Potassium trimethylsilanolate → 2-[4-(4-{4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl}phenyl)bicyclo[2.2.2]octan-1-yl]propanoic acid

HRID 908117Notes

Reaction equation

HRID 908117 reaction equation
[NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]45[CH2:25][CH2:24][C:21]([CH:26]([CH3:31])[C:27]([O:29]C)=[O:28])([CH2:22][CH2:23]4)[CH2:20][CH2:19]5)=[CH:14][CH:13]=3)[C:8]([CH3:33])([CH3:32])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1.C[Si](C)(C)[O-].[K+]>C1COCC1.CS(C)=O.CC#N.O>[NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]45[CH2:23][CH2:22][C:21]([CH:26]([CH3:31])[C:27]([OH:29])=[O:28])([CH2:20][CH2:19]4)[CH2:24][CH2:25]5)=[CH:16][CH:17]=3)[C:8]([CH3:32])([CH3:33])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1

Participants

5

Reactant 2

HCID 23668039Potassium trimethylsilanolateHCID 25258353methyl 2-{4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]bicyclo[2.2.2]oct-1-yl}propanoate2×

Product 1

HCID 250161682-[4-(4-{4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl}phenyl)bicyclo[2.2.2]octan-1-yl]propanoic acidYield 21.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 86584666DMSO MeCN waterSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of methyl 2-{4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]bicyclo[2.2.2]oct-1-yl}propanoate (Intermediate 18; 220 mg, 0.49 mmol) and potassium trimethylsilanolate (315 mg, 2.45 mmol) in THF (5 mL) was heated in a microwave for 35 mins at 100° C. and was then stirred at ambient temperature for 2 days. The solvent was removed under reduced pressure and the residue partitioned between 2M HCl (20 mL) and EtOAc (50 mL) and the aqueous phase was further extracted with EtOAc (50 mL). The organic extracts were combined, dried (MgSO4) and concentrated to leave a gum. This was dissolved in DMSO/MeCN/H2O (7:2:1) and separated by reverse phase chromatography eluting 5-95% water-acetonitrile 0.2% TFA, providing the title compound (45 mg, 0.104 mmol, 21%) as a white solid; 1H NMR δ 1.01 (d, 3H), 1.49-1.55 (m, 3H), 1.62 (s, 6H), 1.64-1.69 (m, 3H), 1.78-1.81 (m, 6H), 2.12 (q, 1H), 7.05 (s, 1H), 7.40 (d, 2H), 7.65 (d, 2H), 7.99 (s, 1H); MS m/e MH+ 435.

Workup

  1. customThe solvent was removed under reduced pressure
  2. customthe residue partitioned between 2M HCl (20 mL) and EtOAc (50 mL)
  3. extractionthe aqueous phase was further extracted with EtOAc (50 mL)
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. customto leave a gum
  7. customseparated by reverse phase chromatography
  8. washeluting 5-95% water-acetonitrile 0.2% TFA

Sources & evidence

ORD record
ord-688399fa0f9947b4be8617faafc097aa
Source dataset
uspto-grants-2011_09
Patent number
US08017603B2

Reaction notes

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