Triethylamine → Pyrrolo[1,2-b]pyridazine-3-carboxylic acid, 4-chloro-, ethyl ester

Temperature

110 °C

To POCl3 (225 mL, 2.42 mmol) at 0° C. was added ethyl 4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylate (50 g, 0.242 mmol) and the mixture was stirred until complete dissolution. At this time, triethylamine (36.8 mL, 0.266 mmol) was added dropwise and the resulting mixture was heated to 110° C. and allowed to stir for ˜16 h. The resulting mixture was allowed to cool and the POCl3 was removed in vacuo to afford a dark brown residue. This material was dissolved in dichloromethane and was cooled to 0° C. and diluted with 375 mL of ethanol. The resulting mixture was stirred at 0° C. for 30 min and then at rt for 1 h. The ethanol was removed under vacuum and the resulting semi-solid was dissolved in dichloromethane and stirred with 10% aqueous NaHCO3 for 1 h. The mixture was filtered through celite and the phases were separated. The aqueous portion was extracted with additional dichloromethane and the combined organic layers were washed with brine, dried over Na2SO4, decanted and the solvent was removed under vacuum to give the crude product. The crude material was purified by flash silica gel column chromatography to yield 47 g (86%) of a solid as the title compound. 1H NMR (400 MHz, CDCl3) δ ppm: 1.43 (t, J=7.2, 6.8 Hz, 3 H), 4.43 (q, J=7.2, 6.8 Hz, 2 H), 6.940-6.99 (m, 2H), 7.84 (q, J=0.8, 1.6 Hz, 1 H), 8.51 (s, 1H)). 13C-NMR (400 MHz, DMS-d6) ppm: 163.30, 141.89, 138.16, 124.86, 120.69, 114.99, 109.90, 105.22, 61.55, 14.21. LCMS (conditions A): m/z 225. HPLC (condition B): Retention time=3.47 min.

1. stirringto stir for ˜16 h
2. temperatureto cool
3. customthe POCl3 was removed in vacuo
4. customto afford a dark brown residue
5. temperaturewas cooled to 0° C.
6. stirringThe resulting mixture was stirred at 0° C. for 30 min
7. customThe ethanol was removed under vacuum
8. dissolutionthe resulting semi-solid was dissolved in dichloromethane
9. stirringstirred with 10% aqueous NaHCO3 for 1 h
10. filtrationThe mixture was filtered through celite
11. customthe phases were separated
12. extractionThe aqueous portion was extracted with additional dichloromethane
13. washthe combined organic layers were washed with brine
14. dry with materialdried over Na2SO4
15. customdecanted
16. customthe solvent was removed under vacuum
17. customto give the crude product
18. customThe crude material was purified by flash silica gel column chromatography

ORD record

ord-b9bd405da95d4d26bd715db8a887cfc9

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09221826B2