula (lll-A) is purified via filtration. Filtration may comprise, for example, pouring the reaction mixture over a bed of diatomaceous earth (e.g., Celite®) and collecting the filtrate.

3.3) Salt formation reaction

The compound of Formula (IV) may be formed by converting the compound of Formula (lll-A) to the corresponding acetate salt. Accordingly, in one aspect, the present disclosure provides a process of preparing a compound of Formula (IV): comprising combining the compound of Formula (lll-A): with acetic acid to provide the compound of Formula (IV).

In some embodiments, the compound of Formula (lll-A) is prepared by the process described hereinabove.

In some embodiments, the compound of Formula (lll-A) and the acetic acid are combined in a solvent. In some embodiments, the solvent is an aprotic solvent. In some embodiments, the solvent is THF. In some embodiments, the solvent is substantially free of water. In some embodiments, the solvent comprises less than about 0.10% water. In some embodiments, the solvent is substantially free of propylene glycol methyl ether (PGME). In some embodiments, the solvent comprises less than about 0.5% PGME.

In some embodiments, the molar ratio of the compound of Formula (lll-A) to the acetic acid is from about 1:1 to about 1:2. In some embodiments, the molar ratio of the compound of Formula (lll-A) to the acetic acid is from about 1:1 to about 1:1.5. In some embodiments, the molar ratio of the compound of Formula (lll-A) to the acetic acid is about 1:1.25.

In some embodiments, the process is performed at a temperature from about 15 °C to about 25 °C. In some embodiments, the process is performed at a temperature from about 15 °C to about 20 °C.

In some embodiments, the compound of Formula (lll-A) and the acetic acid are stirred for about 5 to about 24 hours. In some embodiments, the compound of Formula (lll-A) and the acetic acid are stirred at a temperature of about 20 °C for about 5 to about 20 hours. In some embodiments, the compound of Formula (lll-A) and the acetic acid are stirred at a temperature of about 20 °C for about 5 to about 20 hours and then at a temperature of about 15 °C for about 4 hours.

In some embodiments, the compound of Formula (IV) is isolated by filtration. In some embodiments, the compound of Formula (IV) is purified by washing with THF.

In some embodiments, the compound of Formula (IV) is isolated in high yield. In some embodiments, the compound of Formula (IV) is isolated in at least about 80% yield. In some embodiments, the compound of Formula (IV) is isolated in at least about 85% yield, at least about 86% yield, at least about 87% yield, at least about 88% yield, at least about 89% yield, or at least about 90% yield. In some embodiments, the compound of Formula (III) is isolated in at least about 85% yield. In some embodiments, the compound of Formula (III) is isolated in at least about 87% yield.

In some embodiments, the compound of Formula (IV) is isolated with high purity. In some embodiments, the high purity is determined via gas chromatography. In some embodiments, the compound of Formula (IV) is isolated with at least about 90% purity. In some embodiments, the compound of Formula (IV) is isolated with at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% purity. In some embodiments, the compound of Formula (IV) is isolated with at least about 95% purity. In some embodiments, the compound of Formula (IV) is isolated with at least about 97% purity. In some embodiments, the compound of Formula (IV) is isolated with at least about 99% purity.

3.4) Stepwise synthesis of the compound of Formula (IV)

The compound of Formula (IV) can be provided by sequentially performing the processes disclosed herein. For example, the compound of Formula (IV) can be provided by sequentially performing the following three steps:

A. condensation of a compound of Formula (I) with hydroxylamine to provide a compound of Formula (II);

B. reduction of a compound of Formula (II) to provide a compound of Formula (lll-A); and

C. conversion of the compound of Formula (lll-A) to the corresponding acetate salt, i.e. , the compound of Formula (IV).

A process of preparing the compound of Formula (IV) may, alternately, comprise some, but not all, of the foregoing steps. In some embodiments, the process of preparing the compound of Formula (IV) comprises at least one of the foregoing steps. In some embodiments, the process of preparing the compound of Formula (IV) comprises at least two of the foregoing steps. In some embodiments, the process of preparing the compound of Formula (IV) comprises all three of the foregoing steps. Preferably, the process for preparing the compound of Formula (IV) comprises at least step B: reduction of a compound of Formula (II) to provide a compound of Formula (lll-A).

