Intermediates useful for the preparation of LpxC analogs, 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

Claims

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

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

3. The compound of formula (rc1) described in claim 1 A process for preparing the stereoisomers thereof according to the following rxn-1 procedure, 【Transformation 3】 a) Reacting 3-bromotetrahydrofuran-2(3H)-one (a) with sodium methanesulfinate at a temperature of 40-100°C for 1-24 hours in the presence of solvent A, a phase transfer catalyst, and optionally a dehydrating agent, to prepare the intermediate 3-(methylsulfonyl)-dihydrofuran-2(3H)-one (b), b) Allow the mixture to cool overnight, filter out the solids, and wash with solvent A. c) Reacting the solid with a base at a temperature of 40 to 100°C for a period of 4 to 48 hours in the presence of a phase transfer catalyst, a methylating agent, solvent B, and optionally a dehydrating agent. d) While heating for a further 4 hours, the reactor is filled with additional methylating agents and bases. e) Filtering the solid while retaining the solvent filtrate, f) While retaining the solvent filtrate, wash the solid with solvent B, and then heat the combined filtrate to 65°C while distilling off all but 1.5 volumes. g) Replace the solvent with solvent A, cool and sow seeds, h) A process comprising further cooling to induce crystallization, filtering the crystals, washing them with solvent A to obtain the final product 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1).

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

5. The process according to 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 methyltrioctylammonium chloride, PEG400, or PEG300, and the methylating agent is selected from the group consisting of iodomethane, bromomethane, chloromethane, methyl tosylate, dimethyl sulfate, dimethyl carbonate, and diazomethane.

6. The process according to claim 5, wherein solvent A is isopropanol, solvent B is acetone, the phase transfer catalyst is methyltrioctylammonium chloride or PEG400, 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 at 80°C for 3 hours in the presence of isopropanol, methyltrioctylammonium chloride, and magnesium sulfate to prepare the intermediate 3-(methylsulfonyl)dihydrofuran-2(3H)-one, b) Allow the mixture to cool overnight, isolate the solid by dissolving it in isopropanol, filter the solid, and wash it with isopropanol. c) Reacting the solid with potassium carbonate in acetone at a temperature of 60°C for 7 hours in the presence of methyltrioctylammonium chloride, dimethyl sulfate, and magnesium sulfate. d) While heating for a further 4 hours, the reactor is filled with additional dimethyl sulfate and potassium carbonate. e) Filtering the solid while retaining the acetone filtrate, f) While retaining the acetone filtrate, wash the solid with acetone, and then heat the combined filtrate to 65°C while distilling off all but 1.5 volumes. g) Replace the acetone with isopropanol, cool the mixture to 35°C, and sow the seeds. The process according to claim 6, further comprising cooling to 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) described in claim 1 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 a jacketed reactor for 7 to 11 hours at 50 to 80°C in the presence of a phase transfer catalyst, solvent B, and optionally a dehydrating agent. b) Cool the mixture to room temperature while stirring overnight for 12 hours, filter the reaction mixture, retain the filtrate, and while retaining the filtrate, wash the solids with solvent B. c) The combined filtrate, a methylating agent, a base, and optionally a dehydrating agent are reacted while slowly heating the reaction mixture at 50-80°C for 15-20 hours. d) Add more base and methylating agent to the mixture and heat for a further 3 to 6 hours, e) Allow the mixture to cool, filter it, and remove solid matter while retaining the filtrate. f) While holding the filtrate again, wash the solids with solvent B, heat the combined filtrate to 60-70°C, and then distill off all but 1.5 volumes. g) A process comprising exchanging solvent B with solvent A while cooling to 30-40°C, sowing seeds, and then further cooling to 20-25°C to obtain 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1).

