Pyridine → 4-Chloro-2,6-di(pyrrolidin-1-yl)pyrimidine

HRID 1769892Notes

Reaction equation

HRID 1769892 reaction equation
[NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17]C=1>C1COCC1>[N:1]1([C:7]2[N:8]=[C:9]([N:15]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:10]=[C:11]([Cl:13])[N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 1049PyridineHCID 31268PyrrolidineHCID 773782,4,6-Trichloropyrimidine

Product 1

HCID 7036994-Chloro-2,6-di(pyrrolidin-1-yl)pyrimidine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

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)

Sources & evidence

ORD record
ord-f3692d0a52054944815ecb375831a7fc
Source dataset
uspto-grants-1995_01
Patent number
US05382661

Reaction notes

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