Accordingly, in an aspect, the present disclosure provides a process of preparing a compound of Formula (IV): comprising:

(a) combining a compound of Formula (I): with hydroxylamine, or a salt thereof, and a Lewis base to provide a compound of Formula (II):

(b) combining the compound of Formula (II) with a transition metal catalyst and hydrogen to provide the compound of Formula (lll-A):

(c) combining the compound of Formula (lll-A) with acetic acid to provide the compound of Formula (IV).

Embodiments for the preparation of each of the compounds of Formulas (II), (lll-A), and (IV) are as described herein. Certain embodiments are described below:

In some embodiments, the hydroxylamine of step (a) is hydroxylamine hydrochloride. In some embodiments, the Lewis base of step (a) is pyridine.

In some embodiments, the compound of Formula (II), the transition metal catalyst, and the hydrogen of step (b) are combined in an organic solvent. In some embodiments, the organic solvent comprises THF and propylene glycol methyl ether. In some embodiments, the organic solvent comprises about 95% THF and about 5% PGME by volume.

In some embodiments, the transition metal catalyst of step (b) is a nickel catalyst. In some embodiments, the nickel catalyst is sponge nickel.

In some embodiments, the hydrogen of step (b) is provided in molar excess with respect to the compound of Formula (II).

In some embodiments, step (b) is performed in neutral pH conditions. In some embodiments, the compound of Formula (lll-A) is provided substantially free of a compound of Formula (lll-B):

In some embodiments, step (b) is at least 10 times selective for the compound of Formula (lll-A) over the compound of Formula (lll-B).

3.5) Exo-selective synthesis of 3-aminotropane and analogs thereof

The oxime reduction reaction described hereinabove is especially useful for effecting the conversion of a compound of Formula (II) to a compound of Formula (lll-A). However, it has been discovered that the conditions for providing the compound of Formula (lll-A) are effective at selectively producing diverse exo-3-aminotropane analogs. Accordingly, in one aspect, the present disclosure provides a process for preparing a compound of Formula (VII): or a salt thereof, comprising combining a compound of Formula (VI): with a transition metal catalyst and hydrogen to provide the compound of Formula (VII); wherein:

X is NR ⁴ , NC(O)R ⁵ , O, S, or CH ₂ ;

R ¹ and R ² taken together form a C ₂ -C ₄ alkyl bridge and R ³ is H, or R ¹ and R ³ taken together form a Ci or C ₃ alkyl bridge and R ² is H; and R ⁴ is benzyl, Boc, or C ₁ -C ₆ alkyl;

R ⁵ is C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; wherein the compound of Formula (VII) is selectively provided as the exo isomer. In some embodiments, the compound of Formula (VI), the transition metal catalyst, and the hydrogen are combined in a solvent. In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent comprises a protic organic solvent. Solvents suitable for use in the methods described herein include, but are not limited to, tetrahydrofuran (THF), propylene glycol methyl ether (PGME), 2-methyltetrahydrofuran, methanol, isopropyl alcohol, and tert- amyl alcohol. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises PGME. In some embodiments, the solvent comprises THF and PGME. In some embodiments, the solvent comprises THF and PGME in a ratio (v/v) ranging from about 5:1 to about 50:1. In some embodiments, the solvent comprises THF and PGME in a ratio (v/v) ranging from about 10:1 to about 40:1. In some embodiments, the solvent comprises THF and PGME in a ratio (v/v) of about 19:1.

In some embodiments, the solvent comprises about 85% to about 99% THF by volume. In some embodiments, the solvent comprises about 90% to about 99% THF by volume. In some embodiments, the solvent comprises about 95% THF by volume.

In some embodiments, the solvent comprises about 1% to about 15% PGME by volume. In some embodiments, the solvent comprises about 1% to about 10% PGME by volume. In some embodiments, the solvent comprises about 5% PGME by volume.

