WO2022241188A1 - Synthèse énantiosélective d'un composé aminotropane - Google Patents

Synthèse énantiosélective d'un composé aminotropane Download PDF

Info

Publication number
WO2022241188A1
WO2022241188A1 PCT/US2022/029137 US2022029137W WO2022241188A1 WO 2022241188 A1 WO2022241188 A1 WO 2022241188A1 US 2022029137 W US2022029137 W US 2022029137W WO 2022241188 A1 WO2022241188 A1 WO 2022241188A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
lll
vii
hydrogen
Prior art date
Application number
PCT/US2022/029137
Other languages
English (en)
Inventor
Matteo CONZA
Cyril Ben Haim
Original Assignee
Theravance Biopharma R&D Ip, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Theravance Biopharma R&D Ip, Llc filed Critical Theravance Biopharma R&D Ip, Llc
Publication of WO2022241188A1 publication Critical patent/WO2022241188A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • novel processes for preparing tert- butyl (1R,3s,5S)-3-amino-8- azabicyclo[3.2.1]octane-8-carboxylate or a salt thereof are also provided herein. Also provided herein are enantioselective processes for preparing exo-aminotropane derivatives from tropinone oximes.
  • IBDs ulcerative colitis
  • CD Crohn’s disease
  • 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).
  • COPD chronic obstructive pulmonary disease
  • JAK inhibitors 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.
  • JAK inhibitors 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.
  • 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 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:
  • 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.
  • the present disclosure provides, inter alia, a process for preparing a compound of Formula (lll-A):
  • the compound of Formula (II), the nickel catalyst, and the hydrogen are combined in an organic solvent.
  • 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.
  • the hydrogen is provided in molar excess with respect to the compound of Formula (II).
  • the process is performed in neutral pH conditions.
  • the compound of Formula (lll-A) is provided substantially free of a compound of Formula (lll-B):
  • 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.
  • the hydroxylamine is hydroxylamine hydrochloride.
  • 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):
  • the present disclosure also provides a process for preparing a compound of Formula
  • the present disclosure also provides a process for preparing a compound of Formula
  • 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.
  • the nickel catalyst and the hydrogen are combined in an organic solvent.
  • the organic solvent comprises THF and propylene glycol methyl ether.
  • the nickel catalyst is sponge nickel.
  • the process is performed in neutral pH conditions.
  • the exo isomer of the compound of Formula (VII) is provided substantially free of the endo isomer of the compound of Formula (VII).
  • 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).
  • 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.
  • the hydroxylamine is hydroxylamine hydrochloride.
  • the Lewis base is pyridine.
  • 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
  • R 5 is C 6 -C 10 aryl, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • 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).
  • n is 2 or 3.
  • X is NR 4 or NC(O)R 5 , and when n is 3, X is not N-Bn.
  • R 4 is benzyl, Boc, or methyl.
  • R 5 is phenyl, methyl, or trifluoromethyl.
  • X is selected from the group consisting of:
  • X is selected from the group consisting of: _ provided that when n is 3, X is not
  • 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.”
  • 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.
  • 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.
  • 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.
  • alkyl refers to a straight- or branched-chain alkyl group having the indicated number of carbon atoms in the chain.
  • 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.
  • C1-C3 alkyl refers to a straight- or branched-chain alkyl group having from 1 to 3 carbon atoms in the chain.
  • C1-C6 alkyl refers to a straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain.
  • haloalkyl is used in its conventional sense, and refers to an alkyl group, as defined herein, substituted with one or more halo substituents.
  • 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.
  • halo or “halogen” represent chloro, fluoro, bromo, or iodo.
  • aryl 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.
  • 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.
  • 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.
  • salts 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.
  • 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.
  • suitable solvents for a particular reaction step can be selected.
  • reactions can be carried out in the absence of solvent, such as when at least one of the reagents is a liquid or gas.
  • 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.
  • protic solvent refers to any solvent that contains a labile hydrogen atom.
  • 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.
