반응 #976647

반응 방정식

3-amino-5-(trifluoromethyl)benzonitrile

15A

6-chloro-8-((4-methoxybenzyl)(2-methoxyethyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrile

cesium carbonate

Xantphos

HCl MeCN

triethylsilane

TFA

→

6-((3-cyano-5-(trifluoromethyl)phenyl)amino)-8-((2-methoxyethyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrile

수율 67.3%

용매

methanol

DMA

반응 조건

후처리

1. 1
   기타cap
2. 2
   기타the solvent was purged with argon
3. 3
   기타the suspension was pump/purged three times with argon
4. 4
   온도cooled to room temperature
5. 5
   기타The solids were removed via filtration through CELITE®
6. 6
   세척washed with THF
7. 7
   농축The filtrate was concentrated under reduced pressure
8. 8
   workup.ADDITIONdiluted with water and EtOAc
9. 9
   기타The layers were separated
10. 10
    추출the aqueous phase extracted with EtOAc (3×10 mL)
11. 11
    세척washed with water and brine
12. 12
    건조dried over anhydrous sodium sulfate
13. 13
    여과filtered
14. 14
    농축concentrated
15. 15
    workup.DISSOLUTIONThe crude product was dissolved in DCM
16. 16
    기타purified by flash chromatography (SiO2, hexanes to 40% EtOAc/hexanes, 12 g column, 30 mL/min., 20 min. gradient, monitoring at 254 nm)
17. 17
    농축The fractions were concentrated
18. 18
    workup.DISSOLUTIONdissolved in DCM (1 mL)
19. 19
    기타the volatiles were removed via a stream of nitrogen
20. 20
    기타the residue was triturated with MeOH
21. 21
    기타The solid was isolated via filtration
22. 22
    workup.WAITlyophilized overnight
23. 23
    기타furnishing Example 15, (0.080 g, 0.181 mmol, 67.3% yield) as a gray solid

실험 절차

A solution of 3-amino-5-(trifluoromethyl)benzonitrile (0.075 g, 0.40 mmol) in DMA (1 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was purged with argon. 15A (0.100 g, 0.269 mmol), cesium carbonate (0.351 g, 1.076 mmol), copper (I) iodide (0.026 g, 0.134 mmol), Xantphos (0.031 g, 0.054 mmol), and Pd2(dba)3 (0.025 g, 0.027 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was heated to 125° C. for 45 min. and then cooled to room temperature. The solids were removed via filtration through CELITE® and washed with THF. The filtrate was concentrated under reduced pressure and diluted with water and EtOAc. The layers were separated, and the aqueous phase extracted with EtOAc (3×10 mL). The organics were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was dissolved in DCM and purified by flash chromatography (SiO2, hexanes to 40% EtOAc/hexanes, 12 g column, 30 mL/min., 20 min. gradient, monitoring at 254 nm). The fractions were concentrated, dissolved in DCM (1 mL) and treated with triethylsilane (0.430 mL, 2.7 mmol) and TFA (0.3 mL) at room temperature. After 20 minutes, the volatiles were removed via a stream of nitrogen, and the residue was triturated with MeOH. The solid was isolated via filtration, suspended in 1:1 1N HCl/MeCN, and lyophilized overnight, furnishing Example 15, (0.080 g, 0.181 mmol, 67.3% yield) as a gray solid. HPLC: Rt=4.160 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=402.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.98 (1H, s), 8.52 (1H, s), 8.25 (1H, s), 8.20 (1H, s), 7.82 (1H, s), 7.68 (1H, s), 5.99 (1H, s), 3.54-3.62 (2H, m), 3.40-3.52 (2H, m), 3.30 (3H, s).

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