In some embodiments, the solvent comprises about 95% THF and about 5% PGME by volume.

In some embodiments, the transition metal catalyst is a nickel catalyst or a cobalt catalyst. In some embodiments, the transition metal catalyst is a heterogenous catalyst. In some embodiments, the transition metal catalyst is a nickel catalyst. Transition metal catalysts suitable for use in the methods described herein include, but are not limited to, sponge nickel, Raney nickel, sponge cobalt, Raney cobalt, and Ni on S1O2. In some embodiments, the transition metal catalyst is sponge nickel. In some embodiments, the transition metal catalyst is sponge nickel A-5000. In some embodiments, the transition metal catalyst is sponge nickel A-4000. In some embodiments, the transition metal catalyst is sponge cobalt. In some embodiments, the transition metal catalyst is sponge cobalt A-8B46. In some embodiments, the transition metal catalyst is Raney cobalt. In some embodiments, the transition metal catalyst is Ni on S1O2. In some embodiments, the transition metal catalyst is Ni 65% on S1O2.

In some embodiments, the compound of Formula (VI) and the transition metal catalyst are combined in a ratio from about 1:0.1 (w/w) to about 1:0.9 (w/w). In some embodiments, the compound of Formula (VI) and the transition metal catalyst are combined in a ratio from about 1:0.25 (w/w) to about 1:0.75 (w/w). In some embodiments, the compound of Formula (VI) and the transition metal catalyst are combined in a ratio from about 1:0.25 (w/w) to about 1:0.5 (w/w). In some embodiments, the compound of Formula (VI) and the transition metal catalyst are combined in a ratio of about 1:0.5 (w/w).

In some embodiments, the hydrogen is provided as hydrogen gas. In some embodiments, the pressure of hydrogen gas is maintained from about 0.5 bar to about 10 bar until the compound of Formula (VI) is substantially consumed. In some embodiments, the pressure of hydrogen gas is maintained from about 1 bar to about 10 bar until the compound of Formula (VI) is substantially consumed. In some embodiments, the pressure of hydrogen gas is maintained from about 0.5 bar to about 10 bar until the compound of Formula (VI) is at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% consumed. In some embodiments, the pressure of hydrogen gas is maintained from about 1 bar to about 10 bar until the compound of Formula (VI) is at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% consumed. In some embodiments, the hydrogen is provided in molar excess with respect to the compound of Formula (VI).

In some embodiments, the compound of Formula (VI), the transition metal catalyst, and the hydrogen are combined without the further addition of a basic additive. In some embodiments, the process for preparing the compound of Formula (VII) is performed in neutral pH conditions (e.g., without the addition of acidic or basic reagents). In some embodiments, the process for preparing the compound of Formula (VII) is performed from about pH 6 to about pH 8. In some embodiments, the process for preparing the compound of Formula (VII) is performed from about pH 6.5 to about pH 7.5.

In some embodiments, the process is performed at a temperature from about 50 °C to about 75 °C. In some embodiments, the process is performed at a temperature from about 50 °C to about 65 °C. In some embodiments, the process is performed at a temperature of about 65 °C.

In some embodiments, the compound of Formula (VI), the transition metal catalyst, and the hydrogen are stirred for about 1 to about 18 hours. In some embodiments, the compound of Formula (VI), the transition metal catalyst, and the hydrogen are stirred for about 1 to about 10 hours. In some embodiments, the compound of Formula (VI), the transition metal catalyst, and the hydrogen are stirred for about 4 hours.

In some embodiments, X is NR ⁴ or NC(O)R ⁵ .

In some embodiments, R ⁴ is benzyl, Boc, or C1-C3 alkyl. In some embodiments, R ⁴ is benzyl, Boc, or methyl.

In some embodiments, R ⁵ is phenyl, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, R ⁵ is phenyl, methyl, or trifluoromethyl.

