反应详情

To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (138.0 mg, 0.2984 mmol), 1-hydroxybenzotriazole (40.8 mg, 0.302 mmol), and PS-Carbodiimide (1.37 mmol/g loading; 873 mg, 1.20 mmol) in anhydrous N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (260 μL, 1.5 mmol) was added. A small amount of sonication was used to get majority of solid into solution. 2-(2-Methoxyethoxy)acetic acid (45.7 mg, 0.334 mmol) in anhydrous DMF (1 mL) was added, and the reaction was vigorously shaken at rt for 5.5 h. An additional 0.2 eq of 2-(2-methoxyethoxy)acetic acid (8.1 mg, 0.060 mmol) in anhydrous N,N-dimethylformamide (0.5 mL) was added (after 7 h), and the reaction was shaken overnight at rt. The resin was filtered off (M-size frit) and rinsed several times with DMF. The filtrate was concentrated in vacuo at medium temp (bath temp: max 43° C.), redissolved in MeOH and DCM, and concentrated again under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with MeOH:DCM 2%→5%→10%]. Fractions containing product were combined and concentrated in vacuo, affording the title compound, as an off-white solid. The material was further purified by trituration in MeOH/sonication, affording the title compound, as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ=2.36-2.56 (s, br, rotamers, 2H), 3.19 (s, 3H), 2.38-2.45 (m, 2H), 3.49-3.55 (m, 2H), 3.58 & 3.64 (t, J=5.2 Hz, rotamers, 2H), 4.08 & 4.10 (s, br, rotamers, 2H), 4.14 & 4.18 (s, rotamers, 2H), 6.37 (s, br, 1H), 6.77 & 6.78 (s, rotamers, 1H), 7.80 (dd, J=8.8, 2.0 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 8.28 (s, 1H), 8.85 (s, 1H), 9.17 (s, 1H), 9.54 (s, —NH), 11.95 (d, J=9.2 Hz, —NH). MS (ES+): m/z 465.01 (100) [MH+]. HPLC: tR=2.24 min (ZQ2000, polar—5 min).

1. customA small amount of sonication
2. customto get majority of solid into solution
3. stirringthe reaction was shaken overnight at rt
4. filtrationThe resin was filtered off (M-size frit)
5. washrinsed several times with DMF
6. concentrationThe filtrate was concentrated in vacuo at medium temp (bath temp: max 43° C.)
7. dissolutionredissolved in MeOH
8. concentrationDCM, and concentrated again under reduced pressure
9. customdry loaded
10. custompurified by chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with MeOH:DCM 2%→5%→10%]
11. additionFractions containing product
12. concentrationconcentrated in vacuo