ethyl 6-bromo-2,2-dimethylhexanoate

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: To 20 ml of ethanol were added 1.37 g of p-hydroxy-6-(1-imidazolyl)hexaneanilide and 0.69 g of anhydrous potassium carbonate and the mixture was stirred for 30 minutes with heating under reflux. After cooling, 1.26 g of ethyl 6-bromo-2,2-dimethylhexanoate was added thereto and the mixture was reacted overnight with heating under reflux. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue followed by extracting with chloroform. After the chloroform layer was successively washed with a 1N aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting residue was subjected to silica gel column chromatography. The product was eluted out using a chloroform-methanol liquid mixture (50:1 in a volume ratio). The solvent was removed by distillation under reduced pressure. The resulting crystals were recrystallized from a solvent mixture of n-hexane-ethylacetate to obtain ethyl 6-[p-[6-(1-imidazolyl)hexanamido]phenoxy]-2,2-dimethylhexanoate as white crystals. with heating under reflux After cooling the mixture was reacted overnight with heating under reflux The solvent was removed from the reaction mixture by distillation under reduced pressure Water was added to the resulting residue by extracting with chloroform After the chloroform layer was successively washed with a 1N aqueous sodium hydroxide solution a saturated aqueous sodium chloride solution, it was dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure The product was eluted out The solvent was removed by distillation under reduced pressure The resulting crystals were recrystallized from a solvent mixture of n-hexane-ethylacetate

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

Procedure: p-[3-(1-Imidazolyl)propoxy]phenol and ethyl 7-bromo-2,2-dimethylheptanoate were used as starting compounds in place of p-[5-(1-imidazolyl)pentyloxy]phenol and ethyl 6-bromo-2,2-dimethylhexanoate, respectively, in EXAMPLE 30. The starting compounds were heated and treated in a manner similar to EXAMPLE 30 to give the desired product, ethyl 7-[p-[3-(1-imidazolyl)propoxy]phenoxy]-2,2-dimethylheptanoate, as an oily substance. The starting compounds were heated treated in a manner similar to EXAMPLE 30

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After 300 ml of ethanol was added to 35 g of p-[5-(1-imidazolyl)pentyloxy]phenol and 39 g of potassium carbonate, the mixture was heated at 60° C. with stirring and then cooled to room temperature. A solution of 43 g of ethyl 6-bromo-2,2-dimethylhexanoate in 50 ml of ethanol was added to the reaction mixture, and then the mixture was stirred under reflux overnight. The solvent was removed from the reaction mixture by distillation under reduced pressure and the residue was dissolved in chloroform. The solution was successively washed with a 1N aqueous sodium hydroxide solution, water, a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation over reduced pressure and the residue was subjected to silica gel column chromatography. The product was eluted out using a chloroform-methanol liquid mixture (30:1) as an eluant. The solvent was removed from the eluate by distillation. The residue was recrystallized from a mixture of ethyl acetate-n-hexane to give the desired product, ethyl 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoate. cooled to room temperature the mixture was stirred under reflux overnight The solvent was removed from the reaction mixture by distillation under reduced pressure the residue was dissolved in chloroform The solution was successively washed with a 1N aqueous sodium hydroxide solution, water a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate After drying the solvent was removed by distillation over reduced pressure The product was eluted out The solvent was removed from the eluate by distillation The residue was recrystallized from a mixture of ethyl acetate-n-hexane

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

Procedure: Using ethyl isobutyrate and 1,4-dibromobutane, the same reaction as in Reference Example 16 was conducted to produce the title compound. b.p. 62°-64° C./0.4 mmHg the same reaction as in Reference Example 16

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

Procedure: Using ethyl isobutyrate and 1,4-dibromobutane, the same reaction as in Reference Example 16 was conducted to produce the title compound. b.p. 62°-64° C./0.4 mmHg the same reaction as in Reference Example 16

