Boron trifluoride etherate → 1-(5-Aminohexyl)-3,7-dimethylxanthine

HRID 1742631Notes

Reaction equation

HRID 1742631 reaction equation
B(F)(F)F.CCOCC.O[CH:11]([CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH3:27])[CH:22]=[N:21][C:20]=2[N:19]([CH3:28])[C:17]1=[O:18].C[Si]([N:34]=[N+]=[N-])(C)C.C(OP(OCC)OCC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCC.O>[NH2:34][CH:11]([CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH3:27])[CH:22]=[N:21][C:20]=2[N:19]([CH3:28])[C:17]1=[O:18]

Participants

8

Reactant 5

HCID 8000Boron trifluoride etherateHCID 31215Triethyl phosphiteHCID 57782(+/-)-LisofyllineHCID 78378AzidotrimethylsilaneHCID 521998p-Toluenesulfonic acid monohydrate

Product 1

HCID 98171351-(5-Aminohexyl)-3,7-dimethylxanthineYield 50%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8003PentaneSolvent

Procedure

The method described in Koziara and Zwierzak, Tetrahedron Letters 28:6513-6516,1987 was followed to make CT1520. Briefly, boron trifluoride etherate (0.06 mol) was added dropwise at 10°-30° C. to a stirred solution of 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (0.05 mol) and trimethylsilylazide (0.06 mol) in pentane (50 ml). After 24 hours at room temperature the mixture was poured into 100 mls of water. The organic phase was separated, washed with a 10% solution of sodium bicarbonate, and dried over sodium sulfate. The solution of the azide in pentane was stirred at 25°-30° C., and 0.05 mol of triethylphosphite was added. Stirring was continued for 6 hours, and the solution was left at this temperature for 72 hours. Solvent was evaporated off and the iminophosphorane was dissolved in ethanol (15 mls) and treated with p-toluenesulfonic acid monohydrate (0.05 mol) and water (0.05 mol). The mixture was refluxed for eight hours, evaporated and the residue diluted with 100 mls of ether. The tosyl salt of the amine was precipitated out and was recovered by filtration. Then, 30% aqueous ammonium hydroxide (20 mls) was added to the crystals and the free amine was extracted into dichloromethane (3×15 mls), dried over sodium sulfate and the solvent evaporated to yield the free amine as a viscous oil, 0.7 g with a 50% yield.

Workup

  1. customThe organic phase was separated
  2. washwashed with a 10% solution of sodium bicarbonate
  3. dry with materialdried over sodium sulfate
  4. stirringStirring
  5. waitthe solution was left at this temperature for 72 hours
  6. customSolvent was evaporated off
  7. dissolutionthe iminophosphorane was dissolved in ethanol (15 mls)
  8. temperatureThe mixture was refluxed for eight hours
  9. customevaporated
  10. additionthe residue diluted with 100 mls of ether
  11. customThe tosyl salt of the amine was precipitated out and
  12. filtrationwas recovered by filtration
  13. additionThen, 30% aqueous ammonium hydroxide (20 mls) was added to the crystals
  14. extractionthe free amine was extracted into dichloromethane (3×15 mls)
  15. dry with materialdried over sodium sulfate
  16. customthe solvent evaporated

Sources & evidence

ORD record
ord-eb3f63085c7141038d280655093c12db
Source dataset
uspto-grants-1994_08
Patent number
US05340813

Reaction notes

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