Intermediates useful for the preparation of LpxC analogues, and processes for their preparation

Abstract

This application relates to novel intermediates (rc1) and (rc2) and processes for their preparation. The intermediates are useful for the preparation of the LpxC hydroxamic acid inhibitor (R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (1). JPEG2025511205000039.jpg11582

Description

[Technical field]

[0001] The present invention provides a new process for the preparation of the LpxC hydroxamic acid inhibitor (R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide of formula (1). [ka] [Background technology]

[0002] The LpxC inhibitor (R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)-butanamide (1) is a veterinary hydroxamic acid antibiotic with biological activity against a variety of Gram-negative bacteria. Gram-negative bacteria cause a wide range of diseases, including urinary tract, bloodstream, gastrointestinal, and respiratory tract-associated infections. Gram-negative bacteria have an asymmetric bilayer composed of glycolipids lipopolysaccharide and glycerol phospholipids that make up the bacterial outer membrane. The Gram-negative outer membrane is a critical barrier that provides protection against antibiotics and provides host innate immune molecules, such as cationic antimicrobial peptides, and is a key construct that aids in antimicrobial resistance. Recently, Gram-negative bacteria with resistance to commonly used antibiotics, including quinolones, colistin (polymyxin), carbapenems, cephalosporins, and other β-lactam antibiotics, have been isolated from animals with increasing frequency. The development of new antibiotics targeting Gram-negative bacteria is declining, and drug-resistant infections caused by Gram-negative bacteria are a major medical concern in the future, as organisms resistant to all or most of the clinically useful antibacterial drugs have already been isolated. Therefore, new antibiotics against both sensitive and resistant Gram-negative bacteria are needed.

[0003] Gram-negative bacteria (such as Escherichia coli, Salmonella, and Haemophilus parasuis) have been a significant problem in the swine industry for many years. Pathogens produced by these bacteria not only cause inflammation but also various diseases, making pigs more susceptible to viral infections. Different E. coli strains can cause diarrhea and enterotoxemia in piglets, resulting in reduced weight gain or even sudden death. Salmonella enterica can cause both pneumonia and diarrhea in pigs, as well as food-borne gastroenteritis in humans. Haemophilus parasuis, another important harmful swine bacterium, is a pathogen that can cause fibrotic polyfollicular serositis, meningitis, and arthritis (called Glasser's disease).

[0004] In recent years, many genera and species of bacteria have begun to show a certain resistance to Gram-negative antibiotics. Thus, there is a continuing need for new antibacterial agents to combat these bacteria, especially resistant Gram-negative bacteria. LpxC inhibitors of formula (1) have been shown to have antibacterial effects against Gram-negative bacteria. Prior literature, namely U.S. Pat. No. 8,664,401, describes this molecule and its preparation. However, the described process is not scalable, since it only produces the main enantiomerically pure intermediate (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-butanoic acid (R2) in about 13% yield. Furthermore, the process describes the use of expensive (e.g., Cs2CO3) and dangerous (e.g., NaH) reagents, requires additional synthesis steps, and contains the unstable intermediate ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate. The process described herein provides a novel, scalable process with fewer steps, stable intermediates, no hazardous or expensive reagents, and an overall yield of the (R2) intermediate of 31%. Summary of the Invention

[0005] As described in the art, in view of the number of procedural steps and the use of expensive and hazardous reagents to prepare the lower yields of formula (1), a more robust and efficient process was developed to prepare the compound of formula (1) in higher and less expensive yields. [ka]

[0006] In one embodiment of the invention is the racemic intermediate compound 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1). [ka]

[0007] In another aspect, a process for preparing 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1) intermediate compound according to the following rxn-1 procedure: [ka] a) reacting 3-bromotetrahydrofuran-2(3H)-one (a) with sodium methanesulfinate in the presence of solvent A, a phase transfer catalyst, and optionally a dehydrating agent at a temperature of about 40-100° C. for about 1-24 hours to prepare intermediate 3-(methylsulfonyl)-dihydrofuran-2(3H)-one (b); b) cooling the mixture at ambient temperature overnight and filtering the solids and washing with Solvent A; c) reacting the solid with a base in the presence of a phase transfer catalyst, a methylating agent, solvent B, and optionally a dehydrating agent at a temperature of about 40-100° C. for a period of about 4-48 hours; d) charging the reactor with additional methylating agent and base while heating for an additional 4 hours; e) filtering the solids while retaining the solvent filtrate; f) washing the solids with solvent B while again retaining the solvent filtrate, then heating the combined filtrates to about 65° C. while distilling off all but about 1.5 volumes; g) exchanging the solvent for solvent A, cooling and seeding; h) further cooling to induce crystallization, filtering the crystals and washing with solvent A to obtain the final product 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1).

[0008] In another aspect, there is provided an rxn-1 process for preparing the intermediate compound 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1), comprising: a) reacting 3-bromotetrahydrofuran-2(3H)-one with sodium methanesulfinate in the presence of isopropanol, a phase transfer catalyst, and optionally a dehydrating agent at a temperature of about 50-80° C. for about 1-11 hours to prepare 3-(methylsulfonyl)-dihydrofuran-2(3H)-one; b) cooling the mixture at ambient temperature overnight and filtering the solids and washing with isopropanol; c) reacting the solid with potassium carbonate in the presence of a phase transfer catalyst, dimethyl sulfate, acetone, and optionally a dehydrating agent at a temperature of about 50-80° C. for a period of about 16-24 hours; d) charging the reactor with additional dimethyl sulfate and potassium carbonate while heating for an additional 4 hours; e) filtering the solids while retaining the acetone filtrate; f) washing the solids with acetone, again retaining the acetone filtrate, and heating to about 65° C. while distilling off all but about 1.5 volumes; g) exchanging the acetone for isopropanol, cooling to about 35° C. and seeding; h) further cooling to about 25° C. to induce crystallization, filtering the crystals and washing with isopropanol to obtain 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one.

[0009] In another aspect, there is provided an rxn-1 process for preparing the intermediate compound 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1), comprising: a) reacting 3-bromotetrahydrofuran-2(3H)-one with sodium methanesulfinate in the presence of isopropanol, methyltrioctylammonium chloride, and optionally a dehydrating agent, magnesium sulfate, at a temperature of about 80° C. for about 3 hours to prepare 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one; b) cooling the mixture at ambient temperature overnight, filtering the solids, washing with isopropanol and concentrating the solids; c) reacting the solid with potassium carbonate in the presence of methyltrioctylammonium chloride, dimethyl sulfate and magnesium sulfate, and isopropanol at a temperature of about 60° C. for about 7 hours; d) charging the reactor with additional dimethyl sulfate and potassium carbonate while heating for an additional 4 hours; e) filtering the reaction mixture to remove inorganic salts; f) washing the solids with acetone and heating to about 65° C. while distilling off all but about 1.5 volumes; g) exchanging the acetone for isopropanol, cooling the mixture to about 35° C., and seeding the mixture; h) further cooling to about 25° C. to induce crystallization, filtering the crystals and washing with isopropanol to obtain 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one.

[0010] In another aspect, there is provided an rxn-1 process for preparing the intermediate compound 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1), comprising: a) reacting 3-bromotetrahydrofuran-2(3H)-one with sodium methanesulfinate in the presence of isopropanol, methytrioctylammonium chloride, and magnesium sulfate at a temperature of about 80° C. for about 3 hours to prepare intermediate 3-(methylsulfonyl)dihydrofuran-2(3H)-one; b) cooling the mixture at ambient temperature overnight, isolating the solid by dissolving in isopropanol, filtering the solid and washing with isopropanol; c) reacting the solid with potassium carbonate in the presence of methyltrioctylammonium chloride, dimethyl sulfate, and magnesium sulfate in acetone at a temperature of about 60° C. for about 7 hours; d) charging the reactor with additional dimethyl sulfate and potassium carbonate while heating for an additional 4 hours; e) filtering the solids while retaining the acetone filtrate; f) washing the solids with acetone, again retaining the acetone filtrate, and then heating the combined filtrates to about 65° C. while distilling off all but about 1.5 volumes; g) exchanging the acetone for isopropanol, cooling the mixture to about 35° C. and seeding; h) further cooling to about 25° C. to induce crystallization, filtering the crystals and washing with isopropanol to obtain 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one.

[0011] In another aspect, a telescoped process (rxn-t) for preparing the intermediate compound 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1) according to the following telescoped procedure: [ka] a) reacting 3-bromodihydrofuran-2(3H)-one (a) with sodium methanesulfinate in the presence of a phase transfer catalyst, solvent B, and optionally a dehydrating agent in a jacketed reactor at 50-80° C. for about 7-11 hours; b) cooling the mixture to room temperature with stirring overnight for about 12 hours, filtering the reaction mixture, retaining the filtrate, and washing the solids with solvent B while retaining the filtrate; c) reacting the combined filtrate with a methylating agent, a base, and optionally a dehydrating agent while slowly heating the reaction to about 50-80° C. for about 15-20 hours; d) adding more base and methylating agent to the mixture and heating for about 3 to 6 hours; e) cooling the mixture to ambient temperature and filtering to remove solids while retaining the filtrate; f) washing the solids with solvent B, again while retaining the filtrate, and heating the combined filtrate to about 60-70° C., then distilling off the solvent, retaining about 1.5 volumes; g) exchanging solvent B with solvent A while cooling to about 30-40° C., seeding, and then further cooling to about 20-25° C. to obtain 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one.

[0012] In another aspect, there is provided an rxn-t process for preparing the intermediate compound 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1), comprising: a) reacting 3-bromodihydrofuran-2(3H)-one with sodium methanesulfinate in the presence of a phase transfer catalyst, a dehydrating agent, and acetone in a jacketed reactor at 50-80° C. for about 7-11 hours; b) cooling the mixture to room temperature with stirring overnight for about 12 hours, filtering the reaction mixture, retaining the filtrate, washing the solids with acetone, and again retaining the filtrate; c) reacting the filtrate with dimethyl sulfate, a base, and a dehydrating agent while slowly heating the reaction mixture to about 50-80° C. for about 15-20 hours; d) adding more base and methylating agent to the mixture and heating for about 3 to 6 hours; e) cooling the mixture to ambient temperature and filtering to remove solids while retaining the filtrate; f) washing the solids with acetone, again retaining the filtrate, heating the combined filtrate to about 60-70° C., and then distilling off the acetone, again retaining about 1.5 volumes; g) exchanging the acetone with isopropanol while cooling to about 30-40° C., seeding, and then further cooling to about 20-25° C. to obtain 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one.

