5-(chloromethyl)-1,3-oxazolidin-2-one

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 8.4 grams (0.036 moles) trichloroisocyanuric acid were dissolved in dried methylene chloride. To this suspension were added 5 grams (0.036 moles) 5-Chloromethyl-2-oxazolidinone. The mixture was stirred for several hours before filtering to remove solids. The methylene chloride layer was rotovaped to recover the product, a yellow liquid Proton NMR Data: δ3.7 (m, 4 protons), 4.8(m, 1 proton). Elemental analysis Chlorine found 39.66 (theory 41.7). before filtering to remove solids to recover the product

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 13.55 grams (0.1 mole) 5-chloromethyl-2-oxazolidinone, prepared in Example 1, were dissolved in 90 mL of a 1 M NaOH solution and then cooled to 0° C. 17.6 grams (0.11 moles) bromine were added dropwise, with stirring over a period of fifteen minutes. The product was extracted with methylene chloride. The extracts were then combined, dried and the solvent removed using a rotary evaporator to yield an orange solid. Proton NMR Data: δ3.15 (m, 1 proton), 3.48 (m, 1 proton), 3.7 (m, 2 protons), 4.7 (m, 1 proton) Elemental Analysis: Found (theory), C 24.05 (22.40), H 2.71 (2.35), N 6.98 (6.53), Cl 18.12 (16.53), Br 31.18 (37.26). The product was extracted with methylene chloride dried the solvent removed a rotary evaporator to yield an orange solid

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

Procedure: The title compound, MS: m/e=599.0 (M+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 5-chloromethyl-2-oxazolidinone.

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

Procedure: The title compound, MS: m/e=604.9 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 5-chloromethyl-2-oxazolidinone.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-(Chloromethyl)-1,3-oxazolidin-2-one (500 mg, 3.69 mmol) and iodomethane (0.27 mL, 4.43 mmol) were dissolved in DMF (5 mL) and the resulting solution was cooled to 0° C. Sodium hydride (60%, 177 mg, 4.43 mmol) was added followed by additional DMF (2 mL). The reaction was warmed to room temperature and stirred for 4 hours. Additional iodomethane (0.14 mL, 2.22 mmol) and sodium hydride (60%, 88 mg, 2.2 mmol) were then added and the reaction mixture stirred at room temperature for two hours. The reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (12 to 100% EtOAc/hexanes) to afford racemic 5-(chloromethyl)-3-methyl-1,3-oxazolidin-2-one as a yellow liquid. 1H NMR (500 MHz, CDCl3) δ 4.82-4.60 (m, 1H), 3.81-3.55 (m, 3H), 3.48-3.44 (m, 1H), 2.90 (s, 3H). The reaction was warmed to room temperature the reaction mixture stirred at room temperature for two hours washed with brine dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by column chromatography on silica gel (12 to 100% EtOAc/hexanes)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of potassium phosphate tribasic (6.57 g, 30.9 mmol), 4-iodo pyrazole (2.00 g, 10.3 mmol), and 5-(chloromethyl)-1,3-oxazolidin-2-one (2.80 g, 20.6 mmol) in 1,4-dioxane (103 mL) was sealed in a pressure vessel and heated for 72 hours at 110° C. Upon cooling to room temperature, the mixture was diluted with water and dichloromethane. The organic layer was separated, washed with water, and concentrated under reduced pressure. The residue was triturated with a mixture of methanol and hexanes for several hours at room temperature, and then the precipitate was collected by filtration to afford 5-[(4-iodo-1H-pyrazol-1-yl)methyl]-1,3-oxazolidin-2-one. MS ESI calc'd. for C2H8IN3O2 [M+H]+ 294. found 294. The enantiomers were separated by chiral SFC (supercritical fluid chromatography), IC column with 20% isopropyl alcohol in CO2 to give isomer 1 (faster eluting) and isomer 2 (slower eluting). was sealed in a pressure vessel Upon cooling to room temperature The organic layer was separated washed with water concentrated under reduced pressure The residue was triturated with a mixture of methanol and hexanes for several hours at room temperature the precipitate was collected by filtration

