3-chloro-2,2-dimethylpropanoic acid

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: An 87.2 g. portion of 4-methylthiosemicarbazide and 113.2 g. of 3-chloro-2,2-dimethylpropionic acid were suspended in 300 ml. of dioxane. The mixture was heated to 90°C. and 139.5 g. of phosphorus oxychloride was added dropwise while holding the temperature constant. After the addition was complete, the reaction mixture was stirred at 90°C. for three hours. The mixture was then allowed to cool and stand overnight at room temperature. After the addition to cool stand overnight at room temperature

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The required 3-Chloro-2,2-dimethyl-propionic acid tert-butyl ester was prepared as follows: To a solution of 3-chloro-2,2-dimethylpropionic acid (5.00 g; 36.6 mmol) in DMF (25 mL) was added N,N′-carbonyldiimidazole (5.94 g; 36.6 mmol) and the resulting mixture was stirred for 1 hour at 40° C. Subsequently, tert-butyl alcohol (7.1 mL; 73 mmol) and DBU (5.5 mL; 36.6 mmol) were added and the mixture stirred overnight at 40° C. After cooling to RT, 5% aqueous NaHCO3 solution (50 mL) was added to the mixture and stirred for another 15 minutes. The reaction mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated in vacuo and purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 3-chloro-2,2-dimethyl-propionic acid tert-butyl ester (3.34 g). The required 3-Chloro-2,2-dimethyl-propionic acid tert-butyl ester was prepared the mixture stirred overnight at 40° C After cooling to RT stirred for another 15 minutes The reaction mixture was extracted with EtOAc The organic layer was dried (Na2SO4) concentrated in vacuo purified by column chromatography (SiO2, Et2O:hexanes 1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a well stirred suspension of 125 g of 4-methylthiosemicarbazide and 165 g of β-chloropivalic acid in 500 ml of dioxane was added 186 g of phosphorus oxychloride at a rate which maintained the temperature below 60°. The reaction mixture was then heated at reflux until HCl evolution ceased (about 4 hrs). After cooling, the supernatant liquid was decanted from the plastic mass and 500 ml of water was added. With cooling, sodium hydroxide pellets were added until a pH of 10 was maintained. The resulting precipitate was collected, washed with water and air dried giving 216 g m.p. 91°-93°, (87%). Recrystallization from methylene chloride-ether gave the analytical sample, m.p. 93°-95°. maintained the temperature below 60° The reaction mixture was then heated (about 4 hrs) After cooling the supernatant liquid was decanted from the plastic mass and 500 ml of water was added With cooling sodium hydroxide pellets were added until a pH of 10 was maintained The resulting precipitate was collected washed with water and air dried giving 216 g m.p. 91°-93°, (87%) Recrystallization from methylene chloride-ether gave the analytical sample, m.p. 93°-95°

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a well stirred suspension of 125 g of 4-methylthiosemicarbazide and 165 g of β-chloropivalic acid in 500 ml of dioxane was added 186 g of phosphorus oxychloride at a rate which maintained the temperature below 60°. The reaction mixture was then heated at reflux until HCl evolution ceased (about 4 hrs). After cooling, the supernatant liquid was decanted from the plastic mass and 500 ml of water was added. With cooling, sodium hydroxide pellets were added until a pH of 10 was maintained. The resulting precipitate was collected, washed with water and air dried giving 216 g m.p. 91°-93°, (87%). Recrystallization from methylene chloride-ether gave the analytical sample, m.p. 93°-95°. maintained the temperature below 60° The reaction mixture was then heated (about 4 hrs) After cooling the supernatant liquid was decanted from the plastic mass and 500 ml of water was added With cooling sodium hydroxide pellets were added until a pH of 10 was maintained The resulting precipitate was collected washed with water and air dried giving 216 g m.p. 91°-93°, (87%) Recrystallization from methylene chloride-ether gave the analytical sample, m.p. 93°-95°

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The starting material is prepared as follows: The mixture of 50 g of 3-chloropivalic acid, 4.2 g of potassium thioacetate, 1 g of potassium iodide and 200 ml of ethanol is refluxed for 18 hours. It is cooled to room temperature, filtered, the filtrate evaporated and the residue partitioned between 100 ml of water and 200 ml of diethyl ether. The aqueous layer is extracted with 100 ml of diethyl ether, the combined organic layers dried, evaporated and the residue distilled at 150°-155°/3 mm Hg, to yield the 3-acetylthiopivalic acid. The starting material is prepared is refluxed for 18 hours filtered the filtrate evaporated the residue partitioned between 100 ml of water and 200 ml of diethyl ether The aqueous layer is extracted with 100 ml of diethyl ether the combined organic layers dried evaporated the residue distilled at 150°-155°/3 mm Hg

