Phenol → (S)-1-(4-(cyclopropanecarbonyl)-2-methyl-6-phenoxy-3,4-dihydropyrido[2,3-b]pyrazin-1(2H)-yl)ethanone

HRID 1485752Notes

Reaction equation

HRID 1485752 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11](=[O:13])[CH3:12])[C@@H:9]([CH3:14])[CH2:8][N:7]([C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[C:6]=2[N:20]=1.BrC1C=CC2N(C(=O)C)[C@@H](C)CNC=2N=1.C1(C(Cl)=O)CC1.BrC1C=C2C(=CC=1)N(C(=O)C)[C@@H](C)CN2C(C1CC1)=O.[C:62]1([OH:68])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.[Cu]I.C(#N)C>[CH:17]1([C:15]([N:7]2[CH2:8][C@H:9]([CH3:14])[N:10]([C:11](=[O:13])[CH3:12])[C:5]3[CH:4]=[CH:3][C:2]([O:68][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[N:20][C:6]2=3)=[O:16])[CH2:19][CH2:18]1

Participants

10

Reactant 6

HCID 996PhenolHCID 10796Cesium carbonateHCID 77637Cyclopropanecarbonyl chlorideHCID 118079040(S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydropyrido[2,3-b]pyrazin-1(2H)-yl)ethanoneHCID 118079088(S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydroquinoxalin-1 (2H)-yl)ethan-1-oneHCID 118079164(S)-1-(6-bromo-2-methyl-3,4-dihydropyrido[2,3-b]pyrazin-1(2H)-yl)ethanone

Product 1

HCID 118079143(S)-1-(4-(cyclopropanecarbonyl)-2-methyl-6-phenoxy-3,4-dihydropyrido[2,3-b]pyrazin-1(2H)-yl)ethanoneYield 56%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A 1.5 mL reaction vial was charged with (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-yl)ethanone (synthesized from Intermediate 6 and cyclopropane carbonyl chloride according to the procedure used to prepare Intermediate 15, 6.76 mg, 0.02 mmol), phenol (3.76 mg, 0.040 mmol), copper (I) iodide (0.762 mg, 4.00 μmol), cesium carbonate (0.012 g, 0.036 mmol), and acetonitrile (250 μL). The reaction was heated on a heater shake at 80° C. for 18 hrs. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The aqueous layer was separated and washed with ethyl acetate and the combined organic layers were concentrated under a stream of nitrogen. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford (S)-1-(4-(cyclopropanecarbonyl)-2-methyl-6-phenoxy-3,4-dihydropyrido[2,3-b]pyrazine-1 (2H)-yl)ethanone (0.0039 g, 56%). MS (ESI, pos. ion) m/z 352.

Workup

  1. customA 1.5 mL reaction
  2. washwashed with 1 N aqueous sodium hydroxide solution
  3. customThe aqueous layer was separated
  4. washwashed with ethyl acetate
  5. concentrationthe combined organic layers were concentrated under a stream of nitrogen
  6. customThe crude product was purified by mass
  7. concentrationconcentrated in a Genevac

Sources & evidence

ORD record
ord-fd94ca6335ec4ef39b93041f39372bad
Source dataset
uspto-grants-2016_08
Patent number
US09422281B2

Reaction notes

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