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

HRID 2169562
Notes
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Reaction equation

HRID 2169562 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]([Cl:26])=[CH:22][CH:21]=2)[CH3:19])=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.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.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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]([Cl: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
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866701084-(5-bromo-2-chloropyrimidin-4-yl)-N-((R)-1-(4-chlorophenyl)ethyl)morpholine-3-carboxamide

Product 1

HCID 866701112-chloro-5-((R)-1-(4-chlorophenyl)ethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-oneYield 12.3%

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-((R)-1-(4-chlorophenyl)ethyl)morpholine-3-carboxamide (PREPARATION x31, 574 mg, 1.247 mmol), Xantphos (54.1 mg, 0.094 mmol), potassium phosphate tribasic (265 mg, 1.247 mmol) and palladium(II) acetate (14.00 mg, 0.062 mmol) in dioxane (5 mL) and tert-butanol (1 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 72 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 to give a crude product which was loaded onto an ISCO® silica gel cartridge (40 g) and eluted using an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a white solid (58 mg, 12%). 1H NMR (400 MHz, DMSO-d6) δ 1.68-1.80 (m, 3 H), 2.91-3.02 (m, 1 H), 3.46-3.64 (m, 1 H), 3.64-3.76 (m, 1 H), 3.88-4.01 (m, 1 H), 4.13-4.27 (m, 2 H), 4.41-4.60 (m, 1 H), 5.99-6.24 (m, 1 H), 7.27-7.49 (m, 4 H), 7.50-7.57 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C17H16Cl2N4O2, 379.07; found 379.3.

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. customto give a crude product which
  10. washeluted
  11. customThe product was collected
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-719273c5e68d4655a37acf36be4fcc02
Source dataset
uspto-grants-2015_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09045496B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes