Diethyl chlorophosphate → 2-(4-{[(1E)-5-pyrimidin-2-ylpent-1-en-1-yl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidine

HRID 1723808Notes

Reaction equation

HRID 1723808 reaction equation
[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.P(Cl)(OCC)(OCC)=O.[N:42]1[CH:47]=[CH:46][CH:45]=[N:44][C:43]=1[CH2:48][CH2:49][CH2:50][CH:51]=O>C1COCC1>[N:42]1[CH:47]=[CH:46][CH:45]=[N:44][C:43]=1[CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:1]/[S:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]

Participants

6

Reactant 4

HCID 13139Diethyl chlorophosphateHCID 2733832Lithium HexamethyldisilazideHCID 115283684-(Pyrimidin-2-yl)butanalHCID 575592412-[4-(Methanesulfonyl)piperazin-1-yl]-5-(2,2,2-trifluoroethoxy)pyrimidine

Product 1

HCID 688456502-(4-{[(1E)-5-pyrimidin-2-ylpent-1-en-1-yl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidineYield 96%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

To a stirred suspension of 2-[4-(methylsulfonyl)piperazin-1-yl]-5-(2,2,2-trifluoroethoxy)pyrimidine (850 mg, 2.50 mmol) in THF (25 mL) at −78° C. was added LHMDS (5.5 mL, 5.5 mmol) dropwise and the reaction stirred for 15 minutes. Diethyl chlorophosphate (0.4 mL, 2.75 mmol) was then added and stirred for 15 minutes. The solution was then treated drop wise with a solution of 4-pyrimidin-2-ylbutanal (413 mg, 2.75 mmol) in THF (5 mL), allowed to warm to −20° C. and stirred for 1 hour. The reaction was then quenched by addition of a saturated solution of NH4Cl (100 mL), extracted twice with EtOAc (2×100 mL), combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. This was then purified by flash chromatography (silica gel, 50% EtOAc/hexanes) to give 2-(4-{[(1E)-5-pyrimidin-2-ylpent-1-en-1-yl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidine as a yellow solid (1.13 g, 2.39 mmol, 96%).

Workup

  1. stirringstirred for 15 minutes
  2. stirringstirred for 1 hour
  3. customThe reaction was then quenched by addition of a saturated solution of NH4Cl (100 mL)
  4. extractionextracted twice with EtOAc (2×100 mL)
  5. washcombined organics were washed with brine (100 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto give a yellow oil
  10. customThis was then purified by flash chromatography (silica gel, 50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-e9c846592acd4eb785c6ee4308ab49a1
Source dataset
uspto-grants-2009_02
Patent number
US07485644B2

Reaction notes

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