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

HRID 1465856Notes

Reaction equation

HRID 1465856 reaction equation
O.[OH-].[Cs+].[Cl:4][C:5]1[N:10]=[C:9]([CH2:11][S:12]([CH3:21])(=[O:20])=[N:13]C(=O)C(F)(F)F)[CH:8]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@H:23]2[CH3:28])[N:6]=1.Br[CH2:30][CH2:31]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:4][C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@H:23]2[CH3:28])[CH:8]=[C:9]([C:11]2([S@@:12]([CH3:21])(=[NH:13])=[O:20])[CH2:31][CH2:30]2)[N:10]=1

Participants

6

Reactant 3

HCID 78391,2-Dibromoethane2×HCID 23679066Caesium hydroxide--water (1/1/1)2×HCID 86660215N-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methyl)(methyl)oxido-lambda6-sulfanylidene]-2,2,2-trifluoroacetamide

Product 1

HCID 86660221(3R)-4-(2-chloro-6-(1-((S)-S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholineYield 44%

Reagents, catalysts & solvents 2

HCID 2734117Tetraoctylammonium bromideCatalystHCID 178479889HCID 178479889, compoundSolvent

Conditions

Temperature
20 °C

Procedure

Iodobenzene diacetate (78 g, 243.29 mmol) was added to (3R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (70.5 g, 243.29 mmol), 2,2,2-trifluoroacetamide (55.0 g, 486.57 mmol), magnesium oxide (39.2 g, 973.15 mmol) and rhodium(II) acetate dimer (2.69 g, 6.08 mmol) in DCM (2433 ml) under air. The resulting suspension was stirred at 20° C. for 24 hours. Further 2,2,2-trifluoroacetamide (13.75 g, 121.64 mmol), magnesium oxide (9.81 g, 243.29 mmol), iodobenzene diacetate (19.59 g, 60.82 mmol) and rhodium(II) acetate dimer (0.672 g, 1.52 mmol) were added and the suspension was stirred at 20° C. for 1 day. The reaction mixture was filtered and then silica gel (200 g) added to the filtrate and the solvent removed in vacuo. The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 20 to 50% EtOAc in heptane. Pure fractions were concentrated and the resultant precipitate collected by filtration to afford N—[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-X6-sulfanylidene]-2,2,2-trifluoroacetamide as a 7:1 mixture of S:R isomers (26.14 g, 27%); 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.28 (1H, dd), 3.42 (3H, d), 3.46-3.57 (1H, m), 3.61-3.70 (1H, m), 3.79 (1H, d), 4.02 (1H, dd), 4.65 (1H, d), 4.85 (1H, dd), 6.49 (1H, d); m/z: (ES+) MH+, 400.94 and 402.85. Chiral HPLC: (HP1100 System 4, 5 μm Chiralpak AD-H (250 mm×4.6 mm) column eluting with Heptane/EtOH 50/50) Rf, 4.367 12.5%, 6.053 87.5%. The mother liquers were concentrated in vacuo to yield a colourless gum. The gum was triturated with isohexane to give a solid which was collected by filtration and dried under vacuum to afford N-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide as a 2.8:1 mixture of R: S isomers (47.1 g, 48%); 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.31 (1H, t), 3.42 (3H, d), 3.47-3.57 (1H, m), 3.62-3.70 (1H, m), 3.79 (1H, d), 4.02 (1H, dd), 4.65 (1H, dd), 4.86 (1H, dd), 6.49 (1H, d); m/z: (ES+) MH+, 400.94 and 402.86. Chiral HPLC: (HP1100 System 4, 5 μm Chiralpak AD-H (250 mm×4.6 mm) column eluting with Heptane/EtOH 50/50) Rf, 4.365 73.5%, 6.067 26.4%. b) Cesium hydroxide-hydrate (0.390 g, 3.43 mmol) was added to a 7:1 mixture of S:R isomers of N-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (0.209 g, 0.69 mmol), 1,2-dibromoethane (0.236 ml, 2.74 mmol) and tetraoctylammonium bromide (0.037 g, 0.07 mmol) in methyl THF (2 ml) at 20° C. under nitrogen. The resulting mixture was stirred at 20° C. for 16 hours. Further 1,2-dibromoethane (0.236 mL, 2.74 mmol) was added and the mixture was stirred at 20° C. for 24 hours. A second portion of cesium hydroxide-hydrate (0.390 g, 3.43 mmol) was added and the mixture stirred over a weekend. The reaction mixture was filtered and silica gel (5 g) added to the filtrate. The mixture was concentrated in vacuo and the resultant powder was then 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)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine (0.099 g, 44%); 1H NMR (400 MHz, CDCl3) 1.31 (3H, t), 1.43 (2H, h), 1.67-1.75 (2H, m), 2.33 (1H, s), 3.09 (3H, s), 3.29 (1H, td), 3.53 (1H, td), 3.67 (1H, dd), 3.78 (1H, d), 4.00 (2H, dd+broad s), 4.33 (1H, s), 6.78 (1H, s); m/z: (ES+) MH+, 331.04 and 332.99. Chiral HPLC: (HP1100 System 4, 5 μm Chiralpak AD-H (250 mm×4.6 mm) column eluting with Heptane/IPA/TEA 70/30/0.1) Rf, 5.948 89.5%.]

Workup

  1. additionas a 2.8:1 mixture of R
  2. washChiral HPLC: (HP1100 System 4, 5 μm Chiralpak AD-H (250 mm×4.6 mm) column eluting with Heptane/EtOH 50/50) Rf, 4.365 73.5%, 6.067 26.4%
  3. customat 20° C.
  4. stirringthe mixture was stirred at 20° C. for 24 hours
  5. stirringthe mixture stirred over a weekend
  6. filtrationThe reaction mixture was filtered
  7. additionsilica gel (5 g) added to the filtrate
  8. concentrationThe mixture was concentrated in vacuo
  9. customthe resultant powder was then purified by flash chromatography on silica
  10. washeluting with a gradient of 0 to 5% MeOH in DCM
  11. customPure fractions were evaporated

Sources & evidence

ORD record
ord-e81bec15c5e54830b4cf0fbe9ff5257a
Source dataset
uspto-grants-2015_04
Patent number
US08999997B2

Reaction notes

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