Acetic Acid → 6-[(4R)-4-{[3-(3-Methoxy-6-oxopyrido[2,3-b]pyrazin-5 (6H)-yl)propyl]amino}-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

HRID 1847097Notes

Reaction equation

HRID 1847097 reaction equation
[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH:16]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[NH2:18][C@H:19]1[CH2:23][N:22]([C:24]2[CH:25]=[CH:26][C:27]3[O:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=3[N:33]=2)[C:21](=[O:35])[CH2:20]1.C(OC(=O)N[C@@H]1CC(=O)NC1)(C)(C)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH2:16][NH:18][C@H:19]3[CH2:23][N:22]([C:24]4[CH:25]=[CH:26][C:27]5[O:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=5[N:33]=4)[C:21](=[O:35])[CH2:20]3)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydride2×HCID 71301758tert-Butyl [(3R)-5-oxopyrrolidin-3-yl]carbamateHCID 867249463-(3-Methoxy-6-oxopyrido[2,3-b]pyrazin-5(6H)-yl)propanalHCID 867249916-[(4R)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

Product 1

HCID 867250186-[(4R)-4-{[3-(3-Methoxy-6-oxopyrido[2,3-b]pyrazin-5 (6H)-yl)propyl]amino}-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-oneYield 9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 3-(3-methoxy-6-oxopyrido[2,3-b]pyrazin-5 (6H)-yl)propanal (Reference Example 24, 120 mg, 0.515 mmol) in N,N-dimethylformamide (1.6 ml) were added 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, 22; 166 mg, 0.66 mmol) and acetic acid (0.04 ml, 0.66 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction solution was then cooled on ice and sodium triacetoxyborohydride (141 mg, 0.66 mmol) was added thereto. After stirring overnight, sodium triacetoxyborohydride (282 mg, 1.32 mmol) was added to the reaction solution, which was further stirred at room temperature for 2 days. A sodium hydrogen carbonate aqueous solution was added to the reaction solution, which was then extracted with ethyl acetate and the obtained organic layer was washed with water and saturated sodium chloride solution. The layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained crude product was purified by thin layer chromatography (dichloromethane/methanol) to yield 21 mg (9%) of the title compound.

Workup

  1. customsynthesized
  2. customsynthesized with reference to WO2004/22536 in the same manner as in Reference Examples 20, 21, 22
  3. additionwas added
  4. stirringwas further stirred at room temperature for 2 days
  5. extractionwas then extracted with ethyl acetate
  6. washthe obtained organic layer was washed with water and saturated sodium chloride solution
  7. dry with materialThe layer was dried over anhydrous sodium sulfate
  8. customthe solvent was removed under reduced pressure
  9. customThe obtained crude product
  10. customwas purified by thin layer chromatography (dichloromethane/methanol)

Sources & evidence

ORD record
ord-fa1a15da89864d0e9be1e2bb0259c72e
Source dataset
uspto-grants-2015_02
Patent number
US08952010B2

Reaction notes

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