Acetone Cyanohydrin → HCID 178495760, compound

HRID 714425Notes

Reaction equation

HRID 714425 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH2:19][CH2:20][O:21][CH3:22])[C:11](=[O:18])[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:23](Cl)(=[O:27])[C:24](Cl)=O.C[C:30](=[O:38])[CH2:31][C:32](=O)[CH2:33][CH2:34][CH2:35]C.C(N(CC)CC)C.OC(C)(C)C#N>ClCCl.CN(C)C=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:10]([CH2:19][CH2:20][O:21][CH3:22])[C:11](=[O:18])[C:12]([C:15]([C:24]3[C:23](=[O:27])[CH:33]4[CH2:32][CH:31]([CH2:35][CH2:34]4)[C:30]=3[OH:38])=[O:17])=[CH:13][N:14]=2)[CH:3]=[C:2]([F:1])[CH:7]=1

Participants

8

Reactant 5

HCID 6406Acetone CyanohydrinHCID 8471Triethylamine2×HCID 65578Oxalyl chlorideHCID 841922,4-OctanedioneHCID 679550472-(3,5-Difluorophenyl)-1,6-dihydro-1-(2-methoxyethyl)-6-oxo-5-pyrimidinecarboxylic acid2×

Product 1

HCID 178495760HCID 178495760, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent

Procedure

To 2-(3,5-difluorophenyl)-1,6-dihydro-1-(2-methoxyethyl)-6-oxo-5-pyrimidinecarboxylic acid (i.e. the product from Example 9, Step D) (0.25 g, 0.81 mmol) in 10 mL of dichloromethane was added oxalyl chloride (0.21 g, 1.6 mmol) and one drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The remaining crude oil was re-dissolved in dichloromethane (10 mL) and then treated with bicycle[3.2.1]octane-2,4-dione (0.12 g, 0.88 mmol) (prepared according to U.S. Pat. No. 6,815,563) and triethylamine (0.16 g, 1.6 mmol). After 30 min at room temperature, a catalytic amount of 2-hydroxy-2-methyl-propanenitrile (0.0075 g, 0.088 mmol) and triethylamine (0.16 g, 1.6 mmol) were added and the reaction mixture was stirred at ambient temperature over night. The reaction mixture was then concentrated under reduced pressure and purified by medium pressure liquid chromatography on silica gel eluting with 0 to 10% methanol in chloroform to provide 0.180 g of the title compound (also known as 3-[[2-(3,5-difluorophenyl)-1,6-dihydro-1-(2-methoxyethyl)-6-oxo-5-pyrimidinyl]carbonyl]biciclo[3.2.1]octane-2,4-dione), a compound of the present invention, as a solid.

Workup

  1. concentrationconcentrated under reduced pressure
  2. dissolutionThe remaining crude oil was re-dissolved in dichloromethane (10 mL)
  3. customprepared
  4. waitAfter 30 min at room temperature
  5. stirringthe reaction mixture was stirred at ambient temperature over night
  6. concentrationThe reaction mixture was then concentrated under reduced pressure
  7. custompurified by medium pressure liquid chromatography on silica gel eluting with 0 to 10% methanol in chloroform

Sources & evidence

ORD record
ord-6f897db8edeb41a28db0e5f16591bb0c
Source dataset
uspto-grants-2015_11
Patent number
US09187432B2

Reaction notes

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