Potassium Carbonate → HCID 178496634, compound

HRID 1504346Notes

Reaction equation

HRID 1504346 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[C:29]([NH:42][C:43](=[O:63])[C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54][N:53]([C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:52][C@H:51]3[CH3:62])=[N:46][CH:45]=2)=[CH:30][C:31]([O:37][C:38]([F:41])([F:40])[F:39])=[C:32](B(O)O)[CH:33]=1.C(=O)([O-])[O-:65].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:32]3[CH:33]=[C:28]([Cl:27])[C:29]([NH:42][C:43]([C:44]4[CH:45]=[N:46][C:47]([N:50]5[CH2:55][CH2:54][N:53]([C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH2:58][OH:65])[CH2:52][C@H:51]5[CH3:62])=[CH:48][CH:49]=4)=[O:63])=[CH:30][C:31]=3[O:37][C:38]([F:41])([F:40])[F:39])=[CH:22][CH:21]=2)[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 89541653HCID 89541653, compoundHCID 178496633HCID 178496633, compound

Product 1

HCID 178496634HCID 178496634, compoundYield 41.6%

Reagents, catalysts & solvents 2

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
65 °C

Procedure

To a round bottom flask was added (2S,4S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g, 11.8 mmol) and (R)-5-chloro-4-(6-(2-methyl-4-pivaloylpiperazin-1-yl)nicotinamido)-2-(trifluoromethoxy)phenylboronic acid (6.75 g, 12.4 mmol; Preparation 44), potassium carbonate (5.73 g, 41.4 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium(II) (0.092 g, 0.130 mmol), followed by degassed tetrahydrofuran (50 mL) and water (1.28 mL). The reaction mixture was degassed with nitrogen for 5 min then heated at 65° C. for 4 h, and cooled to RT. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (200 mL). The organic layer was washed with NaOH (2×100 mL), water (2×200 mL) and brine, dried over Na2SO4 and evaporated to give crude product (12.25 g). The crude product was purified by flash chromatography (150 g silica gel, 50-100% EtOAc (10 min), then 100% EtOAc (30 min)) to give the title intermediate (4.2 g; 41% yield) HPLC Method B: Retention time 15.29 min.

Workup

  1. customby degassed tetrahydrofuran (50 mL) and water (1.28 mL)
  2. customThe reaction mixture was degassed with nitrogen for 5 min
  3. temperaturecooled to RT
  4. additionWater (100 mL) was added
  5. extractionthe reaction mixture was extracted with EtOAc (200 mL)
  6. washThe organic layer was washed with NaOH (2×100 mL), water (2×200 mL) and brine
  7. dry with materialdried over Na2SO4
  8. customevaporated
  9. customto give crude product (12.25 g)
  10. customThe crude product was purified by flash chromatography (150 g silica gel, 50-100% EtOAc (10 min)

Sources & evidence

ORD record
ord-7617e83e7b7e4d7ba96f5e594ceccaca
Source dataset
uspto-grants-2015_12
Patent number
US09212168B2

Reaction notes

Loading…