ethyl 5-bromo-2,2-dimethylpentanoate

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: In 50 ml of ethanol was suspended 3 g of 4'-hydroxy-6-(1-imidazolyl)hexaneanilide hydrochloride. While stirring 2.8 g of anhydrous potassium carbonate and 2.4 g of ethyl 5-bromo-2,2-dimethylpentanoate were added to the suspension. The mixture was stirred for 8 hours under reflux. The solvent was removed from the reaction mixture by distillation under reduced pressure and the residue was dissolved in ethylene chloride. The solution was successively washed with a 5% aqueous hydrogen sodium carbonate solution, water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation under reduced pressure. The resulting crystals were recrystallized from ethyl acetate to give the aimed product, ethyl 5-[p-[6-(1-imidazolyl)hexanamido]phenoxy]-2,2-dimethylpentanoate. were added to the suspension under reflux The solvent was removed from the reaction mixture by distillation under reduced pressure the residue was dissolved in ethylene chloride The solution was successively washed with a 5% aqueous hydrogen sodium carbonate solution, water a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate After drying the solvent was removed by distillation under reduced pressure The resulting crystals were recrystallized from ethyl acetate

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

Procedure: A mixture of 30 g of p-hydroxyacetophenone and 30 g of potassium carbonate was stirred in 500 ml of ethanol at 60° C. for 30 minutes. After cooling to room temperature, 52 g of ethyl 5-bromo-2,2-dimethylpentanoate was added to the reaction mixture. The resulting mixture was heated under reflux overnight while stirring. The solvent was removed from the reaction mixture by distillation and, 500 ml of chloroform and 300 ml of a 5% aqueous hydrogen sodium carbonate solution were added to the residue. After stirring the mixture, the chloroform layer was fractionated and washed successively with water and then with a saturated aqueous sodium chloride solution followed by drying over anhydrous sodium sulfate. Removal of chloroform by distillation gave a residual oily substance. The oily substance was subjected to silica gel column chromatography and eluted using chloroform as an eluant to give 42 g of ethyl p-acetylphenoxy-2,2-dimethylpentanoate as an oily substance. The thus obtained oily substance was dissolved in 1.6 l. of anhydrous methylene chloride and 24 g of bromine was dropwise added to the solution under ice cooling while stirring to allow to react for 3 hours. To the reaction mixture was added 1 liter of ice water. After thoroughly stirring, the organic layer was successively washed with water and with a saturated aqueous sodium chloride solution followed by drying over anhydrous sodium sulfate. Removal of methylene chloride by distillation gave the desired product, ethyl 5-[p-(bromoacetyl)phenoxy]-2,2-dimethylpentanoate, as an oily substance. The resulting mixture was heated under reflux overnight The solvent was removed from the reaction mixture by distillation and, 500 ml of chloroform and 300 ml of a 5% aqueous hydrogen sodium carbonate solution were added to the residue After stirring the mixture washed successively with water by drying over anhydrous sodium sulfate Removal of chloroform by distillation gave a residual oily substance eluted

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 28.7 ml of diisopropylamine in 150 ml of tetrahydrofuran was added 126 ml of 1.6M n-butyllithium-hexane with stirring at -5° to 0° C. and the mixture was further stirred for 30 minutes. This reaction mixture was cooled to -78° C. and 26.7 ml of ethyl isobutyrate was added dropwise. The mixture was stirred for 1 hour, after which 41.8 g of 1,3-dibromopropane was added dropwise. The reaction mixture was stirred at -78° C. for 1 hour and then at room temperature for 2 hours. The mixture was then poured in aqueous solution of ammonium chloride and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was then distilled off and the residue was subjected to vacuum distillation to provide 40.3 g of the title compound as colorless oil. b.p. 76°-78° C./0.27 mmHg the mixture was further stirred for 30 minutes The mixture was stirred for 1 hour The reaction mixture was stirred at -78° C. for 1 hour extracted with ethyl acetate The extract was washed with water dried The solvent was then distilled off the residue was subjected to vacuum distillation

