WO2024064745A1 - Synthèse de reldesemtiv - Google Patents

Synthèse de reldesemtiv Download PDF

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Publication number
WO2024064745A1
WO2024064745A1 PCT/US2023/074681 US2023074681W WO2024064745A1 WO 2024064745 A1 WO2024064745 A1 WO 2024064745A1 US 2023074681 W US2023074681 W US 2023074681W WO 2024064745 A1 WO2024064745 A1 WO 2024064745A1
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Prior art keywords
formula
compound
salt
converting
tosyl
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PCT/US2023/074681
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English (en)
Inventor
Matthew W. Peterson
Qing Lu
Bradley P. Morgan
Luke W. Ashcraft
Denise Andersen
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Cytokinetics, Incorporated
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Publication of WO2024064745A1 publication Critical patent/WO2024064745A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • U.S. Patent No. 8,962,632 discloses l-(2-((((trans)-3 -fluoro- 1 -(3 -fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (reldesemtiv), a next-generation fast skeletal muscle troponin activator (FSTA) as a potential treatment for people living with debilitating diseases and conditions associated with neuromuscular or non- neuromuscular dysfunction, muscular weakness, and/or muscle fatigue.
  • FSTA fast skeletal muscle troponin activator
  • a method of preparing a compound of Formula (1): or a salt thereof, comprising:
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof comprises reacting the compound of Formula (3) or a salt thereof with a compound of Formula (4) or a salt thereof.
  • the method further comprises converting a compound of
  • the step of converting the compound of Formula (5) or a salt thereof to the compound of Formula (3) or a salt thereof comprises reacting the compound of Formula (5) or a salt thereof with a compound of Formula (6) wherein X is chloro or fluoro, to obtain the compound of Formula (3) or a salt thereof.
  • the method further comprises obtaining the compound of
  • the method further comprises obtaining the compound of Formula (7) by converting a compound of Formula (8) to the compound of Formula (7).
  • the method further comprises obtaining the compound of Formula (8) by converting a compound of Formula (9) to the compound of Formula (8).
  • the method further comprises obtaining the compound of
  • the method further comprises obtaining methyl 1 -tosyl- 1H- pyrrole-3 -carboxylate by converting l-tosyl-lH-pyrrole-3-carboxylic acid to methyl 1-tosyl- lH-pyrrole-3-carboxylate.
  • the method further comprises obtaining 1-tosyl-lH- pyrrole-3 -carboxylic acid by converting l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one to 1-tosyl-lH- pyrrole-3 -carboxylic acid.
  • the method further comprises obtaining 1-(1 -tosyl- 1H- pyrrol-3-yl)ethan-l-one by converting 1-tosyl-lH-pyrrole to l-(l-tosyl-lH-pyrrol-3-yl)ethan- 1-one.
  • the method further comprises obtaining 1 -tosyl- IH-pyrrole by converting pyrrole to 1 -tosyl- IH-pyrrole.
  • Embodiments also specifically include those compounds, compositions, compositions or methods that are, or that consist of, or that consist essentially of those specified components, elements or steps.
  • the term “comprised of’ is used interchangeably with the term “comprising” and are stated as equivalent terms.
  • disclosed compositions, devices, articles of manufacture or methods that "comprise” a component or step are open and they include or read on those compositions or methods plus an additional component s) or step(s).
  • those terms do not encompass unrecited elements that would destroy the functionality of the disclosed compositions, devices, articles of manufacture or methods for its intended purpose.
  • compositions, devices, articles of manufacture or methods that "consist of' a component or step are closed and they would not include or read on those compositions or methods having appreciable amounts of an additional component(s) or an additional step(s).
  • the term “consisting essentially of’ admits for the inclusion of unrecited elements that have no material effect on the functionality of the disclosed compositions, devices, articles of manufacture or methods for its intended purpose as further defined herein.
  • the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
  • “About” as used herein when used in connection with a numeric value or range of values provided to describe a particular property of a compound or composition indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular property. Specifically, the term “about” when used in this context, indicates that the numeric value or range of values can vary by 5% of the recited value or range of values.
  • Alkyl refers to and includes saturated linear and branched univalent hydrocarbon structures and combination thereof, having the number of carbon atoms designated (z.e., Ci-Cio means one to ten carbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”).
  • alkyl groups are those having 1 to 8 carbon atoms (a “Ci-Cs alkyl”), 3 to 8 carbon atoms (a “Cs-Cs alkyl”), 1 to 6 carbon atoms (a “Ci-Ce alkyl”), 1 to 5 carbon atoms (a “C1-C5 alkyl”), or 1 to 4 carbon atoms (a “C1-C4 alkyl”).
  • alkyl examples include, but are not limited to, groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • Cycloalkyl refers to a C3-C10 saturated or unsaturated nonaromatic hydrocarbon ring group.
  • the cycloalkyl may have a bridge.
  • Examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl.
  • Halo refers to fluoro, chloro, bromo or iodo. In another embodiment, halo is fluoro. In another embodiment, halo is bromo.
  • Optionally substituted as used herein means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different.
  • an optionally substituted group has one substituent.
  • an optionally substituted group has two substituents.
  • an optionally substituted group has three substituents.
  • an optionally substituted group has four substituents.
  • an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5 substituents. It is understood that where a chemical moiety here is “optionally substituted,” the disclosure includes embodiments in which the moiety is substituted and embodiments in which the moiety is unsubstituted.
  • Alkylene diamine refers to a linear or branched alkyl group or cycloalkyl group substituted by two amine groups, each of which is optionally substituted with one substituent.
  • an alklylene diamine is a linear or branched alkyl group or cycloalkyl group substituted by two unsubstituted amine groups.
  • an alklylene diamine is a linear or branched alkyl group or cycloalkyl group substituted by two amine groups, each of which is substituted.
  • an alklylene diamine is a linear or branched alkyl group or cycloalkyl group substituted by two amine groups, each of which is substituted by a Ci-Ce alkyl group.
  • an alklylene diamine is a linear or branched alkyl group or cycloalkyl group substituted by two amine groups, each of which is substituted by a C1-C3 alkyl group.
  • an alklylene diamine is a linear or branched alkyl group or cycloalkyl group substituted by two amine groups, each of which is substituted by a methyl group.
  • an alklylene diamine is a linear alkyl group or a cycloalkyl group substituted by two amine groups, each of which is substituted by a methyl group.
  • exemplary alkylene diamines include trans-N,N'-dimethylcyclohexane-l,2-diamine and N,N’ -dimethylethylenediamine (DMEDA).
  • Each compound disclosed herein may be in a salt form.
  • the compound may contain at least one amino group, and accordingly acid addition salts can be formed with this amino group.
  • Exemplary salts include, without limitation, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(
  • a salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion.
  • the counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the salt can have multiple counter ions. Hence, a salt can have one or more charged atoms and/or one or more counterions.
  • the salt is a pharmaceutically acceptable salt.
  • a method of preparing a compound of Formula (1): or a salt thereof, comprising:
  • the compound of Formula (1) is not a salt.
  • the compound of Formula (1) is l-(2-((((lr,3r)-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide.
  • the compound of Formula (1) is a salt.
  • the compound of Formula (2) is not a salt.
  • the compound of Formula (2) is methyl l-(2- ((((lr,3r)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH- pyrrole-3 -carboxylate.
  • the compound of Formula (2) is a salt.
  • the compound of Formula (3) is not a salt.
  • the compound of Formula (3) is 5-bromo-N-((( l r,3r)-3-fluoro- l -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyrimidin-2-amine
  • the compound of Formula (3) is a salt.
  • none of compound of Formula (1), the compound of Formula (2), and the compound of Formula (3) are salts.
  • the compound of Formula (1), the compound of Formula (2), and the compound of Formula (3) are each salts.
  • one of compound of Formula (1), the compound of Formula (2), and the compound of Formula (3) is a salt.
  • two of compound of Formula (1), the compound of Formula (2), and the compound of Formula (3) are salts.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof comprises reacting the compound of Formula (2) or a salt thereof with formamide in the presence of a base.
