Lithium Hydroxide → 2-tert-Butyl-4-cyclobutyl-6-{4-[3-(pyridin-2-ylsulfanyl)-propyl]-piperazine-1-yl}-pyrimidine hydrochloride

HRID 219720Notes

Reaction equation

HRID 219720 reaction equation
[SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Li+].[I-].[Na+].[C:12]([C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][Cl:31])[CH2:24][CH2:23]2)[CH:19]=[C:18]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:17]=1)([CH3:15])([CH3:14])[CH3:13]>CN(C)C=O>[ClH:31].[C:12]([C:16]1[N:17]=[C:18]([CH:32]2[CH2:33][CH2:34][CH2:35]2)[CH:19]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][S:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:24][CH2:23]2)[N:21]=1)([CH3:15])([CH3:13])[CH3:14]

Participants

6

Reactant 4

HCID 3939Lithium HydroxideHCID 5238Sodium IodideHCID 666731042-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidineHCID 178418616HCID 178418616, compound

Product 1

HCID 690750952-tert-Butyl-4-cyclobutyl-6-{4-[3-(pyridin-2-ylsulfanyl)-propyl]-piperazine-1-yl}-pyrimidine hydrochlorideYield 113%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

0.2 g of 2-mercapto-pyridine (1.8 mmol) were dissolved in 15 ml of dimethylformamide. After addition of 0.04 g of lithium hydroxide (1.8 mmol) and 0.13 g of sodium iodide (0.9 mmol), the reaction mixture was stirred at 70° C. and 0.63 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine (0.9 mmol) were added in portions. The mixture was stirred at 80° C. for 5 h, and, after evaporation of dimethylformamide, the residue was partitioned between 20 ml of ethyl acetate and 15 ml of saturated aqueous sodium chloride solution and 15 ml of water. The aqueous phase was re-extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane, dichloromethane-ethyl acetate (7:3-1:1). Fractions containing the product were combined. After evaporation of the solvent, the residue was re-dissolved in 20 ml of ethyl acetate and a 1 N solution of hydrochloric acid in diethyl ether was added. The precipitated hydrochloride salt was collected by filtration and dried to give 0.47 g of the title compound.

Workup

  1. stirringThe mixture was stirred at 80° C. for 5 h
  2. customafter evaporation of dimethylformamide
  3. customthe residue was partitioned between 20 ml of ethyl acetate and 15 ml of saturated aqueous sodium chloride solution and 15 ml of water
  4. extractionThe aqueous phase was re-extracted twice with ethyl acetate
  5. dry with materialThe combined organic layers were dried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated to dryness
  8. customThe crude product was purified by chromatography on silica gel
  9. additionFractions containing the product
  10. customAfter evaporation of the solvent
  11. dissolutionthe residue was re-dissolved in 20 ml of ethyl acetate
  12. additiona 1 N solution of hydrochloric acid in diethyl ether was added
  13. filtrationThe precipitated hydrochloride salt was collected by filtration
  14. customdried

Sources & evidence

ORD record
ord-3ea4c9d3f3bd4b5193526795df638485
Source dataset
uspto-grants-2012_06
Patent number
US08202868B2

Reaction notes

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