2,2-dimethylbutanoyl chloride

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:

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N,N-diisopropylethylamine (19.9 mL, 120 mmol) and methyl 3-mercaptopropanoate (7.21 60 mmol) in isopropyl acetate (i-PrOAc, 100 mL) was cooled to an internal temperature of 2° C. To this vigorously stirred solution, 2,2-dimethylbutanoyl chloride (8.1 g, 60 mmol) was added dropwise over 10 min. The resulting suspension was stirred at 25° C. for 2 h. The reaction was monitored by checking the disappearance of methyl 3-mercaptopropanoate using thin-layer chromatography (TLC) on silica plates. Spots were stained with iodine (eluent: 5% EtOAc/heptane; Rf of methyl 3-mercaptopropanoate: 0.20). The reaction was quenched by addition of saturated ammonium chloride (100 mL) followed by i-PrOAc (100 mL) and the resultant mixture stirred until all solid dissolved. The phases were separated and the organic phase was washed successively with 1% aqueous hydrochloric acid (100 mL) and then water (2×50 mL). The organic phase was then dried over sodium sulfate, filtered, and concentrated under reduced pressure (45° C. bath, 50 mm Hg) to obtain a crude mixture as a pale yellow liquid. The crude mixture is subjected to column chromatography over silica gel using a heptane to 2% EtOAc:heptane gradient. Fractions comprising the pure product were combined and concentrated to afford 10.5 g (80%) of methyl 3-(2,2-dimethylbutanoylthio)propionate (DMB-S-MMP). The reaction was quenched by addition of saturated ammonium chloride (100 mL) the resultant mixture stirred until all solid dissolved The phases were separated the organic phase was washed successively with 1% aqueous hydrochloric acid (100 mL) The organic phase was then dried over sodium sulfate filtered concentrated under reduced pressure (45° C. bath, 50 mm Hg) to obtain a crude mixture as a pale yellow liquid concentrated

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

Procedure: A solution of N,N-diisopropylethylamine (19.9 mL, 120 mmol) and methyl 3-mercaptopropanoate (7.21 60 mmol) in isopropyl acetate (i-PrOAc, 100 mL) was cooled to an internal temperature of 2° C. (brine ice bath). To this vigorously stirred solution was added 2,2-dimethylbutanoyl chloride (8.1 g, 60 mmol) dropwise over 10 min. The resulting suspension was then stirred at 25° C. for 2 h. The reaction was monitored by checking the disappearance of methyl 3-mercaptopropanoate using thin-layer chromatography (TLC) on silica plates. Spots were stained with iodine (eluent: 5% EtOAc/heptane; Rf of methyl 3-mercaptopropanoate: 0.20). The reaction was then quenched by addition of saturated ammonium chloride (100 mL) followed by i-PrOAc (100 mL) and the resultant mixture was stirred until all solid dissolved. The phases were separated and the organic phase was washed successively with 1% aqueous hydrochloric acid (100 mL) and then water (2×50 mL). The organic phase was then dried over sodium sulfate, filtered, and concentrated under reduced pressure (45° C. bath, 50 mm Hg) to obtain a crude mixture as a pale yellow liquid. The crude mixture was subjected to column chromatography over silica gel using a heptane to 2% EtOAc:heptane gradient. Fractions comprising the pure product were combined and concentrated to afford 10.5 g (80%) of methyl 3-(2,2-dimethylbutanoylthio)propionate. The reaction was then quenched by addition of saturated ammonium chloride (100 mL) the resultant mixture was stirred until all solid dissolved The phases were separated the organic phase was washed successively with 1% aqueous hydrochloric acid (100 mL) The organic phase was then dried over sodium sulfate filtered concentrated under reduced pressure (45° C. bath, 50 mm Hg) to obtain a crude mixture as a pale yellow liquid concentrated

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

Procedure: 2,2-Dimethylbutyric acid (1 g, 8.6 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. The solution was treated with oxalyl chloride (1.2 mL, 13.8 mmol) and DMF (0.07 mL, 0.87 mmol), allowed to warm to RT, and stirred for 2 h for complete conversion to 2,2-dimethylbutyric acid chloride. The solution was cooled to 0° C. and added to a stirred solution of semicarbazide hydrochloride (1.4 g, 12.9 mmol) and NaOH (1.4 g, 34.4 mmol) in a mixture of dioxane (10 mL) and water (2.0 mL) at 0° C. The reaction mixture was allowed to warm to RT and stirred for 12 h. Organic solvent was evaporated in vacuo, and the resultant slurry was diluted with 2 M NaOH (aq) (50 mL, 100 mmol). The suspension was stirred at 100° C. for 24 h. The aqueous solution was saturated with solid NH4Cl and extracted with EtOAc (5×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 3-(tert-pentyl)-1H-1,2,4-triazol-5(4H)-one (0.71 g, 53.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 11.02 (s, 1H), 1.49 (q, J=7.5 Hz, 2H), 1.11 (s, 6H), 0.68 (t, J=7.4 Hz, 3H); MS (ESI) m/z: 156.1 (M+H+). to warm to RT The solution was cooled to 0° C. to warm to RT Organic solvent was evaporated in vacuo The suspension was stirred at 100° C. for 24 h extracted with EtOAc (5×50 mL) The combined organics were dried (Na2SO4) concentrated in vacuo

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

Procedure: 2,2-Dimethylbutyric acid (1 g, 8.6 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. The solution was treated with oxalyl chloride (1.2 mL, 13.8 mmol) and DMF (0.07 mL, 0.87 mmol), allowed to warm to RT, and stirred for 2 h for complete conversion to 2,2-dimethylbutyric acid chloride. The solution was cooled to 0° C. and added to a stirred solution of semicarbazide hydrochloride (1.4 g, 12.9 mmol) and NaOH (1.4 g, 34.4 mmol) in a mixture of dioxane (10 mL) and water (2.0 mL) at 0° C. The reaction mixture was allowed to warm to RT and stirred for 12 h. Organic solvent was evaporated in vacuo, and the resultant slurry was diluted with 2 M NaOH (aq) (50 mL, 100 mmol). The suspension was stirred at 100° C. for 24 h. The aqueous solution was saturated with solid NH4Cl and extracted with EtOAc (5×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 3-(tert-pentyl)-1H-1,2,4-triazol-5(4H)-one (0.71 g, 53.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 11.02 (s, 1H), 1.49 (q, J=7.5 Hz, 2H), 1.11 (s, 6H), 0.68 (t, J=7.4 Hz, 3H); MS (ESI) m/z: 156.1 (M+H+). to warm to RT The solution was cooled to 0° C. to warm to RT Organic solvent was evaporated in vacuo The suspension was stirred at 100° C. for 24 h extracted with EtOAc (5×50 mL) The combined organics were dried (Na2SO4) concentrated in vacuo