1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → 8-(6,7-Dimethoxy-1-piperidin-1-yl-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione

HRID 1745825Notes

Reaction equation

HRID 1745825 reaction equation
Cl.CN(C)[CH2:4][CH2:5][CH2:6][N:7]=[C:8]=NCC.[NH2:13][C:14]1[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:19]=1[NH2:20].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[C:32]([CH2:43][C:44](O)=O)=[CH:31][N:30]=1.[OH-].[Na+].[CH3:49]O>CO.O>[CH3:42][O:41][C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][C:36]=1[O:39][CH3:40])[C:29]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:49][CH2:8]1)=[N:30][CH:31]=[C:32]2[CH2:43][C:44]1[NH:13][C:14]2[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:19]=2[N:20]=1

Participants

7

Reactant 4

HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 41103394,5-Diamino-3-isobutyl-1-methylpyrimidine-2,6-dioneHCID 22226493(1-Chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acidHCID 23721981Sodium hydroxide methanol

Product 1

HCID 692005398-(6,7-Dimethoxy-1-piperidin-1-yl-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.29 g, 1.9 mmol) is added to 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (0.40 g, 1.9 mmol)) and (1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid (0.39 g, 1.78 mmol) in methanol and water and the mixture is stirred at ambient temperature for 2 hours. The methanol is evaporated and the resultant solid collected by filtration and recrystalised from ethylacetate/methanol. The resulting solid is heated under reflux with piperidine for 8 h. The solution is filtered and the resulting solution washed with water and brine, dried over sodium sulphate, filtered and concentrated. Further purification by flash silica column chromatography (eluant: ethylacetate/methanol) yields a solid which is dissolved 20% 1N NaOH/methanol and heated to reflux for 2 h. Concentration, addition of water and extraction with ethyl acetate gives an organic fraction which is washed with water and brine, dried over Na2SO4, filtered and concentrated to give 8-(6,7-dimethoxy-1-piperidin-1-yl-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione, MH+ 507.

Workup

  1. customThe methanol is evaporated
  2. filtrationthe resultant solid collected by filtration
  3. customrecrystalised from ethylacetate/methanol
  4. temperatureThe resulting solid is heated
  5. temperatureunder reflux with piperidine for 8 h
  6. filtrationThe solution is filtered
  7. washthe resulting solution washed with water and brine
  8. dry with materialdried over sodium sulphate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customFurther purification by flash silica column chromatography (eluant: ethylacetate/methanol)
  12. customyields a solid which
  13. temperatureheated
  14. temperatureto reflux for 2 h
  15. concentrationConcentration, addition of water and extraction with ethyl acetate
  16. customgives an organic fraction which
  17. washis washed with water and brine
  18. dry with materialdried over Na2SO4
  19. filtrationfiltered
  20. concentrationconcentrated

Sources & evidence

ORD record
ord-11cc70e8a37f454d818cd1fefa4e4464
Source dataset
uspto-grants-2006_03
Patent number
US07019136B2

Reaction notes

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