[0013] In another aspect, there is provided an rxn-t process for preparing the intermediate compound 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1), comprising: a) reacting 3-bromodihydrofuran-2(3H)-one with sodium methanesulfinate in the presence of methyltrioctylammonium chloride, magnesium sulfate, and acetone in a jacketed reactor for about 9 hours at reflux at about 56° C.; b) cooling the mixture to room temperature with stirring overnight for about 12 hours, filtering the reaction mixture while retaining the filtrate, washing the solids with acetone, and again retaining the filtrate; c) reacting the combined filtrate with dimethyl sulfate, anhydrous potassium carbonate, and anhydrous magnesium sulfate while slowly heating the reaction to reflux at about 56° C. for about 15 hours; d) adding more potassium carbonate and dimethyl sulfate to the mixture and heating for about an additional 4 hours; e) cooling the mixture to ambient temperature and filtering to remove solids while retaining the filtrate; f) washing the solids with acetone, again retaining the filtrate, heating the combined filtrate to about 65° C., and then distilling off the acetone, again retaining about 1.5 volumes; g) exchanging the acetone with isopropanol while cooling to about 35° C., seeding, and then further cooling to about 20° C. to obtain 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one.

[0014] In another embodiment, the reactants used to prepare the intermediate compound 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1) from 3-bromodihydrofuran-2(3H)-one include the following: a preferred base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium phosphate, and cesium carbonate; a preferred methylating agent is selected from the group consisting of iodomethane, bromomethane, chloromethane, dimethyl sulfate, and dimethyl carbonate; a preferred phase transfer catalyst is selected from the group consisting of methyltrioctylammonium chloride, PEG300, and PEG400; a preferred dehydrating agent is selected from the group consisting of magnesium sulfate, sodium sulfate, and calcium chloride; a preferred solvent A is selected from the group consisting of isopropanol, ethanol, methanol, and acetonitrile; and a preferred solvent B is acetone or 2-butanone.

[0015] In another embodiment, the reactants used to prepare the intermediate compound 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) from 3-bromodihydrofuran-2(3H)-one include the following: a more preferred base is potassium carbonate, a more preferred methylating agent is dimethyl sulfate, a more preferred phase transfer catalyst is methyltrioctylammonium chloride, a more preferred dehydrating agent is magnesium sulfate, a more preferred solvent A is isopropanol, and a more preferred solvent B is acetone.

[0016] In another embodiment, a process for making the intermediate compound 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)dihydrofuran-2(3H)-one (b) using potassium carbonate as a base, dimethyl sulfate as a methylating agent, and acetone as solvent B, using a dehydrating agent. In another embodiment, a process for making the intermediate compound 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)-dihydrofuran-2(3H)-one (b) using sodium carbonate as a base, iodomethane as a methylating agent, and acetonitrile as solvent B, using a dehydrating agent. In another embodiment, a process for making intermediate compound 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)dihydrofuran-2(3H)-one (b) using potassium carbonate as base, methyl tosylate as methylating agent, and acetone as solvent B using a dehydrating agent. In another embodiment, a process for making intermediate compound 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)dihydrofuran-2(3H)-one (b) using potassium carbonate as base, iodomethane as methylating agent, and acetone as solvent B using a dehydrating agent. In another aspect, a process for making the intermediate compound 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)-dihydrofuran-2(3H)-one (b) using sodium carbonate as a base, iodomethane as a methylating agent, and acetone as solvent B, with a dehydrating agent. In another aspect, a process for making the intermediate compound 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)-dihydrofuran-2(3H)-one (b) using potassium phosphate as a base, iodomethane as a methylating agent, and acetone as solvent B, with a dehydrating agent.In another aspect, a process for making intermediate compound 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)dihydrofuran-2(3H)-one (b) using sodium carbonate as base, iodomethane as methylating agent, and 2-butanone as solvent B using a dehydrating agent.

[0017] In another embodiment, a process for making the intermediate compound 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)-dihydrofuran-2(3H)-one (b) without a dehydrating agent using potassium carbonate as a base, dimethyl sulfate as a methylating agent, and acetone as solvent B. In another embodiment, a process for making the intermediate compound 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)-dihydrofuran-2(3H)-one (b) without a dehydrating agent using sodium carbonate as a base, iodomethane as a methylating agent, and acetonitrile as solvent B. In another embodiment, a process for making intermediate compound 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)dihydrofuran-2(3H)-one (b) using potassium carbonate as base, methyl tosylate as methylating agent, and acetone as solvent B without the use of a dehydrating agent. In another embodiment, a process for making 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)dihydrofuran-2(3H)-one (b) using potassium carbonate as base, iodomethane as methylating agent, and acetone as solvent B without the use of a dehydrating agent. In another embodiment, a process for making 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)-dihydrofuran-2(3H)-one (b) without a dehydrating agent using sodium carbonate as a base, iodomethane as a methylating agent, and acetone as solvent B. In another embodiment, a process for making the intermediate compound 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)dihydrofuran-2(3H)-one (b) without a dehydrating agent using potassium phosphate as a base, iodomethane as a methylating agent, and acetone as solvent B.In another aspect, a process for making intermediate compound 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) from 3-(methylsulfonyl)dihydrofuran-2(3H)-one (b) using sodium carbonate as base, iodomethane as methylating agent, and 2-butanone as solvent B without the use of a dehydrating agent.

[0018] Another aspect of the invention is the enantiomerically pure intermediate compound (R)-3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (R1). [ka]

[0019] In another embodiment, a process for preparing an enantiomerically pure intermediate compound (R1) from a racemic (rc1) substrate using chiral chromatography according to the following procedure. [ka]

[0020] In another embodiment, chiral separation of the enantiomerically pure intermediate compound (R1) from the racemic substrate (rc1) can be achieved by chiral chromatography. In another embodiment, the chiral chromatography uses a Chiralpak® or Chiracel® column. In another embodiment, the Chiralpak® chromatography column is an AD, AS, AY, AZ, IA, IB, IC, ID, IE, IF, or IG column. In another embodiment, the Chiralpak® chromatography column is an AD Chiralpak® column. In another embodiment, the enantiomerically pure intermediate compound (R1) can be separated from the racemic (rc1) substrate using a Chiralpak® AD chromatography column. In another embodiment, the Chiracel® chromatography column is an OD or OJ Chiracel® column. In another embodiment, the enantiomerically pure intermediate compound (R1) can be separated from the racemic (rc1) substrate using a Chiralcel® OD or OJ chromatography column. In another embodiment, the enantiomerically pure intermediate compound (R1) can be separated from the racemic (rc1) substrate using a Chiralcel® OD chromatography column. In another embodiment, the enantiomerically pure intermediate compound (R1) can be separated from the racemic (rc1) substrate using a Chiralcel® OJ chromatography column.

[0021] In another aspect, a process for preparing (rc2) from (rc1) by reacting (rc1) with pyridinone in the presence of a base and a solvent to prepare intermediate compound (rc2) according to the following procedure: [ka]

[0022] In another embodiment, there is provided a process for preparing the intermediate compound 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (rc2) from 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1), comprising the steps of: a) dissolving potassium tert-butoxide in anhydrous DMSO, followed by addition of 4-chloropyridin-2(1H)-one while maintaining a temperature of about 18-27° C.; b) adding to a mixture of (rc1) and benzyltriethylammonium bromide and heating to about 85° C. for about 2 hours; c) aging the reaction at about 85° C. for about 17-20 hours; d) adding isopropyl acetate and stirring at about 60° C. for about 1 hour; e) cooling to about 20° C. over 1 hour, aging for 1 hour, filtering the solids, washing with isopropyl acetate and drying overnight at about 50° C. to produce the potassium salt of (rc2); f) dissolving the dried solid in water, treating with methanol and methyltetrahydrofuran and charging with concentrated HCl; g) stirring the slurry at room temperature for about 2 hours and then cooling the slurry to about 0-5° C. with stirring for an additional hour; h) filtering the slurry, washing with water:MeOH (8:2) and then drying in vacuum under nitrogen to obtain (rc2).

[0023] In another embodiment, there is provided a process for preparing the intermediate compound 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (rc2) from 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1), comprising the steps of: a) charging PEG, 2-methyl-2-butanol, and 4-chloro-2-hydroxypyridine to a reactor under nitrogen; b) adjusting the reactor temperature to about 18-25°C and adding potassium tert-butoxide with stirring; c) aging the reaction mixture at about 40-50° C. for about 30-60 minutes; d) adding (rc1) to a reactor and heating to about 100° C. for about 15-30 minutes; e) maintaining the temperature at about 95-100°C for about 12-24 hours; f) cooling the reaction to about 50-60° C., diluting with water, and adjusting the pH to about 1-2 with HCl; g) cooling the reaction mixture to about 0-5° C. over about 1-3 hours, aging the mixture for about 1-2 hours, and filtering the resulting solid. h) washing the solid with water and drying to obtain (rc2).

[0024] In another embodiment, there is provided a process for preparing the intermediate compound 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (rc2) from 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1), comprising the steps of: a) charging PEG400, 2-methyl-2-butanol, and 4-chloro-2-hydroxypyridine into a reactor under nitrogen; b) adjusting the reactor temperature to about 20° C. and gradually adding potassium tert-butoxide while stirring; c) aging the reaction mixture at about 40-45° C. for about 30-45 minutes; d) adding (rc1) to a reactor and heating to about 100° C. for about 20 minutes; e) maintaining the temperature at about 95-100° C. for about 16-20 hours; f) cooling the reaction to about 50-60° C., diluting with water, and adjusting the pH to about 1-2 with HCl; g) cooling the reaction to 0° C. over about 2 hours, aging for about 1 hour, and filtering the resulting solid; h) washing the solid with deionized water and drying at about 70°C to obtain (rc2).

[0025] In another embodiment, the intermediate compound 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid, (rc2).

[0026] In another aspect, a process for the preparation of (R2) from (R1) by reacting pyridinone with enantiomerically pure (R)-3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (R1) in a solvent to prepare intermediate compound (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (R2) according to the following procedure: [ka] wherein R' is H or K.

[0027] In another aspect, there is provided a process for preparing the intermediate compound (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (R2) from (R)-3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (R1), comprising the steps of: a) dissolving potassium tert-butoxide in anhydrous DMSO or sulfolane, followed by addition of 4-chloropyridin-2(1H)-one while maintaining a temperature of about 18-27° C.; b) adding to a mixture of (R)-3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (R1) and benzyltriethylammonium bromide and heating to about 85° C. for 2 hours; c) aging the reaction at about 85° C. for about 17-20 hours; d) adding isopropyl acetate and stirring at about 60° C. for about 1 hour; e) cooling to about 20° C. over 1 hour, aging for 1 hour, filtering the solids, washing with isopropyl acetate, and drying overnight at about 50° C. to produce the potassium salt of (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid; f) dissolving the dried solid in water, treating with methanol and methyltetrahydrofuran and charging with concentrated HCl; g) stirring the slurry at room temperature for about 2 hours and then cooling the slurry to about 0-5° C. with stirring for an additional hour; h) filtering the slurry, washing with water:MeOH (8:2), and then drying in vacuum under nitrogen to obtain (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid.

[0028] In another embodiment, the intermediate compound (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid, (R2).

[0029] In another embodiment is the (S)-enantiomerically pure intermediate compound (S1), 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one. [ka] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] [Brief description of the drawings]

[0031] [Figure 1] FIG. 1 shows X-ray powder diffraction patterns of Form 1, Form 2 and Form 3 of the compound of formula (1) (R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)-butanamide.

