Acetic Acid → 6-[(4R)-4-{[3-(6-Methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propyl]amino}-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

HRID 1847092Notes

Reaction equation

HRID 1847092 reaction equation
C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH:19]=O)[C:11]=2[N:21]=1.[NH2:22][C@H:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=3[N:37]=2)[C:25](=[O:39])[CH2:24]1.C(OC(=O)N[C@@H]1CC(=O)NC1)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH2:19][NH:22][C@H:23]3[CH2:27][N:26]([C:28]4[CH:29]=[CH:30][C:31]5[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=5[N:37]=4)[C:25](=[O:39])[CH2:24]3)[C:11]=2[N:21]=1

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 71301758tert-Butyl [(3R)-5-oxopyrrolidin-3-yl]carbamateHCID 867249613-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanalHCID 867249916-[(4R)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

Product 1

HCID 867250156-[(4R)-4-{[3-(6-Methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propyl]amino}-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-oneYield 23%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Acetic acid (0.06 g, 1 mmol) was added dropwise to a mixture of 3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanal (synthesized with reference to WO2008/9700; 0.2 g, 0.85 mmol), 6-[(4R)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (synthesized using [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester synthesized with reference to WO2004/22536 in the same manner as in Reference Examples 20, 21 and 22; 0.25 g, 1.0 mmol) and N,N-dimethylformamide (4 ml). The mixture was cooled on ice and sodium triacetoxyborohydride (0.23 g, 1.1 mmol) was gradually added thereto. The mixture was stirred for 10 minutes under cooling on ice and subsequently stirred at room temperature for 2 hours. The reaction solution was cooled on ice again and a sodium hydrogen carbonate aqueous solution was added thereto. The obtained mixture was extracted with dichloromethane and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol) to yield 90 mg (23%) of the title compound.

Workup

  1. customsynthesized
  2. customsynthesized with reference to WO2004/22536 in the same manner as in Reference Examples 20, 21 and 22
  3. additionwas gradually added
  4. temperatureunder cooling on ice
  5. stirringsubsequently stirred at room temperature for 2 hours
  6. temperatureThe reaction solution was cooled on ice again
  7. extractionThe obtained mixture was extracted with dichloromethane
  8. dry with materialthe extract was dried over anhydrous sodium sulfate
  9. concentrationconcentrated under reduced pressure
  10. customThe obtained crude product
  11. customwas purified by silica gel column chromatography (dichloromethane/methanol)

Sources & evidence

ORD record
ord-dc707dbd97174f599e2ff4a1d4f0244c
Source dataset
uspto-grants-2015_02
Patent number
US08952010B2

Reaction notes

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