  • the base is an organic base.
  • organic bases include, without limitation, amine bases such as N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, ethanolamine; alkoxide bases such as methoxide, ethoxide, tert-butoxide; hydride bases such as sodium hydride; aromatic bases such as pyridine, picoline, lutidine, collidine; and the like.
  • the base is an inorganic base.
  • inorganic bases include, without limitation, carbonate bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; hydroxide bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide; phosphate bases such as potassium phosphate, sodium phosphate; and the like.
  • the base is sodium methoxide.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed in the presence of an organic solvent.
  • organic solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, di chloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), acetone, acetonitrile (MeCN), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetic acid, n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like.
  • the organic solvent is any compatible mixture of organic solvent such as those given as examples herein.
  • the organic solvent is free of water.
  • the organic solvent comprises water.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed in DMSO. It is understood that each description of the solvent may be combined with each description of base, the same as if each and every combination were specifically and individually listed.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed in DMSO in the presence of sodium methoxide.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed at a temperature of about 180 °C, about 170 °C, about 160 °C, about 150 °C, about 140 °C, about 130 °C, about 120 °C, about 110 °C, about 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed at a temperature of less than about 180 °C, about 170 °C, about 160 °C, about 150 °C, about 140 °C, about 130 °C, about 120 °C, about 110 °C, about 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed at a temperature of at least about 180 °C, at least about 170 °C, at least about 160 °C, at least about 150 °C, at least about 140 °C, at least about 130 °C, at least about 120 °C, at least about 110 °C, at least about 100 °C, at least about 90 °C, at least about 80 °C, at least about 70 °C, at least about 60 °C, at least about 50 °C, at least about 40 °C, at least about 30 °C, or at least about 20 °C.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed at a temperature of between about 180 °C and about 20°C, between about 150 °C and about 20°C, between about 110 °C and about 20°C, between about 100 °C and about 20°C, between about 100 °C and about 30°C, between about 90 °C and about 30°C, between about 80 °C and about 40°C, or between about 70 °C and about 50°C.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed at a temperature of about 40 °C to about 80 °C.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed at a temperature of about 60 °C. It is understood that each description of the temperature may be combined with each description of solvent and/or base, the same as if each and every combination were specifically and individually listed.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed in DMSO in the presence of sodium methoxide, at a temperature of about 60°C.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof is performed in DMSO in the presence of sodium methoxide, at a temperature of between about 80°C and about 40°C.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof further comprises crystallizing the compound of Formula (1) in water. In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof further comprises crystallizing the compound of Formula (1) in ethanol. In some embodiments, the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof further comprises crystallizing the compound of Formula (1) in n-propanol and water.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof further comprises crystallizing the compound of Formula (1) in n-propanol and water after heating to a temperature of between about 60°C and about 95°C.
  • the step of converting the compound of Formula (2) or a salt thereof to the compound of Formula (1) or a salt thereof comprises hydrolysis of the methyl ester of the compound of Formula (2) or a salt thereof to a carboxylic acid, and further reacting said carboxylic acid with ammonium hydroxide.
  • a method of preparing the compound of Formula (2) or a salt thereof comprising converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof comprises reacting the compound of Formula (3) or a salt thereof with a compound of Formula (4) or a salt thereof.
  • a compound of Formula (4) or a salt thereof may provide the benefit of lower cost relative to other reagents, such as cyano-lH-pyrrole.
  • the reaction of the compound of Formula (3) with the compound of Formula (4) is performed in the presence of a catalyst.
  • the catalyst is a transition metal catalyst.
  • the reaction is performed in the presence of a palladium catalyst.
  • the reaction is performed in the presence of cuprous iodide. In some embodiments, the reaction is performed in the presence of a base. In some embodiments, the reaction is performed in the presence of an organic base.
  • organic bases include, without limitation, amine bases such as N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, ethanolamine; alkoxide bases such as methoxide, ethoxide, tert-butoxide; hydride bases such as sodium hydride; aromatic bases such as pyridine, picoline, lutidine, collidine; and the like.
  • the base is an inorganic base.
  • inorganic bases include, without limitation, carbonate bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; hydroxide bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide; phosphate bases such as potassium phosphate, sodium phosphate; and the like.
  • the second base is potassium phosphate.
  • the reaction is performed in the presence of an amine, such as mono-, di-, tri-, or tetra substituted amine.
  • the reaction is performed in the presence of an alkylene diamine.
  • Exemplary alkylene diamines include, without limitation: ethyl- 1,2-diamine; N,N-dimethyl-ethyl-l,2- diamine; N,N-dimethyl-N’ -methyl-ethyl- 1 ,2-diamine; N,N-dibutyl-ethyl- 1 ,2-diamine; N,N,N’ ,N’ -tetramethyl-ethyl- 1 ,2-diamine; cylclohexyl- 1 ,2-diamine; trans-N,N’ - di ethylcyclohexyl- 1,2-diamine; trans-N,N’-diisopropylcyclohenxyl-l,2-diamine.
  • the alkylene diamine is trans-N,N'-dimethylcy cl ohexane- 1,2-diamine. In some embodiments, the alkylene diamine is N,N’ -dimethylethylenediamine (DMEDA). It is understood that each description of the catalyst, base, and alkylene diamine may be combined, the same as if each and every combination were specifically and individually listed.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in the presence of cuprous iodide, a base, and an alkylene diamine; in some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in the presence of cuprous iodide, a potassium phosphate, and an alkylene diamine; in some embodiments, the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in the presence of cuprous iodide, a base, and DMEDA.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine.
  • cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine is used in the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine.
  • DMEDA in the syntheses of the compounds described herein may provide the benefit of higher yield and/or the benefit of lower cost relative to other reagents, such as trans-N,N'-dimethylcyclohexane- 1,2-diamine.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in the presence of an organic solvent.
  • organic solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, di chloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), acetone, acetonitrile (MeCN), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetic acid, n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like.
  • the organic solvent is any compatible mixture of organic solvent such as those given as examples herein.
  • the organic solvent is free of water.
  • the organic solvent comprises water.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF. It is understood that each description of the solvent may be combined with each description of catalyst, base, and alkylene diamine, the same as if each and every combination were specifically and individually listed.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed at a temperature of about 110 °C, 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed at a temperature of less than about 110 °C, 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed at a temperature of at least about 110 °C, at least about 100 °C, at least about 90 °C, at least about 80 °C, at least about 70 °C, at least about 60 °C, at least about 50 °C, at least about 40 °C, at least about 30 °C, or at least about 20 °C.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed at a temperature of between about 110 °C and about 20°C, between about 110 °C and about 30°C, between about 110 °C and about 40°C, between about 100 °C and about 40°C, between about 90 °C and about 40°C, between about 90 °C and about 50°C, between about 90 °C and about 60°C, between about 80 °C and about 50°C, between about 80 °C and about 60°C, or between about 80 °C and about 70°C.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed at a temperature of about 75 °C. It is understood that each description of the temperature may be combined with each description of solvent, catalyst, base, and/or alkylene diamine, the same as if each and every combination were specifically and individually listed.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF at a temperature of about between about 50 °C and about 80 °C.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF in the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine, at a temperature of about between about 50 °C and about 80 °C.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF in the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine, at a temperature of about 65 °C, for instance, 65 ⁇ 5 °C.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF in the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine, at a temperature of about 65 °C.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof is performed in THF in the presence of cuprous iodide, potassium phosphate, and N,N’ -dimethylethylenediamine, at a temperature of about 65 °C.
  • the step of converting the compound of Formula (3) or a salt thereof to the compound of Formula (2) or a salt thereof further comprises crystallization of the compound of Formula (2).
  • the compound of Formula (2) is crystallized in methanol and water.
  • the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining the compound of Formula (3) by converting a compound of Formula (5) or a salt thereof, to the compound of Formula (3) or a salt thereof.
