2-((2-((6-Bromohexyl)oxy)ethoxy)methyl)-1,3-dichlorobenzene → 6-{2-[(6-{2-[(2,6-Dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)pyridin-3-ol

HRID 494165Notes

Reaction equation

HRID 494165 reaction equation
[NH2:1][CH2:2][CH:3]([C:5]1[N:10]=[C:9]2[CH2:11][O:12]C(C3C=CC=CC=3)[O:14][C:8]2=[CH:7][CH:6]=1)[OH:4].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:40]>CN(C)C=O.C(N(C(C)C)CC)(C)C>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:1][CH2:2][CH:3]([C:5]1[N:10]=[C:9]([CH2:11][OH:12])[C:8]([OH:14])=[CH:7][CH:6]=1)[OH:4]

Participants

5

Reactant 2

HCID 668449032-((2-((6-Bromohexyl)oxy)ethoxy)methyl)-1,3-dichlorobenzeneHCID 688660332-amino-1-(2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)ethanol

Product 1

HCID 442160716-{2-[(6-{2-[(2,6-Dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)pyridin-3-olYield 99.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 81531DiisopropylethylamineSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 2-amino-1-(2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)ethanol (EP220054A2) (93 mg) and 2-({2-[(6-bromohexyl)oxy]ethoxy}methyl)-1,3-dichlorobenzene (98 mg) in dimethylformamide (1 ml) and diisopropylethylamine (0.2 ml) was heated to 70° C. for 4 h and then at 20° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried and evaporated to dryness. The residue was dissolved in ethanol and applied to an SCX-2 cartridge (10 g) eluting with ethanol, followed by 10% aqueous ammonia in ethanol. The ammoniacal fractions were concentrated under reduced pressure, and the residue was dissolved in acetic acid (5 ml) and water (2 ml) and the mixture was heated to 70° C. for 40 min. The solvent was removed under reduced pressure and the residue was purified by chromatography on a silica SPE cartridge (10 g) eluting with 10% aqueous ammonia in ethanol-dichloromethane (1:9 to 1:3). Appropriate fractions were combined and concentrated and the residue dissolved in acetic acid and re-evaporated to dryness to give the title compound (124 mg). LCMS RT=2.46 min, ES+ve m/z 487/489/491 (M+H)+.

Workup

  1. concentrationThe mixture was concentrated under reduced pressure
  2. customthe residue was partitioned between ethyl acetate and water
  3. washThe organic phase was washed with water, brine
  4. customdried
  5. customevaporated to dryness
  6. dissolutionThe residue was dissolved in ethanol
  7. washeluting with ethanol
  8. concentrationThe ammoniacal fractions were concentrated under reduced pressure
  9. dissolutionthe residue was dissolved in acetic acid (5 ml)
  10. temperaturewater (2 ml) and the mixture was heated to 70° C. for 40 min
  11. customThe solvent was removed under reduced pressure
  12. customthe residue was purified by chromatography on a silica SPE cartridge (10 g)
  13. washeluting with 10% aqueous ammonia in ethanol-dichloromethane (1:9 to 1:3)
  14. concentrationconcentrated
  15. dissolutionthe residue dissolved in acetic acid
  16. customre-evaporated to dryness

Sources & evidence

ORD record
ord-ffbdca865243405aaf70f10caeb2e3b6
Source dataset
uspto-grants-2009_05
Patent number
US07538127B2

Reaction notes

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