Triphenylphosphine → 1-tert-Butyl 2-methyl (2S,4R)-4-[(2-ethoxy-6-vinylquinazolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate

HRID 2045728Notes

Reaction equation

HRID 2045728 reaction equation
[CH2:1](OC1N=C(O)C2C(=CC=C(I)C=2)N=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:47]([O:49][C:50]1[N:59]=[C:58]([O:60][C@H:61]2[CH2:65][N:64]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:63]([C:73]([O:75][CH3:76])=[O:74])[CH2:62]2)[C:57]2[C:52](=[CH:53][CH:54]=[C:55](I)[CH:56]=2)[N:51]=1)[CH3:48].C([B-](F)(F)F)=C.[K+]>C1COCC1.CCO.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:47]([O:49][C:50]1[N:59]=[C:58]([O:60][C@H:61]2[CH2:65][N:64]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:63]([C:73]([O:75][CH3:76])=[O:74])[CH2:62]2)[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([CH:1]=[CH2:2])[CH:56]=2)[N:51]=1)[CH3:48]

Participants

10

Reactant 5

HCID 11776TriphenylphosphineHCID 5462977Diethyl azodicarboxylateHCID 23679353Potassium vinyltrifluoroborateHCID 866495161-tert-butyl 2-methyl (2S,4R)-4-[(2-ethoxy-6-iodoquinazolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylateHCID 178467468HCID 178467468, compound

Product 1

HCID 580914081-tert-Butyl 2-methyl (2S,4R)-4-[(2-ethoxy-6-vinylquinazolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylateYield 33%

Reagents, catalysts & solvents 4

HCID 178418807HCID 178418807, compoundCatalystHCID 702EthanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
20 °C

Procedure

A solution of 2-ethoxy-6-iodoquinazolin-4-ol (2.94 g, 9.30 mmol) and 1-tent-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.28 g, 9.30 mmol) in THF (150 ml) was cooled to 0° C. and treated with Ph3P (2.93 g, 11.16 mmol). DEAD (4.42 ml, 11.16 mmol) was added dropwise, and the mixture was stirred at 20° C. for 4 h. After evaporation of the volatiles, the residue was purified on silica gel (gradient elution, 0-5% EtOAc/(EtOAc:DCM=5:95)) to furnish a 6:4 mixture of 1-tert-butyl 2-methyl (2S,4R)-4-[(2-ethoxy-6-iodoquinazolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate and 1-text-butyl 2-methyl (2S,4R)-4-(2-ethoxy-6-iodo-4-oxoquinazolin-3(4H)-yl)pyrrolidine-1,2-dicarboxylate (3.8 g) LCMS (ES+) m/z 544 (M+H)+. This material was dissolved in EtOH (40 mL) and treated with TEA (0.83 mL, 5.98 mmol). Potassium vinyltrifluoroborate (0.80 g, 5.98 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.32 g, 0.399 mmol) were added, and the mixture was stirred at 90° C. for 2 h. The mixture cooled, diluted with EtOAc and washed with aqueous HCl (1 N) and brine. The organic phase was dried over Na2SO4, filtered and concentrated to give a residue that was purified on silica (gradient elution, 0-20% EtOAc/DCM) to yield the title compound as an oil (1.38 g, 33%). LCMS (ES+) m/z 444 (M+H)+.

Workup

  1. customAfter evaporation of the volatiles
  2. customthe residue was purified on silica gel (gradient elution, 0-5% EtOAc/(EtOAc:DCM=5:95))
  3. customto furnish
  4. stirringthe mixture was stirred at 90° C. for 2 h
  5. temperatureThe mixture cooled
  6. washwashed with aqueous HCl (1 N) and brine
  7. dry with materialThe organic phase was dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto give a residue that
  11. customwas purified on silica (gradient elution, 0-20% EtOAc/DCM)

Sources & evidence

ORD record
ord-fc81858d391f4b8088d33dfcb7eda67a
Source dataset
uspto-grants-2013_11
Patent number
US08591878B2

Reaction notes

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