  • the step of converting the compound of Formula (5) or a salt thereof to the compound of Formula (3) or a salt thereof comprises reacting the compound of Formula (5) or a salt thereof with a compound of Formula (6) wherein X is chloro or fluoro, to obtain the compound of Formula (3) or a salt thereof.
  • X is chloro.
  • X is fluoro.
  • the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed in the presence of a base.
  • the base is an organic base.
  • organic bases include, without limitation, amine bases such as N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, ethanolamine; alkoxide bases such as methoxide, ethoxide, tert-butoxide; hydride bases such as sodium hydride; aromatic bases such as pyridine, picoline, lutidine, collidine; and the like.
  • the base is an inorganic base.
  • inorganic bases include, without limitation, carbonate bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; hydroxide bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide; phosphate bases such as potassium phosphate, sodium phosphate; and the like.
  • the base is sodium bicarbonate.
  • the base is diisopropylethylamine.
  • the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed in the presence of an organic solvent.
  • organic solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, di chloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), acetone, acetonitrile (MeCN), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), acetic acid, n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like.
  • the organic solvent is any compatible mixture of organic solvent such as those given as examples herein. In some embodiments, the organic solvent is free of water. In some embodiments, the organic solvent comprises water. In some embodiments, the reaction is performed in DMAc. In some embodiments, the reaction is performed in a mixture of DMAc and water. In some embodiments, the compound of Formula (5) or a salt thereof is provided as a solution in methanol. In some embodiments, the reaction is performed in a mixture of DMAc and methanol. In some embodiments, the reaction is performed in NMP. It is understood that each description of the solvent may be combined with each description of the compound of Formula (6) and/or the base, the same as if each and every combination were specifically and individually listed.
  • the compound of Formula (6) is 2-chloro-5-bromopyrimidine, and the reaction is performed in DMAc and methanol in the presence of sodium bicarbonate.
  • the compound of Formula (6) is 2-fluoro-5-bromopyrimidine, and the reaction is performed in NMP in the presence of diisopropylethylamine.
  • the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed at a temperature of about 160 °C, about 150 °C, about 140 °C, about 130 °C, about 120 °C, about 110 °C, about 100 °C, about 90 °C, about 80 °C, about 75 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C.
  • the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed at a temperature of less than about 160 °C, about 150 °C, about 140 °C, about 130 °C, about 120 °C, about 110 °C, about 100 °C, about 90 °C, about 80 °C, about 75 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C.
  • the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed at a temperature of at least about 160 °C, about 150 °C, about 140 °C, about 130 °C, about 120 °C, about 110 °C, about 100 °C, about 90 °C, about 80 °C, about 75 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, or about 20 °C.
  • the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed at a temperature of between about 160 °C and about 20°C, between about 150 °C and about 30 °C, between about 120 °C and about 40°C, between about 110 °C and about 50°C, between about 100 °C and about 60°C, or between about 80 °C and about 70°C.
  • the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed at a temperature of about 75 °C.
  • the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed at room temperature or at a temperature of about 25 °C.
  • the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed in DMAc in the presence of sodium bicarbonate, at a temperature of about 75 °C; in some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed in DMAc and methanol in at a temperature of about 75 °C; in some embodiments, the reaction of the compound of Formula (5) or a salt thereof with a compound of Formula (6) is performed in DMAc and methanol in the presence of sodium bicarbonate, at a temperature of about 75 °C.
  • the compound of Formula (3) is isolated as a solid. In some such embodiments, the compound of Formula (3) is precipitated as a solid upon addition of water. In other embodiments, the compound of Formula (6) is 2-fluoro-5-bromopyrimidine, and the reaction is performed in NMP in the presence of diisopropylethylamine, at room temperature.
  • the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining the compound of Formula (5) by converting a compound of Formula (7) to the compound of Formula (5) or a salt thereof.
  • the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof comprises reacting the compound of Formula (7) with H2.
  • the reaction of the compound of Formula (7) with EE is performed at a pressure of about 0.5 MPa or between about 0.45 MPa and about 0.90 MPa.
  • the reaction of the compound of Formula (7) with H2 is performed at a pressure of between about 0.45 MPa and about 0.48 MPa.
  • the reaction of the compound of Formula (7) with H2 is performed at a pressure of 0.465 MPa ⁇ 0.015 MPa.
  • the reaction of the compound of Formula (7) with H2 is performed in the presence of a hydrogenation catalyst, such as a nickel, palladium, or platinum catalyst.
  • a hydrogenation catalyst such as a nickel, palladium, or platinum catalyst.
  • the catalyst is Raney nickel, also known as sponge nickel.
  • the reaction is performed in the presence of a base. Examples of bases include ammonia, sodium hydroxide, or potassium hydroxide. In some embodiments, the reaction is performed in the presence of ammonia.
  • the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed in the presence of an organic solvent.
  • organic solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, 1,4-di oxane, tetrahydrofuran (THF), n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like.
  • the organic solvent is any compatible mixture of organic solvent such as those given as examples herein.
  • the organic solvent is free of water.
  • the organic solvent comprises water.
  • converting the compound of Formula (7) to the compound of Formula (5) comprises reacting the compound of Formula (7) with Fb with Raney nickel in the presence of ammonia in methanol.
  • converting the compound of Formula (7) to the compound of Formula (5) comprises reacting the compound of Formula (7) with Fb at a pressure of between about 0.45 MPa and about 0.48 MPa with Raney nickel in the presence of ammonia in methanol.
  • the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed at a temperature of about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 0 °C, about -10 °C, or about -20 °C. In some embodiments, the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed at a temperature of less than about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 0 °C, about -10 °C, or about -20 °C.
  • the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed at a temperature of at least about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 0 °C, about -10 °C, or about -20 °C.
  • the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed a temperature of between about 60 °C and about -20°C, between about 50 °C and about -10°C, between about 50 °C and about 0°C, between about 50 °C and about 10°C, between about 40 °C and about 20°C, or between about 35 °C and about 25 °C.
  • the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed at a temperature of about 30 °C. It is understood that each description of the temperature may be combined with each description of solvent and/or base, the same as if each and every combination were specifically and individually listed.
  • the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed in methanol in the presence of Fb, Raney nickel, and ammonia, at a temperature of between about 40 °C and about 20°C, at a temperature of between about 35 °C and about 25°C or at a temperature of about 30 °C.
  • the step of converting the compound of Formula (7) to the compound of Formula (5) or a salt thereof is performed in methanol in the presence of Fb at a pressure of between about 0.45 MPa and about 0.48 MPa, Raney nickel, and ammonia, at a temperature of between about 40 °C and about 20°C, of between about 35 °C and about 25 °C, or at a temperature of about 30 °C.
  • the compound of Formula (5) is obtained as a solution in methanol.
  • the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining the compound of Formula (7) by converting a compound of Formula (8) to the compound of Formula (7).
  • the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in the presence of a fluorinating agent.
  • fluorinating agents include, without limitation, diethylaminosulfur trifluoride (DAST), 2,2- difhioro-l,3-dimethylimidazolidine (DFI), Selectfluor, N-fluorobenzenesulfonimide (NF SI), tri ethylamine trihydrofluoride (TREAT -HF), and perfluorobutane sulfonyl fluoride (PBSF).
  • the fluorinating agent is perfluorobutane sulfonyl fluoride (PBSF).
  • the step of converting the compound of Formula (8) to the compound of Formula (7) is performed by subjecting the compound of Formula (8) to PBSF followed by TREAT-HF.
  • PBSF reagents
  • the fluorinating agent is DAST.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in the presence of a base.
  • the reaction is performed in the presence of an organic base.
  • organic bases include, without limitation, amine bases such as N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, ethanolamine; alkoxide bases such as methoxide, ethoxide, tert-butoxide; hydride bases such as sodium hydride; aromatic bases such as pyridine, picoline, lutidine, collidine; and the like.
  • the base is an inorganic base.
  • inorganic bases include, without limitation, carbonate bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; hydroxide bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide; phosphate bases such as potassium phosphate, sodium phosphate; and the like.
