Potassium Phosphate, Tribasic → (S)-2-chloro-5-(2,3-dihydro-1H-inden-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one

HRID 1631736Notes

Reaction equation

HRID 1631736 reaction equation
Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:17]([CH:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19]3)[C:15](=[O:16])[C@@H:10]3[CH2:11][O:12][CH2:13][CH2:14][N:9]3[C:3]=2[N:4]=1

Participants

5

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866701214-(5-bromo-2-chloropyrimidin-4-yl)-N-((S)-2,3-dihydro-1H-inden-1-yl)morpholine-3-carboxamide

Product 1

HCID 86670122(S)-2-chloro-5-(2,3-dihydro-1H-inden-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-oneYield 26.5%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
120 °C

Procedure

To a 5 mL microwave vial were added 4-(5-bromo-2-chloropyrimidin-4-yl)-N—((S)-2,3-dihydro-1H-inden-1-yl)morpholine-3-carboxamide (PREPARATION x48, 407 mg, 0.93 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (26.9 mg, 0.047 mmol), palladium (II)acetate (6.26 mg, 0.028 mmol), and potassium phosphate, tribasic (276 mg, 1.302 mmol). The vessel was evacuated, refilled with nitrogen, and sealed. Dioxane (3.9 mL) and tert-butanol (0.78 mL) were added and the mixture was heated in a microwave to 120° C. for 90 minutes. An additional portion of catalyst was added, and the reaction mixture was heated in the microwave to 120° C. for another 6 hours. The reaction mixture was subsequently partitioned between aqueous saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The dark brown crude product was purified by normal phase column chromatography (SiO2, 60 g) eluting with a gradient of 50-100% EtOAc in hexanes over 20 minutes. The product-containing fractions were combined and concentrated to give the title compound as a white foam (88 mg, 26.5%). ESI-MS m/z [M+H]+ calc'd for C17H17ClN4O2, 357.10. found 357.3.

Workup

  1. customThe vessel was evacuated
  2. additionrefilled with nitrogen
  3. customsealed
  4. additionDioxane (3.9 mL) and tert-butanol (0.78 mL) were added
  5. additionAn additional portion of catalyst was added
  6. temperaturethe reaction mixture was heated in the microwave to 120° C. for another 6 hours
  7. customThe reaction mixture was subsequently partitioned between aqueous saturated NaHCO3 and ethyl acetate
  8. extractionThe aqueous layer was extracted with ethyl acetate
  9. dry with materialthe combined organic layers were dried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe dark brown crude product was purified by normal phase column chromatography (SiO2, 60 g)
  13. washeluting with a gradient of 50-100% EtOAc in hexanes over 20 minutes
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-42e0fb265e4145908a9f4ff40ae9f2ab
Source dataset
uspto-grants-2014_07
Patent number
US08791107B2

Reaction notes

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