Piperazine → 6-Chloro-7-(2,2-difluorethyloxy)-2-piperazin-1-yl-4-pyrrolidin-1-yl-pteridine

HRID 330846Notes

Reaction equation

HRID 330846 reaction equation
[F:1][CH:2]([F:5])[CH2:3][OH:4].C(NC(C)C)(C)C.[Li].[N:14]1([C:19]2[C:28]3[C:23](=[N:24][C:25](Cl)=[C:26]([Cl:29])[N:27]=3)[N:22]=[C:21](Cl)[N:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>O1CCCC1.O>[Cl:29][C:26]1[N:27]=[C:28]2[C:23](=[N:24][C:25]=1[O:4][CH2:3][CH:2]([F:5])[F:1])[N:22]=[C:21]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[N:20]=[C:19]2[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1

Participants

7

Reactant 4

HCID 4837PiperazineHCID 1361872,2-Difluoroethan-1-olHCID 137998844-Pyrrolidin-1-yl-2,6,7-trichloropteridineHCID 45051747Lithium diisopropylamine

Product 1

HCID 875101456-Chloro-7-(2,2-difluorethyloxy)-2-piperazin-1-yl-4-pyrrolidin-1-yl-pteridine

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
-10 °C

Procedure

a)+b) 50 μl (0.82 mmol) 2,2-difluorethanol are dissolved in 12 ml of tetrahydrofuran and under protective gas combined with 410 μl (0.82 mmol) of a 2 molar solution of lithium diisopropylamine in tetrahydrofuran. The mixture is stirred for 30 minutes and then the mixture is added to a solution of 250 mg (0.82 mmol) 4-pyrrolidin-1-yl-2,6,7-trichloro-pteridine in 12 ml of tetrahydrofuran cooled to −10° C. The mixture is stirred for one hour at −10° C., slowly allowed to come up to ambient temperature and stirred for another four hours. The solvent is eliminated in vacuo, the residue is combined with 50 ml of water and extracted with dichloromethane. The organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is taken up in 15 ml of tetrahydrofuran and combined with a solution of 313 mg (3.6 mmol) piperazine in 10 ml of tetrahydrofuran. The mixture is refluxed for approx. 16 hours, cooled to ambient temperature and the solvent is eliminated in vacuo. The residue is mixed with water and extracted with dichloromethane. The organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. Diisopropylether is added and a yellowish solid is obtained. Yield 225 mg (70% of theoretical)

Workup

  1. stirringThe mixture is stirred for one hour at −10° C.
  2. customto come up to ambient temperature
  3. stirringstirred for another four hours
  4. extractionextracted with dichloromethane
  5. customThe organic phase is dried on sodium sulphate
  6. temperatureThe mixture is refluxed for approx. 16 hours
  7. temperaturecooled to ambient temperature
  8. extractionextracted with dichloromethane
  9. customThe organic phase is dried on sodium sulphate
  10. additionDiisopropylether is added
  11. customa yellowish solid is obtained

Sources & evidence

ORD record
ord-c9e898cf8a724378bb3ec9a73efb29b5
Source dataset
uspto-grants-2014_11
Patent number
US08877756B2

Reaction notes

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