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

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

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-[3-Methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.31 mmol), 5-(chloromethyl)-3-methyl-1,3-oxazolidin-2-one (56.2 mg, 0.38 mmol), and cesium carbonate (122 mg, 0.38 mmol) were dissolved in DMA (1 mL). The mixture was then heated by microwave irradiation to 140° C. for 1.5 hours. Additional 5-(chloromethyl)-3-methyl-1,3-oxazolidin-2-one (30 mg, 0.19 mmol) was added and the mixture heated by microwave irradiation to 140° C. for 30 minutes. The reaction was cooled to room temperature, diluted with water (3 mL) and ACN (3 mL) then filtered through a syringe filter and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (45 to 80% ACN/water with 0.1% TFA modifier). The free base was liberated using PL-HCO3 cartridges (Stratospheres™, 0.9 mmol) and lyophilized to afford racemic 3-methyl-5-{[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]methyl}-1,3-oxazolidin-2-one. MS ESI calcd. for C20H20F3N6O2 [M+H]+ 433. found 433. 1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.80 (d, J=3.9 Hz, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.35 (s, 1H), 7.24 (d, J=3.4 Hz, 1H), 7.06 (s, 1H), 4.90-4.79 (m, 1H), 4.45-4.32 (m, 2H), 3.65 (t, J=8.9 Hz, 1H), 3.40 (dd, J=6.2, 9.0, 1H), 2.68 (s, 3H), 2.29 (s, 3H). the mixture heated by microwave irradiation to 140° C. for 30 minutes The reaction was cooled to room temperature then filtered through a syringe filter concentrated under reduced pressure The residue was purified by reverse phase preparative HPLC (45 to 80% ACN/water with 0.1% TFA modifier)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-[3-Methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.31 mmol), 5-(chloromethyl)-3-methyl-1,3-oxazolidin-2-one (56.2 mg, 0.38 mmol), and cesium carbonate (122 mg, 0.38 mmol) were dissolved in DMA (1 mL). The mixture was then heated by microwave irradiation to 140° C. for 1.5 hours. Additional 5-(chloromethyl)-3-methyl-1,3-oxazolidin-2-one (30 mg, 0.19 mmol) was added and the mixture heated by microwave irradiation to 140° C. for 30 minutes. The reaction was cooled to room temperature, diluted with water (3 mL) and ACN (3 mL) then filtered through a syringe filter and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (45 to 80% ACN/water with 0.1% TFA modifier). The free base was liberated using PL-HCO3 cartridges (Stratospheres™, 0.9 mmol) and lyophilized to afford racemic 3-methyl-5-{[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]methyl}-1,3-oxazolidin-2-one. MS ESI calcd. for C20H20F3N6O2 [M+H]+ 433. found 433. 1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.80 (d, J=3.9 Hz, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.35 (s, 1H), 7.24 (d, J=3.4 Hz, 1H), 7.06 (s, 1H), 4.90-4.79 (m, 1H), 4.45-4.32 (m, 2H), 3.65 (t, J=8.9 Hz, 1H), 3.40 (dd, J=6.2, 9.0, 1H), 2.68 (s, 3H), 2.29 (s, 3H). the mixture heated by microwave irradiation to 140° C. for 30 minutes The reaction was cooled to room temperature then filtered through a syringe filter concentrated under reduced pressure The residue was purified by reverse phase preparative HPLC (45 to 80% ACN/water with 0.1% TFA modifier)

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

Procedure: This compound was prepared according to the procedure of Example 1. A mixture of 4.6 g (0.015 mole) of α,α-bis-(p-fluorophenyl)-4-piperidinemethanol, 2.2 g (0.015 mole) of 5-(chloromethyl)-3-methyl-2-oxazolidinone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 50 g of Florisil®. Fractions eluted with 5-20% acetone in benzene were combined and concentrated to give a solid residue. The solid was recrystallized from isopropyl ether-2-propanol to yield 1.5 g (24%) of white solid, m.p. 147°-148° C. This compound was prepared gave a gum as residue The gum was purified by column chromatography on 50 g of Florisil® Fractions eluted with 5-20% acetone in benzene concentrated to give a solid residue The solid was recrystallized from isopropyl ether-2-propanol

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

Procedure: A solution of 64.5 g (0.5 mole) of 1,3-dichloro-2-propanol in 200 ml of methylene chloride was treated with 28.5 g (0.5 mole) of methyl isocyanate and a few drops of triethylamine and allowed to stir at ambient temperature overnight. The solution was concentrated and the residue was dissolved in 200 ml of 95% ethanol and treated with a solution of 33.6 g (0.6 mole) of potassium hydroxide in 300 ml of 95% ethanol. The mixture was stirred at ambient temperature for 3.5 hr and then concentrated. The residue was partitioned between 250 ml of benzene and 100 ml of water. The organic layer was washed successively with 50 ml of a 2N hydrochloric acid solution and 100 ml of brine, dried over anhydrous sodium sulfate and concentrated to give 50.5 g of oil as residue. The oil was subjected to vacuum distillation to yield 36.9 g (49%) of clear oil, b.p. 131°-133° C. at 0.3 mm. The solution was concentrated the residue was dissolved in 200 ml of 95% ethanol The mixture was stirred at ambient temperature for 3.5 hr concentrated The residue was partitioned between 250 ml of benzene and 100 ml of water The organic layer was washed successively with 50 ml of a 2N hydrochloric acid solution and 100 ml of brine dried over anhydrous sodium sulfate concentrated

