(3-Amino-1H-pyrazol-4-YL)(thiophen-2-YL)methanone → Lorediplon
반응식
[NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O>CC(O)C>[F:31][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]참가 물질
4
반응 조건
- 온도
- 5 °C
실험 절차
A 300 L vessel was flushed with nitrogen. Acetic acid (40.0 L) was charged, and then 7.312 kg (37.84 moles) of (5-amino-1H-pyrazol-4-yl)-thiophen-2-yl-methanone and 10.000 kg (37.84 moles) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide were added consecutively. The mixture was heated to 120° C. (±5° C.) with stirring. The reaction was controlled by HPLC until completion (<1% of each starting material), which typically occurs in 4 hours. The reaction mass was cooled to 60-70° C. 2-Propanol (80.0 L) was charged to reaction mixture, cooled to 40-45° C. and aged for at least 1 hour. The mixture was cooled over approximately 2.5 hours to 0-5° C. and aged for at least 2 hours. Solids were filtered and washed twice with 10.0 L of chilled 2-propanol. The solid product was dried under vacuum at 50° C. (±5° C.) to remove residual solvents (<0.5% w/w of acetic acid and <0.5% w/w of 2-propanol). N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide was obtained as a crystalline material (12.686 kg). Yield 85%. Purity ≧95%.