[0032] For purposes of the present invention, as described and claimed herein, the following terms and phrases are defined as follows. "About" when used in connection with a measurable, numerical variable refers to the greater of the stated value of the variable and all values ​​of the variable that are within experimental error of the stated value (e.g., within a 95% confidence interval of the mean) or within 10 percent of the stated value. This term can be easily omitted as a descriptor.

[0033] As used herein, "animal(s)" refers to individual animals that are mammals, unless otherwise indicated. Specifically, mammals refer to non-human vertebrate animals, which are taxonomic members of the class Mammalia. Examples of non-human mammals include companion animals (i.e., cats, dogs, and horses) and livestock (i.e., pigs, cows, sheep, and goats). Preferred livestock are pigs and cows, more preferably pigs.

[0034] As used herein, unless otherwise indicated, "pharmaceutically acceptable" refers to a substance or composition that must be chemically and / or toxicologically compatible with other ingredients comprising the composition (formulation) and / or with the animal being treated therewith. Use of the phrase "and pharmaceutically acceptable salt(s)" can be interchanged with "or pharmaceutically acceptable salt(s)."

[0035] As used herein, unless otherwise indicated, "seeding" refers to the addition of a small sample of a crystalline or polycrystalline material for the final intermediate or product resulting from the reaction (e.g., a reference standard) to a supersaturated reaction mixture to promote the growth of desired crystals, thereby enhancing the intermolecular forces between separate molecules in solution to form the basis of a crystal lattice and eliminating the need for random molecular collisions or interactions.

[0036] As described herein, the following intermediates (compounds) and their respective names are synonymous: (a) = 3-bromodihydrofuran-2(3H)-one, (b) = 3-(methylsulfonyl)dihydrofuran-2(3H)-one, (rc1) = 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (racemic), (rc2) = 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (racemic), (R1) = (R)-3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one, (R2) = (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-butanoic acid, and (S1) = (S)-3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one.

[0037] The LpxC inhibitor formula (1) (R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)-butanamide is a veterinary hydroxamic acid antibiotic with biological activity against a variety of Gram-negative bacteria. The compound can be formulated as a free base with at least one other pharma- ceutically acceptable excipient, or as a salt with at least one other pharma-ceutically acceptable excipient. For purposes of this process, the hydroxamic acid formula (1) compound can be formulated for use in treating Gram-negative bacteria in livestock, i.e., cattle and pigs, and preferably pigs.

[0038] The racemic intermediate compound (rc1) contains a chiral center and therefore a racemic mixture of two enantiomers. Each enantiomer has identical chemical and physical properties, except for the ability to rotate plane polarized light (+ / -) in equal amounts and in opposite directions. Enantiomers are also called optical isomers. An optically active isomer and a mixture of equal parts of its enantiomers have zero net rotation of plane polarized light, since the positive rotation of each (+) form is exactly offset by the negative rotation of each (-) form. Separation of the (R1) enantiomer from the racemic mixture can be achieved by standard chromatographic methods on a chiral adsorbent. Alternatively, the racemate can be coupled with reactant (c) to prepare (rc2), which can be resolved to (R2) by conventional resolution techniques by reacting (rc2) with optically pure (S)-(+)-α-methylbenzylamine.

[0039] Pharmaceutical salts The compounds of formula (1) may be used in their natural form (base) or as salts. The compounds of formula (1) have a basic functional group and can form addition salts with acids. Such salts are included within the scope of the present invention to the extent that they are acceptable for veterinary use. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzeate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodine, isethionate, lact ... These include tate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, icotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate salts.

[0040] Composition / Formulation Pharmaceutical compositions containing a compound of formula (1) can be manufactured by processes well known in the art, for example, by conventional mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping, freeze-drying processes, or spray-drying.

[0041] Pharmaceutical compositions for use according to the compounds of formula (1) can be formulated in a conventional manner using one or more pharma- ceutically acceptable excipients, which facilitate processing of the active compound into a preparation that can be used for pharmaceutical administration to an animal in need thereof. The appropriate formulation depends on the route of administration selected. Pharmaceutically acceptable excipients are generally known to those skilled in the art and are therefore included in the present invention. Such excipients are generally described, for example, in "Remington's Pharmaceutical Sciences", Mack Pub. Co., New Jersey (1991). In one embodiment, compositions containing the compounds of formula (1) are prepared as oral, parenteral (intravenous, intramuscular and subcutaneous) or topical compositions. The preferred route of administration is oral administration, particularly for administration in drinking water. The preferred animals to receive the compositions are farm animals, preferably cows and pigs. Most preferred are pigs. Oral compositions can be formulated with other excipients. Other commonly used excipients for preparing pharmaceutical compositions may include, for example, any one or more of antioxidants (e.g., BHT, BHA, vitamin E, sodium metabisulfite, propyl gallate, etc.), preservatives (e.g., benzyl alcohol, citric acid, alkyl parabens, phenol, meta-cresol, etc.), antifoaming agents (e.g., cetostearyl alcohol, castor oil, stearates, polydimethyl-siloxanes, glycols, etc.), surfactants (e.g., polysorbates, sodium lauryl sulfate, lauryl dimethylamine oxide, polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, polyoxyl 10 lauryl ether, polyoxyl castor oil, cyclodextrin, lecithin, etc.), and hydrotropic agents capable of increasing the water solubility of the compound of formula (1) (e.g., nicotinamide, benzamide, N,N-diethylnicotinamide, nicotinic acid, sodium benzoate, urea, potassium or sodium salicylate, etc.). The compound of formula (1) can be prepared in concentrated amounts, for example, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, 150 mg / mL, 200 mg / mL, 250 mg / mL and greater.The compound of formula (1) can be administered to an animal in need thereof at a dose ranging from about 0.25 to about 2.5 mg / kg, or at a dose of about 0.5 to about 2 mg / kg, or at a dose of about 0.75 to about 1.5 mg / kg, or at a dose of about 1 to about 1.25 mg / kg. The compound of formula (1) can be administered to an animal in need thereof at a dose ranging from 0.25 to 2.5 mg / kg, or at a dose of 0.5 to 2 mg / kg, or at a dose of 0.75 to 1.5 mg / kg, or at a dose of 1 to 1.25 mg / kg.

[0042] Veterinary Use The compounds of formula (1) may be used for the treatment or prevention of infectious disorders, particularly infectious disorders caused by susceptible and multidrug resistant Gram-negative bacteria in animals.Non-limiting examples of such Gram-negative bacteria include Acinetobacter baumannii, Acinetobacter spp., Achromobacter spp., Aeromonas spp., Actinobacillus pleuropneumoniae, Bacteroides fragilis, Bordetella spp., Borrelia spp., Brucella spp., Campylobacter spp., Citrobacter diversus (koseri), Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Francisella tularensis, Fusobacterium spp., Haemophilus parasuis, Helicobacter pylori, Klebsiella oxytoca, Klebsiella pneumoniae, Lawsonia intracellularis, Legionella pneumophila, Moraxella catarrhalis (β-lactamase positive and negative), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus vulgaris, Porphyromonas spp., Prevotella spp., Mannheimia haemolyticus, Pasteurella spp., Proteus mirabilis, Providencia spp., Pseudomonas aeruginosa, Pseudomonas spp., Salmonella spp., (S. enterica) Shigella spp., Serratia marcescens, Treponema spp., Burkholderia cepacia, Vibrio spp., Yersinia spp., and Stenotrophomonas mulophilia.

[0043] Examples of infections that may be treated with the compounds of formula (1) include hospital-acquired pneumonia, urinary tract infections, systemic infections (bacteremia and sepsis), skin and soft tissue infections, pulmonary infections, surgical infections, intraperitoneal infections, etc. A preferred use of the compounds of formula (1) is to treat animals, preferably livestock (e.g., cattle and pigs), and more preferably pigs, against gram-negative bacteria. EXAMPLES

[0044] The following acronyms are used herein: ethanol (EtOH), isopropanol (IPA), methyl (Me), ethyl (Et), ethyl acetate (EtOAc), potassium acetate (KOAc), sodium hydride (NaH), methanol (MeOH), sodium carbonate (Na2CO3), polyethylene glycol (PEG), hydrochloric acid (HCl), acetonitrile (MeCN, CH3CN, Acn), potassium carbonate (K2CO3), oxalyl chloride (CsO2Cl2), potassium phosphate (K3PO4), methyl triflate (MeOTf), methyl tosylate (MeOTs), dimethyl sulfate ((CH3)2SO4), cesium carbonate (Cs2CO3), trifluoroacetic acid (TFA), tetrahydrofuran (THF), calcium oxide (CaO), potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium bromide (NaBr), dichloromethane (DCM), tetrahydropyran (THP), potassium acetate, (KOAc), potassium tert-butoxide (KOtBu), sodium borohydride (NaBH4), hydrobromic acid (HBr), aluminum oxide (Al2O3), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (XPhos), magnesium sulfate (MgSO4), sodium sulfate (Na2SO4), calcium chloride (CaCl2), iodomethane (MeI), dimethyl sulfoxide (DM SO), bromomethane (MeBr), chloromethane (MeCl), methyllithium (MeLi), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), dibromoethane (DBE), lithium hydroxide (LiOH), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II), generation 2 (XPhos PD G2), tetrahydroxydiboron (B2(OH)4), sodium methanesulfinate (MeSO2Na), aqueous solution (aq), equivalent (eq), no more than (NMT), no more than (NLT), catalyst (cat), limit of detection (LOD), volume (vol), minute(s) (min), melting point (mp), and room temperature (RT).

[0045] Schemes 1-3 outline general procedures for the preparation and isolation (or otherwise (i.e., stretching)) of intermediate compounds (b), (rc1), (R1), (rc2), (R2) and compounds of formula (1). However, it should be understood that the invention, fully described and claimed herein, is not intended to be limited by the details of the following schemes or preparative modes. The starting materials and various reactants can be obtained from commercial sources or are readily prepared from commercially available organic compounds using methods well known to those skilled in the art.

[0046] Alternatively, intermediate compound (R2) and the compound of formula (1) can be prepared by the methods described in U.S. Pat. No. 8,664,401 and PCT Publication No. 2019 / 178305. The method for preparing intermediate compound (R2) using the process described herein has many advantages over conventional methods. For example, 1) The number of steps to (R2) is 7, compared with 4 for the chiral separation route and 6 for the conventional separation route. 2) The new lactone intermediate (rc1) eliminates the unstable intermediate 4-bromo-2-methyl-2-(methylsulfonyl)butanoate; 3) Yield increases more than two-fold from 13% to 31% (up to 50%); 4) scalability is improved by eliminating expensive (Cs2CO3) and hazardous (NaH) reagents; and 5) The possibility of an extension (non-isolated) reaction step(s).

[0047] Scheme 1. Preparation of intermediate (R2) [ka] As shown in Scheme 1, commercially available a-bromo-g-butyrolactone (a) was treated with sodium methanesulfinate to give sulfone (b), which could be isolated or carried forward to the next step, depending on the solvent used. Exposure of (b) to base (e.g., sodium carbonate, potassium carbonate, etc.) in the presence of a methylating agent (e.g., methyl iodide, dimethyl sulfate, etc.) gave (rc1). Carboxylic acid (R2) was achieved by two different routes, one relying on conventional resolution and the other on chiral chromatographic resolution. Alkylation of lactone (rc1) with pyridinone (c) [wherein R' is H or K] in the presence of base (e.g., potassium tert-butoxide, sodium tert-amylate, etc.) gave (rc2). Conventional resolution of (rc2) was achieved using chiral amines (e.g., α-methylbenzylamine, ephedrine, phenylglycinol, etc.) to give (R2) as a single enantiomer.

