Hydrochloric Acid → 2-tert-Butyl-4-cyclopropyl-6-{4-[3-(1-methyl-1H-tetrazol-5-ylsulfanyl)-propyl]-piperazin-1-yl}-pyrimidine hydrochloride

HRID 219742Notes

Reaction equation

HRID 219742 reaction equation
[CH3:1][N:2]1[C:6]([SH:7])=[N:5][N: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[CH2:34][CH2:33]2)[N:17]=1)([CH3:15])([CH3:14])[CH3:13].Cl>CN(C)C=O.O1CCOCC1>[ClH:31].[C:12]([C:16]1[N:17]=[C:18]([CH:32]2[CH2:33][CH2:34]2)[CH:19]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][S:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[CH2:24][CH2:23]2)[N:21]=1)([CH3:15])([CH3:13])[CH3:14]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 5238Sodium IodideHCID 690261252-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclopropyl-pyrimidineHCID 178482017HCID 178482017, compound

Product 1

HCID 690262452-tert-Butyl-4-cyclopropyl-6-{4-[3-(1-methyl-1H-tetrazol-5-ylsulfanyl)-propyl]-piperazin-1-yl}-pyrimidine hydrochlorideYield 66.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

0.346 g of 1-Methyl-1H-tetrazole-5-thiol (2.98 mmol), 0.071 g of lithium hydroxide (2.98 mmol), and 0.223 g of sodium iodide (1.49 mmol) were stirred in 25 ml of dimethylformamide at 70° C. A solution of 1 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclopropyl-pyrimidine (2.98 mmol) in 4 ml of dimethylformamide was added slowly within 2 h. After stirring for 2 h at 80° C., the dimethylformamide was evaporated under reduced pressure. The residue was partitioned between 15 ml of aqueous sodium chloride, 15 ml of water and 30 ml of ethyl acetate. The aqueous phase was re-extracted twice with ethyl acetate. The combined ethyl acetate phases were combined and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The crude product obtained was purified by column chromatography on silica gel using dichloromethane-ethyl acetate (7:3). Fractions containing the product were combined. The solvent was evaporated under reduced pressure. The residue was re-dissolved in 12 ml of ethyl acetate and treated with 2 equivalents of hydrochloric acid in dioxane. The supernatant was removed with a pipette, diisopropyl ether was added, the mixture was stirred, and the solvent was evaporated slowly under reduced pressure to yield 0.9 g of the title compound.

Workup

  1. customthe dimethylformamide was evaporated under reduced pressure
  2. customThe residue was partitioned between 15 ml of aqueous sodium chloride, 15 ml of water and 30 ml of ethyl acetate
  3. extractionThe aqueous phase was re-extracted twice with ethyl acetate
  4. dry with materialdried over magnesium sulfate
  5. customThe solvent was evaporated under reduced pressure
  6. customThe crude product obtained
  7. customwas purified by column chromatography on silica gel
  8. additionFractions containing the product
  9. customThe solvent was evaporated under reduced pressure
  10. dissolutionThe residue was re-dissolved in 12 ml of ethyl acetate
  11. customThe supernatant was removed with a pipette, diisopropyl ether
  12. additionwas added
  13. stirringthe mixture was stirred
  14. customthe solvent was evaporated slowly under reduced pressure

Sources & evidence

ORD record
ord-977709eac9e745619c95371a87c302e9
Source dataset
uspto-grants-2012_06
Patent number
US08202868B2

Reaction notes

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