2-Methyltetrahydrofuran → HCID 178461449, compound

HRID 1504344Notes

Reaction equation

HRID 1504344 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@@H:13]3[CH2:17][C@H:16]([CH3:18])[CH2:15][N:14]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[C:28]([NH:41][C:42](=[O:62])[C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:51][C@H:50]3[CH3:61])=[N:45][CH:44]=2)=[CH:29][C:30]([O:36][C:37]([F:40])([F:39])[F:38])=[C:31](B(O)O)[CH:32]=1.C(=O)(O)[O-].[Na+].CC1CCCO1>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.O>[Cl:26][C:27]1[C:28]([NH:41][C:42](=[O:62])[C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:51][C@H:50]3[CH3:61])=[N:45][CH:44]=2)=[CH:29][C:30]([O:36][C:37]([F:40])([F:39])[F:38])=[C:31]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[C:10]([C@@H:13]4[CH2:17][C@H:16]([CH3:18])[CH2:15][N:14]4[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[NH:11][CH:12]=3)=[CH:6][CH:7]=2)[CH:32]=1

Participants

8

Reactant 4

HCID 73012-MethyltetrahydrofuranHCID 516892Sodium BicarbonateHCID 89541653HCID 89541653, compoundHCID 178461444HCID 178461444, compound

Product 1

HCID 178461449HCID 178461449, compoundYield 93%

Reagents, catalysts & solvents 3

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

To a round bottom flask was added (2S,4S)-tert-butyl 2-(4-(4-bromophenyl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (10 g, 24.61 mmol), (R)-(5-chloro-4-(6-(2-methyl-4-pivaloylpiperazin-1-yl)nicotinamido)-2-(trifluoromethoxy)phenyl)boronic acid (14.16 g, 26.1 mmol), sodium bicarbonate (7.24 g, 86 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.17 g, 0.246 mmol), 2 methyltetrahydrofuran (120 mL) and water (44.3 mL) to give a suspension. The reaction mixture was degassed with nitrogen for 10 min then heated at 70° C. overnight. Water (60 mL) was added and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, and evaporated to give crude product (27.3 g). The crude product was purified by flash chromatography (300 g silica gel, 20-100% EtOAc (50 min), then 100% EtOAc (20 min)) to give the title intermediate (18.8 g; 93% yield) HPLC Method B: Retention time 14.99 min.

Workup

  1. customto give a suspension
  2. customThe reaction mixture was degassed with nitrogen for 10 min
  3. additionWater (60 mL) was added
  4. customthe layers were separated
  5. washThe organic layer was washed with brine
  6. dry with materialdried over Na2SO4
  7. customevaporated
  8. customto give crude product (27.3 g)
  9. customThe crude product was purified by flash chromatography (300 g silica gel, 20-100% EtOAc (50 min)

Sources & evidence

ORD record
ord-d7b396af3a1e4a89bb7a53339b9d8bb1
Source dataset
uspto-grants-2015_12
Patent number
US09212168B2

Reaction notes

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