[0048] Alternatively, chromatographic resolution of (rc1) gave (R1) as a single enantiomer. Chromatography was performed according to methods known in the art (Geoffrey B. Cox Preparative Enantioselective Chromatography, Blackwell Publishing, Ltd: Ames, IA; 2005) using a chiral stationary phase (e.g., ChiralPak AD, Chiralcel OJ, etc.) and a mobile phase consisting of a suitable HPLC solvent (e.g., methanol, ethanol, isopropanol, heptane, methyl tert-butyl ether, etc.). Alkylation of lactone (R1) with pyridinone (c) in the presence of a base (e.g., potassium tert-butoxide, sodium tert-amylate, etc.) gave (R2).

[0049] Scheme 2. Preparation of compounds of formula (1) from (R2) [ka] As depicted in Scheme 2, analogs (2.1) were obtained by palladium-catalyzed Suzuki cross-coupling of pyridinone chloride (R2) with borolan (d). Alternatively, 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole can be used instead of (d). Carboxylic acid (2.1) was converted to the corresponding acid chloride (2.2) using typical reagents known in the art, such as oxalyl chloride, thionyl chloride, etc. Substitution of acid chloride (2.2) with tetrahydropyranyl-protected hydroxylamine gave intermediate (2.3). Cleavage of the tetrahydropyranyl group using typical reagents known in the art, such as aqueous acids (e.g., hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, oxalic acid, citric acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, etc.) gave compounds of formula (1). Preferred cleavage reagents are sulfuric acid or maleic acid. Additional chemical descriptions of this process can be found in U.S. Pat. No. 8,664,401 and PCT Publication No. 2019 / 178305.

[0050] Conventional preparation method for Scheme 3-(R2) [ka] According to Scheme 3, ethyl 2-chloropropionate was treated with sodium methanesulfinate, followed by subsequent exposure to sodium hydride and dibromoethane to give the bromide. The chloropyridinone, prepared according to literature procedures (Honraedt and Gallagher SynLett, 2016, 27, 67), was alkylated with the bromide in the presence of cesium carbonate, followed by subsequent saponification of the ester with lithium hydroxide to give (rc2). Conventional resolution of (rc2) with (-)-ephedrine was carried out according to known procedures (i.e., Brown et.al., J.Med.Chem. 2021, 55, 914) known to give (R2) as a single enantiomer.

[0051] As described herein, the enantiomerically pure enantiomer (R1) can be resolved from the racemic mixture (rc1) or substrate by chiral chromatography techniques. For example, Chiralpak® AD, AS, AY, AZ, IA, IB, IC, ID, IE, IF, IG columns, or Chiralcel® OD or OJ columns: both have a solvent mobile phase selected from any one of methanol, ethanol, isopropanol, acetonitrile, acetone, ethyl acetate, THF, CH2Cl2, MTBE and heptane, or mixtures thereof. The preferred HPLC solvent is selected from methanol, ethanol and heptane. The most preferred HPLC solvent is methanol.

[0052] A preferred column for separating the (R1) enantiomer from the racemate (rc1) is a Chiralpak® AD. The column is filled with a coated polysaccharide-based chiral stationary phase prepared by physically coating a polysaccharide derivative onto a silica matrix. Chromatographic separation was carried out at a temperature of about 20-40° C., preferably about 20-35° C., and more preferably about 25° C.

[0053] Non-limiting examples of bases that can be used in the preparation of (R2) from intermediate (b) include, for example, Na2CO3, K2CO3, Cs2CO3, K3PO4, alkali metal tert-butoxides (e.g., potassium-, lithium-, sodium-, and rubidium-tert-butoxide), sodium tert-amylate, etc. Preferred bases are K2CO3, Na2CO3, or K3PO4, and more preferred base is K2CO3.

[0054] Methylation refers to the addition of a methyl group on a substrate, i.e., a form of alkylation, the replacement of an H atom with a methyl group. Non-exclusive methylating agents include, for example, iodomethane (CHI), bromomethane (CHBr), chloromethane (CHCl), methyllithium (CHLi), diazomethane, dimethyl carbonate, dimethyl dicarbonate, dimethyl sulfate, 1,2-dimethylhydrazine, dimethylzinc, methyl fluorosulfinate, methylcobalamin, methylmagnesium chloride, trimethyl phosphate, methyl tosylate, methanesulfonate, N-methyl-N'-nitrosoguanidine, and the like. Preferred methylating agents are selected from dimethyl sulfate, bromomethane, and iodomethane. The most preferred methylating agent is dimethyl sulfate.

[0055] Non-exclusive examples of organic solvents (solvents) include, for example, alcohols (ROH) where R is a straight-chain, branched or cyclic alkyl having 1 to 8 carbon atoms (e.g., methanol, ethanol, propanol, isopropanol, n-propanol, 2-butanol, n-butanol, t-butanol, isobutanol, scylopentanol, phenol, benzyl alcohol, etc.); nitrenes (e.g., acetonitrile, propriononitrile, butyronitrile, isobutyronitrile, 2-methylbutanenitrile, pentanitrile, etc.); ketones (e.g., acetonitrile, propriononitrile, butyronitrile, isobutyronitrile, 2-methylbutanenitrile, pentanitrile, etc.); t-butanone, pentanone, 2-methylpentanone, etc.); ethers (e.g., methoxymethane, methoxyethane, ethoxyethane, ethyl ether, diethyl ether, tetrahydrofuran, methoxybenzene, etc.); esters (e.g., ethyl acetate, methyl formate, methyl acetate, ethyl propionate, isopropyl butyrate, ethyl benzoate, etc.), dimethyl sulfoxide (DMSO), sulfolane, 3-methylsulfolane, dimethylformamide, dimethylacetamide, ethylene glycol, pyridine, toluene, dioxane, etc. Preferred solvents include isopropanol, acetone, acetonitrile, 2-butanol, sulfolane, t-butanol, and DMSO. More preferred solvents are isopropanol, acetone, 2-butanol, acetonitrile, and sulfolane. Preferred solvents A are isopropanol, ethanol, methanol, and acetonitrile. More preferred solvent A is isopropanol. Preferred solvent B is acetone or 2-butanone. More preferred solvent B is acetone.

[0056] Phase transfer catalysts are used to enable reactions in heterogeneous systems between organic compounds that are soluble in organic solvents (solvents) and compounds that are soluble in water, such as inorganic salts. The phase transfer catalyst is soluble in both solvents and carries the anions of the inorganic salts to the organic solvent (solvent) and transfers them back to the aqueous phase. The reactions usually proceed under mild conditions with simple work-up procedures. For this reason, they are also used industrially. Typical phase transfer catalysts These include polyethylene glycols (PEG), quaternary ammonium salts, crown ethers, and phosphonium compounds. Some non-exclusive examples of phase transfer catalysts include, for example, PEG400, PEG300, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, tetrabutylammonium thiocyanate, tetrabutylphosphonium bromide, methyltrioctylammonium chloride (Aliquat® 336), tetrabutylammonium bromide, methyltrioctylammonium bromide, and the like. Preferred phase transfer catalysts are PEG400 and Aliquat® 336. Aliquat® 336 is a methyltrialkyl-ammonium salt with C8 and C10 alkyl groups [(C(8 and 10)3NMe]. The Aliquat trademark is a registered trademark of Henkel Corporation, USA.

[0057] Dehydrating agents may also be used in the reactions described herein to dry and remove water. Non-exclusive examples of dehydrating agents include: MgSO4, Na2SO4, CaCL2, zinc chloride, NaBH4, Al2O3, calcium oxide (CaO), silica gel, and sieves. A preferred dehydrating agent is MgSO4.

[0058] The use of a resolving agent is a common resolution method that converts a racemic mixture of a compound into a mixture of diastereomers by reacting the racemic mixture with a single enantiomer of a chiral agent known as a resolving agent, separating the components of the diastereomeric mixture, and chemically converting each diastereomer into its corresponding enantiomer. Non-exclusive resolving agents for the conventional resolution of (rc2) to (R2) include, for example, (S)-methylbenzylamine, phenylglycinol, ephedrine, cinchonidine, 2-amino-1,2-diphenylethanol, quinine, quinidine, etc. Preferred resolving agents are (S)-methylbenzylamine and phenylglycinol. The most preferred resolving agent is (S)-methylbenzylamine.

[0059] proton(1 H) Nuclear magnetic resonance (NMR) spectra were collected at ambient temperature on a Bruker Avance III 600 MHz spectrometer or a Bruker Avance III HD 400 MHz, each equipped with a 5 mm broadband probe. Chemical shifts are reported in parts per million (δ) relative to tetramethylsilane (δ=0.0) and referenced to residual solvent resonances (CDCl3 δ=7.27, and DMSO-d6 δ=2.50).

[0060] The lactone opening reaction was monitored by the following reverse phase HPLC method. A) Reverse phase HPLC conditions: Agilent 1100 HPLC, 1 mL / min, 40° C. column temperature, 230 nm UV detection, mobile phase: solvent x (0.1% TFA in water), and solvent y (Acn / MeOH (1:1 v / v)). Method: Gradient: 5% to 50% of solvent x in 50 min, then 50% to 100% in 5 min. Column: Supelco Ascentis Express C18 150×4.6 2.7 μm, injection volume 5 μL. Samples were prepared by diluting 10 μL of reaction mixture / mother liquor with 1 mL of water / acetonitrile containing citric acid or 0.5 mg / mL in solvent y for solid samples. Retention times: chloropyridone (4.5 min), O-alkylated pyridine (12.7 min), N-alkylated pyridine (R2; 7.7 min), compound 2.1 (13.6 min), compound 2.3 (18.4 min), and compound of formula (1) (11.8 min). B) Reverse phase chiral HPLC conditions: Agilent 1100 HPLC, 0.7 mL / min, 15° C. column temperature, 218 and 230 nm UV detection, mobile phase: solvent x (0.1% TFA in water) and solvent z (Acn). Method: Isocratic: solvent z 20% for 25 min, and column: Regis(S,S)-Whelk-01 Kromasil® 250x4.6 mm 5 μm Cat#780101, 20 μL injection volume of (rc1) sample at a concentration of 0.1 mg / mL in 1:1 Acn / water. Retention times of 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (rc2): R-enantiomer (R2, 8.98 min), and 9.58 min for the S-enantiomer.

[0061] Preparation of reactants, intermediates (compounds), and formula (1) Potassium 4-chloro-2-oxo-2H-pyridin-1-ide [ka] The compound was prepared by reacting 4-chloropyridin-2(1H)-one in a solvent mixture of toluene / ethanol / water in the presence of KOH at a starting temperature of about 5° C. and an end temperature of about 20° C. Alternatively, the pyridine-ide can be prepared in situ by reacting 4-chloropyridin-2(1H)-one with potassium tert-butoxide (KOtBu).

