methyl 2,2-difluoro-2-fluorosulfonylacetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under cooling with an ice bath, 230 parts of a 30 mass % aqueous sodium hydroxide solution was dripped into a mixture of 100 parts of methyl difluoro(fluorosulfonyl)acetate and 150 parts of ion-exchanged water. The resultant mixture was refluxed at 100° C. for three hours, was cooled, and was neutralized with 88 parts of concentrated hydrochloric acid. The obtained solution was concentrated to obtain 164.4 parts of sodium difluorosulfoacetate (which contains an inorganic salt, and the purity is 62.7%). To a mixture of 1.9 parts of the sodium difluorosulfoacetate (the purity is 62.7%) obtained and 9.5 parts of N,N-dimethylformamide, 1.0 part of 1,1′-carbonyldiimidazole was added, and the resultant mixture was stirred for two hours. The obtained solution was added to a solution which was obtained by adding 0.2 parts of sodium hydride to a mixture of 1.1 parts of 3-hydroxy-1-adamantylmethanol and 5.5 parts of N,N-dimethylformamide, and stirring the resultant mixture for two hours. The resultant solution was stirred for 15 hours to obtain sodium salt of 3-hydroxy-1-adamantylmethyl difluorosulfoacetate, which was used as it was for the subsequent reaction. Under cooling with an ice bath was cooled The obtained solution was concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 230 Parts of 30% aqueous sodium hydroxide solution was added into a mixture of 100 parts of methyl difluoro(fluorosulfonyl)acetate and 250 parts of ion-exchanged water in a ice bath. The added mixture was heated and refluxed at 100° C. for 3 hours. After cooling, the cooled mixture was neutralized with 88 parts of conc. hydrochloric acid and concentrated to obtain 164.8 parts of sodium difluorosulfoacetate (containing inorganic salt purity: 62.6%). The added mixture was heated After cooling concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 230 Parts of 30% aqueous sodium hydroxide solution was added into a mixture of 100 parts of methyl difluoro(fluorosulfonyl)acetate and 250 parts of ion-exchanged water in a ice bath. The added mixture was heated and refluxed at 100° C. for 3 hours. After cooling, the cooled mixture was neutralized with 88 parts of conc. hydrochloric acid and concentrated to obtain 164.4 parts of sodium difluorosulfoacetate (containing inorganic salt, purity: 62.7%). The added mixture was heated After cooling concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 230 Parts of 30% aqueous sodium hydroxide solution was added into a mixture of 100 parts of methyl difluoro(fluorosulfonyl)acetate and 250 parts of ion-exchanged water in a ice bath. The added mixture was heated and refluxed at 100° C. for 3 hours. After cooling, the cooled mixture was neutralized with 88 parts of conc. hydrochloric acid and concentrated to obtain 164.4 parts of sodium difluorosulfoacetate (containing inorganic salt, purity: 62.7%). The added mixture was heated After cooling concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 230 Parts of 30% aqueous sodium hydroxide solution was added into a mixture of 100 parts of methyl difluoro(fluorosulfonyl)acetate and 250 parts of ion-exchanged water in a ice bath. The added mix was heated and refluxed at 100° C. for 3 hours. After cooling, the cooled mixture was neutralized with 88 parts of conc. hydrochloric acid and concentrated to obtain 164.8 parts of sodium difluorosulfoacetate (containing inorganic salt, purity: 62.6%). The added mix was heated After cooling concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-iodo-benzofuran-4-carboxylic acid [3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-thiazolidin-4-ylmethyl]-amide (57 mg), copper (I) iodide (91 mg, 5 eq), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.08 mL, 6.5 eq), HMPA (0.17 mL, 10 eq) in dry DMF (2.5 mL) was stirred at 80° C. for 16 hours under nitrogen. After cooling to rt, the reaction mixture was partitioned between water and EtOAc, the organic phase was washed again with water, dried (MgSO4), filtered and concentrated in vacuo to yield a crude yellow-orange oil. FC (AlO3, EtOAc/n-heptane: 7/3) gave the title compound (4.2 mg, 8%) as a white solid. LC-MS: tR=1.08 min; [m+H]+=546.22. After cooling to rt