In some embodiments, R ¹ and R ² are taken together to form a C2-C4 alkyl bridge and R ³ is H. In some embodiments, R ¹ and R ² are taken together to form a C2-C3 alkyl bridge and R ³ is H. In some embodiments, R ¹ and R ² are taken together to form a C2 alkyl bridge and R ³ is H.

In some embodiments, the process for preparing the compound of Formula (VII) proceeds with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% conversion of the compound of Formula (VI). In some embodiments, the process proceeds with at least 75% conversion of the compound of Formula (VI). In some embodiments, the process proceeds with at least 85% conversion of the compound of Formula (VI). In some embodiments, the process proceeds with at least 90% conversion of the compound of Formula (VI). In some embodiments, the process proceeds with at least 95% conversion of the compound of Formula (VI). In some embodiments, the process proceeds with at least 99% conversion of the compound of Formula (VI).

In some embodiments, the compound of Formula (VII) is produced substantially free of side products. In some embodiments, exo isomer of the compound of Formula (VII) is provided substantially free of the endo isomer of the compound of Formula (VII).

In some embodiments, the process is at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, or at least 10 times more selective for the exo isomer of the compound of Formula (VII) than for the endo isomer of the compound of Formula (VII). In some embodiments, the process is at least 4 times more selective for the exo isomer of the compound of Formula (VII) than for the endo isomer of the compound of Formula (VII). In some embodiments, the process is at least 8 times more selective for the exo isomer of the compound of Formula (VII) than for the endo isomer of the compound of Formula (VII). In some embodiments, the process is at least 10 times more selective for the exo isomer of the compound of Formula (VII) than for the endo isomer of the compound of Formula (VII). In some embodiments, the process is at least 13 times more selective for the exo isomer of the compound of Formula (VII) than for the endo isomer of the compound of Formula (VII). In some embodiments, the process is at least 15 times more selective for the exo isomer of the compound of Formula (VII) than for the endo isomer of the compound of Formula (VII). In some embodiments, the process is at least 20 times more selective for the exo isomer of the compound of Formula (VII) than for the endo isomer of the compound of Formula (VII).

In some embodiments, the process for preparing the exo isomer of the compound of Formula (VII) provides less than about 20% by molar yield of the endo isomer of the compound of Formula (VII). In some embodiments, the process for preparing the exo isomer of the compound of Formula (VII) provides less than about 15% by molar yield of the endo isomer of the compound of Formula (VII). In some embodiments, the process for preparing the exo isomer of the compound of Formula (VII) provides less than about 10% by molar yield of the endo isomer of the compound of Formula (VII). In some embodiments, the process for preparing the exo isomer of the compound of Formula (VII) provides less than about 8% by molar yield of the endo isomer of the compound of Formula (VII).

In some embodiments, the exo isomer of the compound of Formula (VII) is provided substantially free of a compound of Formula (V):

In some embodiments, the process for preparing the exo isomer of the compound of Formula (VII) provides less than about 20% by molar yield of the compound of Formula (V). In some embodiments, the process for preparing the exo isomer of the compound of Formula (VII) provides less than about 15% by molar yield of the compound of Formula (V). In some embodiments, the process for preparing the exo isomer of the compound of Formula (VII) provides less than about 10% by molar yield of the compound of Formula (V). In some embodiments, the process for preparing the exo isomer of the compound of Formula (VII) provides less than about 5% by molar yield of the compound of Formula (V). In some embodiments, the process for preparing the exo isomer of the compound of Formula (VII) provides less than about 3% by molar yield of the compound of Formula (V).

In some embodiments, the compound of Formula (VI) has a structure according to Formula (Vl-A): and the compound of Formula (VII) has a structure according to Formula (Vll-A): wherein: n is 2, 3, or 4;

X is NR ⁴ , NC(O)R ⁵ , O, S, or CH ₂ ;

R ⁴ is benzyl, Boc, or C1-C6 alkyl; and

R ⁵ is C6-C10 aryl, C1-C6 alkyl, or C1-C6 haloalkyl.