  • the base is triethylamine.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in the absence of a base. It is understood that each description of the base may be combined with each description of the fluorinating agent, the same as if each and every combination were specifically and individually listed.
  • converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF in the presence of triethylamine, optionally followed by reaction with triethylamine trihydrofluoride (TREAT- HF).
  • converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF in the presence of tri ethylamine.
  • converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF in the presence of triethylamine, followed by reaction with TREAT -HF.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in the presence of an organic solvent.
  • organic solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, dichloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), acetone, acetonitrile (MeCN), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetic acid, n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like.
  • the organic solvent is any compatible mixture of organic solvent such as those given as examples herein. In some embodiments, the organic solvent is free of water. In some embodiments, the organic solvent comprises water. In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in toluene. In some embodiments, the compound of Formula (8) is provided as a solution in toluene. In some embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in dichloromethane. It is understood that each description of the solvent may be combined with each description of fluorinating agent and/or base, the same as if each and every combination were specifically and individually listed.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF and tri ethylamine in toluene; in other embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF and triethylamine in toluene followed by reaction with TREAT -HF. In other embodiments, the step of converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with DAST in di chloromethane.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) is performed at a temperature of about 110°C, about 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 0 °C, about -10 °C, about -20 °C, about -30 °C, about -40 °C, about -50 °C, about -60 °C, about -70 °C, or about -80 °C.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) is performed at a temperature of less than about 110°C, about 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 0 °C, about -10 °C, about -20 °C, about -30 °C, about -40 °C, about -50 °C, about -60 °C, about -70 °C, or about -80 °C.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) is performed at a temperature of at least about 110°C, about 100 °C, about 90 °C, about 80 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 0 °C, about -10 °C, about -20 °C, about -30 °C, about -40 °C, about -50 °C, about -60 °C, about -70 °C, or about -80 °C.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) is performed at a temperature of between about 110°C and about -80 °C, between about 60°C and about -80 °C, between about 30°C and about -30 °C, between about 20°C and about -20 °C, between about 15°C and about -10 °C, between about 15°C and about -5 °C, between about 10°C and about -5 °C, or between about 10°C and about 0 °C. It is understood that each description of the solvent may be combined with each description of fluorinating agent and/or base, the same as if each and every combination were specifically and individually listed.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) is performed in toluene at a temperature of between about 10 °C and about -5 °C.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF and tri ethylamine in toluene at a temperature of between about 10 °C and about -5 °C.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF and tri ethylamine in toluene at a temperature of between about 10 °C and about -5 °C, followed by reaction with TREAT -HF in toluene at a temperature of between about 10 °C and about -5 °C.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) comprises combining the compound of Formula (8) with DAST in di chloromethane at a temperature of between about -5 °C and about 10°C, followed by heating to a temperature of about 40 °C.
  • the compound of Formula (7) is obtained as a solid.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) is followed by crystallization of the compound of Formula (7).
  • the compound of formula (7) is crystallized in n-propanol and water.
  • the step of converting the compound of Formula (8) to the compound of Formula (7) comprises reacting the compound of Formula (8) with PBSF and tri ethylamine in toluene at a temperature of between about 10 °C and about 0 °C, followed by reaction with TREAT -HF in toluene at a temperature of between about 10 °C and about 0 °C, followed by crystallization of the compound of Formula (7).
  • the reaction yields a mixture of the compound of Formula (7) (the cis isomer) and the trans isomer of the compound of Formula (7), wherein the mixture comprises not more than 1.5% of the trans isomer.
  • the reaction yields a mixture of the compound of Formula (7) (the cis isomer) and the trans isomer of the compound of Formula (7) at a ratio of about 240: 1 (cis:trans).
  • the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining the compound of Formula (8) by converting a compound of Formula (9) to the compound of Formula (8).
  • the step of converting the compound of Formula (9) to the compound of Formula (8) is performed by reacting the compound of Formula (9) with a reducing agent.
  • reducing agents include, without limitation, sodium borohydride, lithium aluminum hydride, borane, triethylsilane, phenylsilane, diphenylsilane, diphenylchlorosilane, trichlorosilane, tetraphenyldisilane, tris(trimethylsilyl)silane, and the like.
  • the reducing agent is a silane.
  • the reducing agent is triethylsilane (TES).
  • the reduction of the compound of Formula (9) to the compound of Formula (8) is a stereoselective reduction.
  • the reducing agent is sodium borohydride.
  • the step of converting the compound of Formula (9) to the compound of Formula (8) comprises a stereoselective reduction of the compound of Formula (9).
  • the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) and the cis isomer of the compound of Formula (8).
  • the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) and its cis isomer at a ratio of about 1.5: 1 (trans:cis).
  • the reducing agent is sodium borohydride.
  • the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) and its cis isomer at a ratio of at least about 20:1.
  • the reducing agent is triethylsilane (TES).
  • the reaction of the compound of Formula (9) with a reducing agent yields a mixture of the compound of Formula (8) (the trans isomer) and its cis isomer, wherein the compound of Formula (8) (the trans isomer) comprises about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% of the mixture.
  • the reducing agent is triethylsilane (TES).
  • the reaction of the compound of Formula (9) with a reducing agent yields a mixture of the compound of Formula (8) (the trans isomer) and its cis isomer, wherein the compound of Formula (8) (the trans isomer) comprises at least about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% of the mixture.
  • the reducing agent is triethylsilane (TES).
  • the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) which is substantially free of the cis isomer.
  • the reducing agent is TES and the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) and its cis isomer at a ratio of between about 23: 1 and about 30:1 (trans:cis).
  • the reducing agent is TES and the reaction of the compound of Formula (9) with a reducing agent yields a mixture of the compound of Formula (8) (the trans isomer) and its cis isomer, wherein the compound of Formula (8) (the trans isomer) comprises at least about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% of the mixture.
  • the step of converting the compound of Formula (9) to the compound of Formula (8) is performed in the presence of a solvent.
  • solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, dichloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), acetone, acetonitrile (MeCN), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), acetic acid, n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like.
  • the solvent comprises an acid.
  • the acid is any compatible mixture of acids.
  • the acid comprises water.
  • the acid is free of water.
  • acid solvents include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidyl acid, trifluoroacetic acid, and the like.
  • the solvent comprises trifluoroacetic acid. It is understood that each description of the acid may be combined with each description of the reducing agent, the same as if each and every combination were specifically and individually listed.
  • converting the compound of Formula (9) to the compound of Formula (8) comprises reacting the compound of Formula (9) with triethylsilane in the presence of trifluoroacetic acid.
  • converting the compound of Formula (9) to the compound of Formula (8) comprises reacting the compound of Formula (9) with triethylsilane in the presence of trifluoroacetic acid, followed by pH adjustment to basic pH.
  • converting the compound of Formula (9) to the compound of Formula (8) comprises reacting the compound of Formula (9) with triethylsilane in the presence of trifluoroacetic acid, followed by pH adjustment to pH of from about 8.5 to about 9.5 using an aqueous base. In some embodiments, converting the compound of Formula (9) to the compound of Formula (8) comprises reacting the compound of Formula (9) with triethylsilane in the presence of trifluoroacetic acid, followed by pH adjustment to pH of about 9 using an aqueous base.
  • aqueous bases include, without limitation, carbonate bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate; hydroxide bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide; phosphate bases such as potassium phosphate, sodium phosphate; and the like.
  • the reducing agent is TES and the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) and its cis isomer at a ratio of between about 23: 1 and about 30: 1.
  • the reducing agent is TES and the reaction of the compound of Formula (9) with a reducing agent yields a mixture of the compound of Formula (8) (the trans isomer) and its cis isomer, wherein the compound of Formula (8) (the trans isomer) comprises at least about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% of the mixture.
  • the step of converting the compound of Formula (9) to the compound of Formula (8) comprises reacting the compound of Formula (8) with sodium borohydride in di chloromethane and methanol.
  • the step of converting the compound of Formula (9) to the compound of Formula (8) is performed at a temperature of about 72 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 5 °C, about 0 °C, about -5 °C, about -10 °C, or about -15 °C.
