Acetic Acid → 4-(1-((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine
Reaction equation
[N:1]1([C:7]2[C:8]3[S:23][C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)=[CH:21][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:35](O)(=O)[CH3:36]>>[CH3:35][C:36]1[N:13]([C:11]2[N:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:8]3[S:23][C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:26]4)=[CH:21][C:9]=3[N:10]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=1Participants
3
Conditions
- Temperature
- 120 °C
Procedure
A mixture of N-[4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl]benzene-1,2-diamine (100 mg, 0.21 mmol) and glacial acetic acid (0.5 mL) was heated at 120° C. for 3 h. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 95:5) followed by reversed phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 172 as a white solid (45 mg, 43%). LCMS (method A): RT=5.65 min, M+H−=506.1. 1H NMR (CDCl3, 400 MHz) δ 8.08-8.03 (m, 1 H), 7.73-7.68 (m, 1 H), 7.30-7.26 (m, 3 H), 4.05 (t, J=4.8 Hz, 4 H), 3.99 (s, 2 H), 3.88 (t, J=4.8 Hz, 4 H), 3.73 (m, 4 H), 3.65 (s, 2 H), 3.18-2.99 (m, 3 H), 2.93 (s, 3 H), 2.34 (m, 4 H)