Ammonium Chloride → (R)-3-isopropyl-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one

HRID 1051816Notes

Reaction equation

HRID 1051816 reaction equation
Cl.[CH:2]([C@H:5]1[NH:10][CH2:9][CH2:8][NH:7][C:6]1=[O:11])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.Cl[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=1.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[CH:2]([C@H:5]1[N:10]([C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH2:9][CH2:8][NH:7][C:6]1=[O:11])([CH3:4])[CH3:3]

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 27739122-Chloro-4-(trifluoromethyl)pyrimidineHCID 89815067(R)-3-isopropylpiperazin-2-one hydrochloride

Product 1

HCID 89814804(R)-3-isopropyl-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-oneYield 96%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of (R)-3-isopropylpiperazin-2-one hydrochloride (2.61 g, 14.62 mmol) and iPr2NEt (7.60 mL, 43.86 mmol) in DMF (20 mL) was added a solution of 2-chloro-4-(trifluoromethyl)pyrimidine (3.47 g, 19.00 mmol) in DMF (2 mL). The resulting solution was stirred at 100° C. under N2 for 3 h at which point the reaction was deemed complete by LC-MS. Sat. aq. NH4Cl (30 mL) was added to quench the reaction, followed by addition of EtOAc (30 mL). The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (3×20 mL). The EtOAc layers were combined, dried using Na2SO4 and evaporated to give nearly pure crude product. Purification on a silica cartridge using ISCO FCC eluting with 100% EtOAc gave 4.03 grams of (R)-3-isopropyl-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (96%) as a slightly orange thick oil. LC-MS m/z 289.17 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 8.52 (d, J=4.8 Hz, 1H), 6.82 (d, J=4.4 Hz, 1H), 6.56 (br, 1H), 5.20 (d, J=6.8 Hz, 1H), 4.83-4.77 (m, 1H), 3.55-3.37 (m, 3H), 2.49-2.41 (m, 1H), 1.15 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H).

Workup

  1. customto quench
  2. customthe reaction
  3. customThe EtOAc layer was separated
  4. extractionthe aqueous layer was extracted with EtOAc (3×20 mL)
  5. customdried
  6. customevaporated
  7. customto give nearly pure crude product
  8. customPurification on a silica cartridge
  9. washeluting with 100% EtOAc

Sources & evidence

ORD record
ord-f7410ab916f14d9ab2a86ee560a5e006
Source dataset
uspto-grants-2016_07
Patent number
US09388190B2

Reaction notes

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