Ammonium → (R)-5-(4,5-Dihydro-1H-imidazol-2-yl)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 525738Notes

Reaction equation

HRID 525738 reaction equation
[C:1]([C:3]1[C:4]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:5][CH:6]=[C:7]([CH:22]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)=[O:9])#[N:2].OS([O-])=O.[Na+].[CH2:34](N)[CH2:35][NH2:36].[NH4+]>CCOC(C)=O>[NH:2]1[CH2:34][CH2:35][N:36]=[C:1]1[C:3]1[C:4]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:5][CH:6]=[C:7]([CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=1)=[O:9]

Participants

6

Reactant 4

HCID 223AmmoniumHCID 3301EthylenediamineHCID 23665763Sodium BisulfiteHCID 89907102(R)-5-cyano-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 89907994(R)-5-(4,5-Dihydro-1H-imidazol-2-yl)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A stirred mixture of (R)-5-cyano-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 70.2, 1 g, 2.55 mmol), NaHSO3 (0.953 g, 15.3 mmol) and ethylenediamine (7.66 g, 1.27 mmol) was treated dropwise with 40% aq. ammonium silfide (4.34 mL, 25.5 mmol) and heated at 100° C. for 18 h. The cooled mixture was treated with EtOAc, washed with sat. aq. NaHCO3 and brine, was dried over anhydrous Na2SO4 and the solvent was evaporated off under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/(5% aq. NH3 in MeOH) from 0 to 40% (5% aq. NH3 in MeOH)) to afford the product as a pale-yellow solid. HPLC (Condition 4) tR=3.89 min, UPLC-MS (Condition 8) tR=0.72 min, m/z=436.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.98 (m, 3H) 3.40-3.75 (m, 8H) 4.30 (br. s, 1H) 4.91 (br. s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.78-7.91 (m, 2H) 8.06 (d, J=2.35 Hz, 1H) 8.71 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).

Workup

  1. washwashed with sat. aq. NaHCO3 and brine
  2. dry with materialwas dried over anhydrous Na2SO4
  3. customthe solvent was evaporated off under reduced pressure
  4. customThe crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/(5% aq. NH3 in MeOH) from 0 to 40% (5% aq. NH3 in MeOH))

Sources & evidence

ORD record
ord-a8875911c93b463a90af15bc332da7be
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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