Lithium Hydroxide → 2-tert-Butyl-4-{4-[3-(4-methyl-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-cyclopropyl-pyrimidine hydrochloride

HRID 219750Notes

Reaction equation

HRID 219750 reaction equation
[CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[C:3]1[SH:8].[OH-].[Li+].[I-].[Na+].[C:13]([C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][Cl:32])[CH2:25][CH2:24]2)[CH:20]=[C:19]([CH:33]2[CH2:35][CH2:34]2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[ClH:32].[C:13]([C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][S:8][C:3]3[N:2]([CH3:1])[C:6]([CH3:7])=[N:5][N:4]=3)[CH2:25][CH2:24]2)[CH:20]=[C:19]([CH:33]2[CH2:34][CH2:35]2)[N:18]=1)([CH3:14])([CH3:15])[CH3:16]

Participants

6

Reactant 4

HCID 3939Lithium HydroxideHCID 5238Sodium IodideHCID 690261252-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclopropyl-pyrimidineHCID 178434152HCID 178434152, compound

Product 1

HCID 690806332-tert-Butyl-4-{4-[3-(4-methyl-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-cyclopropyl-pyrimidine hydrochloride

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
80 °C

Procedure

0.23 g of 4-Methyl-5-methyl-4H-[1,2,4]triazole-3-thiol (1.78 mmol), 0.04 g lithium hydroxide (1.78 mmol) and 0.13 g sodium iodide (0.89 mmol) were dissolved in 20 ml of dimethylformamide. Within 2 h, 0.6 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclopropyl-pyrimidine (1.78 mmol), dissolved in 5 ml dimethylformamide, were added at 70° C. The mixture was stirred for 1 h at 80° C. After cooling to room temperature, the solvent was evaporated and the oily residue partitioned between 30 ml of ethyl acetate and 15 ml of water plus 15 ml of a saturated solution of sodium chloride in water. The aqueous layer was reextracted twice with 20 ml of ethyl acetate each, the organic phases combined, dried over magnesium sulfate, filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel using ethyl acetate, ethyl acetate-methanol 9:1, and ethyl acetate-methanol 1:1. Fractions containing the product were combined. After evaporation of the solvent, the residue was re-dissolved in diisopropylethyl ether and a 1 N solution of HCl in diethylether was added. The precipitated hydrochloride salt was collected by filtration. Yield: 343 mg.

Workup

  1. additionwere added at 70° C
  2. temperatureAfter cooling to room temperature
  3. customthe solvent was evaporated
  4. customthe oily residue partitioned between 30 ml of ethyl acetate and 15 ml of water plus 15 ml of a saturated solution of sodium chloride in water
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. customthe solvent was evaporated
  8. customThe residue was purified by column chromatography on silica gel
  9. additionFractions containing the product
  10. customAfter evaporation of the solvent
  11. dissolutionthe residue was re-dissolved in diisopropylethyl ether
  12. additiona 1 N solution of HCl in diethylether was added
  13. filtrationThe precipitated hydrochloride salt was collected by filtration

Sources & evidence

ORD record
ord-c525d7240aad4a18851121093fd34ebe
Source dataset
uspto-grants-2012_06
Patent number
US08202868B2

Reaction notes

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