Method for preparing the compound carbamoyloxymethyltriazole cyclohexyl acid

Abstract

To provide improved methods and intermediates thereof for preparing carbamoyloxymethyl triazole cyclohexyl acid compounds.SOLUTION: There is provided a method of making a compound represented by a formula (XII) in the figure, or a stereoisomer or a salt thereof, where: R8 and R9 are independently N, CH or C(C1-6 alkyl); R10 is independently C1-4 alkyl or halogen; and R11 is independently Br, Cl or I.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 834,538, filed April 16, 2019, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present invention relates to an improved process for preparing carbamoyloxymethyltriazole cyclohexyl acid compounds and novel intermediates thereof. [Background technology]

[0003] Carbamoyloxymethyltriazole cyclohexyl acid LPA (particularly LPA1) antagonists have been described, which are useful for treating fibrosis.See, for example, WO 2017 / 223016 (US 2017 / 0360759).There is a need for an improved method for producing carbamoyloxymethyltriazole cyclohexyl acid compounds, which provides practical large-scale synthesis, and improves product quality, efficiency and safety. Summary of the Invention

[0004] The present invention provides a novel process for preparing the compound carbamoyloxymethyltriazole cyclohexyl acid, and novel intermediates thereof. Processes for preparing the intermediate compounds, their stereoisomers and salts are also described. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] The features and advantages of the present invention may be more readily understood by those skilled in the art upon reading the following detailed description. It will be appreciated that certain features of the invention that are described above and below in the context of separate embodiments for reasons of clarity may also be combined to form a single embodiment. In contrast, various features of the invention that are described in the context of a single embodiment for reasons of brevity may also be combined to form subcombinations thereof. Those skilled in the art will recognize that some chemical structures described herein may be represented on paper by one or more other resonance forms; or may exist in one or more other tautomeric forms, and even when kinetically depicted, those skilled in the art will recognize that such tautomeric forms represent only a small proportion of the samples of such compounds. Although such resonance forms or tautomers are not explicitly stated herein, it is clear that such compounds are contemplated within the scope of the present disclosure.

[0006] In embodiment 1A, the present invention provides a compound of formula (I): [ka] [In the formula, R 1 is C 1-6 R is alkyl; 2 and R 2a is a halogen] A method for preparing a compound having a structure represented by formula (III): [ka] [In the formula, R 1 is C 1-6 R is alkyl; 2 is a halogen; R 3 is a halogen] contacting a compound represented by the formula: with reagent 2 (an organolithium) in solvent 2 (a polar aprotic or a non-polar aprotic solvent, or a mixture of such solvents) for a time and at a temperature sufficient to effect lithium halogen exchange; followed by contacting with an alkylating agent in a solvent 3 (a polar, polar aprotic, or non-polar aprotic solvent, or a mixture of such solvents) for a time and at a temperature sufficient to effect alkylation; subsequently contacting with a strong acid to produce a compound of formula (I).

[0007] In embodiment 1B, the present invention provides a compound of formula (I): [ka] [In the formula, R 1 is C 1-6 R is alkyl; 2 and R 2a is a halogen] A method for producing a compound having a structure represented by (1) Formula (II): [ka] [In the formula, R 2 and R 3 are independently halogen. The compound represented by the formula: 5 -OM (metal-based alkoxide), M-OH (metal-based hydroxide), M2CO3 (metal-based carbonate), MHCO3 (metal-based bicarbonate), (R 6 ) 3N (tertiary amines), and mixtures thereof) with a solvent 1 (R 4 -OH, polar protic, polar aprotic, or non-polar aprotic solvent, or a mixture of such solvents, where M is a metal element selected from Li, Na, K, and Cs; R 4 , R 5 and R 6 is independently 1-6 followed by adding an alkylating agent for a time and at a temperature sufficient to effect alkylation; Formula (III): [ka] [In the formula, R 1 is C 1-6 R is alkyl; 2 is a halogen; R 3 is a halogen] and (2) contacting a compound of formula (III) with reagent 2 (an organolithium) in solvent 2 (a polar aprotic or a non-polar aprotic solvent, or a mixture of such solvents) for a time and at a temperature sufficient to effect lithium halogen exchange; followed by contacting with an alkylating agent in solvent 3 (a polar, polar aprotic, or a non-polar aprotic solvent, or a mixture of such solvents) for a time and at a temperature sufficient to effect alkylation; followed by contacting with a strong acid to produce a compound of formula (I).

[0008] In embodiment 2A, which is within the scope of embodiment 1A, the present invention provides a method for preparing a compound having a structure according to formula (I), comprising contacting a compound of formula (III) with reagent 2 (selected from n-BuLi, n-HexLi, and PhLi) in solvent 2 (selected from hexane, THF, MeTHF, and mixtures of these solvents) at −30 to −10° C. for a time sufficient to effect lithium halogen exchange, followed by contacting with an alkylating agent (selected from benzyl chloromethyl ether) at −30 to −10° C. for a time sufficient to effect alkylation, and with a strong acid (selected from HBr / acetic acid, or a mixture of acetyl bromide and 2-propanol) in solvent 3 (selected from THF, CHCN, IPAc, MeTHF, and mixtures of these solvents) to produce a compound of formula (I).

[0009] In embodiment 2B, which is within embodiment 1B, the present invention provides a method for preparing a compound having a structure according to formula (I), comprising the steps of: (1) contacting a compound of formula (II) with a metal-based alkoxide (selected from LiOtBu, K2CO3, KHCO3, Et3N, NaOtBu, KOtBu, LiOH, LiOH*H2O, LiOMe, and mixtures thereof) in a solvent 1 (selected from CH3CH2C(CH3)2OH, C(CH3)3OH, CH(CH3)2OH, CH3CH2OH, CH3OH, THF, EtOAc, IPAc, MeTHF, acetone, MIBK, CH3CN, NMP, DMF, DCM, H2O, and mixtures of these solvents) followed by an alkylating agent (selected from methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl tosylate, and mixtures thereof) for a period of 24 to 72 hours and at a temperature sufficient to effect alkylation to produce a compound of formula (III): and (2) contacting a compound of formula (III) with reagent 2 (selected from n-BuLi, n-HexLi, and PhLi) in solvent 2 (selected from hexane, THF, MeTHF, and mixtures of these solvents) for a time and at −30 to −10° C. sufficient to effect lithium halogen exchange, followed by contacting with an alkylating agent (selected from benzyl chloromethyl ether) for a time and at −30 to −10° C. sufficient to effect alkylation, and with a strong acid (selected from HBr / acetic acid, or a mixture of acetyl bromide and 2-propanol) in solvent 3 (selected from THF, CHCN, IPAc, MeTHF, and mixtures of these solvents) to produce a compound of formula (I).

[0010] In embodiment 3A, the present invention provides a compound of formula (Ia): [ka] A method for preparing a compound having a structure represented by formula (IIIa): [ka] with n-BuLi in hexane for <1 hour and at −30 to −10° C. sufficient to effect lithium halogen exchange, followed by benzyl chloromethyl ether for 5 to 24 hours and at −30 to −10° C. sufficient to effect alkylation, and 33 wt % HBr / acetic acid in CHCN to produce a compound of formula (Ia).

[0011] In embodiment 3B, the present invention provides a compound of formula (Ia): [ka] A method for producing a compound having a structure represented by (1) Formula (IIa): [ka] with a mixture of CH3CH2C(CH3)2OH and LiOtBu in THF at <40° C. for 1-2 hours; followed by addition of CH3I and aging for 24-48 hours to give a compound of formula (IIIa): [ka] and (2) contacting a compound of formula (IIIa) with n-BuLi / hexane for <1 hour and at −30 to −10° C. sufficient to effect lithium halogen exchange, followed by contacting with benzyl chloromethyl ether for 5 to 24 hours and at −30 to −10° C. sufficient to effect alkylation, and with 33 wt % HBr / acetic acid in CHCN to produce a compound of formula (Ia).

[0012] In embodiment 4A, the present invention provides a compound of formula (IV): [ka] [In the formula, R a -N(C 1-4 alkyl)2] or a salt thereof, comprising: Formula (V): [ka] [In the formula, R 6 is a halogen] With a compound represented by formula (VI): [ka] [In the formula, R a -N(C 1-4 alkyl)2] or a salt thereof, in the presence of an inorganic base and a phase transfer catalyst in solvent 4, which is a polar aprotic solvent, or a mixture of solvents, for a time and at a temperature sufficient to complete the reaction to produce a compound of formula (IV) or a salt thereof.

[0013] In embodiment 5A, within embodiment 4A, the present invention provides a compound of formula (IVa): [ka] or a salt thereof, comprising: The compound of formula (V) is reacted with a compound of formula (VIa): [ka] or a salt thereof with KHCO3 and (C 1-4 in the presence of 1,3-dialkyl-4NBr in a solvent 4 (selected from DMF, CHCN, NMP, DMAc, HMPA, DMPU, DME, THF, and mixtures of these solvents) for a time sufficient to complete the reaction and at 25-35° C. to produce a compound of formula (IVa) or a salt thereof.

[0014] In embodiment 6A, the present invention provides a compound of formula (IVb): [ka] A method for producing a compound having a structure represented by Formula (Va): [ka] With a compound represented by formula (VIa): [ka] in the presence of KHCO3 and (Et)4NBr in DMF at 25-35°C for a period of time sufficient to complete the reaction, ranging from 4 to 72 hours, to produce a compound of formula (IVb).

[0015] In embodiment 7A, the present invention provides a compound of formula (VII): [ka] [In the formula, R a -N(C 1-4 alkyl)2] or a stereoisomer or salt thereof, comprising the steps of: Formula (VIII): [ka] or a salt thereof, [ka] and, [ka] and 4-DMAP, with or without aqueous base, in solvent 5 (a non-polar solvent or mixture of solvents) for a time and at a temperature sufficient to complete the reaction, to produce a compound of formula (VII) or a stereoisomer or salt thereof.

[0016] In embodiment 8A, within embodiment 7A, the present invention provides a compound of formula (VIIa): [ka] or a salt thereof, comprising: A compound of formula (VIII) or a salt thereof [ka] in the presence of, with or without aqueous KOH, in a solvent 5 (selected from toluene, CHCl, trifluorotoluene, 1,2-dichlorobenzene, and mixtures of these solvents) at 25-35° C. for a time sufficient to complete the reaction to produce a compound of formula (VIIa) or a salt thereof.

[0017] In embodiment 9A, the present invention provides a compound of formula (VIIb): [ka] A method for producing a compound having a structure represented by A compound of formula (VIII) or a salt thereof [ka] in the presence of, with or without aqueous KOH, in toluene at 24-48 hours and 25-35° C. sufficient to complete the reaction, to produce a compound of formula (VIIb).

[0018] In embodiment 10A, the present invention provides a compound of formula (IX): [ka] [In the formula, R a -N(C 1-4 alkyl)2] or a stereoisomer or salt thereof, comprising the steps of: [ka] [In the formula, R a -N(C 1-4 alkyl)2] or a salt thereof, with a transition metal catalyst in the presence of a diprotic acid in solvent 6 (a protic or polar aprotic solvent or mixture of such solvents) for a time and at a temperature sufficient to effect ketone reduction to produce a compound of formula (IX) or a stereoisomer or salt thereof.

[0019] In embodiment 11A within embodiment 10A, the present invention provides a compound of formula (IXa): [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof, with a transition metal catalyst (IrCl4, IrCl4* hydrate or [Ir(COD)Cl]2) in the presence of phosphorous acid in a solvent 6 (IPA, MeOH, EtOH, t-AmOH, HO, NMP, DMF, DMAc, sulfolane, and mixtures of these solvents) at 65-100°C for a time sufficient to effect ketone reduction to produce a compound of formula (IXa) or a salt thereof.

[0020] In embodiment 12A, the present invention provides a compound of formula (IXb): [ka] A method for producing a compound of formula (VIIb): [ka] with IrCl4* hydrate or [Ir(COD)Cl]2 in the presence of phosphorous acid in IPA / HO or a mixture of these solvents at 80-85°C for 24-96 hours sufficient to effect ketone reduction to produce a compound of formula (IXb).

[0021] In embodiment 13A, the present invention provides a compound of formula (Xa): [ka] or a salt thereof, comprising the steps of: (1) Formula (IXa): [ka] or a salt thereof, with a reagent 3 (selected from NaOH, KOH, LiOH, tetraalkylammonium hydroxide, and mixtures thereof) and R 7 -OH (where R 7 is independently 1-6 (XI): [ka] [wherein M is selected from a metal element selected from Li, Na, and K, and a tetraalkylammonium] to produce a compound represented by the formula: (2) contacting an acid in a protic solvent; and (3) contacting with periodic acid in a protic solvent at 20-25° C. for up to 48 hours sufficient to effect oxidation to produce a compound of formula (Xa) or a salt thereof.

[0022] In embodiment 13B, the present invention provides a compound of formula (Xa): [ka] or a salt thereof, comprising the steps of: (1) Formula (XIX): [ka] or a salt thereof, in the presence of an ene reductase biocatalyst, aqueous phosphate buffer, GDH, NADPH and glucose, with or without an organic co-solvent (selected from DMSO, IPA, dioxane, acetone and mixtures thereof), a compound represented by the formula (XX): [ka] for a time and at a temperature sufficient to produce a compound represented by followed by (2) adding a ketoreductase biocatalyst, with or without an organic solvent (selected from DMSO, IPA, dioxane, acetone and mixtures thereof) for an additional time and temperature sufficient to produce a compound of formula (Xa) or a salt thereof.

[0023] In another aspect, the present invention provides a compound of formula (Xa): [ka] or a salt thereof, comprising the steps of: (1) Formula (XIX): [ka] or a salt thereof, in the presence of an ene reductase biocatalyst (selected from ERED-302, ERED-303, and ERED-211) and an aqueous phosphate buffer, GDH, NADPH, and glucose, with or without an organic co-solvent (selected from DMSO, IPA, dioxane, acetone, and mixtures thereof), to produce a compound of formula (XX): [ka] at 25-35° C. for a period of time sufficient to produce a compound represented by followed by (2) adding a ketoreductase biocatalyst with or without an organic solvent (selected from DMSO, IPA, dioxane, acetone and mixtures thereof) for a time and at 25-35° C. sufficient to produce a compound of formula (Xa) or a salt thereof.

[0024] In another aspect, the present invention provides a compound of formula (Xa): [ka] or a salt thereof, comprising the steps of: (1) Formula (XIX): [ka] or a salt thereof, in the presence of an ene reductase biocatalyst (selected from ERED-302, ERED-303, and ERED-211), an aqueous phosphate buffer, GDH, NADPH, and glucose, in an organic co-solvent (selected from DMSO, IPA, dioxane, acetone, and mixtures thereof), to obtain a compound represented by the formula (XX): [ka] contacting at 25-35° C. for at least 14 hours sufficient to produce a compound represented by followed by (2) adding KRED-P2-G03 with or without an organic solvent (selected from DMSO, IPA, dioxane, acetone and mixtures thereof) at 25-35° C. for at least an additional 2 hours sufficient to produce a compound of formula (Xa) or a salt thereof.

[0025] In embodiment 13C, the present invention provides a compound of formula (Xa): [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof, in the presence of an aqueous phosphate buffer, GDH, NADPH, and glucose, with or without an organic solvent (selected from DMSO, IPA, dioxane, acetone, and mixtures thereof), for a time and at a temperature sufficient to produce a compound of formula (Xa) or a salt thereof.

[0026] In another aspect, the present invention provides a compound of formula (Xa): [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof, with a combination of an ene reductase biocatalyst (selected from ERED-302, ERED-303, and bERED-211) and a ketoreductase biocatalyst, in the presence of an aqueous phosphate buffer, GDH, NADPH, and glucose, with or without an organic solvent (selected from DMSO, IPA, dioxane, acetone, and mixtures thereof) at 25-35° C. for a sufficient time to produce a compound of formula (Xa) or a salt thereof.

