Diisopropylethylamine → (1R,5S)-tert-butyl 3-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-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-3a-yl)amino)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

HRID 338644Notes

Reaction equation

[N:1]1([C@:4]23[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:36])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[C@H:43]12[CH2:56][C@H:47]([N:48]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46][NH:45][CH2:44]2.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:33][O:32][C:30]([C:29]1[CH:28]=[CH:27][C:26]([C:13]2[C:14]([CH3:24])([CH3:25])[C@H:15]3[C@:10]([CH3:36])([CH2:11][CH:12]=2)[C@@H:9]2[C@:18]([CH3:23])([C@@:19]4([CH3:22])[C@H:6]([CH2:7][CH2:8]2)[C@H:5]2[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:4]2([NH:1][CH2:2][CH2:3][N:45]2[CH2:44][C@@H:43]5[CH2:56][C@@H:47]([N:48]5[C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:46]2)[CH2:21][CH2:20]4)[CH2:17][CH2:16]3)=[CH:35][CH:34]=1)=[O:31]

Participants

Conditions

Temperature: 100 °C

Procedure

Methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,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 (250 mg, 0.439 mmol) and (1R,5S)-tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (435 mg, 2.194 mmol) were combined in a 20 mL scintillation vial, dissolved in THF (5 mL) and treated with N,N-di-iso-propylethylamine (0.764 mL, 4.39 mmol). The reaction mixture was heated to 100° C. After 112 h, the reaction mixture was cooled to rt, purified by reverse phase HPLC using prep-HPLC method 13 and dried under vacuum to give the title compound (126.6 mg, 0.127 mmol, 29.0% yield) as a white solid. LC/MS: m/e 768.5 (M+H)+, 2.41 min (method 7). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (d, J=8.6 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 5.30 (d, J=4.4 Hz, 1H), 4.79 (s, 1H), 4.70 (s, 1H), 4.17 (d, J=5.9 Hz, 2H), 3.92 (s, 3H), 3.62 (d, J=11.7 Hz, 1H), 3.56-3.44 (m, 3H), 3.43-3.31 (m, 5H), 2.85-2.72 (m, 1H), 2.66-2.56 (m, 1H), 2.12 (dd, J=17.0, 6.5 Hz, 2H), 2.07-1.89 (m, 5H), 1.75 (d, J=11.5 Hz, 1H), 1.70 (s, 3H), 1.65 (br. s., 1H), 1.60-1.50 (m, 5H), 1.48 (s, 9H), 1.46-1.34 (m, 5H), 1.26-1.19 (m, 1H), 1.13 (s, 3H), 1.05 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.94 (br. s., 3H). 13C NMR (101 MHz, CHLOROFORM-d) δ 167.2, 154.9, 148.6, 146.9, 146.3, 130.0, 128.5, 128.0, 123.9, 111.8, 81.7, 77.2, 72.4, 58.3, 53.9, 52.8, 52.0, 49.4, 49.0, 45.3, 42.1, 41.8, 40.7, 37.9, 37.5, 37.2, 36.2, 33.5, 32.6, 29.4, 28.3, 28.3, 27.8, 26.3, 25.4, 25.1, 21.0, 20.9, 19.6, 19.1, 16.5, 15.8, 14.6.

Workup

temperaturethe reaction mixture was cooled to rt
custompurified by reverse phase
customdried under vacuum

Sources & evidence

ORD record: ord-2649a072931740b39af7d628b8302923
Source dataset: uspto-grants-2014_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08889854B2

Reaction notes

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