  • the step of converting the compound of Formula (9) to the compound of Formula (8) is performed at a temperature of less than about 72 °C, about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 5 °C, about 0 °C, about -5 °C, or about -10 °C.
  • the step of converting the compound of Formula (9) to the compound of Formula (8) is performed at a temperature of at least about 70 °C, about 60 °C, about 50 °C, about 40 °C, about 30 °C, about 20 °C, about 10 °C, about 5 °C, about 0 °C, about -5 °C, about -10 °C, or about -15 °C.
  • the step of converting the compound of Formula (9) to the compound of Formula (8) or a salt thereof is performed a temperature of between about 70 °C and about -15°C, between about 60 °C and about -15°C, between about 50 °C and about -15°C, between about 40 °C and about -15°C, between about 30 °C and about -15°C, between about 25 °C and about -15°C, between about 20 °C and about -15°C, between about 15 °C and about -15°C, between about 10 °C and about -15°C, between about 5 °C and about -15°C, between about 5 °C and about -10°C, or between about 5 °C and about -5°C.
  • the step of converting the compound of Formula (9) to the compound of Formula (8) or a salt thereof is performed a temperature of about 0 °C. It is understood that each description of the temperature may be combined with each description of reducing agent and/or acid, the same as if each and every combination were specifically and individually listed.
  • the step of converting the compound of Formula (9) to the compound of Formula (8) or a salt thereof is performed in the presence of triethylsilane and trifluoroacetic acid, at a temperature of about 0 °C.
  • the reducing agent is TES and the reaction of the compound of Formula (9) with a reducing agent yields the compound of Formula (8) (the trans isomer) and its cis isomer at a ratio of between about 23: 1 and about 30: 1.
  • the reducing agent is TES and the reaction of the compound of Formula (9) with a reducing agent yields a mixture of the compound of Formula (8) (the trans isomer) and its cis isomer, wherein the compound of Formula (8) (the trans isomer) comprises at least about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% of the mixture.
  • the compound of Formula (8) is obtained as a solution in toluene.
  • the step of converting the compound of Formula (9) to the compound of Formula (8) comprises reacting the compound of Formula (8) with sodium borohydride in the presence of dichloromethane and methanol at a temperature of about -78° C.
  • the compound of Formula (8) is purified by recrystallization.
  • recrystallization yields the compound of Formula (8) (the trans isomer) and its cis isomer at a ratio of up to 241 : 1.
  • the method of preparing the compound of Formula (1) or Formula (2) further comprises preparing the compound of Formula (9).
  • preparation of the compound of Formula (9) comprises reacting the compound of the Formula (Al) with an aqueous acid to obtain the compound of Formula (9). [0065] In some embodiments, preparation of the compound of Formula (9) further comprises reacting the compound of Formula (A2) with 2-chl oro-3 -fluoropyridine to obtain the compound of Formula (Al). In some such embodiments, preparation of the compound of Formula (9) further comprises converting the compound of Formula (A3) to the compound of Formula (A2). In some such embodiments, preparation of the compound of Formula (9) further comprises converting the compound of Formula (A4) to the compound of Formula (A3). In some such embodiments, preparation of the compound of Formula (9) further comprises converting the compound of Formula (A5) to the compound of Formula (A4).
  • preparation of the compound of Formula (9) comprises reacting l,3-dibromo-2,2-dimethoxypropane with tert-butyl 2-cyanoacetate to obtain the compound of Formula (A2), and converting the compound of Formula (A2) to the compound of Formula (9).
  • preparation of the compound of Formula (9) comprises converting a compound of Formula (Cl) to the compound of Formula (9).
  • preparation of the compound of Formula (9) comprises converting a compound of Formula (C2) to the compound of Formula (Cl), and converting the compound of Formula (Cl) to the compound of Formula (9).
  • the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining the compound of Formula (4) by converting methyl l-tosyl-lH-pyrrole-3-carboxylate to the compound of Formula (4).
  • the step of converting methyl l-tosyl-lH-pyrrole-3- carboxylate to the compound of Formula (4) comprises tosyl deprotection of methyl 1-tosyl- lH-pyrrole-3-carboxylate.
  • the step of converting methyl 1-tosyl-lH- pyrrole-3 -carboxylate to the compound of Formula (4) comprises reacting methyl 1-tosyl-lH- pyrrole-3 -carboxylate with a base.
  • the base is an alkoxide base.
  • the base is sodium methoxide.
  • the step comprises reacting methyl l-tosyl-lH-pyrrole-3-carboxylate with sodium methoxide in methanol. In some embodiments, the step comprises reacting methyl l-tosyl-lH-pyrrole-3-carboxylate with sodium methoxide in methanol at a temperature of between about 30 °C and about 20 °C.
  • the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining methyl l-tosyl-lH-pyrrole-3-carboxylate by converting l-tosyl-lH-pyrrole-3-carboxylic acid to methyl l-tosyl-lH-pyrrole-3-carboxylate.
  • the step of converting l-tosyl-lH-pyrrole-3-carboxylic acid to methyl l-tosyl-lH-pyrrole-3-carboxylate comprises esterification of 1-tosyl-lH- pyrrole-3 -carboxylic acid.
  • the step of converting 1 -tosyl- IH-pyrrole- 3-carboxylic acid to methyl l-tosyl-lH-pyrrole-3-carboxylate comprises reacting 1-tosyl-lH- pyrrole-3 -carboxylic acid with thionyl chloride.
  • the step of converting l-tosyl-lH-pyrrole-3-carboxylic acid to methyl l-tosyl-lH-pyrrole-3-carboxylate comprises reacting l-tosyl-lH-pyrrole-3-carboxylic acid with thionyl chloride in methanol. In some embodiments, the step comprises reacting l-tosyl-lH-pyrrole-3-carboxylic acid with thionyl chloride in methanol at a temperature of between about 60 °C and about 75 °C.
  • the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining l-tosyl-lH-pyrrole-3-carboxylic acid by converting l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one to l-tosyl-lH-pyrrole-3-carboxylic acid.
  • the step of converting l-(l-tosyl-lH-pyrrol-3-yl)ethan-l- one to l-tosyl-lH-pyrrole-3-carboxylic acid comprises reacting l-(l-tosyl-lH-pyrrol-3- yl)ethan-l-one with sodium hypobromite. In some embodiments, the step comprises reacting l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one with sodium hypobromite in water and 1,4-dioxane.
  • the step comprises reacting l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one with sodium hypobromite in water and 1,4-dioxane at a temperature of between about 0 °C and about 10 °C. In some embodiments, the step comprises reacting l-(l-tosyl-lH-pyrrol-3- yl)ethan-l-one with sodium hypobromite in water and 1,4-dioxane at a temperature of between about -5 °C and about 10 °C.
  • the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one by converting 1 -tosyl- IH-pyrrole to l-(l-tosyl-lH-pyrrol-3-yl)ethan-l-one.
  • the step of converting 1-tosyl-lH-pyrrole to 1-(1 -tosyl- 1H- pyrrol-3-yl)ethan-l-one comprises reacting 1 -tosyl- IH-pyrrole with acetic anhydride in the presence of aluminum trichloride. In some embodiments, the step comprises reacting 1-tosyl- IH-pyrrole with acetic anhydride in the presence of aluminum trichloride in dichloromethane.
  • the step comprises reacting 1 -tosyl- IH-pyrrole with acetic anhydride in the presence of aluminum trichloride in di chloromethane at a temperature of between about 0 °C and about 40 °C.
  • the method of preparing the compound of Formula (1) or Formula (2) further comprises obtaining 1-tosyl-lH-pyrrole by converting pyrrole to 1-tosyl- IH-pyrrole.
  • the step of converting pyrrole to 1 -tosyl- IH-pyrrole comprises reacting pyrrole with tosyl chloride in the presence of a base.
  • the base is sodium hydroxide.
  • the step of converting pyrrole to 1 -tosyl- IH-pyrrole comprises reacting pyrrole with tosyl chloride in the presence of sodium hydroxide and dichloromethane.
