Trifluoroacetamide → HCID 86660223, compound

HRID 1465862Notes

Reaction equation

HRID 1465862 reaction equation
C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[Cl:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[CH:20]=[C:19]([C:30]([S:33]([CH3:35])=[O:34])([CH3:32])[CH3:31])[N:18]=1.[O-2].[Mg+2].[F:38][C:39]([F:44])([F:43])[C:40]([NH2:42])=[O:41]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Cl:16][C:17]1[N:18]=[C:19]([C:30]([S:33]([CH3:35])(=[O:34])=[N:42][C:40](=[O:41])[C:39]([F:44])([F:43])[F:38])([CH3:32])[CH3:31])[CH:20]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[N:22]=1

Participants

7

Reactant 4

HCID 67717TrifluoroacetamideHCID 6850729Magnesium monoxideHCID 12217721Iodo benzene diacetateHCID 86660224Morpholine, 4-[2-chloro-6-[1-methyl-1-(methylsulfinyl)ethyl]-4-pyrimidinyl]-3-methyl-, (3R)-

Product 1

HCID 86660223HCID 86660223, compoundYield 31%

Reagents, catalysts & solvents 2

HCID 152122Dirhodium tetraacetateCatalystHCID 6344DichloromethaneSolvent

Procedure

(3R)-4-(2-Chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (1.75 g, 6.04 mmol) was dissolved in DMF (34.6 ml), to this was added slowly NaH (0.604 g, 15.10 mmol) and the reaction mixture was stirred for 5 minutes at RT. To the mixture was rapidly added methyl iodide (0.944 ml, 15.10 mmol) and the mixture was stirred for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (50 mL), extracted with DCM (3×50 mL) and the combined organic layers were passed through a phase separating column and then evaporated to afford a yellow gum. Water (50 mL) was added to the gum and the mixture extracted with EtOAc (3×50 mL). The combined organic layers were dried over MgSO4, filtered and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 3% MeOH in DCM. Pure fractions were evaporated to afford (3R)-4-(2-chloro-6-(2-(methylsulfinyl)propan-2-yl)pyrimidin-4-yl)-3-methylmorpholine (1.693 g, 88%); 1H NMR (400 MHz, DMSO-d6) 1.19 (3H, d), 1.49 (6H, dd), 2.17 (3H, t), 3.19 (1H, dd), 3.37-3.48 (1H, m), 3.57 (1H, dd), 3.71 (1H, d), 3.92 (1H, d), 4.03 (1H, s), 4.41 (1H, s), 6.70 (1H, s); m/z: (ES+) MH+, 318.09 and 320.04. b) Iodobenzene diacetate (1.716 g, 5.33 mmol) was added to (3R)-4-(2-chloro-6-(2-(methylsulfinyl)propan-2-yl)pyrimidin-4-yl)-3-methylmorpholine (1.693 g, 5.33 mmol), magnesium oxide (0.859 g, 21.31 mmol), 2,2,2-trifluoroacetamide (1.204 g, 10.65 mmol) and rhodium(II) acetate dimer (0.059 g, 0.13 mmol) in DCM (100 mL). The resulting suspension was stirred at RT for 18 hours. The reaction mixture was filtered through Celite and then concentrated in vacuo onto silica (15 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to afford N-[(2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}propan-2-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (0.700 g, 31%); 1H NMR (400 MHz, DMSO-d6) 1.20 (3H, dd), 1.83 (6H, d), 3.20 (1H, dd), 3.41 (1H, dddd), 3.56 (1H, d), 3.59 (3H, d), 3.72 (1H, d), 3.94 (1H, dd), 4.07 (1H, s), 4.45 (1H, s), 6.93 (1H, d); m/z: (ES+) MH+, 429.4 and 431.5.

Workup

  1. filtrationThe reaction mixture was filtered through Celite
  2. concentrationconcentrated in vacuo onto silica (15 g)
  3. customThe resulting powder was purified by flash chromatography on silica
  4. washeluting with a gradient of 0 to 10% MeOH in DCM
  5. customPure fractions were evaporated

Sources & evidence

ORD record
ord-cd7db321faed41359e938b7be97d3125
Source dataset
uspto-grants-2015_04
Patent number
US08999997B2

Reaction notes

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