Ammonium Chloride → E-(6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamide

HRID 445939Notes

Reaction equation

HRID 445939 reaction equation
C1(P(=O)(C2C=CC=CC=2)[CH2:8][C:9]2[C:10]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[N:11][C:12]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:13][C:14]=2[CH:15]([CH3:17])[CH3:16])C=CC=CC=1.[CH:38]([C@H:40]1[O:45][C:44]([CH3:47])([CH3:46])[O:43][C@@H:42]([CH2:48][C:49]([N:51]([O:53][CH3:54])[CH3:52])=[O:50])[CH2:41]1)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH3:23][N:18]([C:12]1[N:11]=[C:10]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:9](/[CH:8]=[CH:38]/[C@H:40]2[O:45][C:44]([CH3:47])([CH3:46])[O:43][C@@H:42]([CH2:48][C:49]([N:51]([O:53][CH3:54])[CH3:52])=[O:50])[CH2:41]2)=[C:14]([CH:15]([CH3:16])[CH3:17])[N:13]=1)[S:19]([CH3:22])(=[O:21])=[O:20]

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 2724254Sodium bis(trimethylsilyl)amideHCID 9937035N-(5-((diphenylphosphoryl)methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamideHCID 866815072-[(4R,6S)-6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide

Product 1

HCID 86681509E-(6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamideYield 75.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 21226206Ethyl acetate hexaneSolvent

Procedure

Diphenyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphine oxide (10.9 g), 2-[(4R,6S)-6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (4.5 g), and tetrahydrofuran (90.0 mL) were added to a reactor under nitrogen atmosphere. The reaction mixture was cooled to −40˜−30° C. A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 20.0 mL) was slowly added to the reaction mixture, while maintaining the temperature of −40˜−30° C. The temperature of the reaction mixture was raised to 0˜5° C. for 30 minutes. The reaction mixture was stirred at the same temperature for 2˜3 hours. The reaction was monitored with thin layer chromatography (ethyl acetate/n-hexane=1:3). An ammonium chloride solution (50.0 mL) was added to the reaction mixture. The separated organic layer was washed with 8% sodium bicarbonate solution (50.0 mL) and then concentrated under reduced pressure. Isopropanol (45.0 mL) was added to the resulting residue. The reaction mixture was stirred at 0˜5° C. for 1˜2 hours and then filtered under reduced pressure. The resulting white solid was dried under vacuum to obtain E-(6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamide (7.8 g, yield 75%).

Workup

  1. temperatureThe reaction mixture was cooled to −40˜−30° C
  2. temperaturewhile maintaining the temperature of −40˜−30° C
  3. temperatureThe temperature of the reaction mixture was raised to 0˜5° C. for 30 minutes
  4. washThe separated organic layer was washed with 8% sodium bicarbonate solution (50.0 mL)
  5. concentrationconcentrated under reduced pressure
  6. additionIsopropanol (45.0 mL) was added to the resulting residue
  7. stirringThe reaction mixture was stirred at 0˜5° C. for 1˜2 hours
  8. filtrationfiltered under reduced pressure
  9. customThe resulting white solid was dried under vacuum

Sources & evidence

ORD record
ord-b7e27216a2ca4c4baddb1abd3743577b
Source dataset
uspto-grants-2013_07
Patent number
US08476432B2

Reaction notes

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