Trifluoroacetic acid → 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-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

HRID 85682

Reaction equation

Br[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].C1COCC1.Cl.Cl.[NH2:22][CH2:23][CH2:24][NH:25][C@:26]12[CH2:61][CH2:60][C@@H:59]([C:62]([CH3:64])=[CH2:63])[C@@H:27]1[C@@H:28]1[C@@:41]([CH3:44])([CH2:42][CH2:43]2)[C@@:40]2([CH3:45])[C@@H:31]([C@:32]3([CH3:58])[C@@H:37]([CH2:38][CH2:39]2)[C:36]([CH3:47])([CH3:46])[C:35]([C:48]2[CH:57]=[CH:56][C:51]([C:52]([O:54]C)=[O:53])=[CH:50][CH:49]=2)=[CH:34][CH2:33]3)[CH2:30][CH2:29]1.C(O)(C(F)(F)F)=O>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:44][C@:41]12[C@@:40]3([CH3:45])[C@@H:31]([C@:32]4([CH3:58])[C@@H:37]([CH2:38][CH2:39]3)[C:36]([CH3:46])([CH3:47])[C:35]([C:48]3[CH:57]=[CH:56][C:51]([C:52]([OH:54])=[O:53])=[CH:50][CH:49]=3)=[CH:34][CH2:33]4)[CH2:30][CH2:29][C@@H:28]1[C@H:27]1[C@H:59]([C:62]([CH3:64])=[CH2:63])[CH2:60][CH2:61][C@:26]1([NH:25][CH2:24][CH2:23][NH:22][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1)[CH2:43][CH2:42]2

Participants

Conditions

Temperature: 110 °C

Procedure

In a 1 dram vial under nitrogen were combined (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (CAS#158923-11-6) (2.52 mg, 4.55 mmol), palladium(II) acetate (1.02 mg, 4.55 mmol) and dry DME (0.5 ml). The contents of the vial were stirred for 10 min, and were then added all at once to a separate mixture of 3-bromo-6-methylpyridazine (0.017 g, 0.100 mmol) and sodium tert-butoxide, 2.0M solution in THF (0.200 mL, 0.400 mmol) in dry DME (0.500 mL) contained in a separate 1 dram vial. The resulting mixture was allowed to stir very briefly (1 min) before solid methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylamino)-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 bis HCl salt (0.060 g, 0.091 mmol) was added in one portion. The mixture was heated to 110° C. overnight. Iterative purification of the crude mixture by reverse phase preparative HPLC first using Prep HPLC Method 9 and then repurification by Prep HPLC Method 10 gave the title compound (0.0070 g, 8.3% yield) as a white glassy solid bis TFA salt. LCMS: m/e 665.5 (M+H)+, 2.22 min (method 11). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 7.90 (d, J=8.5 Hz, 2H), 7.49-7.42 (m, 1H), 7.32-7.23 (m, 1H), 7.18 (d, J=8.2 Hz, 2H), 5.27 (dd, J=6.0, 1.4 Hz, 1H), 4.88 (br. s., 1H), 4.72 (br. s., 1H), 3.94-3.84 (m, 1H), 3.84-3.73 (m, 1H), 3.26-3.13 (m, 1H), 2.84 (d, J=12.5 Hz, 1H), 2.57 (s, 3H), 2.12 (dd, J=16.9, 6.3 Hz, 1H), 2.05 (d, J=15.6 Hz, 1H), 2.01-1.91 (m, 2H), 1.91-1.74 (m, 2H), 1.70 (s, 3H), 1.69-1.59 (m, 2H), 1.59-1.43 (m, 4H), 1.43-1.28 (m, 4H), 1.28-1.18 (m, 4H), 1.18-1.06 (m, 2H), 1.05 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H), 0.92 (s, 3H), 0.92-0.89 (m, 3H).

Workup

additionwere then added all at
additionwas added in one portion
customIterative purification of the crude mixture by reverse phase preparative HPLC first using Prep HPLC Method 9
customrepurification by Prep HPLC Method 10

Sources & evidence

ORD record: ord-491e9117b84342af833a22e5d171cd1a
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08846647B2

Linked notes

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