In some embodiments, n is 2 or 3. In some embodiments, n is 2. In some embodiments, X is NR ⁴ or NC(O)R ⁵ . In some embodiments, when n is 3, X is not N-Bn.

In some embodiments, X is NR ⁴ or NC(O)R ⁵ , and when n is 3, X is not N-Bn.

In some embodiments, n is 2 and X is NR ⁴ or NC(O)R ⁵ .

In some embodiments, R ⁴ is benzyl, Boc, or C1-C3 alkyl. In some embodiments, R ⁴ is benzyl, Boc, or methyl.

In some embodiments, R ⁵ is phenyl, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, R ⁵ is phenyl, methyl, or trifluoromethyl.

In some embodiments, X is selected from the group consisting of:

In some embodiments, X is selected from the group consisting of: provided that when n is 3, X is not

In some embodiments, n is 2, and X is selected from the group consisting of

In some embodiments, the compound of Formula (Vll-A) is provided substantially free of a compound of Formula (Vll-B):

(Vll-B).

In some embodiments, the process is at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, or at least 10 times more selective for the compound of Formula (Vll-A) than for the compound of Formula (VII- B). In some embodiments, the process is at least 4 times more selective for the compound of Formula (Vll-A) than for the compound of Formula (Vll-B). In some embodiments, the process is at least 8 times more selective for the compound of Formula (Vll-A) than for the compound of Formula (Vll-B). In some embodiments, the process is at least 10 times more selective for the compound of Formula (Vll-A) than for the compound of Formula (Vll-B). In some embodiments, the process is at least 13 times more selective for the compound of Formula (Vll-A) than for the compound of Formula (Vll-B). In some embodiments, the process is at least 15 times more selective for the compound of Formula (Vll-A) than for the compound of Formula (Vll-B). In some embodiments, the process is at least 20 times more selective for the compound of Formula (Vll-A) than for the compound of Formula (Vll-B).

In some embodiments, the process for preparing the compound of Formula (Vll-A) provides less than about 20% by molar yield of the compound of Formula (Vll-B). In some embodiments, the process for preparing the compound of Formula (Vll-A) provides less than about 15% by molar yield of the compound of Formula (Vll-B). In some embodiments, the process for preparing the compound of Formula (Vll-A) provides less than about 10% by molar yield of the compound of Formula (Vll-B). In some embodiments, the process for preparing the compound of Formula (Vll-A) provides less than about 8% by molar yield of the compound of Formula (Vll-B).

In some embodiments, the process for preparing the compound of Formula (VII) further comprises the step of combining a compound of Formula (V): with hydroxylamine, or a salt thereof, and a Lewis base to provide the compound of Formula (VI) prior to combining the compound of Formula (VI) with the transition metal catalyst and hydrogen.

In some embodiments, the compound of Formula (V), the hydroxylamine, or salt thereof, and the Lewis base are combined in a solvent. In some embodiment, the solvent is a protic solvent. In some embodiments, the solvent comprises water and an alcohol. In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is ethanol or methanol. In some embodiments, the solvent is methanol.

In some embodiments, the hydroxylamine is hydroxylamine hydrochloride.

In some embodiments, the Lewis base has a pK _b greater than about 7. In some embodiments, the Lewis base is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, and pyridine. In some embodiments, the Lewis base is selected from the group consisting of sodium bicarbonate, sodium carbonate, sodium acetate, and pyridine. In some embodiments, the Lewis base is pyridine.

In some embodiments, the molar ratio of the compound of Formula (V) to the hydroxylamine is from about 1:1 to about 1:3. In some embodiments, the molar ratio of the compound of Formula (V) to the hydroxylamine is from about 1:1.5 to about 1:2.5. the molar ratio of the compound of Formula (V) to the hydroxylamine is about 1:2.

In some embodiments, the process is performed at room temperature. In some embodiments, the process is performed at a temperature from about 20 °C to about 25 °C.

In some embodiments, the compound of Formula (V), the hydroxylamine, or salt thereof, and the Lewis base are stirred for about 2 to about 5 hours. In some embodiments, the compound of Formula (V), the hydroxylamine, or salt thereof, and the Lewis base are stirred for about 2 hours.