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

Procedure: A solution of 64.5 g (0.5 mole) of 1,3-dichloro-2-propanol in 200 ml of methylene chloride was treated with 28.5 g (0.5 mole) of methyl isocyanate and a few drops of triethylamine and allowed to stir at ambient temperature overnight. The solution was concentrated and the residue was dissolved in 200 ml of 95% ethanol and treated with a solution of 33.6 g (0.6 mole) of potassium hydroxide in 300 ml of 95% ethanol. The mixture was stirred at ambient temperature for 3.5 hr and then concentrated. The residue was partitioned between 250 ml of benzene and 100 ml of water. The organic layer was washed successively with 50 ml of a 2N hydrochloric acid solution and 100 ml of brine, dried over anhydrous sodium sulfate and concentrated to give 50.5 g of oil as residue. The oil was subjected to vacuum distillation to yield 36.9 g (49%) of clear oil, b.p. 131°-133° C. at 0.3 mm. The solution was concentrated the residue was dissolved in 200 ml of 95% ethanol The mixture was stirred at ambient temperature for 3.5 hr concentrated The residue was partitioned between 250 ml of benzene and 100 ml of water The organic layer was washed successively with 50 ml of a 2N hydrochloric acid solution and 100 ml of brine dried over anhydrous sodium sulfate concentrated

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

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

Procedure: This compound was prepared according to the procedure of Example 2. A mixture of 3.2 g (0.02 mol) of 1-phenylpiperazine, 3.0 g (0.02 mol) of 5-(chloromethyl)-3-methyl-2-oxazolidinone, 8.0 g (0.075 mol) of anhydrous sodium carbonate, and 0.4 g of potassium iodide in 100 mL of 1-butanol gave a brown oil as residue. The oil was converted to the dioxalate and the solid was recrystallized from acetonitrile-dimethylformamide but did not give a correct combustion analysis. The salt was partitioned between methylene chloride and a 4% sodium hydroxide solution. The organic layer was dried (Na2SO4) and concentrated to yield 0.9 g (16%) of white solid, mp 110°-112° C. (2-propanol). This compound was prepared gave a brown oil as residue the solid was recrystallized from acetonitrile-dimethylformamide did not give a correct combustion analysis The salt was partitioned between methylene chloride The organic layer was dried (Na2SO4) concentrated

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

Procedure: A solution of 64.5 g (0.5 mol) of 1,3-dichloro-2-propanol (Eastman, practical) in 200 mL of methylene chloride was treated with 28.5 g (0.5 mol) of methyl isocyanate and a few drops of triethylamine and allowed to stir at ambient temperature overnight. The solution was concentrated and the residue was dissolved in 200 mL of 95% ethanol and treated with a solution of 33.6 g (0.6 mol) of potassium hydroxide in 300 mL of 95% ethanol. The mixture was stirred at ambient temperature for 3.5 h and then concentrated. The residue was partitioned between 250 mL of benzene and 100 mL of water. The organic layer was washed successively with 50 mL of a 2N hydrochloric acid solution and 100 mL brine, dried (Na2SO4) and concentrated to give 50.5 g of oil which was subjected to vacuum distillation to yield 36.9 g (49%) of clear oil, bp 131°-133° C. (0.3 mm). The solution was concentrated the residue was dissolved in 200 mL of 95% ethanol The mixture was stirred at ambient temperature for 3.5 h concentrated The residue was partitioned between 250 mL of benzene and 100 mL of water The organic layer was washed successively with 50 mL of a 2N hydrochloric acid solution and 100 mL brine dried (Na2SO4) concentrated

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-[3-Methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.31 mmol), 5-(chloromethyl)-3-methyl-1,3-oxazolidin-2-one (56.2 mg, 0.38 mmol), and cesium carbonate (122 mg, 0.38 mmol) were dissolved in DMA (1 mL). The mixture was then heated by microwave irradiation to 140° C. for 1.5 hours. Additional 5-(chloromethyl)-3-methyl-1,3-oxazolidin-2-one (30 mg, 0.19 mmol) was added and the mixture heated by microwave irradiation to 140° C. for 30 minutes. The reaction was cooled to room temperature, diluted with water (3 mL) and ACN (3 mL) then filtered through a syringe filter and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (45 to 80% ACN/water with 0.1% TFA modifier). The free base was liberated using PL-HCO3 cartridges (Stratospheres™, 0.9 mmol) and lyophilized to afford racemic 3-methyl-5-{[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]methyl}-1,3-oxazolidin-2-one. MS ESI calcd. for C20H20F3N6O2 [M+H]+ 433. found 433. 1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.80 (d, J=3.9 Hz, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.35 (s, 1H), 7.24 (d, J=3.4 Hz, 1H), 7.06 (s, 1H), 4.90-4.79 (m, 1H), 4.45-4.32 (m, 2H), 3.65 (t, J=8.9 Hz, 1H), 3.40 (dd, J=6.2, 9.0, 1H), 2.68 (s, 3H), 2.29 (s, 3H). the mixture heated by microwave irradiation to 140° C. for 30 minutes The reaction was cooled to room temperature then filtered through a syringe filter concentrated under reduced pressure The residue was purified by reverse phase preparative HPLC (45 to 80% ACN/water with 0.1% TFA modifier)

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)