[0027] In another aspect, the present invention provides a compound of formula (Xa): [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof, with a combination of an ene reductase biocatalyst (selected from ERED-302, ERED-303, and ERED-211) and KRED-P2-G03, in the presence of aqueous phosphate buffer, GDH, NADPH, and glucose, with or without an organic solvent (selected from DMSO, IPA, dioxane, acetone, and mixtures thereof) at 20-35° C. for at least 14 hours sufficient to produce a compound of formula (Xa) or a salt thereof.

[0028] In embodiment 13D, the present invention provides a compound of formula (Xa): [ka] or a salt thereof, comprising the steps of: (1) Formula (XXI): [ka] with a sulfonyl chloride reagent, in an aprotic polar solvent, and an inorganic or organic base for a time and temperature sufficient to effect O-sulfonylation, to produce a compound of formula (XXII): [ka] to produce a compound represented by the formula: (2)(a) A compound of formula (XXII) is reacted with a transition metal catalyst, a phosphine ligand, and an organic or inorganic base and purged with carbon monoxide (C 1-4 and contacting the compound of formula (XXIII): [ka] and subsequently contacting the compound of formula (XXIII) with an aqueous base to produce a compound of formula (XIX): [ka] or a salt thereof, or (b) contacting a compound of formula (XXII) with a transition metal catalyst, a phosphine ligand, in the presence of an inorganic or organic base, in water and another polar aprotic solvent, for a time, temperature and pressure sufficient to effect carbonylation with a carbon monoxide purge, to produce a compound of formula (XIX) or a salt thereof; (3) Reacting a compound of formula (XIX) or a salt thereof with an ene reductase biocatalyst in the presence of an aqueous phosphate buffer, GDH, NADPH and glucose, with or without an organic co-solvent (selected from DMSO, IPA, dioxane, acetone and mixtures thereof) to obtain a compound of formula (XX): [ka] for a time and at a temperature sufficient to produce a compound represented by followed by (4) adding a ketoreductase biocatalyst, with or without an organic solvent (selected from DMSO, IPA, dioxane, acetone, and mixtures thereof) for an additional time and temperature sufficient to produce a compound of formula (Xa) or a salt thereof.

[0029] In embodiment 13E, the present invention provides a compound of formula (Xa): [ka] or a salt thereof, comprising the steps of: (1) Formula (XXI): [ka] with p-toluenesulfonyl chloride in ethyl acetate and triethylamine at 0-10° C. for at least 12 hours sufficient to effect O-sulfonylation to obtain a compound of formula (XXII): [ka] to produce a compound represented by the formula: (2)(a) Compound of formula (XXII) was reacted with palladium(II) acetate, 1,3-bis(diphenylphosphino)propane and N,N-diisopropylethylamine and purged with carbon monoxide (C 1-4 and contacting the compound with the alkyl group of formula (XXIII): at 20-60° C. under carbon monoxide pressure for at least 12 hours sufficient to effect carbonylation. [ka] and subsequently contacting the compound of formula (XXIII) with an aqueous base to produce a compound of formula (XIX): [ka] or a salt thereof, or (b) reacting a compound of formula (XXII) with a transition metal catalyst (selected from Pd(OAc)2, PdCl2(CH3CN)2, and Pd(DPPP)Cl2), a phosphine ligand (selected from 1,3-bis(diphenylphosphino)propane, rac-BINAP, Xantphos, Josiphos SL-J001-1, Josiphos SL-J009-1-G3 palladacycle, and BIPHEP), and an inorganic or organic base (K2CO3, N,N - diisopropylethylamine, triethylamine, t-butyltetramethylguanidine, tetramethylguanidine, KHCO3, DBU, Na2CO3, and KOAc) with water and a polar aprotic solvent (selected from EtOAc, 2-MeTHF, CH3CN, DMAc, THF, and mixtures thereof) at 20-60°C under carbon monoxide pressure and purging with carbon monoxide for at least 12 hours sufficient to effect carbonylation to produce a compound of formula (XIX) or a salt thereof; (3) Reacting a compound of formula (XIX) or a salt thereof with an ene reductase biocatalyst (selected from ERED-302, ERED-303, and ERED-211) in the presence of an aqueous phosphate buffer, GDH, NADPH, and glucose in an organic co-solvent (such as DMSO, IPA, dioxane, or acetone) to obtain a compound of formula (XX): [ka] at 20-35° C. for a period of time sufficient to produce a compound represented by followed by (4) adding a ketoreductase biocatalyst with or without an organic solvent (selected from DMSO, IPA, dioxane, acetone, and mixtures thereof) for an additional time and at 25-35° C. sufficient to produce a compound of formula (Xa) or a salt thereof.

[0030] In embodiment 13F, the present invention provides a compound of formula (Xa): [ka] or a salt thereof, comprising the steps of: (1) Formula (XXI): [ka] contacting a compound of the formula: with a sulfonyl chloride reagent in an aprotic polar solvent and with an inorganic or organic base for a time and temperature sufficient to effect O-sulfonylation; Formula (XXII): [ka] to produce a compound represented by the formula: (2)(a) The compound of formula (XXII) was reacted with a transition metal catalyst, a phosphine ligand, and an organic amine base, and purged with carbon monoxide (C 1-4 and contacting the alkyl group with the alkyl group of formula (XXIII): [ka] and subsequently contacting the compound of formula (XXIII) with an aqueous base to produce a compound of formula (XIX): [ka] or a salt thereof, or (b) contacting a compound of formula (XXII) with a transition metal catalyst, a phosphine ligand, in the presence of an inorganic or organic base, in water and another polar aprotic solvent; purging with carbon monoxide for a time, at a temperature, and at a carbon monoxide pressure sufficient to effect carbonylation to produce a compound of formula (XIX) or a salt thereof; (3) A method is provided, comprising contacting a compound of formula (XIX) or a salt thereof with a combination of an enereductase biocatalyst and a ketoreductase biocatalyst in the presence of an aqueous phosphate buffer, GDH, NADPH, and glucose, with or without an organic solvent (selected from DMSO, IPA, dioxane, acetone, and mixtures thereof), for a time and at a temperature sufficient to produce a compound of formula (Xa) or a salt thereof.

[0031] In embodiment 13G, the present invention provides a compound of formula (Xa): [ka] or a salt thereof, comprising the steps of: (1) Formula (XXI): [ka] with p-toluenesulfonyl chloride in ethyl acetate and triethylamine at 0-10° C. for at least 12 hours sufficient to effect O-sulfonylation to obtain a compound of formula (XXII): [ka] to produce a compound represented by the formula: (2)(a) Compound of formula (XXII) was reacted with palladium(II) acetate, 1,3-bis(diphenylphosphino)propane and N,N-diisopropylethylamine and purged with carbon monoxide (C 1-4 in the presence of alkyl-OH at 20-60° C. and carbon monoxide pressure for at least 12 hours sufficient to effect carbonylation to obtain a compound of formula (XXIII): [ka] to produce a compound represented by the formula: The compound of formula (XXIII) is then contacted with an aqueous base to produce a compound of formula (XIX): [ka] or a salt thereof; or (b) reacting a compound of formula (XXII) with a transition metal catalyst (selected from Pd(OAc)2, PdCl2(CH3CN)2, and Pd(DPPP)Cl2), a phosphine ligand (selected from 1,3-bis(diphenylphosphino)propane, rac-BINAP, Xantphos, Josiphos SL-J001-1, Josiphos SL-J009-1-G3 palladacycle, and BIPHEP), and an inorganic or organic base (K2CO3, diisopropylethylamine, amine, triethylamine, t-butyltetramethylguanidine, tetramethylguanidine, KHCO3, DBU, Na2CO3, and KOAc) in carbon monoxide purged water and a polar aprotic solvent (selected from EtOAc, 2-MeTHF, CH3CN, DMAc, THF, and mixtures thereof) at 20-60° C. and carbon monoxide pressure for a time at least sufficient to effect carbonylation to produce a compound of formula (XIX) or a salt thereof; (3) contacting a compound of formula (XIX) or a salt thereof with a combination of an ene reductase biocatalyst (selected from ERED-302, ERED-303, and ERED-211) and KRED-P2-G03 in the presence of an aqueous phosphate buffer, GDH, NADPH, and glucose, with or without an organic solvent (selected from DMSO, IPA, dioxane, acetone, and mixtures thereof) at 20-35° C. for at least 14 hours sufficient to produce a compound of formula (Xa) or a salt thereof.

[0032] In embodiment 14A, the present invention provides a compound of formula (Xa): [ka] A method for producing a compound represented by the following formula: (1) Formula (IXb): [ka] or a salt thereof, in an aqueous solution of NaOH and IPA, is reacted with a compound represented by the formula (XIa): [ka] contacting at 80-85° C. for at least 12 hours sufficient to produce a compound represented by (2) contacting with aqueous HCl; and (3) contacting periodic acid in aqueous IPA at 20-25° C. for a period sufficient to effect oxidation up to 48 hours to produce a compound of formula (Xa).

[0033] In embodiment 15A, the present invention provides a compound of formula (XII): [ka] [In the formula: R 8 and R 9 are independently N, CH, or C(C 1-6 alkyl); R 10 is independently 1-4 is alkyl or halogen; and R 11 are independently Br, Cl or I. or a stereoisomer or salt thereof, comprising the steps of: [ka] [In the formula: R 8 , R 9 , R 10 and R 11 is as defined above in formula (XII), and R 11a is a halogen] or a salt thereof, [ka] or a stereoisomer or salt thereof, in the presence of a metal alkoxide in solvent 7 (a polar aprotic or nonpolar solvent, or a mixture of such solvents) for a time and at a temperature sufficient to complete the reaction, to produce a compound of formula (XII) or a stereoisomer or salt thereof.

[0034] In embodiment 16A within embodiment 15A, the present invention provides a compound of formula (XIIa): [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof, [ka] or a salt thereof, in the presence of a metal alkoxide (selected from KOtBu, KHMDS, NaHMDS, and potassium amylate), in a solvent 7 (selected from DMF, MTBE, DMAc, NMP, DMPU, THF, 2-MeTHF, CPME, diisopropyl ether, toluene, and mixtures of these solvents) at 25-35° C. for a time sufficient to complete the reaction, to produce a compound of formula (XIIa) or a salt thereof.

[0035] In embodiment 17A, the present invention provides a compound of formula (XIIb): [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof, [ka] or salt thereof, in the presence of KOtBu in a DMF / MTBE mixture at 20-35° C. for 18 to >48 hours sufficient to effect fluoride displacement to produce a compound of formula (XIIb) or salt thereof.

[0036] In embodiment 18A, the present invention provides a compound of formula (XIVc): [ka] [In the formula: R 8 and R 9 are independently N, CH, or C(C 1-6 alkyl); R 10 is independently 1-4 is alkyl or halogen; and R 12 is C 1-4 is alkyl] or a stereoisomer or salt thereof, comprising the steps of: (1) Formula (I): [ka] [In the formula, R 1 is C 1-6 R is alkyl; 2 and R 2a is a halogen] with an organometallic reagent, with or without an inorganic reagent, in a solvent 8 (a polar aprotic or nonpolar solvent, or a mixture of such solvents) for a time and at a temperature sufficient to effect metal-halogen exchange; and (2) Formula (XII): [ka] [In the formula: R 8 and R 9 are independently N, CH, or C(C 1-6 alkyl); R 10 is independently 1-4 is alkyl or halogen; and R 11 is Br or Cl] or a stereoisomer or salt thereof with the product of metal-halogen exchange and a palladium catalyst in a solvent 8 for a time and at a temperature sufficient to effect a C-C coupling; and (3) contacting with a metal binding agent in solvent 8 for a time and at a temperature sufficient to quench the reaction to produce a compound of formula (XIVc) or a stereoisomer or salt thereof.

[0037] In embodiment 19A within embodiment 18A, the present invention provides a compound of formula (XIVd): [ka] [In the formula: R 8 and R 9 are independently N, CH, or C(C 1-4 alkyl); R 10 is independently 1-4 is alkyl or halogen; and R 12 is C 1-4 is alkyl] or a salt thereof, comprising the steps of: (1) contacting a compound of formula (I) with an organometallic reagent (a Grignard reagent selected from i-PrMgCl, i-PrMgCl*LiCl, and i-PrMgBr, or an organolithium reagent selected from methyllithium, n-butyllithium, iso-propyllithium, sec-butyllithium, tert-butyllithium, and phenyllithium), with or without an inorganic reagent (selected from ZnCl2, ZnBr2, and ZnI2), in a solvent 8 (selected from THF, 2-MeTHF, DMF, DMA, DMPU, NMP, 1,4-dioxane, and mixtures thereof) for a time and at −5 to 25° C. sufficient to effect metal-halogen exchange and organozinc formation; (2) Formula (XIIa): [ka] or a salt thereof, with an organometallic reagent, the product of metal-halogen exchange, and a palladium catalyst (selected from PdCl2 (Xantphos), Pd(dppf)Cl2, or Pd(OAc)2 + Brettphos, BINAP, dppf, DPE Phos, and Xantphos) in a solvent 8 for a time and at −5 to 40° C. sufficient to effect a C-C coupling; and (3) contacting with a metal binding agent (selected from sodium ethylenediaminetetraacetate tribasic or sodium ethylenediaminetetraacetate dibasic) in solvent 8 for a time sufficient to quench the reaction and at −5 to 25° C. to produce a compound of formula (XIVd) or a salt thereof.

[0038] In another embodiment within the scope of embodiment 18A, the invention provides a method of making a compound of formula (XIVd) or a salt thereof, comprising the steps of: (1) contacting a compound of formula (I) with an organometallic reagent (Grignard reagent (selected from i-PrMgCl (2.15M in THF), i-PrMgCl*LiCl (1.3M in THF), and i-PrMgBr (2.9M in 2-MeTHF)) or an organolithium reagent (selected from methyllithium, n-butyllithium, iso-propyllithium, sec-butyllithium, tert-butyllithium, and phenyllithium)) with or without an inorganic reagent (selected from ZnCl2, ZnBr2, and ZnI2) in a solvent 8 (selected from THF, 2-MeTHF, DMF, DMA, DMPU, NMP, 1,4-dioxane, and mixtures thereof) for a time and at -5 to 25°C sufficient to effect metal-halogen exchange and organozinc formation; (2) Formula (XIIa): [ka] or a salt thereof, with the product of metal-halogen exchange, which is an organometallic reagent, and a palladium catalyst (selected from PdCl2(xantphos), Pd(dppf)Cl2, or Pd(OAc)2+Brettphos, BINAP, dppf, DPEphos, and Xantphos), in a solvent 8, for a time and at -5 to 40°C sufficient to effect a C-C coupling; and (3) contacting with a metal binding agent (selected from sodium ethylenediaminetetraacetate tribasic or sodium ethylenediaminetetraacetate dibasic) in solvent 8 for a time sufficient to quench the reaction and at −5 to 25° C. to produce a compound of formula (XIVd) or a salt thereof.

