Hydrochloric Acid → (R)-2-tert-Butyl-4-cyclobutyl-6-{4-[2-methyl-3-(pyrimidin-2-yloxy)-propyl]-piperazin-1-yl}-pyrimidine hydrochloride

HRID 219739Notes

Reaction equation

HRID 219739 reaction equation
[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.Cl>CN(C)C=O.C(OC)(C)(C)C.O1CCOCC1.C(OCC)(=O)C.O>[ClH:28].[C:1]([C:5]1[N:6]=[C:7]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[CH:8]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C@@H:18]([CH3:21])[CH2:19][O:20][C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:15][CH2:16]2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

10

Reactant 4

HCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 744042-ChloropyrimidineHCID 69025424(R)-3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-2-methyl-propan-1-ol

Product 1

HCID 69029357(R)-2-tert-Butyl-4-cyclobutyl-6-{4-[2-methyl-3-(pyrimidin-2-yloxy)-propyl]-piperazin-1-yl}-pyrimidine hydrochlorideYield 41.8%

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolventHCID 15413tert-Butyl methyl etherSolventHCID 312751,4-DioxaneSolvent

Procedure

0.755 g of (R)-3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-2-methyl-propan-1-ol (2.18 mmol) were stirred in 7.6 ml of dimethylformamide under argon. 0.105 g of 60% sodium hydride (2.6 mmol) were added and stirred for 10 min. A solution of 0.275 g of 2-chloro-pyrimidine (2.4 mmol) in 2.4 ml of dimethylformamide was added. The reaction mixture was stirred for 16 h, followed by the addition of 30 ml of water and 40 ml of ethyl acetate. The organic layer was separated and the aqueous phase extracted with a further portion of ethyl acetate. The combined extracts were concentrated to dryness and the crude product purified by flash column chromatography eluting with ethyl acetate. The fractions containing the product were combined and evaporated under reduced pressure to give a pale yellow oil. The oil was dissolved in tert-butyl methylether and 4 N hydrochloric acid in dioxan was added to the solution. A white solid separated. The precipitate was collected by filtration, washed with tert-butyl methyl ether and dried in a vacuum oven to yield 0.42 g of the title compound.

Workup

  1. stirringThe reaction mixture was stirred for 16 h
  2. customThe organic layer was separated
  3. extractionthe aqueous phase extracted with a further portion of ethyl acetate
  4. concentrationThe combined extracts were concentrated to dryness
  5. customthe crude product purified by flash column chromatography
  6. washeluting with ethyl acetate
  7. additionThe fractions containing the product
  8. customevaporated under reduced pressure
  9. customto give a pale yellow oil
  10. customA white solid separated
  11. filtrationThe precipitate was collected by filtration
  12. washwashed with tert-butyl methyl ether
  13. customdried in a vacuum oven

Sources & evidence

ORD record
ord-9d975aa1a1a74a58be0ad39f2637f926
Source dataset
uspto-grants-2012_06
Patent number
US08202868B2

Reaction notes

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