Dimethyl Sulfoxide → 4-(Bicyclo[1.1.1]pentan-1-ylamino)-2-(((1R,3S)-3-hydroxycyclo-hexyl)amino)pyrimidine-5-carboxamide

HRID 2201986Notes

Reaction equation

HRID 2201986 reaction equation
[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9](Cl)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[CH2:19]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOC(C)=O.C1COCC1.O>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([NH:17][C@@H:18]4[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[CH2:19]4)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2

Participants

8

Reactant 4

HCID 679Dimethyl SulfoxideHCID 11430Potassium CarbonateHCID 25630532(1S,3R)-3-aminocyclohexanolHCID 1182537854-(Bicyclo[1.1.1]pentan-1-ylamino)-2-chloropyrimidine-5-carboxamide

Product 1

HCID 712372914-(Bicyclo[1.1.1]pentan-1-ylamino)-2-(((1R,3S)-3-hydroxycyclo-hexyl)amino)pyrimidine-5-carboxamideYield 79%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-chloropyrimidine-5-carboxamide (44 g), (1S,3R)-3-aminocyclohexanol (27.6 g), potassium carbonate (38.2 g) and DMSO (300 mL) was heated at 85° C. for 12 h. After cooling to room temperature, water (2 L) and a mixture of THF and EtOAc (1:1, 2 L) were added. The aqueous phase was separated and the organic layer was washed with saturated brine (2 L). The organic layer was concentrated under reduced pressure to give the crude product as a purple foam which was triturated with hot acetonitrile (1 L). After cooling to room temperature the solid was filtered and washed with acetonitrile (200 mL). The solids was dried in a vacuum oven at 50° C. to give 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(((1R,3S)-3-hydroxycyclohexyl)amino)pyrimidine-5-carboxamide as an off-white solid (4 g, 79% yield). 1H NMR (DMSO-d6) δ 0.91-1.31 (m, 4H), 1.60-1.89 (m, 3H), 2.01-2.20 (m, 7H), 3.34 (s, 1H), 3.37-3.52 (m, 1H), 3.58-3.85 (m, 1H), 4.65 (d, J=4.3 Hz, 1H), 6.90 (br. s., 1H), 7.20 (d, J=7.9 Hz, 1H), 7.61 (br. s., 1H), 8.37 (s, 1H), [9.23 (s, 0.14H)], 9.41 (s, 0.86H).

Workup

  1. temperatureAfter cooling to room temperature
  2. additionwere added
  3. customThe aqueous phase was separated
  4. washthe organic layer was washed with saturated brine (2 L)
  5. concentrationThe organic layer was concentrated under reduced pressure
  6. customto give the crude product as a purple foam which
  7. customwas triturated with hot acetonitrile (1 L)
  8. temperatureAfter cooling to room temperature the solid
  9. filtrationwas filtered
  10. washwashed with acetonitrile (200 mL)
  11. customThe solids was dried in a vacuum oven at 50° C.

Sources & evidence

ORD record
ord-bca6934de3ff46bd93251da66bd344dc
Source dataset
uspto-grants-2016_06
Patent number
US09365524B2

Reaction notes

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