[0039] In embodiment 20A, the present invention provides a compound of formula (XIVe): [ka] 1. A method for preparing a compound of formula (I) isolated as either the free acid or a salt thereof selected from the potassium, tetramethylammonium, tert-butylamine, dicyclohexylamine and tromethamine salts, comprising: (1) Formula (Ia): [ka] with i-PrMgCl (2.15 M in THF), with or without ZnCl2, in THF, for a time and at -5 to 25°C sufficient to effect metal-halogen exchange and organozinc formation (if ZnCl2 is present); (2) Formula (XIIb): [ka] or a salt thereof with i-PrMgCl (2.15 M in THF), with or without ZnCl, an organomagnesium (or organozinc) reagent, and PdCl (Xantphos), in THF for >12 hours and at -5 to 40°C sufficient to effect a CC coupling; and (3) sequentially contacting sodium ethylenediaminetetraacetate tribasic or sodium ethylenediaminetetraacetate dibasic in a THF solvent mixture with or without sodium percarbonate and sodium bisulfite (or sodium metabisulfite) for >1 hour and at -5 to 25°C sufficient to quench the reaction to produce a compound of formula (XIVe), which is then isolated as either the free acid or a salt thereof selected from the potassium, tetramethylammonium, tert-butylamine, dicyclohexylamine, and tromethamine salts.

[0040] In embodiment 20B, the present invention provides a compound of formula (XIVe): [ka] 1. A method for preparing a compound of formula (I) isolated as either the free acid or a salt thereof selected from the potassium, tetramethylammonium, tert-butylamine, dicyclohexylamine and tromethamine salts, comprising: (1) Formula (Ia): [ka] with i-PrMgCl (2.15 M in THF) in THF for a time and at -5 to 25°C sufficient to effect metal-halogen exchange; and (2) Formula (XIIb): [ka] or a salt thereof with i-PrMgCl (2.15 M in THF), ZnCl, an organomagnesium reagent, and PdCl (Xantphos) in THF for >12 hours and at -5 to 40°C sufficient to effect C-C coupling; and (3) contacting sodium ethylenediaminetetraacetate tribasic or sodium ethylenediaminetetraacetate dibasic with sodium percarbonate and sodium bisulfite (or sodium metabisulfite) in a THF solvent mixture sequentially for >1 hour and at -5 to 25°C sufficient to quench the reaction to produce a compound of formula (XIVe), which is then isolated as either the free acid or a salt thereof selected from potassium, tetramethylammonium, tert-butylamine, dicyclohexylamine and tromethamine salts.

[0041] In another aspect, the present invention relates to a compound of formula (XIVe): [ka] 1. A method for preparing a compound of formula (I) isolated as either the free acid or a salt thereof selected from the potassium, tetramethylammonium, tert-butylamine, dicyclohexylamine and tromethamine salts, comprising: (1) Formula (Ia): [ka] with i-PrMgCl (2.15 M in THF) and ZnCl2 in THF for a time and at -5 to 25°C sufficient to effect metal-halogen exchange and organozinc formation; (2) Formula (XIIb): [ka] or a salt thereof with i-PrMgCl (2.15 M in THF), an organozinc reagent, and PdCl2 (Xantphos) in THF for >12 hours and at -5 to 40°C sufficient to effect C-C coupling; and (3) contacting with tribasic sodium ethylenediaminetetraacetate in a THF solvent mixture at −5 to 25° C. for 1 hour sufficient to quench the reaction to produce a compound of formula (XIVe), which is then isolated as either the free acid or a salt thereof selected from potassium, tetramethylammonium, tert-butylamine, dicyclohexylamine, and tromethamine salts.

[0042] In embodiment 21A, the present invention provides a compound of formula (XV): [ka] [In the formula: R 8 and R 9 are independently N, CH, or C(C 1-6 alkyl); R 10 is independently 1-4 is alkyl or halogen; and R 12 is C 1-4 is alkyl] or a stereoisomer or salt thereof, comprising the steps of: Formula (XIVc): [ka] or a stereoisomer or salt thereof, with a transition metal catalyst, with or without an inorganic or organic acid, in a solvent 9, which may be a polar protic or polar aprotic solvent, or a mixture of such solvents, for a time and at a temperature sufficient to effect hydrogenolysis, to produce a compound of formula (XV) or a stereoisomer or salt thereof.

[0043] In embodiment 22A within embodiment 21A, the present invention provides a compound of formula (XVa): [ka] [In the formula: R 8 and R 9 are independently N, CH, or C(C1-4 alkyl); R 10 is independently 1-4 is alkyl or halogen; and R 12 is C 1-4 is alkyl] or a salt thereof, comprising the steps of: [ka] or a salt thereof, with a transition metal catalyst (selected from 5-20 wt % Pd / C), with or without an inorganic or organic acid (selected from citric acid, oxalic acid, H2SO4), in a solvent 9 (selected from EtOH, MeOH, water, THF, DMAc, NMP, IPA, t-AmOH, MeTHF, DMF, CH3CN, EtOAc, IPOAc and mixtures of these solvents) for a time and at 20-60°C sufficient to effect hydrogenolysis, to produce a compound of formula (XVa) or a salt thereof.

[0044] In another embodiment within the scope of embodiment 21A, the present invention provides a compound of formula (XVa): [ka] [In the formula: R 8 and R 9 are independently N, CH, or C(C 1-4 alkyl); R 10 is independently 1-4 is alkyl or halogen; and R 12 is C 1-4 is alkyl] or a salt thereof, comprising the steps of: [ka] or a salt thereof, with a transition metal catalyst (selected from 5-20 wt % Pd / C), with or without an inorganic or organic acid (selected from citric acid, oxalic acid, H2SO4), in a solvent 9 (selected from EtOH, MeOH, THF, DMAc, NMP, IPA, t-AmOH, MeTHF, MeTHF, DMF, CH3CN, EtOAc, IPOAc and mixtures of these solvents) for a time sufficient to effect hydrogenolysis and at 20-60°C to produce a compound of formula (XVa) or a salt thereof.

[0045] In embodiment 23A, the present invention provides a compound of formula (XVb): [ka] A method for producing a compound represented by formula (XIVe): [ka] or a salt thereof, with 10 wt % Pd / C, with or without citric acid, in a solvent 9 (selected from EtOH, MeOH, water, THF, DMAc, NMP, and mixtures of these solvents) for >12 hours and at 20-60° C. sufficient to effect hydrogenolysis, to produce a compound of formula (XVb).

[0046] In another aspect, the present invention provides a compound of formula (XVb): [ka] A method for producing a compound represented by formula (XIVf): [ka] with 10 wt % Pd / C and citric acid in a solvent 9 (selected from EtOH, MeOH, THF, DMAc, NMP, and mixtures of these solvents) at 20-60° C. for a time sufficient to effect hydrogenolysis to produce a compound of formula (XVb).

[0047] In embodiment 24A, the present invention provides a compound of formula (XVI): [ka] [In the formula: R 8 and R 9 are independently N, CH, or C(C 1-6 alkyl); R 10 is independently 1-4 is alkyl or halogen; R 12 is C 1-4 is alkyl; and R 14 and R 14a is independently 1-6 is alkyl] or a stereoisomer or salt thereof, comprising the steps of: [ka] or a stereoisomer or salt thereof, with a compound represented by formula (XVII): [ka] [In the formula, R 14 and R 14a is independently 1-6 is alkyl] or a salt thereof, in the presence of a metal alkoxide in a solvent 9 (selected from a polar protic or a polar aprotic solvent, or a mixture of such solvents) for a time and at a temperature sufficient to effect carbamate formation, to produce a compound of formula (XVI) or a stereoisomer or salt thereof.

[0048] In embodiment 25A within embodiment 24A, the present invention provides a compound of formula (XVIa): [ka] [In the formula: R 8and R 9 are independently N, CH, or C(C 1-4 alkyl); R 10 is independently 1-4 is alkyl or halogen; R 12 is C 1-4 is alkyl; and R 14 and R 14a is independently 1-4 is alkyl] or a salt thereof, comprising the steps of: [ka] or a salt thereof, [ka] or a salt thereof, in the presence of a metal alkoxide (selected from KOtBu (20 wt % in THF) or KOtBu (1 M in THF)) in a solvent 9 (selected from t-AmOH, DMF, THF, CHCN, MEK, NMP, DMAc, acetone, MIBK, 2-MeTHF, and mixtures thereof) for a time and at 20-75° C. sufficient to effect carbamate formation, to produce a compound of formula (XVIa) or a salt thereof.

[0049] In embodiment 26A, the present invention provides a compound of formula (XVIb): [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof, with a compound represented by formula (XVIIa): [ka] or a salt thereof, in the presence of KOtBu (20 wt % in THF), in a solvent 9 (selected from t-AmOH, DMF, THF, CHCN, MEK, and mixtures of these solvents) for a time and at 20-75° C. sufficient to effect carbamate formation, to produce a compound of formula (XVIb) or a salt thereof.

[0050] In embodiment 26B, the present invention provides a compound of formula (XVIb): [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof, with a compound represented by formula (XVIIa): [ka] in the presence of KOtBu (20 wt % in THF), in a solvent 9 (selected from t-AmOH, DMF, THF, CHCN, MEK, and mixtures of these solvents) for a time and at 20-75° C. sufficient to effect carbamate formation, to produce a compound of formula (XVIb) or a salt thereof.

[0051] In embodiment 27A, the present invention provides a compound of formula (Ib): [ka] [In the formula, R 1 is C 1-6 R is alkyl; 2 is a halogen] or a salt thereof.

[0052] In embodiment 28A, the present invention provides a compound of formula (Ic): [ka] or a salt thereof.

[0053] In embodiment 29A, the present invention provides a compound of formula (IV): [ka] [In the formula, R a -N(C 1-4 alkyl)2] or a salt thereof.

[0054] In embodiment 30A, the present invention provides a compound of formula (IVa): [ka] or a salt thereof.

[0055] In embodiment 31A, the present invention provides a compound of formula (IVb): [ka] or a salt thereof.

[0056] In embodiment 32A, the present invention provides a compound of formula (VII): [ka] [In the formula, R a -N(C 1-4 alkyl)2] or a stereoisomer or salt thereof.

[0057] In embodiment 33A, the present invention provides a compound of formula (VIIa): [ka] or a salt thereof.

[0058] In embodiment 34A, the present invention provides a compound of formula (VIIb): [ka] or a salt thereof.

[0059] In embodiment 35A, the present invention provides a compound of formula (IX): [ka] [In the formula, R a -N(C 1-4 alkyl)2] or a stereoisomer or salt thereof.

[0060] In embodiment 36A, the present invention provides a compound of formula (IXa): [ka] or a salt thereof.

[0061] In embodiment 37A, the present invention provides a compound of formula (IXb): [ka] The present invention provides a compound represented by the formula:

[0062] In embodiment 38A, the present invention provides a compound of formula (XII): [ka] [In the formula: R 8 and R 9 are independently N, CH, or C(C 1-6 alkyl); R 10 is independently 1-4 is alkyl or halogen; and R 11 are independently Br, Cl or I. or a stereoisomer or salt thereof.

[0063] In embodiment 39A within embodiment 38A, the present invention provides a compound of formula (XIIa): [ka] [In the formula: R 8 and R 9 are independently N, CH, or C(C 1-4 alkyl); R 10 is independently 1-4 is alkyl or halogen; and R 11 are independently Br, Cl or I. or a salt thereof.

[0064] In embodiment 40A, the present invention provides a compound of formula (XIIb): [ka] or a salt thereof.

[0065] In embodiment 41A, the present invention provides a compound of formula (XIV): [ka] [In the formula: R 8 and R 9 are independently N, CH, or C(C 1-6 alkyl); R 10 is independently 1-4 is alkyl or halogen; R 12 is C 1-4 is alkyl; and R 13 are independently H, C 1-4 alkyl or benzyl] or a stereoisomer or salt thereof.

[0066] In embodiment 42A within embodiment 41A, the present invention provides a compound of formula (XIVa): [ka] [In the formula: R 8 and R 9are independently N, CH, or C(C 1-4 alkyl); R 10 is independently 1-4 is alkyl or halogen; R 12 is C 1-4 is alkyl; and R 13 are independently H, C 1-4 alkyl or benzyl] or a salt thereof.

[0067] In embodiment 43A, the present invention provides a compound of formula (XIVb): [ka] [In the formula: R 13 are independently H or benzyl. or a salt thereof.

[0068] In embodiment 44A, the present invention provides a compound of formula (XVIIa): [ka] The present invention provides a compound represented by the formula:

[0069] In embodiment 45A, the present invention provides a compound of formula (XVII): [ka] [In the formula, R 14 and R 14a is independently 1-6 is alkyl] or a salt thereof, comprising the steps of: Formula (XVIII): [ka] The compound represented by NHR 14 R 14ain the presence of a solvent 10 (polar protic, aprotic or non-polar solvent, or mixtures thereof) at −5 to 25° C. for a time sufficient to effect carboxamide formation to produce a compound of formula (XVII).

[0070] In embodiment 46A, the present invention provides a compound of formula (XVIIa): [ka] A method for producing a compound represented by formula (XVIII): [ka] with N-methylpropylamine in the presence of a solvent 10 (selected from DCM, t-AmOH, water, MTBE, acetonitrile, THF, MeTHF, acetone, MEK, MIBK, MeOAc, EtOAc, IPAc, DMF, NMP, DMAc, and mixtures of said solvents) at −5 to 25° C. for at least 1 hour sufficient to form a carboxamide; followed by adding (HO2C)2 to produce a compound of formula (XVIIa).

[0071] In embodiment 47A, the present invention provides a method of making a compound of formula (XVIIa), comprising: contacting a compound of formula (XVIII) with N-methylpropylamine in a solvent 10 (selected from DCM, t-AmOH, water, MTBE, acetonitrile, and mixtures of said solvents) for at least 1 hour sufficient to effect carboxamide formation and at −5 to 25° C.; followed by adding (HO2C)2 to produce a compound of formula (XVIIa).

[0072] In embodiment 48A, the present invention provides a method for making a compound of formula (XVI) or a stereoisomer or salt thereof, comprising: comprising the steps of embodiment 21A; Then, comprising the steps of embodiment 24A; Provided herein is a method wherein all formulas and variables are as defined in embodiments 21A and 24A.

[0073] In embodiment 49A, the present invention provides a method for preparing a compound of formula (XVIa) or a stereoisomer or salt thereof, comprising: comprising the steps of embodiment 22A; Then, comprising the steps of embodiment 25A; Provided herein is a method wherein all formulas and variables are as defined in embodiments 22A and 25A.

[0074] In embodiment 50A, the present invention provides a method for making a compound of formula (XVIb) or a stereoisomer or salt thereof, comprising: comprising the steps of embodiment 23A; Then, comprising the steps of embodiment 26A; Provided herein is a method wherein all formulas and variables are as defined in embodiments 23A and 26A.

[0075] In embodiment 51A, the present invention provides a method for making a compound of formula (XVI) or a stereoisomer or salt thereof, comprising: comprising steps (1), (2), and (3) of embodiment 18A; comprising the steps of embodiment 21A; Then comprising the steps of embodiment 24A; wherein all formulas and variables are as defined in embodiments 18A, 21A and 24A.

[0076] In embodiment 52A, the present invention provides a method for making a compound of formula (XVIa) or a stereoisomer or salt thereof, comprising: comprising steps (1), (2), and (3) of embodiment 19A; comprising the steps of embodiment 22A; Then comprising the steps of embodiment 25A; wherein all formulas and variables are as defined in embodiments 19A, 22A and 25A.

[0077] In embodiment 53A, the present invention provides a method for making a compound of formula (XVIb) or a stereoisomer or salt thereof, comprising: comprising steps (1), (2), and (3) of embodiment 20A; comprising the steps of embodiment 23A; Then comprising the steps of embodiment 26A; Provided are methods wherein all formulas and variables are as defined in embodiments 20A, 23A and 26A.

[0078] In embodiment 54A, the present invention provides a method for making a compound of formula (XVI) or a stereoisomer or salt thereof, comprising: The process of embodiment 15A; Steps (1), (2) and (3) of embodiment 18A; The process of embodiment 21A; Then, comprising the steps of embodiment 24A; wherein all formulas and variables are as defined in embodiments 15A, 18A, 21A and 24A.

