4-Isothiocyanato-2-(trifluoromethyl)benzonitrile → HCID 86683694, compound

HRID 1525683Notes

Reaction equation

HRID 1525683 reaction equation
[N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[CH3:16][NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:22][C:21]=1[F:34])=[O:19]>CN(C=O)C>[CH3:16][NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]([C:2](=[S:3])[NH:1][C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=2)[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:22][C:21]=1[F:34])=[O:19]

Participants

4

Reactant 2

HCID 116155404-Isothiocyanato-2-(trifluoromethyl)benzonitrileHCID 86683692HCID 86683692, compound

Product 1

HCID 86683694HCID 86683694, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (320 mg, 1.51 mmol) 3.2 and ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-β-alaninate (404 mg, 1.51 mmol) 5 (R1=CH3) in DMF (8 ml) was heated at 60° C. in microwave stove for 8 h. The reaction mixture was evaporated in vacuo, and by means of colomn chromatography on SiO2 (eluent—n-hexane:AcOEt=1:2) ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]thiocarbamoyl}-β-alaninate 6(2) (R1=CH3, X═S) was isolated. LCMS (M+H)+ 497. A solution of NaOH (32 mg, 0.8 mmol) in water (0.25 ml) was added to a solution of ester (200 mg, 0.4 mmol) 6(2) in alcohol (1 ml), and the resultant mixture was stirred at 80° C. for 2 h (LCMS control), cooled and neutralized with HCl (69 mkl, 0.8 mmol), evaporated in vacuo, the residue was extracted with hot isopropanol and evaporated in vacuo again. It gave N-[4-(methylcarbamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]thiocarbamoyl}-β-alanine 6(3) (R1=CH3, X═S). LCMS (M+H)+ 469. TBTU (86 mg, 0.36 mmol) and diisopropylethylamine (110 mg, 0.84 mmol) were added to the solution of the prepared acid (114 mg, 0.24 mmol) 6(3) in DMF (1.5 ml). The reaction mixture was stirred at 45° C. for 15 h. When the reaction was completed (LCMS control) the solution was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4, evaporated in vacuo and by HPLC method N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-4-oxo-2-thioxo-tetrahydropyrimidin-1(2H)-yl}-2-fluorobenzamide 1.3.2(2) (R1=CH3, X═S) was isolated; Ki1.3.2(2)=95.2 nM. LCMS (M+H)+ 451. 1H NMR (DMSO-d6, 400 MHz): 8.35 (q, J=4.4 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 7.83 (dd, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.71 (t, J=8.2 Hz, 1H), 7.42 (dd, J1=11.0 Hz, J2=1.8 Hz, 1H), 7.33 (dd, J1=8.2 Hz, J2=1.8 Hz, 1H), 4.13 (t, J=6.8 Hz, 2H), 3.17 (t, J=6.8 Hz, 2H), 2.78 (d, J=4.4 Hz, 3H).

Workup

  1. customThe reaction mixture was evaporated in vacuo

Sources & evidence

ORD record
ord-22a590168a8140aeb33b6f8fc2cc302a
Source dataset
uspto-grants-2015_07
Patent number
US09085539B2

Reaction notes

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