1,8-Diazabicyclo(5.4.0)undec-7-ene → 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid bis-[((R)-1-phenyl-propyl)-amide]

HRID 926393Notes

Reaction equation

HRID 926393 reaction equation
[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15](Br)[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCCN=C1CCCCC2.[C:34]1([C@H:40]([NH2:43])[CH2:41][CH3:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:44](=O)([O-])[OH:45].[Na+]>O1CCCC1>[C:34]1([C@H:40]([NH:43][C:44]([C:15]2[N:16]3[C:17]([CH2:18][O:19][CH2:20][CH2:21]3)=[C:13]([C:11]([NH:10][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH3:9])=[O:12])[CH:14]=2)=[O:45])[CH2:41][CH3:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1

Participants

6

Reactant 4

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 516892Sodium BicarbonateHCID 5324978(R)-1-PhenylpropylamineHCID 1189460386-bromo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide

Product 1

HCID 716605083,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid bis-[((R)-1-phenyl-propyl)-amide]Yield 35%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 6-bromo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 12a) (200 mg, 0.551 mmol), molybdenum(0) hexacarbonyl (44 mg, 0.165 mmol), trans-di-(μ-acetato)bis[2-(di-o-tolylphosphino)benzyl]dipalladium(II) (52 mg, 0.055 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (500 mg, 3.31 mmol) and (R)-1-phenyl-propylamine (745 mg, 5.51 mmol) in dry tetrahydrofuran (5 ml) was heated for 30 min at 130° C. in a microwave reactor, then aqueous sodium hydrogencarbonate was added and the mixture was extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate, evaporated to dryness and the crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 86 mg (35%) of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid bis-[((R)-1-phenyl-propyl)-amide] as white solid. LC/MS (method 4): Rt=1.28 min; m/z=446.38 (M+H+). 1H-NMR: δ (ppm)=8.44 (1H, d), 8.15 (1H, d), 7.25-7.40 (9H, m), 7.22 (2H, q), 4.80-5.00 (4H, m), 4.15 (2H, m), 3.87 (2H, m), 1.73-1.80 (4H, m), 0.85-0.90 (6H, m).

Workup

  1. extractionthe mixture was extracted 3 times with dichloromethane
  2. dry with materialThe combined organic layers were dried over sodium sulfate
  3. customevaporated to dryness
  4. customthe crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-c983cafd01604357b66d5503f4005747
Source dataset
uspto-grants-2016_03
Patent number
US09284333B2

Reaction notes

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