(1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-14-(acetyloxy)-15-[[(2R)-2,3-dimethyl-2-(methylamino)butyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-6-oxo-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid → (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2,3-dimethyl-2-(methylamino)butyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-[[(1-methylethyl)amino]carbonyl]-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-6-oxo-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid

HRID 1931549Notes

Reaction equation

[CH3:1][CH:2]([NH:4][C:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])[CH3:3].C(O[C@@H:16]1[CH2:48][C@:20]23[C:24]4[C@H:33]([CH2:34][CH2:35][C@H:19]2[C@@:18]([CH3:49])([CH2:23][O:22][CH2:21]3)[C@H:17]1[O:50][CH2:51][C@:52]([CH3:58])([NH:56][CH3:57])[CH:53]([CH3:55])[CH3:54])[C@:32]1([CH3:36])[C@:27]([CH3:46])([C@H:28]([C:43]([OH:45])=[O:44])[C@:29]([C@H:38]([CH3:42])[CH:39]([CH3:41])[CH3:40])([CH3:37])[CH2:30][CH2:31]1)[C:26](=[O:47])[CH:25]=4)(=O)C>ClCCCl>[CH3:58][C@@:52]([NH:56][CH3:57])([CH:53]([CH3:55])[CH3:54])[CH2:51][O:50][C@@H:17]1[C@@:18]2([CH3:49])[C@@H:19]3[CH2:35][CH2:34][C@H:33]4[C:24]([C@@:20]3([CH2:21][O:22][CH2:23]2)[CH2:48][C@H:16]1[N:8]1[C:7]([C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6])=[N:11][CH:10]=[N:9]1)=[CH:25][C:26](=[O:47])[C@:27]1([CH3:46])[C@:32]4([CH3:36])[CH2:31][CH2:30][C@@:29]([C@H:38]([CH3:42])[CH:39]([CH3:40])[CH3:41])([CH3:37])[C@H:28]1[C:43]([OH:45])=[O:44]

Participants

Conditions

Temperature: 50 °C

Procedure

N-(1-methylethyl)-1H-1,2,4-triazole-3-carboxamide (82.3 mg, 0.534 mmol) and BF3OEt2 (200 μl, 1.578 mmol) were added to a stirred solution of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-14-(acetyloxy)-15-[[(2R)-2,3-dimethyl-2-(methylamino)butyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-6-oxo-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (free base form of Example 152 in WO2007127012, herein incorporated by reference in its entirety, 70.2 mg, 0.107 mmol) in 1,2-dichloroethane (1.5 ml). The reaction mixture was a light amber solution that was heated to 50° C. After 50 hours, the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the resulting residue was placed under high vacuum. The residue was dissolved in methanol and purified using two HPLC runs (˜35 mg/run) on a 19×150 mm Sunfire Prep C18 OBD 10 μm column by eluting with acetonitrile/water+0.1% TFA. The total flow rate was 15 ml/min and the HPLC method employed a 12 minute 20%-100% acetonitrile/water gradient followed by a 7 minute acetonitrile flush. The product HPLC fractions were combined, the solvent was evaporated under reduced pressure, and the residue was lyophilized from ethanol and benzene to give the title compound (24.2 mg, 0.028 mmol) as a white solid.

Workup

temperaturethe reaction mixture was cooled to room temperature
customthe solvent was evaporated under reduced pressure
dissolutionThe residue was dissolved in methanol
custompurified
washby eluting with acetonitrile/water+0.1% TFA
waitThe total flow rate was 15 ml/min and the HPLC method employed a 12 minute
wait20%-100% acetonitrile/water gradient followed by a 7 minute
customacetonitrile flush
customthe solvent was evaporated under reduced pressure

Sources & evidence

ORD record: ord-60d1655f88fc4d0dbde5ffa79f6099ad
Source dataset: uspto-grants-2012_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08188085B2

Reaction notes

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