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium phosphate tribasic (6.6 g, 31 mmol), 4-iodo-1H-pyrazole (2.0 g, 10 mmol), and 5-(chloromethyl)oxazolidin-2-one (2.8 g, 21 mmol) were suspended in dioxane (0.10 L, 0.10 M). The reaction vessel was heated to 110° C. for 48 hours, then cooled to room temperature and diluted with dichloromethane (0.25 L). The organics were washed with H2O (2×0.20 L) and were concentrated under reduced pressure. The residue was suspended in methanol:hexanes for 3 hours at ambient temperature with stirring. The precipitate was filtered to afford 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidin-2-one. MS ESI calcd. for C7H9IN3O2 [M+H]+ 294. found 294. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.94-4.77 (m, 1H), 4.42-4.32 (m, 2H), 3.54 (t, J=9.0, 1H), 3.24 (dd, J=6.4, 8.8, 1H). The racemic compound, thus obtained, was resolved by chiral super critical fluid chromatography (IC column, 1:4 Isopropanol/CO2) to afford (R or S) 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidin-2-one (early eluting enantiomer): MS ESI calcd. for C7H9IN3O2 [M+H]+ 294. found 294. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.94-4.77 (m, 1H), 4.42-4.32 (m, 2H), 3.54 (t, J=9.0, 1H), 3.24 (dd, J=6.4, 8.8, 1H); and (R or S) 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidin-2-one (late eluting enantiomer), MS ESI calcd. for C7H9IN3O2 [M+H]+ 294. found 294. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.94-4.77 (m, 1H), 4.42-4.32 (m, 2H), 3.54 (t, J=9.0, 1H), 3.24 (dd, J=6.4, 8.8, 1H). cooled to room temperature The organics were washed with H2O (2×0.20 L) were concentrated under reduced pressure The precipitate was filtered

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium phosphate tribasic (6.6 g, 31 mmol), 4-iodo-1H-pyrazole (2.0 g, 10 mmol), and 5-(chloromethyl)oxazolidin-2-one (2.8 g, 21 mmol) were suspended in dioxane (0.10 L, 0.10 M). The reaction vessel was heated to 110° C. for 48 hours, then cooled to room temperature and diluted with dichloromethane (0.25 L). The organics were washed with H2O (2×0.20 L) and were concentrated under reduced pressure. The residue was suspended in methanol:hexanes for 3 hours at ambient temperature with stirring. The precipitate was filtered to afford 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidin-2-one. MS ESI calcd. for C7H9IN3O2 [M+H]+ 294. found 294. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.94-4.77 (m, 1H), 4.42-4.32 (m, 2H), 3.54 (t, J=9.0, 1H), 3.24 (dd, J=6.4, 8.8, 1H). The racemic compound, thus obtained, was resolved by chiral super critical fluid chromatography (IC column, 1:4 Isopropanol/CO2) to afford (R or S) 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidin-2-one (early eluting enantiomer): MS ESI calcd. for C7H9IN3O2 [M+H]+ 294. found 294. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.94-4.77 (m, 1H), 4.42-4.32 (m, 2H), 3.54 (t, J=9.0, 1H), 3.24 (dd, J=6.4, 8.8, 1H); and (R or S) 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidin-2-one (late eluting enantiomer), MS ESI calcd. for C7H9IN3O2 [M+H]+ 294. found 294. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.94-4.77 (m, 1H), 4.42-4.32 (m, 2H), 3.54 (t, J=9.0, 1H), 3.24 (dd, J=6.4, 8.8, 1H). cooled to room temperature The organics were washed with H2O (2×0.20 L) were concentrated under reduced pressure The precipitate was filtered