  • 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- dimethylpropion
  • 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).
  • reactions of the processes described herein can be carried out in air or under an inert atmosphere.
  • 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.
  • 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.
  • 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.
  • DIPEA Diisopropylethylamine
  • 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.
  • 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.
  • 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:
  • 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:
  • 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).
  • the process comprises an oxime-formation reaction.
  • the process comprises an oxime reduction reaction.
  • the process comprises a salt 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).
  • the compound of Formula (I), the hydroxylamine, or salt thereof, and the Lewis base are combined in a solvent.
  • the solvent is a protic solvent.
  • the solvent comprises water and an alcohol.
  • the solvent is an alcohol.
  • the solvent is ethanol or methanol. In some embodiments, the solvent is methanol.
  • the hydroxylamine is hydroxylamine hydrochloride.
  • the Lewis base has a pK b greater than about 7.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • an additional step e.g., salt formation
  • 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).
  • the compound of Formula (II), the transition metal catalyst, and the hydrogen are combined in a solvent.
  • the solvent is an organic solvent.
  • 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.
  • the solvent comprises THF.
  • the solvent comprises PGME.
  • the solvent comprises THF and PGME.
  • 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.
  • 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.
  • 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.
  • the solvent comprises about 95% THF and about 5% PGME by volume.
  • 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.
  • 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).
  • the hydrogen is provided as hydrogen gas.
  • 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.
  • the pressure of hydrogen gas is maintained from about 1 bar to about 10 bar until the compound of Formula (II) is substantially consumed.
  • 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.
  • 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.
  • the hydrogen is provided in molar excess with respect to the compound of Formula (II).
  • the compound of Formula (II), the transition metal catalyst, and the hydrogen are combined without the further addition of a basic additive.
  • 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).
  • the process for preparing the compound of Formula (lll-A) is performed from about pH 6 to about pH 8.
  • the process for preparing the compound of Formula (lll-A) is performed from about pH 6.5 to about pH 7.5.
  • 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.
  • 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).
  • 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):
  • 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).
  • 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).
  • the compound of Formula (lll-A) is provided substantially free of a compound of Formula (I):
  • 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.
  • diatomaceous earth e.g., Celite®
  • 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).
  • the compound of Formula (lll-A) is prepared by the process described hereinabove.
  • the compound of Formula (lll-A) and the acetic acid are combined in a solvent.
  • the solvent is an aprotic solvent.
  • the solvent is THF.
  • the solvent is substantially free of water.
  • the solvent comprises less than about 0.10% water.
  • the solvent is substantially free of propylene glycol methyl ether (PGME).
  • the solvent comprises less than about 0.5% PGME.
  • 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.
  • 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.
  • 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.
  • the compound of Formula (IV) is isolated by filtration. In some embodiments, the compound of Formula (IV) is purified by washing with THF.
  • 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.
  • 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.
  • the compound of Formula (IV) can be provided by sequentially performing the processes disclosed herein.
  • the compound of Formula (IV) can be provided by sequentially performing the following three steps:
  • a process of preparing the compound of Formula (IV) may, alternately, comprise some, but not all, of the foregoing steps.
  • the process of preparing the compound of Formula (IV) comprises at least one of the foregoing steps.
  • the process of preparing the compound of Formula (IV) comprises at least two of the foregoing steps.
  • the process of preparing the compound of Formula (IV) comprises all three of the foregoing steps.