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

10. The process according to claim 8 or 9, wherein solvent B is acetone, the phase transfer catalyst is methyltrioctylammonium chloride or PEG400, 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 a jacketed reactor for 9 hours in the presence of methyltrioctylammonium chloride, magnesium sulfate, and acetone, and refluxing at 56°C. b) Cool the mixture to room temperature while stirring overnight for 12 hours, filter the reaction mixture while retaining the filtrate, wash the solids with acetone, and retain the filtrate again. c) The combined filtrate is reacted with dimethyl sulfuric acid, anhydrous potassium carbonate, and anhydrous magnesium sulfate while slowly heating the reaction mixture, and refluxed at 56°C for 15 hours. d) Add more potassium carbonate and dimethyl sulfate to the mixture and heat for a further 4 hours. e) Allow the mixture to cool, filter it, and remove solid matter while retaining the filtrate. f) While retaining the filtrate, wash the solids with acetone, heat the combined filtrate to 65°C, and then distill off all of the acetone except for 1.5 volumes. The process according to claim 7, comprising: g) replacing the acetone with isopropanol while cooling to 35°C, sowing seeds, and then further cooling to 20°C to obtain 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one.

12. A process for preparing 4-(4-chloro-2-oxopyridine-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (rc2) from 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1), a) Dissolve potassium tert-butoxide in anhydrous DMSO, and then add 4-chloropyridine-2(1H)-one while maintaining a temperature of 18-27°C, b) Add to a mixture of 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1) and benzyltriethylammonium bromide, and heat at 85°C for 2 hours, c) The reaction mixture is aged at 85°C for 17 to 20 hours, d) Add isopropyl acetate and stir at 60°C for 1 hour. e) Cool to 20°C for 1 hour, mature for 1 hour, filter the solids, wash with isopropyl acetate, dry overnight at 50°C to produce the potassium salt of 4-(4-chloro-2-oxopyridine-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid, f) Dissolve the dried solid in water, treat with methanol and methyltetrahydrofuran, and fill with concentrated HCl. g) Stir the slurry at room temperature for 2 hours, then cool it to 0-5°C while stirring for another 1 hour. h) A process comprising filtering the slurry, washing it with water:MeOH (8:2), and then drying it under vacuum under nitrogen to obtain 4-(4-chloro-2-oxopyridine-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid.

13. A process for preparing 4-(4-chloro-2-oxopyridine-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (rc2) from 3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (rc1), a) Filling the reactor with PEG400, 2-methyl-2-butanol, and 4-chloro-2-hydroxypyridine under nitrogen, b) Adjust the reactor temperature to 18-25°C and add potassium tert-butoxide while stirring, c) The reaction mixture is aged at 40-50°C for 30-60 minutes. d) Add 3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one (rc1) to the reactor and heat to 100°C for 15 to 30 minutes, e) Maintain the above temperature at 95 to 100°C for 12 to 24 hours. f) Cool the reaction mixture to 50-60°C, dilute it with water, and adjust the pH to 1-2 with HCl. g) Cool the reaction mixture to 0-5°C for 1-3 hours, allow it to mature for 1-2 hours, and filter the resulting solid. h) A process comprising washing the solid with water and drying it to obtain 4-(4-chloro-2-oxopyridine-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (rc2).

14. A process for preparing (R)-4-(4-chloro-2-oxopyridine-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-butanoic acid (R2) from (R)-3-methyl-3-(methylsulfonyl)-dihydrofuran-2(3H)-one (R1), a) Dissolve potassium tert-butoxide in anhydrous DMSO, and then add 4-chloropyridine-2(1H)-one while maintaining a temperature of 18-27°C, b) Add (R)-3-methyl-3-(methylsulfonyl)dihydrofuran-2(3H)-one to a mixture of benzyltriethylammonium bromide and heat at 85°C for 2 hours, c) The reaction mixture is aged at 85°C for 17 to 20 hours, d) Add isopropyl acetate and stir at 60°C for 1 hour. e) Cool to 20°C for 1 hour, mature for 1 hour, filter the solids, wash with isopropyl acetate, dry overnight at 50°C to produce the potassium salt of (R)-4-(4-chloro-2-oxopyridine-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-butanoic acid, f) Dissolve the dried solid in water, treat with methanol and methyltetrahydrofuran, and fill with concentrated HCl. g) Stir the slurry at room temperature for 2 hours, then cool it to 0-5°C while stirring for another 1 hour. h) A process comprising filtering the slurry, washing it with water:MeOH (8:2), and then drying it under vacuum under nitrogen to obtain (R)-4-(4-chloro-2-oxopyridine-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-butanoic acid.

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