Water → HCID 49868881, compound

HRID 1625501Notes

Reaction equation

HRID 1625501 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([C@@H:19]4[CH2:23][CH2:22][CH2:21][N:20]4[C:24](=[O:34])[C@@H:25]([NH:29][C:30](=O)[O:31]C)[CH:26]([CH3:28])[CH3:27])[NH:17][CH:18]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:35][CH:36]([CH3:68])[C@H:37]([NH:63][C:64](=[O:67])[O:65][CH3:66])[C:38](=[O:62])[N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C:44]1[NH:45][C:46]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][C:47]=2[N:48]=1.[CH2:69](Cl)Cl.C([O-])(O)=O.[Na+].[OH2:77]>C(#N)C>[CH3:69][O:77][C:30](=[O:31])[NH:29][C@H:25]([C:24]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[C:16]1[NH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:50]4[CH:51]=[CH:52][C:46]5[N:45]=[C:44]([C@@H:40]6[CH2:41][CH2:42][CH2:43][N:39]6[C:38](=[O:62])[C@@H:37]([NH:63][C:64]([O:65][CH3:66])=[O:67])[CH:36]([CH3:68])[CH3:35])[NH:48][C:47]=5[CH:49]=4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)=[CH:18][N:17]=1)=[O:34])[CH:26]([CH3:27])[CH3:28]

Participants

7

Reactant 5

HCID 962WaterHCID 6344DichloromethaneHCID 516892Sodium BicarbonateHCID 178502306HCID 178502306, compoundHCID 178502358HCID 178502358, compound

Product 1

HCID 49868881HCID 49868881, compoundYield 19%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
130 °C

Procedure

To a suspension of methyl ((S)-1-((S)-2-(4-(4′-bromo-[1,1′-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (99.6 mg, 0.1896 mmol), methyl ((S)-3-methyl-1-oxo-1-((S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-yl)carbamate and Pd(DPPF)(Cl)2. CH2Cl2 (15.48 mg, 0.01896 mmol) in acetonitrile (2 mL) is added aqueous 1M NaHCO3 (0.284 mL, 0.569 mmol). The reaction mixture is heated in a microwave oven at 130° C. for 10 minutes, cooled to rt, and diluted with water (10 mL). The reaction mixture is extracted by CH2Cl2 (5×10 mL), and the combined organic layers are dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (2 to 20% methanol in CH2Cl2) and is further purified by reverse phase preparative HPLC to give ((S)-1-[(S)-2-[5-(4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-benzoimidazol-5-yl]-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (30 mg, 19%).

Workup

  1. temperaturecooled to rt
  2. extractionThe reaction mixture is extracted by CH2Cl2 (5×10 mL)
  3. dry with materialthe combined organic layers are dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated to dryness
  6. customThe residue is purified by flash column chromatography on silica gel (2 to 20% methanol in CH2Cl2)
  7. customis further purified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-16f2b599eea949a0ada6e09ff788fd93
Source dataset
uspto-grants-2014_07
Patent number
US08779156B2

Reaction notes

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