Diisopropylamine → (17beta)-3-Oxoestra-4,6-dien-17-yl acetate

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Reaction Steps

β-methoxytetralone 1 (0.254 g, 1.4 mmol in 5 ml of THF) was added to a refluxed mixture of (MeO)2CO (2.8 mmol) and sodium hydride (38 mg) in THF (20 ml). The mixture was heated at reflux during the night, cooled, water (25 ml) was added and neutralized with 5% HCL and extracted with ether. The ether was washed with a cooled satured sodium bicarbonate and water. The organic phase was dried with anhydrous MgSO4 and the solvent was removed under reduced pressure. The residue in THF (5 ml) was added to a mixture of sodium hydride (21 mg 0.85 mmol and RcI (CH3I, 8.5 mmol) in THF (15 ml) and HMPA (1.7 mmol). The mixture was stirred during the night, water (25 ml) was added and neutralized with 5% HCL and extracted with ether. The ether was washed with a cooled satured sodium bicarbonate and water. The organic phase was dried with anhydrous MgSO4 and the solvent was removed under reduced pressure and the compound 2 (Rc =CH3) was obtained in the yield of 80%. The action of MeOCOCN (0.1 ml, 10 min at -78° C.) on the compound 2 (Rc =CH3) (200 mg in 5 ml THF) in presence of LDA (lithium diisopropyl amine prepared from 0.13 ml diisopropyl amine and 1.6M butyl lithium (0.6 ml at -25° C., 30 min ) and HMPA (0.15 ml) yield in 83% the compound 3 (Rc =CH3). To this compound (290 mg) in THF (20 ml) was added 35% potassium hydride (119 mg, 0.72 mmol) 18-crown-6 (24 mg 0.06 mmol and the mixture stirred 8 h at 25° C. and then I(CH2)8OTBDMS (657 mg, 1.9 mmol) was added and the mixture heated at reflux 6 h. The extraction with ethyl acetate yield the compound 4 (n=8, Rc =CH3)(98%). The decarboalkoxylation with lithium bromide in pyridine yield the compound 5 (n=8, Rc =CH3 ) which was treated by the Grignard's reagent of 3-bromo-anisole followed by acidic treatment. The resulting compound 6 (n=8, Rc =CH3) was converted into amide 7 (n=8, Ra =CH3, Rb =C4H9, Rc =CH3) Thus a cooled solution compound 6 (n=8, Rc =CH3) (700 mg) in acetone (17 ml) was added Jones' reagent (8N-chromic acid solution, 0.77 ml). After 30 minutes, isopropanol (5 ml) was added and the mixture was poured in water and extracted three times with ethyl acetate. The organic layer was washed twice with brine, dried over magnesium sulfate and evaporated to dryness. The crude acid was used in the next step without purification. To its solution in anhydrous methylene chloride (4 ml) at -10° C. was added, under stirring, triisobutylamine (470 μl, 1.96 mmol and isobutylchloroformate (280 μl, 2.1 mmol). After 40 minutes, N-methylbutylamine (1.5 ml) was added and the mixture was stirred at room temperature during 1 hour. Methylene chloride (50 ml) was added. The organic solution was washed with 1N HCl, saturated sodium bicarbonate solution and water (3X), dried on magnesium sulfate and evaporated to dryness. The residue was purified by "Flash chromatography" on silica gel (Kieselgel 60, Merck, under 0.063 mm, 50 g). Elution with a mixture of hexane-ethyl acetate gave the amide 7 (n=8, Ra =CH3, Rb =C4H9, Rc =CH3) (63%) The removal of the protection into compound 8 (EM 736, n=7, Ra =CH3, Rb =C4H9, Rc =CH3) is performed with pyridine-HCl.

Provenance & Evidence