[0079] In embodiment 55A, the present invention provides a method for making a compound of formula (XVIa) or a stereoisomer or salt thereof, comprising: The process of embodiment 16A; Steps (1), (2) and (3) of embodiment 19A; The process of embodiment 22A; Then, comprising the steps of embodiment 25A; Provided are methods wherein all formulae and variables are as defined in embodiments 16A, 19A, 22A and 25A.

[0080] In embodiment 56A, the present invention provides a method for making a compound of formula (XVIb) or a stereoisomer or salt thereof, comprising: The process of embodiment 17A; Steps (1), (2) and (3) of embodiment 20A; The process of embodiment 23A; Then, comprising the steps of embodiment 26A or 26B; Provided are methods wherein all formulae and variables are as defined in embodiments 17A, 20A, 23A, and 26A or 26B.

[0081] In another aspect, the present invention provides a process for preparing a compound of formula (XVIb) or a stereoisomer or salt thereof, comprising the steps of: The process of embodiment 17A; Steps (1), (2) and (3) of embodiment 20A; The process of embodiment 23A; Then, comprising the steps of embodiment 26A; Provided herein are methods wherein all formulae and variables are as defined in embodiments 17A, 20A, 23A and 26A.

[0082] In another aspect, the present invention provides a process for preparing a compound of formula (XVIb) or a stereoisomer or salt thereof, comprising the steps of: The process of embodiment 17A; Steps (1), (2) and (3) of embodiment 20A; The process of embodiment 23A; Then, comprising the steps of embodiment 26B; Provided herein are methods wherein all formulae and variables are as defined in embodiments 17A, 20A, 23A, and 26B.

[0083] definition The presence of reaction and / or process impurities can be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectroscopy, and / or infrared spectroscopy.

[0084] Other embodiments include those described in the detailed description and / or claims. In order to facilitate understanding of the disclosure described herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless otherwise specified, all technical and scientific terms used herein generally have the same meaning as commonly understood by those of ordinary skill in the art to which this disclosure belongs.

[0085] As used herein, with respect to a formulation, composition or ingredient, the term "acceptable" means having no lasting deleterious effects on the general health of the subject being treated. "API" means active pharmaceutical ingredient. The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0086] The term "alkyl" refers to a hydrocarbon chain, which may be a straight or branched chain, containing the indicated number of carbon atoms. For example, C 1-10 indicates that the group may have 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with an independently selected halo. The term "alkoxy" refers to an -O-alkyl group (eg, -OCH3). The term "haloalkoxy" refers to an -O-haloalkyl group (eg, -OCF3). The term "alkylene" refers to a branched or unbranched divalent alkyl (eg, -CH2-).

[0087] The term "aryl" refers to a 6 carbon monocyclic, 10 carbon bicyclic, or 14 carbon tricyclic aromatic ring system in which 0, 1, 2, 3, or 4 atoms of each ring may be substituted by substituents, in which the ring containing the monocyclic group is aromatic and at least one of the fused rings containing the bicyclic or tricyclic group is aromatic, e.g., tetrahydronaphthyl. Examples of aryl groups include phenyl, naphthyl, and the like.

[0088] The term "cycloalkyl" as used herein includes saturated cyclic hydrocarbon groups having 3 to 10 carbons, preferably 3 to 8 carbons, more preferably 3 to 6 carbons, where the cycloalkyl group may be optionally substituted. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "cycloalkylene" as used herein refers to a divalent cycloalkyl.

[0089] The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 N, O, or S heteroatoms, respectively, if monocyclic, bicyclic, or tricyclic), where 0, 1, 2, 3, or 4 atoms of each ring are optionally substituted by substituents, and where the ring containing the monocyclic group is aromatic and at least one of the fused rings containing the bicyclic or tricyclic group is aromatic, but not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl. Examples of heteroaryl groups also include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like.

[0090] The term "heterocyclyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, selected from O, N, or S (e.g., a carbon atom and 1-3, 1-6, or 1-9 N, O, or S heteroatoms, respectively, if monocyclic, bicyclic, or tricyclic), where 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of heteroaryl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. The term "heterocycloalkylene" refers to a divalent heterocyclyl.

[0091] The term "Brönsted acid" refers to an acid that is + ) donor. The term "Lewis acid" refers to a chemical species that can accept an electron pair from an electron donor compound. The term "Brønsted base" refers to a proton (H + ) receptor. The term "Lewis base" refers to a chemical species that can donate an electron pair to an electron acceptor compound. The term "transition metal catalyst" refers to a coordination complex having any of a variety of metallic elements, such as palladium and nickel, that have valence electrons in two shells instead of just one, and that, when added to a chemical reaction, increases the rate of the reaction.

[0092] A protic solvent is a solvent in which a hydrogen atom is bonded to either an oxygen (such as a hydroxyl group) or a nitrogen (such as an amine group). Aprotic solvents refer to solvents that are not hydrogen bond donors. Polar solvents are solvents with large dipole moments or partial charges; they contain bonds between atoms of very different electronegativities, such as oxygen and hydrogen. A solvent mixture refers to a combination of two or more solvents.

[0093] In addition, atoms constituting the compounds of the embodiments of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 Contains C.

[0094] Working Example The following examples are presented to provide a person skilled in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments have been performed or are all that may be performed. It should be understood that the exemplary descriptions written in the present tense have not necessarily been performed, but rather, that the descriptions may be performed to obtain the data, etc., of the characteristics described herein. Efforts have been made to ensure accuracy with respect to the numerical values ​​used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0095] The starting materials used in the synthetic sequences of the present invention are known, prepared by known methods, or are commercially available. Those skilled in the art will also understand that the conditions and reagents described herein can be replaced with other equivalents recognized in the art. For example, in one reaction, hydrochloric acid can be replaced with other acids such as hydrobromic acid, sulfuric acid, etc.

[0096] Those skilled in the art will understand, for example, 1 It will be appreciated that various analytical methods may be used to characterize the compounds described herein, including H nuclear magnetic resonance spectroscopy (NMR), heteronuclear NMR, mass spectrometry (MS), liquid chromatography (LC), and infrared (IR) spectroscopy. The examples provided above are a subset of the characterization methods available to one of skill in the art and are not intended to be limiting.

[0097] The above invention is further described in detail using the following non-limiting exemplary synthetic schemes. Modifications of these examples within the scope of the claims are within the discretion of a person skilled in the art, and such modifications are considered to be within the scope of the invention as described and claimed in the claims. Those who read this specification will recognize that those skilled in the art to whom this disclosure is provided and those skilled in the art can make and use the invention even without the exhaustive examples.

[0098] The following abbreviations have the indicated meanings: [Table 1] [Table 2] [Table 3] [Table 4]

[0099] A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

[0100] Experimental Method Example 1: Preparation of 4,5-dibromo-1-methyl-1H-1,2,3-triazole [ka]

[0101] A 10 L reactor under nitrogen protection was charged with t-AmOH (2.0 L, 4.0 mL / g) and the temperature was adjusted to 20° C. The reaction mixture was successively charged with 4,5-dibromo-1H-1,2,3-triazole (500 g, 1.0 eq., limiting reagent), and THF (175 g, 1.1 eq.), followed by portionwise charging LiOtBu (195 g, 1.1 eq.) to the reactor while maintaining the internal temperature at <40° C. The reaction mixture was allowed to warm to 40° C. and stirred for 1 h; then CHI (470 g, 1.5 eq.) was charged and aging at 40° C. was continued for 24 h. The reaction mixture was allowed to warm to 50° C. and concentrated under vacuum (80 torr) to 3.0 mL / g while maintaining the internal temperature at <60° C.; then IPA (1.0 L, 2.0 mL / g) and water (4.0 L, 8.0 mL / g) were charged. The reaction mixture was allowed to warm to 60° C. and aged for 2 h. The resulting homogeneous solution was then cooled to 0° C. over 5 h and aged overnight. The resulting slurry was filtered and washed successively with IPA:H2O (35:65) pre-cooled to 0-5° C. (1.0 L, 2 mL / g), followed by ambient temperature water (1.5 L, 3 mL / g), and dried under vacuum at 50° C. to give 430 g (82-81% yield) of 4,5-dibromo-1-methyl-1H-1,2,3-triazole as a white solid.

[0102] 1 H NMR(400MHz, CDCl3) δ 4.10(s,3H); 13 C NMR: (100MHz, CDCl3) δ 122.70, 112.98, 36.89; LC / MS (ESI) Calculated value ([C3H3Br2N3+H] + as) = ​​239.88, measured value = 239.88 UHPLC method conditions: Column: Phenomenex Kinetex C8, 1.7 μm, 2.1x50 mm; Mobile phase A: 0.05% TFA in acetonitrile:water (5:95); Mobile phase B: 0.05% TFA in acetonitrile:water (95:5); Temperature: 40 °C; Gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); Flow rate: 1.0 mL / min; 220 nm; UPLC RT 1.02 min

[0103] Example 2: Preparation of 5-((benzyloxy)methyl)-4-bromo-1-methyl-1H-1,2,3-triazole bromide salt [ka]

[0104] A 10 L reactor under nitrogen protection was charged with THF (4.0 L, 4.0 mL / g) and 4,5-dibromo-1-methyl-1H-1,2,3-triazole (1.00 kg, 1.0 equiv., limiting reagent) at 20° C. The solution was cooled to −25° C. and n-BuLi (2.5 M solution in n-hexane, 1.26 kg, 1.1 equiv.) was charged dropwise while maintaining the internal temperature at <−20° C. After an additional 20 min, BOMCI (0.75 kg, 1.15 equiv.) was charged to the thick suspension while maintaining the internal temperature at <−20° C. After 2 h, the reaction mixture was charged with a 33% HBr solution in AcOH (0.10 kg, 0.10 equiv.) and stirred at −20° C. for 30 min. The reaction mixture was then allowed to warm to 15° C. and concentrated under vacuum (50 torr) to 2.0-2.5 mL / g while maintaining an internal temperature of <40° C.; CH3CN (5.0 L, 5 mL / g) was then charged to the concentrated solution and distillation of the batch was continued to 2.0-2.5 mL / g while maintaining an internal temperature of <40° C. The reaction mixture was charged with CH3CN (3.0 L, 3.0 mL / g) and the suspension was allowed to warm to 20° C. and aged for 1 hour. The reaction slurry was filtered and the unwanted solids were washed with IPAc (2×2.0 L, 2×2.0 mL / g). The filtrates were combined, then adjusted to 20° C. and charged dropwise with a 33% HBr solution in AcOH (1.07 kg, 1.05 equiv.) over at least 1 hour. After an additional hour, the resulting slurry was filtered, washed successively with IPAc:CH3CN (1:1) (3.0 L, 3 mL / g) followed by IPAc (3.0 L, 3 mL / g) and dried under vacuum at 40 °C to give 1.27 g (83% yield) of 5-((benzyloxy)methyl)-4-bromo-1-methyl-1H-1,2,3-triazole bromide salt as a white solid.

[0105] 1 H NMR: (500MHz, DMSO-d6) δ 7.29-7.37(m,5H), 6.35(brs,1H), 4.61(s,2H), 4.51(s,2H), 4.04(s,3H); 13C NMR: (100MHz, DMSO-d6) δ 137.48, 132.61, 128.42, 127.86(2C's), 121.01, 71.86, 58.62, 36.02; LC / MS (ESI) calculated value ([C 11 H 12 BrNO+H] + as) = ​​282.02, measured value = 282.02 UHPLC method conditions: Column: Phenomenex Kinetex C8, 1.7 μm, 2.1x50 mm; Mobile phase A: 0.05% TFA in acetonitrile:water (5:95); Mobile phase B: 0.05% TFA in acetonitrile:water (95:5); Temperature: 40 °C; Gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); Flow rate: 1.0 mL / min; 220 nm; UPLC RT 1.32 min.

[0106] Example 3: Preparation of dimethyl 2-((4-(dimethylamino)benzoyl)oxy)malonate [ka]

[0107] A 5 L reactor under nitrogen protection was charged with DMF (900 mL, 3.0 mL / g) and the temperature was adjusted to 20° C. 4-Dimethylaminobenzoic acid (299.4 g, 1.05 equiv., limiting), potassium bicarbonate (203.5 g, 1.20 equiv.), and Et4NBr (35.6 g, 0.10 equiv.) were charged in succession, followed by additional DMF (900 mL, 3.0 L / kg) as a rinse. The reaction mixture was then warmed to 30° C. and dimethyl chloromalonate (300.0 g, 94.0 wt. %, 1.69 moles, limiting reagent) was charged and aging was continued at 30° C. overnight. The reaction mixture was cooled to 15-20° C. and water (2.7 L, 9.0 mL / g) was charged slowly over 2 hours. After an additional 4 h, the resulting slurry was filtered, washed successively with DMF:HO (1:1.5) (750 mL, 2.5 mL / g) followed by 2-propanol (2x750 mL, 2x2.5 mL / g) and dried under vacuum at 45-50 °C to give 473 g (95% yield) of dimethyl 2-((4-(dimethylamino)benzoyl)oxy)malonate as a white solid.

[0108] 1 H NMR (400MHz, DMSO): δ 7.81(d,J=9.1Hz,2H), 6.76(d,J=9.1Hz,2H), 5.80(s,1H), 3.78(s,6H), 3.02(s,6H); 13 C NMR (100 MHz, DMSO): δ 165.17, 164.36, 153.82, 131.29, 113.48, 110.88, 71.50, 53.04, 39.53; Found: 295.11 g / mol LC / MS (ESI) calculated ([C 14 H 17 NO6+H] + as) = ​​296.11, measured value = 296.11 UHPLC method conditions: Column: Supelco Ascentis Express C18, 2.7 μm, 2.1x50 mm; Mobile phase A: 0.05% TFA in MeOH:water (20:80); Mobile phase B: 0.05% TFA in MeOH:acetonitrile (20:80); Temperature: 40 °C; Gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); Flow rate: 1.0 mL / min; 229 nm; UPLC RT 1.25 min.

[0109] Example 4: Preparation of dimethyl (S)-2-((4-(dimethylamino)benzoyl)oxy)-2-(3-oxocyclohexyl)malonate [ka]

[0110] A 2 L reactor under nitrogen protection was charged with toluene (100 mL, 1.0 mL / g) and 1-((1S,2S)-2-aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea hydrochloride (7.07 g, 0.05 equiv.) at 20° C. 1N aqueous KOH (50 mL, 0.5 mL / g) was charged and agitated for 1 h. The bottom aqueous layer was then removed and the remaining top toluene layer was charged sequentially with dimethyl 2-((4-(dimethylamino)benzoyl)oxy)malonate (100.0 g, 335.3 mmol, 1.0 equiv., limiting reagent), 4-pyrrolidinopyridine (2.54 g, 0.05 equiv.) and separate toluene (300 mL, 3.0 mL / g). The reaction mixture was allowed to warm to 33° C. to produce a homogeneous solution, then 2-cyclohexen-1-one (39.42 g, 1.2 equiv.) was charged in one portion. After 48 h, the resulting slurry was charged with 2-propanol (63 mL, 0.63 mL / g) in one portion, followed by heptane (800 mL, 8.0 mL / g) slowly over 3 h. The slurry was cooled to 20° C. and aged overnight before being filtered and washed successively with 5% IPA in 2:1 heptane:toluene (300 mL, 3.0 mL / g) followed by heptane (300 mL, 3.0 mL / g) and dried under vacuum at 45-50° C. to give 114.7 g (87-88% yield) of dimethyl (S)-2-((4-(dimethylamino)benzoyl)oxy)-2-(3-oxocyclohexyl)malonate as a white solid.

