1,8-Diazabicyclo(5.4.0)undec-7-ene → 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione

HRID 1022486Notes

Reaction equation

HRID 1022486 reaction equation
[CH2:1]([O:8][C:9]1[C:10]([F:36])=[CH:11][C:12]([NH:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:13]([CH:28]=1)[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:38](OC1C=CC([N+]([O-])=O)=CC=1)=[O:39].CCN(C(C)C)C(C)C.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:28]=[C:13]2[C:12](=[CH:11][C:10]=1[F:36])[N:29]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:38](=[O:39])[N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[C:14]2=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 81531DiisopropylethylamineHCID 821294-Nitrophenyl chloroformateHCID 674964045-(benzyloxy)-N-(3,4-dimethoxybenzyl)-4-fluoro-2-(tetrahydro-2H-pyran-4-ylamino)benzamide

Product 1

HCID 667325316-(benzyloxy)-3-(3,4-dimethoxybenzyl)-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dioneYield 70.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 1.0 g of the compound obtained in Step 4.5, 1.223 g of 4-nitrophenyl chloroformate and 0.915 g of DIEA in 15 ml of THF is irradiated in a microwave field for 15 minutes at 80° C. 0.616 g of DBU is then added and the mixture is stirred for 1 hour at room temperature. The reaction medium is evaporated under reduced pressure. The residue is taken up in EtOAc and washed twice with saturated aqueous NaHCO3 solution, then with aqueous 1M KHSO4 solution and then with water. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (60/40, v/v) to give 0.74 g of the expected product.

Workup

  1. customis irradiated in a microwave field for 15 minutes at 80° C
  2. customThe reaction medium is evaporated under reduced pressure
  3. washwashed twice with saturated aqueous NaHCO3 solution
  4. dry with materialThe organic phase is dried over Na2SO4
  5. filtrationfiltered
  6. customthe filtrate is evaporated under reduced pressure
  7. customThe residue is chromatographed on silica gel
  8. washeluting with a DCM/EtOAc mixture from (100/0

Sources & evidence

ORD record
ord-3b6ea1718f3c41c2a1411ad702131848
Source dataset
uspto-grants-2014_05
Patent number
US08722659B2

Reaction notes

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