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 2105683Notes

Reaction equation

HRID 2105683 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 −1° 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
  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-e03d2c0aa43947d9b78b86c08c4feacd
Source dataset
uspto-grants-2009_08
Patent number
US07579354B2

Reaction notes

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