Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → 2-{5-Chloro-2-[12-(2-methoxy-ethyl)-12-aza-tricyclo[7.2.1.0(2,7)]dodeca-2(7),3,5-trien-4-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide

Participants

Reaction Conditions

Reaction Steps

12-(2-Methoxy-ethyl)-12-aza-tricyclo[7.2.1.0(2,7)]dodeca-2(7),3,5-trien-4-ylamine (101 mg, 0.435 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (0.140 g, 0.443 mmol), and 10-Camphorsulfonic acid (0.141 g, 0.607 mmol) were combined in Isopropyl alcohol (4 mL) and heated with microwave irradiation to 120° C. for a total of 1.5 h. The mixture was treated with Macroporous carbonate resin (3.16 mmol/g loading; 0.45 g, 1.4 mmol) and stirred for 30 min, concentrated in vacuo and chromatographed (ISCO 2×12 g SiO2, 0-10% MeOH:DCM). The amide product elutes with 10% MeOH, while the ester elutes before in ˜8% MeOH. 2-{5-Chloro-2-[12-(2-methoxy-ethyl)-12-aza-tricyclo[7.2.1.0(2,7)]dodeca-2(7),3,5-trien-4-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was isolated as a yellow solid (95 mg, 43%). m.p.=233-236° C.; LCMS (m/e) 511 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 9.30 (s, 1H), 9.22 (s, 1H), 8.53 (m, 1H), 8.17 (s, 1H), 7.51 (m, 2H), 7.42 (m, 1H), 7.15 (m, 1H), 6.77 (s, 1H), 3.59 (m, 1H), 3.41 (m, 3H), 3.28 (m, 1H), 3.23 (s, 3H), 2.95 (m, 1H), 2.75 (m, 3H), 2.55 (m, 1H), 2.25 (m, 1H), 2.04 (m, 2H), 1.45 (m, 2H).

Provenance & Evidence