Dichloromethane → HCID 178502432, compound

HRID 1625494Notes

Reaction equation

HRID 1625494 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:41]1[CH:66]=[CH:65][C:44]2[NH:45][C:46]([C@@H:48]3[CH2:52][C@H:51]([CH3:53])[CH2:50][N:49]3[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[N:47][C:43]=2[CH:42]=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:41]4[CH:66]=[CH:65][C:44]5[NH:45][C:46]([C@@H:48]6[CH2:52][C@H:51]([CH3:53])[CH2:50][N:49]6[C:54](=[O:64])[C@@H:55]([NH:59][C:60]([O:61][CH3:62])=[O:63])[CH:56]([CH3:57])[CH3:58])=[N:47][C:43]=5[CH:42]=4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[N:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 516892Sodium BicarbonateHCID 178461446HCID 178461446, compoundHCID 178502434HCID 178502434, compound

Product 1

HCID 178502432HCID 178502432, compoundYield 38%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
80 °C

Procedure

To a suspension of (2S,4S)-4-methyl-2-{4-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (138 mg, 0.2606 mmol), methyl ((S)-1-((2S,4S)-2-(5-iodo-1H-benzo[d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (126.2 mg, 0.2606 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (21.3 mg, 0.02606 mmol) in 2-propanol (1.4 mL) is added 1M aqueous NaHCO3 (1.3 mL, 1.3 mmol). The reaction mixture is heated at 80° C. for 19 hours, cooled to RT, and extracted with dichloromethane (2×10 mL). The organic layer is dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (50 to 100% EtOAc in hexanes) to give (2S,4S)-2-[4-(4′-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-1H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (75 mg, 38%). HPLC: Waters symmetry shield RP18 3.5 μm 4.6 mm×50 mm, solvent A: 0.01% TFA in acetonitrile, solvent B: 0.01% TFA in water, gradient: 15:85 A:B to 90:10 A:B over 10 minutes, RT=4.87 min.

Workup

  1. temperaturecooled to RT
  2. extractionextracted with dichloromethane (2×10 mL)
  3. dry with materialThe organic layer is dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated to dryness
  6. customThe residue is purified by flash column chromatography on silica gel (50 to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-3790733f70b94eb38f48d43fcb531158
Source dataset
uspto-grants-2014_07
Patent number
US08779156B2

Reaction notes

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