Acetic Acid → 4-(2-Fluoro-3-{[5-oxo-1-(3-oxo-3,4-dihydro-2H-1,4benzoxazin-6-yl)pyrrolidin-3-yl]amino}propyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one

HRID 1847023Notes

Reaction equation

HRID 1847023 reaction equation
[F:1][CH:2]([CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[N:9][C:8]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[N:16][C:7]1=2)[CH:3]=O.[NH2:19][CH:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[C:22](=[O:36])[CH2:21]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.ClCCl>[F:1][CH:2]([CH2:3][NH:19][CH:20]1[CH2:21][C:22](=[O:36])[N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[CH2:24]1)[CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[N:9][C:8]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[N:16][C:7]1=2

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 24436Sodium SulfateHCID 5049666Sodium triacetoxyborohydrideHCID 824984066-(4-Amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-oneHCID 867249512-Fluoro-3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanal

Product 1

HCID 867249504-(2-Fluoro-3-{[5-oxo-1-(3-oxo-3,4-dihydro-2H-1,4benzoxazin-6-yl)pyrrolidin-3-yl]amino}propyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-oneYield 41%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A crude product of 2-Fluoro-3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanal (323 mg), 6-(4-amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (Reference Example 6; 227 mg, 0.917 mmol) were mixed in a mixed solution of dichloromethane (30 ml) and N,N-dimethylformamide (3 ml). Acetic acid (0.105 ml, 1.834 mmol) and anhydrous sodium sulfate (450 mg) were added to the solution and the mixture was stirred for 12 hours. Sodium triacetoxyborohydride (389 mg, 1.834 mmol) was added to the reaction solution, the mixture was stirred for 4 hours and then the solvent was removed under reduced pressure. A lower layer solvent of chloroform/methanol/water (7:3:1) was added to the residue and the resultant was alkalized by adding saturated sodium bicarbonate water under cooling on ice. The mixture was extracted with a lower layer solvent of chloroform/methanol/water (7:3:1), the extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) and preparative layer chromatography (silica gel, chloroform/methanol=20:1) to yield 180 mg (41%) of the title compound in the form of a light orange solid.

Workup

  1. stirringthe mixture was stirred for 4 hours
  2. customthe solvent was removed under reduced pressure
  3. additionA lower layer solvent of chloroform/methanol/water (7:3:1) was added to the residue
  4. additionby adding saturated sodium bicarbonate water
  5. temperatureunder cooling on ice
  6. extractionThe mixture was extracted with a lower layer solvent of chloroform/methanol/water (7:3:1)
  7. dry with materialthe extract was dried over anhydrous sodium sulfate
  8. customthe solvent was removed under reduced pressure
  9. customThe residue was purified by silica gel column chromatography (chloroform/methanol) and preparative layer chromatography (silica gel, chloroform/methanol=20:1)

Sources & evidence

ORD record
ord-a73e80160a7e4dce9f79b3ec7c41d6ea
Source dataset
uspto-grants-2015_02
Patent number
US08952010B2

Reaction notes

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