Process for manufacturing an lpxc analog

A process for preparing 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:

• a) dissolving potassium tert-butoxide in anhydrous DMSO and then adding 4-chloropyridin-2 (1H)-one while maintaining the temperature between about 18-27° C.;
• b) adding in 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 reactants for about 17-20 hours at about 85° C.;
• d) adding isopropyl acetate and stirring for about 1 hour at about 60° C.;
• e) cooling to about 20° C. over an hour and aged for an hour;
• filtering the solids and washing with isopropyl acetate and drying overnight at about 50° C. to yield the potassium salt of 4-(4-chloro-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl) butanoic acid;
• f) dissolving the dried solids in water and treating with methanol and methyl tetrahydrofuran and charging with concentrated HCl;
• g) stirring the slurry at room temperature for about 2 hours and cooling to about 0-5° C. while stirring for an additional hour;
• and
• h) filtering the slurry and washing with water:MeOH (8:2) and then drying in vacuo under nitrogen to afford 4-(4-chloro-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl) butanoic acid.

A process for preparing 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:

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

A process for preparing (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:

• a) dissolving potassium tert-butoxide in anhydrous DMSO and then adding 4-chloropyridin-2 (1H)-one while maintaining the temperature between about 18-27° C.;
• b) adding in 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 reactants for about 17-20 hours at about 85° C.;
• d) adding isopropyl acetate and stirring for about 1 hour at about 60° C.;
• e) cooling to about 20° C. over an hour and aged for an hour;
• filtering the solids and washing with isopropyl acetate and drying overnight at about 50° C. to yield the potassium salt of (R)-4-(4-chloro-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-butanoic acid;
• f) dissolving the dried solids in water and treating with methanol and methyl tetrahydrofuran and charging with concentrated HCl;
• g) stirring the slurry at room temperature for about 2 hours and cooling to about 0-5° C. while stirring for an additional hour;
• and
• h) filtering the slurry and washing with water:MeOH (8:2) and then drying in vacuo under nitrogen to afford (R)-4-(4-chloro-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-butanoic acid.