Water → N-(2-(4-cyano-2-fluorophenylamino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide

HRID 578583Notes

Reaction equation

HRID 578583 reaction equation
[NH2:1][CH2:2][CH2:3][N:4]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1F)[C:25]#[N:26].CCN(C(C)C)C(C)C.O>CS(C)=O>[C:25]([C:24]1[CH:27]=[CH:28][C:29]([NH:1][CH2:2][CH2:3][N:4]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)(=[O:7])=[O:6])=[C:22]([F:21])[CH:23]=1)#[N:26]

Participants

6

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 5872033,4-DifluorobenzonitrileHCID 49781871HCID 49781871, compound

Product 1

HCID 49783398N-(2-(4-cyano-2-fluorophenylamino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
120 °C

Procedure

The primary amine of N-(2-aminoethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide (19) was arylated with 3,4-difluorobenzonitrile on a 0.337 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-cyano-2-fluorophenylamino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide was obtained as a white foam (111 mg, 79%): δH (500 MHz, DMSO-d6) 0.83-0.77 (m, 2H, 2 CH (cyclohexylmethyl)), 1.09 (br, 3H, 3 CH (cyclohexylmethyl)), 1.62-1.51 (m, 6H, 6 CH (cyclohexylmethyl)), 3.06 (d, J=7.5 Hz, 2H, NCH2CH (cyclohexyl)), 3.42-3.34 (m, 4H, SO2NCH2CH2N), 6.54 (br, 1H, NHAr), 6.80 (t, J=8.5 Hz, 1H, CH (Ar)), 7.45 (dd, J=11.5, 1.5 Hz, 1H, CH (Ar)), 7.53 (dd, J=8.5, 1.5 Hz, 1H, CH (Ar)), 7.66 (m, 1H, CH (Py)), 7.93 (m, 1H, CH (Py)), 8.07 (m, 1H, CH (Py)), 8.71 (m, 1H, CH (Py)); δC (125 MHz, DMSO-d6) 25.1, 25.9, 30.0, 35.7, 37.1, 41.3, 47.5, 55.5, 61.8, 94.4, 122.2, 127.1, 130.4, 138.7, 140.7, 142.5, 150.1, 156.9, 179.7; HRMS (ES+) calcd for [C21H25FN4O2S+H] 417.1760. found 417.1749. N-(2-(4-Cyano-2-fluorophenylamino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide was then alkylated with 5-chloromethyl-1H-imidazole.HCl on a 0.216 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-cyano-2-fluorophenyl)((1-methyl-1H-imidazol-5-yl)methyl)amino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide was afforded as a white foam (90 mg, 81%): δH (500 MHz, CDCl3) 0.68-0.75 (m, 2H, 2 CH (cyclohexylmethyl)), 1.03 (br, 3H, 3 CH (cyclohexylmethyl)), 1.23-1.32 (m, 1H, CH (cyclohexylmethyl)), 1.50-1.60 (m, 5H, 5 CH (cyclohexylmethyl)), 2.80 (s, 2H, NCH2CH (cyclohexylmethyl)), 3.34-3.47 (m, 4H, SO2NCH2CH2N), 3.54 (s, 3H, CH3 (Im)), 4.46 (s, 2H, CH2Im), 6.61 (br, 1H, CH (Ar)), 6.95 (s, 1H, CH (Im)), 7.11 (m, 1H, CH (Ar)), 7.26 (br, 1H, CH (Ar)), 7.53 (m, 2H, CH (Py), CH (Im)) 7.65 (br, 1H, CH (Py)), 8.26 (m, 1H, CH (Py)), 8.69 (m, 1H, CH (Py)); δC (125 MHz, CDCl3) 25.5, 26.1, 30.5, 31.3, 31.8, 36.6, 45.7, 47.3, 50.4, 56.4, 102.9, 118.1, 119.5, 120.2, 122.4, 126.5, 128.7, 129.3, 138.8, 141.3, 149.8, 153.9, 157.6, 162.4; HRMS (ES+) calcd for [C26H31FN6O2S+H] 511.2291. found 511.2265; HPLC (I) tR=18.69 min (99.3%), (II) tR=36.03 min (99.7%).

Workup

  1. customthe reaction
  2. temperatureto cool
  3. extractionthe crude product was extracted with EtOAc (×3)
  4. extractionThe EtOAc extractions
  5. washwashed with water (×3), brine
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customAfter work-up and purification by silica gel flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1)

Sources & evidence

ORD record
ord-19587684c32842a99d0379a146bd25af
Source dataset
uspto-grants-2015_05
Patent number
US09040563B2

Reaction notes

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