Hydrochloric Acid → methyl {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}acetate

HRID 908115Notes

Reaction equation

HRID 908115 reaction equation
[NH2:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[N:6][C:7]=1[NH2:8].Cl.Br[C:12]([CH3:35])([CH3:34])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]23[CH2:28][CH2:27][C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH2:25][CH2:26]2)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=O>O.C(O)C>[NH2:8][C:7]1[C:2]2[N:1]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]45[CH2:28][CH2:27][C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH2:25][CH2:26]4)[CH2:23][CH2:22]5)=[CH:19][CH:20]=3)[C:12]([CH3:35])([CH3:34])[O:9][C:3]=2[N:4]=[CH:5][N:6]=1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 25258107Methyl {4-[4-(2-bromo-2-methylpropanoyl)phenyl]bicyclo[2.2.2]oct-1-yl}acetate2×HCID 178508814HCID 178508814, compound

Product 1

HCID 25258352methyl {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}acetateYield 64.2%

Reagents, catalysts & solvents 2

HCID 702EthanolSolvent2×HCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 5,6-diaminopyrimidin-4-ol (280 mg, 2.2 mmol) in water (8 mL), absolute ethanol (25 mL) and 1M HCl (2.2 mL, 2.2 mmol) was added a solution of methyl {4-[4-(2-bromo-2-methylpropanoyl)phenyl]bicyclo[2.2.2]oct-1-yl}acetate (Intermediate 9; 877 mg, 2.15 mmol) in absolute EtOH (80 mL). The solution was heated to 100° C. overnight then allowed to cool to ambient temperature, evaporated to dryness, and the residue treated with 2M NaOH to adjust the pH to 10. The resulting suspension was filtered to provide a yellow solid which was purified on a 12 g presearch silica cartridge dry loading on silica (2 g) and eluting with 0-2.5-5% MeOH-DCM to provide the title compound as a white solid (601 mg, 1.38 mmol, 64%)1H NMR δ 1.59-1.63 (12H, m), 1.79-1.83 (6H, m), 2.16 (2H, s), 3.59 (3H, s), 6.91 (2H, s), 7.39 (2H, d), 7.64 (2H, d), 7.95 (1H, s); MS m/e MH+ 435.

Workup

  1. temperatureto cool to ambient temperature
  2. customevaporated to dryness
  3. additionthe residue treated with 2M NaOH
  4. filtrationThe resulting suspension was filtered
  5. customto provide a yellow solid which
  6. customwas purified on a 12 g presearch silica cartridge
  7. customdry loading on silica (2 g)
  8. washeluting with 0-2.5-5% MeOH-DCM

Sources & evidence

ORD record
ord-c809db5ba6d84ee78d5892c48f3cbccb
Source dataset
uspto-grants-2011_09
Patent number
US08017603B2

Reaction notes

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