[0062] Process for preparing (rc1) (rxn-1): 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one: [ka]

[0063] Intermediate (b): 3-(methylsulfonyl)dihydrofuran-2(3H)-one A 4-neck round bottom flask (500 mL) equipped with overhead stirring, heating mantle, and temperature controller was charged with 3-bromotetrahydrofuran-2(3H)-one ((a), 100.0 g, 0.576 mol, 1.00 eq) under nitrogen. Sodium methanesulfinate (90.0 g, 85% potency, 0.750 mol, 1.30 eq), Aliquat® 336 (1.5 g, 3.7 mmol, 0.0064 eq), magnesium sulfate (6.0 g), and isopropanol (250 mL). The resulting mixture was heated to 80° C. After 3 h, 1 H-NMR showed the reaction was complete. The reaction mixture was cooled to room temperature using ice bath cooling. The resulting solid was isolated by filtration, washed with isopropanol (100 mL) and dried in vacuum to give 176 g of a mixture of intermediate (b) and inorganic salts. Alternatively, the desired product (b) can be cleanly isolated by dissolving in acetone, filtering off the NaBr and solvent evaporating the acetone filtrate. The dried solid from above was used in the next step to prepare (rc1).

[0064] Intermediate (rc1): 3-Methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one Intermediate (b) (94 g, 0.576 mol, 1.00 eq) from the above solid mixture was extracted with acetone (2×100 mL) at 45° C. (complete extraction was verified by gravimetric analysis (total weight loss 94 g) and HPLC (no product detected in the cake after the second extraction)). The acetone extract was then charged under nitrogen with potassium carbonate (325 mesh 100 g, 0.724 mol, 1.26 eq), Aliquat® 336 (1.5 g, 3.7 mmol, 0.0064 eq), dimethyl sulfate (68 mL, 0.719 mmol, 1.25 eq), and magnesium sulfate (6.0 g). The reaction mixture was heated to 60° C. for 7 h. 1H NMR analysis indicated 3% of (b) remained. An additional 7 g of dimethyl sulfate, 10 g of potassium carbonate were charged to the reactor and heating was maintained for an additional 4 hours. The reaction mixture was filtered to remove inorganic salts. The solids were washed with acetone (100 mL). The filtrate was heated to 65° C. and acetone was distilled from the kettle until 200 mL or approximately 1.5 volumes of liquid remained. At this point, a solvent exchange to isopropanol (200 mL) was performed at a constant reactor volume. The isopropanol solution was cooled to 35° C. and seeded. It was further cooled to 25° C. to induce crystallization. The crystals were filtered and washed with 100 mL of isopropanol. 93 g of (rc1) was isolated as an off-white crystalline solid (91%). mp 74° C., 1 H NMR (600 MHz, chloroform-d) δ ppm 4.49-4.56 (m, 1H), 4.35-4.44 (m, 1H), 3.16-3.22 (m, 1H), 3.08 (s, 3H), 2.31 (dt, J = 14.63, 8.83 Hz, 1H), 1.74 (s, 3H).

[0065] Alternatively, (rc1) can be prepared without isolating intermediate (b) by stretching the reaction (rxn-t) as shown below. [ka]

[0066] A 30 L jacketed reactor equipped with overhead stirring, temperature control, and reflux condenser was charged with 3-bromotetrahydrofuran-2(3H)-one (a) (2.5 kg, 96% potency, 14.4 mol, 1.00 eq) under nitrogen. Sodium methanesulfinate (2.0 kg, 85% potency, 16.7 mol, 1.16 eq), Aliquat® 336 (30 g, 74.2 mmol, 0.005 eq), magnesium sulfate (120 g, 0.07 eq), and acetone (7.5 L, 3 vol). The resulting mixture was heated to reflux (56° C.). After 9 hours, HPLC indicated less than 1% starting material. The reaction mixture was cooled to ambient temperature and stirred overnight. The reaction mixture was filtered and the solid was washed with 200 mL of acetone. A 2 mL sample of the acetone filtrate was concentrated in vacuo to give solid (b). 1 H NMR (600MHz, DMSO-d6)d 4.75 (dd, 1H), 4.37 (m, 2H), 2.64 (m, 2H).

[0067] Acetone filtrate from above (8.3 kg) was added to a 30 L jacketed reactor equipped with overhead stirring, temperature control, and reflux condenser. To this solution was added anhydrous potassium carbonate (2.73 kg, 325 mesh, 1.37 eq), dimethyl sulfate (2.27 kg, 1.25 eq), and anhydrous magnesium sulfate (120 g, 0.07 eq). The mixture was slowly heated to reflux (56° C.). After 15 hours at reflux, additional potassium carbonate (200 g, 0.1 eq) and dimethyl sulfate (200 g, 0.11 eq) were added and reflux was continued for another 4 hours. The mixture was cooled to ambient temperature and the reaction mixture was filtered to remove inorganic salts. The solids were washed with acetone (2 L, 0.8 vol). The mother liquor was heated to 65° C. and acetone was distilled from the kettle until 3 L of liquid remained. At this point, a solvent exchange from acetone to isopropanol (4 L) was performed at a constant reactor volume. Once all the isopropanol had been dripped into the reactor, the solution was cooled to 35° C. and seeded. It was further cooled to 25° C. to induce crystallization. The mixture was further cooled to 20° C. and held at that temperature for 1 hour. The crystals were filtered and washed with 2 L of isopropanol. The wet cake was dried under vacuum at 40° C. overnight to give 2.0 kg of (3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one as an off-white crystalline solid (78%). mp 74° C., 1 H NMR (600 MHz, chloroform-d) δ ppm 4.49-4.56 (m, 1H), 4.35-4.44 (m, 1H), 3.16-3.22 (m, 1H), 3.08 (s, 3H), 2.31 (dt, J = 14.63, 8.83 Hz, 1H), 1.74 (s, 3H).

[0068] A separate synthesis to prepare (rc1) from intermediate (a) using the procedure described above but without the use of the dehydrating agent magnesium sulfate during the sulfonylation and methylation reactions gave (rc1) in 64% yield.

[0069] A separate synthesis to prepare intermediate (b) from intermediate (a) without magnesium sulfate and replacing acetone with isopropanol gave an 83% yield of intermediate (b). A two-necked round-bottom flask equipped with a magnetic stir bar, heating mantle, and temperature controller was charged with 3-bromotetrahydrofuran-2-one ((a), 4.0 g, 24.2 mmol, 1.00 eq), sodium methanesulfinate (3.0 g, 28.3 mmol), 1.2 eq), Aliquat® 336 (0.12 g, 0.50 mmol, 0.02 eq), and isopropanol (12 mL) under nitrogen. The resulting mixture was heated to 80° C. After 3 hours, the mixture was cooled to 70° C. and cooled to 70° C. 1 H-NMR (600 MHz, DMSO-d6) showed the reaction was complete. The reaction mixture was cooled to ambient temperature using an ice bath. The resulting solid was isolated by filtration, washed with isopropanol (5 mL) and concentrated in vacuo to give a white solid. The solid was reslurried in acetone (20 mL) and filtered to remove sodium bromide. The mother liquor was concentrated in vacuo to give a white solid, 3.3 g (83%), Table 1.

[0070] A similar preparation of sulfonyl lactone (b) from intermediate (a) without magnesium sulfate was carried out using different solvents as shown in Table 1.

[0071] Table 1. Various solvents for preparing intermediate (b). [Table 1]

[0072] Small scale preparations of methylsulfonyl lactone (rc1) from intermediate (b) as described above were carried out without the use of the dehydrating agent magnesium sulfate, varying the base, methylating agent and / or solvent. The yields of (rc1) from each of these reactions are shown in Table 2.

[0073] Table 2. Various reactants and / or solvents for the preparation of (rc1). [Table 2]

[0074] General procedure for lactone ring-opening: synthesis of intermediate 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (rc2) [ka] Reactions were carried out under nitrogen in 125 mL Mettler Easy Max® reactors (stirring speed 400 RPM) or 40 mL scintillation vials equipped with magnetic stirrers. Potassium tert-butoxide (9.89 g, 87.3 mmol, 1.01 eq) was dissolved in anhydrous dimethyl sulfoxide (23 mL) and added to 4-chloro-2-hydroxypyridine (i.e., 4-chloropyridin-2(1H)-one (tautomer)) (11.2 g, 86.5 mmol, 1.00 eq) in anhydrous dimethyl sulfoxide (11 mL) while maintaining an internal temperature of 18-27 °C. After 15 min, a mixture of (rc1) 16.5 g, 92.6 mmol, 1.07 eq) and benzyltriethylammonium bromide (1.21 g, 4.44 mmol, 0.0514 eq) was added in one portion. The reaction mixture was heated to 85° C. for 2 hours and sampled for HPLC analysis. The HPLC chromatogram showed 30.7% chloropyridone, 65.2% (rc2), and 4.1% O-alkylated product, 5-((4-chloropyridin-2-yl)oxy)-2-methyl-2-(methylsulfonyl)pentanoic acid. The reaction mixture was aged at 85° C. for 17 hours (total reaction time 19 hours) and resampled. HPLC showed 5% chloropyridone, 88.1% (rc2), and 2.4% O-alkylated compound. While hot, the reaction mixture was treated with isopropyl acetate (50 mL) and transferred to a 400 mL reactor. The mixture was treated with additional isopropyl acetate (100 mL) and stirred for 1 hour at a jacket temperature of 60° C. The jacket was cooled to 20° C. over 1 hour and aged for 1 hour. The resulting solid was isolated by filtration, washed with isopropyl acetate (2×30 mL) and dried at 50° C. overnight to give 25.75 g (86%) of (rc2) (potassium salt) as an off-white solid.

[0075] Synthesis of free carboxylic acid (rc2) 5.0 g of the above potassium salt was dissolved in water (15 mL) and treated with methyl alcohol (10 mL) and Me-THF (4 mL). 1.8 mL of concentrated HCl was then charged. The pH of the slurry was about 1. The slurry was stirred at room temperature for 2 h, then cooled to 0-5° C. and stirred at that temperature for 1 h. The slurry was filtered, washed with water:methanol (8:2), and then dried in vacuo with a nitrogen sweep to give 4.04 g of (rc2) (90.8%). 1 H NMR(600MHz,DMSO-d6)δ ppm 1.55(s,3H)2.14(ddd,J=13.39,10.18,4.86Hz,1H)2.42(ddd,J=13.34,10.22,5.96Hz,1H)3.14(s,3H)3.92(ddd,J=12.84,10.18,5. 96Hz,1H)4.03(ddd,J=12.88,10.22,4.95Hz,1H)6.37(dd,J=7.34,2.38Hz,1H)6.52(d,J=2.38Hz,1H)7.76(d,J=7.15Hz,1H)13.85(br s,1H). 13 C NMR (151 MHz, DMSO-d6) δ ppm 14.70, 31.65, 36.91, 44.20, 69.36, 106.82, 117.74, 139.97, 145.66, 160.33 and 169.18.

