反应详情

2-{5-Chloro-2-[3-(2-hydroxy-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide (100 mg, 0.183 mmol) and N-α-(tert-Butoxycarbonyl)glycine (32 mg, 0.183 mmol) were dissolved in dry Methylene chloride (2.00 mL, 31.2 mmol), and a catalytic amount of 4-Dimethylaminopyridine (2 mg, 0.02 mmol) was added and stirred for 20 minutes. N,N′-Dicyclohexylcarbodiimide (37.7 mg, 0.183 mmol) was then added and the reaction was stirred for 15 h at room temperature. The reaction was filtered to remove urea ppt. The filtrate was concentrated onto celite. ISCO flash column 0-8% MeOH:DCM. Product fractions were concentrated to a white solid. The Boc protected product was refluxed in DCM with 50 μL of TFA. After 3 hours reaction was sluggish and an additional 500 μL of TFA was added. The reaction was concentrated to dryness. The residue was triturated in H2O and filtered. A white solid containing no desired product was removed and the filtrate was lyophilized. The resulting white solid showed 4 TFA salts by NMR. It also contained a small amount (8%) of starting material. The solid was extracted and freebased with bicarb/DCM. The organic layer was concentrated to dryness and purified by preperative HPLC. The product was worked up again using bicarb/DCM. The product was isolated as a white foam (40 mg, 36%). mp: 77-79° C., MS (ESI+): 604 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.36 (s, 1H), 8.55 (d, J=8 Hz, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.57 (t, 1H), 7.51 (s, 1H), 7.27 (m, 1H), 6.67 (s, 1H), 4.30 (t, J=7 Hz, 2H), 3.89 (s, 3H), 3.48 (s, 2H), 2.87-2.83 (m, 4H), 2.77-2.71 (m, 13H).

1. stirringthe reaction was stirred for 15 h at room temperature
2. filtrationThe reaction was filtered
3. customto remove urea ppt
4. concentrationThe filtrate was concentrated onto celite
5. concentrationProduct fractions were concentrated to a white solid
6. temperatureThe Boc protected product was refluxed in DCM with 50 μL of TFA
7. customAfter 3 hours reaction
8. concentrationThe reaction was concentrated to dryness
9. customThe residue was triturated in H2O
10. filtrationfiltered
11. additionA white solid containing no desired product
12. customwas removed
13. extractionThe solid was extracted
14. concentrationThe organic layer was concentrated to dryness
15. custompurified by preperative HPLC