the reaction mixture was partitioned between water and EtOAc the organic phase was washed again with water dried (MgSO4) filtered concentrated in vacuo to yield a crude yellow-orange oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The ester (compound D, Scheme 1) can be treated with NIS in DMF to provide the C6 iodide (B). The resulting iodide (B) can be converted to trifluoromethylpyridinedione (C) by the treatment with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of copper (I) iodide in a solvent such as DMF. The ester (C) can be hydrolyzed using an aqueous hydroxide base such as lithium hydroxide or sodium hydroxide with a co-solvent such as tetrahydrofuran or methanol to provide the acid (D). The acid (D) can be coupled to an amine (RNH2) using standard peptide coupling conditions such as PyBOP/DIPEA or EDC/HOBT/DIPEA in a solvent such as dichloromethane or THF to produce the amide (E). The methoxy group on amide (E) could be cleaved using boron tribromide-methyl sulfide complex, boron tribromide solution in dichloromethane or boron trichloride to provide the pyridinedione (F).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The ester (compound D, Scheme 1) can be treated with NIS in DMF to provide the C6 iodide (B). The resulting iodide (B) can be converted to trifluoromethylpyridinedione (C) by the treatment with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of copper (I) iodide in a solvent such as DMF. The ester (C) can be hydrolyzed using an aqueous hydroxide base such as lithium hydroxide or sodium hydroxide with a co-solvent such as tetrahydrofuran or methanol to provide the acid (D). The acid (D) can be coupled to an amine (RNH2) using standard peptide coupling conditions such as PyBOP/DIPEA or EDC/HOBT/DIPEA in a solvent such as dichloromethane or THF to produce the amide (E). The methoxy group on amide (E) could be cleaved using boron tribromide-methyl sulfide complex, boron tribromide solution in dichloromethane or boron trichloride to provide the pyridinedione (F).

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 424 Parts of 30% aqueous sodium hydroxide solution was added into a mixture of 500 parts of methyl difluoro(fluorosulfonyl)acetate and 750 parts of ion-exchanged water in a ice bath. The added mixture was heated and refluxed at 100° C. for 2.5 hours. After cooling, the cooled mixture was neutralized with 440 parts of conc. hydrochloric acid and concentrated to obtain 802.82 parts of sodium difluorosulfoacetate (containing inorganic salt, purity: 64.2%). The added mixture was heated After cooling concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 424 Parts of 30% aqueous sodium hydroxide solution was added into a mixture of 500 parts of methyl difluoro(fluorosulfonyl)acetate and 750 parts of ion-exchanged water in a ice bath. The added mixture was heated and refluxed at 100° C. for 2.5 hours. After cooling, the cooled mixture was neutralized with 440 parts of conc. hydrochloric acid and concentrated to obtain 802.82 parts of sodium difluorosulfoacetate (containing inorganic salt, purity: 64.2%). The added mixture was heated After cooling concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 424 Parts of 30% aqueous sodium hydroxide solution was added into a mixture of 500 parts of methyl difluoro(fluorosulfonyl)acetate and 750 parts of ion-exchanged water in a ice bath. The added mixture was heated and refluxed at 100° C. for 2.5 hours. After cooling, the cooled mixture was neutralized with 440 parts of conc. hydrochloric acid and concentrated to obtain 802.82 parts of sodium difluorosulfoacetate (containing inorganic salt, purity: 64.2%). The added mixture was heated After cooling concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 424 Parts of 30% aqueous sodium hydroxide solution was added into a mixture of 500 parts of methyl difluoro(fluorosulfonyl)acetate and 750 parts of ion-exchanged water in a ice bath. The added mixture was heated and refluxed at 100° C. for 2.5 hours. After cooling, the cooled mixture was neutralized with 440 parts of conc. hydrochloric acid and concentrated to obtain 802.82 parts of sodium difluorosulfoacetate (containing inorganic salt, purity: 64.2%). The added mixture was heated After cooling concentrated