3.6) Exemplary advantages of the processes described herein

The novel processes described herein provide a concise, industrially scalable synthetic route to the compound of Formula (IV), a starting material in the synthesis of the pan-JAK inhibitor (3-((1R,3s,5S)-3-((7-((5-methyl-1/-/-pyrazol-3-yl)amino)-1,6 -naphthyridin-5- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile). The processes proceed with high yield and produce the final product in high purity and with high selectivity for the exo isomer. In particular, it has been demonstrated that the processes described herein can be performed at the 100-gram scale and produce the compound of Formula (IV) with greater than 99% purity in at least 81% yield.

Accordingly, in some embodiments, the processes described herein can be performed at the industrial scale. In some embodiments, the processes described herein can be performed at least at the 100-gram scale. In some embodiments, the processes described herein can be performed at least at the 200-gram scale.

In some embodiments, the overall yield of the three-step process is at least about 65%. In some embodiments, the overall yield of the three-step process is at least about

70%. In some embodiments, the overall yield of the three-step process is at least about

75%. In some embodiments, the overall yield of the three-step process is at least about

80%. In some embodiments, the overall yield of the three-step process is at least about

75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, or at least about 80%. In some embodiments, the overall yield of the three-step process is about 81%.

In some embodiments, the compound of Formula (IV) afforded via the three-step process is at least about 90% pure. In some embodiments, the compound of Formula (IV) afforded via the three-step process is at least about 95% pure, at least about 96% pure, at least about 97% pure, at least about 98% pure, or at least about 99% pure. In some embodiments, the compound of Formula (IV) afforded via the three-step process is at least about 95% pure. In some embodiments, the compound of Formula (IV) afforded via the three-step process is at least about 97% pure. In some embodiments, the compound of Formula (IV) afforded via the three-step process is at least about 99% pure.

A key step in the processes described herein is the enantioselective reduction of the compound of Formula (II) to the compound of Formula (lll-A) (or, more broadly, the enantioselective reduction of a compound of Formula (VI) to the exo isomer of the compound of Formula (VII)). It is essential that the reaction exhibit increased selectivity for the exo isomer in order to subsequently provide the pan-JAK inhibitor with the desired stereochemistry. While enantioselective syntheses for producing aminotropanes have been reported, these protocols overwhelming favor the endo product. Indeed, investigation of hydrogenation conditions for reducing the compound of Formula (II) confirmed that heterogenous catalysts such as palladium, platinum, rhodium, and ruthenium preferentially give the endo isomer. Other catalysts such as Raney-Co, Raney-Ni, and Ni-AI alloy exhibited low exo selectivity. These catalysts also exhibited a dramatic solvent effect, where protic solvents appeared to have a beneficial effect on conversion.

Where procedures are, instead, reportedly selective for the exo product, the conditions make scaling to the industrial level prohibitive. The single most common, bordering on ubiquitous, method for obtaining the exo aminotropane described in the scientific literature entails reduction of the oxime with metallic sodium in an alcoholic solvent. While tests have confirmed that this procedure yields the exo isomer with high selectivity, the use of elemental sodium as a reagent hinders adaption of the procedure to large or industrial scales, primarily for safety reasons. An alternate approach that was considered was the use of transaminases to directly reduce the compound of Formula (I) (i.e., the ketone starting material) to the compound of Formula (lll-A). A broad screening of commercially available transaminases revealed that a few were able to provide high exo selectivity. However, the transaminases exhibited poor activity and required high loading (50 to 1000 wt%) and long reaction times (ca. two days). Accordingly, enzyme engineering would be necessary for such an approach to be feasible at large or industrial scales.

