Acetonitrile → 4-(6-Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydropyrimidin-5-ylcarbamoyl)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester

HRID 480159Notes

Reaction equation

HRID 480159 reaction equation
Cl.[NH2:2][C:3]1(CCC)[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[C:4]1([NH2:14])CCC.C(N([CH2:23][CH3:24])CC)C.[CH3:25][O:26][C:27]([C:29]12[CH2:36][CH2:35][C:32]([C:37](Cl)=[O:38])([CH2:33][CH2:34]1)[CH2:31][CH2:30]2)=[O:28].N[C:41]1([CH2:53]CC)NC(=O)NC(=O)[C:42]1(N)CCC.[C:56](#N)C>>[CH3:25][O:26][C:27]([C:29]12[CH2:36][CH2:35][C:32]([C:37](=[O:38])[NH:14][C:4]3[C:5](=[O:10])[N:6]([CH2:56][CH2:23][CH3:24])[C:7](=[O:9])[N:8]([CH2:42][CH2:41][CH3:53])[C:3]=3[NH2:2])([CH2:33][CH2:34]1)[CH2:31][CH2:30]2)=[O:28]

Participants

6

Reactant 5

HCID 6342Acetonitrile2×HCID 8471TriethylamineHCID 13761775Bicyclo[2.2.2]octane-1-carboxylic acid, 4-(chlorocarbonyl)-, methyl ester2×HCID 131724213Diaminodipropyluracil hydrochlorideHCID 131724214Diaminodipropyluracil

Product 1

HCID 865917464-(6-Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydropyrimidin-5-ylcarbamoyl)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester

Conditions

Temperature
2.5 °C

Procedure

Diaminodipropyluracil hydrochloride (VI, 1.36 wt) is suspended in acetonitrile (12.5 vol), cooled to 0 to 5° C. and triethylamine (2.46 vol) is added between 0 to 10° C. The mixture is then cooled to 0 to 5° C. A mixture of 4-chlorocarbonylbicyclo[2.2.2]-octane-1-carboxylic acid methyl ester (V, Example 82) in acetonitile is added to the diaminodipropyluracil mixture between 0 to 20° C. The reaction mixture is then warmed to 15 to 25° C. and stirred for 15 to 20 hours by which time all of the 4-chlorocarbonylbicyclo[2.2.2]octane-1-carboxylic acid methyl ester (V) is consumed (TLC; dichloromethane/methanol, 9/1; visualization Bromocresol green). The reaction mixture is diluted with water (3.12 vol) and concentrated under reduced pressure at 40 to 45° C. (18 to 20 vol of solvent is removed). The concentrate is extracted with ethyl acetate (3×6 vol) and the combined organics are washed sequentially with citric acid (10%, 3×3.12 vol), hydrochloric acid (1M, 2.5 vol), water (3.12 vol), saturated sodium bicarbonate (3.12 vol) and saline (3.12 vol). The mixture is dried over magnesium sulphate (0.75 wt) for 5 to 15 min, filtered, washed with ethyl acetate (1 vol) and the solvent removed under reduced pressure at 40 to 45° C. to give the title compound.

Workup

  1. temperatureThe mixture is then cooled to 0 to 5° C
  2. temperatureThe reaction mixture is then warmed to 15 to 25° C.
  3. customis consumed (TLC; dichloromethane/methanol, 9/1; visualization Bromocresol green)
  4. additionThe reaction mixture is diluted with water (3.12 vol)
  5. concentrationconcentrated under reduced pressure at 40 to 45° C.
  6. custom(18 to 20 vol of solvent is removed)
  7. extractionThe concentrate is extracted with ethyl acetate (3×6 vol)
  8. washthe combined organics are washed sequentially with citric acid (10%, 3×3.12 vol), hydrochloric acid (1M, 2.5 vol), water (3.12 vol), saturated sodium bicarbonate (3.12 vol) and saline (3.12 vol)
  9. dry with materialThe mixture is dried over magnesium sulphate (0.75 wt) for 5 to 15 min
  10. filtrationfiltered
  11. washwashed with ethyl acetate (1 vol)
  12. customthe solvent removed under reduced pressure at 40 to 45° C.

Sources & evidence

ORD record
ord-379f6be6e4e346ca8e9f8949fef86dd8
Source dataset
uspto-grants-2003_11
Patent number
US06649600B1

Reaction notes

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