Aniline → HCID 67959593, compound

HRID 1529390Notes

Reaction equation

HRID 1529390 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[N:29]=[C:28]([O:30][C@H:31]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:32]32[CH2:34][CH2:33]3)[CH:27]=[N:26][CH:25]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(OC(C)C)=CC(OC(C)C)=CC=2OC(C)C)CCCCC1>[C:2]1([NH:1][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=[C:12]3[C:24]2[N:29]=[C:28]([O:30][C@H:31]3[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:32]43[CH2:34][CH2:33]4)[CH:27]=[N:26][CH:25]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 6115AnilineHCID 2733832Lithium HexamethyldisilazideHCID 67959732HCID 67959732, compound

Product 1

HCID 67959593HCID 67959593, compoundYield 59.8%

Reagents, catalysts & solvents 2

HCID 67958338HCID 67958338, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
70 °C

Procedure

Aniline (0.019 ml, 0.205 mmol), dicyclohexyl(2′,4′,6′-triisopropoxy-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (brettphos) (5.00 mg, 8.55 μmol), brettphosprecatalyst (7.24 mg, 8.55 μmol), and (4R)-tert-butyl 4-((6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (0.100 g, 0.171 mmol) were combined in 0.37 mL THF under argon. Lithium bis(trimethylsilyl)amide, 1.0 m solution in THF (0.376 ml, 0.376 mmol) was added. The dark red solution was sealed and heated in a 70° C. bath for 5 h. The reaction was cooled partitioned between saturated aqueous NH4Cl and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25 g column) using 0-30% EtOAc/hexane. The product-containing fractions were combined and concentrated to give (4R)-tert-butyl 4-((6-(5-(phenylamino)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (0.061 g, 0.102 mmol, 59.8% yield) as a sticky brown oil. MS (ESI, pos. ion) m/z: 597 (M+1).

Workup

  1. customThe dark red solution was sealed
  2. temperatureThe reaction was cooled
  3. custompartitioned between saturated aqueous NH4Cl and DCM
  4. extractionThe aqueous layer was extracted with DCM 3 times
  5. dry with materialthe combined organics were dried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. additionThe material was treated with DCM
  9. custompurified by silica gel chromatography (25 g column)
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-3e2f29e4ac6f4dc29a47af6dbf2a2150
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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