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The starting material is prepared as follows: The mixture of 50 g of 3-chloropivalic acid, 4.2 g of potassium thioacetate, 1 g of potassium iodide and 200 ml of ethanol is refluxed for 18 hours. It is cooled to room temperature, filtered, the filtrate evaporated and the residue partitioned between 100 ml of water and 200 ml of diethyl ether. The aqueous layer is extracted with 100 ml of diethyl ether, the combined organic layers dried, evaporated and the residue distilled at 150°-155°/3 mm Hg, to yield the 3-acetylthiopivalic acid. The starting material is prepared is refluxed for 18 hours filtered the filtrate evaporated the residue partitioned between 100 ml of water and 200 ml of diethyl ether The aqueous layer is extracted with 100 ml of diethyl ether the combined organic layers dried evaporated the residue distilled at 150°-155°/3 mm Hg

反応条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Example 75 can be prepared as demonstrated in the literature (reference Musker, W. K.; et al. J. Org. Chem. 1996, 51, 1026-1029). Sodium methanethiolate (1.0 g, 14 mmol, 2.0 equiv) was added to a stirred solution of 3-chloro-2,2-dimethylpropanoic acid (1.0 g, 7.2 mmol, 1.0 equiv) in N,N-dimethylformamide (3.7 mL) at 0° C. The resulting brown suspension was allowed to warm to 23° C. and stirred for 24 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (300 mL) and washed with diethyl ether (3×75 mL). The aqueous layer was acidified to pH≈1 with concentrated hydrochloric acid and extracted with diethyl ether (3×75 mL). The combined organic layers were dried (sodium sulfate), gravity filtered, and concentrated to afford a colorless oil (1.2 g, 99% crude yield). 1H NMR (300 MHz, CDCl3) δ 2.76 (s, 2H), 2.16 (s, 3H), 1.30 (s, 6H). Example 75 can be prepared washed with diethyl ether (3×75 mL) extracted with diethyl ether (3×75 mL) The combined organic layers were dried (sodium sulfate), gravity filtered concentrated to afford a colorless oil (1.2 g, 99% crude yield)

反応条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Example 75 can be prepared as demonstrated in the literature (reference Musker, W. K.; et al. J. Org. Chem. 1996, 51, 1026-1029). Sodium methanethiolate (1.0 g, 14 mmol, 2.0 equiv) was added to a stirred solution of 3-chloro-2,2-dimethylpropanoic acid (1.0 g, 7.2 mmol, 1.0 equiv) in N,N-dimethylformamide (3.7 mL) at 0° C. The resulting brown suspension was allowed to warm to 23° C. and stirred for 24 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (300 mL) and washed with diethyl ether (3×75 mL). The aqueous layer was acidified to pH≈1 with concentrated hydrochloric acid and extracted with diethyl ether (3×75 mL). The combined organic layers were dried (sodium sulfate), gravity filtered, and concentrated to afford a colorless oil (1.2 g, 99% crude yield). 1H NMR (300 MHz, CDCl3) δ 2.76 (s, 2H), 2.16 (s, 3H), 1.30 (s, 6H). Example 75 can be prepared washed with diethyl ether (3×75 mL) extracted with diethyl ether (3×75 mL) The combined organic layers were dried (sodium sulfate), gravity filtered concentrated to afford a colorless oil (1.2 g, 99% crude yield)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: An 87.2 g. portion of 4-methylthiosemicarbazide and 113.2 g. of 3-chloro-2,2-dimethylpropionic acid were suspended in 300 ml. of dioxane. The mixture was heated to 90° C. and 139.5 g. of phosphorus oxychloride was added dropwise while holding the temperature constant. After the addition was complete, the reaction mixture was stirred at 90° C. for three hours. The mixture was then allowed to cool and stand overnight at room temperature. After the addition to cool stand overnight at room temperature

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: prepared as follows: To a solution of 3-chloro-2,2-dimethylpropionic acid (5.00 g; 36.6 mmol) in DMF (25 mL) was added N,N′-carbonyldiimidazole (5.94 g; 36.6 mmol) and the resulting mixture was stirred for 1 hour at 40° C. Subsequently, tert-butyl alcohol (7.1 mL; 73 mmol) and DBU (5.5 mL; 36.6 mmol) were added and the mixture stirred overnight at 40° C. After cooling to RT, 5% aqueous NaHCO3 solution (50 mL) was added to the mixture and stirred for another 15 minutes. The reaction mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated in vacuo and purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 3-chloro-2,2-dimethyl-propionic acid tert-butyl ester (3.34 g). prepared the mixture stirred overnight at 40° C After cooling to RT stirred for another 15 minutes The reaction mixture was extracted with EtOAc The organic layer was dried (Na2SO4) concentrated in vacuo purified by column chromatography (SiO2, Et2O:hexanes 1:1)