  • 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).
  • the present disclosure provides a process of preparing a compound of Formula (IV): comprising:
  • the hydroxylamine of step (a) is hydroxylamine hydrochloride.
  • the Lewis base of step (a) is pyridine.
  • the compound of Formula (II), the transition metal catalyst, and the hydrogen of step (b) are combined in an organic solvent.
  • the organic solvent comprises THF and propylene glycol methyl ether.
  • the organic solvent comprises about 95% THF and about 5% PGME by volume.
  • the transition metal catalyst of step (b) is a nickel catalyst. In some embodiments, the nickel catalyst is sponge nickel.
  • the hydrogen of step (b) is provided in molar excess with respect to the compound of Formula (II).
  • step (b) is performed in neutral pH conditions.
  • the compound of Formula (lll-A) is provided substantially free of a compound of Formula (lll-B):
  • step (b) is at least 10 times selective for the compound of Formula (lll-A) over the compound of Formula (lll-B).
  • 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.
  • the compound of Formula (VI), the transition metal catalyst, and the hydrogen are combined in a solvent.
  • the solvent is an organic solvent.
  • 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.
  • 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.
  • 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.
  • 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.
  • the solvent comprises about 95% THF and about 5% PGME by volume.
  • 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.
  • 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).
  • the hydrogen is provided as hydrogen gas.
  • 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.
  • the pressure of hydrogen gas is maintained from about 1 bar to about 10 bar until the compound of Formula (VI) is substantially consumed.
  • 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.
  • 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.
  • the hydrogen is provided in molar excess with respect to the compound of Formula (VI).
  • the compound of Formula (VI), the transition metal catalyst, and the hydrogen are combined without the further addition of a basic additive.
  • 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).
  • the process for preparing the compound of Formula (VII) is performed from about pH 6 to about pH 8.
  • the process for preparing the compound of Formula (VII) is performed from about pH 6.5 to about pH 7.5.
  • 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.
  • 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.
  • X is NR 4 or NC(O)R 5 .
  • R 4 is benzyl, Boc, or C1-C3 alkyl. In some embodiments, R 4 is benzyl, Boc, or methyl.
  • R 5 is phenyl, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, R 5 is phenyl, methyl, or trifluoromethyl.
  • 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.
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • the exo isomer of the compound of Formula (VII) is provided substantially free of a compound of Formula (V):
  • 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).
  • 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
  • R 5 is C6-C10 aryl, C1-C6 alkyl, or C1-C6 haloalkyl.
  • 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.
  • X is NR 4 or NC(O)R 5 , and when n is 3, X is not N-Bn.
  • n 2 and X is NR 4 or NC(O)R 5 .
  • R 4 is benzyl, Boc, or C1-C3 alkyl. In some embodiments, R 4 is benzyl, Boc, or methyl.
  • R 5 is phenyl, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, R 5 is phenyl, methyl, or trifluoromethyl.
  • X is selected from the group consisting of:
  • X is selected from the group consisting of: provided that when n is 3, X is not
  • n is 2, and X is selected from the group consisting of
  • the compound of Formula (Vll-A) is provided substantially free of a compound of Formula (Vll-B):
  • 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).
  • 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).
  • 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).
  • 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.
  • the compound of Formula (V), the hydroxylamine, or salt thereof, and the Lewis base are combined in a solvent.
  • the solvent is a protic solvent.
  • the solvent comprises water and an alcohol.
  • the solvent is an alcohol.
  • the solvent is ethanol or methanol. In some embodiments, the solvent is methanol.
  • the hydroxylamine is hydroxylamine hydrochloride.
  • the Lewis base has a pK b greater than about 7.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • the overall yield of the three-step process is at least about
  • the overall yield of the three-step process is at least about
  • the overall yield of the three-step process is at least about
  • the overall yield of the three-step process is about 81%.
  • 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.
  • 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.
  • transaminases 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.
  • 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
  • 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).

