5-methylhexanoyl 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:; See reaction.notes.procedure_details.

Procedure: The procedure is as in example 7, but starting with 2-(7-methyl-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (3.7 g), 5-methylhexanoyl chloride (7.8 g), triethylamine (12 cc) and 4-diemthylaminopyridine (50 mg). After the solid obtained after treatment has been recrystallized in methylcyclohexane, 2-(7-methyl-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (3.8 g), m.p. 144° C., is obtained. After the solid obtained after treatment has been recrystallized in methylcyclohexane

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

Procedure: The procedure is as in Example 7, but starting with 2-(7-bromo-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (8.55 g) in methylene chloride (110 cc), triethylamine (11.1 g), 5-methylhexanoyl chloride (7 g) and 4-dimethylaminopyridine (50 mg). After the residue obtained has been crystallized in hexane and then recrystallized in ethanol, 2-(7-bromo-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (7.5 g), m.p. 136° C., is obtained. After the residue obtained has been crystallized in hexane recrystallized in ethanol

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

Procedure: The procedure is as in Example 7, but starting with 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (6.8 g) in methylene chloride (100 cc), triethylamine (10.1 g), 5-methylhexanoyl chloride (6.4 g) and 4-dimethylaminopyridine (50 mg). The residue obtained after treatment is purified by chromatography on silica gel (0.063-0.2 mm; 100 g) contained in a column 2.8 cm in diameter (eluant: methylene chloride), collecting 30-cc fractions. Fractions 19 to 94 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After the residue obtained has been recrystallized in heptane (75 cc), 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (5.6 g), m.p. 105° C., is obtained. The residue obtained after treatment is purified by chromatography on silica gel (0.063-0.2 mm; 100 g) collecting 30-cc fractions concentrated to dryness under reduced pressure (2.7 kPa) After the residue obtained has been recrystallized in heptane (75 cc)

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

Procedure: To a solution of 5-methylhexanoic acid (0.53 g, 4 mmole) in dichloromethane was added oxalyl chloride (0.77 g, 6 mmole). The reaction mixture was stirred at room temperature for 2 hours and then evaporated under vacuum to give crude 5-methylhexanoyl chloride. To a solution of 4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-5-amine-N,N-1,5-dimethyl-1H-imidazole (0.60 g, 1.76 mmole) in dichloromethane (15 mL) was added 5-methylhexanoyl chloride and pyridine (0.42 g, 5 mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (20:1 to 50:50). The crude product (0.42 g, 85%) was treated with HCl in ether and recrystallized from dichloromethane-methanol-petroleum ether to give the title compound as a white solid: mp 112°-114°; MS m/e 456 (M+ +H); 1H NMR (CDCl3 /TMS) δ 0.90(s,3H,CH3), 0.93(s,3H,CH3), 1.27(m,2H,CH2), 1.67(m,3H,CH2CH), 2.47(m,2H,CH2), 3.00(s,3H,NCH3), 3.23(s,3H,NCH3), 7.03(s,1H,CH), 7.33(m,2H,Harom), 8.00(m,2H,Harom). evaporated under vacuum

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

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

Procedure: To a solution of 5-methylhexanoic acid (0.53 g, 4 mmole) in dichloromethane was added oxalyl chloride (0.77 g, 6 mmole). The reaction mixture was stirred at room temperature for 2 hours and then evaporated under vacuum to give crude 5-methylhexanoyl chloride. To a solution of 4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-5-amine-N,N-1,5-dimethyl-1H-imidazole (0.60 g, 1.76 mmole) in dichloromethane (15 mL) was added 5-methylhexanoyl chloride and pyridine (0.42 g, 5 mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (20:1 to 50:50). The crude product (0.42 g, 85%) was treated with HCl in ether and recrystallized from dichloromethane-methanol-petroleum ether to give the title compound as a white solid: mp 112°-114°; MS m/e 456 (M+ +H); 1H NMR (CDCl3 /TMS) δ 0.90(s,3H,CH3), 0.93(s,3H,CH3), 1.27(m,2H,CH2), 1.67(m,3H,CH2CH), 2.47(m,2H,CH2), 3.00(s,3H,NCH3), 3.23(s,3H,NCH3), 7.03(s,1H,CH), 7.33(m,2H,Harom), 8.00(m,2H,Harom). evaporated under vacuum

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

Procedure: 14 ml of nitrobenzene are cooled in an ice-bath and then mixed in succession with 3.8 g of AICl3 and 3.7 g of 5-methyl-hexanoyl chloride in 5 ml of nitrobenzene. The mixture is stirred and then treated with 2.7 ml of 2-fluoro-anisole. The solution is stirred overnight, then poured into ice-water and extracted with methylene chloride. The extracts are washed with water and 10% aqueous NaCl solution, and thereafter dried and concentrated and recrystallized using pentane. 5.31 g of 1-(3-fluoro-4-methoxy-phenyl)-5-methyl-hexan-1-one, MS: m/e 238 (M+), are obtained. The solution is stirred overnight extracted with methylene chloride The extracts are washed with water and 10% aqueous NaCl solution dried concentrated recrystallized

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

Procedure: 14 ml of nitrobenzene are cooled in an ice-bath and then mixed in succession with 3.8 g of AlCl3 and 3.7 g of 5-methyl-hexanoyl chloride in 5 mi of nitrobenzene. The mixture is stirred and then treated with 2.7 ml of 2-fluoro-anisole. The solution is stirred overnight, then poured into ice-water and extracted with methylene chloride. The extracts are washed with water and 10% aqueous NaCl solution, and thereafter dried and concentrated and recrystallized using pentane. 5.31 g of 1-(3-fluoro-4-methoxy-phenyl)-5-methyl-hexan-l-one, MS: m/e 238 (M+), are obtained. The solution is stirred overnight extracted with methylene chloride The extracts are washed with water and 10% aqueous NaCl solution dried concentrated recrystallized

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

Procedure: A mixture of 5-methylhexanoic acid (25 mL, 175 mmol) and thionyl chloride (50 mL, 0.69 mol) was stirred at reflux for 90 minutes. The mixture was concentrated, then distilled at reduced pressure to give the desired product (22.35 g). at reflux for 90 minutes The mixture was concentrated distilled at reduced pressure

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

Procedure: 14 ml of nitrobenzene are cooled in an ice-bath and then mixed in succession with 3.8 g of AlCl3 and 3.7 g of 5-methyl-hexanoyl chloride in 5 ml of nitrobenzene. The mixture is stirred and then treated with 2.7 ml of 2-fluoro-anisole. The solution is stirred overnight, then poured into ice-water and extracted with methylene chloride. The extracts are washed with water and 10% aqueous NaCl solution, and thereafter dried and concentrated and recrystallized using pentane. 5.31 g of 1-(3-fluoro-4-methoxy-phenyl)-5-methyl-hexan-1-one, MS: m/e 238 (M+), are obtained. The solution is stirred overnight extracted with methylene chloride The extracts are washed with water and 10% aqueous NaCl solution dried concentrated recrystallized