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

Procedure: According to the procedure described for the synthesis of 206e (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818), 205c (500.0 g, 2.0 mol) was reacted with LiBH4 (65.0 g, 3.0 mol) and methanol (95.0 g, 3.0 mol) in CH2Cl2 (6.0 L) to afford 206c (417.0 g, 99%) as an oil. 1H NMR (CDCl3): δ 3.38 (t, 2 H, J=7.4), 3.50-3.40 (br. s, 1 H, OH), 3.22 (d, 2 H, J=5.6), 1.85 (qv, 2 H, J=7.4), 1.50-1.35 (m, 2 H), 1.30-1.20 (m, 2 H), 0.85 (s, 6 H). 13C NMR (CDCl3) δ 71.4, 37.5, 34.9, 33.9, 33.4, 23.7, 22.4.

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyllithium (1.6M, 63 ml, 0.10 mol) in hexane was added dropwise to a solution of diisopropylamine (10.1 g, 0.10 mol) in anhydrous tetrahydrofuran (100 ml) at -50° C. The mixture was stirred for 0.5 hours. The mixture was cooled to -70° C. and a solution of ethyl isobutyrate (12.2 g, 0.105 mol) in tetrahydrofuran (20 ml) was added. The resulting mixture was stirred at -70° C. for 1 hour. 1,4-Dibromobutane (30.4 g, 0.14 mol) was added to the mixture followed by hexamethylphosphoramide (30 g). The resulting mixture was maintained at -70° C. for 0.5 hours and then warmed to room temperature over 1 hour. The solvent was evaporated off under reduced pressure and the residue was treated with saturated aqueous ammonium chloride (500 ml) and extracted with ethyl acetate (2×150ml). The combined extracts were washed with water (100ml), hydrochloric acid (1N, 2×100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure and the residue was distilled to yield ethyl 2,2-dimethyl-6-bromohexanoate as a pale yellow oil, having a boiling point of 73° C., 0.06 mm.Hg and the following physical characteristics: The resulting mixture was stirred at -70° C. for 1 hour The resulting mixture was maintained at -70° C. for 0.5 hours warmed to room temperature over 1 hour The solvent was evaporated off under reduced pressure the residue was treated with saturated aqueous ammonium chloride (500 ml) extracted with ethyl acetate (2×150ml) The combined extracts were washed with water (100ml), hydrochloric acid (1N, 2×100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml) dried over anhydrous magnesium sulfate The solvent was evaporated off under reduced pressure the residue was distilled

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyllithium (1.6M, 63 ml, 0.10 mol) in hexane was added dropwise to a solution of diisopropylamine (10.1 g, 0.10 mol) in anhydrous tetrahydrofuran (100 ml) at -50° C. The mixture was stirred for 0.5 hours. The mixture was cooled to -70° C. and a solution of ethyl isobutyrate (12.2 g, 0.105 mol) in tetrahydrofuran (20 ml) was added. The resulting mixture was stirred at -70° C. for 1 hour. 1,4-Dibromobutane (30.4 g, 0.14 mol) was added to the mixture followed by hexamethylphosphoramide (30 g). The resulting mixture was maintained at -70° C. for 0.5 hours and then warmed to room temperature over 1 hour. The solvent was evaporated off under reduced pressure and the residue was treated with saturated aqueous ammonium chloride (500 ml) and extracted with ethyl acetate (2×150ml). The combined extracts were washed with water (100ml), hydrochloric acid (1N, 2×100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure and the residue was distilled to yield ethyl 2,2-dimethyl-6-bromohexanoate as a pale yellow oil, having a boiling point of 73° C., 0.06 mm.Hg and the following physical characteristics: The resulting mixture was stirred at -70° C. for 1 hour The resulting mixture was maintained at -70° C. for 0.5 hours warmed to room temperature over 1 hour The solvent was evaporated off under reduced pressure the residue was treated with saturated aqueous ammonium chloride (500 ml) extracted with ethyl acetate (2×150ml) The combined extracts were washed with water (100ml), hydrochloric acid (1N, 2×100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml) dried over anhydrous magnesium sulfate The solvent was evaporated off under reduced pressure the residue was distilled