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 28.7 ml of diisopropylamine in 150 ml of tetrahydrofuran was added 126 ml of 1.6M n-butyllithium-hexane with stirring at -5° to 0° C. and the mixture was further stirred for 30 minutes. This reaction mixture was cooled to -78° C. and 26.7 ml of ethyl isobutyrate was added dropwise. The mixture was stirred for 1 hour, after which 41.8 g of 1,3-dibromopropane was added dropwise. The reaction mixture was stirred at -78° C. for 1 hour and then at room temperature for 2 hours. The mixture was then poured in aqueous solution of ammonium chloride and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was then distilled off and the residue was subjected to vacuum distillation to provide 40.3 g of the title compound as colorless oil. b.p. 76°-78° C./0.27 mmHg the mixture was further stirred for 30 minutes The mixture was stirred for 1 hour The reaction mixture was stirred at -78° C. for 1 hour extracted with ethyl acetate The extract was washed with water dried The solvent was then distilled off the residue was subjected to vacuum distillation

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

Procedure: According to the procedure given for the synthesis of 206e, 205a (94.0 g, 0.37 mol) was reduced with LiBH4 (12.97 g, 0.60 mol) and methanol (19.04 g, 0.60 mol) in CH2Cl2 (400 mL) to give 206a (78.0 g, 100%) as an oil. 1H NMR (DMSO-d6); δ 4.42 (s, 1 H), 3.45 (t, 2 H, J=6.6), 3.08 (s, 2 H), 1.84-1.69 (m, 2 H), 1.27 (t, 2 H, J=8.3), 0.78 (s, 6 H). 13C NMR (DMSO-d6); δ 69.7, 35.7, 34.5, 27.4, 24.0.

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

Procedure: 5 g of diethyl malonate was dissolved in 30 ml of N,N-dimethylformamide and 1.550 g of sodium hydride (60% oily) was added thereto under ice-cooling. Next, 7.04 g of ethyl 2,2-dimethyl-5-bromopentanoate was added to the reaction mixture and the resulting mixture was stirred at 80° C. for 2 hours. After ice-cooling the reaction mixture again, 1.550 g of sodium hydride (60% oily) was added thereto. After stirring for 25 minutes, 7.4 g of 2-chloro-5-nitropyridine was added and the resulting mixture was stirred at 80° C. for 1.5 hours. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of sodium chloride and repeatedly extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 9.71 g of the title compound as a yellow oily substance. under ice-cooling After ice-cooling the reaction mixture again After stirring for 25 minutes the resulting mixture was stirred at 80° C. for 1.5 hours After the completion of the reaction repeatedly extracted with ethyl acetate The extracts were dried over anhydrous sodium sulfate filtered The filtrate was distilled under reduced pressure the obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane)

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

Procedure: According to the procedure given for the synthesis of 206e, 205a (94.0 g, 0.37 mol) was reduced with LiBH4 (12.97 g, 0.60 mol) and methanol (19.04 g, 0.60 mol) in CH2Cl2 (400 mL) to give 206a (78.0 g, 100%) as an oil. 1H NMR (DMSO-d6): δ 4.42 (s, 1H), 3.45 (t, 2H, J=6.6), 3.08 (s, 2H), 1.84-1.69 (m, 2H), 1.27 (t, 2H, J=8.3), 0.78 (s, 6H). 13C NMR (DMSO-d6): δ 69.7, 36.9, 35.7, 34.5, 27.4, 24.0.

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

Procedure: According to the procedure given for the synthesis of 206e, 205a (94.0 g, 0.37 mol) was reduced with LiBH4 (12.97 g, 0.60 mol) and methanol (19.04 g, 0.60 mol) in CH2Cl2 (400 mL) to give 206a (78.0 g, 100%) as an oil. 1H NMR (DMSO-d6): δ 4.42 (s, 1H), 3.45 (t, 2H, J=6.6), 3.08 (s, 2H), 1.84-1.69 (m, 2H), 1.27 (t, 2H, J=8.3), 0.78 (s, 6H). 13C NMR (DMSO-d6): δ 69.7, 36.9, 35.7, 34.5, 27.4, 24.0.