Dimethyl Sulfoxide → HCID 178521578, compound

HRID 1963955Notes

Reaction equation

HRID 1963955 reaction equation
[Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[N:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[NH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]2)=[N:6][CH:7]=1

Participants

5

Reactant 3

HCID 679Dimethyl SulfoxideHCID 66937030HCID 66937030, compoundHCID 178511715HCID 178511715, compound

Product 1

HCID 178521578HCID 178521578, compoundYield 55.6%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (375 mg, 1.162 mmol), DMSO (3.5 ml) and trans-4-aminocyclohexanol (1204 mg, 10.46 mmol) was stirred at 100° C. for 18 hours and the progress was followed by LCMS. The reaction mixture was let cool, added 300 ml of ethyl acetate, washed with saturated sodium bicarbonate solution (3×), water (2×), saturated salt solution (1×), dried with sodium sulfate, filtered and concentrated to crude solid. The crude material was purified by silica gel chromatography using 40 g column, eluting slowly from (80%> ethyl acetate 20% heptane with 2% MeOH) to 100% ethyl acetate with 2% MeOH. The desired fractions are concentrated to a constant mass, lyophilized from 1:1 ACN/water (does not fully dissolve), re-lyophilized from 80 ml of (60/40) ACN/water solution with sonicating to dissolve solid, giving 270 mg of title compound as free base. LCMS (m/z): 418.3 (MH+), retention time=0.52 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.19-1.55 (m, 6H) 1.71 (d, J=12.89 Hz, 2H) 1.85-2.15 (m, 5 H) 3.28-3.32 (dMeOH, 2H App.) 3.40 (td, J=11.72, 1.76 Hz, 2H) 3.50-3.73 (m, 2H) 3.94 (dd, J=11.28, 3.08 Hz, 2 H) 6.66 (s, 1 H) 7.86 (s, 2H) 7.99 (s, 1 H)

Workup

  1. temperatureThe reaction mixture was let cool
  2. washwashed with saturated sodium bicarbonate solution (3×), water (2×), saturated salt solution (1×)
  3. dry with materialdried with sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated to crude solid
  6. customThe crude material was purified by silica gel chromatography
  7. washeluting slowly from (80%> ethyl acetate 20% heptane with 2% MeOH) to 100% ethyl acetate with 2% MeOH
  8. concentrationThe desired fractions are concentrated to a constant mass
  9. dissolutiondoes not fully dissolve), re-lyophilized from 80 ml of (60/40) ACN/water solution
  10. customwith sonicating
  11. dissolutionto dissolve solid

Sources & evidence

ORD record
ord-cba52ab15e7548f5a0502b991d823584
Source dataset
uspto-grants-2013_04
Patent number
US08415381B2

Reaction notes

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