Potassium Phosphate, Tribasic → HCID 86708781, compound

HRID 1751580Notes

Reaction equation

Br[C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:16]4[CH:17]=[CH:18][C:19]5[N:23]=[C:22]([C@@H:24]6[CH2:28][CH2:27][CH2:26][N:25]6[C:29](=[O:38])[CH:30]([NH:34][C:35](=[O:37])[O-:36])[CH:31]([CH3:33])[CH3:32])[NH:21][C:20]=5[CH:39]=4)=[CH:10][C:11]=3[CH2:12][CH2:13]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)[C:42](C)(C)O1.C([O-])(=O)C.[K+].Br[C:64]1[NH:68][C:67]([C@@H:69]2[CH2:73][CH2:72][CH2:71][N:70]2[C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])=[N:66][CH:65]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(COC)OC>[CH3:42][O:36][C:35]([NH:34][C@@H:30]([CH:31]([CH3:33])[CH3:32])[C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:24]1[C:22]1[NH:21][C:20]2[CH:39]=[C:16]([C:9]3[CH:10]=[C:11]4[C:6]([C:5]5[CH:14]=[CH:15][C:2]([C:64]6[NH:68][C:67]([C@@H:69]7[CH2:73][CH2:72][CH2:71][N:70]7[C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])=[N:66][CH:65]=6)=[CH:3][C:4]=5[CH2:13][CH2:12]4)=[CH:7][CH:8]=3)[CH:17]=[CH:18][C:19]=2[N:23]=1)=[O:38])=[O:37]

Participants

Conditions

Temperature: 100 °C

Procedure

A mixture of methyl S)-1-((S)-2-(6-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (376 mg, 0.62 mmol), bis(pinacolato)diboron (167 mg, 0.66 mmol), PdCl2(dppf) (23 mg, 0.03 mmol) and potassium acetate (184 mg, 1.9 mmol) in dioxane (3 mL) was degassed with a stream of argon for twenty minutes. The reaction was heated to 100° C. After 1 hour, the mixture was cooled to room temperature. To the reaction was added (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (296 mg, 0.94 mmol), 2M aqueous potassium phosphate solution (0.94 mL, 1.9 mmol) and dimethoxyethane (4 mL). The reaction was degassed with a stream of argon for twenty minutes. The reaction was heated in a microwave to 130° C. for twenty minutes. After cooling, more PdCl2(dppf) (23 mg, 0.03 mmol), 2M aqueous potassium phosphate solution (0.47 mL, 0.94 mmol), and (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (98 mg, 0.31 mmol) were added and the reaction was heated in a microwave to 120° C. for 140 minutes. The reaction was removed from the microwave and heated at 110° C. overnight. After 14 hours, the reaction was diluted with ethyl acetate, and the organic phase was washed with saturated aqueous NaHCO3 solution and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield (S)-tert-butyl 2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (174 mg, 37%).

Workup

customwas degassed with a stream of argon for twenty minutes
temperaturethe mixture was cooled to room temperature
customThe reaction was degassed with a stream of argon for twenty minutes
temperatureThe reaction was heated in a microwave to 130° C. for twenty minutes
temperatureAfter cooling
temperaturethe reaction was heated in a microwave to 120° C. for 140 minutes
customThe reaction was removed from the microwave
temperatureheated at 110° C. overnight
waitAfter 14 hours
additionthe reaction was diluted with ethyl acetate
washthe organic phase was washed with saturated aqueous NaHCO3 solution and brine
dry with materialdried (Na2SO4)
concentrationconcentrated
customThe crude material was purified by flash column chromatography

Sources & evidence

ORD record: ord-7d5513be903646ae9c6baa80bd8f3275
Source dataset: uspto-grants-2015_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09156823B2

Reaction notes

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