| 53.3% |
With ammonium chloride; iodine; magnesium; In tetrahydrofuran; water; |
Preparation of 3,3-ethylenedioxy-5alpha,17alpha,20-trihydroxy-11beta-[4-(N,N-dimethylamino)phenyl]-21-methoxy-19-norpregn-9-ene (17) A dry 250 mL 3-necked flask was equipped with a stirring bar, a reflux condenser, and two rubber septa. Magnesium (1.18 g, 48.5 mmol) was added and the entire apparatus dried further with a heat gun, under a stream of nitrogen. The apparatus was allowed to cool slightly and one crystal of iodine was added. After cooling completely, 20 mL of dry THF was added, followed by the addition of one drop of 1,2-dibromoethane. A solution of 4-bromo-N,N-dimethylaniline (8.81 g, 44.05 mmol) in THF (10 mL) was added via transfer needle and rinsed with additional THF (10 mL). The mixture was heated gently with a heat gun to reflux to initiate reaction (as evidenced by bleaching of color and consumption of magnesium) and then allowed to stir for a period of 1/2 hr at room temperature. <strong>[7758-89-6]Copper (I) chloride</strong> (480 mg, 4.85 mmol) was added as a solid and stirring was continued for a period of 1/2 hr. A solution of the epoxide (16, 3.58 g, 8.81 mmol) in THF (20 mL) was added via transfer needle and rinsed in with additional THF (10 mL). After stirring for another 2 hr. at room temperature, the reaction was quenched by the addition of saturated NH4Cl solution (70 mL). Air was drawn through the mixture for period of 1/2 hr with vigorous stirring. The resulting mixture was transferred to a separatory funnel, and water and ether were added. The organic and aqueous layers were allowed to separate. The organic fraction was washed again with water (1*) and brine (1*). The combined ether extracts (3*) were dried by filtration through sodium sulfate and evaporated in vacuo to recover 7.7 g of a dark purple oil. The oil was filtered through a short bed of silica (125 g) on a sintered glass funnel. Elution with ether (4*200 mL) removed all of the aniline by-products. The product was eluted with EtOAc (8*100 mL). The EtOAc washes were evaporated in vacuo to recover a beige foam. Trituration with pentane produced a solid. The solid was dried overnight under high vacuum to give 2.48 g of 17 as a beige powder in 53.3% yield. A small portion (250 mg) was purified by flash chromatography (5% isopropanol in methylene chloride) for analysis. Only fractions of the highest purity were combined and evaporated to recover a colorless gum. Trituration with pentane produced a solid. The sample was dried in vacuo at 80 C. to recover 56.9 mg of 17 as a white powder; m.p.=120-126 C. (softens). FTIR (KBr, diffuse reflectance): vmax 3487, 2930, 1614, 1559, 1517, 1445, 1374, 1198, and 1120 cm-1. NMR (300 MHZ, CDCl3): delta0.424 (s, 3H, C18-CH3), 2.908 (s, 6H, -N(CH3)2), 3.361 (s, 3H, C21-OCH3), 3.461 (dd, 1H, C21-CH, J1=9.76 Hz, J2=2.79 Hz), 3.527 (dd, 1H, C21-CH, J1=9.76 Hz, J2=6.45 Hz), 3.783 (dd, 1H, C20-CH, J1=6.45 Hz, J2=2.79 Hz), 3.996 (m, 4H, C3-OCH2CH2 O-), 4.210 (d, 1H, C11beta-CH, J=8.70), 6.666 (d, 2H, 3',5'-aromatic CH, J=8.70 Hz) and 7.093 (d, 2H, 2',6'-aromatic CH, J=8.70 Hz). MS (EI) m/z (relative intensity): 527 (M+, 15.1), 509 (14.6), 238 (6.2), 134 (32.4), 121 (100), and 99 (15.1). Anal. Calcd for C31H45NO6.H2O: C, 69.77; H, 8.62; N, 2.62; Found: C, 69.80; H, 8.61; N, 2.43. |
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