[0111] 1H NMR (400 MHz, DMSO-d6) δ: 7.81 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 9.1 Hz, 2H), 3.72 (s, 3H), 3.72 (s, 3H), 3.02 (s, 6H), 2.72-2.58 (m, 1H), 2.54-2.34 (m, 3H), 2.28-2.16 (m, 2H), 2.08-1.95 (m, 1H), 1.93-1.80 (m, 1H), 1.69-1.52 (m, 1H); Note: The singlet at 3.72 corresponds to the methyl ester peak. Theoretically, the singlets should not be diastereomeric and thus be magnetically equivalent and rotate slowly, giving rise to a 6H singlet, but in fact they appear as two overlapping 3H singlets, and thus the two peaks at 3.72 are not a typographical error. 13 C NMR: (100 MHz, DMSO-d6) δ: 208.29, 165.92, 164.47, 153.74, 131.29, 114.11, 110.85, 82.94, 52.77, 43.19, 41.95, 40.18, 25.37, 23.41; (1 carbon signal not observed): LC / MS (ESI) calculated ([C 20 H 25 NO7+H] + as) = ​​392.17, measured value = 392.17

[0112] UHPLC method conditions: Column: Supelco Asentis Express C18, 2.7 μm, 2.1x50 mm; Mobile phase A: 0.05% TFA in MeOH:water (20:80); Mobile phase B: 0.05% TFA in MeOH:acetonitrile (20:80); Temperature: 40 °C; Gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); Flow rate: 1.0 mL / min; 229 nm; UPLC RT 1.28 min. Chiral HPLC method conditions: Column: PhenomenexLux Cellulose-2, 3 μm, 4.6x150 mm; Mobile phase A: 0.05% TFA in MeOH:water (20:80); Mobile phase B: 0.05% TFA in MeOH:acetonitrile (20:80); Temperature: 30 °C; Gradient: 0 min (20% B), 2.0 min (20% B), 5.0 min (55% B), 12.0 min (63% B), 18.0 min (100% B), 21.0 min (100% B); Flow rate: 1.2 mL / min; 229 nm; HPLC RT (desired enantiomer): 11.89 min; HPLC RT (undesired enantiomer) 9.94 min.

[0113] Example 5: Preparation of dimethyl 2-((4-(dimethylamino)benzoyl)oxy)-2-((1S,3S)-3-hydroxycyclohexyl)malonate [ka]

[0114] A 5 L reactor under nitrogen protection was charged with dimethyl (S)-2-((4-(dimethylamino)benzoyl)oxy)-2-(3-oxocyclohexyl)malonate (364 g, 930 mmol, 1.0 equiv., limiting reagent), phosphoric acid (114.4 g, 1.50 equiv.), 2-propanol (730 mL, 2.0 mL / g), HO (1100 mL, 3 mL / g), and [Ir(COD)Cl] (3.27 g, 0.005 equiv.) in that order at 20° C. The reaction mixture was then warmed to reflux (internal temperature of about 80° C.), and the mixture was observed to become homogenous upon warming. After 24 hours, the reaction mixture was cooled to 20° C., forming a suspension. The reaction mixture was then charged with HO (182 mL, 0.5 mL / g) in one portion, aged for 5 h, then charged with HO (1638 mL, 4.5 mL / g) over 2 h. The resulting slurry was then aged overnight, filtered, and washed successively with 1:4 2-propanol:HO (1100 mL, 3.0 mL / g) and then with HO (1100 mL, 3.0 mL). The wet cake was dried under vacuum at 50° C. with a N2 sweep to give 333 g (91% corrected isolated yield) of dimethyl 2-((4-(dimethylamino)benzoyl)oxy)-2-((1S,3S)-3-hydroxycyclohexyl)malonate as a white solid.

[0115] Alternatively, a 4 L reactor under nitrogen protection was charged with 2-propanol (200 mL, 2.0 mL / g), dimethyl (S)-2-((4-(dimethylamino)benzoyl)oxy)-2-(3-oxocyclohexyl)malonate (100 g, 255.5 mmol, 1.0 equiv., limiting reagent), phosphoric acid (33 g, 1.50 equiv.), IrCl4·xH2O (0.89 g, 0.01 equiv.), 2-propanol (200 mL, 2.0 mL / g), and H2O (50 mL, 0.5 mL / g) in that order at 20 °C. The reaction mixture is not homogenous at 20 °C. The reaction mixture was then warmed to reflux (internal temperature 80-82 °C) and the mixture was observed to become homogenous during warming. After 48 h, the reaction mixture was cooled to 20 °C. The reactor was charged with HO (350 mL, 3.5 mL / g) over 2 h. Following this addition, dimethyl 2-((4-(dimethylamino)benzoyl)oxy)-2-((1S,3S)-3-hydroxycyclohexyl)malonate seeds (100 mg, 0.01 equiv.) were charged at 20° C. and the mixture was aged overnight. The next day, HO (1200 mL, 12.0 mL / g) was charged over 6 h. The resulting slurry was aged overnight. The next day, the slurry was filtered and washed successively with 1:4 2-propanol:HO (300 mL, 3.0 mL / g) and then HO (300 mL, 3.0 mL). The wet cake was dried under vacuum at 50 °C with a N2 sweep to give 90 g (82% corrected isolated yield) of dimethyl 2-((4-(dimethylamino)benzoyl)oxy)-2-((1S,3S)-3-hydroxycyclohexyl)malonate as a solid.

[0116] 1 H NMR (400MHz, DMSO-d6) δ 7.79(d,J=9.1Hz,2H), 6.75(d,J=9.1Hz,2H), 4.03-3.96(m,1H), 3.67(s,6H), 3.01(s,6H), 2.66-2.54(m,1H), 1.74-1.56(m,4 H), 1.54-1.43(m,1H), 1.43-1.11(m,3H); 13LC / MS (ESI) Calculated value([C 20 H 27 NO7+H] + as) = ​​394.19, measured value = 394.19 UHPLC method conditions: Column: Supelco Asentis Express C18, 2.7 μm, 2.1x50 mm; Mobile phase A: 0.05% TFA in MeOH:water (20:80); Mobile phase B: 0.05% TFA in MeOH:acetonitrile (20:80); Temperature: 40 °C; Gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); Flow rate: 1.0 mL / min; 229 nm; UPLC RT 1.24 min. Chiral HPLC method conditions: Column: Phenomenex Lux Cellulose-2, 3 μm, 4.6x150 mm; Mobile phase A: 0.05% TFA in MeOH:water (20:80); Mobile phase B: 0.05% TFA in MeOH:acetonitrile (20:80); Temperature: 30 °C; Gradient: 0 min (50% B), 2.0 min (50% B), 11.0 min (80% B), 12.0 min (100% B), 15.0 min (100% B); Flow rate: 1.2 mL / min; 229 nm; HPLC RT (desired trans enantiomer) 10.8 min; HPLC RT (undesired trans enantiomer) 5.9 min; HPLC RT (undesired major cis enantiomer) 5.0 min; HPLC RT (undesired minor cis enantiomer) 9.8 min.

[0117] Example 6: Preparation of (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid [ka]

[0118] A 5 L jacketed reactor under nitrogen protection was charged at 20° C. with 2-propanol (300 mL, 1 mL / g), water (450 mL, 1.5 L / kg), dimethyl 2-((4-(dimethylamino)benzoyl)oxy)-2-((1S,3S)-3-hydroxycyclohexyl)malonate (300 g, 1.00 equiv., limiting reagent), and 2-propanol (60 mL, 0.2 L / kg) as rinse. The resulting suspension was then charged with 10 N aqueous NaOH (460 mL, 6.0 equiv.), and water (300 mL, 1.0 L / kg) as rinse. The reaction mixture was then heated to 80-85° C. and aged for at least 16 hours. The reaction mixture was then cooled to 5-15°C and 6M hydrochloric acid (620mL, 4.88eq) was charged over at least 2h while maintaining an internal temperature of <15°C. After an additional 4h, the reaction mixture was filtered and washed with water (2x300mL, 2x1mL / g). The filtrates were then combined, transferred to a new reactor and washed with MTBE (1500mL, 5mL / g). The lower reactant rich aqueous layer was then transferred to a new reactor and rinsed with water (150mL, 0.5mL / g) followed by a charge of 2-propanol (300mL, 1mL / g). The reaction stream was then charged with a solution of H5IO6 (435g, 2.50eq) in water (300mL, 1mL / g) over at least 2h while maintaining an internal temperature of <22°C. After an additional 17 hours, potassium chloride (600 g, 2 g / g) was charged, and after an additional 1.5 hours, the mixture was filtered and the solids washed with 20 wt% aqueous potassium chloride (2x300 mL, 2x1 mL / g). The filtrates were then combined and washed twice in succession with 2-methyltetrahydrofuran (2x1200 mL, 2x4 mL / g). The organic layers were then combined and charged with 20 wt% aqueous sodium chloride (1200 mL, 4 mL / g) and cysteine ​​hydrochloride (120 g, 0.40 g / g). After mixing for at least 0.5 hours, the layers were separated and the upper organic layer was washed with 20 wt% aqueous sodium chloride (1200 mL, 4 mL / g).

[0119] The product-rich organic layer was then concentrated under vacuum (internal temperature <40° C.), charged with 2-methyltetrahydrofuran (900 mL, 3 mL / g), concentrated, and then charged with 2-methyltetrahydrofuran (900 mL, 3 mL / g). The solution was then concentrated to 1 g / mL, followed by distillation with additional 2-methyltetrahydrofuran (3×300 mL, 3×1 mL / g). The resulting solution of about 1 mL / g was applied to a polished filter and charged with a mixture of heptane:toluene (3:1, 300 mL, 1 g / mL). The resulting slurry was then aged at 15-25° C. for at least 2 hours, followed by the addition of heptane:toluene (3:1, 900 mL, 3 g / mL) over at least 1 hour. After aging overnight, the slurry was cooled to 0° C., aged for at least 3 hours, filtered, washed with toluene (300 mL, 1 g / mL), and dried in a vacuum oven overnight at 50° C. with a N2 sweep to give 72.2 g of (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid as an off-white solid (66% “uncorrected” yield).

[0120] Alternatively, a 1 L jacketed reactor under nitrogen protection was charged with 10 M sodium hydroxide (200 mL, 2 mL / g, ca. 8 equiv.) followed by water (300 mL, 3 mL / g) at 20° C. Dimethyl 2-((4-(dimethylamino)benzoyl)oxy)-2-((1S,3S)-3-hydroxycyclohexyl)malonate (91.12 g, 95.13% QNMR availability, 1.00 equiv., limiting reagent) followed by 2-propanol (100 mL, 1 mL / g). The suspension was heated to reflux (internal temperature ca. 82° C.) and aged for 14.5 hours. The reaction mixture was then cooled to 7-8° C. and charged with 3 M aqueous hydrochloric acid (569 mL, ca. 5.7 mL / g, ca. 7.75 equiv.) over 4 hours. After another 26 hours at 7-8°C, the reaction mixture was allowed to warm to 20°C, filtered, and washed with water (200mL, 2mL / g). The filtrates were combined and then transferred to a new reactor, which was charged with water (50mL, 0.5mL / g) and 2-propanol (200mL, 2mL / g). The reaction stream was then charged with a solution of periodic acid (232.09g, 4.00eq) in water (200mL, 2mL / g) over 2.5 hours to control for gas emissions, followed by aging for another 27 hours. Potassium chloride (199.9g, 2g / g) was then charged, and after another 18 hours, the mixture was filtered and the solids were washed with 20wt% aqueous potassium chloride (200mL, 2mL / g). The filtrates were then combined and washed twice successively with 2-methyltetrahydrofuran (2x400mL, 800mL total, 8mL / g). The lower aqueous layer was then washed with additional 2-methyltetrahydrofuran (800mL, 8mL / g). The organic layers were combined and then charged with 20wt% aqueous potassium chloride (500mL, 5mL / g) and cysteine ​​hydrochloride (25g, 0.25g / g). The layers were separated and the upper organic layer was washed with 20wt% aqueous potassium chloride solution (500mL, 5mL / g) and cysteine ​​hydrochloride (25g, 0.25g / g). The upper organic layer was then washed with 20wt% aqueous potassium chloride (500mL, 5mL / g).

[0121] The cloudy product-rich organic layer was then concentrated under vacuum to 2 mL / g (rotovap; bath temperature: 50° C.) followed by the addition of 2-methyltetrahydrofuran (200 mL, 2 mL / g). The mixture was then charged with activated charcoal (Darco G-60; 2 g; 0.02 g / g) and after stirring overnight (approximately 18 hours), the mixture was filtered and washed with 2-methyltetrahydrofuran (2×50 mL, 2×0.5 mL / g). The filtrates were combined and then concentrated under vacuum (internal pressure: 200 Torr, internal temperature of the solution at steady state distillation: 39-41° C.) to about 100 mL (about 1 mL / g), cooled to 20° C., and charged continuously with heptane (45 mL, 0.45 mL / g) over 25 min, followed by (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid seeds (369 mg, 0.0037 g / g). After aging overnight (about 16 h), the slurry was charged with additional heptane (355 mL, 3.55 mL / g) over 4-6 h, filtered, and washed with 1:4 2-methyltetrahydrofuran:heptane (100 mL, 1 mL / g) followed by heptane (100 mL, 1 mL / g). The wet cake was then reslurried (with stirring) with toluene (100 mL, 1 mL / g) and the solvent removed under vacuum, followed by further drying in a vacuum oven at 50 °C overnight with a N2 sweep to give 20.76 g of (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid as an off-white solid ( 1 95.01% potency by H QNMR, 62.1% corrected isolated yield)

[0122] 1 H NMR (400MHz, d4-MeOH) δ 3.93-4.00(m,1H), 2.67-2.75(m,1H), 1.65-1.85(m,4 H), 1.45-1.63(m,4 H); 13 C NMR:(100MHz, d4-MeOH) δ 179.64, 66.88, 39.11, 36.51, 33.75, 29.27, 21.05; LC / MS(DCI) calculated value ([C7H 12 O3+H] +as) = ​​145.086, measured value = 145.0865 HPLC method conditions: Column: Supelco Asentis Express C18, 2.7 μm, 4.6x150 mm; Mobile phase A: 0.05% MSA in water:CH3CN (98:2); Mobile phase B: 0.05% MSA in water:CH3CN (10:90); Temperature: 25 °C; Gradient: 0 min (0% B), 7.0 min (100% B), 9.0 min (100% B); Flow rate: 0.8 mL / min; 210 nm; HPLC RT 4.62 min. Chiral HPLC method conditions: Column: Chiralpak AD-3, 3 μm, 4.6 x 150 mm; Mobile phase A: 0.03% MSA in heptane:EtOH (85:15), isocratic for 15 min; Temperature: 25 °C; Flow rate: 1.0 mL / min; 210 nm; HPLC RT desired trans enantiomer 7.67 min; HPLC RT undesired trans enantiomer 9.29 min; HPLC RT undesired major / minor cis diastereomers 6.89 min.

