Tetrahydrofuran → 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester

HRID 562435Notes

Reaction equation

HRID 562435 reaction equation
[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][CH3:18])[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2].C1COCC1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=S)=[C:30]([CH3:37])[CH:29]=1.NC(N)=S>CN(C1C=CN=CC=1)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=3[CH3:37])[N:17]([CH3:18])[C:12]=2[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 2723790ThioureaHCID 27373994-Fluoro-2-methylphenyl isothiocyanateHCID 110661612-(4-Amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester

Product 1

HCID 668323242-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl esterYield 52.2%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 3283Diethyl EtherSolvent

Procedure

To a 250 mL round-bottom flask was added 2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (10.8 g, 37.4 mmol), DMAP (228 mg, 1.87 mmole), and THF (80 mL). The solution was stirred with gentle heating until all the material was fully dissolved. The reaction mixture was then concentrated under vacuum to achieve a final volume of approximately 20 mL. After cooling to room temperature, 4-fluoro-1-isothiocyanato-2-methyl-benzene (9.36 g, 56.0 mmole) was added in one portion, and stirring was continued at room temperature for 12 hours, after which time all the diamine had been converted to the corresponding thiourea as determined by TLC analysis. To the reaction mixture was then added mercuric oxide (12.15 g, 56 mmole) and the resulting slurry stirred at room temperature. The slurry rapidly became black, indicating the formation of mercuric sulfide. After 1 hour, the reaction was complete as determined by TLC analysis. Silica gel was added to the mixture and the resulting thick slurry was filtered through a pad of celite, washing with several volumes of EtOAc. The clear filtrate was concentrated to produce a dark gray solid. To the solid was added diethylether, and the insoluble material was isolated by filtration to provide 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (8.25 g, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.46-7.42 (m, 2H), 7.14 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.06 (td, 1H, J1=2.7 Hz, J2=8.6 Hz), 6.87 (d, 1H, J=8.6 Hz), 4.28-4.19 (m, 2H), 3.95 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 1.81 (s, 3H), 1.23 (t, 3H, J=7.4 Hz); ESMS (m/z): 423 (M+1)+.

Workup

  1. temperaturewith gentle heating until all the material
  2. dissolutionwas fully dissolved
  3. concentrationThe reaction mixture was then concentrated under vacuum
  4. stirringstirring
  5. waitAfter 1 hour
  6. additionSilica gel was added to the mixture
  7. filtrationthe resulting thick slurry was filtered through a pad of celite
  8. washwashing with several volumes of EtOAc
  9. concentrationThe clear filtrate was concentrated
  10. customto produce a dark gray solid
  11. customthe insoluble material was isolated by filtration

Sources & evidence

ORD record
ord-bd1ed561b08c42889440474dca23eb5c
Source dataset
uspto-grants-2011_11
Patent number
US08067395B2

Reaction notes

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