  • the step of converting pyrrole to 1 -tosyl- IH-pyrrole comprises reacting pyrrole with tosyl chloride in the presence of sodium hydroxide and di chloromethane at a temperature of between about 0 °C and about 30 °C.
  • the methods of preparing a compound of Formula (1) or a salt thereof further comprise crystallization of the compound of Formula (1).
  • crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) in an organic solvent.
  • solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-di oxane, di chloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), acetone, acetonitrile (MeCN), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetic acid, n-butanol, isopropanol, n-propanol, ethanol, and methanol and the like.
  • the solvent is any compatible mixture of solvent such as those given as examples herein.
  • the solvent is free of water.
  • the solvent comprises water.
  • the solvent is n-propanol.
  • the solvent is n-propanol and water.
  • the crystallization of the compound of Formula (1) is performed at a temperature of about 97 °C, about 95 °C, about 90 °C, about 85 °C, about 80 °C, about 75 °C, about 70 °C, or about 65 °C.
  • the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) in the solvent at a temperature of at least about 97 °C, about 95 °C, about 90 °C, about 85 °C, about 80 °C, about 75 °C, about 70 °C, or about 65 °C. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) in the solvent at a temperature of less than about 97 °C, about 95 °C, about 90 °C, about 85 °C, about 80 °C, about 75 °C, about 70 °C, or about 65 °C.
  • the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) in the solvent at a temperature of between about 97 °C and about 65 °C, between about 97 °C and about 75 °C, between about 97 °C and about 80 °C, between about 95 °C and about 80 °C, or between about 90 °C and about 80 °C.
  • the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) in the solvent at a temperature of about 85 °C.
  • the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) in the solvent, followed by stepwise cooling of the compound of Formula (1) in the solvent.
  • the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) to about 85 °C in a mixture of water and n-propanol, followed by stepwise cooling of the compound of Formula (1) in the solvent. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) to about 85 °C in a mixture of water and n-propanol, followed by cooling to about 70 °C. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) to about 85 °C in a mixture of water and n-propanol, followed by cooling to about 70 °C, followed by cooling to about 40 °C.
  • the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) to about 85 °C in a mixture of water and n- propanol, followed by cooling to about 70 °C, adding seed crystals, and cooling to about 40 °C. In some embodiments, the crystallization of the compound of Formula (1) comprises heating the compound of Formula (1) to about 85 °C in a mixture of water and n-propanol, followed by diluting with additional water and n-proppanol, cooling to about 70 °C, adding seed material of the compound of Formula (1), and cooling to about 40 °C.
  • seed material of the compound of Formula (1) is obtained from a previous batch of crystalline compound of Formula (1). In some embodiments, seed material of the compound of Formula (1) is obtained by heating the compound of Formula (1) in ethanol. In some embodiments, seed material of the compound of Formula (1) is obtained by refluxing the compound of Formula (1) in ethanol. In some embodiments, seed material of the compound of Formula (1) is obtained by refluxing the compound of Formula (1) in ethanol followed by polish filtration. In some embodiments, seed material of the compound of Formula (1) is obtained by refluxing the compound of Formula (1) in ethanol followed by polish filtration and cooling to a temperature of 20 °C to 25 °C.
  • a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent.
  • protecting groups may be used to protect certain functional groups (amino, carboxy, or side chain groups) from reaction conditions, and that such groups are removed under standard conditions when appropriate.
  • enantiomer of a compound may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g. a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described. [0082] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • Scheme 1 A illustrates a scheme of synthesizing the compound of Formula (9).
  • Scheme IB illustrates an alternative scheme of synthesizing the compound of
  • Scheme 1C illustrates a second alternative scheme of synthesizing the compound of Formula (9).
  • Scheme 2 A illustrates a scheme converting the compound of Formula (9) to the compound of Formula (5).
  • Scheme 2B illustrates an alternative scheme converting the compound of Formula (9) to the compound of Formula (5).
  • Scheme 3A illustrates a scheme of converting the compound of Formula (5) to the compound of Formula (1).
  • Scheme 3B illustrates an alternative scheme of converting the compound of
  • Scheme 4 illustrates a scheme of synthesizing a compound of Formula (4).
  • Scheme 5 illustrates a synthetic route to the preparation of the compound of Formula (1) from the compound of Formula (9).
  • Scheme 6 illustrates a synthetic route to the preparation of the compound of Formula (1) from the compound of Formula (9).
  • a first reactor was charged with methylene chloride (699.2 kg) and aluminum chloride (294.2 kg, 3.7 eq.). The reaction mixture was cooled to 0 - 5 °C. Acetic anhydride (158.2 kg, 2.6 eq.) was added, and the mixture was stirred for not less than 10 minutes, while maintaining a temperature of between 20 - 25 °C.
  • a second reactor was charged with methylene chloride (349.6 kg) and N-tosyl pyrrole (131.9 kg, 1.0 eq.). The N-tosyl pyrrole solution was slowly added to the first reactor and the mixture was stirred for not less than 2 hours, while maintaining the temperature below 40 °C (Target 35 °C).
  • the organic layer was concentrated under reduced pressure at a temperature of not more than 70 °C to yield solid l-(l-tosyl-lH-pyrrol- 3-yl)ethan-l-one.
  • Methylene chloride (349.6 kg) was added to the solids and the mixture was heated to 30 - 35 °C to dissolve the solids.
  • Heptane (902.4 kg) was added, and the mixture was stirred for not more than 2 hours at 20 - 25 °C to crystallize the solids.
  • the solids were isolated by filtration and washed with heptane (90.2 kg). The solids were isolated and dried for not less than 8 hours at 45 - 55 °C to yield 123.5 kg l-(l-tosyl-lH-pyrrol-3-yl)ethan-l- one (79% yield).
  • a first reactor was charged with water (1632.7 kg) and sodium hydroxide (301.3 kg, 15.8 eq.) and the mixture was cooled to a temperature of -5 - -10 °C.
  • Bromine 234.2 kg, 3.0 eq.
  • a second reactor was charged with 1,4-dioxane (1946.0 kg), 1-(1- tosyl-lH-pyrrol-3-yl)ethan-l-one (124.5 kg, 1.0 eq.), and water (753.6 kg) and the mixture was cooled to 0 °C.
  • the content of the first reactor were transferred to the second reactor over the course of approximately 1.5 hours, at a rate to maintain an internal temperature below 10 °C.
  • the mixture was stirred for 2 hours.
  • Hydrochloric acid (35%) (602.8 kg) was added to acidify the reaction mixture to a pH of 1 - 2.
  • Methylene chloride (1664.1 kg) was added and the mixture was stirred for not less than 1 hour.
  • the organic layer was isolated.
  • Anhydrous sodium sulfate (80.0 kg) was added and the mixture was stirred for 30 minutes.
  • a reactor was charged with methanol (800.1 kg) and N-tosylpyrrole-3 -carboxylic acid (97.0 kg, 1.0 eq.).
  • Thionyl chloride (65.6 kg, 1.5 eq.) was added to the reaction mixture over approximately 30 minutes, at a rate to maintain an internal temperature below 55 °C.
  • the reaction mixture was then heated to a temperature of 65 - 75 °C for not less than 1 hour.
  • the reaction mixture was concentrated under reduced pressure at a temperature of not more than 70 °C.
  • the crude residue containing methyl N-tosylpyrrole-3-carboxylate was used directly in the next reaction.
  • reaction mixture was concentrated under reduced pressure at a temperature of not more than 70 °C.
  • a reactor was vacuumed to ⁇ -0.08MPa and then inerted with nitrogen to atmosphere; this was repeated 3 times.
  • the reactor was charged with MeOH (290 kg) and stirring was started.
  • 3 -oxocyclobutanecarboxylic acid (compound of Formula (A5)) (70.7 kg, 619.6 mol, 1.0 eq.), Amberlyst-15 ion exchange resin (7.2 kg, 10% w/w), and trimethoxymethane (164 kg, 1545 mol, 2.5 eq.) were charged to the reactor.