[0123] Example 7: Preparation of 1-((1S,2S)-2-aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea hydrochloride [ka]

[0124] A 4 L reactor under nitrogen protection was charged successively with 2-MeTHF (280 mL, 1.0 mL / g), a solution of (1S,2S)-(+)-1,2-diaminocyclohexane (235.8 g, 2.0 equiv.) in 2-MeTHF (840 mL, 3 mL / g), and 2-MeTHF (280 mL, 1.0 mL / g) as a rinse. The resulting solution was cooled to -10°C, and then a solution of 3,5-bis(trifluoromethyl)phenyl isocyanate (280 g, 1032 mmol, 1.0 equiv., limiting reagent) in 2-MeTHF (840 mL, 3 mL / g) was charged over 4.5 h. The reaction mixture was then slowly charged with 6N aqueous HCl (560 mL, 2.0 mL / g) over 30 min, while maintaining the internal temperature at <20°C. After an additional 10 min, the layers were separated and the lower aqueous layer was discarded. The upper organic layer was then concentrated under vacuum (320 mbar) to 4.0 mL / g while maintaining an internal temperature of 40-45° C. Fresh 2-MeTHF (560 mL, 2.0 mL / g) was charged and concentration continued to 3.0 mL / g. The reaction mixture was then placed under 1 atm N2 and the internal temperature was adjusted to 40-45° C. Heptane (2520 mL, 9.0 mL / g) was charged slowly over 3.5 h and the resulting slurry was cooled from 40-45° C. to 20° C. over 2 h. After aging overnight, the slurry was filtered, washed successively with heptane:2-MeTHF (3:1) (840 mL, 3.0 mL / g) followed by heptane (840 mL, 3.0 mL / g) and dried under vacuum at 45-50 °C to give 298 g (74-75% yield) of 1-((1S,2S)-2-aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea hydrochloride as a white solid.

[0125] 1H NMR (400MHz, DMSO-d6) δ 10.75-11.24(m,1H), 8.77-8.99(m,1H), 8.26-8.45(m,2H), 7.96-8.26(m,3H), 7.60-7.76(m,1H), 5.70-5.73(m,1H) , 4.23-4.43(m,1H), 2.95-3.17(m,1H), 1.94-2.18(m,2H), 1.59-1.80(m,2H), 1.39-1.57(m,1H), 1.11-1.39(m,3H); 13 C NMR: (100MHz, DMSO-d6) δ 181.3, 142.7, 130.5(q,J=33.0Hz), 122.0, 123.7(q,J=272.9Hz), 116.3, 55.0, 53.5, 30.9, 29.6, 24.3, 23.6;LC / MS (ESI) Calculated value ([C 15 H 17 F6N3S+H] + as) = ​​386.11, measured value = 386.11 HPLC method conditions: Column: Supelco Asentis Express C18, 2.7 μm, 4.6x50 mm; Mobile phase A: 0.05% TFA in acetonitrile:water (5:95); Mobile phase B: 0.05% TFA in acetonitrile:water (95:5); Temperature: 50 °C; Gradient: 0 min (0% B), 15.0 min (100% B), 18.0 min (100% B); Flow rate: 1.2 mL / min; 229 nm; HPLC RT 6.53 min.

[0126] Example 8: Preparation of (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid [ka]

[0127] A 100 mL reactor under nitrogen protection was charged with MTBE (45 mL, 7.5 mL / g) followed by KOtBu (11.2 g, 2.4 equiv.) at 20° C. In a separatory addition funnel, DMF (45 mL, 7.5 mL / g) was charged followed by (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid (6.0 g, 1.0 equiv., limiting reagent), which readily dissolved resulting in a clear solution. The contents of the addition funnel were then added dropwise over 90-120 min to the MTBE / KOtBu mixture, maintaining the internal temperature below 30° C. After an additional 30 min, 6-bromo-3-fluoro-2-methylpyridine (7.84 g, 1.00 equiv.) was charged to the resulting well-dispersed suspension and the reactor contents were heated to 33° C. After 6 hours, KOtBu (2.4 g, 1.00 equiv.) was added as a solid followed by 6-bromo-3-fluoro-2-methylpyridine (1.96 g, 0.25 equiv.). After an additional 24 hour ageing, the reactor contents were cooled to 25° C. and water (48 mL, 8.0 mL / g) was charged dropwise while maintaining the internal temperature below 30° C. After an additional 15 minutes, MTBE (24 mL, 4.0 mL / g) was charged and the resulting biphasic solution was stirred for 15 minutes at 25° C. The layers were then separated and the top organic layer was discarded. The bottom product-rich aqueous layer was then washed with additional MTBE (24 mL, 4.0 mL / g) and the top organic layer was discarded. The product-rich aqueous layer was then charged with MeTHF (60 mL, 10.0 mL / g) and acidified to pH 5-7 with 6N HCl (18 mL, 3.0 mL / g). The layers were then separated and the resulting upper product-rich organic layer was washed twice with water (2x18 mL, 2x3 mL / g) and concentrated under reduced pressure at 45°C to 6.0 mL / g. The resulting solution was subjected to a solvent exchange with toluene (48 mL, 8.0 mL / g) under constant volume distillation conditions and the resulting solution was treated with carbon Zeta Plus 55SP (0.9 g, 0.15 equiv.) for 2 h and filtered. The resulting solution was then concentrated under reduced pressure and seeded with 1 wt% of the desired product to crystallize, followed by the addition of heptane (108 mL, 18.0 mL / g) over 4-6 h.After aging overnight, the resulting slurry was filtered, washed successively with a toluene / heptane (1:3) mixture (18 mL, 3.0 mL / g), heptane (18 mL, 3.0 mL / g), and dried under vacuum at 45° C. to give 10.1 g (78% yield) of the desired product as a brown solid.

[0128] Alternatively, [ka]

[0129] A 100 mL reactor under nitrogen protection was charged with MTBE (45 mL, 7.5 mL / g) followed by KOtBu (14.0 g, 3.0 equiv.) at 20° C. In a separatory dropping funnel, DMF (45 mL, 7.5 mL / g) was charged followed by (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid (6.0 g, 1.0 equiv., limiting reagent). (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid dissolved readily to give a clear solution. The contents of the dropping funnel were then added dropwise over 15-30 min to the MTBE / KOtBu mixture while maintaining the internal temperature below 30° C. After an additional 30 min, 6-bromo-3-fluoro-2-methylpyridine (9.8 g, 1.25 equiv.) was charged to the resulting well-dispersed suspension and the reactor contents were heated to 33° C. After 24 hours, the reactor contents were cooled to 25° C. and water (48 mL, 8.0 mL / g) was charged dropwise to maintain the internal temperature below 30° C. After an additional 15 minutes, MTBE (18 mL, 3.0 mL / g) was charged and the resulting biphasic solution was stirred at 25° C. for 15 minutes. The layers were then split and the top organic layer was discarded. The product-rich aqueous layer was then charged with toluene (48 mL, 8.0 mL / g) and acidified to pH 5-7 with 6N HCl (18 mL, 3.0 mL / g). The layers were then split and the resulting top product-rich organic layer was concentrated under vacuum to 6.0 mL / g at 45° C. The resulting solution was then charged dropwise with heptane (108 mL, 18.0 mL / g) over 2-4 hours and aged overnight. The resulting slurry was then filtered, washed successively with a mixture of toluene / heptane (1:3) (18 mL, 3.0 mL / g) and heptane (18 mL, 3.0 mL / g) and dried under vacuum at 45° C. to give 7.9 g (61% yield) of (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid as a brown solid.

[0130] 1H NMR (400MHz, CDCl3) δ 11.61-10.99(m,1H), 7.27-7.14(m,1H), 7.07-6.95(m,1H), 4.68-4.50(m,1H), 2.91-2. 77(m,1H), 2.56-2.39(m,3H), 2.15-2.04(m,1H), 2.04-1.82(m,3H), 1.81-1.57(m,4H); 13 C NMR (100MHz, CDCl3) δ 181.3, 151.2, 150.9, 130.1, 125.5, 121.9, 72.3, 38.2, 31.8, 29.4, 27.9, 20.2, 19.1; LC / MS (ESI) calculated value ([C 13 H 16 BrNO3+H] + as) = ​​314.04, measured value = 314.04 Analysis: Column: Phenomex Kinetex C8, 150x4.6mm, 2.6μm; Mobile phase A: 0.05% TFA in water; Mobile phase B: 0.05% TFA in methanol:acetonitrile (80:20); Temperature: 27°C; Gradient: 0 min (44% B), 1.0 min (44% B), 17.0 min (60% B), 18.0 min (60% B), 25.0 min (90% B), 28.0 min (90% B), 30.0 min (100% B), 30.1 min (44% B), 35 min (44% B); Flow rate: 0.8mL / min; 220nm; HPLC RT 14.88 min

[0131] Example 9: Preparation of (1S,3S)-3-((6-(5-((benzyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid tert-butylamine salt [ka]

[0132] Preparation of Organomagnesium - A 250 mL jacketed Chemglass reactor equipped with an overhead stirring paddle was charged with 5-((benzyloxy)methyl)-4-bromo-1-methyl-1H-1,2,3-triazole bromide salt (36.05 g, 1.3 equiv.) and tetrahydrofuran (209 mL, 8.5 mL / g). The reactor was sealed, fitted with a nitrogen inlet, and the slurry was degassed by subsurface sparging with nitrogen for 30 min. The slurry was cooled to an internal temperature of 5° C. and aged for 10 min. Isopropylmagnesium chloride (103 mL, 2.55 equiv., 1.90 M in THF) was charged over 30 min (Caution: gas evolution!). After addition was complete, the reactor was allowed to warm to 20° C. After 3 h, the homogeneous organomagnesium solution was used immediately in the subsequent Negishi coupling (see below).

[0133] Negishi Coupling - A separate jacketed 1 L Chemiglass reactor equipped with an overhead stirring paddle was charged with (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (25.00 g, 1.0 equiv., limiting reagent), anhydrous zinc chloride (3.65 g, 0.35 equiv.), and tetrahydrofuran (85 mL, 3.4 mL / g). The reactor was sealed, fitted with a nitrogen inlet, and the headspace was flushed with nitrogen for 5 min. The resulting homogeneous solution was cooled to 0° C. and aged with agitation for 10 min. Isopropylmagnesium chloride (37.8 mL, 0.95 equiv., 1.90 M in THF) was charged over 15 min (Caution: gas evolution!). After an additional 15 min, the reactor was allowed to warm to 20° C. and PdCl2 (Xantphos) (1.44 g, 0.025 eq) was charged in one portion. The resulting heterogeneous solution was degassed by subsurface sparging with nitrogen for 30 min. After degassing, the solution was allowed to warm to 40° C. and aged with stirring for 10 min. The organomagnesium solution (see below) was charged slowly and steadily over 10-15 min. The resulting solution was stirred at 40° C. for 16 h, after which it was cooled to 23° C. The reaction was quenched with tribasic sodium ethylenediaminetetraacetate (11.67 g, 0.45 eq) in water (300 mL) for 1 h. The pH of the solution was adjusted to 4.0-5.0 with 6N HCl (1.1 eq) and the biphasic mixture was stirred for 30 min. The phases were allowed to clear for 30 min and then separated. The organic layer was treated with a freshly prepared solution of sodium percarbonate (2.43 g, 0.20 equiv.) in water (80 mL, 3.2 mL / g) [Caution: gas (CO2) evolution!]. The resulting homogeneous mixture was stirred at 20 °C for 4 h. Oxidation was carried out with sodium metabisulfite (2.87 g, 0.20 equiv.) in 15 wt. % NaCl. aq(80 mL, 3.2 mL / g). Toluene (75 mL, 3.0 mL / g) was charged and the resulting biphasic mixture was agitated for 30 min. The phases were allowed to clear for 30 min and then separated. The organic stream was concentrated under reduced pressure (100-150 Torr) to a solution with a volume of 4 mL / g. The product-rich organic layer was diluted with fresh toluene (150 mL, 6.0 mL / g) and then concentrated under reduced pressure (100-150 Torr) to a solution with a volume of 6 mL / g. The product-rich organic layer was diluted with toluene (25 mL, 1.0 mL / g) and tetrahydrofuran (25 mL, 1.0 mL / g). The resulting solution was transferred through a polished filter to a clean 250 mL jacketed Chemi-Glass reactor and allowed to warm to 55° C. One third of a solution of tert-butylamine (1.90 mL, 1.2 equiv.) in toluene (83 mL, 3.3 mL / g) and tetrahydrofuran (17 mL, 0.7 mL / g) was added in one portion, followed by seeds of the desired product (0.125 g, 0.5 wt%). The remaining two thirds of the amine solution was added dropwise over 60 min. After 30 min, the slurry was slowly cooled to 0° C. over 2 h. The slurry was aged at 0° C. for 14 h. The solid was collected by filtration. The solid was washed successively with toluene:tetrahydrofuran (5:1) (75 mL, 3.0 mL / g) followed by toluene (75 mL, 3.0 mL / g) and dried under oven vacuum at 65° C. with a nitrogen sweep to give 35.96 g (93.4%) of the desired product as a white solid.

[0134] Alternatively, [ka]

[0135] A 20 mL vial was charged with 5-((benzyloxy)methyl)-4-bromo-1-methyl-1H-1,2,3-triazole bromide salt (1.7059 g, 1.5 equiv.). The vial was sealed with a cap equipped with a PTFE-septum. The vial was fitted with a nitrogen inlet and the headspace was flushed with nitrogen for 5 min. Tetrahydrofuran (8.90 mL, 8.95 mL / g) was charged to the vial. The resulting slurry was cooled to 0° C. and aged for 10 min. Isopropylmagnesium chloride (4.11 mL, 3.0 equiv., 2.15 M in THF) was charged for 15 min (Caution: gas evolution!). After 2 h, the vial was allowed to warm to 23° C. and brought into a nitrogen atmosphere glovebox. Anhydrous zinc chloride (0.601 g, 1.5 equiv.) was charged in one portion and the solution was stirred in a nitrogen atmosphere glove box at 23° C. After 1 h, the homogeneous organozinc solution was removed from the nitrogen atmosphere glove box and used immediately in the subsequent Negishi coupling (see below).

[0136] Negishi Coupling - A separate 40 mL vial was charged with (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (1.00 g, 1.0 equiv., limiting reagent). The vial was sealed with a cap equipped with a PTFE-septum. The vial was fitted with a nitrogen inlet and the headspace was flushed with nitrogen for 5 min. Tetrahydrofuran (4.03 mL, 4.0 mL / g) was charged to the vial. The resulting homogeneous solution was cooled to 0° C. and aged for 10 min. Isopropylmagnesium chloride (1.30 mL, 0.95 equiv., 2.15 M in THF) was charged over 15 min (Caution: gas evolution!). After 15 min, the vial was allowed to warm to 23° C. and PdCl2 (Xantphos) (0.0665 g, 0.03 equiv.) was charged in one portion. The resulting heterogeneous solution was degassed by subsurface sparging with nitrogen for 5 min. After the solution was degassed, the organozinc solution (see above) was added over 10 min. The resulting solution was vigorously stirred at 23° C. After 21 h, a solution of tribasic sodium ethylenediaminetetraacetate (2.16 g, 2.0 equiv.) in water (12.0 mL) was added over 1 h. The phases were separated and the organic layer was concentrated under reduced pressure (100 Torr) to a solution volume of 4 mL / g. The product-rich organic layer was diluted with fresh tetrahydrofuran (8.0 mL, 8 mL / g). The solvent was removed under reduced pressure (100 Torr) to a solution volume of 4 mL / g. The product-rich organic layer was diluted with fresh tetrahydrofuran (8.0 mL, 8 mL / g). The solvent was removed under reduced pressure (100 Torr) until the volume of the solution was 4 mL / g. The product-rich organic layer was diluted with toluene (8.0 mL, 8 mL / g). One-third of a solution of tert-butylamine (0.33 mL, 1.0 equiv.) in toluene (1.0 mL, 1.0 mL / g) was added in one portion, followed by (1S,3S)-3-((6-(5-((benzyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, tert-butylamine salt (0.010 g, 1.0 wt %).The remaining two-thirds of the amine solution was added dropwise over 20 min. After 15 h, the slurry was filtered and the solid collected. The solid was washed successively with toluene:tetrahydrofuran (2:1) (6.0 mL, 6.0 mL / g) followed by toluene (6.0 mL, 6.0 mL / g) and dried under oven vacuum at 50° C. with a nitrogen sweep to give 1.22 g (76%) of (1S,3S)-3-((6-(5-((benzyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, tert-butylamine salt as a white solid.