Abstract

La présente invention concerne des procédés de préparation de fert-butyl (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate ou d'un sel de celui-ci. La présente invention concerne également des procédés énantiosélectifs de préparation de dérivés d'exo-aminotropane à partir d'oximes de tropinone.
PCT/US2022/029137 2021-05-14 2022-05-13 Synthèse énantiosélective d'un composé aminotropane WO2022241188A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163188644P 2021-05-14 2021-05-14
US63/188,644 2021-05-14

Publications (1)

Publication Number Publication Date
WO2022241188A1 true WO2022241188A1 (fr) 2022-11-17

Family

ID=81927609

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2022/029137 WO2022241188A1 (fr) 2021-05-14 2022-05-13 Synthèse énantiosélective d'un composé aminotropane

Country Status (1)

Country Link
WO (1) WO2022241188A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5968929A (en) * 1996-10-30 1999-10-19 Schering Corporation Piperazino derivatives as neurokinin antagonists
CN1451660A (zh) * 2002-04-19 2003-10-29 浙江海正药业股份有限公司 一种制备格拉司琼及其盐的方法
WO2006113471A2 (fr) * 2005-04-19 2006-10-26 Merck & Co., Inc. Antagonistes de nmda/nr2b a base de n-alkyl-azacycloalkyle
US9725470B2 (en) 2015-05-28 2017-08-08 Theravance Biopharma R&D Ip, Llc Substituted naphthyridines as JAK kinase inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5968929A (en) * 1996-10-30 1999-10-19 Schering Corporation Piperazino derivatives as neurokinin antagonists
CN1451660A (zh) * 2002-04-19 2003-10-29 浙江海正药业股份有限公司 一种制备格拉司琼及其盐的方法
WO2006113471A2 (fr) * 2005-04-19 2006-10-26 Merck & Co., Inc. Antagonistes de nmda/nr2b a base de n-alkyl-azacycloalkyle
US9725470B2 (en) 2015-05-28 2017-08-08 Theravance Biopharma R&D Ip, Llc Substituted naphthyridines as JAK kinase inhibitors
US10072026B2 (en) 2015-05-28 2018-09-11 Theravance Biopharma R&D Ip, Llc Crystalline form of 3-((1R,3s,5S)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY, pages: 1418
BRATT MARK ET AL: "The Stereoselective Formation of an Exo Amine by Epimerisation of the Endo Isomer An IP.com Prior Art Database Technical Disclosure The Stereoselective Formation of an Exo Amine by Epimerisation of the Endo Isomer", IP.COM, 18 August 2006 (2006-08-18), XP055944838, Retrieved from the Internet <URL:https://priorart.ip.com/IPCOM/000139280> [retrieved on 20220721] *
BRATT, M.PERKINS, J.: "The stereoselective formation of an exo amine by epimerization of the endo isomer", IP.COM JOURNAL, vol. 6, no. 9A, 2006, pages 5
DACENKO OLEKSANDR P. ET AL: "Improved Synthesis of Monoprotected 5- and 6-Amino-2-azanorbornanes", SYNTHETIC COMMUNICATIONS, vol. 41, no. 7, 3 March 2011 (2011-03-03), US, pages 981 - 992, XP055945306, ISSN: 0039-7911, DOI: 10.1080/00397911003707196 *
GREENE ET AL.: "Protective Groups in Organic Synthesis", 2007, WILEY & SONS

Similar Documents

Publication Publication Date Title
JP6696986B2 (ja) ジアリールチオヒダントイン化合物の調製方法
WO2010015935A2 (fr) Sels de cinacalcet insaturé et procédés de préparation du chlorhydrate de cinacalcet
CN112047888A (zh) 一种合成恩杂鲁胺的方法
EP2281801B1 (fr) Procédé pour la préparation de 3,3-diphénylpropylamines
JP6985367B2 (ja) 新規化合物および方法
UA125595C2 (uk) Проміжні сполуки, корисні для синтезу селективного інгібітора щодо протеїнкінази, і способи їх отримання
KR19990076521A (ko) 보호된 4-아미노메틸-피롤리딘-3-온의 제조방법
WO2012004391A1 (fr) Procédé de préparation de maléate de flupirtine
NO328627B1 (no) Fremgangsmate for fremstillingen av iopamidol og de nye intermediater deri
EP3498695B1 (fr) Procédé de synthèse d&#39;acide 3- (difluorométhyl)-1-méthyl-1 h-pyrazole-4-carboxylique
WO2022241188A1 (fr) Synthèse énantiosélective d&#39;un composé aminotropane
TWI796701B (zh) 用於製備雜環化合物的中間體立體選擇性合成
CN110078636A (zh) 一种制备碘普罗胺中间体的方法
KR101427221B1 (ko) 플루복사민 자유 염기의 정제방법 및 이를 이용한 고순도 플루복사민 말레이트의 제조방법
KR101874659B1 (ko) 이민 수소화로써의 치환된 ｎ-(벤질)시클로프로판아민의 제조 방법
KR100743617B1 (ko) 고광학순도를 갖는 키랄 3-히드록시 피롤리딘 및 그유도체를 제조하는 방법
WO2007024113A1 (fr) Procédé de synthèse d&#39;un composé chiral de type 3-hydroxypyrrolidine et de dérivés dudit composé de pureté optique élevée
JP5704763B2 (ja) トランス−４−アミノシクロペンタ−２−エン−１−カルボン酸誘導体の製造
CN113816955B (zh) 一种ret激酶抑制剂中间体及其制备方法
JP5396841B2 (ja) α−トリフルオロメチル−β−置換−β−アミノ酸類の製造方法
KR101299720B1 (ko) 3-아미노-5-플루오로-4-디알콕시펜탄산 에스테르의 새로운제조방법
JP4001380B2 (ja) アミノアゾビシクロアルカンのオキシムからの製法
KR20020032589A (ko) 할로겐화 일차 아민의 제조
WO2023102800A1 (fr) Synthèse de 5, 7-dichloro-1, 6-naphtyridine
JP2022529000A (ja) 置換２－［２－（フェニル）エチルアミノ］アルカンアミド誘導体の製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22727687

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE