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Triethylamine → N-(2-tert-butyl-4-cyano-1-(2-hydroxyethyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

HRID 1847910
Notes
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Reaction equation

HRID 1847910 reaction equation
[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:25]2[N:24]([CH2:28][CH2:29][OH:30])[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:22][C:21]=2[C:20]=1[C:35]#[N:36].C(N(CC)CC)C>ClCCl>[C:31]([C:23]1[N:24]([CH2:28][CH2:29][OH:30])[C:25]2[C:21]([CH:22]=1)=[C:20]([C:35]#[N:36])[C:19]([NH:18][C:14]([C:11]1([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]1)=[O:15])=[CH:27][CH:26]=2)([CH3:34])([CH3:32])[CH3:33]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 575168501-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl chlorideHCID 581832225-amino-2-tert-butyl-1-(2-hydroxyethyl)-1H-indole-4-carbonitrile

Product 1

HCID 46199645N-(2-tert-butyl-4-cyano-1-(2-hydroxyethyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

Reagents, catalysts & solvents 1

HCID 6344
Dichloromethane
Solvent
2×

Procedure

1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (196 mg, 0.75 mmol) was added to a solution of 5-amino-2-tert-butyl-1-(2-hydroxyethyl)-1H-indole-4-carbonitrile (150 mg, 0.58 mmol) and triethylamine (242 μL, 1.74 mmol) in dichloromethane (2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with 1N HCl solution (×2), saturated NaHCO3 solution (×2), brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield the product, N-(2-tert-butyl-4-cyano-1-(2-hydroxyethyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 481.2. found 482.5 (M+1)+. Retention time 1.99 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.28 (s, 1H), 5.05 (t, J=5.6 Hz, 1H), 4.42 (t, J=6.8 Hz, 2H), 3.70-3.65 (m, 2H), 1.51-1.48 (m, 2H), 1.44 (s, 9H), 1.19-1.16 (m, 2H).

Workup

  1. extractionextracted with 1N HCl solution (×2), saturated NaHCO3 solution (×2), brine
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. dissolutionThe residue was dissolved in DMSO
  6. custompurified by reverse-phase HPLC

Sources & evidence

ORD record
ord-9672812fdaa4447aaab00a77ad9f6fcb
Source dataset
uspto-grants-2015_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08952049B2

Reaction notes

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