Pivaloyl chloride → (s)-2-(2-Amino-propionylamino)-5-[3-(2-methoxy-phenyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]-n,n-dimethyl-benzamide hydrochloride

온도

0 °C

Into a Scintillation vial were added BOC-Ala-OH (50.8 mg, 0.268 mmol), iPr2NEt (50 μL, 0.41 mmol) and methylene chloride. The solution was cooled in an ice-water bath for 3 min, then trimethylacetyl chloride (33 μL, 0.40 mmol) was added. The solution was stirred at 0° C. for 45 min then 2-amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (96.9 mg, 0.179 mmol) was added, the ice-bath was removed, and the solution was stirred at rt for 2 d. The reaction mixture was concentrated then re-dissolved in MeOH (1 mL), and cooled to 0° C. and treated with 50 μL 50% (w/w) aqueous KOH for 30 min or until Ts-removal was complete. The reaction was quenched by addition of 500 μL glacial acetic acid and then concentrated in vacuo. The crude residue was dissolved in EtOAc and filtered (to remove KOAc), then purified by flash column chromatography on SiO2 gel eluting with a 0 to 100 [(10% MeOH in EtOAc):hexanes] gradient. The purified BOC-protected compound was then dissolved in 1 mL methanol and treated with 4M HCl/1,4-dioxane solution (2 mL) for 2.5 h. Lyophilization afforded 149.2 mg of the title compound as a yellow powder. 1H-NMR (500 MHz, d6-DMSO) δ 12.01 (br.s, 1H), 10.16 (br.s, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.26 (app.d, 2H), 8.21 (d, J=2.0 Hz, 1H), 7.80 (dd, J=2, 8 Hz, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.60 (dd, J=1.5, 7.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.27 (t, J=7 Hz, 1H), 7.11 (d, 8.0 Hz, 1H), 7.04 (t, J=6 Hz, 1H), 4.05 (m, 1H), 3.80 (s, 3H), 2.97, 2.85 (br.s, 6H), 1.41 (d, J=7 Hz, 3H); MS: m/z 558.2 [M+H+].

1. temperatureThe solution was cooled in an ice-water bath for 3 min
2. customthe ice-bath was removed
3. stirringthe solution was stirred at rt for 2 d
4. concentrationThe reaction mixture was concentrated
5. dissolutionthen re-dissolved in MeOH (1 mL)
6. temperaturecooled to 0° C.
7. additiontreated with 50 μL 50% (w/w) aqueous KOH for 30 min or until Ts-removal
8. customThe reaction was quenched by addition of 500 μL glacial acetic acid
9. concentrationconcentrated in vacuo
10. dissolutionThe crude residue was dissolved in EtOAc
11. filtrationfiltered
12. custom(to remove KOAc)
13. custompurified by flash column chromatography on SiO2 gel
14. washeluting with a 0 to 100 [(10% MeOH in EtOAc):hexanes] gradient
15. dissolutionwas then dissolved in 1 mL methanol
16. additiontreated with 4M HCl/1,4-dioxane solution (2 mL) for 2.5 h

ORD 기록

ord-3252dfd614344fdc9f07c77bcc072f35

출처 데이터셋

uspto-grants-2009_10

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US07601839B2