[0137] 1 H NMR (400MHz, DMSO-d6) δ 8.54-7.37(brs,3H), 7.81(d,J=8.6Hz,1H), 7.54(d,J=8.6Hz,1H), 7.33-7.19(m,5H), 5.18(s,2H), 4.6 9(brs,1H), 4.53(s,2H), 4.06(s,3H), 2.33-2.35(m,1H), 2.32(s,3H), 2.00-1.42(m,8H), 1.19(s,9H); 13 C NMR: (100 MHz, DMSO-d6) δ 178.3, 151.2, 148.1, 144.5, 141.8, 138.4, 131.4, 128.7, 128.1, 128.0, 120.4, 119.5, 73.2, 72.0, 59.7, 49.8, 40.4 (overlap with DMSO-d6), 35.4, 33.4, 30.6, 29.1, 29.0, 21.3, 19.8; LC / MS (ESI) calculated ([C 24 H 28 N4O4+H] + as) = ​​437.22, measured value = 437.22 Analysis: Column: Phenomenex Kinetics C8 2.6 μm 4.6x150 mm; Mobile phase A: 0.05% TFA in H2O; Mobile phase B: 0.05% TFA in MeOH:CH3CN (80:20); Temperature: 27 °C; Gradient: 0 min (44% B), 1.0 min (44% B), 17.0 min (60% B), 18.0 min (60% B), 25.0 min (90% B), 28.0 min (90% B), 30.0 min (100% B), 30.1 min (44% B), 35.0 min (44% B); Flow rate: 0.8 mL / min; 220 nm; HPLC RT 17.849 min

[0138] Example 10: Preparation of (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid [ka]

[0139] A stainless steel high pressure reactor was charged with (1S,3S)-3-((6-(5-((benzyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid tert-butylamine salt (1.00 g, 1.0 equiv., limiting reagent), citric acid monohydrate (0.411 g, 1.00 equiv.), Pd / C (10 wt.%, wet) (0.100 g, 0.10 g / g), ethanol (6.0 mL, 6.0 mL / g) and water (2.0 ml, 2.0 ml / g). The reactor was sealed and overhead stirring was started. The atmosphere in the reactor was first replaced with nitrogen. The atmosphere in the reactor was then pressurized to 30 PSI with hydrogen and the reactor was allowed to warm to 40° C. After 25 hours, the reactor was cooled to 20-25° C. and filtered. The reactor and filter cake were then washed with ethanol:water (3:1) (2×2.0 mL, 2×2.0 mL / g). The filtrates were combined and then concentrated under reduced pressure (<10 Torr) to a solution volume of 5.0 mL / g. Water (7.0 mL, 9.0 mL / g) was then added over 2 hours. The resulting slurry was filtered and the solid was washed successively with water:ethanol (3:1) (3.0 mL, 3.0 mL / g), followed by water (3.0 mL, 3.0 mL / g), then dried in a vacuum oven at 50° C. with a nitrogen sweep to give 0.622 g (90%) of the desired product as a white solid.

[0140] Alternatively, [ka]

[0141] A stainless steel high pressure reactor was charged with (1S,3S)-3-((6-(5-((benzyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid tert-butylamine salt (1.00 g, 1.0 equiv., limiting reagent), anhydrous citric acid (0.508 g, 1.34 equiv.), Pd / C (10 wt.%, wet) (0.100 g, 0.10 g / g) and ethanol (200 proof) (10.0 mL, 10.0 mL / g). The reactor was sealed and overhead stirring was started. The atmosphere in the reactor was replaced with nitrogen. The atmosphere in the reactor was pressurized to 30 PSI with hydrogen and the reactor was allowed to warm to 40° C. After 25 hours, the reactor was cooled to 23° C. and filtered. The reactor and filter cake were washed twice with ethanol (2×2.0 mL, 2×2.0 mL / g). The organic layers were combined and concentrated under reduced pressure (<10 Torr) to a solution volume of 3.0 mL / g. Water (9.0 mL, 9.0 mL / g) was added over 2 hours. The solid was filtered and the solid was washed successively with water:ethanol (3:1) (3.0 mL, 3.0 mL / g) followed by water (3.0 mL, 3.0 mL / g) and then dried in a vacuum oven at 50° C. with a nitrogen sweep to give 0.491 g (71%) of (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid as a white solid.

[0142] 1 H NMR (500MHz, DMSO-d6) δ 12.09(brs,1H), 7.73(d,J=8.4Hz,1H), 7.35(d,J=8.5Hz,1H), 5.69(brs,1H), 4.89(brs,2H), 4.63(brs,1H), 3 .94(s,3H), 3.28(brs,1H), 2.37(brs,2H), 2.31(s,3H), 1.90-1.80(m,1H), 1.75-1.55(m,3H), 1.55-1.31(m,4 H); 13C NMR: (125MHz, CDCl3) δ 176.4, 150.2, 147.7, 143.1, 142.0, 134.6, 120.6, 119.2, 71.5, 51.8, 37.7, 35.0, 31.7, 28.8, 27.8, 19.9, 19.4; LC / MS (ESI) Calculated value ([C 17 H 22 N4O4+H] + as) = ​​347.17, measured value = 347.17 Analysis: Column: Phenomenex Kinetics C8 2.6 μm 4.6x150 mm; Mobile phase A: 0.05% TFA in H2O; Mobile phase B: 0.05% TFA in MeOH:CH3CN (80:20); Temperature: 27 °C; Gradient: 0 min (44% B), 1.0 min (44% B), 17.0 min (60% B), 18.0 min (60% B), 25.0 min (90% B), 28.0 min (90% B), 30.0 min (100% B), 30.1 min (44% B), 35.0 min (44% B); Flow rate: 0.8 mL / min; 220 nm; HPLC RT 5.003 min

[0143] Example 11: Preparation of N-methyl-N-propyl-1H-imidazole-1-carboxamide oxalate [ka]

[0144] A 4 L reactor was charged with t-AmOH (900 mL, 6.0 mL / g) and 1,1'-carbonyldiimidazole (353 g, 1.05 equiv). The addition port was rinsed with additional t-AmOH (150 mL, 1.0 mL / g). The resulting heterogeneous slurry was cooled to 0° C. and N-methylpropylamine (150 g, 1.0 equiv, limiting reagent) was added over 1 h. After 17 h, the solution was allowed to warm to 20° C. The reaction was quenched with water (525 mL, 3.5 mL / g) (Caution: gas evolution!). When gas evolution ceased, the reactor was charged with 6 N HCl. aq (228 mL, 0.67 equiv.) and sodium chloride (92 g, 0.76 equiv.). The phases were separated and the organic layer was retained in the reactor. The reactor was charged with 15 wt. % NaClaq (525mL, 3.5mL / g) and 6N HCl aq (51 mL, 0.15 equiv.). The phases were separated and the organic layer was retained in the reactor. The reactor was charged with 15 wt. % NaCl aq (525mL, 3.5mL / g) and 6N HCl aq (41 mL, 0.12 equiv.). The phases were separated and the organic layer was retained in the reactor. The reactor was charged with 15 wt. % NaCl aq (525mL, 3.5mL / g) and 6N HCl aq (10 mL, 0.03 equiv.) was charged. The phases were separated. The solution was allowed to warm to 45° C. and concentrated under reduced pressure (75 torr) to a solution volume of 4 mL / g. The reactor was charged with fresh toluene (750 mL, 5.0 mL / g) and further concentrated under reduced pressure (75 torr) to a solution volume of 4 mL / g. The reactor was then charged with fresh toluene (900 mL, 6.0 mL / g) and allowed to cool to 23° C. The resulting slurry was polished filtered and the resulting product-rich organic layer was charged to a clean 4 L reactor. The solution was allowed to warm to 65° C. and a solution of anhydrous oxalic acid (190 g, 1.0 equiv.) in 2-propanol (750 mL, 5.0 mL / g) was added over 3 hours. The resulting slurry was aged at 65° C. for 8 h and then cooled to 0° C. for 4 h. The solid was filtered, washed successively with toluene:2-propanol (7:1) (450 mL, 3.0 mL / g) followed by toluene (450 mL, 3.0 mL / g) and dried in a vacuum oven at 50° C. with a nitrogen sweep to give 406 g (77%) of N-methyl-N-propyl-1H-imidazole-1-carboxamide oxalate as a white solid.

[0145] 1H NMR (400MHz, DMSO-d6) δ 14.41-13.65(brs,2H), 8.31-8.04(m,1H), 7.62-7.50(m,1H), 7.19-7.06(m,1H), 3 .32(t,J=7.3Hz,2H), 3.00(s,3H), 1.60(sextet, J=7.3Hz,2H), 0.84(t,J=7.5Hz,3H); 13 C NMR: (100MHz, CDCl3) δ 162.02, 151.28, 137.40, 128.01, 119.27, 51.79, 36.48, 20.29, 11.31; LC / MS (ESI) calculated value ([C8H 13 NO+H] + as) = ​​168.11, measured value = 168.11 Analysis: Column: Supelco Asentis Express C18 2.7 μm 4.6x100mm; Mobile phase A: 0.01M NH4OAc in CH3CN:H2O (5:95); Mobile phase B: 0.01M NH4OAc in CH3CN:H2O (95:5); Temperature: 30 °C; Gradient: 0 min (0% B), 2.0 min (0% B), 15.0 min (25% B), 20.0 min (100% B), 24.0 min (100% B); Flow rate: 1.2 mL / min; 210 nm; HPLC RT 8.934 min

[0146] Example 12: Preparation of (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid [ka]

[0147] A 40 mL vial equipped with a magnetic stir bar and N2 inlet was charged sequentially with (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (0.446 g, 1.29 mmol, 1.0 equiv., limiting reagent), N-methyl-N-propyl-1H-imidazole-1-carboxamide oxalate (0.596 g, 2.32 mmol, 1.8 equiv.), and 2-methyl-2-butanol (5.4 mL, 12 L / kg). The resulting thick slurry was then warmed to 55-60 °C and KOtBu (20 wt % in THF, 4.7 mL, 7.8 mmol, 6.0 equiv.) was charged dropwise over 45 min via syringe pump. After an additional 2 hours, the resulting less viscous reaction mixture was cooled to ambient temperature and water (6.7 mL, 15 L / kg) was charged. 6N aqueous HCl (1 mL, 1.2 L.kg) was then added dropwise to adjust the pH of the aqueous layer to 4.0 (target pH 3.0-4.5). The layers were separated and the lower aqueous layer was back extracted with 2-methyl-2-butanol (4.0 mL, 9 L / kg). The product-rich aqueous layers were combined and then washed with NaCl (2 g / L, 4.0 mL, 9.0 L / kg) and the resulting organic layer was concentrated to near dryness on a rotovap. The residue was then dissolved in DCM (5.5 mL, 12 L / kg) and washed with water (4.0 mL, 9 L / kg). The layers were then separated and the lower product-rich DCM layer was applied to a polished filter. The filter was then washed with DCM (2.0 mL, 4.5 L / kg) to give a solution of (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid in DCM.

[0148] 1H NMR (500MHz, CDCl3) δ 7.96(d,J=8.4Hz,1H), 7.22(d,J=8.5Hz,1H), 5.76(d,J=9.9Hz,2H), 4.71(brs,1 H), 4.14(s,3H), 3.28-3.22(m,1H), 3.15-3.07(m,1H), 2.99-2.85(m,3H), 2.81( brs,1H), 2.50(s,3H), 2.19-2.11(m,1H), 2.09-1.86(m,3H), 1.82-1.72(m,1H), 1.71-1.62(m,3H), 1.60-1.54(m,1H), 1.48-1.38(m,1H), 0.90-0.71(m,3H)*; Note: The peak at 0.90-0.71 is actually observed as two broad singlets, each of which integrates at 1.5H in support of the API and exists as a mixture of rotamers in CDCl3. 13 C NMR: (125 MHz, CDCl3) δ 179.7, 155.8, 155.7, 150.7, 148.8, 145.3, 141.2, 129.9, 119.4, 118.9, 71.4, 55.1, 50.7, 38.0, 35.2, 35.1, 34.5, 33.8, 31.8, 29.2, 27.9, 20.8, 20.4, 20.1, 19.5, 10.84, 10.76; the 27 carbons (versus the theoretical 22) are due to the observed mixture of rotamers. LC / MS (ESI) calculated ([C 22 H 31 N5O5+H] + as) = ​​446.24, measured value = 446.24 HPLC method conditions: Column: Waters XBridge C8, 3.5 μm, 4.6x150 mm; Mobile phase A: 0.01M NH4OAc in acetonitrile:water (20:80); Mobile phase B: 0.01M NH4OAc in acetonitrile:water:MeOH (75:5:20); Temperature: 40°C; Gradient: 0 min (0% B), 9.6 min (25% B), 19.2 min (100% B), 27.0 min (100% B); Flow rate: 1.0 mL / min; 233 nm; HPLC RT 14.20 min.

[0149] Example 13. Preparation of (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid [ka]

[0150] A 40 mL vial equipped with a magnetic stir bar and N2 inlet was charged sequentially with CDI (0.842 g, 1.8 eq) and THF (4.0 mL, 4.0 mL / g). The reaction mixture was cooled to 0° C. and N-methylpropylamine (0.40 g, 1.89 eq) was added dropwise over 20-45 min. After aging at 0-5° C. for an additional 30 min, the reaction mixture was allowed to warm to room temperature and charged with 13-C (1.0 g, 1.0 eq, limiting reagent) and 2-methyl-2-butanol (8.0 mL, 8 L / kg). The resulting solution was then allowed to warm to 45-50° C. and KOtBu (20 wt % in THF, 3.8 mL, 2.4 eq) was charged dropwise over 45 min via syringe pump. After an additional 2 hours, the resulting less viscous reaction mixture was cooled to ambient temperature and water (3.0 mL, 3 L / kg) was charged. 6N aqueous HCl (2.4 mL, 2.4 L.kg) was then added dropwise to adjust the pH of the aqueous layer to 4.0 (target pH 3.0-4.5). The lower aqueous layer was discarded and the product-rich organic layer was then washed with aqueous NaCl (3 g / L, 3.0 mL, 3.0 L / kg) to give a solution of the final product in t-AmOH.

[0151] Biocatalytic synthesis of (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid: [ka]

[0152] Example 14. Preparation of 3-oxocyclohex-1-en-1-yl 4-methylbenzenesulfonate A 5L Chemiglass reactor under nitrogen was charged sequentially with 1,3-cyclohexanedione (140.0g, 1249mmol, 1.0eq, limiting reagent), p-toluenesulfonyl chloride (250.0g, 1311mmol, 1.05eq), and ethyl acetate (1400mL, 10L / kg). The resulting slurry was then cooled to 0-5°C and trimethylamine (151.6g, 1498mmol, 1.2eq) was charged dropwise over approximately 35 minutes via the addition funnel, keeping the internal temperature <10°C. After addition was complete, the addition funnel was rinsed with ethyl acetate (10mL, 1L / kg). After aging at 0-5°C for an additional hour, the reaction mixture was allowed to warm to ambient temperature. After aging overnight, water (700 mL, 5 L / kg) and ethyl acetate (700 mL, 5 L / kg) were charged and the resulting layers were separated. The top product-rich organic layer was then washed with sodium chloride (14 wt%) / water (140 mL, 2 L / kg) and the resulting product-rich organic layer was dried over MgSO4 (140 g, 1 kg / kg), filtered, and washed with ethyl acetate (78 mL, 0.6 L / kg) to give a crude solution of the desired product in EtOAc. The solution was determined to contain approximately 15.6 wt% 3-oxocyclohex-1-en-1-yl 4-methylbenzenesulfonate by comparing the peak for the desired product with the ethyl acetate peak, based on a total mass of the solution of 2114.36 g and 329 g of desired product (99% yield of solution).

