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

HRID 2169563Notes

Reaction equation

HRID 2169563 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]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH3:19])=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(O)(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:17]([C@H:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[CH3:19])[C:15](=[O:16])[CH:10]3[CH2:11][O:12][CH2:13][CH2:14][N:9]3[C:3]=2[N:4]=1

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866701094-(5-bromo-2-chloropyrimidin-4-yl)-N-((S)-1-(p-tolyl)ethyl)morpholine-3-carboxamide

Product 1

HCID 888681662-chloro-5-((S)-1-(p-tolyl)ethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 6386tert-ButanolSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
105 °C

Procedure

To an oven dried vial were added 4-(5-bromo-2-chloropyrimidin-4-yl)-N-((S)-1-p-tolylethyl)morpholine-3-carboxamide (PREPARATION x32, 588 mg, 1.337 mmol), potassium phosphate tribasic (284 mg, 1.337 mmol), Xantphos (58.0 mg, 0.100 mmol) and palladium(II) acetate (15.01 mg, 0.067 mmol) in dioxane (15 mL) and tert-butanol (3 mL). The reaction mixture was degassed for 5 minutes with N2. The vial was then sealed and heated to 105° C. and the contents were stirred for 18 hours to give a brown suspension. The reaction mixture was subsequently diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×5 mL and brine (3×5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was loaded onto an ISCO® silica gel cartridge (40 g) and eluted using an ethyl acetatehexane gradient to give two diastereomers whose absolute configuration was not assigned (Diastereomer 1, higher Rf, 97 mg; Diastereomer 2, lower Rf, 91 mg; 39% overall). Diastereomer 1: 1H NMR (400 MHz, DMSO-d6) δ 1.69 (d, J=7.33 Hz, 3 H), 2.29 (s, 3 H), 2.89-3.04 (m, 1 H), 3.46-3.67 (m, 2 H), 3.89-4.01 (m, 1 H), 4.13-4.27 (m, 2 H), 4.50-4.63 (m, 1 H), 6.16-6.30 (m, 1 H), 7.13-7.29 (m, 4 H), 7.29-7.38 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H19ClN4O2, 359.12; found 359.3. Diastereomer 2: 1H NMR (400 MHz, DMSO-d6) δ 1.75 (d, J=7.07 Hz, 3 H), 2.28 (s, 3 H), 2.90-3.04 (m, 1 H), 3.51-3.62 (m, 1 H), 3.64-3.75 (m, 1 H), 3.89-3.98 (m, 1 H), 4.16-4.26 (m, 2 H), 4.43-4.51 (m, 1 H), 6.06-6.17 (m, 1 H), 7.18 (d, J=2.53 Hz, 4H), 7.47 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H19ClN4O, 359.12; found 359.3.

Workup

  1. customTo an oven dried vial
  2. customThe reaction mixture was degassed for 5 minutes with N2
  3. customThe vial was then sealed
  4. customto give a brown suspension
  5. washwashed with aqueous saturated NH4Cl (3×5 mL and brine (3×5 mL)
  6. dry with materialThe combined organic layers were dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. washeluted
  10. customto give two diastereomers whose absolute configuration

Sources & evidence

ORD record
ord-b30ff165a791423b8a3bf29450f60f43
Source dataset
uspto-grants-2015_06
Patent number
US09045496B2

Reaction notes

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