Trifluoroacetamide → N-[(4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}tetrahydro-2H-pyran-4-yl)(methyl)oxido-lambda6-sulfanylidene]-2,2,2-trifluoroacetamide

HRID 1038910Notes

Reaction equation

HRID 1038910 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]2([S:36]([CH3:38])=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:18]=1.[O-2].[Mg+2].[F:41][C:42]([F:47])([F:46])[C:43]([NH2:45])=[O:44]>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]2([S:36]([CH3:38])(=[O:37])=[N:45][C:43](=[O:44])[C:42]([F:47])([F:46])[F:41])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[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 86660225(3R)-4-(2-chloro-6-(4-(methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine

Product 1

HCID 86660226N-[(4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}tetrahydro-2H-pyran-4-yl)(methyl)oxido-lambda6-sulfanylidene]-2,2,2-trifluoroacetamideYield 88.2%

Reagents, catalysts & solvents 2

HCID 152122Dirhodium tetraacetateCatalystHCID 6344DichloromethaneSolvent

Procedure

Sodium hydroxide (50% w/w) (20.04 ml, 379.60 mmol) was added to (3R)-4-(2-chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (2.2 g, 7.59 mmol), 1-bromo-2-(2-bromoethoxy)ethane (3.79 ml, 30.37 mmol) and tetraoctylammonium bromide (0.415 g, 0.76 mmol) in methyl THF (20.05 ml). The resulting mixture was stirred at RT for 90 minutes. The reaction mixture was diluted with methyl THF (50 mL), and washed sequentially with water (50 ml) and saturated brine (5 ml). The organic layer was dried over MgSO4, filtered and then evaporated onto silica (30 g). The resulting powder 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-(4-(methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine (1.360 g, 50%); 1H NMR (400 MHz, DMSO-d6) 1.84-1.96 (1H, m), 2.02 (1H, td), 2.09 (3H, d), 2.27-2.45 (2H, m), 3.14 (1H, d), 3.10-3.26 (3H, m), 3.24 (1H, d), 3.33-3.41 (1H, m), 3.45 (1H, td), 3.60 (1H, dd), 3.71 (1H, d), 3.78-3.87 (1H, m), 3.87-3.97 (2H, m), 4.07 (1H, d), 4.32-4.48 (1H, m), 6.76 (1H, s); m/z: (ES+) MH+, 360.11 and 362.06. b) Iodobenzene diacetate (0.788 g, 2.45 mmol) was added to (3R)-4-(2-chloro-6-(4-(methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine (0.88 g, 2.45 mmol), magnesium oxide (0.394 g, 9.78 mmol), 2,2,2-trifluoroacetamide (0.553 g, 4.89 mmol) and rhodium(II) acetate dimer (0.027 g, 0.06 mmol) in DCM (20 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 (50 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 20 to 60% EtOAc in isohexane. Pure fractions were evaporated to afford N-[(4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}tetrahydro-2H-pyran-4-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (1.018 g, 88%); 1H NMR (400 MHz, DMSO-d6) 1.34 (3H, dd), 2.49 (1H, td), 2.63 (2H, ddd), 2.75-2.82 (1H, m), 3.26 (3H, d), 3.29-3.41 (3H, m), 3.49 (1H, s), 3.51-3.60 (1H, m), 3.63-3.73 (1H, m), 3.80 (1H, d), 3.98-4.11 (4H, m), 6.68 (1H, d); m/z: (ES−) M-H−, 469.04 and 471.03.

Workup

  1. filtrationThe reaction mixture was filtered through Celite
  2. concentrationconcentrated in vacuo onto silica (50 g)
  3. customThe resulting powder was purified by flash chromatography on silica
  4. washeluting with a gradient of 20 to 60% EtOAc in isohexane
  5. customPure fractions were evaporated

Sources & evidence

ORD record
ord-a2688dcbbaaf4ed1ad75cbc8f0c09691
Source dataset
uspto-grants-2013_10
Patent number
US08552004B2

Reaction notes

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