Thionyl Chloride → HCID 19800162, compound

HRID 1646941Notes

Reaction equation

HRID 1646941 reaction equation
[CH2:1]([O:7][C:8]1[C:9]([C:14]2(O)[CH:19]3[CH2:20][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][C:14]1([C:9]2[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:13][CH:12]=[CH:11][N:10]=2)[CH:19]2[CH2:20][N:16]([CH2:17][CH2:18]2)[CH2:15]1

Participants

4

Reactant 2

HCID 24386Thionyl ChlorideHCID 19800163HCID 19800163, compound

Product 1

HCID 19800162HCID 19800162, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A mixture of 4.8 g of (26) (0.021 mol) and 125 ml of hexanol that had reacted with 1.5 g of Na (0.065 mol) was heated to 80° C. for 45 min. The reaction was cooled to ambient, 100 ml of 1N HCl was added, and the hexanol was azeotroped off with water. The residue was made basic with 1N NaOH and extracted 3× with 50 ml of CH2Cl2. The extracts were washed with brine, dried, and the solvent evaporated to give a dark solid. Recrystallization of the solid from ether gave 3.83 g of 3-(3-hexyloxypyrazinyl)-1-azabicyclo[2.2.1]heptan-3-ol (26a) as a floculent yellow solid. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.65 (7H, m), 1.85 (2H, m), 2.25-3.07 (6H, m), 3.1 (1H, d), 3.75 (2H, d), 4.45 (2H, t), 8.01 (1H, d), 8.07 (1H, d). A solution of 1.5 g of (26a) (0.0052 mol) in 75 ml of CH2Cl2 was cooled to 0° C. as 1.1 ml of thionyl chloride in 10 ml of CH2Cl2 was added dropwise. The cooling was removed and after 1.5 h the reaction was heated to reflux for 45 min. The reaction was cooled to ambient, water was added, and the reaction made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2 the washed with brine, dried, and the solvent evaporated to give a yellow oil. Radial chromatography eluting with 2.5% ethanol-0.25% NH4OH-CHCl3 gave 1.2 g 3-chloro-3-(3-hexyloxypyrazinyl)-1-azabicyclo[2.2.1]heptane (26b) as a pinkish liquid. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.95 (10H, m), 2.25-3.9 (7H, m), 4.4 (2H, t), 8.0-8.1 (2H, m). A mixture of 1.2 g of (26b) (0.0039 mol) and 0.5 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated for 1 h at 60 psi H2. The catalyst was removed, the solvent evaporated, the residue suspended in water, and the mixture made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts dried, and the solvent evaporated. Tlc shows two major spots, 10% ethanol-1% NH4OH-CHCl3. The less polar of the two component was not well separated. The more polar component was treated with HCl in isopropanol and thoroughly evaporated. The residue was recrystallized from ether to give 0.15 g of (27) as slightly hygroscopic colorless crystals, mp 117°-118° C. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.55 (8H, m), 1.85 (3H, m), 3.2-3.75 (6H, m), 4.05 (2H, m), 4.38 (2H, m), 8.05 (1H, d), 8.08 (1H, d). Anal. C16H25N3O-HCl-0.5H2O requires C: 59.89; H: 8.48; N: 13.10%. Found C: 59.83; H: 8.31; N: 12.95%.

Workup

  1. additionwas added dropwise
  2. customThe cooling was removed and after 1.5 h the reaction
  3. temperaturewas heated
  4. temperatureto reflux for 45 min
  5. temperatureThe reaction was cooled to ambient, water
  6. additionwas added
  7. extractionThe mixture was extracted 3× with 25 ml of CH2Cl2 the
  8. washwashed with brine
  9. customdried
  10. customthe solvent evaporated
  11. customto give a yellow oil
  12. washRadial chromatography eluting with 2.5% ethanol-0.25% NH4OH-CHCl3

Sources & evidence

ORD record
ord-e25b3c89cf864141ba14a91682eb0962
Source dataset
uspto-grants-1993_01
Patent number
US05182283

Reaction notes

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