[0076] Alternatively, (rc2) was prepared according to the following reaction scheme: A 400 mL reactor was charged under nitrogen with the following: PEG400 (15.6 g, 38.6 mmol, 0.20 equiv), 2-methyl-2-butanol (175 mL, 7V), and 4-chloro-2-hydroxypyridine (25.0 g, 193 mmol, 1.0 equiv). The jacket temperature was adjusted to 20 °C and potassium tert-butoxide (23.0 g, 201 mmol, 1.041 eq) was added while stirring using mechanical stirring (300-600 rpm). NOTE: The internal temperature rose from 19 °C to 42 °C. The addition of KOtBu was added in small portions to control the exotherm at large scale. The reaction mixture was aged at 40-45°C for 30-45 min and then charged with 3-methyl-3-methylsulfonyl-tetrahydrofuran-2-one (38.6 g, 212 mmol, 1.10 eq) (1 portion). The reactor jacket was heated to 100°C over 20 min and maintained for 16-20 h (internal temperature was 95-98°C). The reaction was deemed complete when 4-chloro-2-hydroxypyridine was less than 5% a / a (HPLC or NMR). The reaction mixture was then cooled to 50-60°C, diluted with water (63 mL, 2.5 V) and the pH was adjusted to 1-2 using concentrated HCl (ca. 20 mL). The reaction mixture was then cooled to 0°C over 2 h, aged for 1 h and the resulting solid was isolated by filtration. The product was washed with deionized water (2×40 mL) and dried to constant weight under high vacuum at 70° C. to give 46.5 g (78.3%) of 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid as an off-white crystalline solid. HPLC purity 98.4% a / a (230 nm).1H NMR(600MHz,DMSO-d6)δ ppm 1.55(s,3H)2.14(ddd,J=13.39,10.18,4.86Hz,1H)2.42(ddd,J=13.34,10.22,5.96Hz,1H)3.14(s,3H)3.92(ddd,J=12.84,10.18,5. 96Hz,1H)4.03(ddd,J=12.88,10.22,4.95Hz,1H)6.37(dd,J=7.34,2.38Hz,1H)6.52(d,J=2.38Hz,1H)7.76(d,J=7.15Hz,1H)13.85(br s,1H). 13C NMR (151 MHz, DMSO-d6) δ ppm 14.70, 31.65, 36.91, 44.20, 69.36, 106.82, 117.74, 139.97, 145.66, 160.33 and 169.18.

[0077] Conventional decomposition of (rc2) into (R2) To a slurry of (rc2) (1.0 eq) in methanol (5 mL / g) was added slowly (30-60 min) a solution of (S)-(+)-α-methylbenzylamine (1.05 eq) in methanol (1 vol) while maintaining the temperature at 55°C-65°C. The reaction was heated at 65°C for 30 min and subsequently cooled slowly to 60°C. The mixture was seeded, cooled to 0°C over a period of 5 h and aged for 2 h. The slurry was filtered, washed with IPA (2 x 1 vol) and dried under vacuum at 55°C overnight to give the desired diastereomeric salt (18.95 kg, 44% yield, 98.93% purity).

[0078] Synthesis of (R2) from (R1) A sample of (R2) was prepared using the general procedure described above for (rc2) to (R2) starting from 4-chloro-2-hydroxypyridine (1.14 g, 8.80 mmol) and (R1), 3-methyl-3-methylsulfonyl-tetrahydrofuran-2-one (1.65 g, 9.26 mmol). 1.63 g of (R2) was isolated (60%). HPLC purity 96.4% (achiral); chiral HPLC R f 8.98 minutes, 99.9% purity.

[0079] Chiral chromatography to separate (R1) from (rc1), (R)-3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one and (S)-3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one [ka] A total of 5g of racemic body (rc1) The fractions were run on a preparative Sepiatec SFC 250 instrument equipped with a 30×250 mm 5μ Daicel Chiralpak® AD-H column with UV detection at 230 nm. The column was eluted with mobile phase A (CO2) and mobile phase B (MeOH), isocratic 25% B, 90 / mL / min, 140 bar back pressure. The (R) enantiomer was the first eluting peak at 2.4 min and the second eluting peak (S) eluted at 2.8 min. The eluent was evaporated using a rotary evaporator and the residue was lyophilized from an acetonitrile / water mixture. The first peak (2.15 g, 43%) had an HPLC chiral purity of >99% and the second peak (2.32 g, 46%) had an HPLC chiral purity of 96.0%. Peak assignment was performed by comparing the retention time of each peak with that of its respective reference standard. Reference Standards: (R)-3-Methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one Optical rotation -0.198[α] 20 589 =-9.960° (2, 0.5, MeOH) and melting point 94°C (S)-3-Methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one Optical rotation +0.184[α] 20 589 = +9.250° (2, 0.5, MeOH) and melting point of 92°C

[0080] Synthesis of (S)-1-phenylethan-1-aminium (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate [ka] A 400 mL reactor was charged with 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (rc2), 49.95 g, 162.3 mmol, 1.0 eq), followed by methanol (200 mL, 4 vol). The reaction mixture (slurry) was heated to 55-60 °C (target internal temperature of 60 °C) over a period of 0.5-1.5 h. In a separate reactor, a solution of (S)-α-methylbenzylamine (20.76, 171.3 mmol, 1.056 eq) in methanol (25 mL, 0.5 vol) was prepared. The solution of (S)-α-methylbenzylamine in methanol was transferred to the reactor containing the racemate over a period of 30 min. After 80% of the solution had been added, the slurry became a clear solution. The reactor and transfer lines were rinsed with methanol (12 mL, 0.25 vol) and added to the reaction mixture. The reaction mixture was then heated to reflux (65° C.) over a period of 0.5-1 h, aged at 65° C. for 0.5-1 h, and cooled to 60° C. over 30 min. The reaction mixture was seeded with (S)-1-phenylethan-1-aminium (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (0.250 g, 0.5% of racemic input). NOTE: Once the seeds have dissolved, cool to 55 °C over 30 min and re-seed the mixture with (S)-1-phenylethan-1-aminium (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (0.250 g, 0.5% of racemic input). The reaction mixture was aged at 60 °C for 1-3 h to initiate crystallization and then cooled to -5 °C (target 0 °C) over 4-10 h (target 5 h). The reaction mixture was aged at -5 °C for 1 h and the resulting solid was isolated by filtration. The product was washed with IPA (2 × 25 mL, 0.5 vol each) and dried under vacuum at 55-65 °C for >10 h to give 30.6 g of (S)-1-phenylethan-1-aminium (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate as a white crystalline solid (44%).

[0081] Synthesis of (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid, (R2) [ka]

[0082] A 30 L glass reactor was charged with (S)-1-phenylethan-1-aminium (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (2.655 kg, 5.757 mol, 1.0 eq) and 25% IPA in water (15 L, 5.6 vol). The resulting mixture was heated to 35-45 °C (target 40 °C) over 30 min and, while maintaining the temperature, concentrated HCl (0.264 L / kg, 1.25 eq, ca. 11 N) was slowly charged until the pH was 1.0-2.0. NOTE: In this example, 662 mL of concentrated HCl was added to achieve a pH of 1.4. The mixture was aged at ca. 45 °C for 0.5 h, then cooled to 0 °C over a 2 h period and aged at 0 °C for 0.5 h. The resulting solid was isolated by filtration, washed with water (2 x 2 L, 0.75 vol each) and dried under vacuum at 65°C with a nitrogen bleed to give 1.785 kg of (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (R2) (100%). Optical rotation = +0.425 [α] 23 589 =+42.500 o (2, 0.5, MeOH)

[0083] Borylation: Synthesis of 2-(4-(1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole [ka] A solution of 2,2'-bi(1,3,2-dioxaborolane) in ethanol was prepared by mixing tetrahydroxydiboron (0.398 kg, 4.306 mol, 1.50 eq), ethylene glycol (0.481 kg, 7.753 mol, 2.699 eq), and 200 proof ethyl alcohol (4 L, 8 vol) in a suitable vessel (12 L flask, vessel 1) equipped with a mechanical stirrer and temperature indicator. The slurry was stirred without heating at approximately 20-25 °C until a clear solution was observed (NLT 3 hours). The solution can be stored under a nitrogen purge at ambient temperature for up to 24 hours. A separate vessel (vessel 2) was charged with ethanol (4.8 L, 9.5 vol), acetic acid (84.5 g 1.4 mol, 0.489 eq), and the resulting solution was degassed using nitrogen for approximately 10 minutes. Then 2-(4-chlorophenyl)-2H-1,2,3-triazole (0.516 kg, 2.872 mol, 1.000 eq), pre-dried potassium acetate (0.691 kg, 6.97 mol, 2.43 eq), XPhosG2 (4.43 g, 5.52 mmol, 0.002 eq), and XPhos (5.37 g, 11.0 mmol, 0.004 eq) were added. The reaction mixture was heated to approximately 50-60 °C, aged for 15-30 min, and then cooled to reach an internal temperature of approximately 40-50 °C. The solution in vessel 1 was degassed with nitrogen for approximately 10 min, then transferred to the reaction mixture in vessel 2 using nitrogen pressure while maintaining an internal temperature of approximately 45-60 °C (Note: the reaction is exothermic). The transfer lines were rinsed with degassed ethanol (1 vol). The reaction mixture was aged at an internal temperature of 50-60 °C for approximately 1 h and sampled to check reaction conversion. The reaction was considered complete when the residual aryl chloride was less than 0.5% (a / a). If the residual aryl chloride is greater than 0.5% aa, additional tetrahydroxydiboron (1.5 eq) may be added per % of unreacted 2-(4-chlorophenyl)-2H-1,2,3-triazole. NOTE: The limiting reagent in this step is 2-(4-chlorophenyl)-2H-1,2,3-triazole. Alternatively, the boration step can be carried out in a one-pot process.

[0084] Alternatively, 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole can be prepared for the Suzuki coupling reaction. [ka]

[0085] The complex [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (280 mg, 0.34 mmol) were added to a mixture of 2-(4-bromophenyl)-2H-1,2,3-triazole (255 mg, 1.14 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (350 mg, 1.38 mmol), and potassium acetate (340 mg, 3.46 mmol) in 1,4-dioxane (10 mL). The reaction mixture was heated to 80° C. and stirred at this temperature overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 mL) and brine (30 mL). The mixture was filtered through Celite (approximately 1 inch). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography using an Analogix SF15-12g column and a gradient of 0-10% ethyl acetate in n-heptane to give an orange solid (240.6 mg, 78%). 1H NMR (400MHz, CDCl3) δ 8.10 (d, J = 8.59 Hz, 2H), 7.94 (d, J = 8.59 Hz, 2H), 7.83 (s, 2H), 1.36 (s, 12H). LCMS: m / z 272.4 [M+H]+.

