Hydrochloric Acid → N-(2-((4-cyanophenyl)((1-methyl-1H-imidazol-5-yl)methyl)amino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide

HRID 578582Notes

Reaction equation

HRID 578582 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][N:12]([CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:15])=[O:14])=[CH:5][CH:4]=1)#[N:2].ClCC1NC=NC=1.Cl.[H-].[Na+].Cl[CH2:40][C:41]1[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=1>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:40][C:41]2[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=2)[CH2:10][CH2:11][N:12]([CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:15])=[O:14])=[CH:7][CH:8]=1)#[N:2]

Participants

8

Reactant 5

HCID 313Hydrochloric Acid2×HCID 24758Sodium hydrideHCID 2173254-(Chloromethyl)-1h-imidazoleHCID 142396955-(Chloromethyl)-1-methyl-1H-imidazoleHCID 49783397HCID 49783397, compound2×

Product 1

HCID 49783194N-(2-((4-cyanophenyl)((1-methyl-1H-imidazol-5-yl)methyl)amino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

The primary amine of N-(2-aminoethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide (19) was arylated with p-fluorobenzonitrile on a 0.336 mmol scale. To a stirring solution of the primary amine (1 equiv) in DMSO (0.2 M) were added the aryl fluoride (1.2 equiv) and DIPEA (3 equiv). The reaction mixture was heated to 120° C. for 48 h. After allowing the reaction to cool, H2O was added, and the crude product was extracted with EtOAc (×3). The EtOAc extractions were combined, washed with water (×3), brine, dried (Na2SO4), filtered and concentrated. After work-up and purification by silica gel flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1), N-(2-(4-cyanophenylamino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide was obtained as a colorless gum (119 mg, 89%): δH (500 MHz, DMSO-d6) 0.77-0.83 (m, 2H, 2 CH (cyclohexylmethyl)), 1.09 (br, 3H, 3 CH (cyclohexyl)), 1.48-1.63 (m, 6H, 6 CH (cyclohexylmethyl)), 3.06 (d, J=6.4 Hz, 2H, NCH2CH (cyclohexylmethyl)), 3.28-3.38 (m, 4H, SO2NCH2CH2NHAr), 6.61 (d, J=8.5 Hz, 2H, 2 CH (Ar)), 6.70 (t, J=6.4 Hz, 1H, NH), 7.45 (d, J=8.5 Hz, 2H, 2 CH (Ar)), 7.66 (m, 1H, CH (Py)), 7.94 (m, 1H, CH (Py)), 8.07 (m, 1H, CH (Py)), 8.73 (m, 1H, CH (Py)); δC (125 MHz, DMSO) 25.1, 25.8, 29.9, 35.8, 41.5, 47.7, 55.6, 95.9, 111.6, 120.3, 122.2, 127.1, 133.3, 138.6, 150.1, 151.6, 157.0; HRMS (ES+) calcd for [C21H26N4O2S+H] 399.1855. found 399.1857. N-(2-(4-Cyanophenylamino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide was then alkylated with 5-chloromethyl-1H-imidazole.HCl on a 0.117 mmol scale. The secondary aniline (1 equiv) was dissolved in DMF (0.07 M), then the reaction was cooled to 0° C. After 15 min, NaH (3 eq.) was added in one portion. After a further 15 min, 5-chloromethyl-1-methyl-1H-imidazole.HCl (1.1 eq) was added. The reaction was allowed to stir at 0° C. from 2-3 h, when TLC indicated the reaction was complete or had stalled. Upon quenching the reaction with brine (approximately 1 mL), the reaction was diluted with water and extracted with EtOAc (×3). The EtOAc extractions were combined, and washed with 5% NaHCO3 (×3), brine, dried (Na2SO4), filtered and concentrated. After work-up and chromatography over silica gel (eluent CH2Cl2/MeOH/NH4OH, 192:7:1), the title compound N-(2-((4-cyanophenyl)((1-methyl-1H-imidazol-5-yl)methyl)amino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide was furnished as a glassy film (46 mg, 80%): δH (500 MHz, CDCl3) 0.84-0.78 (m, 2H, 2 CH (cyclohexylmethyl)), 1.06-1.14 (m, 3H, 3 CH (cyclohexylmethyl)), 1.35-1.27 (m, 1H, CH (cyclohexylmethyl)), 1.66-1.59 (m, 5H, 5 CH (cyclohexylmethyl)), 2.95 (d, J=7.0 Hz, 2H, NCH2CH (cyclohexyl)), 3.36 (t, J=7.9 Hz, 2H, SO2NCH2CH2N), 3.61 (s, 3H, CH3 (Im)), 3.65 (t, J=7.9 Hz, 2H, SO2NCH2CH2N), 4.55 (s, 2H, CH2Im), 6.85 (d, J=9.0 Hz, 2H, 2 CH (Ar)), 6.88 (s, 1H, CH (Im)), 7.47-7.44 (m, 3H, 2 CH (Ar), CH (Im)), 7.71 (s, 1H, CH (Py)), 7.91-7.86 (m, 2H, 2 CH (Py)), 8.61 (m, 1H, CH (Py)); δC (125 MHz, CDCl3) 25.6, 26.2, 30.6, 32.0, 36.9, 44.3, 46.8, 49.4, 57.1, 99.5, 112.3, 119.9, 122.5, 126.6, 127.2, 127.7, 133.8, 137.9, 138.7, 149.9, 150.4, 157.5; HRMS (ES+) calcd for [C26H32N6O2S+H] 493.2386. found 493.2364.

Workup

  1. waitAfter a further 15 min
  2. customUpon quenching
  3. customthe reaction with brine (approximately 1 mL)
  4. extractionextracted with EtOAc (×3)
  5. extractionThe EtOAc extractions
  6. washwashed with 5% NaHCO3 (×3), brine
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-75698639c47146fcb14ae79d4335deef
Source dataset
uspto-grants-2015_05
Patent number
US09040563B2

Reaction notes

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