Piperazine → 4-(Piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine

HRID 2209883Notes

Reaction equation

HRID 2209883 reaction equation
[NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9](Cl)[N:8]=1.Cl[C:16]1[N:21]=[CH:20]N=[CH:18][CH:17]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1COCC1.N1C=CC=CC=1.C(OCC)(=O)C>[N:1]1([C:7]2[N:12]=[C:11]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:10]=[C:9]([N:21]3[CH2:16][CH2:17][CH2:18][CH2:20]3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

8

Reactant 4

HCID 4837PiperazineHCID 31268PyrrolidineHCID 773782,4,6-TrichloropyrimidineHCID 6428344-Chloropyrimidine

Product 1

HCID 145852434-(Piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine

Reagents, catalysts & solvents 3

HCID 1049PyridineSolvent2×HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of pyrrolidine (80 g) in THF (500 ml) is chilled in an ice water bath and stirred mechanically under nitrogen. With a syringe pump of 2,4,6-trichloropyrimidine (50 g) is added over 35 minutes. The reaction is stirred in the ice bath for 1 hour and is then warmed to 20°-25° over 4 h. Pyridine (100 ml) is added to the reaction and the mixture stirred at 20°-25° overnight. The reaction is concentrated. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is concentrated and the residue chromatographed on silica gel (10% ethyl acetate/hexane) to yield 51 g of crystalline 2,4-bis]pyrrolidino]-6-chloropyrimidine. Immediately after the initial addition of reagents, two spots are seen with 25% ethyl acetate on a silica gel plate. These are the 2- and the 4- adducts. The bis product forms over time. It moves between these first two spots. The 51 g of product is reacted with piperazine (40 g) in 100 ml of dry pyridine at 100° for 50 h. The reaction is concentrated. The residue is partitioned between methylene chloride and sodium bicarbonate solution. The organic phase is dried and concentrated. The residue is chromatographed on silica gel eluting with methylene chloride to 10% methanol/1% ammonia/methylene chloride to give the title compound, NMR (CDCl3) 1.90, 2.9, 3.35 and 4.80 δ.

Workup

  1. temperatureis then warmed to 20°-25° over 4 h
  2. stirringthe mixture stirred at 20°-25° overnight
  3. concentrationThe reaction is concentrated
  4. customThe residue is partitioned between methylene chloride and aqueous sodium bicarbonate
  5. concentrationThe organic phase is concentrated
  6. customthe residue chromatographed on silica gel (10% ethyl acetate/hexane)
  7. customto yield 51 g of crystalline
  8. additionImmediately after the initial addition of reagents, two spots
  9. concentrationThe reaction is concentrated
  10. customThe residue is partitioned between methylene chloride and sodium bicarbonate solution
  11. customThe organic phase is dried
  12. concentrationconcentrated
  13. customThe residue is chromatographed on silica gel eluting with methylene chloride to 10% methanol/1% ammonia/methylene chloride

Sources & evidence

ORD record
ord-3f3f0761e2094cdb864be834278685a8
Source dataset
uspto-grants-1995_10
Patent number
USRE035053

Reaction notes

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