Ethyl Acrylate → HCID 86683692, compound

HRID 1525682Notes

Reaction equation

HRID 1525682 reaction equation
CNC(=O)C1C=CC(N2CCC(=O)N(C3C=CC(C#N)=C(C(F)(F)F)C=3)C2=O)=CC=1.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33].C1CCN2C(=NCCC2)CC1.[NH2:49][C:50]1[CH:59]=[CH:58][C:53]([C:54]([NH:56][CH3:57])=[O:55])=[C:52]([F:60])[CH:51]=1>CS(C)=O>[CH3:57][NH:56][C:54]([C:53]1[CH:58]=[CH:59][C:50]([NH:49][CH2:33][CH2:32][C:31]([O:35][CH2:36][CH3:37])=[O:34])=[CH:51][C:52]=1[F:60])=[O:55]

Participants

6

Reactant 4

HCID 8821Ethyl AcrylateHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 441395214-Amino-2-fluoro-N-methylbenzamideHCID 86683693HCID 86683693, compound

Product 1

HCID 86683692HCID 86683692, compound

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

Synthesis of N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-2,4-dioxo-tetrahydropyrimidin-1(2H)-yl}benzamide 1.3.2(1), (X═O, R1=CH3). Ethyl acrylate (8 g, 80 mmol) and DBU (0.81 g, 5.4 mmol) were added to a solution of 4-amino-N-methyl-2-fluorobenzamide (9 g, 53.6 mmol) in DMSO (90 ml) and stirring was continued for 24 h at 70° C. (LCMS control). The reaction mixture was subjected to lyophilization, the residue was recrystallized from aqueous alcohol. It gave ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-β-alaninate 5. LCMS (M+H)+ 269. 1H NMR (DMSO-d6, 400 MHz) δ 7.57 (br. s, 1H), 7.48 (t, J=8.8 Hz, 1H), 6.47 (br. s, 1H), 6.42 (d, J=8.8 Hz, 1H), 6.33 (d, J=14.8 Hz, 1H), 4.07 (q, J=7.2 Hz, 2H), 3.32 (br. m, 2H), 2.73 (d, J=4.4 Hz, 3H), 2.55 (t, J=6.4 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H). The solution of 4-isocyanato-2-(trifluoromethyl)benzonitrile (425 mg, 1.87 mmol) 3.1 and ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-β-alaninate (500 mg, 1.87 mmol) 5 (R1=CH3) in CH2Cl2 (10 ml) was stirred for 5 h. The reaction mixture was evaporated in vacuo, and the product was isolated by colomn chromatography on SiO2 (eluent—n-hexane:AcOEt:Et3N=1:1:0.03). It gave ethyl N-[4-(methylcabamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]-carbamoyl}-β-alaninate 6(1) (R1=CH3, X═O). LCMS (M+H)+ 481. HCl (2.5 ml) was added to the solution of ethyl N-[4-(methylcabamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]-carbamoyl}-β-alaninate (500 mg, 1.04 mmol) 6(1) in AcOH (5 ml) and the resultant mixture was stirred for 15 h. The reaction mixture was poured into water, the product was extracted with EtOAc. Organic layer was dried over Na2SO4, evaporated in vacuo and by means of colomn chromatography on SiO2 (eluent—n-hexane:AcOEt=1:1) N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-2,4-dioxo-tetrahydropyrimidin-1(2H)-yl}benzamide 1.3.2, (X═O, R1=CH3) was isolated; Ki1.3.2(1)=85.6 nM, LCMS (M+H)+ 435. 1H NMR (DMSO-d6, 400 MHz): δ 8.29 (d, J=7.6 Hz, 1H), 8.23 (br. m, 1H), 8.11 (s, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.67 (t, J=8.4 Hz, 1H), 7.39 (d, J=12.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 4.02 (t, J=6.4 Hz, 2H), 3.03 (t, J=6.4 Hz, 2H), 2.77 (d, J=4.4 Hz, 3H).

Workup

  1. customthe residue was recrystallized from aqueous alcohol

Sources & evidence

ORD record
ord-87f4b3a1a9984db5938c5c38572a17c2
Source dataset
uspto-grants-2015_07
Patent number
US09085539B2

Reaction notes

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