Hydrochloric Acid → 5-(2-{[3-(1-Piperazinyl)-2-pyrazinyl]oxy}ethoxy)quinoxaline, Hydrochloride

온도

65 °C

TMAD (0.55 g, 3.20 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2), 5-hydroxyquinoxaline* (0.45 g, 3.08 mmol) and PPh3 (0.85 g, 3.24 mmol) in THF (20 mL). The reaction was stirred at room temperature for 1.5 h and at 65° C. for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica using toluene/EtOAc (1:1) as eluent. The resulting solid was crystallized twice from diethyl ether/petroleum ether to remove PPh3O. The recrystallized material (0.50 g) was dissolved in MeOH (15 mL) and 1 M HCl (3.5 mL) was added. The resulting mixture was stirred at room temperature for 4 h (only 10% N-Boc-deprotection had occurred according to HPLC/MS). The mixture was concentrated and the residue was treated with CH2Cl2/TFA/H2O (50:45:5; 20 mL) for 1 h. After concentration in vacuo, the residue was dissolved in 0.1 M aqueous HCl and washed with toluene. The water phase was lyophilized to give a yellow oil that was dissolved in 1 M HCl. The solution was concentrated and MeOH and diethyl ether was added. The precipitate formed was collected and dried in vacuum to give 0.32 g (76%) of the title product. Pos-EI-MS shows M+ and 8 ions supporting the stated structure. HRMS m/z calcd for C18H20N6O2 (M)+ 352.1648, found 352.1662.

1. concentrationThe reaction mixture was concentrated
2. customthe residue was purified by column chromatography on silica
3. customThe resulting solid was crystallized twice from diethyl ether/petroleum ether
4. customto remove PPh3O
5. dissolutionThe recrystallized material (0.50 g) was dissolved in MeOH (15 mL)
6. addition1 M HCl (3.5 mL) was added
7. stirringThe resulting mixture was stirred at room temperature for 4 h (only 10% N-Boc-deprotection
8. concentrationThe mixture was concentrated
9. additionthe residue was treated with CH2Cl2/TFA/H2O (50:45:5; 20 mL) for 1 h
10. concentrationAfter concentration in vacuo
11. dissolutionthe residue was dissolved in 0.1 M aqueous HCl
12. washwashed with toluene
13. customto give a yellow oil that
14. concentrationThe solution was concentrated
15. additionMeOH and diethyl ether was added
16. customThe precipitate formed
17. customwas collected
18. customdried in vacuum

ORD 기록

ord-f9b85fe183ad4228955f0e558e06d47c

출처 데이터셋

uspto-grants-2002_10

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US06465467B1