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Cesium carbonate → HCID 178420809, compound

HRID 525279
Notes
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Reaction equation

HRID 525279 reaction equation
CS([O:5][CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)(=O)=O.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[C:27](O)[C:28]3[N:29]=[CH:30][CH:31]=[N:32][C:33]=3[CH:34]=2)[CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[O:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([O:5][C:27]2[CH:26]=[C:25]([N:22]3[CH2:21][CH2:20][O:19][CH2:24][CH2:23]3)[CH:34]=[C:33]3[C:28]=2[N:29]=[CH:30][CH:31]=[N:32]3)[CH2:7][CH2:8]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 90413334(4-Pyrimidin-2-yloxycyclohexyl) methanesulfonateHCID 1366295107-Morpholinoquinoxalin-5-ol

Product 1

HCID 178420809HCID 178420809, compoundYield 13.4%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolvent
HCID 31275
1,4-Dioxane
Solvent

Conditions

Temperature
110 °C

Procedure

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.

Workup

  1. customwas sealed in a 5 mL microwave tube
  2. temperatureThe reaction mixture was cooled to room temperature
  3. filtrationfiltered through diatomaceous earth which
  4. washwas subsequently washed with ethyl acetate
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customthe residue purified via preparative reversed-phase HPLC (10-90% CH3CN/water gradient containing 0.1% TFA)
  7. additionFractions containing
  8. additiona mixture of cis and trans isomers
  9. customwere further purified via SFC
  10. washeluting with 40% MeOH in CO2

Sources & evidence

ORD record
ord-e6837d38e79e45eebebf3bbcda4f576b
Source dataset
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09340557B2

Reaction notes

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