1,8-Diazabicyclo(5.4.0)undec-7-ene → (R)-4-chloro-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-5-carbonitrile

HRID 1851123Notes

Reaction equation

HRID 1851123 reaction equation
[NH2:1][C@H:2]([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].Cl.N[C@@H](C)C(OC)=O.[Cl:16][C:17]1[C:24]([C:25]#[C:26][Si](C)(C)C)=[C:23](F)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20].C1CCN2C(=NCCC2)CC1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:16][C:17]1[C:18]([C:19]#[N:20])=[CH:21][CH:22]=[C:23]2[C:24]=1[CH:25]=[CH:26][N:1]2[C@@H:2]([C:3]([OH:5])([CH3:6])[CH3:4])[CH3:7]

Participants

7

Reactant 5

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 516892Sodium BicarbonateHCID 2733257Alanine methyl ester hydrochlorideHCID 10725304(R)-3-Amino-2-methylbutan-2-olHCID 86709177HCID 86709177, compound

Product 1

HCID 86709179(R)-4-chloro-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-5-carbonitrileYield 7%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
140 °C

Procedure

To a solution of (R)-3-amino-2-methylbutan-2-ol (made in a manner similar to Example 21G using commercially available (S)-methyl 2-aminopropanoate, hydrochloride) (0.1084 g, 1.051 mmol) and 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.212 g, 0.841 mmol) in anhyd NMP (4 mL) at rt was added DBU (0.475 mL, 3.15 mmol), dropwise via syringe. The reaction vial was sealed with a crimp top and subjected to microwave heating (140° C.) for 40 min. Upon cooling the mixture was poured into satd NaHCO3 and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (C18 stationary phase, MeCN/water gradient with 0.1% TFA additive) affording (R)-4-chloro-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-5-carbonitrile (0.0188 g, 7% yield) as a tan film: 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=3.4 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 6.74 (d, J=3.3 Hz, 1H), 4.41 (q, J=7.0 Hz, 1H), 1.60 (d, J=7.0 Hz, 3H), 1.33 (s, 3H), 1.10 (s, 3H); MS (LCMS ES+) m/z 263 ([M+H]+, 52%), 304 ({[M+H]+MeCN}+, 100%).

Workup

  1. customat rt
  2. customThe reaction
  3. customvial was sealed with a crimp top
  4. temperatureUpon cooling the mixture
  5. extractionextracted with EtOAc (×3)
  6. washCombined organics were washed (water, brine)
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by preparative HPLC (C18 stationary phase, MeCN/water gradient with 0.1% TFA additive)

Sources & evidence

ORD record
ord-c0508e1290974f3dba559d45188212ff
Source dataset
uspto-grants-2015_02
Patent number
US08957104B2

Reaction notes

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