[0086] Suzuki Coupling: Synthesis of (R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (2.1) [ka] A separate reactor (vessel 3) was charged with deionized water (6 L, 6.9 vol), sodium carbonate (0.745 g, 7.036 mol 2.5 eq), (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (0.866 kg, 2.814 mol, 1.0 eq) and stirred at approximately 20-30 °C until a solution was observed. The sodium carbonate solution was degassed using nitrogen for approximately 10 minutes. The degassed solution was then added to the reaction mass in vessel 2 containing 2-(4-(1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole while maintaining an internal temperature of approximately 50-60 °C. Once the addition was complete, the original vessel and transfer lines were rinsed with degassed deionized water (1 vol). The reaction mixture was heated to approximately 70-80 °C, aged for 3 h, and sampled for HPLC analysis. The reaction was considered complete when the residual 2-(4-(1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole was less than 0.5% a / a. If the residual 2-(4-(1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole was greater than 0.5% aa, additional (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-butanoic acid (0.025 eq) may be added. The reaction mixture was cooled to approximately 50-60 °C and charged with 2-methyltetrahydrofuran (3.2 L, 3.7 vol), maintaining the internal temperature at 50-60 °C. The mixture was further cooled to achieve an internal temperature of approximately 40-50 °C. Concentrated hydrochloric acid (961 mL, 1.11 vol) was then slowly charged while maintaining an internal temperature of approximately 40-50 °C. If no solids are observed, additional concentrated hydrochloric acid (0.1 vol) was charged. The reaction mixture was aged at an internal temperature of approximately 40-50 °C for approximately 1 h, then the pH was adjusted to 1 using concentrated HCl (961 mL, 1.1 vol) while maintaining an internal temperature of approximately 40-50 °C. CAUTION: The pH should be NMT1. Finally, the batch was cooled to approximately 0-10 °C and aged for ≥ 1 h. The product was isolated by filtration and the wet cake was washed with a mixture of ethanol / deionized water (4 L) (1:1 v / v) followed by deionized water (1.65 L).The product was transferred to a dryer and dried under vacuum at a jacket temperature up to 65° C. until the LOD was less than 0.5 w / w%, yielding 1.153 g of (R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (2.1) as a light beige solid (98%). 1 H-NMR(600MHz,DMSO-d6)δ ppm 1.55(s,3H)2.14(m,1H)2.42(m,1H)3.14(s,3H)3.92(m,1H)4.03(m,1H)6.37(dd,1H)6.52(d,1H)7.76(d,1H)13.85(br s,1H).

[0087] Acid chloride formation: Synthesis of (R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoyl chloride (2.2) [ka] A dry 30 L jacketed glass reactor connected to a basic scrubber (the reaction removes gaseous HCl, CO, and CO) is charged under nitrogen at 20 °C with dichloromethane (10 L, 10 vol), followed by oxalyl chloride (0.908 kg, 7.150 mol, 2.980 eq), and N,N-dimethylformamide (10 mL, 129 mmol, 0.0538 eq). Next, slowly charge (R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid, 2.1 (1.000 kg, 2.401 mol, 1.0 eq) (NLT 30 min) while maintaining an internal jacket temperature of approximately 20-35 °C. NOTE: Gas evolution is expected. The reaction mixture was aged at 20-40 °C (target 30 °C) for 90-120 min and sampled for HPLC analysis. The reaction was considered complete when the carboxylic acid was less than 5% (target less than 3%). NOTE: Conversion was determined by quenching 2 drops of raw material with 2 mL of anhydrous methanol. Excess oxalyl chloride / DCM was distilled off at atmospheric pressure to a thick slurry (minimum volume 1-2 L) and then charged with heptane (5 L, 5 volumes). Distillation was continued until the jacketed internal temperature reached 96-98 °C (thick slurry). NOTE: The mixture of acid chloride in heptane may be stored overnight at room temperature under nitrogen. The final volume in the tank was approximately 1-2 L. Alternatively, the excess oxalyl chloride can be removed via a series of decantations / DCM dilutions or by adding a controlled amount of water at low temperature (-5-5 °C).

[0088] Amide Bond Formation - Synthesis of (2R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide (2.3) [ka] The above reaction was cooled to 20-30 °C and diluted with dichloromethane (7.3 L, 7.3 vol) and then cooled to -5-5 °C. To the cold reaction mixture was slowly charged 4-methylmorpholine (0.777 kg, 7.682 mol, 3.199 eq) while keeping the temperature below 10 °C. NOTE: It is especially important to control moisture. The 4-methylmorphine must be reagent grade or better. In a separate reactor, prepare a solution of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (THP-ONH2, 0.337 g, 2.885 mol, 1.202 eq) in dichloromethane (3.4 L, 3.4 vol). The water content of the solution should be less than 500 ppm if azeotropic drying above 500 ppm needs to be performed as follows: distill 40% of the batch volume, add anhydrous DCM, sample for Karl Fischer titration, repeat until the water is less than 500 ppm. The THP-ONH2 solution was transferred slowly to the acid chloride over 40 min while keeping the temperature below 10 °C (target -5 to 5 °C). The transfer line was then rinsed with dichloromethane (1 L, 1 vol). The apparent pH of the reaction mixture was checked using pH paper. If not between 7 to 10, additional 4-methyl-morpholine should be charged until the apparent pH is adjusted to the desired range. The reaction mixture was then aged at -5 to 5 °C for 1 to 2 h, warmed to 20 to 30 °C over 1 to 3 h, and held at 20 to 30 °C for ≥ 30 min. The reaction mixture was sampled and conversion was confirmed using HPLC. Residual acid chloride was measured by converting the acid chloride to a methyl ester. The reaction was deemed complete when the acid chloride was less than 0.5%. A small amount of water (330 mL) was then charged and the reaction mixture was aged for ≥30 min. The product was isolated as follows: The reaction mixture was concentrated by distillation at atmospheric pressure (reactor jacket temperature 60° C.) to remove 7 L of DCM and then diluted with methanol (8 L, 8 vol). Distillation continued at atmospheric pressure with a jacket temperature of 60-80° C. to remove 7-8 volumes of DCM / MeOH. Finally, methanol (5 L, 5 vol) was charged and distillation at atmospheric pressure continued with a jacket temperature of 80-90° C. until the internal temperature reached 65-70° C. (target 67° C.).Approximately 5 L of distillate was collected. The reaction mixture was then cooled to -5 to 5 °C (target 0 °C) over 2 h, aged at the target temperature for 1 h, and the resulting solid was isolated by filtration. The product was washed with methanol (3 x 1 L), pooled, dried for 30 min, and dried under vacuum at 50-60 °C to give 1.223 kg of product (98.8% yield) (HPLC purity 95.9%). 1 H-NMR(600MHz,DMSO-d6)δ ppm 1.53(m,3H)1.59(d,3H)1.69(m,3H)2.14-2.27(m,1H)2.37-2.48(m,1H)3.11(d,3 H)3.44-3.63(m,1H)3.65-3.93(m,1H)3.96-4.11(m,1H)4.11-4.32(m,1H)4.98(br s,1H)6.61-6.77(m,1H)6.79(m,1H)7.79(dd,1H)7.96(m,2H)8.04-8.16(m,2H)8.18(s,2H)11.63(br s,1H)

[0089] Synthesis of formula (1): (R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide [ka] A 30 L glass reactor was charged with (2R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide, 2.3 (2104 g, 4.08 mol, 1.00 eq), 2-propanol (21 L, 10 vol), and HCl (1 mol / L) in water (6.3 L, 6.30 mol, 1.54 eq). Alternatively, 0.025-1 equivalent of sulfuric acid in the reaction solvent or about 1 equivalent of maleic acid in the reaction solvent can also be used. The resulting mixture was heated to 60-70° C. while stirring at a speed of about 210 rpm and aged to 62-63° C. for about 40-60 minutes. The reaction was then sampled to confirm completion (i.e., <0.5%). If not, the reaction was continued for up to about 4 hours. After completion of the reaction, the reaction mixture was cooled to 20°C (± 5°C) over 2-4 hours and aged at 20°C for 1-2 hours. The final product (Formula (1)) was isolated by filtration, washed with 2-propanol (4L, 2vol), water (2 x 1.5L) and dried at 55-65°C using house vacuum to give 1.665kg (95%). 1 H-NMR(600MHz,DMSO-d6)δ ppm 1.59(s,3H)2.18-2.21(m,1H)2.40-2.48(m,1H)3.11(s,3H)3.76-3.79(m,1H)4.12-4.16(m,1H)6.71(d d,1H)6.78(d,1H)7.79(d,1H)7.85-8.04(m,2H)8.04-8.15(m,2H)8.17(s,2H)9.24(s,1H)11.15(s,1H).

[0090] Alternatively, the final removal of THP can be achieved in the presence of a strong acid (e.g., HCl or HBr) in a solvent such as ethanol, isopropanol, acetone, acetic acid / tetrahydrofuran, etc. Alternatively, the compound of formula (1) can be prepared according to the procedural steps described in PCT Publication No. 2019 / 178305, or according to the procedural steps described in U.S. Patent No. 8,664,401, with the iodopyridinone or with the chloropyridinone substituted.

[0091] Crystal morphology Several polymorphic forms of (R)-4-(4-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)-butanamide were prepared as API slurries in several protic and aprotic solvents (forms 1, 2, and 3). With the exception of acetonitrile, methyl ethyl ketone, and tetrahydrofuran, the use of aprotic solvents such as ethyl acetate, butyl acetate, or propyl acetate results in form 1. With the exception of water, the use of protic solvents such as butyl alcohol, propyl alcohol, and ethyl alcohol promotes the formation of form 2. An unstable form 3 was also exhibited. The presence of water in the alcohol increased the rate of isolation of form 2 from solution. Initial experiments used pure water as the solvent which produced primarily form 1, but scale-up experiments showed that the solids isolated from pure water and rapidly analyzed by XRD were primarily form 2. The three forms are structurally related and solvated and / or hydrated. The propensity of this API to form solvates indicates that other crystalline solvates not described herein may be formed when the API is dissolved in solution and then crystallized by means such as antisolvent addition, cooling, or solvent evaporation.

[0092] The relative stability of the three isolated solid forms appears to be different as suspensions compared to isolated solids. As isolated solids, Form 1 is likely to be the most stable form. As suspensions, the relative stability of these solvates depends on the solvent or solvent / water mixture present. Form 2 may be more stable than Form 1 in solution under certain conditions, but Form 2 is metastable compared to Form 1 as an isolated solid. Form 3 appears to be a kinetic form, metastable, and converts to Form 2. No XRD pattern of Form 3+Form 1 was observed, suggesting that Form 3 converts to Form 2 and Form 2 converts to Form 1.

[0093] The powder X-ray diffraction (XRD) patterns (Figure 1 (Forms 1, 2, 3)), and the relative peak positions, intensities and d-spacings (Tables 3a and 3b) of Forms 1 and 2 are very similar, strongly suggesting that these three phase forms share a substantially similar set of structural motifs. These three solvated solids are nearly isostructural and very likely differ in subtle ways related to how they fill the solvation sites within the structure with solvent or water. There is increasing complexity in the XRD patterns, with Form 1 being the most complex (most peaks) and Form 3 being the least peaked. This pattern complexity (F1>F2>F3) parallels the apparent stability of the dried isolated samples. Of the 384 solvent mixtures, a total of 90 samples were mixtures rather than pure phase forms.

