Ammonium Chloride → 6-chloro-5-cyano-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 525740Notes

Reaction equation

HRID 525740 reaction equation
C[Al](C)C.[F:5][C:6]([F:16])([F:15])[O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.C([O:19][C:20](=O)[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[C:24]([Cl:29])=[N:23][CH:22]=1)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:29][C:24]1[C:25]([C:27]#[N:28])=[CH:26][C:21]([C:20]([NH:12][C:11]2[CH:13]=[CH:14][C:8]([O:7][C:6]([F:15])([F:16])[F:5])=[CH:9][CH:10]=2)=[O:19])=[CH:22][N:23]=1

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 6008484-(Trifluoromethoxy)anilineHCID 16682925TrimethylaluminumHCID 57506169Ethyl 6-chloro-5-cyanonicotinate

Product 1

HCID 899068936-chloro-5-cyano-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution trimethylaluminium 2 M in toluene (20.77 mL, 41.5 mmol) was added to a stirred solution of 4-(trifluoromethoxy)aniline (2.247 mL, 16.62 mmol) in toluene (150 mL) under an argon atmosphere. After 30 min, a solution of 6-chloro-5-cyanonicotinic acid ethyl ester (3.5 g, 16.62 mmol) in toluene (10 mL) was added and the RM was stirred at 25° C. for 1 h. After cooling to 5° C., the RM was treated dropwise with a solution of sat. aq. NH4Cl (50 mL) and EtOAc (50 mL) was added. The mixture was stirred for 60 min, filtered over Hyflo® and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 0 to 30% EtOAc) and recrystallized from n-hexane/DCM to afford the title compound as a yellow crystalline solid. m.p. 198-200° C., HPLC (Condition 4) tR=6.24 min, UPLC-MS (Condition 8) tR=1.14 min, m/z=340.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.15-7.34 (m, 2H), 7.67 (d, J=8.99 Hz, 2H), 8.02 (br. s, 1H), 8.53 (d, J=2.35 Hz, 1H), 9.05 (d, J=2.35 Hz, 1H).

Workup

  1. temperatureAfter cooling to 5° C.
  2. additionwas added
  3. stirringThe mixture was stirred for 60 min
  4. filtrationfiltered over Hyflo®
  5. extractionextracted with EtOAc
  6. dry with materialThe combined extracts were dried over Na2SO4
  7. customthe solvent was evaporated off under reduced pressure
  8. customto give a crude product which
  9. customwas purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 0 to 30% EtOAc)
  10. customrecrystallized from n-hexane/DCM

Sources & evidence

ORD record
ord-0c245defa8b94318bd7558355f742788
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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