HCID 57488517, compound → 1H-Indole-1-ethanol, 5-aMino-2-[1,1-diMethyl-2-(phenylMethoxy)ethyl]-6-fluoro-α-[(phenylMethoxy)Methyl]-, (αR)-

HRID 575997Notes

Reaction equation

HRID 575997 reaction equation
[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][CH2:10][C@@H:11]([OH:21])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([C:22]#[C:23][C:24]([CH3:35])([CH3:34])[CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1>C(#N)C.[Cu]I>[NH2:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[N:9]([CH2:10][C@@H:11]([OH:21])[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:23]([C:24]([CH3:35])([CH3:34])[CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:22]2

Participants

4

Reactant 1

HCID 57488517HCID 57488517, compound

Product 1

HCID 545757771H-Indole-1-ethanol, 5-aMino-2-[1,1-diMethyl-2-(phenylMethoxy)ethyl]-6-fluoro-α-[(phenylMethoxy)Methyl]-, (αR)-Yield 27%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

Bis-acetonitriledichloropalladium (0.1 eq) and CuI (0.1 eq) are charged to the reactor and then suspended in a solution of (R)-1-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol obtained above (1 eq) in acetonitrile (9.5 vol total). The mixture is sparged with nitrogen gas for 1 h and then is heated to 80° C. The reaction progress is monitored by HPLC and the reaction is typically complete within 1-3 h. The mixture is filtered through Celite and the cake is washed with acetonitrile. A solvent swap into ethyl acetate (7.5 vol) is performed. The ethyl acetate solution is washed with aqueous NH3—NH4Cl solution (2×2.5 vol) followed by 10% brine (2.5 vol). The ethyl acetate solution is then stirred with silica gel (1.8 wt eq) and Si-TMT (0.1 wt eq) for 6 h. After filtration, the resulting solution is concentrated down. The residual oil is dissolved in DCM/heptane (4 vol) and then purified by column chromatography. The oil thus obtained is then crystallized from 25% EtOAc/heptane (4 vol). Crystalline (R)-1-(5-amino-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-1-yl)-3-(benzyloxy)propan-2-ol is typically obtained in 27-38% yield. 1H NMR (400 MHz, DMSO) δ 7.38-7.34 (m, 4 H), 7.32-7.23 (m, 6 H), 7.21 (d, 1 H, J=12.8 Hz), 6.77 (d, 1H, J=9.0 Hz), 6.06 (s, 1 H), 5.13 (d, 1H, J=4.9 Hz), 4.54 (s, 2H), 4.46 (br. s, 2 H), 4.45 (s, 2 H), 4.33 (d, 1 H, J=12.4 Hz), 4.09-4.04 (m, 2 H), 3.63 (d, 1H, J=9.2 Hz), 3.56 (d, 1H, J=9.2 Hz), 3.49 (dd, 1H, J=9.8, 4.4 Hz), 3.43 (dd, 1H, J=9.8, 5.7 Hz), 1.40 (s, 6 H).

Workup

  1. customThe mixture is sparged with nitrogen gas for 1 h
  2. filtrationThe mixture is filtered through Celite
  3. washthe cake is washed with acetonitrile
  4. washThe ethyl acetate solution is washed with aqueous NH3—NH4Cl solution (2×2.5 vol)
  5. filtrationAfter filtration
  6. concentrationthe resulting solution is concentrated down
  7. dissolutionThe residual oil is dissolved in DCM/heptane (4 vol)
  8. custompurified by column chromatography
  9. customThe oil thus obtained
  10. customis then crystallized from 25% EtOAc/heptane (4 vol)

Sources & evidence

ORD record
ord-1677191a7ced4a7bb57268d844fac59d
Source dataset
uspto-grants-2015_05
Patent number
US09035072B2

Reaction notes

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