[0094] As will be appreciated by a skilled crystallographer, the relative intensities, positions and spacings of the various peaks reported in Tables (3a and b) and Figure (1) herein may vary due to many factors, such as the effect of crystal orientation within the X-ray beam, or the purity of the material being analyzed, or the crystallinity of the sample. The XRD peak positions may also shift with variations in sample height, but the peak positions, as specified in the tables, will not change substantially. A skilled crystallographer will also appreciate that measurements using different wavelengths will result in different shifts according to the Bragg equation -nA, = 2ci sinθ. Such additional XRD patterns produced by the use of alternative wavelengths are considered to be alternative representations of the XRD patterns of the crystalline materials of the present invention, and are therefore within the scope of the present invention.

[0095] X-ray diffractograms were obtained on a Scintag X1 powder diffractometer equipped with a Peltier-cooled solid-state detector. Data were collected from 4 to 40 degrees 2θ using a 0.03° step size, and data acquisition times for sample characterization were 45 to 60 min. Data collection for isolated solids from the majority of small-scale preliminary experiments was from 7 to 37 degrees 2θ over 15 min with a 0.04° step size. Copper Kα radiation (λ = 1.54056 Å) was utilized, and tube voltage and amperage were set at 45 kV and 40 mA, respectively. Instrument calibration was performed using a quartz reference standard.

[0096] The thermal data does not allow for a clear distinction between forms that can be easily distinguished based on the XRD patterns. The thermal data indicates that all three solid forms are solvated, but the solvent content is variable. All samples, regardless of form, have the same DSC melting point endotherm maximum peak within 1°C. [ka] Thermal analysis (differential scanning calorimetry (DSC)) of these samples was performed on a TA Instruments DSC 2920. The samples were placed in aluminum DSC pans and the weights were accurately recorded. The lid and pan were attached together but not crimped to allow volatile components to escape. The samples were heated to 300° C. at 10° C. per minute. [Table 3-1] [Table 3-2] [Table 4-1] [Table 4-2]

Claims

1. Compound of formula (rc1) which is 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one 【Chemistry 1】 and its stereoisomers.

2. Compound of formula (R1) which is (R)-3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one 【Chemistry 2】 2. The compound of claim 1 ,

3. The compound of formula (rc1) according to claim 1 and a process for preparing the stereoisomers thereof according to the following rxn-1 procedure: 【Chemistry 3】 a) reacting 3-bromotetrahydrofuran-2(3H)-one (a) with sodium methanesulfinate in the presence of solvent A, a phase transfer catalyst, and optionally a dehydrating agent at a temperature of about 40-100° C. for about 1-24 hours to prepare intermediate 3-(methylsulfonyl)-dihydrofuran-2(3H)-one (b); b) cooling the mixture at ambient temperature overnight and filtering and washing the solids with Solvent A; c) reacting said solid with a base in the presence of a phase transfer catalyst, a methylating agent, a solvent B, and optionally a dehydrating agent at a temperature of about 40-100° C. for a period of about 4-48 hours; d) charging the reactor with additional methylating agent and base while heating for an additional 4 hours; e) filtering the solids while retaining the solvent filtrate; f) washing the solids with solvent B while again retaining the solvent filtrate, then heating the combined filtrates to about 65° C. while distilling off all but about 1.5 volumes; g) exchanging the solvent for solvent A, cooling and seeding; h) further cooling to induce crystallization, filtering the crystals and washing with solvent A to obtain the final product 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1).

4. 4. The process of claim 3 further comprising a dehydrating agent selected from the group consisting of sodium sulfate, calcium chloride, and magnesium sulfate.

5. 5. The process of claim 3 or 4, wherein solvent A is methanol, ethanol, or isopropanol, solvent B is acetone or n-butanol, the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate, the phase transfer catalyst is selected from methylenetrioctylammonium chloride, PEG 400, or PEG 300, and the methylating agent is selected from the group consisting of iodomethane, bromomethane, chloromethane, methyl tosylate, dimethyl sulfate, dimethyl carbonate, and diazomethane.

6. 6. The process of claim 5, wherein solvent A is isopropanol, solvent B is acetone, the phase transfer catalyst is methylenetrioctylammonium chloride or PEG 400, the methylating agent is dimethyl sulfate, and the base is sodium carbonate or potassium carbonate.

7. a) reacting 3-bromotetrahydrofuran-2(3H)-one with sodium methanesulfinate in the presence of isopropanol, methytrioctylammonium chloride, and magnesium sulfate at a temperature of about 80° C. for about 3 hours to prepare intermediate 3-(methylsulfonyl)dihydrofuran-2(3H)-one; b) cooling the mixture at ambient temperature overnight and isolating the solid by dissolving in isopropanol, filtering and washing said solid with isopropanol; c) reacting the solid with potassium carbonate in the presence of methylenetrioctylammonium chloride, dimethyl sulfate, and magnesium sulfate in acetone at a temperature of about 60° C. for about 7 hours; d) charging the reactor with additional dimethyl sulfate and potassium carbonate while heating for an additional 4 hours; e) filtering the solids while retaining the acetone filtrate; f) washing the solids with acetone while again retaining the acetone filtrate and then heating the combined filtrates to about 65° C. while distilling off all but about 1.5 volumes; g) exchanging the acetone for isopropanol, cooling the mixture to about 35° C. and seeding; h) further cooling to about 25° C. to induce crystallization, filtering the crystals and washing with isopropanol to obtain 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1).

8. The compound of formula (rc1) according to claim 1 and a process for preparing the stereoisomers thereof according to the following rxn-t procedure: 【Chemistry 4】 a) reacting 3-bromodihydrofuran-2(3H)-one (a) with sodium methanesulfinate in the presence of a phase transfer catalyst, a solvent B, and optionally a dehydrating agent in a jacketed reactor for about 7-11 hours at 50-80° C.; b) cooling the mixture to room temperature with stirring overnight for about 12 hours, filtering the reaction mixture, retaining the filtrate, and washing the solids with Solvent B while retaining the filtrate; c) reacting the combined filtrate with a methylating agent, a base, and optionally a dehydrating agent while slowly heating the reaction to about 50-80° C. for about 15-20 hours; d) adding more base and methylating agent to the mixture and heating for about 3-6 hours; e) cooling the mixture to ambient temperature and filtering to remove solids while retaining the filtrate; f) washing the solids with solvent B while again retaining the filtrate, heating the combined filtrate to about 60-70° C., then distilling off all but about 1.5 volumes; g) exchanging solvent B with solvent A while cooling to about 30-40° C., seeding, and then further cooling to about 20-25° C. to obtain 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1).

9. 9. The process of claim 8 further comprising a dehydrating agent selected from the group consisting of sodium sulfate, calcium chloride, and magnesium sulfate.

10. 10. The process of claim 8 or 9, wherein solvent B is acetone, the phase transfer catalyst is methylenetrioctylammonium chloride or PEG 400, the methylating agent is selected from the group consisting of iodomethane, bromomethane, chloromethane, methyl tosylate, and dimethyl sulfate, and the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate.

11. a) reacting 3-bromodihydrofuran-2(3H)-one with sodium methanesulfinate in the presence of methyltrioctylammonium chloride, magnesium sulfate, and acetone in a jacketed reactor at reflux at about 56° C. for about 9 hours; b) cooling the mixture to room temperature with stirring overnight for about 12 hours, filtering the reaction mixture while retaining the filtrate, washing the solids with acetone, and again retaining the filtrate; c) reacting the combined filtrate with dimethyl sulfate, anhydrous potassium carbonate, and anhydrous magnesium sulfate while slowly heating the reaction to reflux at about 56° C. for about 15 hours; d) adding more potassium carbonate and dimethyl sulfate to the mixture and heating for about an additional 4 hours; e) cooling the mixture to ambient temperature and filtering to remove solids while retaining the filtrate; f) washing the solids with acetone while again retaining the filtrate, heating the combined filtrate to about 65° C., and then distilling off all but about 1.5 volumes of the acetone; g) exchanging the acetone with isopropanol while cooling to about 35° C., seeding, and then further cooling to about 20° C. to obtain 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one.

12. A process for the preparation of 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (rc2) from 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1), comprising the steps of: a) dissolving potassium tert-butoxide in anhydrous DMSO, followed by addition of 4-chloropyridin-2(1H)-one while maintaining a temperature of about 18-27° C.; b) adding to a mixture of 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1) and benzyltriethylammonium bromide and heating to about 85° C. for 2 hours; c) aging the reaction at about 85° C. for about 17-20 hours; d) adding isopropyl acetate and stirring at about 60° C. for about 1 hour; e) cooling to about 20° C. over 1 hour, aging for 1 hour, filtering the solids, washing with isopropyl acetate, and drying overnight at about 50° C. to produce the potassium salt of 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid; f) dissolving the dried solid in water, treating with methanol and methyltetrahydrofuran, and charging with concentrated HCl; g) stirring the slurry at room temperature for about 2 hours and then cooling the slurry to about 0-5° C. with stirring for an additional hour; h) filtering the slurry, washing with water:MeOH (8:2), and then drying in vacuum under nitrogen to obtain 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid.

13. A process for the preparation of 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (rc2) from 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1), comprising the steps of: a) charging PEG 400, 2-methyl-2-butanol, and 4-chloro-2-hydroxypyridine to a reactor under nitrogen; b) adjusting the reactor temperature to about 18-25° C. and adding potassium tert-butoxide with stirring; c) aging the reaction mixture at about 40-50° C. for about 30-60 minutes; d) adding 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) to the reactor and heating to about 100° C. for about 15 to 30 minutes; e) maintaining said temperature at about 95-100° C. for about 12-24 hours; f) cooling the reaction to about 50-60° C., diluting with water and adjusting the pH to about 1-2 with HCl; g) cooling the reaction to about 0-5° C. over about 1-3 hours, aging for about 1-2 hours, and filtering the resulting solid; h) washing the solid with water and drying to obtain 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (rc2).

14. A process for the preparation of (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-butanoic acid (R2) from (R)-3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (R1), comprising the steps of: a) dissolving potassium tert-butoxide in anhydrous DMSO, followed by addition of 4-chloropyridin-2(1H)-one while maintaining a temperature of about 18-27° C.; b) adding to a mixture of (R)-3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one and benzyltriethylammonium bromide and heating to about 85° C. for 2 hours; c) aging the reaction at about 85° C. for about 17-20 hours; d) adding isopropyl acetate and stirring at about 60° C. for about 1 hour; e) cooling to about 20° C. over 1 hour, aging for 1 hour, filtering the solids, washing with isopropyl acetate, and drying at about 50° C. overnight to produce the potassium salt of (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-butanoic acid; f) dissolving the dried solid in water, treating with methanol and methyltetrahydrofuran, and charging with concentrated HCl; g) stirring the slurry at room temperature for about 2 hours and then cooling the slurry to about 0-5° C. with stirring for an additional hour; h) filtering the slurry, washing with water:MeOH (8:2), and then drying in vacuum under nitrogen to obtain (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-butanoic acid.

15. The compound is 4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid or (R)-4-(4-chloro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid.

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