  • the reaction mixture was heated to 60 ⁇ 5°C; the reaction was continued for 5.5 hour at 60 ⁇ 5°C.
  • the reactor was sampled for HPLC 3 -oxocyclobutanecarboxylic acid ⁇ 0.2%; then the mixture was cooled to below 15°C and centrifuged. The filter cake was washed with MeOH. The filtrate was pumped to the reactor and the solution was concentrated under vacuum below 55°C until the system was not more than 2 volumes (-142 L). The reactor was charged with MeOH (113 kg) and the solution was concentrated under vacuum below 55°C until the system is not more than 2 volumes. The reactor was charged again with MeOH (113 kg) and the solution was concentrated under vacuum below 55°C until the system is not more than 2 volumes. The solution was sampled for GC: Trimethoxymethane ⁇ 0.2 %.
  • Example 6 The solution from Example 6 was diluted with MeOH (434 kg) and cooled below 0°C. Continued to inject NH3 gas for 6 hr. Stirred for 5 days at 20°C ⁇ 25°C. Sampled for HPLC: Compound of formula (A4) ⁇ 0.6%. Concentrated the solution under vacuum below 55°C until the system is not more than 2 volumes (-142 L). Cooled to below 25°C. Charged TBME (160 kg) to reactor. Concentrated the solution under vacuum below 50°C until the system is not more than 2 volumes. Charged PE (130 kg) to reactor. Concentrated the solution under vacuum below 50°C until the system is not more than 2 volumes. Charged PE (260 kg) to reactor. Cooled to 5 ⁇ 5°C.
  • a reactor was vacuumed to ⁇ -0.08 MPa and then inerted with nitrogen. The process was repeated for three times.
  • the reactor was charged with toluene (394.4 kg) and stirred.
  • 3, 3 -dimethoxy cy cl obutane-1 -carboxamide (compound of formula (A3)) (90.0 kg, 565.4 mol, 1.0 eq.) and TEA (127.7 kg, 1262 mol, 2.2 eq) were charged to the reactor.
  • the reaction mixture was cooled to below 5°C.
  • TFAA 127.36 kg, 606 mol, 1.07 eq.
  • the organic phase was combined with the organic phase in batch l.
  • the aqueous phase was extracted with ethyl acetate (112 kg).
  • the organic phase was washed with sat. NaCl (169.35 kg).
  • the collected organic phases were concentrated under vacuum below 70°C until the system was not more than 2 volumes (-136 L).
  • the organic phases were sampled for HPLC 95% and the concentrated l-(3-fluoropyridin-2-yl)-3,3- dimethoxycyclobutane-1 -carbonitrile (compound of formula (Al)) residue was used in the next step.
  • a reactor was charged with water (608 kg) and stirred. The reactor was charged portionwise with cone. HC1 (176.33 kg) while maintaining the temperature below 35°C. l-(3- fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-l-carbonitrile (compound of formula (Al)) from Example 9 was charged to the reactor. The reaction mixture was heated to 50 ⁇ 5°C and was reacted for 4.5 hours at 50 ⁇ 5°C after completion addition.
  • the reaction mixture was cooled to below 30°C, and extracted with EtOAc (644.5 kg). The aqueous phase was extracted with EtOAc twice (439 kg, 229 kg).
  • the organic phases were combined and washed with a solution of NaHCOs (9% w/w) 315.5 kg and then a solution of sat.NaCl 365 kg.
  • the organic phases were concentrated under vacuum below 60°C until the system was not more than 2 volumes (-140 L).
  • the organic phases were cooled to below 40 °C, and the reactor was charged with i-propanol (159 kg).
  • the organic phases were concentrated under vacuum below 55°C until the system is not more than 1 volume.
  • the organic phases were cooled to below 25°C, and stirred for 2 hours at 25 ⁇ 5°C.
  • the reactor was charged with PE(164 kg), cooled to below 10°C, and stirred for 5 hour at 5 ⁇ 5°C, followed by centrifugation.
  • the wet cake was collected and sampled for HPLC anlaysis (purty 99.1%).
  • the filter cake was placed into vacuum oven and dried at 30 ⁇ 5°C for at least 10 hours.
  • the solid was packaged under nitrogen and stored at room temperature. 70.33 kg of 1 -(3 -fluoropyri din-2 -yl)-3 -oxocyclobutanecarbonitrile were obtained as an off-white solid. Yield 65.4% in three steps from 3,3-dimethoxycyclobutane-l-carbonitrile (compound of formula (A2)).
  • Trifluoroacetic acid (1120 L, 8.0 vol.) was added to a reactor followed by l-(3- fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile (the compound of formula (9)) (140.0 kg, 0.74 kmol, 1.00 equiv.) then triethylsilane (256.8 kg, 2.21 kmol, 3.00 equiv.) was added.
  • the upper layer was set aside, the middle layer was discarded to waste, and the lower layer was processed further.
  • the lower layer was extracted twice with toluene (420 L each, 3.0 vol.).
  • the toluene layers were combined and the upper organic layer that was set aside from the extraction was added.
  • the combined organic layer was washed twice with 5% aqueous sodium bicarbonate (420.0 L each of water + 22.1 kg each of sodium bicarbonate).
  • the organic layer was then washed with water (420 L, 3.0 vol.).
  • Two silica gel pressure filters were prepared with silica gel (56.0 kg, 40 wt% each) and toluene (350 L, 2.5 vol. each).
  • Seed crystal material (140 g, 0.1 wt%) was added and the slurry was stirred for 3 hours at 20 °C.
  • the seed material can be obtained from a previous batch following the procedure of this example, or can be prepared following the procedure described in Example 18.
  • the slurry was cooled to 0 °C over 3 hours and water (700 L, 5.0 vol.) was added.
  • the solid product was isolated from the heterogeneous mixture by centrifugation whereby the cake was washed twice with water (140 L each, 1.0 vol).
  • the reaction vessel was vacuum purged three time with nitrogen and then three times with Eb.
  • the vessel was pressurized to 0.465 ⁇ 0.015 MPa at 30 °C for 24 hours.
  • the reaction mixture was then purged with nitrogen and the spent catalyst was then removed by filtration and washed with methanol (225 L, 2.0 vol.).
  • the methanol fractions were combined and distilled to 338 L at ⁇ 40 °C, but not lower than 25 °C. Additional methanol (338 L, 2.0 vol.) was added and the mixture was again concentrated to 338 L at ⁇ 40 °C, but not lower than 25 °C.
  • reaction solids were isolated by centrifugation and the wet cake was washed with a 20% aqueous solution of NA -di methyl acetamide (451 L, water + 113 L of N,N- dimethylacetamide) and then with water (240 L, 2.1 vol.).
  • reaction vessel and charge lines were thoroughly flushed with nitrogen then THF (2044 L, 10.0 vol.) and TV, TV ’-dimethylethylene diamine (DMEDA), (60.9 kg, 0.69 kmol, 1.20 equiv.) were added.
  • the mixture was agitated at 65 °C for 20 hours and then cooled to 40 °C.
  • Additional THF (1022 L, 5.0 vol.) was added followed by celite (61.3 kg, 30 wt%), the suspension was cooled to 25 °C stirred at this temperature for 1 hour. The suspension was filtered.
  • the insoluble material, reactor and filter were washed with THF (818 L, 4.0 vol.).
  • the combined THF filtrates were concentrated at ⁇ 50 °C, and not below 25 °C, to 15.0 volumes (-3066 L) of residue.
  • the filtrate was washed four times with 10% NH4Q aqueous solution (613 L of water each + 68.1 kg of NH4Q each) until copper content was below 100 mg/L.
  • the reaction mixture was then washed with 10% aqueous sodium chloride solution (613 L of water + 153.3 kg of sodium chloride).
  • the organic layer was subsequently concentrated under reduced pressure to 5.0 volumes at a temperature of ⁇ 50 °C, and not below 25 °C.
  • Methanol (1022 L, 5.0 vol.) was then added over 30 minutes at 20 °C and the mixture was stirred at this temperature for an additional 2 hours.
