反应详情

Preparation of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate. To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.160 g, 0.276 mmol) in a mixture of acetonitrile (25 mL) and dichloroethane (5 mL) was added anhydrous potassium phosphate (0.25 gm, 1.18 mmol). The resulting suspension was heated to 120° C. under nitrogen in a thick-walled tube for 24 hours. The cooled reaction suspension was filtered through a short bed of silica gel (Type-H), washed with ethyl acetate (60 mL). The clear filtrate was concentrated in vacuo to give a white solid (0.150 g, 96%). LCMS: m/e 570.5 (M+H)+, 3.32 min (method 12, but modified to gradient over 3 minutes). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.95 (d, J=8.3 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 5.31 (dd, J=6.1, 1.6 Hz, 1H), 4.81-4.73 (m, 1H), 4.67-4.59 (m, 1H), 3.93 (s, 3H), 2.82-2.45 (m, 1H), 2.19-2.04 (m, 1H), 1.88-1.74 (m, 1H), 1.71 (s, 3H), 1.68 (br. s., 1H), 1.63-1.21 (m, 7H), 1.11 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.95 (s, 6H). Step 2. To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.150 g, 0.264 mmol) in a mixture of methanol (2 mL) and THF (6 mL) at rt was added a stock solution of lithium hydroxide (1.0 Molar, 2 mL, 2.0 mmol) forming a thick suspension. The mixture was kept at 50° C. under nitrogen for 60 hours. The reaction mixture was neutralized with HCl (0.5 Molar, 10 mL), the organic material was extracted into ethyl acetate (30 mL). While the 2-phase mixture was stirred at rt, a white precipitate slowly separated out. It was filtered to give 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid as a white solid (99 mg, 68%). LCMS: m/e 592.5 (M+MeOH+Na)+, 3.03 min (method 12, but modified to gradient over 3 minutes). Selected 1H NMR (400 MHz, CHLOROFORM-d) δ 8.01 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 5.28 (m, 1H), 4.94 (br. s, 1H), 4.73 (br. s, 1H), 1.74 (s, 3H), 1.20 (s, 3H), 1.09 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H).

1. customm/e 570.5 (M+H)+, 3.32 min (method 12, but modified to gradient over 3 minutes)
2. customforming a thick suspension
3. extractionthe organic material was extracted into ethyl acetate (30 mL)
4. customa white precipitate slowly separated out
5. filtrationIt was filtered