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

HRID 219719Notes

Reaction equation

HRID 219719 reaction equation
[SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH: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][N:5]=[CH:4][CH: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 178418431pyridine-4-thiol

Product 1

HCID 690805262-tert-Butyl-4-cyclobutyl-6-{4-[3-(pyridin-4-ylsulfanyl)-propyl]-piperazin-1-yl}-pyrimidine hydrochlorideYield 129.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

0.21 g of 4-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 2 h, and after evaporation of dimethylformamide, 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 reextracted 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 with ethyl acetate and ethyl acetate-methanol (9:1). Fractions containing the product were combined. After evaporation of the solvent, the residue was re-dissolved in 15 ml of ethyl acetate and 1 N solution of hydrochloric acid in diethyl ether was added. The precipitated hydrochloride salt was collected by filtration and dried to give 0.54 g of the title product.

Workup

  1. stirringThe mixture was stirred at 80° C. for 2 h
  2. customafter evaporation of dimethylformamide
  3. custompartitioned between 20 ml of ethyl acetate and 15 ml of saturated aqueous sodium chloride solution and 15 ml of water
  4. dry with materialThe combined organic layers were dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated to dryness
  7. customThe crude product was purified by chromatography on silica gel with ethyl acetate and ethyl acetate-methanol (9:1)
  8. additionFractions containing the product
  9. customAfter evaporation of the solvent
  10. dissolutionthe residue was re-dissolved in 15 ml of ethyl acetate
  11. addition1 N solution of hydrochloric acid in diethyl ether was added
  12. filtrationThe precipitated hydrochloride salt was collected by filtration
  13. customdried

Sources & evidence

ORD record
ord-1c33b3b73bab49a498f0f99f5933d74d
Source dataset
uspto-grants-2012_06
Patent number
US08202868B2

Reaction notes

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