  • Example 16 Preparation of l-(2-((((lr,3i')-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (compound of Formula (1)) fhioro-l-(3-fhioropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxylate (the compound of formula (2)), (205.7 kg, 0.52 kmol, 1.00 equiv.) was charged to a reaction vessel, followed by formamide (1029 L, 5.0 vol.) and DMSO (411.4 L, 2.0 vol.).
  • the mixture was heated to 85 °C to form a clear solution, filtered, and additional w-propanol (145 L, 0.75 vol.) and water (48 L, 0.25 vol.) were added.
  • the mixture was cooled to 70 °C and seed material (193 g, 0.10 wt%) was charged. (Seed material can be obtained from a previous batch following the procedures of this example or can be prepared as described in Example 18).
  • the reaction mixture was stirred for 5 hours and then cooled to 40 °C over 3 hours.
  • the reaction mixture was further cooled to 20 °C over 4 hours and stirring was continued for 2 hours then the reaction mixture was cooled to 0 °C over 2 hours and stirring was continued for an additional 2 hours.
  • Example 18 Alternate Crystallization of l-(2-((((lr,3 )-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (compound of Formula (1))
  • Batch 1 l-(2-((((lr,3r)-3-luoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (crude compound of formula (1)) (2.18 kg, 0.0057 kmol, 1.00 equiv.) was charged to a reactor and ethanol (87.7 L, 40 vol.) was added. The mixture was heated to reflux to dissolve the solids. The solution was polish filtered and then cooled to 20 °C.
  • Batch 2 The remaining portion of l-(2-((((lr,3r)-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-lH-pyrrole-3-carboxamide (compound of formula (1)) (2.17 kg, 0.0056 kmol, 1.00 equiv.) was then charged and ethanol (87.5 L, 40 vol.) was added. The heterogeneous mixture was heated to reflux and polish filtered.
  • Example 19 Alternate preparation of methyl 3,3-dimethoxycyclobutane-l-carboxylate (compound of formula (A4)) [0119] A reactor was vacuumed to 0.02 MPa or less and then inerted with nitrogen to atmosphere for three times.
  • Example 21 Alternate preparation of 3,3-dimethoxycyclobutane-l-carbonitrile (compound of Formula (A2)) MeO OMe TFAA y
  • a reactor was vacuumed to 0.02 MPa or less and then inerted with nitrogen to atmosphere three times.
  • Toluene (500.00 kg), 3,3-dimethoxycyclobutane-l-carboxamide (compound of formula (A3)) (112.54kg, 706.9 mol, 1.0 eq.), and TEA (158.00 kg, 1561.3 mol, 2.20 eq) were charged into the reactor and the resulting mixture was cooled to 0+ 5°C.
  • TFAA 164.00 kg, 781 mol, 1.10 eq.
  • the resulting mixture was stirred for 10 hours at 20 ⁇ 5°C and cooled below 5 ⁇ 5°C.
  • H2O (110.00 kg) was charged into the reactor at below 15 °C. The resulting mixture was stirred for 30 minutes and the water phase was separated. The aqueous phase was extracted with toluene (190.00 kg) twice. The organic phases were combined and washed with H2O (111.00 kg). H2O was removed by azeotrope until the water content was no more than 0.03%. The resulting solution was cooled to below 20°C to give 3, 3 -dimethoxy cy cl obutane-1 -carbonitrile (compound of formula (A2)) solution in toluene (492.00 kg with 17.83% assay content, 87.9% yield).
  • Example 22 Alternate preparation of l-(3-fluoropyridin-2-yl)-3,3- dimethoxycyclobutane-l-carbonitrile (compound of Formula (Al))
  • a reactor was vacuumed to 0.02 MPa or less and then inerted with nitrogen to atmosphere three times.
  • the 3, 3 -dimethoxy cyclobutane-1 -carbonitrile (compound of formula (A2)) solution in toluene prepared as described in Example 21 (246.00 kg of a 17.8% solution of 3,3-dimethoxycyclobutane-l-carbonitrile in toluene, 1.05 eq.) and 2-chl oro-3 - fluoropyridine (39.17 kg, 297.9 mol, 1.00 eq.) were charged into the reactor.
  • the reactor was vacuumed to 0.02 MPa and less and then inerted with nitrogen to atmosphere for three times.
  • Soft water (112.00 kg) was charged into the reactor and the aqueous phase was separated and collected.
  • the aqueous phase was extracted with ethyl acetate (70.00 kg) and an organic phase was collected.
  • the organic phase was washed with sat. NaCl (106.00 kg) and collected.
  • the above steps were repeated to obtain another batch of organic phase.
  • the two batches of organic phase were concentrated under vacuum below 70°C until the system had no more than 2 volumes.
  • the resulting solution was cooled to below 30°C to give a l-(3-fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-l-carbonitrile (compound of formula (Al)) solution.
  • a reactor was vacuumed to 0.02 MPa and less and then inerted with nitrogen to atmosphere for three times. Water (603.00 kg) was added to the reactor and was stirred. Concentrated HC1 (157.30 kg) was charged into the reactor at below 35°C. The l-(3- fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-l-carbonitrile (compound of Formula (Al)) solution prepared as described in Example 22 (206.00 kg) was charged into the reactor and the resulting mixture was heated to 50 ⁇ 5°C and reacted for 3 hours at 50 ⁇ 5°C.
  • the mixture was reacted until the content of l-(3-fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-l- carbonitrile was no more than 2.0% as measured by HPLC.
  • the reaction mixture was cooled to below 30°C and extracted with ethyl acetate (771.00 kg). An aqueous phase was collected and extracted with ethyl acetate (770.00 kg). The organic phases were combined and the combined organic phase was washed with soft water (290.00 kg) and brine (385.30 kg). The organic phase was concentrated under vacuum at below 60°C until the system had no more than 2 volumes. Propan-2-ol (218.00 kg) was charged into the reactor.
  • the organic phase was concentrated under vacuum at below 60°C until the system had no more than 1 volume.
  • PE (191.00 kg) was charged into the reactor at 40 ⁇ 5 °C and the resulting mixture was heated to 60 ⁇ 5 °C and stirred for 1 hour at 60 ⁇ 5 °C. The mixture was then slowly cooled to 5 ⁇ 5 °C and stirred for 5 hours at 5 ⁇ 5 °C. The mixture was centrifuged and the filter cake was washed with PE (48.00 kg) and the wet filter cake was collected. Water (80.00 kg), concentrated HC1 (2.20 kg), propan-2-ol (65.00 kg), and the wet filter cake were charged in this order into a drum. The resulting mixture was stirred for 10 minutes at 20 ⁇ 5 °C.
  • the mixture was centrifuged and the filter cake was washed with a mixture solution containing 18.00 kg of propan-2-ol, 22.50 kg of soft water, and 0.60 kg of concentrated HC1.
  • the filter cake was put into a vacuum oven and dried at 30 ⁇ 5°C for at least 10 hours. The filter cake was dried until the weight did not change to give 1 -(3 -fluoropyridin-2-yl)-3 -oxocyclobutanecarbonitrile (compound of formula (9)) as off-white solid (77.15 kg, 68.0% yield).
  • Example 24 Second alternate preparation of 3,3-dimethoxycyclobutane-l-carbonitrile (compound of Formula (A2))
  • Example 26 Second alternate preparation of l-(3-fluoropyridin-2-yl)-3-oxocyclobutane- 1-carbonitrile (compound of Formula (9))
  • Example 28 Alternate preparation of (ls,3s)-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutane-l-carbonitrile (compound of Formula (7))
  • Example 29 Alternate Preparation of ((lr,3i')-3-fluoro-l-(3-fluoropyridin-2- yl)cyclobutyl)methanamine (compound of Formula (5)).

Abstract

L'invention concerne un procédé de préparation de reldesemtiv et de sels de ce dernier. L'invention concerne également des intermédiaires utilisés dans ce procédé et leur préparation.
PCT/US2023/074681 2022-09-21 2023-09-20 Synthèse de reldesemtiv WO2024064745A1 (fr)

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