[0153] 1 H NMR (500MHz, CDCl3) δ 7.75(d,J=8.3Hz,2H), 7.33(d,J=8.3Hz,2H), 5.70(s,1H), 2.41-2.38(m,5 H), 2.25-2.22(m,2H), 1.93-1.87(m,2H) HPLC method conditions: Column: Supelco Asentis Express C18, 50x2.1mm, 2.7μm; Mobile phase A: 0.05% TFA in acetonitrile:water (5:95); Mobile phase B: 0.05% TFA in acetonitrile:water (95:5); Temperature: 40°C; Gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); Flow rate: 1.0mL / min; 232nm; UHPLC RT 1.35 min.

[0154] Example 15. Preparation of methyl 3-oxocyclohex-1-ene-1-carboxylate A mixture of palladium(II) acetate (935.0 mg, 4.165 mmol, 0.05 equiv.), 1,3-bis(diphenylphosphino)propane (2.06 g, 4.99 mmol, 0.06 equiv.) and methanol (40 mL, 1.8 L / kg) was prepared. A 300 mL autoclave reactor was charged with 3-oxocyclohex-1-en-1-yl 4-methylbenzenesulfonate / EtOAc (141.7 g solution, ca. 15.6 wt. %, 22.1 g 3-oxocyclohex-1-en-1-yl 4-methylbenzenesulfonate, 83.03 mmol, 1.0 equiv., limiting reagent). The autoclave was charged with a mixture of Pd(OAc)2 / DPPP / MeOH followed by N,N-diisopropylethylamine. The autoclave was sealed and purged with 30 psi nitrogen three times, followed by 3 times with carbon monoxide. The autoclave was then pressurized to 30 psi and heated to 60° C. with 700 RPM agitation. After 15 hours, the autoclave was purged with nitrogen and the contents were transferred to an amber glass bottle. The above process was then repeated seven more times, combining to purify all eight reaction streams (theoretical product yield=102.35 g). The reaction mixtures were combined and concentrated under vacuum, and the resulting residue was charged first with n-heptane (160 mL), EtOAc (80 mL), and water (160 mL). The residue did not completely dissolve, and the liquid was decanted and set aside. The remaining residue was then dissolved by adding EtOAc (240 mL), water (160 mL), and warming to 40° C. The reserved mixture of n-heptane / EtOAc / water was then added to the biphasic solution of EtOAc / water and the layers were separated. The lower aqueous layer was back-extracted with a mixture of n-heptane (160 mL) and EtOAc (160 mL). The organic layers were combined and then concentrated on a rotovap to give 110.39 g of an orange residue. The residue was then dissolved in EtOAc (200 mL) and charged onto silica gel 60 (150 g), filtered, and washed with EtOAc (160 mL).The filtrates were combined and concentrated on a rotovap to give 98.16 g of an orange liquid, which was then purified by ISCO chromatography using DCM / EtOAc as the mobile phase to give 79.16 g (77% yield) of methyl 3-oxocyclohex-1-ene-1-carboxylate as a yellow oil.

[0155] 1 H NMR (400MHz, CDCl3) δ 6.74(s,1H), 3.84(s,3H), 2.61-2.58(m,2H), 2.47-2.44(m,2H), 2.10-2.03(m,2H) HPLC method conditions: Column: Acquity UHPLC HSS C18, 50x2.1mm, 1.8μm; Mobile phase A: 0.05% TFA in acetonitrile:water (5:95); Mobile phase B: 0.05% TFA in acetonitrile:water (95:5); Temperature: 40°C; Gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); Flow rate: 1.0mL / min; 240nm; UHPLC RT 1.16 min

[0156] Example 16. Preparation of 3-oxocyclohex-1-ene-1-carboxylic acid [ka]

[0157] A clean 500 mL reactor was charged with sodium carbonate (54.6 g, 515 mmol, 1.2 equiv) and water (400 mL, ca. 6 L / kg). After complete dissolution, methyl 3-oxocyclohex-1-ene-1-carboxylate (69.58 g, 429 mmol, 1.0 equiv, limiting reagent) was charged and allowed to warm to 35° C. After ca. 24 h, additional water (70 mL, ca. 1 L / kg) was added and the lower aqueous layer was separated from a small amount of upper orange oil. 3N aqueous HCl was charged slowly until the pH reached ca. 1, then the prdt was back extracted with DCM (5×100 mL). The organic layers were combined, then dried over Na2SO4, filtered, and concentrated on a rotovap to give 46.72 g of a yellow solid. The solid was then charged with DCM (125 mL, ca. 1.8 L / kg), heated to 30-35° C., and then n-heptane (650 mL, ca. 9.3 L / kg) was charged dropwise over >1 h to induce crystallization. The resulting slurry was then filtered, washed with n-heptane (2×50 mL, 2×0.7 L / kg), and dried in a vacuum oven at 50° C. to give 42.60 g (67% yield) of 3-oxocyclohex-1-ene-1-carboxylic acid as a pale yellow solid.

[0158] Alternatively [ka]

[0159] A pressure-rated 4 mL vial was charged in a glove box with a stock solution of Pd(DPPP)Cl2 in DCE (337.5 mg solution, prepared with 1.67 g DCE and 7.96 mg Pd(DPPP)Cl2, corresponding to 1.60 mg Pd(DPPP)Cl2, 0.0027 mmol, 0.04 equiv.) and a solution of 3-oxocyclohex-1-en-1-yl 4-methylbenzenesulfonate in EtOAc (150 mg solution, approximately 13.4 wt. %, 20.1 mg 3-oxocyclohex-1-en-1-yl 4-methylbenzenesulfonate, 0.075 mmol, 1.0 equiv., limiting reagent). The mixture was concentrated to dryness (Genevac, full vacuum, ca. 1 h) and then sequentially charged with KOAc (18.4 mg, 0.187 mmol, 2.5 eq.) and wet CH3CN (0.75 mL, stock solution made with 3.7 mL CH3CN and 67.5 mg water, corresponding to ca. 10 eq. water). The vial was then sealed and subjected to three pump / pump cycles to 30 psi with nitrogen. The vial was then pressurized to 55 psi with carbon monoxide and warmed to 60° C. while shaking on an orbital shaker set at 500 RPM. After >12 h, the vial was evacuated / backfilled with nitrogen and determined to have 99 AP of 3-oxocyclohex-1-ene-1-carboxylic acid by UPLC analysis.

[0160] 1 H NMR (500MHz, CDCl3) δ 6.86(t,J=1.9Hz,1H), 2.61(td,J=6.1, 1.9Hz,2H), 2.52-2.47(m,2H), 2.14-2.06(m,2H). HPLC method conditions: Column: Aquity UHPLC HSS C18, 50x2.1mm, 1.8μm; Mobile phase A: 0.05% TFA in acetonitrile:water (5:95); Mobile phase B: 0.05% TFA in acetonitrile:water (95:5); Temperature: 40°C; Gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); Flow rate: 1.0mL / min; 240nm; UHPLC RT 0.85 min.

[0161] Example 17. (1S,3S)-3-Hydroxycyclohexane-1-carboxylic acid [ka]

[0162] Stepwise reaction (pathway A): To a 50 mL reactor, ERED-302 (450 mg, 45 wt%), GDH-105 (100 mg, 10 wt%) and NADPH (50 mg, 0.05 wt%) were added. 0.5 M sodium phosphate buffer (pH 8.0, 17 mL, 17 L / Kg) was then added and stirred at 500 rpm. The reaction was aged for 30 minutes to allow the biocatalyst to dissolve. The pH was then checked and adjusted to 8.0 with 2.5 M NaOH, followed by a charge of D-glucose (3.75 g, 3 equiv). At this point, the temperature was set to 32.5° C. and the pH of the reaction was maintained at 8.0 using a pH stat. In a separate vessel, 3-oxocyclohex-1-ene-1-carboxylic acid (1.0 g, limiting reagent), 0.5 M sodium phosphate buffer, pH 8.0 (3 mL, 3 L / Kg) was charged and stirred for 10 minutes. The pH of this solution was then adjusted to pH 8.0 by adding 2.5 M NaOH. The biocatalyst solution was then charged to this solution via syringe pump over 6 hours. After 16 hours, the reaction was deemed complete (<1 LCAP 3-oxocyclohex-1-ene-1-carboxylic acid) and 4 M aqueous HCl was charged and the pH was adjusted to 6.0. A solution of KRED-P2-G03 (200 mg, 20 wt%) in 0.4 M sodium phosphate buffer (1 mL, 1 L / Kg) was then added to the pH stat to maintain pH=6.0. After 16 hours the reaction was judged to be complete (<1 LCAP 3-oxocyclohex-1-ene-1-carboxylic acid).

[0163] Cascade reaction (pathway B): To a 100 mL reactor, ERED-302 (750 mg, 45 wt%), GDH-105 (100 mg, 10 wt%), NADPH (50 mg, 0.05 wt%) and KRED-P2-G03 (100 mg, 10 wt%) were added. 0.5 M sodium phosphate buffer (pH 7.0, 57 mL, 57 L / Kg) was then added and stirred at 500 rpm. The reaction was aged for 30 minutes to allow the biocatalyst to dissolve. The pH was then adjusted to pH 7.0 with 2.5 M aqueous NaOH, followed by the addition of D-glucose (3.75 g, 2 equiv). At this point, the temperature was set to 32.5° C. and the pH of the reaction was maintained at 7.0 using a pH stat. In a separate vessel, BMT-203387-01 (1.0 g, limiting reagent), 0.5 M sodium phosphate buffer (pH 8.0, 3 mL, 3 L / Kg) was charged and stirred for 10 minutes. The pH of this solution was then adjusted to pH 7.0 by adding 2.5 M NaOH. The biocatalyst solution was then charged to this solution via syringe pump for 6 hours. After 16 hours, the reaction was deemed complete (>99 LCAP (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid).

[0164] Analysis: Working concentration: 1 mg / mL, Injection volume: 1 μL, Column: DB-FFAP 15 m x 0.32 mm x 0.50 μm, Carrier gas: Helium, Flow rate: 1.4 mL / min (constant flow), Front inlet temperature: 250 °C, Injection mode: Separation, Separation ratio: 10, Separation flow: 14; Oven program: Hold at 50 °C for 1 min, then 230 °C at 10 °C / min, hold for 3 min, then 250 °C at 20 °C / min, hold for 2 min (25 min run time); Detector type: FID, Detector temperature: 250 °C, Fuel flow rate: 30 mL / min, Oxidizer flow rate: 300 mL / min, Make-up gas: Helium, Make-up gas flow rate: 30 mL / min

Claims

1. Formula (XII): 【Chemistry 1】 [In the formula, R ８ and R ９ are independently N, CH or C(C １－６ alkyl); R １０ is independently １－４ is alkyl or halogen; and R １１ are independently Br, Cl or I. or a stereoisomer or salt thereof, comprising the steps of: Formula (XIII): 【Chemistry 2】 [In the formula, R ８ , R ９ , R １０ and R １１ is as defined above in formula (XII), and R １１ａ is a halogen. or a salt thereof, 【Chemistry 3】 or a stereoisomer or salt thereof, in the presence of a metal alkoxide in solvent 7, where solvent 7 is a polar aprotic or non-polar solvent, or a mixture of such solvents, for 18 to 48 hours or more and at 20 to 35° C. to complete the reaction, to produce a compound of formula (XII) or a stereoisomer or salt thereof.

2. Formula (XIIa): 【Chemistry 4】 or a salt thereof, comprising the steps of: 【Chemistry 5】 or a salt thereof, 【Chemistry 6】 or a salt thereof, in the presence of a metal alkoxide, wherein the metal alkoxide is selected from KOtBu, KHMDS, NaHMDS, and potassium amylate, in a solvent 7, wherein the solvent 7 is selected from DMF, MTBE, DMAc, NMP, DMPU, THF, 2-MeTHF, CPME, diisopropyl ether, toluene, and mixtures thereof, for a time period of 18 to 48 hours or more and at 20 to 35° C. to complete the reaction, to produce a compound of formula (XIIa) or a salt thereof.

3. Formula (XIIb): 【Chemistry 7】 or a salt thereof, comprising the steps of: 【Chemistry 8】 or a salt thereof, 【Chemistry 9】 or a salt thereof, in the presence of KOtBu in a mixture of DMF / MTBE for 18 to 48 hours or more and at 20 to 35° C. to effect fluoride displacement to produce a compound of formula (XIIb) or a salt thereof.

4. Formula (XII): 【Chemistry 10】 [In the formula: R ８ and R ９ are independently N, CH or C(C １－６ alkyl); R １０ is independently １－４ alkyl or halogen; R １１ are independently Br, Cl or I. or a stereoisomer or salt thereof.

5. Formula (XIIa): 【Chemistry 11】 [In the formula: R ８ and R ９ are independently N, CH or C(C １－４ alkyl); R １０ is independently １－４ alkyl or halogen; R １１ are independently Br, Cl or I. The compound according to claim 4, wherein the compound is represented by the formula:

6. Formula (XIIb): 【Chemistry 12】 6. The compound according to claim 4 or claim 5, wherein:

7. Formula (XIV): 【Chemistry 13】 [In the formula: R ８ and R ９ are independently N, CH or C(C １－６ alkyl); R １０ is independently １－４ is alkyl or halogen; R １２ is C １－４ is alkyl; R １３ are independently H, C １－４ alkyl or benzyl. or a stereoisomer or salt thereof.

8. Formula (XIVa): 【Chemistry 14】 [In the formula: R ８ and R ９ are independently N, CH or C(C １－４ alkyl); R １０ is independently １－４ is alkyl or halogen; R １２ is C １－４ is alkyl; R １３ are independently H, C １－４ alkyl or benzyl. The compound according to claim 7, wherein the compound is represented by the formula:

9. Formula (XIVb): 【Chemistry 15】 [In the formula: R １３ are independently H or benzyl.

9. The compound according to claim 7 or claim 8, wherein:

10. Formula (XVII): 【change】 [In the formula, R １４ and R １４ａ is independently １－６ is alkyl] or a salt thereof, comprising reacting a compound represented by formula (XVIII): 【Chemistry 16】 The compound represented by the formula: １４ R １４ａ in a solvent 10, where solvent 10 is a polar protic, aprotic, or non-polar solvent, or a mixture of solvents, for at least 1 hour and at -5 to 25°C to effect carboxamide formation to produce a compound of formula (XVII).

11. Formula (XVIIa): 【Chemistry 17】 A method for producing a compound represented by formula (XVIII): 【Chemistry 18】 contacting a compound of formula (I) with N-methylpropylamine in the presence of a solvent 10 (selected from DCM, t-AmOH, water, MTBE, acetonitrile, THF, MeTHF, acetone, MEK, MIBK, MeOAc, EtOAc, IPAc, DMF, NMP, DMAc, and mixtures of said solvents) for at least 1 hour and at −5 to 25° C. to effect carboxamide formation; 11. The method of claim 10, further comprising the subsequent addition of (HO2C)2 to produce the compound of formula (XVIIa).

12. Formula (Xa): 【Chemistry 19】 or a salt thereof, comprising the steps of: 【Chemistry 20】 or a salt thereof, in the presence of an aqueous phosphate buffer, GDH, NADPH and glucose, with or without an organic solvent, the organic solvent being selected from DMSO, IPA, dioxane, acetone and mixtures thereof, for at least 16 hours and at 32.5° C. to produce a compound of formula (Xa) or a salt thereof.

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