A single report of exo selective hydrogenation of the oxime using a Ni-AI alloy under basic conditions was identified. However, this procedure is shown herein to have limited versatility (see Example 3, below). In particular, benzyl protection of the ring-bound nitrogen atom of the oxime appears to be essential for preserving exo selectivity. Replacing the benzyl group used in the procedure as originally reported with a Boc group, as in the compound of Formula (II), all but extinguishes the enantioselectivity of the reaction. In contrast to previously reported procedures, the present disclosure provides an industrially scalable and enantioselective process for preparing a Boc-protected exo- aminotropane from the corresponding tropinone oxime. Further, whereas previously reported procedures were found to have limited tolerance for protecting group exchange or derivatization of the tropinone oxime scaffold, the reduction processes described herein are versatile in that they can accommodate an array of protecting and functional groups at the ring-bound nitrogen atom of the tropinone oxime scaffold without significantly sacrificing enantioselectivity (see Example 4, below). EXAMPLES

Abbreviations as used herein have respective meanings as follows:

Compound II was synthesized according to the procedure depicted in Scheme 1. A flask was charged with Compound I (200 g, 887.78 mmol, 1.00 eq), methanol (500 ml_, 2.5V), and pyridine (175.56 g, 2.219.45 mmol, 2.50 eq), followed by the addition of NH2OH HCI (123.38 g, 1.775.56 mmol, 2.00 eq). The mixture was stirred for 1-2 h at 25 °C. After the reaction was complete (monitored by in-process GC), H2O (750 g, 3.75V) was added at 20 °C over the course of 1 h, and a precipitate was formed. After stirring for 18 h, H2O (980 g, 4.9 V) was added at 20 °C over the course of 1 h, and the reaction mixture was cooled to 0 °C. After stirring for 2 h at 0 °C, the solid was isolated by filtration. The resulting wet cake was washed with a 3:1 mixture (V/V) of MeOH/water (800 ml_, 4V) and dried at 40 °C under vacuum. 196 g (815.65 mmol) of Compound II was isolated as a white solid in 91.9% yield. Purity (GC): 99.7%. GC-MS: 240.10 [M] ⁺ . ¹ H NMR (400 MHz, CDCI3) d ppm 1.47 (s, 9 H) 1.65 (br, 2 H) 1.97 (br, 2 H) 2.15 (br, 1 H) 2.20 (d, J= 14.8 Hz, 2 H) 2.59 (br, 1 H) 3.12 (d, J= 15.6Hz, 1 H) 4.33 (br, 2 H) 9.09 (br, 1 H).

Example 2: Synthesis of acetic acid-tert-butyl (1R 3s 5S)-3-amino-8- azabicvclo[3.2.1loctane-8-carboxylate (1/1) via tert- butyl (1R 3s 5S)-3-amino-8- azabicvcio[3.2.1loctane-8-carboxylate

Compound IV was synthesized according to the procedure depicted in Scheme 2. A stainless steel 1L pressure reactor was charged with Compound II (100 g, 416.15 mmol, 1.00 eq), PGME (10 ml_, 0.1V), and THF (490 ml_, 4.9 V), followed by the addition of Sponge-Ni (A-5000) catalyst (50 g, 0.5 eq) which was previously rinsed with 200 ml THF (5 times). The reactor was purged with N23 times, and then with H26 times. The temperature was adjusted to 65°C, and the H2 flow was adjusted to 1 bar. The reaction was stirred (900 rpm) for 4 h. An in-process control (I PC) performed at this time indicated that 0.06% of Compound II remained, and that 92.8% of the exo isomer (compound lll-A) was formed as compared to 6.8% of the endo isomer (compound lll-B) (ratio exo/endo= 13.6). The reaction mixture was then cooled to 20-25°C, filtered over a bed of diatomaceous earth (e.g.,

Celite®) to remove the catalyst, and rinsed with THF (400 ml_, 4V). 842 g filtrate was obtained (molar yield of 92.1%; IPC KF: 1.11%). Subsequently, the filtrate was concentrated under reduced pressure to 1V. THF (900 ml_, 9V) was added to the mixture, and the filtrate was concentrated under reduced pressure to 1V to reduce the amount of H2O (< 0.10%) as well as residual PGME (< 0.5 %) in the filtrate. THF (900 ml_, 9V) was added to the filtrate (KF: 0.06%, residual PGME in THF: 0.41%), and the solution was stirred (150 rpm) at 20 °C under N2. AcOH (30 g, 499.57 mmol, 1.25 eq) was added dropwise over 5 h at 20°C, and a precipitate formed. The stirring speed was adjusted to 300 rpm, and the contents of the flask were stirred for 12 h at 20 °C and then for 4h at 15°C. The solid was isolated by filtration.

