Reaktion #2287958

Reaktionsgleichung

(4-pyrimidin-2-yloxycyclohexyl) methanesulfonate

7-morpholinoquinoxalin-5-ol

Cs2CO3

→

4-(8-(((trans)-4-(pyrimidin-2-yloxy)cyclohexyl)oxy)quinoxalin-6-yl)morpholine

Ausbeute 13.4%

Lösungsmittel

dioxane

EtOAc

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigewas sealed in a 5 mL microwave tube
2. 2
   TemperaturThe reaction mixture was cooled to room temperature
3. 3
   Filtrationfiltered through diatomaceous earth which
4. 4
   Waschenwas subsequently washed with ethyl acetate
5. 5
   EinengenThe filtrate was concentrated under reduced pressure
6. 6
   Sonstigethe residue purified via preparative reversed-phase HPLC (10-90% CH3CN/water gradient containing 0.1% TFA)
7. 7
   workup.ADDITIONFractions containing
8. 8
   workup.ADDITIONa mixture of cis and trans isomers
9. 9
   Sonstigewere further purified via SFC
10. 10
    Wascheneluting with 40% MeOH in CO2

Vorschrift

As shown in step 7-iv of Scheme 7, a mixture of (4-pyrimidin-2-yloxycyclohexyl) methanesulfonate (105 mg, 0.386 mmol), 7-morpholinoquinoxalin-5-ol (178.3 mg, 0.7712 mmol), and Cs2CO3 (125.6 mg, 0.3856 mmol) in dioxane (1.5 mL) was sealed in a 5 mL microwave tube and heated to 110° C. for 14 hours using an oil bath. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through diatomaceous earth which was subsequently washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue purified via preparative reversed-phase HPLC (10-90% CH3CN/water gradient containing 0.1% TFA). Fractions containing a mixture of cis and trans isomers were further purified via SFC using a chiral OJ column and eluting with 40% MeOH in CO2 to provide 21 mg of 4-(8-(((trans)-4-(pyrimidin-2-yloxy)cyclohexyl)oxy)quinoxalin-6-yl)morpholine (compound 34): 1H NMR (300 MHz, Chloroform-d) δ 8.69 (dd, J=3.4, 1.9 Hz, 1H), 8.62 (dd, J=3.6, 1.9 Hz, 1H), 8.51 (dd, J=4.8, 2.2 Hz, 2H), 7.01-6.83 (m, 3H), 5.18 (tt, J=7.0, 3.4 Hz, 1H), 4.79 (tt, J=6.9, 3.1 Hz, 1H), 4.00-3.85 (m, 4H), 3.34 (dq, J=4.8, 2.6 Hz, 4H), 2.44-2.16 (m, 4H), 1.92 (tdd, J=16.4, 7.7, 2.8 Hz, 4H); ESMS (M+H+)=408.56, and 22 mg of 4-(8-(((cis)-4-(pyrimidin-2-yloxy)cyclohexyl)oxy)-quinoxalin-6-yl)morpholine (compound 42): 1H NMR (300 MHz, Chloroform-d) δ 8.70 (d, J=1.9 Hz, 1H), 8.63 (d, J=1.9 Hz, 1H), 8.52 (d, J=4.8 Hz, 2H), 7.01-6.87 (m, 3H), 5.17 (ddt, J=8.7, 6.7, 3.4 Hz, 1H), 4.76-4.58 (m, 1H), 4.00-3.87 (m, 4H), 3.40-3.27 (m, 4H), 2.43-2.22 (m, 4H), 2.05-1.87 (m, 2H), 1.86-1.71 (m, 2H); ESMS (M+H+)=408.56.

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