1,2-Dibromoethane → (3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine

HRID 1749060Notes

Reaction equation

HRID 1749060 reaction equation
[OH-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([CH2:10][S:11]([CH3:20])(=[O:19])=[N:12]C(=O)C(F)(F)F)[CH:7]=[C:6]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[CH3:27])[N:5]=1.Br[CH2:29][CH2:30]Br>[Br-].C([N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC)CCCCCCC.CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[Cl:3][C:4]1[N:5]=[C:6]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[CH3:27])[CH:7]=[C:8]([C:10]2([S:11]([CH3:20])(=[NH:12])=[O:19])[CH2:30][CH2:29]2)[N:9]=1

Participants

6

Reactant 3

HCID 78391,2-Dibromoethane2×HCID 14798Sodium HydroxideHCID 86660215N-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methyl)(methyl)oxido-lambda6-sulfanylidene]-2,2,2-trifluoroacetamide

Product 1

HCID 86660214(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholineYield 66.1%

Reagents, catalysts & solvents 2

HCID 2734117Tetraoctylammonium bromideCatalystHCID 178479889HCID 178479889, compoundSolvent2×

Conditions

Temperature
20 °C

Procedure

Sodium hydroxide (Sigma-Aldrich 415413, d=1.515 g/ml, 217 ml of a 50% solution, 4059.84 mmol) was added to N-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (27.12 g, 67.66 mmol), 1,2-dibromoethane (23.32 ml, 270.66 mmol) and tetraoctylammonium bromide (3.70 g, 6.77 mmol) in methyl THF (1000 ml) at 20° C. under nitrogen. The resulting mixture was stirred at 20° C. for 24 hours. Further 1,2-dibromoethane (23.32 ml, 270.66 mmol) was added and the mixture was stirred at 20° C. for a further 24 hours. The reaction mixture was diluted with methyl THF (1000 ml) and the aqueous layer separated. The organic layer was diluted further with EtOAc (1000 ml) and washed with water (1500 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to afford (3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine (14.80 g, 66%); 1H NMR (400 MHz, DMSO-d6) 1.21 (3H, d), 1.39 (3H, m), 1.62-1.71 (1H, m), 3.01 (3H, s), 3.43 (1H, tt), 3.58 (1H, dd), 3.72 (1H, d), 3.82 (1H, d), 3.93 (1H, dd), 4.01 (1H, s), 4.38 (1H, s), 6.96 (1H, d); m/z: (ES+) MH+, 331.46 and 333.43.

Workup

  1. stirringthe mixture was stirred at 20° C. for a further 24 hours
  2. customthe aqueous layer separated
  3. additionThe organic layer was diluted further with EtOAc (1000 ml)
  4. washwashed with water (1500 ml)
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. customevaporated
  8. customThe residue was purified by flash chromatography on silica
  9. washeluting with a gradient of 0 to 5% MeOH in DCM
  10. customPure fractions were evaporated

Sources & evidence

ORD record
ord-b36c53154c694c029340c0b2484f27bd
Source dataset
uspto-grants-2015_10
Patent number
US09155742B2

Reaction notes

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