The resulting wet cake was washed with THF (200ml_, 2V), and dried at 35 °C under vacuum. 105 g (366.66 mmol) of Compound IV was isolated as a white solid in 88.7 % yield (yield calculated from amount of Compound II used). Purity (GC): 99.7%; GC-MS: 286.90 [M] ⁺ . ¹ H NMR (400 MHz, CDCI ₃ ) d ppm 1.47 (s, 9 H) 1.65 (br, 4 H) 1.87 (br, 2 H) 1.95 (s, 3 H) 1.97 (br, 2 H) 3.34 (br, 1 H) 4.22 (br, 2 H) 7.40 (br, 2 H).

A procedure for selectively converting N- benzyl tropinone oxime to the exo amine product reported in the IP.com journal (Bratt, M.; Perkins, J. The stereoselective formation of an exo amine by epimerization of the endo isomer. IP.com Journal, 2006, 6(9A), 5) was performed using Compound II as a starting material, as depicted in Scheme 3. The procedure was performed in duplicate and results were analyzed via gas chromatography. In a 10 ml_ vial equipped with a magnetic stirrer, Compound II (0.3 mmol; 72 mg), Ni-AI alloy (36 mg; 2:3.2 Ni:AI), and NaOH (0.425 equiv; 30.6 mg) were added. Next, MeTHF (0.8 ml_) was added, and then H2O (0.1 ml_) was added slowly to the vial. The vial was capped and transferred to a B48 reactor. The vial was degassed and kept under a N2 pressurized atmosphere (3-4 bar). The vial was heated at 60 °C for 2 h, and then the vial was degassed and filled with H2 gas (3 bar). The reaction was allowed to proceed for another 2.5 h. Then the reactor was cooled down to 25 °C and the vial was taken outside the reactor. A sample of 0.1 ml_ was withdrawn for GC analysis (entries 1 and 2 in Table 1).

The IP.com journal article indicated that following the first stage of the reaction, the exo/endo ratio could be further increased in favor of the exo product by subsequently adding additional oxime and further heating the mixture under nitrogen atmosphere to epimerize any endo product present. Accordingly, an additional portion of Compound II (7 mg; 10 wt%) was added to the vial. The vial was capped and heated to 78 °C for 6 h under N2 (1 atm). An aliquot of the reaction mixture (0.1 ml_) was withdrawn for GC analysis (entries 1-epim and 2-epim in Table 1).

Results of GC analysis of the samples prior to and following the epimerization step are described in Table 1.

While the data in the journal article illustrate the utility of the procedure for the reduction of the benzyl-protected tropinone oxime, the data presented in Table 1 demonstrate that the utility does not translate to the Boc-protected derivative. Prior to the epimerization step, minimal selectivity was observed with respect to the exo isomer (ratios of 1.3/1 or 1.2/1). While the epimerization step reportedly converted the remaining benzyl- protected endo isomer to the corresponding exo isomer, the same conditions failed to significantly enhance the exo/endo ratio of the Boc-protected products.

A series of aminotropane derivatives were synthesized from the corresponding tropinone oxime derivatives as depicted in Scheme 4 and Table 1. The procedure described in Example 2 was performed up through the diatomaceous earth filtration for each oxime. The reaction mixtures were then analyzed via gas chromatography to determine relative amounts of exo isomer product (Compound Vll-A) and endo isomer product (Compound VII- B) as well as any unreacted oxime and any ketone side product having the following structure:

The results of these trials are described in Table 2:

* n.d = not detected

** isomers separated but not identified via GC *** N.C. = not confirmed A number of embodiments have been described herein. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other embodiments are within the scope of the following claims.